Terpenoids and Steroids Volume 12
A Specialist Periodical Report ~~
Terpenoids and Steroids Volume 12 A Review of th...
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Terpenoids and Steroids Volume 12
A Specialist Periodical Report ~~
Terpenoids and Steroids Volume 12 A Review of the Literature Published between September 1980 and August 1981
Senior Reporter
.
J R. Hanson ScboolofMolecular Sciences, University of Sussex Reporters D. V. Banthorpe University College, London R. B. Boar Chelsea College, London S. A. Branch University College, London G. Britton University of Liverpool D. N. Kirk Westfield College, London B. A. Marples University of Technology, Loughborough J. S. Roberts University of Stirling
The Royal Society of Chemistry Burlington House, London W1V OBN
ISBN 0-85186356-6 ISSN 0300-5992
Copyright 0 1983 The Royal Society of Chemistry All Rights Reserved No part of this book may be reproduced or transmitted in any form or by any means-graphic, electronic, including photocopying, recording, taping or information storage and retrieval systems-without written permission from The Royal Society of Chemistry
Typeset by Bath Typesetting Ltd., Bath and printed by Adlard and Son Ltd., Bartholomew Press, Dorking Made in Great Britain
Introduction This is the last of the ‘Terpenoids and Steroids’ Specialist Periodical Reports. This title along with ‘Aliphatic and Related Natural Product Chemistry’, ‘The Alkaloids’ and ‘Biosynthesis’, has been subsumed into a review journal entitled Natural Product Reports. Whilst maintaining the thoroughness of coverage which has characterized the individual reports, the new journal will aim to avoid overlap and, because it will appear more frequently, the time delay between the completion of a chapter and publication which arises in the present reports from the irregular completion of manuscripts. The title of the new journal allows for a greater flexibility in scope and it will contain reports, particularly on techniques, which cut across the traditional boundaries between the individual groups of natural product. I should like to thank all those contributors who have made the present series a success and I wish the chairman of the Editorial Board, Professor Pattenden, good luck in this new venture.
J. R. HANSON
Contents
Part / Terpenoids Chapter 1 Monoterpenoids
3
By D. V. Banthorpe and S. A. Branch 1 Introduction
3
2 Physical Methods: Chirality Spectral and Other Physical Data Chirality
4 4 7
3 General Synthetic Methods
8 14 14 15 19
4 The Acyclic Class Occurrence Synthesis of the C,, Skeleton Reactions of 3,7-Dimethyloctadienesand their Derivatives Reactions with Metal Complexes Oxidation and Reduction Cyclizations, Isomerizations, etc.
23 25
5 Tetramethylcyclohexanesand Related Compounds
29
6 The Menthane Class General Formation of the Menthane Skeleton Oxidation, Reduction, and Related Reactions Alkylation, Homologation, and Related Processes General Reactions
32 32 33 35 39
7 The Camphane Class Occurrence; Synthesis of the Skeleton Oxidation-Reduction General Reactions
44 44 45 45
8 The Isocamphane Class
47
9 The Pinane Class Occurrence Rearrangement, Oxidation, Reduction, Simple Functionalizations Ring-opening Homologation, More Complicated Functionalization Norpinane Derivatives
48 48 48 50 51 52
vii
22
41
Terpenoids and Steroids
viii 10 The Fenchane Class
53
11 The Thujane Class Occurrence Reactions
53
12 The Carane Class
Reactions Preserving the Carane Skeleton Formation of Bicycle[ 3.1 .O]hexane Derivatives Formation of Menthane or Cyclopropane Derivatives
53 54 55 55 56 56
13 The Cyclopentane (‘Iridane’) Class Occurrence Synthesis and Reactions
57 57 60
14 The Irregular Classes
61 62 62
Occurrence Syntheses and Reactions 15 Cannabinoids and Other Phenolic Monoterpenoids
Cannabinoids Thymol Derivatives Occurrence Reactions 16 Biogenesis, Chemotaxonomy, Biological Applications Labelling Patterns; Cell-free Extracts Tissue Cultures, Microbial Transformations Chemotaxonomy Metabolism, Biological Activity, Miscellaneous
Chapter 2 Sesquiterpenoids
65 65 66 66 67 67 68 72 73 73 75
By J. S. Roberts 1 Farnesane
75
2 Mono- and Bi-cyclofarnesane
78
3 Bisabolane
88
4 Sesquicamphane, Sesquipinane
89
5 Cuparane, Herbertane, L a m e , Trichothecane
92
6 Chamigrane, Widdrane
99
7 Acorane, Carotane, Cedrane, Zizaane
100
8 Cadinane, Cubebane, Oplopanane, Picrotoxane, Sativane, Copacamphane
106
9 Himachalane, Longifolane, Longipinane
114
10 Caryophyllane, Humulane, and Related Sesquiterpenoids
115
11 Germacrane
140
ix
Contents 12 Elemane
155
13 Eudesmane
156
14 Vetispirane and Related Sesquiterpenoids
163
15 Eremophilane, Ishwarane
169
16 Guaiane, Pseudoguaiane, Patchoulane, Seychellane
172
17 Aromadendrane, Nardosinane, Neolemnane, Bicyclogermacrane
181
18 Pinguisane
183
19 Miscellaneous
184
Chapter 3 Diterpenoids
186
By J. R. Hanson 1 Introduction
186
2 Acyclic and Related Diterpenoids
186
3 Bicyclic Diterpenoids Labdanes Clerodanes
187 187 189
4 Tricyclic Diterpenoids Naturally Occurring Substances Chemistry of the Tricyclic Diterpenoids
192 192 193
5 Tetracyclic Diterpenoids Kaurenoid Diterpenoids Gibberellins Grayanotoxins At iserenes
195 195 197 199 199
6 Macrocyclic Diterpenoids
199
7 Miscellaneous Diterpenoids
201
8 Diterpenoid Total Synthesis
203
Chapter 4 Triterpenoids
207
By R. 8.Boar 1 Introduction
207
2 Squalene Group and Triterpenoid Biosynthesis
207
3 Fusidane-Lanostane Group
210
Terpemids and Steroids
X
4 Dammaran+Euphane Group Tetranortriterpenoids Pentanortriterpenoids Quassinoids
21 5 21 7 222 222
5 Lupane Group
225
6 Oleanane Group
226
7 UrsaneGroup
230
8 Hopane Group
23 1
9 Miscellaneous
232
10 Triterpenoid Saponins
Chapter 5 Carotenoids and Polyterpenoids By
234
235
G.Britton
1 Carotenoids Introduction Reviews New Structures and Stereochemistry Carotenoids New Natural Products, Related to Carotenoids Carotenoid-Protein Complexes Synthesis and Reactions Carotenoids Retinoids Carotenoid-like Compounds Physical Methods Separation and Assay N.M .R. Spectroscopy Circular Dichroism Raman and Infrared Spectroscopy Electronic Absorption Spectroscopy Photoacoustic Spectroscopy Miscellaneous Physical Chemistry Photoreceptor Pigments Biosynthesis and Metabolism Biosynthesis Metabolism
235 235 235 236 236 238 238 239 239 246 25 1 255 255 256 256 257 258 259 259 259 259 260 262
2 Polyterpenoids and Quinones Polyterpenoids Isoprenylated Quinones Chemistry Physical Methods Biosynthesis
264 264 265 265 266 266
xi
Contents
Part I! Steroids
Chapter 1 Physical Methods
269
By D. N. Kirk 1 Structure and Conformation
269
2 N.M.R. Spectroscopy lH Spectra 13CSpectra lSFand 2HSpectra
273 273 274 277
3 Chiroptical Phenomena
277
4 Infrared Spectroscopy
278
5 Mass Spectrometry and Gas Chromatography-Mass Spectrometry Chemical Ionization Mass Spectrometry Gas Chromatography-Mass Spectrometry
278 280 280
6 High-performance Liquid Chromatography and Other Chromatographic Methods
281
7 Immunoassays
283
8 Miscellaneous
285
Chapter 2 Steroid Reactions and Partial Syntheses
288
By 6. A. Marples Section A: Steroid Reactions 1 General
288
2 Alcohols and Carboxylic Acids and their Derivatives, Halides, and Epoxides Solvolysis, Substitution, Elimination, and Reduction Epoxide Ring Opening Ester, Carboxylic Acids, and Ethers
288 288 290 29 1
3 Unsaturated Compounds Electrophilic Addition Other Addition Reactions Other Reactions of Unsaturated Steroids Aromatic Compounds
292 292 294 294 295
4 Carbonyl Compounds Reduction 0t her Reactions Reactions Involving Enols or Enolic Derivatives Oximes
296 296 297 299
300
Terpenoids and Steroids
xii
5 Compounds of Nitrogen, Selenium, Sulphur, and Tellurium
300
6 Molecular Rearrangements
303
7 Functionalization of Non-activated Positions
308
8 Photochemical Reactions
309
Section B: Partial Syntheses 9 Cholestane Derivatives and Analogues
31 1
10 Vitamin D, Its Metabolites, and Related Compounds
318
11 Pregnaiies
321
12 Androstanes and Oestranes
324
13 Cardenolides
325
14 Heterocyclic Steroids
327
15 Microbiological Reactions
328
Author Index
330
Part I TERPENOIDS
1 Monoterpenoids BY D. V. BANTHORPE AND S. A. BRANCH
1 Introduction
Owing to a chain of misfortunes, this subject has not been reviewed since Volume 9. Consequently the present survey has to cover the literature from autumn 1978 to that dated 3 1.12.81 (as recorded in Chemical Abstracts and Current Contents up to 1.6.82). Dr A. F. Thomas of Firmenich SA, Geneva, kindly gave access to his card index covering the period and we are extremely grateful to him: we also thank the Royal Society of Chemistry for providing selected abstracts. The present half-litre pot has to contain the distillate of some 6000 monoterpenoidrelated papers: although most are trivial for the present, or indeed any, purpose, there has obviously had to be a change of presentation from that usual in these Reports. We have had to abandon all pretence of comprehensive coverage, and in particular have had to be highly selective in the following categories: (a) the vast patent literature which, although no doubt of industrial importance, often seems to cynical eyes to be vague, trivial, and repetitive; (b) the seemingly endless reports on occurrence and distribution of monoterpenes in plants; (c) studies on analogues of monoterpenes (e.g. homologues of pyrethrinoids and cannabinoids) ; and ( d ) reports in journals unavailable in the U.K., and inadequately abstracted. Iridoids are discussed but terpene alkaloids are excluded. Even with the above restrictions, rigorous selection had to be made on the remaining bulk of the literature. Lack of space has precluded much criticism, crossreference, and magisterial comment that are such a feature of previous Reports. We have made an attempt to select salient papers-often those giving leading references to earlier work within the period-but we would urge any authors who feel that their contributions have been ignored or maltreated to send in reprints for transmission to future Reporters. In the following sections, the plant species that are sources of monoterpenes are not recorded unless of some special significance, and similarly for points of stereochemistry, absolute configuration, reagents, and reaction conditions. Excellent reviews have appeared on the synthesis of monoterpenoids,l of cannabinoids,2 and of the use of isoprene in terpenoid ~ynthesis,~ and also on terpenoids from marine sponge^,^ the base-catalysed isomerization of mono-
* *
A. F. Thomas and Y. Bessiere, in ‘TheTotal Synthesis of Natural Products’, ed. J. W. ApSimon. Wiley, New York, 1981, vol. 4, p. 451. R. K. Razdan, in ref. 1. p. 185. G. Cainelli and G. Cardillo, Acc. Chem. Res., 1981, 14, 89. L. Minale, Marine Natural Products: Chem. Biof.Project., 1, 175.
3
Terpenoids and Steroids
4
t e r p e n e ~ ,and ~ iridoids.6-s Books on secondary metabolism in plants contain chapters on mon~terpenes,~-ll and detailed but overlapping reviews deal with the biosynthesis of mono and other terpenoid~?~-l~ and others cover the stereochemistry of chain-lengthening and c y c l i z a t i ~ n , ~ the ~ Jimportance ~ of membrane systems in monoterpene biosynthesis,20the metabolism of monoterpene epoxides,21 the production of monoterpenes (inter a h ) in tissue culture,22chemotaxonomy,23 and the functions of terpenoids in plants.24 2 Physical Measurements: Chirality
Spectral and Other Physical Data.-13C N.m.r. studies on hydroxy- and chloromenthanes have revealed that certain shifts are very sensitive and reliable probes
(1)
(2)
for ring onf formation,^^ and similar studies are available of menthyl enol ethers26 and of 13C--13Ccoupling in limonene and ca~vone.~’ A detailed analysis of relaxation times has been made from the 13Cspectrum for solid camphor,28and such spectra of J. Verghese, Perfum. Flavours, 1981, 6, 23. H. Inouye, Planta Medica, 1978, 33, 193. L. J. El-Naggar and J. L. Beal, J. Nut. Prod., 1980, 43, 649. * 0. P. Verma, S. Kumar, and B. C. Joshi, Herba Pol., 1980, 26, 133. T. Robinson, ‘Organic Constituents of Higher Plants’, Corduis Press, Amherst, Mass., 4th Edn., 1980, 352 pp. l o R. B. Herbert, ‘Biosynthesis of Secondary Metabolites’, Chapman and Hall, London, 1981, 250 pp. l1 M. Vickery and B. Vickery, ‘Secondary Plant Metabolism’, University Park Press, Baltimore Md., 1981, 335 pp. l2 H. R. Schuelte, Prog. Bot., 1976, 38, 129. S.Nozoe and A. Kawaguchi, Methods Chim., 1978,11,223. l4 B . V. Charlwood and D. V. Banthorpe, Prog. Phytochem., 1978, 5,65. l6 R. Croteau, Soap, Perfum. Cosmet., 1980, 53,428. l6 R. Croteau in ‘Flavor and Fragrance Substances’, ed. R. Croteau, D. and P. S. Verlag, Pattensen (W. Germany), 1980, p. 13. l7 W. D. Loomis and R. Croteau in ‘The Biochemistry of Plants’, ed. P. K. Stumpf, Academic Press, New York, 1980, vol. 4, p. 363 l 8 0. Cori (and nine others), Mol. Biol. Biochem. Biophys., 1980, 32, 97. l9 D. E. Cane, Tetrahedron, 1980, 36, 1109. 2 o J. P. Corde, C. Bernard-Dagan, and M. Gleizes, Dev. PZant Biol., 1980, 6, 441. 21 S. Voight and M. Luckner, Pharmazie, 1978, 33, 632. ea D. K. Dougall, in ref. 17, 1981, vol. 7, p. 21 *3 V. H. Heywood, J. B. Harborne, and B. L. Turner, ‘Biology and Compositae’, Academic Press, London, 1977, two vols., 1189 pp. e4 V. Herout, 7th International Congress on Essential Oils, 1977, vol. 7, p. 75. 25 D. Dauzonne, N. Goadsdoue, and N. Platzer, Org. Magn. Reson., 1981, 17, 18. 2s M. P. Stribel, C. G. Andrien, D. Paquer, M. Vazeux, and C. C. Pham, Nouv. J. Chim., 1980,4, 101. 27 G. Lukacs and A. Neszmelyi, Tetrahedron Lett., 1981, 22, 5053. R. Wasylishen and M. R. Graham, Mol. Cryst. Liq. Cryst., 1979, 49, 225. li
Monoterpenoids
5
norpinanes and homopinanes have been fully a n a l ~ s e d'H . ~ ~N.m.r. studies with shift reagents have enabled the conformations of the verbenols to be elu~idated~~131 and the stereochemistry of derivatives of camphor oxime has been analysed.32 Corrected structures for the isomeric bornane-trans-2,3-diols have been proposed.33 Analysis of the n.m.r. frequencies of the methyl groups of fenchone has assisted analysis of the structure of the sesquiterpene c e d r a n ~ n e13C . ~ ~and lH n.m.r. spectra of a variety of i r i d i o l ~ and ~ ~their glycosides have been i n v e ~ t i g a t e dand ~ ~ .spectra ~~ of methylcyclopentanes have been analysed for use as models in the interpretation of those of i r i d i o l ~ . ~ ~ Routine, but useful, interpretations of the mass spectral fragmentation patterns under electron impact have been reported for esters of the menthane and camphane s e r i e ~ for , ~ thioketones ~~~~ with the thujane, pinane, camphane, and fenchane ~ k e l e t afor ,~~ [2H]limonene,42for c a n n a b i n o i d ~ , and ~ ~ -for ~ ~ the volatile components from Pinus seedlings.47 Raman optical activity of menthane derivative^^^*^^ and of pinenes, carenes, and related compounds50has been studied. The technique has been used to investigate the interconversion of the pseudoaxial and pseudoequatorial forms of a-phellandreiie at low temperature^.^^ Chiroptical methods have enabled the assignment of absolute configurations and of conformations of iridoid g l y c o ~ i d e s of , ~ ~allylic alcohols of the menthane and pinane classes (as their p-nitrobenzoate~),~~ and of camphor derivatives (l).54Methylpulegene (2) is anomalous in showing no absorption maximum above 210 nm (pulegene; A,,, 232 nm), but it does exhibit a c.d. Cotton effect :55 presumably the 3-methyl substituent prevents the diene system 29
P. Brun, J. Casanova, J. Hatem, J. P. Zahrar, and B. Waegell, Org. Magn. Reson., 1979, 12, 537.
2o
3a
33 34 35
30
37 38 3g
40 41
C. Nishino and H. Takayanagi, Agric. Biol. Chem., 1979, 43, 1967. C. Nishino and N. Takayanagi, Agric. Biol. Chem., 1979, 43, 2323. A. K. Singh and S. M. Verma, Zndian J. Chem., Sect. B, 1981, 20, 33. M. A. Johnson and M. P. Fleming, Can. J. Chem., 1979,57, 318. M. Rodriguez and J. F. Bertran, Org. Magn. Reson., 1980, 13, 263. P. W. Thies, E. Finner, and S . David, Planta Med., 1981, 41, 15. S. Damtoft, S. R. Sensen, and B. J. Nielsen, Phytochemistry, 1981, 20, 2717. R. K. Chaudhuri, F. U. AM-Yazar, T. Winkler, and 0. Sticher, Tetrahedron, 1980, 36,2317. A. Bianco, C. Bonini, M. Guiso, C. Iavarone, and C. Trogolo, Tetrahedron, 1981, 37, 1773. A. M. Bambagiotti, S. A. Coran, V. Giannellini, G. Moneti, F. F. Vincieri, A. Selva, and P. Traldi, Biomed. Mass Spectrom., 1981, 8, 343. A. M. Bambagiotti, S. A. Coran, and P. Traldi, Biomed. Mass. Spectrom., 1981, 8, 356. D. Paquer, L. Morin, M. Vazeux, and C. G. Andrieu, Red. Trav. Chim. Pays-Bas, 1981,100, 52.
D. Harris, S. MacKinnon, and R. K. Boyd, Org. Mass Spectrom., 1979, 14, 265. 43 D. J. Harvey, Biomed. Mass Spectrom., 1980, 7, 28. 44 D. J. Harvey, Biomed. Mass Spectrom., 1981, 8, 366. Is D. J. Harvey, Biomed. Mass Spectrom., 1980, 7 , 278. 40 D. J. Harvey, Biomed. Mass Spectrom., 1981, 8, 575. 47 R. Hiltunen, S. Raisanen, and M. von Schantz, Planta Med., 1980, Suppl., p. 112. 4a P. L. Polavarapu, M. Diem, and L. A. Nafie, J. Am. Chem. SOC.,1980, 102, 5449. 4 * L. D. Barron and B. P. Clark, J. Chem. SOC.,Perkin Trans. 2, 1979, 1164. K O L. D. Barron and B. P. Clark, J . Chem. SOC., Perkin Trans. 2, 1979, 1171. 51 L. D. Barron and J. Vrbancich, J. Chem. SOC.,Chem. Commun., 1981, 771. L.-F. Tietze, U. Niemeyer, P. Marx, K.-H. Glusenkamp, and L. Schwenen, Tetrahedron, 1980, 42
53 s4
36, 735. N. Harada, J. Iwabuchi, Y. Yokota, and H. Uda, J. Am. Chem. SOC.,1981, 103, 5590. A. Forni, I. Moretti, G. Tome, and E. Vignudelli, Tetrahedron Lett., 1979, 907. D. A. Lightner and B. V. Crist, Tetrahedron, 1981, 37, 685.
Terpenoids and Steroids
6
from attaining planarity. 7 he relationship between the polarizibility ellipsoids of the C=C and the C, ring in pinmes, the absolute configurations, and the optical rotations has been theoretically explored.56 Detailed and impressive consistent force-field calculations have been made on the c.d. of menthane derivative^.^' Several important studies have appeared concerning the detailed geometry of certain monoterpene skeletons. Almost always (one exception; cf. ref. 58) the thujane skeleton has been previously shown to adopt a boat conformation. A 1H n.m.r study of a variety of bicyclo[3.1.O]hexanes and thujane derivatives, allied to calculations of the effect of ring buckling, has suggested that an alkyl substituent at the bridgehead of the [3.1.O]-bicyclo-system (as in the thujanes) causes the boat to twist, although this can be reduced by an axial substituent at C-4.58More refined analysis suggests that in the thujanes the C, ring is much flatter than in less substituted bicyclo[3.1.O]hexanes: e.g. in (3), a is 10-13", rather than 2.130" in the latter. In particular, a was deduced to be -3" for (+)-thujone (4) (cf. ref. 59); i.e. the C, ring was virtually planar! This compares with values of 25" and 15" for a in (+)-thujone and the epimeric (-)-isothujone deduced from microwave spectroscopy.60 It was suggested that the latter analysis was in error as the spectra were interpreted using the parameters determined for the parent bicyclo[3.1.O]hexaneand no allowance was made for twisting of the ring in the more substituted derivatives. Computed dihedral angles for the C4 rings of pinanols were in quantitative agreement with those determined by X-ray diffraction.61The preferred conformations of trans- and cis-2-pinanol are chair and boat respectively (with reference to the C6 ring carrying one methyl substituent), and both pinocampheols that were studied also favoured the boat conformation-but these boats were best described as 'twisted semi-boats'. Theoretical calculations on the conformations of chrysanthemyl compounds were reported,6z and both the favoured conformations and also the configurations at C-1 and C-8 of certain iridoid glucosides have been elucidated by use of lH or 13C n.m.r. and m . ~Details . ~ ~ of the stereochemistry of the adducts of Fe(CO), with a-terpinene and o-menthadienes have appeared.64 X-Ray studies of (5)-(7) gave the expected i n f o r m a t i ~ n . ~ ~ - ~ ~ G.c.-Fourier-transform i.r. appears to be a technique of great potential for the identification of monoterpenes in plant extracts: in some cases it is claimed to be superior to g.c.-m.s. but generally the methods are complementary.68 Another recent procedure is droplet counter-current chromatography which is a modification 66 67
6O
61 6z
63 64 66 68
67
S. G. Vulfson and V. F. Nikolaev, Izv. Akad. Nauk SSSR, Ser. Khim., 1981, 2259. R. D. Singh and T. A. Keiderling, J. Am. Chem. SOC.,1981, 103, 2387. J. C. Rees and D. Whittaker, Org. Magn. Reson., 1981, 15, 363. (4) has traditionally been known as (+)-isothjone. We here adopt a more rational, if little used, nomenclature; cf. S. P. Achorya et al. J . Org. Chem., 1969,34,3015. Z. Kisiel and A. C. Legon, J . Am. Chem. SOC.,1978, 100, 8166. J. Texter and E. S. Stevens, J. Org. Chem., 1979, 44, 3222. G. Castellani, R. Scordamaglia, and C. Tosi, Gazz. Chim. Ztal. 1980, 110, 457. L.-F. Tietze, U. Niemayer, P. Marx, and K.-H. Glusenkamp, Tetrahedron, 1980, 36, 1231. A. J. Birch and 17 others, Tetrahedron Supplmt., NO. 1, 1981, 37, 289. R. A. Pauptit and J. Troffer, Can. J . Chem., 1980, 58, 2805. V. G. Andrianov, Yu. T. Struchkov, V. A. Blinova, and I. I. Kritskaya, Zzv. Akud. Nuuk SSSR, Ser. Khim., 1979, 2021. R. Rogues, J. Sotiropoulous,G. Feuillerat, G. Germain, and J. P. Declercq, J . Chern. Res. (S), 1980, 370.
J. T. McDonard and V. F. Valasinsky, Proc. SPIE, Int. SOC.Opt. Eng., 1981, 154.
Monoterpenoids
7
P (3)
(4)
of counter-current distillation. This has been applied very successfully to the bulk separation of iridoid g l ~ c o s i d e sA. ~method ~ ~ ~ ~has been claimed for the identification of terpene alcohols at the pg level:71this involved g.c.-m.s. after reduction over platinum with lithium aluminium hydride. As a result, different substrates were said to give a pattern of products with characteristic skeleta: thus borneol yielded camphane or tetramethylcyclopentanes. Photoelectron spectra of fenchone derivative^'^ and e.s.r. spectra of the paramagnetic adducts between organic Si-, Ge-, and Sn-centred radicals and camphor and t h i ~ c a r n p h ohave r ~ ~ been studied.' Chirality.-The simultaneous presence of (8) and (9) (L= Yb"', GaIII, or Prrrl splits the lH and lSC n.m.r. signals of chiral a-pinene, limonene, and camphene. As a consequence the enantiomeric purities could be readily determined :74 previously, hydrocarbons were not amenable to such techniques. Compound (9) augmented the Ag salt shift but did not interact alone. Ally1 boronates of substituted camphor diols (10) added to acetaldehyde to yield (1 l), which on base treatment cleaved to give 86 % optically pure pent-4-en-
K. Hostettmann, M. Hostettmann-Kaldas, and 0. Sticher, Helv. Chim. Acta, 1979, 62, 2079. R. K. Chaudhuri, 0. Salama, and 0. Sticher, Planta Med., 1980, 40, 164. 71 B. A. Bierl-Leonhardt and E. D . Devilbiss, Anal. Chem., 1981, 53,936. l e D. C. Frost, N. P. C. Westwood, and N. H. Werstiuk, Can. J. Chem., 1980,58, 1659. 73 A. Alberti, M. Guerra, and G. F. Pedulli, J. Am. Chem. Soc., 1981,103,6604. 74 W. Offermann and A. Mannschreck, Tetrahedron Lett., 1981,22,3227.
6@ 70
8
Terpenoids and Steroids
2-01: pinane diols were less effective.75 B-3-Pinanyl-9-borabicycl0[3.3.1 Inonane [prepared from ( +)-x-pinene] proved an exceptionally effective reagent for the stereospecific reduction of [I -2H,]-aldehydes to [2H,]-primary alcohols : thus [CHO-2H,]benzaldehyde was converted into optically-pure ( +)-[ 1-2H,]benzyl A detailed mechanistic discussion of the reaction was appended. The chiral titanium compound (1 2) converted benzaldehyde into l-phenylethanol in low (ca. 14 %) optical yield. 7 7 Chiral amines, e.g. N-isopropyl-( -)-menthylamine, were used as bases in asymmetric condensations between bromoacetates and ketones in Reformatsky-type reactions, but the optical yields were generally poor, at a maximum 400/;j.78The rhodium complex (13) was resolved: the enantiomers were both yellow, although the racemic mixture was red-green. 7 9
3 General Synthetic Methods
Monoterpenes are widely used as substrates in the development of new synthetic reagents and routes. However, many of these studies refer to a one-off use of a particular compound as one of many models and such are not discussed here unless of especial interest. We rather review the salient work involving specific functionalization and modification of the class.
,,,,*ao
Me,C=CHCH,MgBr-CuI
75
76
77 76 78
>
pcl
T. Herold, U. Schrott, R. W. Hoffmann, G . Schnelle, W. Ladner, and K. Steinbuch, Chem. Ber., 1981, 114, 359 M. M. Midland, S. Green, A. Tramontano, and S . A . Zderic, J . Am. Chem. SOC.,1979, 101, 2352. M. T. Recti, R. Steinbach, B. Wenderoth, and J. Westermann, Chem. fnd. (London), 1981, 541. S. Brandange, S . Josephson, L. Morch, and S . Vallen, Acta Chem. Scand., Ser. B, 1981,35,273. V . Schurig, Angew. Chem. Int. Ed. Eng., 1981, 20, 807.
Mono terpenoids
9
The ene reaction of aldehydes with alkenes provides a potentially valuable route
to homoallylic alcohols [cf. (14a) + (14b)l. Coupling of isoprene with 3-methylbutan-1-a1 yielded ( 1 5) in excellent yield, and limonene similarly, reacted (at the
Cii
lii
6 H COMe
3 OH
Reagents: i, AgSbF6; ii, H,O; iii, MeMgI; iv, MeOH
Scheme 1
exocyclic double bond) to yield a hydroxybisabolane. 8o Dimethylaluminium chloride (a mild Lewis acid and also a proton scavenger) catalysed the process and proton-initiated reactions did not occur. A novel synthetic method has been developed for the synthesis of optically active terpenes by the ring-opening of (R)-( +)-p-methyl-propiolactone :81 the sequence to citronellic acid (1 6) and pulegone (17) utilized the previously developed step whereby a regiospecific attack of a Grignard reagent on the substrate was catalysed by cuprous iodide. An elegant new route to monoterpenes could possibly be developed to give specific labelling with tracer: the key intermediate was an oxonium salt (18), and pathways to cis-terpin (19), 1,8-cineole (20), and a-terpineol (21) are shown in Scheme 1.B2 An effective method of converting camphor into epicamphor and menthone into carvomenthone involved the route (22)-+(23).83 A very detailed study has been made of the linkage of C, units, via the elaboration of a C,,-cyclopropyl 8o
BB 88
B. B. Snider and D. J. Rodini, Tetrahedron Lett., 1980, 21, 1815. T. Sato, T. Kavara, A. Nishizawa, and T. Fujisawa, Tetrahedron Lett., 1980, 21, 3377. J. P. Begue, M. Charpentier-Morize, D. Bonnet-Delpon, and J. Sansoulet,J . Org. Chem., 1980, 45, 3357. T. Nakai and T. Mimura, Tetrahedron Lett. 1979, 531.
Terpenoids and Steroids
10
intermediate (24) formed from reaction of C,-carbenes and a C,-alkene. Typically, acid treatment of (24) led to a product showing head-to-tail linkage of the units (25), whereas base treatment followed by acidification gave irregular structures (26) (Scheme 2):84 treatment of (24) and its analogues with dissolving metals or peracids also led to novel, functionalized but regular structure^.^^ Methods for the formation of allylsilanes from geraniol, linalool, and myrtenola6 and
A -
-
- Li
NNHTs
NNTs
BuLi,
MeSSMe
-
+
Li NNTs
w
7
e
+
-
(23) from verbenola7 have been reported. The gem-di-(trimethylsilane) derived from geraniol reacts with acid to yield citronellene (3,7-dimethylocta- 1,6-diene)87. A general route has been developed to a,p-unsaturated aldehydes of homomonoterpenes,8s and various monoterpene y- and 8-lactones have been synthesized by the Wittig-Horner reaction. 8 9 Geraniol and also pinane derivatives have been elaborated into a-substituted methylacrylates via a Claisen-o-ester rearrangement with trimethyl p-methoxyorthopropionate using trimethylbenzoic acid as catalyst,g0
liii
OMe
Reagents : i, BF, etherate-MeOH; ii, KOBut-DMSO ; iii, H+-MeOH
Scheme 2 E4 B6
B6 87
L. Crombie, P. J. Maddocks, and G. Pattenden, Tetrahedron Lett. 1978, 3479. L. Crombie, P. J. Maddocks, and G. Pattenden, Tetrahedron Lett. 1978, 3483. C. Biran, J. Dunogues, R. Callas, J. Gerval, and T. Tskhovrebachvili, Synthesis, 1981, 220. D . Pandy-Szekeres, G. Deleris, J. P. Picard, J.-P. Pillot, and R. Callas, Tetrahedron Lett., 1980, 21, 4267. T. Hiyama, A. Kanakura, H. Yamato, and H. Nozari, TetrahedronLett. 1978,3051. H. Biedrzycki, K. Witkiewks, and Z. Chabudzinski, Pol. J . Chern., 1980, 54, 45. S. Raucher, J. E. Macdonald, and R. F. Lawrence, Tetrahedron Lett., 1980, 21,4335.
Monoterpenoids
11
e.g. (27) -+ (28), and the epoxides of pulegone and piperitone have been prepared by the Wittig reaction.g1 Treatment of ally1 acetates of the menthane and pinane classes (e.g. those of carveols and myrtenol) with sodium diethylmalonate in the presence of diphenylphosphinoethane and a Pd catalyst effected the transformation (29) -+ (30), with obvious scope for further modification. 92 Another reaction leading to valuable synthetic intermediates is the addition of dichlorocarbene to camphene followed by reduction to yield (31) and (32);93 P-pinene and limonene behaved similarly.
LoH * MeO(CH,),C(OMe),catalyst
(28)
&Ac
R
~
R
R
4rb
+O2EO,
R (30)
(29)
(31)
(32)
The reactions of metal complexes of monoterpenes continue to be actively explored and many specific examples will be found in later sections. Of general interest are the dimerization of x-allyl-Pd complexes of or- and P-pinenes and of carvone that are effected by irradiation at 366 nmg4and the thermal decompositions of (x-ally1)nickel halide complexes of, e.g., isoprene (33), to form m ~ r c e n e . ~ ~ Hydrosilylation of I ,3-dienes (e.g. isoprene, myrcene, ocimene) was found to be a regiospecific 1,6addition for Pd complexes but followed the alternative route for Rh compounds; a good discussion is appended.96 A series of dimers of isoprene
vTNiBrl2 (33)
-OH
--+
&OH
(34) v
OH -&OH (35) O3 9'
OS
N. Bensel, J. Hohn, H. Marschall, and P. Weyerstahl, Chem. Ber., 1979, 112, 2256. J. C. Fiand and J. L. Malleron, Tetrahedron Lett., 1980, 21,4437. S. Watanabe, T. Fujita, K. Suga, and K. Kasahara, Aust. J . Chem., 1981, 34, 1161. J. Muzart and J. P. Pete, J . Chem. SOC.,Chem. Commun., 1980, 256 L. S. Hegedus and S. Varaprath, Organometallics, 1982, 1, 259. I. Ojima and M. Kumagi, J . Organomet. Chem., 1978, 157, 359.
12
Terpenoids and Steroids
bonded at 1-2, 1-3, 1-4, 2-4, 3-4, and 4-4 positions were prepared by suitable regiocontrolled catalysis by transition metals of the coupling of 2-methylbut-2ene- 1,6diylmagnesium or 3-methylbut-2-enylmagnesium chloride with C,-alkenyl halides.97 Various terpene amines have been obtained in excellent yields by Pdcatalysed telomerization of isoprene with NH,. 98 Conditions have been worked out for the conversion of allylic alcohols into 1,3-dienes (e.g. nerol-tmyrcene, geraniol+trans+P-ocimene) by a sequence involving epoxidation, trimethylsilylation, ring-opening, desilylation, formation of diol, then of dibromides, and debromination, e.g. (34) --f (35).99 Reaction of a variety of monoterpenes with HOCl-CH,Cl, resulted in addition of chlorine followed by shift of the double bond: dechlorination (Zn) led to a-olefins (60-80 %), and the chloro-derivative of citronellol could be efficiently converted into rose oxide [2-(2-methylprop-1-enyl)-4-methyltetrahydropyran] by successive treatment with acid and base.loO Dehydrations of allylic monoterpenols with carbodiimideslOlaand anhydrous C U S O , were ~ ~ ~effective. ~ Hydroalumination of p-pinene, camphene, and a-thujene in the presence of 0, gave after work-up the product of anti-Markovnikov addition (73 % trans-product, 85 % endo, and non-stereoselective, respectively).102 In contrast, hydroboronation (TiC1,-NaBH,) gave 85 % cisproduct from p-pinene and mainly isopinocampheol from ~ c - p i n e n e . ~ ~ ~ A very useful functionalization of the isopropylidene terminus of isoprenoids led to the formation of terminal trans-allylic alcohols (36) * (37), e.g. 10-hydroxy-
geraniol. Step (i) was highly regioselective and (ii) could be very effectively carried out by the Evans procedure.lo4Preoccupations with the reactions of monoterpenes (thujenes, menthenes, and carenes) and other 1-methylcyclohexenes has obscured the fact that 1-methylcycloalkenes with four-, five-, seven-, eight-, or twelve-membered rings show predominantly syn-side addition in the ene oxidation with photochemically generated singlet oxygen (38 ; route i). 1-Methylcyclohexenes, however, show anti-side addition (route ii): the theoretical reasons for this dichotomy have been very convincingly The PdCl, complex from carvone was conY. Kajihara, K. Ishikawa, H . Yasuda, and A. Namarnura, Bull. Chem. SOC.J . , 1980, 53,3035. W. Keim and M. Roper, J . Org. Chem., 1981, 46, 3702. Bs A. Yasuda, S. Tanaka, H. Yamamoto, and N. Nozaki, Bull. Chem. SOC.J., 1979, 52, 1752. looS. G. Hegde and M. K. Vogel, Tetrahedron Left., 1980, 21, 441. lo1‘ A. Trius, A. Trivino, and A. Virgili, Anales de Quim., 1980, 76, 58. l 0 l b R. V. Hoffmann, R. D. Bishop, F. M. Fitch, and R. Harderstein, J . Org. Chem., 1980, 45, 917. l o 2 A. V. Kuchin, L. I. Alkmetor, V. P. Yurev, and G . A. Tolstikov, Zh. Obshch. Khim., 1979, 49, 1567. l o 3 S. Kano, Y. Tanaka, and S. Hibino, J . Chem. SOC.,Chem. Commun., 1980, 414. lo*Y. Masaki, K . Hashimoto, and K. Kaji, Tetrahedron Lett., 1978, 4539. K. H. Schulte-Elte and V. Rautenstrauch, J. Am. Chem. SOC.,1980, 102, 1738, 97
88
Monoterpenoids
13
verted by irradiation in the presence of 0, into (39)lo6whereas treatment of carveol or myrtenol with Pd in the presence of PPh, and a base yielded the ketone.lo7 Geraniol and carveol were oxidized at the alcohol group by 0, in the presence of [ R U C ~ , ( P P ~ ~ and ) J , ~menthol ~~ was converted into menthone by Methods have been developed for the epoxidation of a variety of types of monoterpenes with t-butyl hydroperoxides over metal catalysts.l1°
a,@-Unsaturatedketones (e.g. pulegone) were specifically reduced at the 1,2positions by Lu"l-NaBH,"l and the conjugated double bond of citral was selectively attacked by (MeO),SiH in the presence of [ R U C ~ ~ ( P P ~Pulegone ,)~].~~~ and its analogues were readily reduced with $-branched trialkylaluminium compounds: the yield and stereoselectivity were highly dependent on the solvent, and asymmetric induction could occur when chiral reducing agents were used.l13 Chiral menthyl or neomenthyl groups were ligated to Rh-phosphine complexes to form soluble catalysts for enantioselective hydrogenation of geranic acid.l14J16Catalytic reductions of a-pinene, limonene, and others have been studied.l16J1' Ca(NH,),Me,CHOH-Me,CHCH,OH was claimed to be more effective than a Birch reagent for the reduction of phenol ethers (e.g. methyl thymyl ether) to a,@unsaturated ketones.l18 Such ketones (carvone, pulegone) were rapidly reduced (to saturated ketones after work-up) by the liquid reagent 'lithium bronze', Li(4NH3); this was more convenient than the traditional use of blue solutions of Li in NH,.l19
J. Muzart, P. Pale, and J. P. Pete, J . Chem. SOC.,Chem. Commun., 1981, 668.
lo6
Y.Tamaru, K, Inoue, Y. Yamada, and Z. Yoshida, TetrahedronLett., 1981,22,1801.
lo7
M. Matsumato and S. Ito, J. Chem. SOC.,Chem. Commun., 1981, 907 Y. Masuyama, A. Tsuhako, and Y. Kurusu, Tetrahedron Lett., 1981, 22, 3973. D. V. Banthorpe and S. E. Barrow, Chem Znd. (London), 1981, 502. 111 A. L. Gemal and J. L. Luche, J. Am. Chem. SOC.,1981, 103,5454. M. Matsumoto, Y . Hoshino, and Y. Nagai, Bull. Chem. SOC.J., 1981, 54, 1279 113 G. Giacomelli, A. M. Caporusso and L. Lardicci, Tetrahedron Lett., 1981, 22, 3663, 114 D.Valentine, K.K. Johnson, W. Priester, R. C. Sun, K . Toth, and G. Saucy, J . Org. Chem.,
lo8 log
1980,45,3698. 115 116 117 11*
D.Valentine, R.C. Sun, and K. Toth, J . Org. Chem., 1980, 45, 3703. A. Fischli and P. M. Muller, Helv. Chim. Acta, 1980, 63, 1619. A. Fischli and P. M. Muller, Hefv. Chim. Acta, 1980, 63, 4529. V. V. Bazylchik, T. N. Overchuk, and P. I. Fedorov, Zh. Org. Khim., 1978, 14, 2085. R. H. Mueller and J. G . Gillick, J . Org. Chem., 1978, 43, 4647.
Terpenoids and Steroids
14
It was recommended that alkali-metal-NH, reduction of ketones should be conducted in the presence of NH,+: this follows from the finding that reduction of [3,3-2H2]camphorand quenching in the absence of the ion gave epimeric alcohols with one or two atoms of tracer and complex products formed by disproportionation, abstraction of H from the medium, and pinacolic coupling. In the presence of NH,Cl, exclusively [3,3-2H2]-alcohols were formed with Li, Na, or K. It was concluded that a mechanism proposed by House (1972) predominated when NH4+ was the proton source.12o
Novel regioselective electrochemical ene-type chlorinations (40) -+(41) to yield ally1 chlorides have been developed although the product selectivity was highly dependent on the choice of halide ion and the solvent: e.g. allylic chlorides, chlorohydrins, dichlorides, or epoxides may be formed.121Electrochemical oxyselenation-deselenation (involving addition of PhSeOH) in the presence of ROH (R = alkyl) also led to allylic-type addition of OR with shift of the double The synthesis of chiral monoterpenesulphonic acids for use in the resolution of amino-acids has been as has the enzymic resolution of chiral acyclic monoterpenols via the asymmetric hydrolysis of the corresponding acetates by rnicro-organism~.~~~ Lipases from micro-organisms catalysed the formation of esters from geraniol and lower fatty acids in up to 50% yields.lZ5Other interesting papers dealt with methods for acylation126and carbonylation,lZ7isomerization of monoterpene hydrocarbons on heating in dipolar aprotic solvents,12*and the dehydrogenation of terpenoids on c h r o r n ~ p l a t e s . ~ ~ ~ 4 The Acyclic Class
Occurrence.-In this, and later sections, only novel (or so-claimed !) compounds or known compounds in unexpected environments will be considered. A variety of mono- and di-hydroxy-linalools [e.g. (42), (43)] substituted at C-6 and C-7 have been found in grapes 130-132 and may be the precursors of more volatile usual V. Rautenstrauch, B. Willhalm, W. Thommen, and U. Burger, Helv. Chim. Acta, 1981, 64, 2109. lz1 S. Torii, K. Uneyama, T. Nakai and T. Yasuda, Tetrahedron Lett., 1981, 22, 2291. S. Torii, K. Uneyama, M. Ono, and T. Banou, J . Am. Chem. SOC.,1981,103,4606. I z 3 S. C. Traynor and B. J . Kane, J . Org. Chem., 1979,44, 1557. 12* T. Oritani and M. Yamashita, Agric. Biol. Chem., 1980, 44, 2407. l Z 5 M. Iwai, S. Okumura, and Y . Tsujisaka, Agric. Biol. Chem. 1980, 44, 2731. 128 R. Couffignal and J. L. Moreau, Tetrahedron Lett., 1978, 3713. 12' S. D. Pirozhkov, N. V. Puzitski, T. N. Myshewnova, N . G. Ryabova, and S. S. Poddubnaya, Izv. Akad. Nauk SSSR, Ser. Khim., 1979, 784. 128 A. Matawowski, Polish J . Chem., 1980, 54,469. 129 J. C. Kholi, R. Gupta, A. K. Arora, and K. Ushminder, J . Chromatogr., 1981, 210, 370. I 3 O P. J . Williams, C. R. Straws, and B. Wilson, Phytochemistry, 1980, 19, 1137. H. Etoh, K. Ina, and M. Iguchi, Agric. Biol. Chem., 1980, 44, 2999. 138 A. Rapp, W. Knipser, and L. Engel, Vitis, 1980, 19, 226 (Chem. Abstr., 1981, 94, 82 103).
pH PH
Mono terpenoids
15
\
COZH
OH
(43)
(45)
m o n o t e r p e n e ~Two . ~ ~ 5-ketolinaloyl ~ derivatives (previously ~ynthesizedl~~) occur in Citrus ~ p p . , 1and ~ ~ a corresponding 4-hydroxy-compound (cornusol) has been isolated from a Curnus spp.136The acid (44)was the monoterpenoid moiety of a ~ap0nin.l~'Geranyl-p-D-glucoside was readily formed, transported, and metabolized when apples were injected with the alcohol;13s this and the linaloyl glucoside that occur in tea shoots were cleaved on mechanical disruption.139 These results suggest that glycosides may generally be storage and/or transportable forms of certain monoterpenols. 3,7-Dimethylocta-(Z)3,6-dien-1-al,1407-hydroxycitronellic acid,141geranic geranyl dihydroquinones and the corresponding aromatics,l43 and sulphur derivatives of m y ~ c e n e[e.g. l ~ ~ (45)] have been isolated from a variety of plant species. Halogenated dimethyloctadienes, e.g. 8-bromo-3,7-dichloro-2,6dimethyl-octa-1, (E)S-diene, continue to be found in marine red algae.145-147 Synthesis of the C,, Skeleton.-Isoprene in the presence of Pdo catalysts1@or telomerized with its gave mainly citronellene (3,7-dimethylocta- 1,6diene) and geranyl chloride respectively, although an interesting minor product (7 %) of the latter reaction was 2,7-dimethyl-3-chloro-octa-1,6-diene-anirregular P. J. Williams, C. R. Strauss, and B. Wilson, J . Agric. Food Chem., 1980, 28, 766. 0. S. Park, Y.Grillasia, G. A. Garcia, and L. A. Maldonado, Synth. Cornrnun., 1977, 7 , 345. lS6 T. Kitahara, Y. Takagi, and M. Matsui, Agric. Biol. Chem., 1980, 44, 897. T. Kurihara and M. Kikuchi, Yukuguku Zasshi, 1978, 98, 969. 13' Y.Okada, K. Koyama, K. Takahashi, T. Okuyama, and S . Shibata, Plantu Med., 1980,40,185. R. B. H. Wills and F. M. Scriven, Phytochemistry, 1979, 18, 785. 139 T. Takeo, Phytochemistry, 1981, 20, 2145. 140 J, M. Sandra and P. Cunat, Phytochemistry, 1980, 19, 89. 141 M. L. Sethi, S. C. Taneja, K. L. Dhar, and C. K. Atal, Indian Perfum., 1979,23,167. A. Nahrstedt, U. Vetter, and F. J. Hammerschmidt, Planta Med., 1981, 42, 313. 143 R. J, Capon, E. L. Ghisalberti, and P. R. Jefferies, Phytochemistry. 1981, 20, 2598. 144 T. L. Peppard and J. A. Elvidge, Chem. Znd. (London), 1979, 552. Ips R. W. Dunlop, P. T. Murphy, and R. J. Wells, Aust. J . Chem., 1979, 32, 2735. 146 D.B. Stierle, R. M. Wing, and J. J. Sims, Tetrahedron, 1979, 35, 2855. P. Bates, R. W. Blunt, M. P. Hartshorn, A. J. Jones, M. H. G. Munro, W. T. Robinson, and S . C. Yorke, Aust. J . Chem., 1979, 32,2545. 14* K. Nozaki, Eur. P., 19 960/1980. 149 A. Erm, M. Heinvali, T. Valimae, and K. Laats, Eesti, NSV. Tead. Akad. Toim., Keem., 1981, 133 134
30, 56.
16
Terpenoids and Steroids
nerol, isogeraniol (51) Reagents: i, H+; ii, -CH,O;
iii, -H,O;
iv, Me,C=CHCH,CI-BuLi;
v, N a or electrochemical
Scheme 3 product of tail-to-tail linkage. Dimerization with PdO and MeC0,H led (on work-up) to 2,6-dimethylocta-2,7-dien-1-01 (regu1ar)l5Oor, under activation by Mg in the presence of B(OBU"),,~~~ to a mixture of regular (e.g.geraniol and oc-geraniol) and tail-to-tail linked alcohols. With Zr complexes the products were exclusively tail-to-tail linked trienes.15, Isoprene on treatment with Mg formed a series of dimeric and polymeric complexes in equilibrium, which on addition of 2-chloromethylbutadiene gave myrcene and irregular hydrocarbons formed by 1-2 and 1-3 linking.153Coupling of the trimethylsilyl derivative (46) of isoprene with 3-methylbutyraldehyde gave ipsenol (47) .154 A very detailed mechanistically orientated study of theaction of HC104, F3C0,H, and HC02H on the 1,l and 3,3-dimethylallyl alcohols has secured conditions for 'biomimetic' condensations leading to 3,7dimethylocta-6-ene-l,3-diol(86 %; and thence to geraniol) and also to lavandulyl compounds (irregular).155Use of other suitably functionalized isoprenes has led to the sequences (48)+(49)156 and (50)+(5 I) (Scheme 3).157J58 Other interesting routes for the construction of an acyclic Clo skeleton from C, precursors are the selective y-alkylation of Cu enolates derived from oc,p-unsaturTakagago Perfumery Co., Jap. P., 39 366/1980. B. Ceskis, A. M. Moiseenkov, M. I. Struchkova, and A. V. Semenovski, Izv. Akud. Nuuk SSSR, Ser. Khim., 1981, 365. 152 H. Yasuda, Y. Kajihara, K . Nagasuna, K. Mashima, and A. Nakamura, Chem.Lett., 1981,719. lS3 Y.Kajihara, K. Ishikawa, H. Yasuda, and A. Nakamura, Bull. Chem. SOC. J., 1980, 53, 3035. 150 A. Hosomi, M. Saito, and H. Sakurai, Tetrahedron Lett., 1979, 429. 156 D. Babin, J.-D. Fourneron, and M. Julia, Bull. SOC.Chim. France, Part IZ, 1980, 588. 156 N. A. Romanov, E. A. Kantor, R. S. Musavirov, R. A. Karakhanov, and D. L. Rakhmankulov, Zh. Org. Khim., 1981, 17, 1762. lS7 A. M. Moiseenkov, E. V. Polunin, and A. V. Semenovsky, Tetrahedron Lett., 1979, 4759. lS8 A. M. Moiseenkov, E. V. Polunin, and A. V. Semenovsky, Angew. Chem. Znt. Ed. Engl., 1981,
150 151
20, 1057.
Mono terpeno ids
17
Me& =CHCH,Br
c02h (53)
+
A X LOSiMe, i
+
L
S
P0 h
+
w; OSiMe,
(54)
(55) ated e.g. (52)+(53) ;the use of 3-methylbuta-l,3-dienyl phenylsulphoneas a Michael acceptor of lithiated and protected cyanohydrins, e.g. (54)455)160 (this has led to routes to tagetones and ocimenones); and y-alkylation via metalated unsaturated amides, e.g. (56)-+(57).l6l
+o NHMe
i: ~ ~ c = , , c ~ s ~ r
$NHMe
+
fHMe
(56)
(57) An ingenious method of linking two C , units to give ultimately 10-hydroxygeraniol, a precursor for loganin and iridodial, involved photochemical coupling of 2,5-dihydro-3-methylthiophenSS-dioxide (58) with citraconic anhydride (59) followed by thermal extrusion of SOz, Cope rearrangement of the resulting divinyl ester, and suitable functionalization (Scheme 4).162 This work demonstrates that (58) and its analogues offer an alternative method to the use of cyclobutenes for the stereospecific synthesis of cis- 1,2-divinyl systems and trans,trans- 1,5-dienes. P. M. S a w and J. A. Katzenellenbogen, J . Org. Chem., 1981,46,239. E. Guittet and S. Julia, Synth. Cummun., 1981, 11, 709, M. Majewski, G. B. Mpango, M. T. Thomas, A. Wu, and S. Snieckus,J . Org. Chem., 1981,46.
lSn
160
2029.
J. R. Williams and C. Liu, J . Chem. Suc., Chem. Cummun., 1981, 752.
18
Terpenoids and Steroids
K-q--;:: OH
Reagents: i, h v ; ii, CH,N,, A ; iii,A
Scheme 4 A variety of routes have been explored for linkage of (rn + n) units (m + n = 10;m,n # 5.) Methylhexenone (60) could be converted into the terminal acetylene (61) and thence into (E)-trisubstituted olefins such as g e r a n i ~ I , ~ and ~ ~ Jcould ~ * also
be protected, oxidized at a gern-dimethyl, and functionalized to give 10-hydroxyl i n a l o 0 1 ~or~ ~converted into [1,2J4C2]geranial and thence into ionones.166Hydromagnesiation of prop-Zynylic alcohols proceeds with stereo- and regio-specificity
.
,
(64)
under mild conditions in almost quantitative yields: thus nerol has been synthesized from (62).16' Procedures involving coupling of (C, + C,) units (Me,C=CH(CH2),C1 + MeCOCHClCH2C1) to give geranyl acetate168and of (C, + C,) units 163
E. Negishi, A. 0. King, W. L. Klina, W. Patterson, and A. Silveira, J . Org. Chem., 1980, 45, 2526.
16'
N. Okukado and E. Negishi, Tetrahedron Lett., 1978, 2357. 0. P. Vig, S . S. Bari, I. R. Trehan, and R. Vig, Indian J . Chem., Sect. B, 1979, 17, 619. R. R. Muccino and C. A. Wasiowich, J. Labelled Comp. Radiopharm., 1980, 17,463. F. Sato, H. Ishikawa, H. Watanabe, T. Miyanke, and M. Sato, J . Chem. SOC.,Chem. Commun.,
16@
K. K. Mathew, P. S . Raman, and T. G . B. Antbarjanam, Indian J. Chem.,Sect. B, 1981,20,340.
1°* 165
1981, 718.
19
Monoterpenoids
5
_.,
SPh
q S i M e 3 SPh
SiMe, SPh J,iii
oxidation ; reduction
t o
Reagents : i, NaH-Me,SiCH,I ; ii, Grignard ; iii, SO&l,-Et,N, HMPA-LiCl Scheme 5
[(63)+(64)] have been worked out. Compound (63) has been proposed as a new key intermediate for the synthesis of a variety of acyclic m o n ~ t e r p e n e s .PhS ~~~ groups are well known to migrate to an adjacent positive centre, and by incorporation of a Me,% group into the molecule it has been possible to encourage rearrangement from a secondary to a secondary or even a secondary to a tertiary migration terminus. The method was illustrated by the efficient synthesis of geraniol/ nerol and l i n a l ~ ofrom l ~ ~ (65) ~ as shown in Scheme 5 . Trimethylsilyl-enol ethers of pentane-2,4-dione and methyl acetoacetate reacted with linalool at room temperature without catalysts to yield the trimethylsilyl ether (85 %), excellent for g.1.c. or m.s.171 Other interesting routes involving couplings of (C, + C4) and (C, + C,) units to give myrcene have been r e p ~ r t e d ~and ~~J~~ elegantly conceived several-stage syntheses of (I?)-( -)-ipsdienol and the (S)-( +)isomer [a pheromone of Ips beetles (66)] were based on a previously developed route to ipsenol (47) and utilized (I?)-( +)-glyceraldehyde and (R)-( +)-malic acid respectively as starting rnate~ia1s.l'~
J?
HO
Reactions of 3,7-Dimethyloctadienes and their Derivatives.-Geraniol and nerol were sequentially converted into their chlorides and cyanides with no allylic rearrangement on treatment with (Bu"),P-CCl,-KCN in the presence of crown ether.17s 2,4,6-Trichloro-4-bromocyclohexa-2,5-dienone selectively brominated geraniol derivatives (functionalized at C-1) under mild conditions to give the T. Mandai, H. Yamaguchi, K. Nishikawa, M. Kawada and J. Otera, Tetrahedron Lett., 1981,
lo@
22,763. 170
171 178
17a
17* 17ti
I. Fleming, I. Paterson, and A. Pearce, J. Chem. SOC.,Perkin Trans. I , 1981, 256. T. Veysoglu and L. A. Mitscher, Tetrahedron Lett., 1981, 22, 1303. H. Kleijn, H. Westmijze, J. Meijer, and P. Vermeer, Recl. Trav. Chim.Pays-Bas, 1980,99,340. Y. Ueno, H. Sano, S. Aoki, and M. Okawara, Tetrahedron Lett., 1981, 22, 2675. K. Mori, T. Takigawa, and T. Matsuo, Tetrahedron, 1979, 35, 933. A. Mizuno, Y. Hamada, and T. Shioiri, Synthesis, 1980, 1007.
20
Terpenoids and Steroids
6,7-dibromo-compounds together with products substituted at C- 10 and at C-6.17s 10-Bromogeranyl methyl ether was readily isomerized to the 8-bromo-compound and products of allylic rearrangement.l 7 7 The isomers of 2,3-epoxygeraniol yielded 1 ,2-dihydroxy-myrcene and -0cimene on treatment with Ti(OPr'), : however,
(70) erythro-l,2-epoxylinalool(hydroxy and epoxy cis) with vanadium catalysts gave dihydroxymenthanes whereas the threo-isomer was decomposed; Ti(OPri), catalysed the reaction of the erythro-compound but threo was recovered unchanged. These results were rationalized by 'OH-assisted delivery' of the metal to the oxiran ring.17s The synthetic uses of bisulphite adducts of citrals have been explored.17B Myrcene deuteriated at (C-8 + C-10) has been prepared,lsOandthe 3-fluoromethyl-, 3-difluoromethyl-, and 3-trifluoromethyl-geraniols have been synthesized for use as substrates of prenyltransferase.lsl The key reaction that defined the stereochemistry of the double bond was the syn-addition of a (4-methylpent-3-en- 1-yl) copper reagent to derivatives of ethyl but-Zynoate bearing the appropriate functional group at C-4. Several interesting studies have been directed towards the synthesis of insect pheromones (see also ref. 174). (3R)-( +)-Frontalin (67), an aggregation factor of beetle species which can be regarded, at least from the synthetic viewpoint, as a bis-nor-monoterpene, has been obtained (25 % ;five steps) from (3R)-(-)-linal~ol:~*~ the key step was (68)+(69) using the reagent Me,SiCMe(Li)Cl; this, as a source of carbanion in carbonyl addition followed by intramolecular displacement of chlorine, would seem an important general route to a,P-epoxysilanes. The diol (70), a butterfly pheromone, has resulted from geraniol by site-specific olefin functionalization and the subsequent anionic (2,3)-sigmatropic rearrangement of the methoxycarbonylethylallylic sulphide.lS3 Other insect pheromones of diverse size (C&-C29) have been synthesized using citronellol, citronellal, or citronellic R 0 NMe, 0 NMe,
xy (71)
176
177 178
1'9
180
181
----+
a,
3
X
(72)
(73) X
=
C0,H or C0,Et
T. Kato and 1. Ichinose, J. Chem. SUC., Perkin Trans. I , 1980, 1051. T. Kumagai, F. Ise, I. Uyehara, and T. Kato, Chem. Lett., 1981, 25. D. J. Morgans, K. B. Sharpless, and S. G. Traynor, J. Am. Chem. SOC.,1981, 103,462. M. B. Erman, L. V. Shmelev, I. M. Pribytkova, and I. S. Aulchenko, Zhr. Org. Khim., 1979, l!~, 1598. Y. Stenstrou and L. Skattebol, Actu Chem. Scund., Ser. B. 1980, 34, 131. C. D. Poulter, P. L. Wiggins, and T. L. Plummer, J. Org. Chem., 1981, 46, 1532. P. Magnus and G. Roy, J. Chem. SOC.,Chem. Commun., 1978, 297. Y. Masaki, K. Sakuma, and K. Kaji, Chem. Lett., 1980, 1061.
Monoterpenoids
21
acid as chiral source^.'*^-^^^ p-Sinensal (which exhibits JH activity) was prepared from myrcene; the last steps utilized a possibly general reaction whereby a thioncarbamate (71) was rearranged in situ to an allylic thiolcarbamate (72), which could be functionalized to give an (E)-product (73).18' Many reports concern homologization or coupling of monoterpenes to give non-terpenoid products. Of especial interest are the reactions of allyl formates with Wittig reagents to give substituted allyl vinyl ethers, e.g. (74)+(75), which can undergo Claisen rearrangement to y,bunsaturated carbonyl compounds (76),188
focHo
(74)
-;"' PhaPCHPh
-Ph
~
f
(75) (76)
and the reaction of isolinalool (77) to give (78).lS9Citronellyl acetate (79) coupled with acetylenic esters in the presence of AlC13 to give (80), and the use of ethylaluminium dichloride as a catalyst allowed the isolation of pure products from acid-sensitive alkenes.lgoMe,Cu,Li, (prepared from CuI and MeLi-LiC1)converted a,P-unsaturated aldehydes such as geranial efficiently into @-methylaldehydes and, unlike Me,CuLi, it usually gave a negligible amount of the 1,2-adduct (l-methylgeraniol) even when a quaternary carbon was generated in the reaction.lgl Other studies have recorded the coupling of myrcene with organic acids in the presence of sodium naphthalenidelg2and with vinyl cyanide and vinyl phenylsulphone to give l-(4-methyl-pent-3-enyl)cyclohexenes1g3~1g4 and reaction of citral with substituted acetophenones to give, e.g. (81),lg5with allyl iodide (SnF, catalyst) to give chain extension at C-1,1g6with bis-anions derived from furoic acid to give (82),197 with U. Jensen and H.-J. Schafer, Chem. Ber., 1981, 114, 292. T. Sumki, Agric. Biol. Chem., 1980, 44, 2519. IB6 K. Mori, S. Masuda, and T. Suguro, Tetrehedron, 1981, 37, 1329. T. Mimura, Y. Kimura, and T. Nakai, Chem. Lett., 1979, 1361. lS8 M. Suda, Chem. Lett., 1981, 967. F. Naf, Ger. P., 2 849 332/1979. 1 9 0 B. B. Snider, D. J. Rodini, R. S. E. Conn, and S. Sealfon, J. Am. Chem. SOC.,1979, 101, 5283. 191 D. L. J. Clive, V. Farina, and P. Beaulieu, J . Chem. SOC.,Chem. Commun., 1981, 643. 192 T. Fujita, S. Watanabe, K. Suga, and H. Nakagama, Synthesis, 1979, 310. 198 R. V. C. Carr and L. Paquette, J. Am. Chem. Soc., 1980,102,853. 194 0. P. Vig, I. R. Trehan, G. L. Kad, and A. L. Bedi, IndianJ. Chem., Sect. A , 1979,17,555. S. Y.Dike and J. R. Merchant, Indian J . Chem., Sect. B., 1978, 16, 1111. T. Mukaiyama, T. Harada, and S. Shoda, Chem. Lett., 1980, 1507. D. W. Knight, Tetrahedron Lett., 1979, 469.
184
2
22
Terpenoids and Steroids
p-
carbazoles to give pyran0[2,3a]carbazoles,19~and with dihydroxycoumarones to give (amongst others) an intermediate en route to e r i o b r u c i n ~ l . ~ ~ ~
OAc
HC = CC0,Me
(79)
(80)
Reactions with Metal Complexes.-Pd (mainly Pd") complexes catalyse or otherwise mediate several synthetically useful processes. Myrcene with aqueous [(MeCN),PdC12] yielded (83) + (84) which on basification gave nerol and citral, but no geranio1.200The same complex catalysed the conversion of linaloyl acetate into neryl and geranyl acetates in low yield, but 6,7-dihydrolinaloyl acetate was very effectively (90 %) isomerized.201Geranyl and neryl acetates underwent hydrogenolysis with PdO and ammonium formate to give largely unrearranged 1-olefins,2O2 and the same substrates were converted with regio- and stereo-control into allylic p-tolyl sulphones by sodium p-tolylsulphinate and [Pd(PPh3)4].203Pd and Ni
(83)
lS8 lSs
(84)
(85) X
=
S0,Ph or C0,Me
D. P. J. Patel, Synth. Commun., 1981, 11, 823. L. Crombie, S. D. Redshaw, D. A. Slack, and D. A. Whiting, J . Chem. Soc., Chem. Commun., 1979,628.
2oo
202
*03
(86)
M. Takahashi, H. Suzuki, Y. Moro-Oka, and I. Ikawa, Chem. Lett., 1979, 53. L. E. Overman and F. M. Knoll, Tetrahedron Lett., 1979, 321. J. Tsuji and T. Yamakawa, Tetrahedron Lett., 1979, 613. K. Inomata, T. Yamamoto, and H. Kotake, Chem. Lett., 1981, 1357.
Monoterpenoids
23
complexes catalysed the alkylation of myrcene with NaCH(C0,Me)2,204and this reagent or NaCH(SO,Ph)CO,Me alkylated geranyl acetate in the ally1 positions in the presence of PdO complexes to give (85) and small amounts of (86).205Geranyl derivatives (87) [X = acetate, halogen, OAlR,, OPO(OR),, or OSiR,] coupled with dimethylalkenyl aluminium compounds, e.g. to give (88).,06 Oxidation and Reduction.-Geraniol on treatment with t-butyl hydroperoxide and Ti catalysts in the presence of ( +)-diethy1tartrate gave the (2S,3S)-oxide,whereas t-Butyl in the presence of the (-)-tartrate the other isomer was hydroperoxide and vanadium catalysts converted (R)-(-)-linalool into 2,3epoxycitronellol (89), which on reduction and photosensitized oxidation yielded
(93)
(94)
(90) : this was cyclized to two products which were separately dehydrated to nerol oxide (91) and its enantiomer, each in 95 % optical purity.20sNerol oxide from rose oil is racemic and it was suggested that this was produced by the direct photoxidation of nerol [natural (-)-rose oxide is believed to be similarly produced from ( -)-citronellol]. The rose oxide was also converted into sesqui-rose oxides.208a Epoxidations, carbene additions, etc. of 2,3-epoxycitral have been A very detailed investigation of the dye-sensitized photoxidation of a-nerol (92) showed the formation of the diols (93) and (94) with no cyclized products.210 Allo-ocimene and myrcene on autoxidation in DMF or DMSO give an odd variety
*04 *05 *06 *07 ao8
R. Baker and R. J. Popplestone, Tetrahedron Lett., 1978, 3575. B. M. Trost and T. R. Verhoeven, J . Am. Chem. SOC.,1980,102,4730. E. Negishi, S. Chatterjee, and H. Matsushita, Tetrehedron Lett., 1981, 22, 3737. T. Katsuki and K. B. Sharpless, J. Am. Chem. SOC.,1980, 102, 5974. G. Ohloff, W. Giersch, K. H. Schulte-Elte, P. Enggist, and E. Demole, Helv. Chim. Acta, 1980,63, 1582.
G. Ohloff, W. Giersch, R. Decorzant, and G. Biichi, Helv. Chim. Actu, 1980,63, 1589. L. P. Glushko, V. N . Samsonova, M. S. Malinovskii, and L. A. Yanovskaya, Zsv. A k d . Nauk SSSR, Ser. Khim., 1980, 1048. *lo K. H. Schulte-Elte, B. L. Mulier, and H. Pamingle, Helv. Chim. Actu, 1979, 62, 816. *Ow
*09
24
Terpenoids and Steroids
OH (95)
R'
R'
(97)
R'
(98)
(99)
of products,211and geranic acid was formed in 92% yield from citral by sodium chlorite in the presence of 2-methyl-but-2-ene (a C1. scavenger).212Benzyl ethers of nerol were oxidized at the 6,7-bond to give poor yields of products required as intermediates for the synthesis of the antibiotic moenocinol, but epoxidation and conversion into the sulphone (95) allowed epoxidation to (96) in good (60%) yields.213 Electrochemical oxidations have been previously mentioned.122A novel application is the regioselective epoxidation (80 % conversion ; 90 % selectivity) at the 6,7bond of geranyl and neryl esters and phenyl ~ u l p h o n e sAnother . ~ ~ ~ is the one-step conversion of olefins into allylic alcohols via electrooxidative-oxyselenylationdeselenylation, e.g. (97)+(99). This method has been applied to the synthesis of (100) which can be converted (70%) into marmelolactone [(101) from quince], and
h0-r+ 0
MeSO&l-Et.N
,
ho0
(100)
to the synthesis of rose oxide (102) from citronellol (103).215[l-2H]Citralcould be reduced to [l-2H]geraniol with an optical purity of 90 % by use of a chiral complex aluminium hydride.21aIsotopically normal citral was efficiently reduced to geraniol 211 212
213 214 216
?16
M. Nomura, Y. Fujihara, and Y. Matsubara, Nippon Kogaka Zaishi, 1980, 779. B. S. Bal, W. E. Childers, and H. W. Pinnick, Tetrahedron. 1981, 37, 2091. P. J. Kocienski, J . Org. Chem., 1980, 45, 2037. S. Torii, K. Uneyama, M. Ono, H. Tazawa, and S. Matsunami, TetrehedronLett., 1979, 4661. S. Torii, K. Uneyama, and M. Ono, TetrahedronLett., 1980, 21, 2653. M. Nishizawa and R. Noyori, Tetrahedron Lett., 1980, 21, 2121.
Monoterpenoids
25
(W Reagents: i, Ni(OAc),NaBH,;
ii, ROCl; iii,
;iv, CuBr-PBr,, -78°C
scheme 6
with no 1,6addition by EtCH(OMgBr)2217or to citronellol over metallic catalysts.218-220Geraniol and nerol were reductively deoxygenated with preservation of the E- or 2-geometry by LiAlH, and [Cp2TiC12]as catalyst.221Dehydrolinalool was effectively reduced over Pd to l i n a l o 0 1 , ~as~was ~ ~ geranic ~ ~ ~ acid to dihydrogeranic acid over K-gra~hite.~~* The trimethylsilyl group continues to be used as a protecting or directing group in synthesis, viz. the sequences (104)+( 105)225and ( 1 0 6 ) j (107) (Scheme 6).226Also, a variety of A2-butenolides may be synthesized via oxidation of the 0-trimethylsilylcyanohydrinsof ct,p-unsaturated aldehydes with pyridinium dichromate in DMF, cf. (108)-+(109).227 Cyclizations, Isomerizations, etc.-(See also rose oxidezo8).Citral on irradiation at relatively elevated temperatures ( > 80 "C) gave two new products (1 10a and b) (5-10%) and a biradical route was proposed. It was demonstrated that these products did not arise from cleavage of (1 1l), a previously known product of the reaction: the latter gave (1 12) and (1 13) under these conditions.228A more detailed *17
J. H. Babler and B. J. Invergo, TetrahedronLett., 1981, 22, 621. D. V. Sokolskii, A. M. Pak, and S. R. Konuspaev, Zh. Prikl. Khim., 1981, 51, 1145. D. V. Sokolskii, A. M. Pak, S. M. Turganbaeva, S. R. Konuspaev, and M. A. Ginzburg, Zh. Prikl. Khim., 1981, 54, 1574. A. M. Pak, S. R. Konuspaev, and D. V. Sokolskii, Kinet. Catal. Lett., 1981, 16, 339. F. Sato, Y. Tomuro, H. Ishikawa, T. Oikawa, and M. Sato, Chem. Lett., 1980, 103. A. M. Pak, D. V. Sokolskii, 0. I. Kartonozhkina, and R. E. Kumetsova, Dokl. Akad. Nauk SSSR, 1980, 253, 170. A. M. Pak, D. V. Sokolskii, 0.I. Kartonozhkina, 0.V. Vyaznikovtseva, and E. N. Lituyakova, Zh. Prikl. Khim., 1980, 53, 2065. M. Oontento, D. Savoia, C. Trombini, and A. Umani-Ronchi, Synrhesis, 1979, 30. R. Calas, J.-P. Pillot, and J. Dunogues, C. R. Hebd. Seances Acad. Sci., Ser. D, 1981,292,669. A. Yasuda, S. Tanaka, H. Yamamoto, and H. Nozaki, Bull. Chem. SOC.J., 1979, 52, 1752. E. J. Corey and G. Schmidt, TetrahedronLett., 1980, 21, 731. S. Wolff, F. Barany, and W. C. Agosta, J. Am. Chem. SOC.,1980, 102,2378.
lao
*28
2Z4 a25
aa7
26
Terpenoids and Steroids
po j
y
? o
-
(110a)
+CHO
E C H O
(1lab)
&\
CHO
study showed that on 'n,x* excitation (A > 347 nm) the products were (1 11) and (1 14), whereas on %,x* excitation (A = 254 nm) (1 14) and (1 1 9 , but not (1 1l), were formed. An intramolecular [2 + 21 photocycloaddition that was shown to be a triplet process was found on h,x* or lx,x* excitation of (1 16) to give (1 17) only, whereas broad-spectrum irradiation (A > 280 nm) of (1 17) gave isomers of (1 18) which photoisomerized to the oxetans (1 19).229Irradiation of citronellyl iodide gave citronellene and various m e n t h e n e ~ . ~ ~ ~ Lao
M. Yoshioka, K. Ishii, and H. R. Wolf, Helv. Chim. Acta, 1980, 63, 571. K. M. Saplay, R. Sahui, N. P. Damodaran, and S. Dev, Tetrahedron, 1980,36, 1455.
Mono terpenoids I
27
0
Hp$-JH
HO
(123) ( 124) Several new, or adaptations of old, cyclizations to furan and pyran derivatives have appeared. Geranyl acetate with RuOl gave the isomers of (120)and also (121) (51 % and 12 %),231 A more stereocontrolled synthesis yielded the bis-tetrahydrofurans (122)and (123)containing four chiral centres (each in 90% isomeric purity) in a four-step route from geranyl or neryl chlorides that involved two stereoselective cyclizations. The epoxide ring of (123) could be opened by an allylic Grignard reagent and the resulting product dimerized to give (124).232 Two new routes to rose oxide have been claimed; one from citronellyl acetate233and the other from cyclization of 3,7-dimethylocta-(Z)2,5,7-triene,which can be easily obtained from iso~rene.~~~
An elegant stereocontrolled synthesis of the cis- and trans-linalool oxides (125) has been developed involving iodocyclization of 2,6-dimethylocta-(E)6-ene-2,3-diol: the cis-isomer was favoured on steric grounds.? The isomers (125) were also formed in an alleged biogenetic-type ( !) process from 6,7-epo~ylinalool.~~~ Hydroxylated linalool derivatives have been demonstrated as likely precursors for (I 25), its dehydration products, and other furanoid and pyranoid compounds formed on heating g r a p e j u i ~ eLinalool . ~ ~ ~ was cyclized by HgOAc to give (126)but demercura231 232 233 234
236 z36 437
P. H. J. Carlsen, T. Katsuki, V. S. Martin, and K. B. Sharpless,J . Org. Chem., 1981,46,3936. A. Amouroux, G. Folefoc, F. Chastrette, and M.Chastrette, Tetrahedron Lett., 1981, 22,2259. S. G. Hegde and seven others, Tetrahedron Lett., 1980, 21, 441. T. Yamato and N. Nakamura, 7th International Congress on Essential Oils, pp. 287, 997 (Chem. Abstr., 1980, 92, 129 093). S. D. Rychnovsky and P. A. Bartlett, J . Am. Chem. SOC.1981,103, 3963. T. Kametani, H. Nemoto, and K. Fukamoto, Bioorg. Chem., 1978, 7 , 215. P. J. Williams, C. R. Strauss, and B. Wilson, J. Agric. Food Chem., 1980, 28, 766.
28
Terpenoids and Steroids
tion (NaBH,) led to bicyclic ethers [e.g. (127)l. The unexpected formation of the C-C bond is presumably due to the proximity of the Hg and the vinyl group in the organomercurial intermediate.23s In contrast, treatment of linalool with Hg2+ salts under different conditions was claimed to lead to mainly (128).239
pq3f I
OH (128)
g
0 (131)
(132)
(129)
$q
OHC
OH (1 30)
P (134) O H
p
A detailed mechanistic study records the products of solvolysis of geranyl chloride, phosphate, and pyrophosphate under a variety of conditions : the prevalence of cyclization or of double-bond rearrangement was correlated with the lifetimes of the carbocations and the possibility of their achieving the most favoured conformation^.^^^ As did most Lewis acids, Me2A1CI cyclized citronella1 to menthane derivative^.^^' Similar cyclizations of 6,7-epoxylinalyl acetate to menthanes (after initial ring-opening with PhSeOH and treatment with F3CC02H-CH2C12) were claimed to be biogenetic-type processes.242Treatment of allo-ocimene with acrolein led to (129) together with some of the epimer at the carbon a to the aldehyde group: the proportion of the latter was increased on heating.243cisOcimenol was partly converted into its trans-isomer on irradiation in the presence of PhSSPh (presumably owing to the formation of PhS -244) and ( +)-citronello1 gave ( +)-dihydrocitronellal in the presence of [Fe(CO),] via a succession of 1,3-hydride shifts without apparent dissociation of the Allylic rearrangement caused by treatment of ipsdienol (66) with HBF4 gave (130) together with dehydration products that show pheromone activity towards Ips beetles,246and NN-dimethylgeranylamine (easily formed by base-catalysed condensation of isoprene with dimethylamine) could readily be converted into the phenylselenide (PhSe-; Ru catalyst), which on oxidation and rearrangement gave linalool in 83% overall yield.247 238 23* 240
241 242
243 244
246 246
241
Y. Matsuki, M . Kodama, and S. Ito, Tetrahedron Lett., 1979, 4081. Y. Matsuki, M. Kodama, and S. Ito, Tetrahedron Lett., 1979, 291. C. A. Bunton, 0. Cori, D. Hachey, and J. P. Leresche, J . Org. Chem., 1979,44, 3238. M. Karras and B. B. Snider, J . Am. Chem. SOC.,1980, 102,7951. T. Kametani, H. Kurobe, and H. Nemoto, J. Chem. Soc., Chem. Commun., 1980, 762. G. J. Ferber and J. A. Botten, U.K. P., 2 050 365/1981 (Chem Abstr., 1981, 95, 12 589). K. H. Schulte-Elte, Swiss. P., 610 580/1980. E. Weissberger, A. Stockis, D. Carr, and J. Giebfried, Buff.SOC.Chim. Belg., 1980, 89, 281. W. Francke, P. Saverwein, J. P. Vile, and D. Klimetzet, Naturwissenschaften 1980, 67, 147. S. I. Murahashi and T. Yano, J . Am. Chem. SOC.,1980,102,2456.
Mono terpenoids
(136)
29
(137)
(138)
(139)
(140)
Nerol was cyclized on treatment with Tl(ClO,), to 6-oxabicyclo[3.2.1]octane derivatives (131) and (132):248it had previously been shown (in 1976) that geraniol gave 6,9-dioxabicyclo[3.3.1Inonane derivatives under the same conditions. Similar reactions of citral led to a novel 6,8-dioxabicyclo[3.2.l]octane (133) that has the skeleton of certain pheromones of bark beetles.249Nerol and related (Z)-allylic alcohols could be cyclized with Tic,-PhNHMe complex. Nerol yielded a-terpinyl chloride, whereas (134) gave (135) : chlorine in the latter could not be displaced in SN2reactions but conversion into the Bu",Sn derivative and oxidation gave (136), which could be readily elaborated to nezukone (137).250Cycloheptyl compounds [e.g. (138)] could also be made by hydroboronation and cyanidation of linaloyl acetate or by carbene addition to p i p e r i t e n ~ n eCyclo-octyl .~~~ ketones [e.g. (140)] resulted from cyclization of the enol form of (E)-ocimenone ( 1 39).252
5 Tetramethylcyclohexanes and Related Compounds Safranal (141) was formed by cyclization of (142) and functionalization. The intermediate was obtained by treatment of the epoxide of geranyl acetate with PhSe-.253Cationic cyclization of geranyl cyanide and related compounds via their bromohydrins gave isomeric products (143 ; R = CH2CN) that could be modified to give certain marine natural products, e.g. [143;R = CH,C(Me)OHCH=CH2].2S4 Dimethylgeranylamine (cf. ref. 247) was cyclized by 40 % H2S04to (144) whereas treatment of the diethylamine with BF, etherate gave the exo-isomer. Treatment of
24t3
35O 251
z62 263 854
Y. Yamada, H. Sanjoh, and K. Iguchi, Tetrahedron Lett., 1979, 1323. Y. Yamada, H. Sanjoh, and K. Iguchi, Tetrahedron Lett., 1979, 423. T. Saito, A. Itoh, K. Oshimo, and H. Nozaki, Bull. Chem. SOC.J . , 1981, 54, 1456. R. Murphy and R. H. Prager, Aust. J. Chem., 1981, 34, 143. R. C. Cookson, S. Sakdarat, and M. Webster, J. Chem. SOC.,Chem. Commun., 1980, 281. T. Kametani, K. Suzuki, H. Kurobe, and H. Nemoto, Chem.Pharm. Bull., 1981,29,105. A. Murai, A. Abiko, K. Kato, and T. Masumune, Chem. Lett., 1981, 1125.
Terpenoids and Steroids
30
(144) with ethyl chloroformate gave (145), whereas conversion of the exo-isomer into the amine oxide and Cope elimination formed (146).255-256 Two elegant
(150) Reagents: i, Me,C=CHCH,Br; ii, SnCI,; iii, NaH; iv, ClPO(OEt),; v, LiMe2Cu; (iii, iv: conversion to enol phosphate); vi, HC0,Et-NaH
Scheme 7
/,iii-v
0
1
(151) Reagents: i, H,-Pd; ii, HN0,-AcCH; iii, KOH; iv, H+; v, LiAlH,; vi, BunLi; vii, TiC1,-LiAlH, ; viii, 1-methyl-2-fluoropyridinium salts
Scheme 8 25b
eaa
K. Takabe, T. Yamada, and T. Katagin, Chem. Ind. (London), 1980, 540. K. Takabe, T. Yamada, T. Sato, and T. Katagin, J . Chem. SOC.J., Ind. Chem. Sect., 1980, 776.
Monoterpenoids
31
pathways to interesting and potentially synthetically useful intermediates based on the 1,1,2,3-tetramethylcyclohexane skeleton are (147)+( 148)257and (149)+( 150) (Scheme 7);258paths to related diene and monoene esters have also been developed.259-261 An impressive route has been established to karahara ether (151) (Scheme 8):262 the last dehydration with ring closure by use of a 1-methyl-2-fluoropyridinium salt is especially noteworthy. FCyclocitral (152) has been converted into ~ h l o r o -and ~ ~ lactonized ~ comp o u n d the ~ ~a-isomer ~~ has been f u n c t i ~ n a l i z e dand ~ ~used ~ as starting material for a synthesis of a-damascones.266Thirteen new halogenated and oxygenated monoterpenes with the I 1-dimethyl-3-ethylcyclohexaneskeleton [so-called ochtodane (153)] have been isolated from red marine and a weevil pheromone (154) has been synthesized from dimedone using ethoxyvinyl-lithium(a new acetaldehyde equivalent).268 2,4,4,5-Tetramethylcyclohex-2-en-l-oneoccurs in rhizomes of iris.269 A compound from Curium spp. is p-cyclolavandulic acid (2,4,4-trimethylcyclohex- 1-en-l-oic acid), not a keto-acid as previously reported.268aNor-monoterpenes, e.g. 3,5,5-trimethylcyclohex-2-en-l-one,were oxidized at the allylic positions by cultures of Aspergillus species.27o
F. W. Sam and L. Weiler, J. Am. Chem. SOC.,1979, 101,4401. D. Gullerm, G. Boussac, J. Lalande, P. Lemaitre, and J.-Y. Lallemand, Synth. Commun., 1981, 11, 627. a69
m0 e61 26z
263 864
266
26e
269
F. Rouessac and H. Zamarlik, Tetrahedron Lett., 1979, 3417. M. Alderice and L. Weiler, Can. J. Chem., 1981, 59, 2239. I. Kitagawa, and seven others, Chem. Pharm. Bull., 1981, 29, 2548. T. Mukayama, N. Iwasawa, T. Tsuji, and K. Narasaka, Chem. Lett., 1979, 1175. S. G. Hegde and J. Wolinsky, Tetrahedron Lett., 1981, 22, 5019. A. W. Frank, J. Heterocycl. Chem., 1981, 18, 549. R. Pelliciari, E. Castognino, R.Friguelli, and S. Corsano, Tetrahedron Lett., 1979, 481. H. J. Liu, H. K. Hung, G. L. Mhehe, and M. L. D. Weinberg, Can. J. Chem., 1978,56,1368. V,J. Paul, 0. J. McConnell, and W. Fenical, J. Org. Chem,, 1980, 95, 3401. R. H. Wollenberg and R. Peries, Tetrahedron Lett., 1979, 297. A. Sattar, M. Ashref, M. K, Bhatty, and N. H. Christi, Phytochemistry, 1978, 17, 559. J. Garner0 and D. Joulain, Bull. SOC.Chim. Fr., Part IZ, 1979, 455. Y. Mikami, Y. Fukunaga, M. Arita, Y. Obi, and T. Kisaki, Agric. Biol. Chem., 1981,445, 791.
32
Terpenoids and Steroids 6 The Menthane Class
General.-Reviews, some unfortunately badly out-of-date, have appeared on p-menth- 1-ene,271~ - m e n t h - 3 - e n em-menthane ,~~~ derivatives,273dihydrocar~one,~74 P - t e r p i n e ~ land , ~ ~on ~ aspects of the chemistry of a ~ c a r i d o l eThe . ~ ~enantiomers ~ of (155), together with products of cleavage of the dioxide bond (but no a~caridole),~~’ 1-hydroxy- and 1,4-dihydroxy-derivativesof ~ - m e n t h - 2 - e n e other , ~ ~ ~ oxygenated p - m e n t h e n e ~ ,and ~ ~ ~various 2-nitro-p-rnenthadiene~~~O have been isolated from assorted plants.( -)-Mint lactone (156) and its epimer at C-3 occur in Mentha spp. and have been prepared by oxidation of menthofuran.281More extensively functionalized p-menthanes, e.g. (1 57),282(1 58) (R= Et or Pri),283and 1-vinyl-p-menth-4(8)ene284also occur naturally. Two new glucosides [schizonepetosides (1 59 ; isomers)] occur in Schizonepeta s p ~ .and , ~ menthyl-p-D-glucosides ~ ~ were found in Mentha spp. :z8s the latter have been prepared and the isomers separated by g.c. of acetyl derivatives.287Pyrolysis of an incense derived from Boswelliu spp. gave (160) and
fiH (159)
QPh 0 II
271
279
275 270
277
478 279 280
281
283 284 28s 280
J. Verghese, Perfum. and Flavorist, 1980, 5, 18. J. Verghese, Perfum. and Flavorist, 1979, 4, 31. J. Verghese, Perfum. and Flavorist, 1980, 5, 47. J. Verghese, Perfum. and Flavorist, 1980, 5, 23. J. Verghese, Perfum. and Flavorist, 1980, 5 , 39. M. Balci, Chem. Rev., 1981, 81, 91. J. de Pascual, I. S . Bellido, C. Torres, B. A. Sast,e, and M. Grande, Phyrochemistry, 1981, 20, 163. H. P. Schenk and D. Lamparsky, J . Chromatogr., 1981, 204, 391. J. M. Sendra and P. Cunat, Phytochemistry, 1980, 19, 89. S . Escher, U . Keller, and B. Willhalm, Helv. Chim. Acta, 1979, 62, 2061. K. Takashashi, T. Someya, S. Muraki, and T. Yoshida, Agric. Biol. Chem., 1980, 44, 1535. F. Bohlmann, C. Zdero, and A. G. R. Nair, Phytochemistry, 1979, 18, 1062. A. F. Thomas, M. Schouwey, and J. C. Egger, Helv. Chim. Acta, 1981, 64, 1488. S . B. Singh, A. Goswami, M. C. Nigam, and R. S . Thakur, Phytochemistry, 1980, 19, 2466. H. Sasaki, H. Taguchi, T. Endo, I. Yosioka, and Y . Iitaka, Chem. Pharm. Bull., 1981,29,1636. I. Sakata and K. Koshimizu, Agric. Biol. Chem., 1978, 42, 1959. I. Sakata and H. Iwamura, Agric. Biol. Chem., 1979, 43, 307.
Monoterpenoids
33
related corn pound^.^^^^^^^ The optical properties (c.d. etc.) of conjugated cisoid dienss, and enones including pulegone and cx-phellandrene, have been studied.”O A menthofuran derivative was a main constituent of an Anethum species:291menthofuran itself has been efficiently synthesized from a - p ~ l e g o l p , ~u~l e~ g 0 n e , ~ ~or~ ~ ~ ~ 4 2-carboxyethyl-5-methylcyclohexanone.295A synthesis of the related (R)-(-)evodone (161) from (R)-(+)-citronellic acid confirmed the natural isomer to the (R)c o m p o ~ n d96. ~ A mixture of o-menthanes resulted from reduction of o-cymene with Ca(NH3),,2S7 and a neat route to the o-menthane skeleton involved photochemical addition of allene to 3-methylcyclohex-2-en-1-one and opening of the cyclobutyl ring with BF3.2980-Menthadi- and tri-enes resulted from pyrolysis of ~ e r b e n e n e . Acid~~Q and base-promoted isomerizations of o-menthadienes300 and dehydration of cis- and trans- o-menthan-8-01s with a variety of reagents have been re~orded.3~1 Optically active 2-methyl-4-isopropenylcyclohexanone(which is a useful precursor for rn-menthane derivatives) has been prepared by pyrolysis of chiral2,2,5-trimethylbicyclo[3.1.l]heptan-2-0ne.~~~ Formation of the Menthane Skeleton.-Isoprene cyclodimerized in the presence of Ni303 or Fe304$305 catalysts to mixtures of m- and p-menthadienes, 1,4-dimethyl-4vinyl- and 1,3-dimethyl-3-vinyl-cyclohexenes,and dimethylcyclooctadienes. An improved synthesis of piperitone from mesityl oxide and methyl vinyl ketone has been devised,306and the latter condensed (NaH) with methyl 2-methyl-1-carboxymethylpropyl ketone to yield (162), which could be cyclized under appropriate conditions to give excellent ( > 80 %) yields of either 0- or p men then one^.^^' Myrcene yielded p-cymene on heating with metal ( +)-citronella1 was selectively cyclized to (-)-isopulegol by Zn halides,309and the 288
M. Pailer, 0. Scheidl, H. Gutwillinger, E. Klein, and H. Obermann, Monatsh. Chem., 1981, 112, 595.
289
M. Pailer, 0. Scheidl, H. Gutwillinger, E. Klein, and H. Obermann, Monarsh. Chem., 1981, 112, 987.
280
293
D. A. Lightner and six others, J . Am. Chem. SOC., 1981, 103, 5314. P. Schreier, F. Drawert, and I. Heindze, Lebensm. Wiss. Technol., 1981, 14, 150. Z. U. Din, T. L. Ho, and S. G. Traynor, U.S. P., 4 240 969/1980 (Chem. Abstr., 1981, 95, 7510).
T. Sato, M. Tada, and T. Takahashi, Bull. Chem. SOC. J., 1979, 52, 3129. S. C. Taneja, K. L. Dhar, and C. K. Atal, Indian J. Chem., Sect. B, 1980, 19, 714. 2S5 S. Tsubio, K. Shimozuma, and A. Takeda, J. Org. Chem., 1980, 45, 1517. 286 Y. Masaki, K. Sakuma, K. Hashimoto, and K. Kaji, Chem. Lett., 1981, 1283. 2 e 7 V. V. Bazylchik, P. I. Fedorov, and N. M. Ryabushkina, Zh. Org. Khim., 1978, 14, 969. z88 D. K. M. Duc, M. Fetizon, I. Hanna, and S. Lazare, Synthesis, 1981, 139. 2nQ V. V. Bazylchik, P. I. Fedorov, E. D. Skatovski, and L. I. Vinogradov, Zh. Org. Khim., 1981, 293
ZQ4
17, 320. 300 301 302 303 304 305
306
307 308
30s
V. V. Bazylchik and P. I. Fedorov, Zh. Org. Khim., 1979, 16, 1422. V. V. Bazylchik and E. I. Ionova, Zh. Org. Khim., 1978, 14, 538. A. Yoshikoshi, K. Takagi, T. Nishimura, M. Iwamoto, and K. Kojo, Jap. P., 132 541/1978. P. W. N. M. van Leeuwen and C. F. Roobeck, Tetrahedron, 1981, 37, 1973. E. Leroy, D. Huchette, A. Mortreux, and F. Petit, Nouv. J . Chem., 1980, 4, 173. R. Petiaud and Y. B. Taarit, J. Chem. SOC.,Perkin Trans. I , 1980, 1385. 0. Namanishi, M. Fusitani, I. Ichimoto, and H. Ueda, Agric. Biol. Chem., 1980, 44, 1667. W. Kreiser and P. Below, Tetrahedron Lett., 1981, 22,429. M. A. Ryoshentseva, E. P. Belanova, K. M. Minachev, M. M. Emelyanov, and A. V. Semenovski, Izv. Akad. Nauk SSSR,Ser. Khim., 1980, 1659. Y. Natakani and K. Kawashima, Jap. P, 11 648/1978 (Chem. Abstr., 1979, 90, 876494).
34
Terpenoids and Steroids
bisulphite compound of citra1310or the PhSeOH adduct (at C-6 to C-7) of linaloyl acetate311 (cf. ref. 242) readily cyclized to p-menthane derivatives. Long-term (8 months) treatment of citral with HCl gave a variety of oxygenated derivatives of p-cymene and of piperitone that were responsible for the odour of deteriorated lemon oil?, The benzylimine derived from citronellal was cyclized by SnCl, to give (after reduction and debenzylation) menthylamine together with its neo- and neo-iso-isomers (75 % total; 7: 1: 2):312athis shows that an imido function can initiate acid-catalysed cyclization of polyenes, and an additional advantage of the method is that chirality may be introduced by reason of a chiral group linked to N (e.g. 36 % chiral induction when chiral citronella1 was used). More defined rou+te_shave been developed to specific compounds. Use of five equivalents of Me,PCH, under 'salt free' conditions (necessary) converted 4carboxyalkylcyclohexanones into p-menth- 1(10),7-diene.,13 An example of a general ketone to enone homologation is the reactign of 4-methylcyclohexanone with the anion from alkylchlorosulphoxides [R(Cl)CSOPh] to yield (after intramolecular displacement of C1) the epoxide (163), which on pyrolysis gave (164) that could be easily converted into p-menth-3-en-8-01.~~~ A highly stereoselective route to both diastereoisomers of p-menth-1 -en-Pol was developed using kinetically controlled alkylations and epimerization of the lactone (165) to control the stereochemistry :315 the intermediate was synthesized from 6-methylcyclohex-2-en-1-01. Silyl-Li reagents mixed with Cu' salts reacted with enones to give @-silylketones in good yield. These could be used in synthesis without risk to the silyl groups and the enone grouping could be restored by bromination-desilylbromination with CuBr,. The method is illustrated by an efficient synthesis of carvone (166) (Scheme 9).3l6
Jiii, iv
y&L
PhMe,Si*
(166) Reagents: i, (PhMe,Si),CuLi; ii, MeI; iii, MeLi; iv, H,O+;
V,
CuBr2-(PhC02), vi, Ac20
Scheme 9 alo
M. B. Erman, L. V. Shmelev, I. M . Pribytokova, and I. S. Aulchenko, Zh. Org Khim., 1979, 15,1598.
sll 312
alea 313 314
s16
T.-Kametani,H. Kurobe, and H. Nemeto, J . Chem. SOC.,Perkin Trans. I 1981, 756, K. Kimura, E. Doi, H. Nishimura, and I. Iwata, J . Agric. Chem. SOC.Jpn., 1981, 55, 1073. G. Demailly and G. Solladie, J . Org. Chem., 1981, 46, 3102. A. P. Uijttewaal, F. L. Jonkers, and A. van der Gen, J . Org. Chem., 1979,44, 3157. D. F. Taber and B. P. Gum, J. Org. Chem., 1979,44,450. P. A. Bartlett and C. F. Pizzo, J. Org. Chem., 1981, 46, 3896. D. J. Ager, I. Fleming, and S. K. Patel, J. Chem. SOC.,Perkin Trans. I , 1981, 1510.
Monoterpenoids
35
Another impressive use of silyl reagents came in the sequence leading to 8terpineol (167).,17 Homologation of 5-methylcyclohex-2-en-1-onecatalysed by FeO complexes led (after appropriate functionalization) to menthone and isom e n t h ~ n ewhereas , ~ ~ ~ Pd'I-catalysed coupling of 2-bromopropene with l-methylcyclohexa-1,3-diene gave p-mentha- 1,3,8-triene Treatment of a-pinene with Bz,02 and Cu' salts gave the benzyl derivative of trans-carveol, which could be converted into carvone in 46% overall yield:320the phenylurethane of pinol formed (1 68) on pyrolysis.321 II
I
C0,Me
II
C0,Me OH
(168)
(167)
Oxidation, Reduction, and Related Reactions.-Anthem01 (169) which has hardly been reported since its claimed discovery in 1879 has been synthesized (44 %) in a one-pot (presumably general) metallation of a-terpinene (BuLi-ButOK), followed by reaction with fluorodimethyloxyborane and oxidation (alkaline KMn04).322 6-Terpinene and other non-conjugated p-menthadienes were quantitatively aromatized by KMnO,-C,H,-crown ether, whereas the conjugated isomers (e.g. a-terpinene) were unaffected.323Ammonoxidation of limonene (NH, + 0,; Fe or U-Sb catalysts) gave various terpinenes, pulegones, and trimethylpyridines ( !): the intermediacy of such as (170), which cyclized to, e.g., (171) and (172) was Oxidation of limonene with Pb(OAc), led to (173; 82%), which is a component of Bulgarian rose oi1,325932sin contrast, hydroboration (BH,Cl) and oxidation gave (174).327Quinquevalent organobismuth reagents (e.g. Ar,BX,; X = ester or halogen) oxidized allylic alcohols under mild conditions: thus carveol gave ~ a r v o n e . ~ ~ ~ Pulegone and menthone formed (1 75) and (1 76) respectively on autoxidation in alkaline media.329Pulegone also underwent a conventional Baeyer-Villiger oxidation 317
318 31g
320 321 322
323 324 386
386
327
S. R. Wilson, L. R. Phillips, and K. J. Natalie, J. Am. Chem. SOC.,1979, 101, 3340. T. C. T. Chang and M. Rosenblum, J. Org. Chem., 1981, 46,4103. B. A. Patel, L. C. Kao, N. A. Cortese, J. V. Minkiewicz, and R. F. Heck, J . Org. Chem., 1979, 44,918. W. Liang-Liu and Y. S. Cheng, Proc. Natl. Sci. Counc. Repub. China, 1980, 5, 21. H. Starzemska and K. Piatkowski, Pol. J . Chem., 1980, 54,939. M. Schlosser, M. Bosshardt, A. Walde, and M. Stahle, Angew. Chem. Znt. Ed. Engl., 1980, 19, 308. A. Poulose and R. Croteau, J . Chem. SOC.,Chem. Commun., 1979, 243. S. R. Dolhyj and L. J. Velenyi, Ind. Eng. Chem., 1980, 47, 320. M. Nomura, Y. Fujihara, and Y. Matsubara, J . Chem. SOC.Jpn., Chem. Ind. Chem., 1979, 305. N.Nomura, Y. Fujihara, and Y. Matsubara, Nipon Nogei Kagaku Kaishi, 1978, 1182, (Chem. Abstr. 1979, 90, 23 274). I. Uzarewicz and A. Uzarewicz, Pol. J . Chem., 1979, 53, 1989.
D. H. R. Barton, J. P. Kitchin, D. J. Lester, W. B. Motherwell, and M. T. B. Papoula, Tetrahedron, Suppl. 9, 1981, 37, 73. A. Horinaka, E. Yo, 0. Mori, and K. Naya, Bull. Chem. SOC.J., 1979, 52, 2372.
36
Terpenoids and Steroids
A
?G
A
CHO
(40 % lactone formed).330 Menthone (57 %) resulted from Jones oxidation of menthyl benzyl ether,331but (177) proved surprisingly difficult to convert into the acid except by treatment with NaC10,.332 Conventional oxidations of the 3carboxymethyl derivative of 7,8-dih~drocarvone~~~ and of p-menth-7-en-9-01~~~ have been recorded. A good discussion and reference to previous results accompanies a study of the kinetics of reaction of conjugated p-menthadienes with singlet 0,.335 Photosensitized oxidation of the isomeric trimethylsilylenol ethers of menthone yielded p-menth- 1-en-3-one and -4-en-3-0ne,,~~ and pulegone formed (1 78) and (179) : the former (75% yield) was reduced (PPh,) to (180). In contrast, similar oxidation of p-menth-4(8)-ene gave only the hydroperoxide at C-4 with shift of the double bond.337The hydroperoxides of limonene formed by ene oxidation at C-1 or C-2 have been separated and Photo-oxidation of menth-1-ene in the presence of FeC1, formed 1-chloro-p-menth-2-one (Cl, Pr' cis), together with ring-opened mono- and d i - ~ h l o r i d e s . ~ ~ ~ ~ ~ ~ ~ J. R. Handley, A. A. Swigar, and R. M . Silverstein,J . Org. Chem., 1979, 44, 2954. B. S. Bal, K. S. Kochhar, and H. W. Pinnick, J . Org. Chem., 1981,46, 1492. 332 B. S. Bal, W. E. Childers, and H. W. Pinnick, Tetrahedron, 1981, 37, 2091. s33 H. Irie, J. Katakawa, M . Tomita, and Y. Mizuno, Chem. Lett., 1981, 637. 334 T. J. Brocksom and J. T. B. Ferreira, J . Chem. Res. ( S ) , 1980, 412. 336 B. M. Monroe, J . Am. Chem. SOC.,1981, 103, 7253. 336 E. Friedrich and W. Lutz, Chem. Ber., 1980, 113, 1245. 337 H. E. Ensley, R. V. C. Carr, R. S. Morton, and T. E. Pierce, J . Am. Chem. SOC., 1980,102,2836. 338 B. B. Jones, B. C. Clark, and G. A. Iacobucci, J . Chromatogr., 1980, 202, 127. 339 A. Kohda and T. Sato, J . Chem. SOC.,Chem. Commun., 1981, 951. 340 T. Sato, K. Maemoto, and A. Kohda, J . Chem. SOC.,Chem. Commun., 1981, 1116. 330 331
Monoterpenoids
37
A plethora of papers records the epoxidation (both mono- and di-) ofp-menthenes and p-menthadienes and their derivatives, and the products (usually very predictable) formed on ring-opening of the epoxides with a variety of reagents. A selection comprises reactions of p-menth- l-ene,341p342 p-menth-7-ene (en route to p-menthenp-menth-8-en-7-01,~~ limonene,3429346-349 puleolides), 8-~hloro-p-menth-l-ene,~*~ gone,350g351 piperit~ne,~~~ carveol, 355-357 and 2,8-cineolederivatives.358 The most interesting paper of this reports the radical-induced ringopening of the epoxide and provides a convenient alternative to the Wharton rearrangement. As generalized from the example studied, Bun3Sn reduction of an a,P-epoxy-o-thiolcarbonylimidazolide derivative of an alcohol led, via
(1 8 5 ) 341 342
343 344
345 346
347 348
340
350
351 352
a53 s54 355 358
3J7
358
Takasago Perfumery, Co. Ltd., Jap. P., 154 929/1980 (Chem. Abstr., 1981, 94, 157 112). K. Arata and K. Tanabe, Bull. Chem. SOC.J., 1980, 53, 299. T. J. Brocksom and J. T. B. Ferreira, Synth. Commun., 1981, 11, 105. R. Mestres, M. C. Polo, and M. J. Valero, An. Quim., 1979, 75,970. T.J. Brocksom, J. T. B. Ferreira, and A. L. Braga, J. Chem. Res. ( S ) , 1981, 334. F. Delay and G. Ohloff, Helv. Chim. Acta, 1979, 62, 2168. R. W. Rickards and W. P. Watson, Aust. J. Chem., 1980, 33,451. 0.P. Vig, S. D. Sharma, S. S. Bori, and M. Lal, Indian J. Chem., Sect. B, 1978, 16, 739. L. A. Mukhamedova, F. G. Nasybullina, and M. I. Kudryavtseva, Izv. Akad. Nauk SSSR, Ser. Khim., 1979, 847. J. Sepulveda, M. C. Polo, and R. Mestres, An. Quim., 1979, 75, 398. A. Horunka and K. Naya, Bull. Chem. SOC.J . , 1979, 52, 1964. A. Baragliu, G. Grandolini, C. Rossi, and C. G. Casinovi, Tetrahedron, 1980, 36, 645. H. Orszanska, K. Witkiewicz, and Z. Chabudzinski, Pol. J. Chem., 1980, 54,45. L. Friedman and J. G. Miller, Science, 1971, 272, 1044. A.Yasuda, H. Yamamoto, and H. Nozaki, Bull. Chem. SOC.J., 1979, 52, 1757. D.H. R. Barton, R. S. H. Motherwell, and W. B. Motherwell, J. Chem. SOC.,Perkin Trans. I, 1981, 2363. A. Itoh, K. Oshima, S. Sasaki, H. Yamamoto, T. Hiyama, and H. Nozaki, Tetrahedron Lett., 1979, 4751. D. Mrozinska and K. Piatkowski, Pol. J. Chem., 1980, 54, 693.
38
Terpenoids and Steroids
ring-opening, to an allylic alkoxyl radical. By a suitable choice of conditions this could either be quenched by H transfer from the stannane or rearranged to give more complex products [e.g. carveol gave (1Sl)]. Another significant development is a method for the reduction of an epoxide in the presence of a carbonyl group. The oxiran ring of (182) was opened by PhTe- or PhSe- and the resulting product reduced with Ph,SnH under mild (25-80 "C) conditions.35Q Ascaridole yielded the 1,2:3,4-diepoxide in the presence of a cobalt catalyst.36o 1,3,5The same product, together with a-terpineol and 2-methyl-5-isopropylhexatriene was formed on irradiation (1 85 nm) of the same substrate in cyclohexane:361 the excised oxygen all reacted with the solvent. The formation of p-menthenolides by oxidation and lactonization of menthol derivatives362and ring-openings of P-pinene epoxide to give perilla esters and related compounds have been recorded.363g364 Useful synthetic intermediates result from oxidative cleavage (sometimes ~*~~~ followed by degradation) of the cyclohexane rings of l i m 0 n e n e , 3 ~ diosphenol (autoxidation in the presence of cationic micelle~),3~~ i s o p ~ l e g o l c, ~a~r ~v ~ n e , ~ ~ ~ menthone (en route to rose a~caridole,3~l and 1,8-cineole (mediated by a Pseudomonas ~ p p . ) . ,The ~ ~ isopropenyl group of carvone can be effectively cleaved off.373
Isolimonene (p-mentha-2,7-diene) was specifically reduced in the side chain (H2 over Ru or Pd).374p375 Carvone was reduced at the endocyclic double bond by K,[Co(CN),H] under phase-transfer catalysis (transxis-products, 6 :1),378 by ~ ~ NaBH,-p~ridine,~~~ ~ or by Na-NH3NaBH,-Te (100 % t r ~ n s - p r o d u c t ) ,by 358
380 381
D. L. J. Clive and eight others, J. Am. Chem. Soc., 1980, 102,4438. J. D. Boyd, C. S. Foote, and D. K. Imagawa, J. Am. Chem. Soc., 1980, 102, 3641. R. Srinivasan, K. H. Brown, J. A. Ors, L. S. White, and W. Adam, J. Am. Chem. SOC.,1979, 101,7424.
B. S. Bal and H. W. Pinnick, Heterocycles, 1981, 16,2091. 363 H. Miyawaki and S. Miyazaki, Jap. P., 76 55011979 (Chem. Abstr., 1980, 92, 59 032). 384 G. Ohloff and W. Giersch, Helv. Chem. Acta, 1980, 63, 76. 365 J. Podlejski, J. Kula, and R. A. K. Riechst, Aromen, Kosmet., 1980, 30,41. 366 R. R. Heath, R. E. Doolittle, P. E. Sonnet, and J. H. Tumlinson,J. Org. Chem., 1980,45,2910. 3 1 3 ~M. Utaka, S. Matsushita, H. Yamashita, and A. Takeda, Tetrahedron Lett., 1980, 21, 1063. SB8 K. Shankaran and A. S. Rao, Indian J. Chem., Sect. B, 1979, 18, 507. 3~ K. Tanida and K. Mori, J. Chem. Soc. Jpn., Chem. Ind. Chem., 1981, 635. 3 7 0 S. Takano, K. Masuda, and K. Ogasawara, Heterocycles, 1981, 16, 1509. 371 G.Rucker and U. Molls, Liebigs Ann. Chem., 1979, 205. 372 I. C. MacRae, V. Alberts, R. M. Carman, and I. M. Shaw, Aust. J. Chem. 1979, 32, 917. 373 S.L. Schreiber, J. Am. Chem. SOC.,1980, 102,6163, 3 7 4 J. 0. Bledsoe and C. G. Cardenas, U S . P., 4 249 028/1981. 375 J. 0. Bledsoe, U.S. P., 4 204 080/1979. 370 D. L. Rieger, M. M. Habib, and D. J. Fauth, Tetrahedron Lett., 1979, 115. 3 7 7 M. Yamashita, Y. Kato, and R. Suemitsu, Chem. Lett., 1980, 847. 3 7 e S. Raucher and K.-J. Hwang, Synth. Commun., 1980, 10, 133. 361
Monoterpenoids
39
Fe111.379It was reduced at the exo-bond by H2-[Ph3P),RhC1].3so Pulegone yielded menthone (99 %; isomers not stated) with NaBH4-Te,377or menthone and isomenthone (3 :2) with an Ir catalyst.3s1Methods have also been worked out for the conversion of piperitol into isomenthone using Co complexes382and for the reduction (Na-NH,) of p-mentha-2,7-dien-9-01 to i s o l i m ~ n e n e .Liquid-phase ~~~ hydrogenation (Pd-C) of the epoxides of limonene and carvomenthene yielded hydrocarbons and p-menthan-1-01s and -2-01s: it was deduced from a mechanistic study that, for limonene, reaction involved an intermediate wherein the exo-double bond had migrated into the ring.384Under similar conditions trans-1,Zdihydroxylimonene gave the dihydroxymenthane with the same configuration at C-4 as in substrate together with its epimer (3:2): with PtO, as catalyst only the former epimer was obtained.385Wolff-Kishner reduction of chiral carvone gave racemic limonene and presumably involved a free carbanion as intermediate.385a Alkylation, Homologation, and Related Processes.-Acid-catalysed (HC0,HCH2CI2)coupling of chiral limonene with 3,3-dimethylallyl alcohol gave a mixture of C& products from which chiral a-bisabolol and epi-8-a-bisabolol could be i~olated.~8~ Limonene condensed with methyl vinyl ketone (AlC13 catalyst) at C-9 to gave a product that could be converted into B-bisabolene (50 %).387 Carvone was the starting material for an efficient synthesis of the sesquiterpenes P-agarofuran and dihydroagar~furan,~~~ and also for p h y t ~ b e r i n Piperitone .~~~ has been elaborated into the sesquiterpene ~ h y o b u n o n e and , ~ ~ ~pulegone was ring-opened to give dihydrogeranic acid en route to (R,R)-phyt~l,~~l and has also been condensed with dicyanomethane to yield Z-amin0-4,7-dimethyl-5,6,7,8-tetrahydro1-naphthalene c a r b ~ n i t r i l e Cyclobutene .~~~ derivatives can act as isoprene equivalents in the elaboration of Clo into C15 compounds. Thus piperitone underwent the sequence (1 83)+( 185).393C14 compounds that should be convertible into guaiane and eremophilane derivatives resulted from similar reactions of piperitone with the di-TMS derivative of 1,2-dihydroxycyclobut-1-ene.394-395 Perilla aldehyde underwent the Wittig reaction,39s and also reacted with 1methoxy-1-thiophenoxycyclopropaneto give (I 86).397The 5,6-epoxide of carvone 379
3B0
381
383
G. S. R. Subbarao and N. S. Sundar, J. Chem. Res. ( S ) , 1979, 282. S. G. Levine and B. Gopalkrishnan, Tetrahedron Lett., 1979, 699. J. W. Suggs, S. D. Cox, R. H. Crabtree, and J. M. Quirk, Tetrahedron Lett., 1981, 22, 303. Takasago Perfumery Ltd., Jap. P., 2627/1980. S. D. Sharma, A. S. Sethi, A. L. Bedi, and R. C. Aggarwal, Indian J. Chem., Sect. B., 1980, 19, 811.
G. Accrombessi, P. Geneste, J. L. Olive, and A. A. Pavia, Tetrahedron, 1981, 37, 3135. A. A. Pavia, P. Geneste, and J. L. Olive, Bull. SOC.Chim. Fr., Part 21, 1981, 24. 385a A. Akhila and D. V. Banthorpe, Indian J. Chem., Sect. B, 1980, 19, 998. 3ae D. Babin, J. D. Fourenon, and M. Julia, Tetrahedron, Suppl. 9, 1981, 37, 1. 3 8 7 G. Mehta and A. V. Reddy, Tetrahedron Lett., 1979, 44, 546. G. Buchi and H. Wuest, J. Org. Chem., 1979, 2625. 38B J. A. Findlay, D. N. Besai, G. T. Lonergan, and P. S. White, Can. J. Chem., 1980, 58, 2827. 0.P. Vig, M. L. Sharma, A. S. Sethi, and S. D. Sharma, Indian.J. Chem., Sect. B, 1980,19, 176. 3g1 T, Fujisawa, T. Sato, T. Kawara, and K. Ohashu, Tetrahedron Lett., 1981, 22, 4823. J. Sepiol, J. Mirek, and R. L. Soulen, Pol. J . Chem., 1978, 52, 1389. 393 S. R. Wilson, L. R. Phillips, Y. Pelister, and J. C. Huffman, J. Am. Chem. Soc., 1979,101,7373. 394 M. van Audenhove, D. De Keukeleire, and M. Vandewalle, Bull. SOC.Chim. Belg., 1981, 90, 255. 395 F. Andenaert and M. Vandewalli, Tetrahedron Lett., 1981, 22, 4521. T. Lok Ho, Synth. Cummun., 1981, 11,605. 3 B 7 T. Cohen and J. R. Matz, Tetrahedron Lett., 1981, 22, 2455. 384 385
Terpenoids and Steroids
40
also underwent a Wittig addition of .CH,CO,R followed by cyclization to (187).39s CsF in the presence of Si(OR), (R = alkyl) appeared to be an efficient catalyst for Michael addition to a,p-unsaturated ketones : carvone and pulegone both thus reacted with a c e t o p h e n ~ n e .Trimethylvinylsilane ~~~ in the presence of TiCl4 similarly transferred its vinyl group to p u l e g ~ n e . ~ ~ ~ 3,3,5,5-Tetramethyl-limonene resulted from the condensation of 1,1,3-trimethylbut-2-en- 1-01 catalysed by H,S0,-pentane,401 and the corresponding 3,5-dimethyl compound and also 3,5-dimethyl-a-terpineolresulted from treatment of 1,3dimethylbut-2-en- 1-01with T ~ O H - p e n t a n eTetramethylated .~~~ carvone and carveols have been prepared by the regio-controlled opening of tetramethyl-limonene oxide.4031,2-Dihydrocarvone reacted with PhSeCH,CHO followed by MsC1-Et3N to yield (188).404Such vinylations a to a ketone group should provide ready access to a variety of substrates useful for the Cope-Claisen reactions and in the synthesis of natural products. Methods have been developed for the functionalization of limonene at C-9 with -CH,C02H,405.C(OH) (C0,Et),,406 or S C H = C H C O ~ M ~ , ~ O ~ and also of p-menth-l-ene at C-6 with the last Carvomenthene was methylated at C-4 by MeI-KI.408 A hydroxymethyl group was introduced at C-1 of 1,2-dihydrocarvone on treatment with p a r a f ~ r m a l d e h y d e ,and ~ ~ ~the same substrate reacted with 3,3-dimethylacrylic acid-Et2NLi to yield (1 89).410Acetone added electrophilically in the presence of BuLi-TMEDA to the endocyclic double bond of protected carvone to give products with shift of u n ~ a t u r a t i o n . ~ ~ ~ Selected from numerous other, apparently randomly studied, reactions are : carboxylation of menthol or menth-l-ene at C-1, C-3, C-4, and C-8 on treatment with CO-BF3-ClCH2C02H,412coupling of limonene at C-2 and C-4 to xylenols in the presence of Amberlite IR-120 resin,413dimerization (C-3 to C-3 linkage) of carvone induced by FeC1,,414and the aromatization observed in the BF,-catalysed reaction of terpinolene and tetrahydrogeraniol to give cymen-8-yl tetrahydrogeranyl ether.
308 380 400 Ool
Oo2 403 Oo4 Oo5 406
Oo7
H. Orszanska, K. Witkiewicz, and Z. Chabudzinski, Pol. J . Chem., 1980, 54,45. J. Boyer, R. J. P. Corriu, R. Perz, and C. Reye, J . Chem. Soc. Chem. Commun., 1981, 122. R. Pardo, J.-P. Zahra, and M. Santelli, Tetrahedron Lett., 1979, 4557. €3. M . R. Hoffmann, and H . Vathke-Ernst, Chem. Ber., 1981, 114, 1182. H. Vathke-Ernst and H. M. R. Hoffman, Chem. Ber., 1981,114,1548. R. J. Giguere and H. M. R. Hoffman, Tetrahedron Left., 1981, 22, 5039. C. J. Kowalski and J. S . Dung, J. Am. Chem. SOC.,1980, 102, 7950. N. Fukamiya, M. Oki, M. Okano, and T. Aratani, Chem. Znd. (London), 1981, 96. S. N. Pardo, S. Ghosh, and R. G. Salomon, Tetrahedron Lett., 1981, 22, 1885. B. B. Snider, D. M. Roush, D. J. Rodini, D. Gonzalez, and D. Spindell, J . Org. Chem., 1980, 45,2773.
408 408
410
41i
412
013 414
(16
Taiyo Perfumery Co. Ltd., Jap. P., 162 712/1980 (Chem. Abstr., 1981, 94, 127 159). J. A. Findlay, D. N. Desai, and J. B. Macaulay, Can. J . Chem., 1981, 59, 3303. I. Casinos, R. Mestres, and M. Valero, An. Quim., 1980, 76, 70. D. Hoppe, R. Hanko, A. Bronneke, and F. Lichtenberg, Ang. Chem. tnt. Ed. Engl, 1981, 20, 1024. S. D. Pirozhkov, K. V. Puzitskii, T. N. Myshenkova, K. C. Ryabora, and S. S . Poddubnaya, tzv. Akad. Nauk SSSR, Ser. Khim., 1979, 841. E. Pother, Bull. SOC.Chim. Fr., Part I t 1981, 335. R. H. Frazier and R. L. Harlow, J . Org. Chem., 1980, 45, 5408. K. Nagai and M. Nakayama, Bull. Chem. SOC.J., 1981,54, 3607.
Monoterpenoids
41
General Reactions.-( -)-Limonene racemized on pyrolysis and formed a variety of compounds. Thus (190) gave (191)-(193).4161417 It also cyclized to chiral aterpineol on treatment with chloroacetic acid and a cationic resin4lSor isomerized and polymerized on heating with P205.419Terpinolene and acetylosulphoacetic acid gave a-fenchyl acetate (I 1 %) in addition to expected acetates with the menthane Isolimonene (p-mentha-2,8-diene) isomerized to p-mentha-2,4(8)and the 7-sulphito-derivative of p-menth- 1-ene could be pyrolysed diene with Na,421 to p-phellandrene (89 %).422 (-)-Menthone on treatment with NBS and quinoline followed by the Shapiro procedure gave p-mentha-2,4-diene :the same paper reports a five-step synthesis of a-phellandrene from ethyl 4-methylpentan-2-en-0ate.~~~
(192)
(193) Products of addition of IF424and of N-chlorosulphonamides425 to p-menth-1-ene, of Br, to y - t e ~ i n e n e of , ~ ~NOCl ~ to ~-menth-3-ene,~~' and of hydration of at e r p i n e 0 1 have ~ ~ ~ been characterized. An interesting example of remote and selective
GH GBUn3 i, NaH-CS,-Me1
m-CIC,H,CO,H
P
H
ii, Bun,SnH
(194)
(195)
S. G . Traynor, K. J. Crowley, and W. Cocker, J . Chem. Res. (S), 1981, 175. 417 K. J. Crowley and S. G . Traynor, Tetrahedron, 1978, 34, 2783. Y . Matsubura, K. Tanaka, M. Urata, T. Fukungaga, M. Kuwata, and K. Takahoshi, Bull. Chem. Soc. J., 1979,52, 1757. A. I. Lamatkin, Y . P. Klynev, and A. G . Gordon, Khim. Khim. Tekhnol. (Minsk). 1980,15, 112. 420 R. Luft, J . Org. Chem., 1979, 44, 523. 4B1 A. N. Misra, M. R. Sarma, R. Soman, and S. Dev, Indian P, I46086/1976 (Chem. Abstr., 1980,93, 235 705). a2 L. M. Hirschy, B. J. Kane, and S. G. Traynor, U.S. P., 4 136 126/1979. 483 L. A. Paquette and R. F. Doehner, J . Org. Chem., 1980, 45, 5105. 424 S. Rozen and M. Brand, Tetrahedron Lett., 1980, 21,4543. laSZ . Rykowski and J. Wrzesien, Pol. J. Chem., 1981, 55, 371. 426 R. M. Carman, and J. K. L. Maynard, A m . J . Chem., 1981, 32, 217. ta7 V. Sadasivan and J. Verghese, Indian J. Chem., Sect. B, 1979, 17, 546, 428 P. C. Mathew and J. Verghese, Indian J. Chem., Sect. B., 1979, 17, 172. 416
42
Terpenoids and Steroids
electrophilic fluorination at a C-H bond has been discovered: reaction of F, and menthyl p-nitrobenzoate gave substitution at C-8 (and, on forcing, at C-1). Treatment of the former product with BF3 etherate yielded the ester of isopulegeo1.429 It is rare for a non-radical process involving fluorine to proceed in reasonable yield and with high selectivity. A new method for 1,3-transposition of OH of allylic alcohols via stannanes has been developed, e.g. (194)4( 195).430This procedure is especially valuable for the preparation of alcohols with the thermodynamically less stable exo-double bond. The hydrolysis of a-terpinyl chloride to a - t e r p i n e ~ lthe , ~ ~formation ~ of dimenthylphosphorous chloride from the cyclization of 8-aminomenthanes via iminium intermediates to give 1-aza-adamantane derivatives,433and the [3,3]sigmatropic rearrangement of the lactone derived from hydration of menth- 1-en-9-oic have been reported. Substitution of 6-substituted carveyl diethylphosphates with organoaluminium compounds (Me,AlX; X = OPh, SPh, or NHPh) proceeded with predominant inversion, but with R3Al (R = alkyl) dimerization occurred.435 The product distribution and the high P-deuterium isotope effect (kH/kD= 2.5) indicated that the S,1 solvolysis of neomenthyl tosylate proceeds via ratelimiting sluft of hydride ion followed by elimination.436The presumed syn-elimination of the di-isopropylaluminium derivative of menthol required a lower temperature than decomposition of the acetate or xanthate, and gave better yields, although there was some i s ~ m e r i z a t i o n This . ~ ~ ~paper gives an excellent list of references to elimination reactions of menthol and its derivatives. 8,9-Dihydroxylimonene yielded p-menth-l-ene-l O-al (a component of Bulgarian rose oil) on treatment with KHSOl or SOCI,, but oxalic acid gave I O-hydroxylirn~nene.~~~ Menthone was elegantly transposed into carvomenthone by the sequence (196)+( 197).439Piperitol was isomerized into isomenthone over cobalt catalysts.uo Piperitone, p-menth-3-en-2-oneY and 8,9-dihydrocarvone can by pyrolysed to aromatics that have lost the Pr' group in fair yields (30-50%),441 and menthone can be converted into piperitone and other p-menthen-3-ones via bromination and Zn treatment.442Pulegone on reaction with HOCl formed 4-chloro-p-menth-8-en3 - 0 n e , ~and ~ ~ O-acetylated dienolates of pulegone have been prepared.444Carvomenthene oxide was isomerized to p-menth- 1(7)-en-2-01, carvotanacetol, and cyclopentane derivatives over solid acids and bases,445and 6-thiophenoxy-8,9p28 430
p31
S. Rozen, C. Gal, and Y. Faust, J . Am. Chem. SOC.,1980, 102, 6860. Y. Ueno, H. Sano, and M. Okawara, Synthesis, 1980, 1011. S. Anandaraman, K. N. Gurudutt, C. P. Natarajan, and B. Ravindranath, Tetrahedron Lett., 1980, 21,2189.
433
433 434
435
436
p37
438 438
440 441
442 443 p44
445
H. W. Krause and A. Kinting, J . Prakt. Chem., 1980, 322, 85. A. Pancrazi, 1. Kabore, B. Delpech, and Q. Khuong-Huu, Tetrahedron Lett., 1979, 3729. G. Frater, Helv. Chim. Acta, 1979, 62, 641. A. Itoh, S . Ozawa, K. Oshima, S. Sasaki, H. Yamamoto, T. Hiyama, and H. Nozaki, Bull. Chem. Soc. J . , 1980,53,2357. S. Hirsl-Starcevic,Z . Majerski, and D . E. Sunko, J . Org. Chem., 1980, 45, 3388. E. Brieger, S. W. Watson, D. G. Barar, and A. L. Schene, J . Org. Chem., 1979,44, 1340. M. Nomura, Y . Fujihara, and Y. Matsubara, Nippon Kagaku Kaishi, 1979, 305. W. E. Fristad, T. R. Bailey, and L. A. Paquette, J . Org. Chem., 1980, 45, 3028. H. Kumobayashi, H. Taketomi, and S. Akutogawa, Jap. P., 2628/1980. G. L. Lange, V. A. Pereira, and M. Weedle, Can. J . Chem., 1980, 58, 1639. C. Metge and C. Bertrand, C . R . Hebd. Seances Acad. Sci., Ser. C , 1980, 291, 255. S. G. Hegde and J. Wolinsky, Tetrahedron Lett., 1981, 22, 5019. R. Pardo and M. Santelli, Tetrahedron Lett., 1981, 22, 3843. K. Arata, S. Akutagawa, and K. Tanabe, Bull. Chem. SOC.J., 1978, 51, 2289.
Monoterpenoids
43
(1 96) (1 97) dihydrocarvonehas been reported.44sPhotochemicallyinduced addition of allene to piperitone gave (198), which underwent acid-catalysed rearrangement to (199).447 Irradiation of terpinen-4-01 in the presence of HgO-Iz gave 2-iodo-l,4-cineole which could be reduced to 1,4-cineole (79 %).448 Iodometric assay of ascaridole gave 15 products, some iodinated, some derivatives of 1 , 4 - t e r ~ i nLimonene .~~~ reacted
with 'PhSeOH' to give a product which after removal of selenium (Bu",SnH) yielded 1 , 8 - ~ i n e o l eBamford-Stevens .~~~ reaction of the tosylhydrazone of 2-keto1,8-cineole yielded cyclopentane derivatives and dimers derived from carbenoid intermediate^.^^^ Pinol [the 6,8-cineole derivative (200)] reacted with NBS to form 2,6-dibromo-1 , 8 - ~ i n e o l e or , ~ ~could ~ be oxidized with Hg" salts to 4a-hydroxyp i n 0 1 . ~Hydroboration ~~ of (201), followed by conversion into the N-oxide and Cope elimination, gave the unusual compound (202).454 Studies using 2H-labellinghave indicated that allylic alkylation of carveyl acetate catalysed by PdO complexes involve a symmetrical x-ally1 intermediate;455 this refutes a previous mechanism.456 The chirality of (203) was establishedby conversion
OMe
(203) P. Bakuzis and M. L. F. Bakuzis, J . Org. Chem., 1981, 46, 235. D. K. M. Duc, M. Fetizon, I. Hanna, A. Olesker, C. Pascard, and T. Prange, J . Chem. SOC., Chem. Commun., 1980, 1209. u* H. Takahashi and M. Ito, Chem. Lett., 1979, 373. E. Rucker and U. Molls, Arch. Pharm. (Weinheim, Cer.), 1980, 31, 237. ~0 R. M. Scarborough, A. B. Smith, W. E. Barnette, and K. C. Nicolaou, J . Org. Chem., 1979,44, 44a
1742. 461
46a 458 464
F. Bondavalli, A. Ranise, P. Schenone, and S. Lanteri, J . Chem. SOC.,Perkin Trans. I , 1979,885. D. Mrozinska, A. Siemienink, K. Piatkowski, and H. Kuczynski, Pol. J. Chem., 1979,53,2213. B. A. Arbuzov, Z. G. Isaeva, and V. V. Ratner, Zzv. Akad. Nauk SSSR, Ser. Khim., 1981,1888. F, Bondavalli, P. Schenone, A. R. Anise, and S. Lanteri, J . Chem. SOC.,Perkin Trans. I , 1980, 2626.
B. M. Trost and N. R. Schmuff, Tetrahedron Lett., 1981, 22, 2999. u6J. C. Fiaud and J. L. Malleron, Tetrahedron Lett., 1981, 22, 1399. 466
Terpenoids and Steroids
44
into chiral a - p h e l l a n d ~ e n e Chiral . ~ ~ ~ terpenes have been used in several studies as adjuvants for asymmetric synthesis. The x-allyltitanium complex (204) (R = H or Me) reacted with CO, under mild conditions to form a C-C bond (205; 18% enantiomeric excess, e.e.) : this provides the first example of asymmetric fixation of C02.458A phosphorus-containing cationic rhodium complex incorporating ( -)-a-phellandrene catalysed asymmetric reductions (95 % e.e.),459and asymmetrical co-ordination of prochiral dienes to form chiral Fe(CO), complexes has been achieved (25 % e.e.) by direct transfer of the Fe(CO), group from its complex with ( +)-~ulegone.~~O Metallation and alkylation (MeI) of aldimines derived from various chiral terpene methoxyamines (e.g. 1-methoxy-2-amino-p-menthane) and octanal produced, after hydrolysis, ( +)-2-methyloctanal (1 1-75 % e.e.).461 (-)-Menthol could be converted into (+)-(neoisomenthylsulphony1)methyl isocyanide, which reacted with 1,3-dibromobutane to give, in two steps, the enantiomers of 2-methylcyclobutanone.462(This reaction is well known for RCH,NC, where R = Tos etc.) The conformationally locked adjuvant (206) has been prepared from ( + ) - ~ u l e g o n e ~ and ~ , used in a synthesis of ( -)-mevalonolactone.464 1
7 The Camphane Class See also reference 120.
Occurrence; Synthesis of the Skeleton.-Bornyl chloride has been identified (g.c.-m.s.) in Thymus spp.: it was considered an artifact of a - ~ i n e n ebut ~ ~the ~ origin of the required HCl was not explained. Campholenic aldehyde and exo-6hydroxy-2,3-dimethylnorborn-2-ene occur in Cistus and Abies spp. re~pectively.~66*467 Treatment of 1,3-dibromo-3,7-dimethylocta-6-en-2-one with [Fe,(CO),] gave camphor (38 %).468 Acid treatment of the phenylhydrazone of campholenic aldehyde gave 2,f~dinitrogen-bridged~ a m p h a n eDiels-Alder .~~~ coupling of cyclopentadiene with acetylenic esters led to esters of n ~ r b o r n e n e . ~ ~ ~ A. J. Birch, W. D. Raverty, and G. R. Stephenson, J . Chem. SOC.,Chem. Commun., 1980,857. F. Sato, S. Iijima, and M. Sato,J. Chem. SOC.,Chem. Commun., 1981, 180. 45B M. Lauer, 0. Samuel, and H. B. Kagan, J . Organometal. Chem., 1979, 177, 309. 460 A. J. Birch, W. D. Raverty, and G. R. Stephenson, Tetrahedron Lett., 1980,21,197. u1 A. I. Meyers, Z. Brich, E. W. Erickson, and S. G. Traynor, J . Chem. SOC.,Chem. Commun., 1979, 566. 462 D. van Leusen, P. H. F. M. Rouwette, and A. M. van Leusen, J . Org. Chem., 1981,46, 5159. 463 E. L. Eliel and J . E. Lynch, Tetrahedron Lett., 1981, 22, 2855. 464 E. L. Eliel and K. Soai, Tetrahedron Lett., 1981, 22, 2859. 465 V. P. Papagorgiou and N . Argyriadou, Phytochemistry, 1981, 20, 2295. 466 P. Proksch, P. G . Guelz, and H. Budziekiewicz, 2. Nuturforsch., Tie1 C , 1980, 35, 529. 467 A. Koedam, J. C. Scheffer, and A. B. Svendsen, J . Agric. Food Chem., 1980,29,862. R, Noyori and seven others, J . Am. Chem. SOC.,1979, 101,221. IeS B. Fouchet, M. Joucla, and J. Hamelin, Tetrahedron Lett., 1981, 22, 1333. 4 7 0 F. M. Simmross and P. Wegerstahl, Liebigs Ann. Chem., 1981, 1089.
457
458
45
Mono t erpenoids
Oxidation-Reduction.-Chemical oxidation (Cr0,-HOAc) of (-)-bornyl acetate yielded a mixture of 3-, 5-, and 6-oxobornyl acetates whereas microbiological oxidation (Helminthosporum spp.) gave the 5-0x0- and the 2,5- and 2,6-dioxoderivatives. The latter type of oxidation of ( +)-bornyl acetate occurred exclusively at (2-5. Fusarium spp. hydroxylated both substrates at C-5, but now without concomitant cleavage of acetate.47f Bornylmagnesium bromide with MOO,pyridine-HMPA gave borneol with retention of configuration. If general, this method should be important for the stereoselective conversion of bromides into Ozonolysis of camphor in the presence of vinyl acetate gave camphor lactones.473e474 10-Chlorocamphor-10-sulphme (easily prepared from (-)-camphor10-sulphonyl chloride) was ozonized to the 10-oxychloro-derivative,which is useful for the optical resolution of Camphor and camphor-3-carboxylic acid were reduced with NaBH, or NH,-BH, to different proportions of exo- and endoproduct^.^^^,^^^ The enantiomeric camphorquinones have been stereoselectively reduced by chiral models for NAD(P)H.478Camphor was reductively aminated by f o ~ m a r n i d e .The ~ ~ ~exo-ester of 3-bromocamphor-3-carboxylic acid was both debrominated and decarboxylated by strong bases: NaBH, in MeOH gave debromination only, whereas in diglyme decarboxylation General Reactions.-The potassium salts of cis- and trans-pinane-2-01s in DMSO or in the pinanols as solvent were more effective dehydrohalogenating agents for bornyl chloride or 2,6-dichlorocamphane than was KOBu' in DMS0.481Treatment of 3-bromocamphor with N-methylaniline yielded camphene, tricyclene, and b ~ r n y l a n i l i n e ,and ~ ~ ~with lithium hexamethyldisilazide-LiBuf gave the novel a-ketodianion equivalent (207), which on quenching with ,H20 yielded [3,3-,H,]camphor.483The rates of base-catalysed ,H-exchange of thiocamphor were 23- and 12-fold greater (exo and endo) than those for camphor. The reasons for the rate enhancements are fully Thiocamphor reacted in sequence with Na,
& fi
&i OLi (207) 471
Li (208)
(209)
M. S. Allen, N. Darby, P. Salisbury, E. R. Sigurdson, and T. Money, Can.J . Chem., 1979,57, 733.
47z 478 474
476 476
477 478 479 480
481 482
,1133
N. J. Lewis and S. Y. Gabhe, Aust, J . Chem., 1978, 31, 2091. R. Lapalme, H. J. Borschberg, P. Soucy, and P. Deslongchamps, Can.J . Chem., 1979,57,3272. R. Barba, A. Guirado, M. L. Segura, and A. Soler, An. Quim., 1979, 75, 967. M. F. Haslanger and J. Heikes, Synthesis, 1981, 801. G. C. Andrews and T. C. Crawford, Tetrahedron Lett., 1980, 21, 693. R. Antkowiak, Bull. Acad. Pol. Sci., Ser. Sci. Chim., 1979, 27, 103. A. Ohno, T. Goto, J. Nakai, and S. Oka, Bull. Chem. SOC.J., 1981, 54, 3478. I. I. Bardyshev and N. G. Kozlov, Dokl. Akad. Nauk SSSR, 1979,23,630. R. Antkowiak and W. Antkowiak, Bull. Acad. Pol. Sci., Ser. Sci. Chim., 1978, 26, 933. S. G. Traynor, B. J. Kane, J. B. Coleman, and C. G. Cardenas, J . Urg. Chem., 1980,45,900. A. G. Giumanini and M. M. Musiani, J. Prakt. Chem., 1980, 322,423. C. J. Kowalski, M. L. O'Dowd, M. C. Burke, and K. W. Fields, J . Am. Chem. SOC.,1980,102, 5411.
484
N. H. Werstiuk, H. Nick, and P. Andreis, Can. J . Chem., 1978, 56, 2605.
46
Terpenoids and Steroids
[Fe(CO),] and acid chloride to give 2-thioesters of b ~ r n e n e Transposition .~~~ of camphor into its 3-oxo-isomer via hydroboration of the eneamine, oxidation, and elimination,486decarbonylation of camphor in glow its metallation at C-3,488the products of its Beckmann rearrangement,4sgpreparation of bornylamines from bornyl chloride.490and mercuration of b ~ r n e n e have ~ ~ l also been reported. Camphor tri-isopropylbenzenesulphonylhydrazonereacted with lithium alkyls and BunI to yield the vinylcarbanion equivalent (208) which can be quenched with a variety of electrophiles (e.g. Br+, Bu+, Me2C0).492Aryl vinyl selenoxides and the lithium enolate of camphor gave the spiro-cyclopropyl derivative at C-3.493 (-)-endo-Bornyl-l,2,4-triazolinedionewas used as a dieneophile in cycloaddition to cyclo-octatetraene (the first step of the resolution of the latter).4w Bornyl-A3-1,3,4-oxadiazolin-2-ones(epimers at C-1) decomposed concertedly to give either diazocamphane or camphor.495 Bornyl- 1 , 2 - d i a z e n e ~and ~~~~~~~ -tria~enes4~8 have been prepared. The endo-configuration at C-6 in a 6,8-dibromocamphor has been proved by bridging of C-6 to C-8 with a -(NW2- linkage.499 Ring-opening of the camphane skeleton to give derivatives of camphoric acid or 1,2,2,3-tetramethylcyclopentaneresulted from camphor ( +HN03),50010-sulphitocamphor ( + KOH),501camphonic anhydride ( + RNH2),502and N-nitrobornylimine ( +A);503 derivatives of 1,1,2,2-tetrarnethylcyclopentane (i.e. via methyl migration) resulted from photolysis of c a m p h o r q ~ i n o n e3,3-Dibromocamphor .~~~ ( +AgNO,) gave 4-bromo-l,2,2-trimethylcyclohex-3-enecarboxylic acid and its 3-bromo-isomer : the former could be cyclized (H2S04)to (209).505 Tricyclen-lO-oic acid was oxidized (KMnO,) to the 3-ketone, which was cleaved to S-bromocamphan-2-one- 10-oic acid;506the tosylhydrazone of tricyclen-3-one (and also of isotricyclen-Zone) underwent Bamford-Stevens decomposition in ROH solvent to the 3- or 2-OR 8-bromotricyclene was coupled (RLi) with isoprene oxide to give a sesquiterpene endo-3-AminoH. Alper, B. Marchand, and M. Tanaka, Can. J . Chem., 1979, 57, 598. F. Bondavalli, P. Schenone, and A. Ramise, J . Chem. Res ( S ) , 1980, 257. 4 8 7 G. Kruppa and H. Suhr, Liebigs Ann. Chem., 1980, 677. 4 8 8 0. A. Kruglaya, L. I. Belousova, D. V. Gendin, I. D. Kalikhman, and N. S. Vyazankin, J . Organometal. Chem., 1980, 201, 69. 489 G. R. Krow and A . Szczepanski, Tetrahedron Lett., 1980, 21,4593. 490 M. E. Spiridonova, 0. I. Korobkova, L. A. Tilchourova, and G . I. Sterligova, Khim. Prir. Soedin., 1981, 673. 491 E. V. Skorobogatova, L. N. Povelikina, and V. R. Kartashov,Zh. Org. Khim., 1980,16,2318. 482 F. T. Bond and R. A. Dipietro, J . Org. Chem., 1981, 46, 1316. M. Shimizu and I. Kuwajima, J . Org. Chem., 1980, 45, 2921. a4J. M. Gardlik and L. A. Paquette, Tetrahedron Lett., 1979, 3597. 495 A. J. Paine and J. Warkentin, Can. J . Chem., 1979, 57, 2681. 496 M. J. Kulshreshtha and N. M. Khanna, Indian J . Chem., Sect. B, 1979, 18, 90. 4 8 7 W. E. Hahn and E. Kozlowskagramsz, Pol. J . Chem., 1979, 53, 1729. 4 9 8 S. Treppendahl and P. Jakobsen, Acta Chem. Scand., Ser. B, 1980, 34, 303. S. Nagai, N. Oda, and I. Ito, Heterocycles, 1979, 12, 1275. I. Kitagawa and seven others, Chem. Pharm. Bull., 1981, 29, 2540. 601 H. J. Liu and W. H. Chan, Can. J . Chem., 1979, 57, 708. K. H. Bell, Aust. J . Chem., 1981, 34, 665. 603 G. Buchi and H. Wuest, J . Org. Chem., 1979, 44,4116. 604 M. B. Rubin and A. Gutman, 7th IUPAC Symposium on Photochemistry, 1978, p. 287. R. M. Carman and R. Fielden, Aust. J . Chem., 1979, 32, 2331. L. Borowiecki, B. Makowski, and W. Wodzki, Pol. J. Chem., 1979, 53, 2267. L. Borowiecki and M. Welniak, Pol. J . Chem., 1978, 52, 2173. 'Oa M. Tamura and G . Suzukamo, Tetrahedron Lett., 1981, 22, 577. 486
486
Mono terpenoids
47
(212) (213) camphor on deamination gave isotricyclen-Zone(13 %) :509 opening of the C, ring of the latter gave bicyclo[2.2.1lheptane d e r i v a t i ~ e s .Fenchocamphorone ~~~*~~~ (210) was oxidized (Se0,) to the quinone and functionalized (CH2N2; Pd-H,) to (21 l).512Carvonecamphor (212) gave (hv, MeOH; Br,; A) the isomers of (213). The epimer of the initial product (exo-Me) resulted from cleavage of the C4 ring to a biradical which r e c y c l i ~ e d . ~ ~ ~ 8 The Isocamphane Class
New routes to camphenilone and dehydrocamphene derivatives using alkenes514 or allenic esters as dienophiles in Diels-Alder reactions515have been developed. Lewis acid-catalysed coupling of a$-unsaturated methyl ketones with cyclopentadiene favoured exo-products except when TiCl, was used,51g and led to isocamphanes that were s p a s m ~ l y t i c s The . ~ ~ ~tricyclene (2 14) could be converted
(214) (2 15) (2 16) into 5-iodocamphene and 5,6-dihydrocamphene, and so provides a route to otherwise inaccessible homoallylic functionalizations of c a m ~ h e n e . (-)-Camphene ~l~ resulted from syn-elimination of derivatives of ( +)-isocamphenilanic a~id.51~~5~0 The absolute configuration of the acid was established by X-ray analysis.52o This confirms the previously deduced stereochemistry of (-)-camphene as (1S,4R) but is in conflict with an earlier report of the conversion of (-)-camphene into the (-)-acid. An efficient route to 7-oxocamphene involved as its key step the solvolytic rearrangement of 3,3-ethylenedioxyisobornyl tosylate (derived from camphorq ~ i n o n e )Brief . ~ ~ (3 ~ min; 0 "C) treatment (PCl,-CaCO,) of borneol gave excellent yields of camphene hydrochloride: longer reaction times gave bornyl 0.E. Edwards, J. Dixon, J. W. Elder, J. R. Kolt, and M. Lesage, Can.J. Chem., 198 1,59,2096. A. Garcia-Martinez and A. Garcia-Fraile, An. Quim., 1980, 76, 127. m A. Garcia-Martinezand A. Garcia-Fraile, An. Quim., 1980, 76, 327. 612 R.F. Childs and C. V. Rogerson, J . Am. Chem. SOC.,1980, 102,4159. T. Gibson, J. Org. Chem., 1981, 46, 1073. 614 E. Dworan and G. Buchbauer, Chem. Ber., 1981, 114, 2357. 2.M. Ismail and H. M. R. Hoffmann, J. Org. Chem., 1981,46, 3549. 616 J. Bachner, U. Huber, and G. Buchbauer, Monatsh. Chem., 1981,112,3517. 617 G. Buchbauer, W. Pernold, D. Rassl, and B. Black, Monatsh. Chem., 1981, 112, 517. 618 S. N. Sunyawanshi and U. R.Nayak, Tetrahedron Lett., 1979, 269. a8 G. W. Hana and H. Koch, Chem. Ber., 1978,111,2527. I B 0J. M. Midgley and six others, J. Chem. Soc., Perkin Trans. I , 1978, 1312. 621 D. G. Patil, H. P. S. Chawla, and S . Dev, Tetrahedron, 1979, 35, 527. OZ8 R. W. Carman and I. M. Shaw, Aust. J. Chem., 1980, 33, 1631. 510
Terpenoids and Steroids
48
Camphene could be hydroaluminated and oxidized to endo- and e ~ o - l O - o l sand ,~~~ (-)-camphor was converted (eight and nine steps respectively) into (-)-5,6dihydroxycamphene and 1,4-diformyl-2,3,3-trirnethylcyclopentene, the latter for testing as a p h y t ~ h o r m o n e . ~ ~ ~ Camphene condensed with methyl propiolate under the influence of Lewis acids to give spiro-cyclobutene derivatives525and with PC1,Me-AlCl, to form C-3-C-8 bridged phosphorus a d d u ~ t s Isocamphan.~~~ 10-a1 condensed with rhodanine to yield a fungicidal Camphenyl-lithium can readily be converted into the tetra-alkyl-chromium or -uranium Nojigiku alcohol (2 I5), previously synthesized from camphene or tricyclene, has been prepared from (-)-isobornyl acetate by remote oxidation (cf. ref. 471) and functionalization (seven steps) : this confirms the absolute configuration of the natural Camphenilone and camphene oxide were starting materials for the synthesis of albene (a C12 c o m p o ~ n d )and ~ ~(~+)-@-santalol ?~~~ (C4532respectively. The norcamphene (2 16) with PdCl, yielded a bis-n-allyldichloro-di-Pd complex that could be methylated (CdMe,; MeMgI) at C-3 to give exo-isosantene (90 %), which is otherwise difficult to
9 The Pinane Class See also references 30 and 31 (structure) and 62 (stereochemistry). Occurrence.-Myrtenol was the main component of the oil of a Chrysanthemum spp. ;534 Filipendulol (7-hydroxy-a-pinene) occurred in Achillea spp.,535W3 4Shydroxychrysanthemyl acetate and 3s-hydroxyisochrysanthemyl acetate in Diotis ~ p p . , and ~ ~ 'benzoyloxypaeoniflorin (217 ; G = 6-benzoyl-@-glucose;Bz = benzoyl) and the related paeoniflorigenone in roots of Paconia and Paeoniae spp,53S,539 Rearrangement, Oxidation, Reduction, Simple Functiona1izations.-( +)-a-Pinene was converted into the rare (+)-P-pinene (optical yield 90%) via conversion into A. V. Kuchin, L. I. Akhmetov, V. P. Yurev, and G. A. Tolstikov,Zh. Obschch. Khim., 1979,49, 401. 524 M. S. Allen, N. Lamb, T. Money, and P. Salisbury, J. Chem. SOC.,Chem. Commun., 1979, 112. 625 B. B. Snider, D . J. Rodini, R. S. E. Conn, and S. Sealfon, J. Am. Chem. SOC.,1979,101,5283. 526 E. Vilkas, M. Vilkas, J. Sainton, B. Meunier, and C. Pascard, J. Chem. SOC., Perkin Trans. 1, 1980, 2136. 527 G. Buchbauer and M. Kern, Arch. Pharm. (Weinheim, Cer.), 1980, 315, 1043. 5 2 8 A. N. Nesmeyanov, I. V. Shchirina-Eingoru, G. M. Khvostik, V. N. Sokoloy, and I. I. Kritskaya', Izv. Akad. Nauk SSSR, Ser. Khim., 1979, 2826. 528 N. Darby, N. Lamb, and T. Money, Can. J. Chem., 1979, 57, 742. 6ao W. Kreiser, L. Janitschke, W. Voss, L. Ernst, and W. S. Sheldrick, Chem. Ber., 1979,112,397. 531 W. Kreiser and L. Janitschke, Chem. Ber., 1979, 112, 408. 532 P. A. Christenson and B. J. Willis, J. Org. Chem., 1979, 44, 2012. 533 Y. Castanet and F. Petit, Tetrahedron Lett., 1979, 3221. 534 Y. Uchio, K. Tomosue, N. Nakayama, A. Yamamura, and T. Waki, Phytochemistry, 1981,20, 2691. 535 A. D . Dembitski, R. A. Yurina, A. E. Lyuts, and M. I. Goryaev, Khim. Prid. Soedin., 1979, 862. 536 A. D. Dembitski, R. A. Yurina, and M. I. Goryaev, Izv. Akad. Nauk Kaz. SSR, Ser. Khim. 1980, 55. 537 J. D e Pascual Teresa, A. F. Barrero, E. Caballero, and M. Medarde, An. Quim., 1979,75,323. 538 I. Kitagawa, M. Yoshikawa, K. Tsunaga, and T. Tani, Shoyakugaku Zasshi, 1979, 33, 171 (Chem. Abstr., 1980, 92, 169 115). 63B M. Shimizu and eight others, Tetrahedron Lett., 1981, 22, 3069. 523
Monoterpenoids
49
myrtenyl diethylphosphonate followed by reduction (LiA1H4).540Catalysts have been evaluated for the isomerization of ~ t - p i n e n e and ,~~~ its conversion into camphene was increased 100-fold by the addition of TiO, to the usual optimum catalysts.642p-Pinene was converted in low yield into the a-isomer in the presence of Mg0,643and this isomerization, catalysed by NaH-[2H,]DMS0, involved relatively fast uptake of one atom of tracer transferred from the face trans to the gemdimethyl bridge (owing to steric hindrance) ;544 cis and trans-6-Pinenes resulted from acid-treatment of ( +)-4-trimethyl~tannylpinane.~~~
,*.
CD,
b b \
Photo-oxygenation of a-pinene in MeCN-H,O differed from that in aprotic media: the main hydroperoxide was the same but it was accompanied by (218).64s Similar reaction of the P-isomer in the presence of metal oxides gave myrtenol, myrtenal, nopinone, and p i n o c a r ~ o n e .a-Pinene ~~~ was reduced to cis-pinane (96 % stereoselective) over R u ,and ~ ~electrochemical ~ reduction of 2,4-dibromopinocamphone gave a variety of products devoid of Br.549Hydroboration of aminoand a z i d o - p i n a n e ~and ~ ~ ~the conversion of a-pinene into 2-hydroxy-3-amino- and 3-hydroxy-5-amino-pinaneshave been r e p ~ r t e d . ~ syn-Addition ~ l - - ~ ~ ~ of 2HCl to the 640
641 643
b43 644
645
640 647 648
64a 660
661 66*
663
L. M. Hanvood and M. Julia, Synthesis, 1980, 456. S. Battalova, T. R. Mukitanova, and N. D. Pak, Dokl. Akad. Nauk SSSR, 1978,242,111. A. A. Popov and V. A. Vyrdov, Lesokhim. Pohochka, 1978, 2, 6 (Chem. Abstr., 1978, 89, 90 223). H. Hattori, K. Tanabe, K. Hayano, H. Shirahama, and T. Matsumato, Chem. Lett., 1979, 133. R. Ohnishi, J . Chem. SOC.,Perkin Trans. 2, 1980, 530. A. N. Kashin, V. N. Bakunin, I. P. Beletskaya, and 0. A. Reutov, Izv. Akad. Nauk SSSR, Ser. Khim., 1981, 1180. P. Capdevielle and M. Maumy, Tetrahedron Lett., 1980, 21, 2417. M. A. Fox and C. C. Chen, J . Am. Chem. SOC.,1981, 103,6757. M. S. Pavlin, U.S. P., 4 310 714/1980. A. J. Fry and G. S. Ginsburg, J . Am. Chem. SOC.,1979, 101, 3927. I. Uzarewicz and A. Uzarewicz, Pol. J . Chem., 1978, 52, 1907. K. Burak and Z . Chadbudzinski, Poi. J. Chem., 1978, 52, 1721. Z. Rykowski and J. Wrzesien, Pol. J . Chem., 1981, 55, 371. K. Burak and Z . Chadbudzinski, Pol. J. Chem., 1981,55,387.
50
Terpenoids and Steroids
less hindered side of a-and p-pinenes was demonstrated by a combination of 13Cand lH n.m.r : the resulting tertiary chloride was configurationally pure and isomerized solely to bornyl chloride. The rapidity of the isomerization with the probable conversion of a tertiary into a secondary carbocation was rationalized by calculations of strains:554in contrast, acetolysis of cc-pinene appeared to involve approach of H+ from both exo- and endo-sides, with the participation of a bridged intermediate in the addition The ArSeCl-catalysedreaction of a-pinene with N-chlorosuccinimide OsO, in the presence of trimethylwas anomalous and led to pinocarveyl amine N-oxide-pyridine effectively hydroxylated the hindered double bond in 10-substituted a - p i n e n e ~ .Surprisingly, ~~~ pinan-2-01 could only be efficiently converted into a-pinene with SOC1,-pyridine : use of POC1,-pyridine and other conventional methods led to rearrangement.lS0 Potassium cis- or trans-pinan-2oxides are the most basic alkoxides known558and effectively promoted the ringopening of trans-pinene oxide to trans-pinocarveol and trans-pin-3-en-2-01.~~~ The cyclic ether (219) was converted into (220), which underwent rearrangement to (221) in a manner analogous to the celebrated norcaradiene ring-walk: stereochemical analysis of the rearrangement indicated predominant inversion of configuration for both the photolytic and thermal processes and so symmetry considerations of the Woodward-Hoffman type may not be relevant to these (or at least the thermal) processes.559Esters of pinocarveol were converted into myrtenyl compounds by C U O A C . ~cis~ * and trans-Verbenyl and verbanyl acetates,661@2 related and 2-methylverban0ne~~~ have been synthesized for evaluation as attractants for cockroaches. Ring-opening.-=- and p-Pinenes with various metal salts or acids were converted into carvey1565~566 or ~ r - t e r p i n y l compounds. ~ ~ ~ - ~ ~ ~ p-Pinene with Pb(OAc), gave 2-, 7-, and 8-acetylated p-menthenes and d i e n e and ~ ~ on ~ ~treatment with HSiC13 and Ni catalyst formed the 7- and 10-trichlorosilyl derivatives of p-menth-1 -ene(77 %) and endo-isocamphane respectively.570a-Pinene was converted into 2,2-dimethyl3-cis-(2-methylpropenyl)cyclobutane-l-carboxylicacid and its t r ~ n s - i s o m e r ~ ~ ~ (analogues of the chrysanthemic acids), and a similar ring fission and derivatization led to (222).572Pinenes could be thermally isomerized over Na or K salts to myrcene 664 666 666
667
668
66B 680
Oel 662
683 664
565
667
66s
c70 671
E. F. Weigand and H. J. Schneider, Chem. Ber., 1979, 112, 3031. R. Muneyuki, Y. Yoshimura, and K. Tori, Chem. Lett., 1979, 49. T. Hori and K. B. Sharpless, J . Org. Chem., 1979,44,4208. R . Ray and D. S. Matteson, Tetrahedron Lett., 1980, 21,449. B. J. Kane, G . Marcelin, and S. G. Traynor, J . Org. Chem., 1980, 45, 895. W. T. Borden, J. G. Lee, and S. D. Young, J . Am. Chem. SOC.,1980, 102,4841. H. Miyawaki, Jap. P., 59 25311979. C. Nishino and H. Takayanagi, Comp. Biochem. Physiol., 1981,70A, 229. H. Takayamagi and C. Nishino, J. Chem. SOC.J., Chem. Ind. Chem., 1981, 629. C. Nishino and H. Takayamogi, Agric. Biol. Chem., 1979, 43, 1967. Mitsubishi Chem. Industries Co. Ltd., Jap. P., 30 940/1981 (Chem. Abstr., 1981, 94, 150 956). U. Lipnicka, A. Rykowski, J. Wrzesien, and Z. Z . Chabudzinski, Pol. J. Chem., 1980,54,2373. A. V. Pol, V. G. Naik, and H. R. Sonawane, Indian J . Chem., 1980, 19, 603. A. Watanabe and I. Iwata, Eiyo to Shokuryo, 1980,33,305 (Chem. Abstr., 1981, %,23 155). N. Bluthe, J. Ecoto, M. Fetizon, and S. Lazare, J . Chem. SOC.,Perkin Trans. 1, 1980, 1747. K. Yokoi and Y. Matsubara, Nippon Kagaku Kaishi, 1979, 641. V. V. Kaverin and six others, Izv.Akad. Nauk SSSR, Ser. Khim., 1980, 2657. H. D. Scharf, H. Kalkoff, and J. Janus, Tetrahedron, 1979, 35, 2513. M. Gannon, A. Postlewhite, and R. S. McElhinney, J. Chem. Res. ( S ) , 1979, 393.
Mono terpenoids
51
(222) (223) (224) (225) and 2-methyland a l l o - o ~ i m e n e . ~ Pyrolysis ~~ of 3-methylnorpinan-2-0ne~~~ ~ e r b a n o n egave ~ ~ ~the expected o-menth-3-ones but trans-verbenol was cleaved differently to give 4-0x0-1,3,3-trimethylcyclohex-1-ene.576a-Pinene oxide was but over salts converted into carvacrol over Group 8 transition metals at 200 0C,577 of other metals campholenaldehyde and its 4-methyl isomer were mainly (ca. 90 %) formed.578 P-Pinene oxide yielded p-menth-1-ene-7,8-diol on treatment with Hg2+.57 9 Homologation, More Complicated Functiona1ization.-As an example of a genera1 synthesis of methylenecycloalkanesfrom cycloalkenes, a-pinene was coupled with B-(cycloalkylmethyl)-9-BBN. The product was treated with CO, reduced, and 10-Trimethylfinally decomposed with PhCHO to yield 3-methylene-ci~-pinane.~~~ silyl-a-pinene on acylation (RCOC1-A1Cl3, -90 "C) gave (223) (R = Me or CH=CMe,). The reaction also proceeded for the 7-silyl derivative of p-menth-lene, formed from P-pinene under slightly different 5-( 1,2-Diethylhepty1)resorcinol was coupled at C-4 of myrtenyl trimethylacetate to yield an analgesic compound;582the 4-SnMe3,5834-PhS02, 4-CH20H, and 4 - m e t h ~ l e n e ~ ~ ~ derivatives have also been prepared. The lactone (224) resulted from (10-piny1)acetic acid + A c C ~and , ~ the ~ ~corresponding saturated and unsaturated lactones derived from the (3-0x0- lO-pinyl)-a~id~~~ and also from (225)587have been reported. Addition of dichlorocarbeneto a- or P-pinene followed by treatment with Me3SiC1Li yielded (for the a-isomer) products (226) and (227).588Diels-Alder adducts of 10-methylene-a-pinene589 and products of annelation (with extrusion of SO2) of @-pinenewith tetrachlorothiophen 1,l-dioxide have been M. Nomura, Y. Fujihara, and Y . Matsubara, Yukuguku, 1979,28,919. A. Yoshikoshi, K. Takagi, T. Nishimura, M. Iwamoto, and K. Kojo, Jap. P., 132 541/1978 (Chem. Abstr., 1979, 90, 187 171). 676 J. P. Konopelski, P. Sunderaraman, G. Barth, and C. Djerassi, J . Am. Chem. Soc., 1980,102, 2737. 6 7 6 S. Escher, W. Giersch, and G. Ohloff, Helv. Chim. Actu, 1981, 64, 934. 6 7 7 T. Kurata, Yukuguku, 1981, 30, 562. 578 K. Arata and K. Tanabe, Chem. Lett., 1979, 1017. 678 S. L. Ecoto, Eur. P., 21 952/1979. 6 B 0 H. C. Brown and T. M. Ford, J. Org. Chem., 1981, 46, 647. 681 J. P. Pillot, G. Deleris, J. Dinogues, and R. Calas, J . Org. Chem., 1979,44,3397. 6*2 R. Mechoulam, N. Lander, and S. Dikstein, U.K. P., 2 027 021/1980 (Chem. Abstr., 1981,95, 80 289). A. N. Kashin, V. N. Bakunin, Y . K. Grishin, I. P. Beletskaya, and 0. A. Reutov, Izv. Akud. Nauk SSSR, Ser. Khim., 1980, 1950. 684 H. Takayanage and C. Nishino, Agric. Biol. Chem., 1980,44,2877. 686 J. J. Becker, Ger. P., 3 016 111/1981 (Chem. Abstr., 1981, 94, 65 471). 686 J. J. Becker and G. Ohloff, Ger. P., 3 025 449/1981. 6a7 Z. Rykowski and Z. Chabudzinski, Pol. J . Chem., 1980, 54,741. M. Laguerre, M. Grignon-Dubois, and J. Dunogues, Tetrahedron, 1981, 37, 1161. 68Y S. W. Markowicz and B. Bouchwic, Pol. J . Chem., 1979, 53, 221. 690 M. S. Raasch, J. Org. Chem., 1980, 45, 856. 673
674
52
Terpenoids and Steroids *!fSiMe3 Me,Si --- SiMe,
(226) (227) (228) Myrtanyl derivatives (i.e. a-pinene substituted at C- 10)with NHNH2,591SC(CN)NR2,592OCH,SMe, and OCH,CN593 and trans-pinane substituted at C-10 with CH,CH,NO, (from reaction of p-pinene with nitroethylene-a possibly useful ~ y n t h o n and ) ~ ~alkylated ~ at C-10 and formylated at C-3 (as intermediates en route to prostaglandin analogues in which ether links were replaced by carbon groupi n g ~ have ) ~ ~ been ~ reported. N-Alkylmyrtenylamines are useful for optical resolution of The use of chiral pinane derivatives-in asymmetric syntheses has been expanded: ( +)-(3,2,1O-q-pinene)-PdI1 acetate in the presence of Cu" and 0, catalysed the asymmetric cyclization of 2-allylphenols to benzo[b]furan derivatives,597and chiral aminyl oxides [e.g. (228)] effected enantiomeric oxidation (7 % e.e.) of benzoin to b e n ~ i l This . ~ ~is~a rare example of asymmetric induction in atom transfer from carbon. The adduct of monoisopinocamphenylborane with NNN'N'-tetramethylethylenediamine is stable and readily prepared : treatment with BF, liberated the free b ~ r a n e . ~ ~ ~ Norpinane Derivatives.-Apopinene (6,6-dimethylnorpin-2-ene)underwent ring cleavage on treatment with PdC1,-AcOH to give 1,2,3-trimethylbenzene by a concerted path involving a Pd complex; this is believed to be the first reported opening of the C4 ring of the pinane skeleton by C-1-C-7 cleavage.600Nopinone (6,6-dimethylnorpin-2-one) was easily synthesized from ethyl 4-oxocyclohexane-lcarboxylate,601and was readily alkylated at C-3 by organosilicon reagents802and in the presence of ,H,O-NaOH rapidly took up one atom of tracer at C-3 via base attack from the cis-face (steric hindrance).544The ketone has also been ring-opened and converted into 2,2-dimethyl-4-t-butylcyclohexan-l-one603 and converted into apoverbenone and its ring-opened The 6,6-dimethylnorpinane skeleton and also that of camphane were coupled via C-3 and C-4 to the N-phenyl2,4-disulphotetrahydropyrimidinering J . N. Shah, Indian J. Chem., Sect. B., 1979, 18, 488. K . Friedrich and M. Zamkanei, Chenz. Ber., 1979, 112, 1916. 593 J. A. Schwindeman and P. D. Magnus, Tetrahedron Lett., 1981, 22,4925. 5 84 D. Ranganathan, C. B. Rao, S. Ranganathan, A. K. Mehrotra, and R. Iyengar, J. Org. Chem., 1980,45, 1185. 5 95 M. F. Ansell, M. P. L. Caton, M. N. Palfreymer, and K. A. J. Stuttle, Tetrahedron Lett., 1979, 4497. 5 96 S . W. Markowicz, Pol. J. Chem., 1979, 53, 157. 5 9 7 H . Hosakawa, T. Uno, S. Inui, and S. I. Murahashi, J. Am. Chem. SOC.,1981, 103, 2318. 6 9 8 C. Berti and M. J. Perkins, Angew. Chem. Int. Ed. Engl., 1979, 18, 864. 5 9 9 H. C. Brown, J . R. Schwier, and B. Singaram, J. Org. Chem., 1978, 43,4395. 6 0 0 R. M. Giddings and D. Whittaker, Tetrahedron Lett., 1978, 4077. 801 G . S. S.Murthi and A. Mazumder, Indian J. Chem., Sect. B, 198L 20, 339. 602 T. Yanami, M. Miyashita, and A. Yoshikoshi, J. Org. Chem., 1980, 45, 607. 803 J. P. Konopelski and C. Djerassi, J. Org. Chem., 1980, 45, 2297. 604 M. T. Edgar, G. Barth, and C. Djerassi, J. Org. Chem., 1980, 45, 2680. 605 A. M. Lamazouene and J. Sotiropoulos, Teirahedron, 1981, 37,2451. 5 91 5 92
Monoterpenoids
53
10 The Fenchane Class
Diels-Alder reaction of methylcyclopentadiene and CH,= CCl(CN) gave 1-methylnorborn-5-en-2-one (57 %), which was hydrogenated and methylated to fenchone (30 %).606 endo-Fenchol on dehydration (KHS04) gave a mixture of fenchenes and c y c l o f e n ~ h e n e s .Fenchone, ~~~ on treatment with Ph,PCH(Li)OMe-a reagent allegedly good for homologation of sterically hindered, enolizable ketones-gave the endo-formylated derivative : menthone under similar conditions gave a 79 % yield of expected products, but camphor only 10 %.608 Fenchone preferentially complexed with P - c y c l o d e ~ t r i nand ~ ~ ~underwent Wittig addition followed by functionalization;610and the addition of the 2-lithio-derivative of anisole.6112-Diphenylmethylenefenchane (from Wittig reaction of fenchone) underwent photochemical WagnerMeerwein rearrangement, forming (229) ?, this singlet-state reaction, which in the ground state is characteristic of species with electron-deficient carbon atoms at the rearrangement terminus, suggests the intermediacy of a twisted excited state of the substrate.
4i$&@ (230)
(231)
(229) The chloride of fenchane-2-carboxylic acid decomposed (Et,N, hv) to tricyclof e n ~ h a n e . ~Thiofenchone ’~ on irradiation gave (230) and the corresponding disulphide ; thiocamphor behaved similarly.614 Selenofenchone could easily be converted into syn-2,2’-bifenchylidene (231) : this is an excellent model system for the study of hindered 01efins.~~~ 11 The Thujane Class
See also ref. 58 (stereochemistry). Occurrence.-Sabinene and trans-sabinyl acetate (ester and C,-moiety trans) were the main components of the seed oil and foliage of Thujopsis and Arternisia 606
607 608 608
610
Ell
612
613 614
615
G . Buchbauer and H. C. Rohner, Liebigs Ann. Chem., 1981, 2093. Y. Mutsubara and K. Yokoi, J . Chem. SOC.J., Chem. Znd. Chem., 1979, 955. E. J. Corey and M. A. Tius, Tetrahedron Lett., 1980, 21, 3535. J. Michon and A. Rassat, J . Am. Chem. SOC.,1979, 101, 995. E. W. Meijer and H. Wynberg, Tetrahedron Lett., 1979, 3997. J. L. Fry and J. W. West, J . Org. Chem., 1981, 46, 2177. S. S. Hixson, R. 0. Day, C. S. Franke, and V. Ramachandra Rao, J . Am. Chem. SOC.,1980, 102,412. W. Kirmse and W. Spaleck, Angew. Chem. Int. Ed. Engl., 1981, 20, 776. D. S. L. Blackwell, K. H. Lee, P. de Mayo, G . L. R. Petrasiunas, and G . Reverdy, N o w . J . Chim., 1979, 3, 123. F. S. Guziec and C. J. Murphy, J . Org. Chem., 1980, 45, 2890.
3
54
Terpenoids and Steroids
a novel compound, was isolated spp. r e ~ p e c t i v e l y . ~cis-Thujan-4-en-2-acetate, ~~*~~' from a Tanaceturn sp.618
Reactions.-3-Isopropylcyclopent-2-en- 1-one reacted with Me-SOI-NaH to give sabina ketone and sabinene oxide;619the latter could be cleaved to p-menthan-l0 1 . Thujone ~ ~ ~ and isothujone (for nomenclature see ref. 59) coupled with methyl vinyl ketone under basic conditions to give an adduct that could be modified to sesquithujane (e.g. cubebane) derivatives.621( -)-Isothujone with HCHO formed the 1-hydroxymethyl derivative that underwent Jones oxidation and decarboxylation to ( + ) - t h ~ j o n e . ~ ~ ~ ? ~ ~ ~ trans-Sabinene oxide was also efficiently formed on photo-oxidation (a-diketones as sensitizers) of ~ a b i n e n eSimilar . ~ ~ ~ reactions of a-thujene yielded trans-thujene-3, 4-oxide, which could be converted (LiA1H4625,626 or Ni-H,627) into trans-sabinyl hydrate (90 %). a-Thujene could be converted into the trans-4-hydroperoxyderivative of p-thujene (83%) by use of other sensitizers.628An adduct, resulting from ring-opening and acyl-Fe(CO), insertion to yield a complex involving both 0- and n-ally1 bonding, was obtained from photolysis of ( +)-a-thujene in the presence of [Fe(CO),] or thermolysis in the presence of [Fe(CO),,]. (-)-Urnbellulone gave an intractable complex that readily decomposed to racemic starting material. The mechanisms of these unusual reactions are fully Photolysis of the thujones resulting in isomeric 1,4-dienes by extrusion of CO have been reexamined.630The lack of stereospecificity had suggested biradical mechanisms rather than concerted chelatropic reactions with conservation of orbital symmetry. The present work with the monoterpenes and with other bicyclo[3.1.O]hexaneswith stereochemical markers at C-2 and C-4 led to fresh speculations about the intermediates possible within the biradical formulation. Use of deuterium tracer in substrate and solvent showed that the isomeric thujan-3-01s and their halides underwent super-acid (e.g. FS0,H-S02) catalysed ring-opening to the 2,3-dimethyl4-isopropylcyclopenteniumion by at least two routes that initially formed either a carbocation or an olefin.6311632 Thujone was oxidized (KMnO,) to the a-thujaketonic
S. Hasegawa and Y . Hirose, Phytochemistry, 1981, 20, 508. 0. Vostrowsky, T. Brosche, H. Ihm, R. Zintl, and K . Knoblauch, Z . Naturforsch., Ted C,1981, 36, 369, E. Hethelyi and seven others, Phytochemistry, 1981, 20, 1847. O l e A. Nagakura, M. Moroe, H. Tsuruta, and T. Yoshida, Jap. P., 103 85311979 (Chem. Abstr., 1980, 92, 75 979). e 2 0 M. Higo, H. Toda, K. Suzuki, and Y . Nishida, Ger. P., 2 814 558/1978 (Chem. Abstr., 1979,90, 23 330). 621 J. P. Kutney, J. Balsevich, and P. Grice, Can. J . Chem., 1980, 58, 2641. e22 C. H. Brieskorn and W. Schwack, Tetrahedron Lett., 1980, 21, 255. e23 C. H. Brieskorn and W. Schwack, Chem. Ber., 1981, 114, 1993. 624 Lion Dentifrice K. K., Jap. P., 124 864/1978. e25 Lion Dentifrice, K. K., Jap. P. 124 862/1978. m e T. Shimpo, Jap. Pat., 51 030/1980. 02' T. Shimpo, H. Toda, H. Saga, K. Suzuki, and Y.Nishida, Jap. Pat., 28 965/1980. e 2 8 Lion Corp., Jap. Pat., 75 472/1981. S. Sarel and G . Chriki, J . Org. Chem., 1978, 43, 4971. 030 R. S. Cooke and G. D. Lyon, J . Am. Chem. Soc., 1981,103,7317. 631 J. C. Rees and D. Whittaker, J . Chem. Soc., Chem. Commun., 1978, 1096. J. C. Rees and D. Whittaker, J. Chem. SOC.,Perkin Trans. 2, 1981, 953.
Monoterpenoids
55
acids (232) and their ring-opened products, which were starting materials for efficient syntheses of pyrethrin a n a l o g ~ e s . ~ ~ ~ . ~ ~ ~
12 The Carane Class
A review of the class635and a detailed conformational analysis of the carane-2,3d i 0 1 s ~have ~ ~ appeared. No new naturally occurring carane derivatives, or any unusual sources of known compounds, have been reported, but much detailed chemistry based on (+)-car-3-ene has been carried out directed towards the wmmercial exploitation of this major component of Indian turpentine. Syntheses of car-2-, car-3-, and car-3( 10)-enes from cyclohex-3-en-1-one have been developed.637
Reactions Preserving the Carane Skeleton.-Many straightforward reactions of ( +)-car-3-ene gave expected products (usually accompanied by more or less minor amounts of ring-opened compounds) : thus oxymercuration-demercura t i ~ nh,y~d r~~ ~g e n a t i o n formylation ,~~~ at C-3,640carbene addition,641and epoxidation followed by cleavage of the oxiran ring have been The Prins reaction gave 4-hydro~ymethylcar-2-ene~~~ (known) together with several interesting new minor oxygenated products :644 the main product underwent Jones oxidation to an acid and a dimeric ester.643FriedelLCrafts acetylations gave the 4-substituted derivatives of each carene isomer,645and the products could be e p o ~ i d i z e d , ~ ~ ~ * ~ ~
J. P. Kutney, M. K. Choudhury, J. M. Decesare, H. Jacobs, A. K. Singh, and B. R. Worth, Can. J . Chem., 1981,59,3162. 634 J. P. Kutney, M. J. McGrath, R. N. Young, and B. R. Worth, Can. J. Chem., 1979, 57,3145 635 J. Verghese, Perfum. Flavorist, 1979, 4, 23. 636 B. A. Arbuzov, Z. G. Isaeva, I. P. Povodyreva, and V. V. Ratner, Izv. Akad. Nauk SSSR, Ser. Khim., 1979, 2831. 637 W. Cocker and N. W. A. Geroghty, J. Chem. Soc., Perkin Trans. I , 1978, 1370. 638 E. F. Buinova, N. G. Yaremchenko, T. R. Urbanovich, and L. V. Izotova, Khim. Prir. Soedin., 1979, 646 (Chem. Abstr., 1980, 94, 175 271). 639 I. I. Bardyshev, G. V. Deshchits and A. A. Vakhrameeva, Vestsi Akad. Navuk B. S S R , Ser. Khim. Navuk, 1980,69. 040 M. L. Glowka, Z. Galdecki, H. Sadowska, and J. Cora, Pol. J. Chem., 1980, 54,2091. 641 D. A. Baines, W. Cocker, D. H. Grayson, P. H. Ladwa, and N. W. A. Geroghty, Proc. R. Irish. Acad., Sect. B, 1977, 77, 323. B. A. Arbuzov, V. V. Ratner, Z. E. Isaeva, V. N. Gudova, N. R. Rubinova, and M. E. Belyaeva, Izv. Akad. Nauk SSSR, Ser. Khim., 1979, 1294. 643 N. E. Bhat, P. P. Pai, and G. H. Kulkarni, Chem. Ind. (London), 1981, 94. 644 N. E. Bhat, P. P. Pai, and G. H. Kulkarni, Indian J. Chem., Sect. B, 1980, 19, 316. 045 L. N. Misra and M. C. Nigam, Chem. Ind. (London), 1980, 294. 646 P. P. Pai, G. D. Joshi, K. G. Gore, and G. H. Kulkarni, Indian J. Chem., Sect. B, 1979,18,549. 6 p 7 B. B. Arbuzov, N. D. Ibragimova, and I. P. Povodyreva, Izv. Akad. Nauk, SSSR, Ser. Khim., 633
1980, 1052.
56
Terpenoids and Steroids
hydrated,64s and further modified.649trans-4-Acetylcar-3-ene oxide was reduced (NaBH,) to a 35 % enantiomeric excess of the I 1 R - a l c o h 0 1 . ~ ~ ~ ~ ~ ~ ~ Formation of Bicyclo [3.1.0]hexane Derivatives.-Attempted Favorskii rearrangement of 5-0x0-car-3-ene oxide mainly gave the 4-hydroxy- and the transposed 3-0x0-compound (80 %), but the remainder was the keto-acid (233).652Car-3-ene was converted into (234), which could be cleaved to cyclopentane derivatives, by treatment with (i) HOBr, (ii) AgNO,, and (iii) Baeyer-Villiger but a more efficient route utilized Tl(N03)3.654 Oxidative cleavage of the same substrate and degradative ring closure formed 6,6-dimethylnorthujan-2-01,~~~ Several routes have been adapted or discovered from the oxide or bromohydrin of car-3-ene to derivatives of the transposed thujane skeleton (235).656-65s
Formation of Menthane or Cyclopropane Derivatives.-Acid treatment of 4acetylcar-2-ene oxide gave p-menthane derivatives whereas base (NaOMe) cleaved the oxiran ring but preserved the carane In contrast, base treatment (pyridine) of 2,3-dibromo-4-acetylcarane gave both p - and rn-menthane compounds 51 :49),660and dehydrogenation of car-3-ene at 4 0 0 4 5 0 "C over chromia-alumina yielded varying proportions of p- and m-cymenes depending on the contact times.661@2The last procedure may be of use for modifying Indian turpentine in toto: the high content of car-3-ene allows autoxidation and renders the crude material almost useless commercially. Chromic oxidation of car-3-ene gave rn-cymene together with small (ca. 3 %) amounts of a dimethyldihydrotr~polone.~~~ B. M. Mane, K. G. Gore, and G. H. Kulkarni, Indian J . Chem., Sect. B, 1979, 18, 395. Z. G. Isaeva, G. S. Bikbulatova, 0.B. Skripuik, and I. P. Povodyreva, Izv. Akad. Nauk SSSR, Ser. Khim., 1979, 1107. 6 5 0 B. A. Arbuzov, A. N. Vereshchagin, Z. G. Isaeva, S. G. Vulfson, N. D. Ibragimova, and A. 1. Donskova, Izv. Akad. Nauk SSSR, Ser. Khim., 1979, 1156. 651 Z. G. Isaeva, N. D . Ibragimova, I. P. Povodyreva, and T. N. Timoshina, Zzv. Akad. Nauk SSSR, Ser. Khim., 1979, 1299. 652 B. A. Arbuzov, Z . E. Isaeva, A. N. Karaseva, and V. V. Karlin, Dokl. Akad. Nauk SSSR, 1981, 261, 887. B. M. Mane and G. H. Kulkarni, Curr. Sci., 1981, 50, 715. 654 A. V. Pol, V. G . Naik, and H. R. Sonawane, Indian J . Chem., Sect. B, 1980, 19, 603. 655 M. Walkowicz, S. Lochynski, and C . Walkowicz, Pol. J . Chem., 1981, 55, 135. 656 B. M. Mane, K. G. Gore, and G. H. Kulkarni, Zndian J . Chem., Sect. B, 1979, 18, 395. 657 B. A. Arbuzov, Z. G. Isaeva, and R. R. Dyakonova, Izv. Akad. Nauk SSSR, Ser. Khim., 1980, 2141. 658 B. A. Arbuzov, Z . G. Isaeva, and R. R. Dyakonova, Izv. Akad. Nauk SSSR, Ser. Khim., 1980, 2778. 6 5 8 P. P. Pai, G. D. Joshi, K. G. Gore, and G. H. Kulkarni, Indian J . Chem., Sect. B., 1979,18,549. 660 L. N. Misra, and M. C . Nigam, Chem. Znd. (London), 1981, 607. V. Krishnasamy, Aust. J . Chem., 1980, 33, 1313. w2 V. Krishnasamy, Can. J . Chem., 1978, 56, 1994. 663 P. P. Pia, B. M. Mane, R. S. Joshi, and G . H. Kulkami, Curr. Sci., 1979, 48, 155.
648
648
Mono terpenoids
57
Derivatives of m-menthenes and m-menthadienes were also almost exclusively produced on treatment of car-4-ene or 5-acetylcar-2-ene with HCl. Reaction of car-3-ene oxide with ZnBr, gave rn-menth-5-en-2-0ne.~~~ Car-3-ene is known to be a convenient starting material for access to the irregular chrysanthemyl skeleton (see Section 14). The (+)-olefin has been again stereospecifically converted (viahydration and oxidation) into ( +)-dihydrochrysanthemolactone and ( +)-methyl cis-chry~anthemate.~~~’~~~ Other 1,2-cis-cyclopropane derivatives have resulted from oxidative cleavage of derivatives of the same sub~trate.~~~g-~~~
13 The Cyclopentane (‘Iridane’) Class See also refs. 6-8 (reviews), 35-37 69,70 (separation).
(n.m.r.), 52,63 (absolute configuration), and
Occurrence.-A review covers the I3C and lH n.m.r. of iridoid glucosides and includes data on new These compounds have been produced by cultured cells of a Gardenia sp.673The insect antifeedant properties of the glucoside ipolamide have been The iridoid glycosides (and to a much lesser extent the irregular monoterpenes, Section 14) are the only naturally occurring monoterpenes that are still being discovered in large numbers. Many new iridane derivatives with a bewildering variety of exotic names have been reported from a range of plant genera, not all of which produce terpene alkaloids. They are
e0 OR2
664 665
667
10
..q0 CO,Me
H
’
0-,3-G
G. S . Bikbulatova, Izv. Akad. Nauk SSSR, Ser. Khim., 1978, 2380. B. A. Arbuzov, A. N. Karaseva, and Z. G. Isaeva, Dokl. Akad. Nauk SSSR, 1979,247,364, G . L. K. Hunter and B. C. Clark, U S . P., 4 136 119/1979 (Chem. Abstr., 1979,90, 187 172) B. M. Mane, K. G. Gore, and G. H. Kulkarni, Indian J . Chem., Sect. B, 1980, 19,605. N. G. Bhat, B. M. Mane, G. H. Kulkarni, and R. B. Mitra, Indian J. Chem., Sect. B, 1981,20, 204.
B. M. Mane, K. G. Gore, and G. H. Kulkarni, Indian J. Chem., Sect. B, 1980, 19, 711. M. Kozlowska and W. Sobotka, Pol. J. Chem., 1980, 54,957. R. B. Mitra, A. S. Khanra, and A. R. A. S . Deshmukh, Indian J. Chem., Sect. B, 1981,20,436. 672 S. Damtoft, S. R. Jensen, and B. J. Nielsen, Phytochemistry, 1981, 20, 2717. 6 7 3 S. Ueda, K. Kobayashi, T. Muramatsu, and H. Inouye, Planta Med., 1981, 41, 186. w4 E. Bernays and C . Deluca, Experientia, 1981, 37, 1289.
670
58
Terpenoids and Steroids
mainly iridoid glucosides (236 ; R2 = p-glucose) [ring numbering in (237)], although other sugars may be P-linked. The most comprehensive and informative papers can be grouped into four classes dealing with the differing groups of compounds. First (236) (R1= CO,Me, or less usually, C02H, CH20H, or CHO; R2 = pglucose.) The simplest of this group is 8-epiloganin (238) ;675 others have unsaturation in the C, ring, OH groups (sometimes oxidized, esterified, or etherified), predominantly at C-8 and C-10 but also at C-5, C-6, C-7. and C-9, and substituents (either a or p) in the C, ring: all functionalization can be alone or in combination.676-687An interesting sub-class has a 7,8-oxiran ring.688The second class comprises (236; R1= H, R2 = p-glucose) with similar functional groups to the first class,689-s92 and/or with 7,8- or 8,lO-oxiran rings.693-697 A noteworthy member is globularidin [from Globuluria spp. (239 ; R = trans-cinnamyl)] with saturation at C-3-C-4.697 (See also refs. 706, 707.) The third class comprises (236) (as in the previous two classes but with R2 sugars other than glucose). Examples are compounds with cellobiose or gentiobiose p-linked at C- 1,698-700 functionalized glucose
A. Bianco and P. Passacantilli, Phytochemistry, 1981, 20, 1871. L. Jahodar, I. Liefertova, and M. Lisa, Pharmazie, 1978, 33, 536. 6 7 7 A. Bianco, M. Guiso, C. Iavarone, P. Passacantilli, and C . Trogolo, Gazz. Chim. Ztal., 1979, 108, 13. 6 7 8 Y. Ozaki, S . Johne, and M. Hesse, Helv. Chim. Acta, 1979, 62, 2708. 0 7 0 L. M. Khatri and M. A. Kazi, J . Chem. SOC. Pak., 1979, 1, 25. H. Achenback, R. Waibel, and 1. Addae-Mensah, Tetrahedron Lett., 1980, 21, 3677. 081 C. W. Ford and M. R. Bendall, Aust. J . Chem., 1980, 33, 509. S. R. Jensen and B. J. Nielsen, Phytochemistry, 1980, 19, 2685. 683 F. Bailleul, P. Delaveau, and M. Koch, Phytochemistry, 1980, 19, 2763. 684 E. Davini, P. Esposito, C. Iavarone, and C. Trogolo, Phytochemistry, 1981, 20, 1583. m5 J. T. Huang, Arch. Pharm. (Weinheim, Ger.), 1981, 314, 831. S . Kobayashi, Y. Imakura, Y . Yamahara, and T. Shingu, Heterocycles, 1981, 16, 1475. 6 8 7 0. Sticher and 0. Salama, Helv. Chim. Acta, 1981, 64, 78. S. R. Jensen, C. B. Mikkelsen, and B. J. Nielsen, Phytochemistry, 1981, 20, 71. 680 K. Verma, G. R. Sood, S. R. Gupta, and V. K. Gujval, J . Chem. SOC.,Perkin Trans. I , 1979, 2473. 6 8 0 R. K. Chaudhuri, 0. Salama, and 0. Sticher, Helv. Chim. Acta, 1981, 64, 2401, R. K. Chaudhuri and 0. Sticher, Helv. Chim. Acta, 1980, 63, 117. Oo2 R. K. Chaudhuri, 0. Sticher, and T. Winkler, Tetrahedron Lett., 1979, 3149. w3 F. U. Afifi-Yazar and 0. Sticher, Helv. Chim. Acta, 1980, 63, 1905. 6B4 0. Sticher and F. U. Afifi-Yazar, Helv. Chim. Acta, 1979, 62, 530. C. Bonini, E. Davini, C . Iavarone, and C. Trogolo, Phytochemistry, 1981, 20, 1587. S.R. Elnaggar and R. W. Doskotch, Lloydia, 1980, 43, 524. Oo7 R. K. Chaudhuri and 0. Sticher, Helv. Chim. Acta, 1981, 64, 3. 6 s 8 A. Bianco, D. Bolli, and P. Passacantilli, Gazz. Chim. Ztal., 1981, 111, 91. H. Achenbach, R. Waibel, B. Raffelsberger, and I. Addae-Mensah, Phytochemistry, 1981, 20, 1591. ' 0 ° F. Murai and M. Tagawa, Planta Med., 1979, 37, 234. 675 0'16
Mono terpenoids
59
p-linked at C- I , 701?702 diglucosides (e.g. B-glucose residues at C- 1 and C-5),703 and other sugars linked at C-6.704, 705 An oddity is (240) from a Valeriana sp. 706 The last of the four classes comprises iridoids with no sugar residue,707-709 sometimes extensively functionalized into a tetracyclic skeleton.710 It is not often clear whether such compounds exist as such in vivo or whether the sugar is lost during isolation. Several new secoiridoid g l u c ~ s i d e s ~ ~and ~ - ~a ~bis-diglucoside * composed of linked iridoid and seco-iridoid units715have been isolated and characterized. Of numerous other reports on these compounds, a selection is noteworthy in recording new c o m p ~ u n d s , ~ascertaining ~ ~ - ~ ~ ~ or correcting structures of known com701
F. U. Afifi-Yazar, 0. Sticher, S. Uesato, K. Nagajima, and H. Inouye, Helv. Chim. Acta, 1981, 64,16.
?02
7 oa 704
A. Bianco. D. Bolli, and P. Passacantilli. Guzz. Chim. Ital., 1981, 111,479. L. Swiatek, D. Lehmann, R. K. Chaudhuri, and 0. Sticher, Phytochemistry, 1981, 20, 2023. A. Bianco, M. Guiso, C. Iavarone, P. Passacantilli, and 0. R. Gottlieb, Phytochemistry, 1981, 20,465.
706
A. Bianco, M. Guiso, C. Iavarone. P. Passacantilli, and C . Trogolo, Phytochemistry, 1981,20, 571.
7 06 707 708
70s 710 711
W. Kucaba, P. W. Thies, and E. Finner, Phytochemistry, 1980, 19, 575. P. D. L. Chao and G . H. Svoboda, Lloydia, 1980,43,571. T. Sakai, K. Nakajima, and T. Sakan, Bull. Chem. SOC.J., 1980, 53, 3683. H. G. Grant, P. J. O'Regan, R. J. Park, and M. D. Sutherland, Aust. J . Chem., 1980, 33, 853. E. K. Adesogan, Phytochemistry, 1979, 18, 175. S . Uesato, T. Hashimoto, Y . Takeda, K. Uobe, and H. Inouye, Chem. Pharm. Bull., 1981,29, 3421.
712
713
D. Sainty, F. Bailleul, P. Delaveau, and H. Jaequemin, Lloydia, 1981, 44, 576. H. Inouya, Y. Takeda, S. Uesato, K. Uobe, T. Hashimoto, and T. Shingu, Tetrahedron Lett.,
1980, 21, 1059. S. Uesato, T. Hashimoto, and H. Inouye, Phytochemistry, 1979, 18, 1981. 715 S . R. Jensen, S . E. Lyse-Petersen, and B. J. Nielsen, Phytochemistry, 1979, 18, 273. 716 F. Bailleul, A. Rabaron, M. Koch, and P. Delaveau, Plantu Med., 1979, 37, 316. 71? A. Bianco, M. Guiso, C. Iavarone, L. Pocaia, and C. Trogolo, Gazz. Chim. Ztul., 1979,109,561. 718 M. Tagawa and F. Murai, Planta Med., 1980,39, 144. 7 1B T . Tsuneya, M. Ishihara, H. Shiota, and M. Shiga, Agric. Biol. Chem., 1980, 44, 957. 72 0 0. Sticher, B. Meier, D . Lehman, and I. Swiatek, PIanta Med., 1980, 38, 246. 721 S . G . Chung, B. Z . Ahn, and P. Pachaly, Arch. Pharm. (Weinheim, Ger.), 1980, 313, 702. 7aa T. Yamauchi, F. Abe, and M. Taki, Chem. Pharm. Bull., 1981, 29, 3051. 723 J. Ruhdorfer and H. Rimpler, 2. Nuturforsch., Teil C , 1981, 36, 697. 724 J. Ruhdorfer and H. Rimpler, Tetrahedron Lett., 1981, 22, 839. 785 D. Sainty, F. Bailleul, P. Delaveau, and H. Jacquemin, Pluntu Med., 1981, 42, 260. 726 L. Swiatek, D. Lehmann, and 0. Sticher, Pharm. Actu Helv., 1981, 56, 37. 727 H. Sasaki, H. Taguchi, T. Endo, I. Yosioka, and Y. Iitrara, Chem. Phurm. Bull., 1981,29,1636. 728 Y. Nishihama, H. Masuda, M. Yamaki, S . Takagi, and K. Sakina, Pluntu Med., 1981, 43,28. 729 P. Junior, PIanta Med., 1981, 43, 34. 730 A. Bianco, M. Guiso, C. Iavarone, P. Passacantilli, and C . Trogolo, PIuntu Med., 1981, 41, 75. 731 A. Bianco, P. Passacantilli, and G . Polidori, Lloydiu, 1981, 44, 732. 732 A. Bianco, D. Bolli, and P. Passacantilli, Lloydiu, 1981, 44,448. 733 C. Adriani, C. Bonini, C. Iavarone, and C. Trogolo, Lloydiu 1981,44, 739. 734 H. Thomas and H. Budzikiewicz, Phytochemistry, 1980, 19, 1866.
714
60
Terpenoids and Steroids
pounds, 735-737 and documenting rare occurrences and unexpected sources. 738-745 Of especial interest is a revision of the structure of xylomollin: synthetic and spectroscopic studies and X-ray analysis of the 1-0-acetyl derivative show it to be the first characterized example of a naturally occurring trans-fused iridoid. 746
Synthesis and Reactions.-The absolute configuration of boschnaloside has been elucidated by chemical correlation with asperuloside. 747 Several routes to simple cyclopentane derivatives have been modified or discovered : a particularly elegant synthesis involved cycloaddition of trimethylenemethane complexed to transition metals, e.g. from reaction of (241) or (242) with [Pd(PPh,),], to cyclopent-2-en-lone to give a bicyclo[3.3.0]octane derivative that could be ring-opened to chrysomelidial (243).748Compound (243), together with (244), was formed by a six-stage route from l i r n ~ n e n and e ~ ~it~was proved that the latter was not g a s t r ~ l a c t o n e , ~ ~ ~ which was suggested to be the isomeric 7-ene.749This supposition was confirmed by a six-step synthesis from carvenolide. 751 Compound (243) was also synthesized in a multi-step process from diethyl 2-cyclopenten-1-ylmalonate.752 Routes from geraniol to (245) and thence to ( f)-iridomyrmecin, 753 from 2-methyl-5-chlorocyclopentane-1-carboxylicacid to the nepetalinic acids and photocitral A,754and to other key intermediates for the synthesis of iridoids have been described. 755 Cyclocitral was converted into trans,cis-d~lichodial~~~ and p-menth- 1-ene into chamigrene and acorenone B.757A synthesis of the alleged genipic acid by photoannelation unambiguously showed that the proposed structure (which had been doubted by some) was incorrect.758 735
G . J. Kapadia, Y. N. Shukla, A, K . Bose, H. Fujiwara, and H. A. Lloyd, Tetrehedron Lett., 1979, 1937.
736 737
738 73n 740
742 743
744
745
M. R. Bendall, C. W. Ford, and D. M. Thomas, Aust. J . Chem., 1979,32,2085. S . R. Jensen, B. J. Hielsen, C. B. Mikkelsen, J. J. Hoffman, S. D. Jolad, and J. R. Cole, Tetrahedron Lett., 1979, 3261. A. Sutarjadi, T. M. Malingre, and F. H. L. van Os, Phytochemistry, 1978, 17, 564. R. K. Chaudhuri and 0. Sticher, Plantu Med., 1980, 39, 140. Y. Takeda and T. Fujita, Planta Med., 1981, 41, 192. C. B. Rao, E. K. S. Vijayakumar, and K. U. Vijayalakshmi, Planta Med., 1981, 41, 80. G. Lammel and H. Rimpler, Z . Nuturforsch., Teil C, 1981, 36, 708. R. K . Chaudhuri, 0. Salama, and 0. Sticher, Tetrahedron Lett., 1981, 22,4061. A. Bianco, A. Francesconi, and P. Passacantilli, Phytochemistry, 1981, 20, 1421. E. K. Adesogan and F . N. Morah, Phytochemistry, 1981, 20,2585. M. Nakane, C. R. Hutchinson, D. van Engen, and J. Clardy, J. Am. Chem. SOC.,1978, 100,
7079. F. Murai and M. Tagawa, Chem. Pharm. Bull., 1980,28, 1730. '748 B. M. Trost and D. M. T. Chan, J . Am. Chem. SOC., 1981,103, 5972. 748 T. H . Jones, M. S . Blum, and H. M. Fales, Tetrahedron Lett., 1980,21, 1701. 750 M. S. Blum, J. B. Wallace, R. M. Duffield, J. M. Brand, H. M. Fales, and E. A . Sokoloski, J . Chem. Ecol., 1978, 4,47. 751 T. H. Jones and M. S . Blum, Tetrahedron Lett., 1981, 22,4373. 7 5 2 K. Kon and S . Isae, Tetrahedron Lett., 1980, 21, 3399. 753 Y. Yamada, H . Sanjoh, and K. Iguchi, Chem. Lett., 1978, 1405. 754 T. Sakai, K. Morita, C. Matsumura, A. Sudo, S. Tsuboi, and A. Takeda, J . Org. Chem., 1981, 46,4774. 755 T. Imagawa, T. Sonobe, H. Ishiwari, T. Akiyama, and M. Kawanisi, J . Org. Chem., 1980,45, 2005. 756 C. Beaupin, J. C. Rossi, J. P. Vidal, J. P. Girard, and J. Passet, Phytochemistry, 1980,19, 1541. 7 5 7 J. D. White, J. F. Ruppert, M. A. Avery, S . Torii, and J. Nokami, J . Am. Chem. SOC.,1981,103, 1813. 768 S . W. Baldwin and M. T. Crimmins, J . Am. Chem. SOC.,1980, 102, 1198. 747
Monoterpenoids
61
Dolichodiol was converted into iridoid lactones by the N-halogenosuccinimide-Me,S complex. 759 A new synthesis of loganin and related compounds started with the regioselective sulphenylation of P-keto-esters (such as ethyl 2-oxocyclopentane- l-carboxylate) followed by conversion into the p-thioalcohols, oxidative cleavage, and c y c l i ~ a t i o nA. ~most ~ ~ impressive route to the skeleton (237) involved a rare type of intramolecular ene reaction of (246).761Cyclization of (247). prepared by Wittig reaction of diethyl oxomalonate, gave elenolic acid. 762 Eight- to sixteen-step syntheses of isoiridomyrmecin and verbenalol, 763 iridomyrrne~in'~* allodolicholactone (first synthesis), iridomyrmecin and its i ~ o - e p i m e r ~ ~ ~ and ~ a r r a c e n i nhave ~ ~ ~been reported. The aglycones of a s p e r ~ l o s i d o and l ~ ~ ~its derivatives76s rearranged in acid to tetracyclic acetals : under similar conditions other iridoid glucosides (harpagide, antirrhide) opened to cyclopentane derivatives,768 and lamiigenin was similarly cleaved by NaBH, in a Knoevenagel-type process. 769 C a t a l p 0 1 ~and ~ ~ other lactones771 have been reduced and functionalized, geniposide has been converted by a biogenetic-type transformation into p l ~ m i e r i d e , ~ aucubin ~, has been used as a starting material for prostaglandin and attempts have been made to convert the aglucone of kingiside into xylomollen. 774 Secologanin on enzymic cleavage, acid treatment, and oxidation gave elenolide (248), and the sequence established the chirality as shown at the point of attachment of the side-chain. 7 7 5 [10-13C]Secologaninwas synthesized in a seven-step process from ethylene a ~ e t a lHop . ~ ~ether ~ (249), the irioid most simply related to geraniol, was synthesized in six steps from the protected lactol form of 3-formyl-2-methoxycarbonylcyclopentanol. 7 7 7
14 The Irregular Classes The chemistry of the pyrethroid acids has been reviewed.778In the following sections; A, S, and L represent compounds with the artemisyl, santolinyl, and lavandulyl skeleta respectively. F. Bellesia, R. Grandi, U. M. Pagoni, and R. Trave, J. Chem. SOC.,Perkin Trans. 1, 1979, 851. K. Hiroi, H. Miura, K. Kotsuji, and S . Sato, Chem. Lett., 1981,559. B. B. Snider and J. V. Duncia, J. Org. Chem., 1980, 45, 3461. B. B. Snider, D. M. Roush, and T. A. Killinger, J. Am. Chem. SOC.,1979, 101,6023. 763 P. Callant, R. Ongena, and M. Vandewalle, Tetrahedron, 1981, 37, 2085. 704 P. A. Grieco and C. V. Srinivasan, J. Org. Chem., 1981, 46, 2591. 765 K. Schaffner and M. Demath, Chimia, 1981, 35,437. 788 J. K. Whitesell, R. S. Mathews, M. A. Minton, and S. M. Helbling, J. Am. Chem. SOC.,1981,
750
760
103,3468. 767
768
76*
'70 771
A. Bianco, M. Guiso, C. Iavarone, P. Passacantilli, and C. Trogolo, Tetrahedron, 1980, 36, 1613. A. Bianco and P. Passacantilli, Guzz. Chim. Ztul., 1981, 111, 223. A. Bianco, D. Budai, M. Guiso, C. Iavarone, R. M. Bettolo, and C. Trogolo, Guzz. Chim. Ztul., 1979,109, 517. K. Weinges, H. von der Eltz, and D. Tran-Viet, Angew. Chem. Znt. Ed. Engl., 1980, 19, 628.
F. Bellesia, U. M. Pagnoni, R. Trave, G. D. Andreetti, G. Bocelli, and P. Sgarabotto, J. Chem. SOC.,Perkin Trans. 2, 1979, 1341.
772 773
775
776 777
778
K. Inoue, Y. Takeda, H. Nishimura, and H. Inouye, Chem. Pharm. Bull., 1979, 27, 3115. M. Naruto, K. Ohno, and N. Naruse, Chem. Lett., 1978, 1419. S. B. Hassam and C. R. Hutchinson, Tetrahedron Lett., 1980, 21, 1209. L. F. Tietze and H. C. Uzar, Angew. Chem. Znt. Ed. Engl., 1979, 18, 539. L. F. Tietze and S. Henke, Angew. Chem. Znt. Ed. Engl., 1981, 20,970. T. Imagawa, N. Murai, T. Akiyama, and M. Kawanisi, Tetrahedron Lett., 1979, 1691. D. Arlt, M. Jautelat, and R. Lantzsch, Angew. Chem. Znt. Ed. Engl., 1981, 20, 703.
62
Terpenoids and Steroids
Occurrence.-( +)-Artemisia alcohol [rather than the usual (-)-enantiomer], yomogi alcohol (class A), santolina alcohol and triene, lyratol (class S), and epoxyartemisia ketone occur in Artemisia779?780 and Chrysanthemum Santolinide B (250) and lesser amounts of isomeric lactones occur in Arternisia spp. According to the revised hypothesis concerning the biosynthesis of the A, S , and L classes, (lR,3S)-cis-chrysanthemyl alcohol should be the precursor of these lactones as they possess the S-configuration at C-3. 782 Achillene (2,5-dimethyl-3-vinylhexa1,4diene; class S) has been isolated from an Achillea sp.784One of the many investigated chemotypes of Tanaceturn vulgare produced y-campholenol (251), a new compound, as well as artemisyl and lyratyl derivatives.618The claimed first C,, acetylenic lactone was found in a Senecio sp.,785but this had the 2-methylnonane skeleton and may not be of isoprenoid origin ; 1,5,5-trimethylcyclohepta-l,3,6triene occurs in a Pinus sp.;786 nor-monoterpenes with the 2,5- and 2,6-dimethylheptane skeleta are insect sex pheromones, 7 8 7 and ilex lactone is a bis-nor-monote~pene.~~~ 782p783
(253)
(254)
Syntheses and Reactions.-Coupling of 3-methyl-1-trimethylsilylbut-2-ene with 3,3-dimethylacryl chloride yielded artemisia ketone. 7 8 9 Reaction of 2,5-dimethylhexa-2,4-diene with ClCH2CN (CuC1, 2,2'-bipyridyl catalysts) gave l-cyano2,2,5-trimethylhexa-3,5-diene (Class A). 790 Lavandulol has been efficiently (3055 %) synthesized from 6-chloro-2,6-dimethylhept-2-ene, 791 2,6-dimethylhepta-2,5diene,792-794 and 3,3-dimethylacryl acetate795and by coupling of the lithiated 77g 780
781 782 783 784
785
786 787
R. Segal, A. Brever, and I. Feuerstein, Phytochemistry, 1980, 19, 2761. R. Haf-Muller, W. Pickenhagen, and B. Willhalm, Helv. Chim. Acta, 1981, 64, 1424. F. Bohlmann and U . Fritz, Phytochernistry, 1979, 18, 1888. W. W. Epstein and L. A. Gaudioso, J . Org. Chern., 1979, 44, 31 13. S. K. Pakniker and J. Veeravalli, Indian J . Chern., Sect. B., 1979, 18, 269. A. Dembitskii, M. I. Goryaev, R. A. Yurina, A. E. Lyuts, and S . M. Vasilyuk, Izv. Akad. Nauk Kaz. S S R , Ser. Khim., 1978, 28,45. F. Bohlmann, C. Zdero, R . M. King, and H. Robinson, Phytochemistry, 1981, 20, 2425. E. M. Manukov, V. A. Chuiko, and P. V. Kuzmichkin, Khim. Prir. Soedin., 1979, 783. M. Uchida, K. Nakagawa, T. Negishi, S . Asano, and K. Mori, Agric. Biol. Chem., 1981, 45, 369.
788 789
7g0
7g1 7g2
7e3
784
'g6
H. Thomas and H. Budzikiewicz, Phytochemistry, 1980, 19, 1866. G. Delaris, J. P. Pillot, and R. C. Rayer, Tetrahedron, 1980, 36, 2215. M. Julia, G. Lethuillier, and L. Saussine, J . Organomet. Chem., 1979, 177, 211. H. E. Du Preez, C . F. Garbers, and J. A. Steenkamp, S . Afr. J . Chem., 1980, 33, 21. M. Takami, Y.Omura, K. Itoi, and T. Kawaguchi, Jap Pat., 98 915/1978 (Chem. Abs., 1979, 90, 23 328). R. C. Cookson and N. A. Mirza, Synth. Commun., 1981, 11, 299. Y .Ueno, S . Aoki, and M. Okawara, J . Chem. Soc., Chem. Commun., 1980,683. M. Julia, C. Perez, and L. Saussine, J . Chem. Res. ( S ) , 1978, 311.
Monoterpeno ids
*
63
derivative of an A"'-disubstituted amide of 3,3-dimethylacrylic acid with 3,3dimethylallyl the last is an interesting example of a general reaction whereby the lithium derivative reacts with a variety of electrophiles to give a deconjugated, a-alkylated product. Isodihydrolavandulo17g7and the furanomonoterpene evodone (class L)798have been synthesized from (I?)-( +)-citronelk acid. Syntheses of chiral lyratyl acetate,799artemiseole (252),800~s01 the lactone (253),801~802 and m a r m e l ~ l a c t o n ehave ~ ~ ~been reported: the last is a rare example of a 'tail-totail' linked monoterpene.
A few cyclobutane derivatives have been investigated. Lineatin (254), a beetle pheromone, was prepared in a route allowing optical resolution of an intermediate, and hence synthesis of both e n a n t i o m e r ~Filifolone .~~~ (255) can be obtained from intramolecular alkylation of (256) : the latter was easily prepared from heptadienyl nitrile and was claimed to be useful generally as a terpene Photolysis of verbanone gave a substituted cyclobutaldehyde that could be elaborated to the pheromone (257),806and (258) was prepared from methyl cyclobut-l-enecarboxylate.807 Eucarvone resulted from an elegant ring expansion of 5,5-dimethylcyclohex-2-en-l-one.808 Amino and hydroxyl derivatives of e u c a r v ~ n eand ~~~ karahanaenone810 and other 2,2,5-trimethyl~ycloheptanones~~~ have been synthesized. y,&Epoxyeucarvone was rearranged into isomeric trimethylcyclopenta[b]furans. 812 Friedel-Crafts acylation of tropone irontricarbonyl gave a mixture of tautomers which were convertible into P-thujaplicir~.~~~ Cryptone (a nor-monoterpene) resulted from Lewis acid-catalysed ring cleavage of nopinone. 814 The volume of work on the chrysanthemyl class reflects the importance of these compounds as insecticides. Several new syntheses of the isomeric chrysanthemic M. Majewski, G. B. Mpango, M. T. Thomas, A. Wu, and V. Snieckus, J. Org. Chem., 1981, 46,2029. 7 8 7 J. N. Shoolery and E. W. Southwick, J. Agric. Food Chem., 1980, 28, 302. Y. Masaki, K. Sakuma, K. Hashimoto, and K. Kaji, Chem. Lett., 1981, 1283. R. G. Gaughan and C. D. Poulter, J. Org. Chem., 1979, 44, 2441. D. V. Banthorpe and P. N. Christou, Phytochemistry, 1979, 18, 666. D. V. Banthorpe and P. N. Christou, J. Chem. SOC.,Perkin Trans. I , 1981, 05. S . Yamagiwa, H. Kosugi, and H. Uda, Bull. Chem. SOC.J., 1978, 51, 301 1. K. Mori and M. Sasaki, Tetrahedron, 1980, 36, 2197. 804 T. Hudlicky and T. Kutchan, Tetrahedron Lett., 1980, 21, 691. A. B. Smith, B. H. Toder, S. J. Branca, and R. K. Dieter, J. Am. Chem. SOC. 1981,103, 1996. *06 B. A. Bierl-Leonhardt, D. S. Moreno, M. Schwarz, J. Fargerlund, and J. R Plimmer. Tetruhedron Lett., 1981, 22, 389. 807 R. D. Clark, Synth. Commun., 1979, 9, 325. L. Blanco, N . Slougui, G. Rousseau, and J. M. Conia, Tetrahedron Lett., 1981, 22, 6 4 5 . Bop I. Mielczarek and F. Rulko, Pol. J . Chem., 1980, 54,419. N. Shimuzu and Y. Tsuno, Chem. Lett., 1979, 103. A. Itoh, K. Oshima, H. Yamamoto, and H. Nozaki, Bull. Chem. SOC.J., 1980, 53, 2050. K. Tsutsumi and H. R. Wolf, Helv. Chim. Actu, 1980, 63, 2370. M. Franck-Neumann, F. Brion, and D. Martha, Tetrahedron Lett., 1978, 5033. B. B. Snider, D. J. Rodin, and J. van Straten, J. Am. Chem. SOC.,1980, 102, 5872. 786
64
Terpenoids and Steroids
acids have been developed.815-822Perhaps the two most intere$ng used 2,5dimethylhex-3-yne-2,5-diol (commercially available) as starting materia1,"l or involved addition to 3,3-dimethylacrylate esters of the thiovinylcarbene formed on photolysis of gern-dimethyl-5-ethylthiopyra-a~olenine.~~~ Ethyl 2-bromo-3,3-dimethylacrylate is a new synthon for p y r e t h r o i d ~ and , ~ ~ ~useful intermediates for these compounds could be prepared from ~ a r - 3 - e n eThe . ~ ~ difference ~ of the 13C n.m.r of the gem-dimethyls shows whether chrysanthemate derivatives are cis or trans;825homogenous Pd complexes are excellent catalysts for the cis+trans isomerizations.826 Photosensitized oxidation of trans-chrysanthemic acid gave the expected the epoxides of both cis- and trans-acids and of pyrethrins were decarboxylated readily ( e . g . o n t.l.c.).82R A variety of chrysanthemic ester analogues with ~ h l o r i n e ~ or ~ ~other -*~~ substituents (e.g. Br, SMe, or CN)833-836 on the double bond or on the ring,837and of substituted cyclobutanones that are precursors of pyrethroids, have been obtained by more or less standard routes. 838-840 The absolute configurations of synthetic pyrethroids containing the a-ethylvinyl alcohol moiety have been determined84L and p h o t ~ c h e r n i c a l ~ and ~ ~enzymic - ~ ~ ~ (esterases from worm larvae)846degradations of pyrethroids have been elucidated.
M. J. de Vos and A. Krief, Tetrahedron Lett., 1979, 1511. M. J. De Vos and A. Krief, Tetrahedron Lett., 1979, 1891. B. J. Fitzsimmons and B. Fraser-Reid, J . Am. Chem. Soc., 1979, 101, 6123. M. Franck-Neumann and C. D. Buchecter, Tetrahedron Lett., 1980, 21, 671. N. G. Bhat, G . D. Joshi, K. G. Gore, G . H. Kulkerni, and R. B. Mitra, Indian J . Chem., Sect. B., 1981, 20, 558. 820 D. Babin, J. D. Fourneron, L. M. Harwood, and M. Julia, Tetrahedron, 1981, 37, 325. 821 J. P. Gen&t, F. Piau, and J. Ficini, Tetrahedron Lett., 1980, 20, 3183. 822 M. Franck-Neuman and J. J. Lohmann, Tetrahedron Lett., 1979, 2075. 823 J. H. Babler and B. J. Invergo, Tetrahedron Lett., 1981, 21, 2743. 824 T. L. Ho and Z. U. Din, Synth. Commun., 1981, 10, 921. 825 L. Crombie, G. Kneen, G . Pattenden, and D. Whybrow, J . Chem. Soc., Perkin Trans. I , 1980 1711. 828 J. L. Williams and M. F. Rettig, Tetrahedron Lett., 1981, 21, 385. 827 A. A. Frimer, Zsr. J . Chem., 1981, 21, 194. 828 I. H. Smith and J. E. Casida, Tetrahedron Lett., 1981, 21, 203. P. Martin, H. Greuter, and D. Bellus, J . Am. Chem. Soc., 1979, 101, 5853. 830 W. G . Taylor, Synthesis, 1980, 554. 831 T. Shono, H. Ohmizu, S. Kawakami, S. Nakamo, and N. Kise, Tetrahedron Lett., 1981,21,871. 832 P. D. Klemmenson, H. Kolind-Andersen, H. B. Modsen, and A. Svendsen, J . Org. Chem., 1979, 44,416. 833 D. Holland and D . J . Milner, J . Chem. Res. ( S ) , 1979, 317. 834 M. B. Green, G. S. Hartley, and T. F. West, 'Chemicals for Crop Protection and Pest Control', Pergamon, Oxford, 1977, p. 83. 835 0. Ruel, B. Cazes, and S . Julia, Synth. Commun., 1980, 10, 743. 836 J. P. Gen&tand F. Piau, J . Org. Chem., 1981, 46, 2414. 8 3 7 M. J. DeVos and A. Drief, Tetrahedron Lett., 1979, 1515. 838 P. Martin, H. Greuter, G. Rihs, T. Winkler, and D. Bellus, Hefv. Chim. Acta, 1981, 64, 2571. 839 P. Martin, E. Steiner, and D. Bellus. Helv. Chim. Acta, 1980, 63, 1947. 8 4 0 P. Martin, H. Greuter, and D. Bellus, Helv. Chim. Acta, 1981, 64, 64. 841 N. Matsuo, T. Yano, and H. Yoshida, Agric. Biol. Chem., 1981, 45, 1915. 842 L. 0. Ruzo and J. E. Casida, J . Chem. Soc., Perkin Trans. I , 1980, 728. 843 Y. Kawano, K. Yanagihara, T. Miyarnoto, and 1. Yamamato, J . Chromatogr., 1980, 198, 317. 844 L. 0. Ruzo, L. C. Gaughan, and J. E. Casida, J . Agric. Food Chem., 1980, 28, 256. 845 L. 0. Ruzo and J. E. Casida, J . Agric. Food Chem., 1981, 29, 702. 848 A. A. I. Yehia and D. M. Soderlund, Pestic. Biochem. Physiol., 1980, 14, 282.
el5
Monoterpenoids
65
15 Cannabinoids and Other Phenolic Monoterpenoids
See also ref. 2 (review). Cannabinoids.-New compounds (259; OH at C-8 or at C-10)S47and (259; OH at both C-9 and C-10)S4Shave been isolated from Cannabis sativa. p-Menth-2-ene-1,8diol is an excellent synthon for the Ag-tetrahydrocannabinol (THC) skeleton, coupling (ZnC1,-catalysed) with olivetol (3-n-pentylresorcinol) to form the (-)parent compound, and forming the biologically potent 3-OH metabolite by appropriate modification of the reaction.S49The structurally equivalent substrate p-menth- 1,8-dien-l-ol reacted with other substituted resorcinols and led to AS- and A9-THC analogues differing in the side-chain attached at C-3.S50-S51 Use of the synthon (260) in a similar manner gave 2', I 1 -dihydroxy-Ag-THC: this was claimed
n
'i QH
?! OH
(259) . ,
(260) to be the first synthesis of a metabolite functionalized in both the terpenoid moiety and in the ~ i d e - c h a i nCoupling .~~~ of pulegone with 3-X-resorcinols (X= C5HII or Me), protection of the phenolic group with SiMe,Bu', bromination and aromatization (NBS,hv) of the C, ring, and deprotection gave improved routes, claimed the best available, to cannabinol and cannabiorcol respectively.853The bis-tetrahydropyranyl homocuprate of olivetol reacted with dehydrolinalool (in a reaction general for propargylic halides and acetates) to give a versatile synthesis of cis-6a,lOa-AsTHC. 854 A modification of a previously described synthesis of this by condensation of olivetol with citral opened a convenient route to the t r a n s - i ~ o m e r AS-THC .~~~ with a modified side-chain at C-3 resulted from reaction of the appropriate resorcIn yet another inol derivative with trans-verbenol in the presence of a Lewis variant of the general method, substituted resorcinols reacted with the enolate of ( +)-citronella1 to give an intermediate which underwent a stereocontrolled [4 + 21 heterodiene cycloaddition to give (261). The structure and conformation of
847
848 849
850 851
863 854
E55
M. A. Elsohly, E. E. Boeren, and C. E. Turner, Experienfia, 1978, 34, 1127. E. G. Boeren, M. A. Elsohly, and C. E. Turner, Experientiu, 1979, 35, 1278. G. R. Handrick, D. B. Uliss, H. C. Dalzell, and R. K. Razdan, TetrahedronLett., 1979, 681, I. Franke and M. Binder, Helv. Chim. Actu, 1980, 63, 2508. C. G. Pitt, H. H. Seltzman, Y . Sayed, C. E. Twine, and D . L. Williams,./. Org. Chem., 1979,44, 677. R. P. Duffley, G . Lambert, H. C. Dalzell, and R. K. Razdam, Experientia, 1981, 37, 931. P. C. Meltzer, H. C. Dalzell, and R. K. Razdam, Synthesis, 1981, 985. J. M. Luteijn and H. J. W. Spronck, J . Chem. SOC.,Perkin Trans. I , 1979, 201. V. Chandrasekharan, P. Unnikrishnan, G . D. Shah, and S . C . Bhattacharyya, Indim J . Chem. Sect. B, 1980, 19, 746.
66
Terpenoids and Steroids
this were elucidated by 13Cn.m.r. and X-ray analysis.856Less general syntheses have been carried through for hydroxylated and oxidized derivatives of AS-THC functionalized in the ~ i d e - c h a i or n ~at~ ~C-1 1,868-859 for derivatives of As-THC with the side-chain completely modified (262) (R = Ar or CR=CR2),s60and for sidechain analogues of AsaJoa-THC.8s1Most of the compounds were required for testing as potential therapeutic agents. A8-THC glucoronide has been synthesized and its metabolism in rats investigated.s62 [ 1 1-2H,]-cis-6a,10a-A9(11)-THC and its trans-isomer were easily prepared from [ 1-2H, ] g e r a n i ~ and l ~ ~14C~ and 1251-labelled cannabinoids have also been ~ynthesized.~~~9 865 Citronella1 condensed with barbituric acid and related compounds to form enantiomeric tricyclic dihydropyrans that are cannabinoid analogues. 866 Bucourt’s method for estimation of torsional strain can be successfully applied to the THC ring system to give a surprisingly good quantitative estimate of the relative stability of the various double-bond isomers, in particular of the position of equilibrium for As +A9 for the parent and model compounds demethylated at C-6. 667 The long-range 1,5-substituent effect of an ester group at C-1 was held to be responsible for the base-catalysed conversion of a methoxycarbonyl group at C-9 from an equatorial to an axial position. The axial isomer was unchanged in the reaction conditions. A similar effect, presumably due to flexing of the carbocyclic skeleton, was found in elimination : dehydrochlorination of the 9-chloro- l-hydroxycompound and of the 9-chloro- 1-methoxy-compound gave the isomeric As- and 119-compoundsrespectively.s68The degradation of As- and AS-THC via the epoxy and hydroxylated derivatives has been reported. s69
Thymol Derivatives.-Occurrence. Several new thymol derivatives have been isolation of (263) from roots of a obtained from a variety of plant Marshallia sp. was claimed to have chemotaxonomic significence.872 Isothymol (rn-menthane skeleton) and its esters occur n a t ~ r a l l y a; ~phenolic ~ ~ ~ ~ ether ~~ L. F. Tietze, G. von Kiedrowski, K. Harms, W. Clegg, and G. Sheldrick, Angew. Chem. Znt. Ed. Engl., 1980, 19, 134. 857 A. Ohlsson, S. Agurell, K. Leander, J . Dahmen, H. Edery, G . Porath, S. Levy, and R. Mechoulam, Acta Pharm. Suec., 1979, 16, 21 (Chem Abs., 1979, 91, 108092). R. S. Wilson, B. R. Martin, and W. L. Dewey, J. Med. Chem., 1979, 22, 879, 859 R. S. Wilson, E. L. May, and W. L. Dewey, J. Med. Chem., 1979,22, 886. 860 P. Unnikrishnan, V. Chandrasekharan, G . D. Shah, and S. C. Bhattacharyya, ZndimJ. Chem., Sect. B, 1979, 17, 250. P. C. Meltzer, H. C. Dalzell, and R. K. Razdan, J. Chem. Soc., Perkin Trans. I , 1981, 2825. 862 H. Yoshimura, K . Watanabe, and K. Oguri, Chem. Pharm. Bull., 1979, 27, 3009. 863 R. A. Driessen and C. A. Salemink, Recl. Trav. Chim. Pays-Bas, 1981, 100, 342. 864 Y. Shoyama, H. Hirano, and 1. Nishioka, J. Labelled Comp. Radiopharm., 1978, 14, 835. 865 C. G. Pitt, H. H. Seltzman, S. R. Setzer, and D. L. Williams, J. Labelled Comp. Radiopharm., 1980, 17, 68 1 . L. F. Tietze and G. von Kledrowski, Tetrahedron Lett., 1981, 22, 219. H . C. Dalzell, D. B. Uliss, G. R. Handrick, and R. K . Razdan, J. Org. Chem., 1981, 46, 949. 8E8 R. Mechoulam, N. Lander, I. Tamir, Z. Ben-Zvi, and Y. Kimmel, Angew. Chem. Znt. Ed. Engl., 1980, 19, 543. 869 C. E. Turner and M. A. Elsohly, J. Heterocycl. Chem., 1979, 16, 1667. F. Bohlmann and J . Jakupovic, Phytochemistry, 1979, 18, 631. F. Bohlmann, A. Krishendhar, and M. Ahmeij, Phytochemistry, 1980, 19, 1850. 8 7 2 F. Bohlmann, J . Jakupovic, R. M. King, and H. Robinson, Phytochemistry, 1980, 19, 1815. 8 7 3 F. Bohlmann, A. A. Natu, and K. Kerr, Phytochemistry, 1979, 18,489. . 3 R. ~ Shmitz, G . Shaden, and H. Kating, Arch Pharm. (Weinheim, Ger.), 1979, 312, 65. 856
Monoterpenoids
67
f OCOBut
(OCOPr’
QAc
previously isolated875is the 3-methyl-2-isopropenyl derivative (rather than the 2-methyl-3-isopropenyl compound).876 Reactions. Grignard reaction and hydrogenation of the appropriate methyl aryl ketone yielded i s o t h y m 0 1 . ~Carvacrol ~~ was formed in excellent (83 %) yield on heating p-menth-l-ene oxide with Pd.878Aromatic aldehydes can be protected in situ by formation of a-aminoalkoxides and their O-trimethylsilyl ethers : thus 4-formylbenzoic acid could be protected and elaborated (Grignard reaction) into (264).879 Esters of thymol underwent photo-Fries rearrangement to 2-acyl derivatives of thymo1.880Thymol methyl ether was brominated in the isopropyl group and also para to the methoxy-group by NBS.881Earlier work on the spectrum of mono-, di-, and tri-brominated products in the side-chain of p-cymene formed by reaction of NBS has been amended and corrected.882Oxidation of thymol acetate with benzyltrimethylarnmonium permanganate gave 3-hydroxy-4-isopropylbenzoic acid, which could be elaborated to the natural product (265).883Compound (266), also naturally occurring, was synthesized by base-promoted ring-opening of (267).884
16 Biogenesis, Chemotaxonomy, Biological Applications See also refs. 9-11 (books), 12-20 (reviews), 22 (tissue culture), 23 (chemotaxonomy), and 24 (biological functions).
876 876 877
879 880
882
884
R. Sangaiah and G. S. Krishna Rao, Tetrahedron Lett., 1981, 22, 1843. R. Bohlmann and A. Suwita, Phytochemistry, 1978, 17, 560, A. S. Dinge, J. K. Kirtany, and S. K. Paknikar, Indian J. Chem., Sect. B, 1981, 20, 245. T. Kurata, Yukugaku, 1979, 28,407. D. L. Comins and J. D. Brown, Tetrahedron Lett., 1981, 22, 4213. V. P. Pathak and R. N. Khanna, Synthesis, 1981, 882. V. V. Dhekne, A. R.A. S.Deshumkh, and A. S. Rao, Indian J . Chem., Sect. B, 1980,19, 188. B. Ravindranath and P. Srinivas, Indian J. Chem., Sect. B, 198 1, 20, 165. R. Sangaiah and G. S. Krishna Rao, Synthesis, 1980, 1018. Y.S. Sanghui and A. S . Rao, Indian J. Chem., Sect. B, 1980, 19, 952.
68
Terpenoids and Steroids
Labelling Patterns; Cell-free Extracts.-C-I0 of geraniol, synthesized in Rosa spp. was exclusively derived from C-2 of MVA.885This had been previously tacitly assumed and used in mechanistic discussions concerning IPP-isomerase. Feeding of 14C- and 3H-labelled geraniol and MVA to a Mentha sp. showed that: (i) oxidation of limonene or its biogenetic equivalent to form carvone involved shift of the endocyclic double bond and (ii) the exocyclic double bond in the product was not formed regiospecifically.886 The gem-dimethyls of pulegone were also scrambled in its formation from [10-14C]geraniol by another Mentha sp.887 Measurement of isotope ratios in car-3-ene biosynthesized in a Pinus sp. from 14C,3H-labelledMVA and geraniol revealed that the carane skeleton was constructed from its presumed monocyclic precursor with migration of a double bond together with an unexpected 1,2-shift of a proton to the site of the original unsaturation. The detailed stereochemistry of the processes allowed a two-step mechanism to be inferred for the cyclization, in whch a bonded intermediate was involved,888e . g . (268)+(269), Z
and Y being enzymic binding sites. Incorporation of 3H,14C-labelledgeraniol into 1,8-cineole in a Rosmarinius sp. occurred without loss of tracer from C-1 of the precursor, whereas nerol did lose tracer on similar cyclization. No plausible explanation was offered for these observations,889 which invalidate the often suggested proposal for redox-mediated conversion of geraniol into nerol prior to cyclization to menthane and other alicyclic derivatives. Other evidence (cf. ref. 91 1) also appears to refute the redox mechanism. Nevertheless the initial isomerization appeared operative in Rosa spp. In flowerheads conversion of geraniol into nerol involved loss of the pro-1S hydrogen, whereas the pro-1R atom was lost in the reverse process (presumably catalysed by a different enzyme). NADPf-NADPHdependent cell-free extracts were also obtained that catalysed these processes. 890 The role of geraniol and nerol as precursors of cyclic monoterpenes is complicated by the finding that linaloyl phosphate, linaloyl pyrophosphate, and linalool were more highly incorporated than geraniol or nerol and their esters (both in vivo and in cell-free extracts) into a-terpineol in a Mentha sp. and into limonene and perilla aldehyde in Citrus and Perilla spp.891Thus linalool (or its biogenetic equivalent) 885
887
A. Akhila and D. V. Banthorpe, Phytochemistry, 1980, 19, 1429. A. Akhila, D. V. Banthorpe, and M. G. Rowan, Phytochemistry, 1980, 19, 1433. A. Akhila and D. V. Banthorpe, 2.Pflunzenphysiol., 1980, 99, 277. A. Akhila and D. V. Banthorpe, Phytochemistry, 1980, 19, 1691. F. Orsini and F. Pelizzoni, Gazz. Chim. Itul., 1980, 110, 553. D. V. Banthorpe and I. Poots, Phytochemistry, 1979, 19, 1297. T. Suga, T. Shishibori, and H. Morinaka, J . Chem. SOC.,Chem. Commun., 1980, 167.
Mono terpenoids
69
may be an obligatory intermediate en route from geraniol to cyclic monoterpenes, or indeed may be directly formed by condensation of C, units. It has been long known that the TPP- and DMAPP-derived moieties of monoterpenoids arise from different metabolic pools in vivo, e.g. the former is very predominantly labelled by MVA. It has now been demonstrated for a variety of terpene classesin several species that co-feeding of MVA and leucine or valine resulted in the IPP-moiety being derived from MVA whereas the DMAPP-derived unit was derived from the aminoacid. The former moiety was also labelled by [14C]alanine.892-894 Thiamine may be
(270a) R = CH=CMe,, R1= Me (270b) R = CH,C6H4-p-OH, R1= Me
(272)
(271)
1
-6 O H
a coenzyme in the biosynthesis of certain monoterpenes. It was speculated (without, hewever, any direct evidence) that thiamine adducts (270a,b; the former from leucine) reacted nucleophilically with DMAPP (R1= Me) or geranyl pyrophosphate [R1= (CH,),CH=CMe,] to give an artemisyl compound or bakuchiol (271) respectively.895 [3H,14C]MVA was incorporated into la,2a,3p-trihydroxy-p-menthane by a Fusicoccum sp., and the labelling pattern suggested that p-menth-Zen- 1-01 was generated from an a-terpinyl cation by a 1,3-hydride shift, followed by formation of the a-epoxide and cleavage.896 Ips beetles converted [2H]myrcene(the isotopically normal substrate being obtained in nature from Pinus spp.) into ipsdienol and K. Tange, T. Hirata, and T. Suga, Chem. Lett., 1979,269. K. Tange, H. Okita, Y. Nakao, T. Hirata, and T. Suga, Chem. Lett., 1981, 777. m4 K. Tange, Bull. Chem. SOC. J., 1981, 54, 2763. m5 G. E. Risinger, K. Karimian, S. Jungk, and J. B. Simpson, Experientia, 1978, 34, 1121. eo6 G. Randazzo, A. Eridente, A. Boccalotte, and C. Rossi, Phytochemistry, 1981, 20, 2177. epz
eOs
Terpenoids and Steroids
70
i p s i n 0 1 , ~and ~ ~ further studies have confirmed that ipsdienol is an obligatory precursor of the Geniposide may easily be chemically converted into lO-hydro~yloganin,~~~ but neither the latter nor 7-epi- 10-hydroxyloganin (unlike deoxyloganic acid or loganin) was a precursor of secologanin in Loniceru spp.SOO In the course of studies on indole alkaloids it was demonstrated that the 10-0x0derivatives of geraniol and nerol were converted into secologanin in a Cuthmunthus sp. 901 8-epi-Deoxyloganin was efficiently incorporated into lamiide and ipolamiide in a Hebenstreitiu sp.9022H N.m.r. studies (one of few such applications to biosynthesis) showed that label at C-8 of deoxyloganin was retained during its conversion into cornin (the 6-0x0-derivative) in a Verbena sp. This shows that oxidation occurred at an unactivated position, i.e. there was no double bond at C-7-C-8 in the immediate precursor of cornin. 903 Semburin (273) and isosemburin (epimeric at the point of vinyl attachment) from a Swertiu sp. were the first 2,8dioxabicyclo[3.3.1Inonane derivatives encountered naturally : they were presumed formed from sweroside (272).904 Biogenetic speculations have also been formulated for details of the routes to A9- and A8-THCand cannabin01.~~~ The establishment of cell-free extracts that can sustain monoterpene synthesis has always been difficult, but recently such systems have been developed, and this has resulted in impressive conclusions concerning mechanistic and enzymatic details. The main improvement in methodology, which, however, has not proved successful in other hands, seems to be the use of very young plant material. This probably eliminates many of the problems associated with tough cell walls and the presence of phenolics that bedevil work with older tissue. However, extensive cultivation schemes may be necessary to develop sufficient biomass for such studies. A preliminary characterization of bornyl pyrophosphate synthetase (MW cu. 95 000 dalton) from a Sulviu sp. has been reported, and geranyl pyrophosphate (rather than the neryl ester) was the preferred substrate. 906 A detailed proposed mechanism that accommodates this choice of substrate and the formation of a pyrophosphate ester (rather than an alcohol) involved formation (perhaps via linaloyl pyrophosphate) and collapse (with bicyclization) of an intimate ion-pair comprising pyrophosphate as the anionic component. Extracts from the same plant contained separable terpinyl phosphatases and pyrophosphatases : the latter type included a system highly specific for bornyl pyrophosphate (the cleavage of which is essential for camphor formation) together with one which preferentially accepted geranyl pyrophosphate. The latter enzymic system has undoubtedly proved a source of potential interference in studies on Cl0 cyclization processes.908 Another fraction 9069907
goo
Oo2
Oo3 Oa4 Oo5
Oo8
L. B. Hendry and six others, Nature, 1980, 284, 485. R. H . Fish, L. E. Browne, D. L. Wood, and L. B. Hendry, Tetrahedron Lett., 1979, 1465. K. Inoue, Y. Takeda, T. Tanahashi, and H. Inouye, Chem. Pharm. Bull., 1981, 29, 970. K. Inoue, Y. Takeda, T. Tanahashi, and H. Inouye, Chem. Pharm. Bull., 1981, 29, 981. A. R. Battersby, M. Thompson, K. H. Glusenkamp, and L. F. Tietze, Chem. Ber., 1981, 114, 3430. S. Damtoft, J . Chem. SOC.,Chem. Commun., 1981, 228. S. Damtoft, S. R. Jensen, and B. J. Nielsen, J . Chem. Soc., Chem. Commun., 1980, 42. T. Sakai, H . Naoki, K. Takaki, and H. Kameoka, Chem. Lett., 1981, 1257. C. E. Turner and M. A. Elsohly, J . Heterocycl. Chem., 1979, 16, 1667. R. Croteau and F. Karp, Arch. Biochem. Biophys., 1979, 198, 512. D. E. Cane, R. Iyengar, and M. S. Shiao, J . Am. Chem. Soc., 1981, 103, 914. R. Croteau and F. Karp, Arch. Biochem. Biophys., 1979, 198, 523.
Monoterpenoids
71
from Salvia was worked up to a partially pure (MW ca. 91 000) dehydrogenase that oxidized (+)-borne01 to (+)-camphor. It is possibly the same as a thujol dehydrogenase extracted from a Tunucetum sp. 909 Another soluble enzyme from the same source catalysed the conversion of geranyl pyrophosphate into a- and p-pinenes, limonene, and camphene. Two cyclase preparations (MW 95 000 and 57 OOO) formed a-pinene, and both a-and p-pinenes respectively,910 It was shown that the different preparations from SaZvia produced products of different structural classes (a-pinene, camphene, borneol, limonene, 1,8-cineole) from [ 1 3H2, U-14C]geranyl pyrophosphate without loss of 3H,and thus eliminated a mechanism involving redox interconversion of geraniol and nerol in favour of a scheme whereby the E-precursor was cyclized directly by way of a bonded linaloyl intermediate.g11The key enzymes for the conversion of geranyl pyrophosphate into camphor in Salvia were at their highest levels of activity during the period of maximum leaf expansion. This was held to indicate that immature leaves synthesized and accumulated camphor most rapidly,912but it may also reflect the ease of extraction of the enzymes from these sources rather than from more mature tissue. A soluble preparation from a Foeniculum sp. converted geranyl and neryl pyrophosphates into fenchol and f e n ~ h o n e Unlike . ~ ~ ~ the situation for borneol, fenchyl pyrophosphate was not produced as a primary product and partial purification showed that the activities for the two percursors were coincident and presumably one enzyme was implicated for both. N o evidence was found (via isotope dilution techniques) for a- or P-pinene or pinanols or their pyrophosphates as free intermediates although the formation of fenchone was considered to involve the generally accepted rearrangement of some pinane derivative. 914 Further fractionation gave a preparation (NADP+-dependent) that oxidized fenchol to fenchone, and a similar preparation (for thujan-3-ol+thujone) was obtained from a Tanacetum sp. Specificity studies indicated that only a narrow range of monoterpenols related to the structural classes produced in vivo were oxidized by these enzyme systems.915 Time-course studies with 14C02showed that in a Thymus sp., y-terpinene was converted into p-cymene and thymol in sequence,916and the appropriate y-terpinene synthetase (MW ca. 96 000) was partially purified. Tracer studies indicated that loss of a proton from C-5 of the a-terpinyl-like precursor to form the A*-unsaturation was accompanied, perhaps concertedly, by a 1,Zhydride shift from C-4 to C-8 to form y-terpinene. 917 Neomenthyl-p-D-glucoside was a major metabolite of menthone in Mentha s p ~ . , and ~ l ~a cell-free extract also acetylated menthol.919 Detailed in vivo and in vitro investigations revealed that in leaf discs the bulk of the neomenthol and menthol (produced from menthone) was converted into the glucoR. Croteau, C. L. Hooper, and M. Felton, Arch. Biochem. Biophys., 1978, 188, 182. Gambliel and R. Croteau, Plant Physiol., 1980, 65, Suppl., 96. Q1l R. Croteau and M. Felton, Arch. Biochem. Biophys., 1981, 207, 460. Q12 R. Croteau, M. Felton, F. Karp, and R. Kjonaas, Plant Physiol., 1981, 67, 820. Q13 R. Croteau, M. Felton, and R. C. Ronald, Arch. Biochem. Biophys., 1980, 200, 524. @ l PR. Croteau, M. Felton, and R. C. Ronald, Arch. Biochem. Biophys., 1980, 200, 534. @15 R. Croteau and N. M. Felton, Phytochemistry, 1980, 19, 1343. Q16 A. J. Poulose and R. Croteau, Arch. Biochem. Biophys., 1978, 187, 307. Q17 A. J. Poulose and R. Croteau, Arch. Biochem. Biophys., 1978, 191, 400. Q18 R. Croteau and C. Martinkus, Plant Physiol., 1979, 64, 169. Q19 R. Croteau and C. L. Hooper, Plant Physiol., 1978, 61, 737. QOQ
@ l oH.
72
Terpenoids and Steroids
side and acetate respectively. This was not due to the specificity of the transferring enzymes but was rather the result of the compartmentation of each stereospecific dehydrogenase (forming menthol and neomenthol) with the appropriate unspecific transferase. Indeed, a UDP-glucose : monoterpenol glucosyltransferase was partially purified which accepted either ( +)-neomenthol or (-)-menthol as glucose a c c e p t ~ rOther . ~ ~ cell-free ~ ~ ~ ~extracts ~ from Mentha spp. reduced the Al- and A4double bonds of piperitenone, piperitone, and pulegone: at least five different enzyme systems were implicated, specific for substrate and the stereochemistry of the reduction. Treatment of the mint extracts with ion-exchange resins removed endogenous monoterpenes and thus made it possible to assay terpene interconversions by quantitative g.c., without labelled substrates, and to identify the products by g.c.m.s.922 Cell-free extracts from a Chenopodiurn sp. catalysed the oxidation of a-terpinene to ascaridole by singlet 0, and also the formation of allylic hydroperoxides from limonene. 923 Chemical studies have shown that hydrolysis of geranyl pyrophosphate by Mn2+ seems a better model for enzymic reactions than does acid hydrolysis.924 Tissue Cultures, Microbial Transformations.-Little success has rewarded the search for cell cultures that effectively biosynthesize monoterpenes de now. The most impressive studies utilize cultures from a variety of Mentha spp. : yields of oil were some 60 (w/v) of those in the parent plants, but the monoterpene products were generally more oxidized (i.e. ketones; extra C = C bonds predominated). In vitro, oxidation at C-3 of the menthane skeleton was also restricted, apparently owing to an inhibition of the enzymic reduction of the 4(8) double bond in the intermediates formed. Colchicine stimulated synthesis of essential oil by Mentha cultures. 927 Iridoid glucosides have been produced by cultured cells of Gardenia spp.673Menthone was biotransformed to neomenthol by Mentha suspension cultures,g28and Nicoriana lines oxidized linalool and its derivatives at C-10 to aldehydes and alcohols,929and also ‘foreign’ substrates such as a-terpineol (at C-6 and C-7) and trans-p-menthan-9-en- 1-01 (at C-4 and C- lo). 930 Monoterpenols were esterified by lipases from various micro-organisms (especially Aspergillus ~pp.),’~l and (*)-caw1 acetates were hydrolysed by other species to give chiral carveols together with (unreacted) acetates of the enanti~ m e r The . ~ metabolic ~ ~ pathways for the conversions of (-)-carvone into (-)9259
R. Kyonaas, C. Martinkus-Taylor, and R. Croteau, Plant Physiol., 1980, 65, Suppl., 96. C. Martinkus and R. Croteau, Plant Physiol., 1981, 68, 99. 9 2 2 A. J. Burbott and W. D. Loomis, Plant Physiol,, 1980, 65, Suppl., 96. 923 M. Johnson and R. Croteau, Plant Physiol., 1980, 65, Suppl., 96. 924 M. V. Vial and six others, Tetrahedron, 1981, 37, 2351. s25 J. Bricout, M. J. Garcia-Rodriguez, C. Paupurdin, and R. Saussay, C . R. Hebd. Seances Acad. Sci., Ser. D . , 1978, 287, 611. 826 C. Paupardin, Prod. Subst. Nut. Cult. In Vitro Tissue Cell. Veg., J . Etud., 1979, 119. O Z 7 J. Bricout, M. J. Garcia-Rodriguez, and C. Paupurdin, C. R . Hebd. Seances Acad. Sci., Ser. D, 1978, 286, 1585. 928 D. Aviv, E. Krochmal, A. Dantes, and E. Galun, Planta Med., 1981, 42, 236. T. Hirata, T. Aoki, Y. Hirano, I. Ito, and T. Suga, Bull. Chem. SOC.J., 1981, 54, 3527. g30 T. Suga and six others, Chem. Lett., 1980, 229. 831 M. Iwai, S . Okumura, and Y. Tsujisaka, Agric. Biol. Chem., 1980, 44, 2731. 032 T. Oritani and K. Yamashita, Agric. Biol. Chem., 1980, 44, 2637. 820
Monoterpenoids
73
carveols and thence to dihydrocarveols in Streptomyces and Nocardia spp. have been elucidated, 933 as have the microbial transformations of A1-THC.934 Anaerobic bacteria growing on a-pinene as carbon source in simulated seawater conditions yielded a pattern of G-C, hydrocarbons including toluene. 935 Chemotaxonomy.-Reports of monoterpenes produced by particular species and genera are legion: most retread old paths or are of very limited significance. Some notable work of real chemotaxonomic interest has, however, been reported concerning Pinus spp. 936-938 (including analyses of species resistant to bark beetles93g), Abies ~ p p . , ~Juniperus ~O spp.,941-943Tanacetum ‘chemical races’,61s and various liverworts. 944-946 The chemotaxonomic significance of the distribution of acetylenic r n o n ~ t e r p e n e and s ~ ~ i~r i d o i d ~has ~ ~been ~ discussed. Related studies record the change in monoterpene corporation during maturation of Sequoia spp.949and the similar variations of menthol and its p-glucoside in Mentha. 950 Hybridization experiments have shown that the occurrence of 60-90 % pulegone in certain strains of Mentha spp. resulted from the lack of the genes necessary to reduce this ketone to menthone or to oxidize it to m e n t h o f ~ r a n . ~ ~ ’ A detailed genetic analysis of menthone-isomenthone production in Mentha spp. has also been described. 95a Metabolism, Biological Activity, Miscellaneous.-Camphene was converted into its 1,2-diol in rabbit,953and the pathways from a- and p-pinenes and car-3-ene to hydroxylated, ring-opened, and decarboxylated compounds have been determined.954The 9,lO-oxide of THC was initially hydroxylated at C-8(p), and in the side-chain byrat;g55 All-THC was hydroxylated at C-8, C-10, and in the side-chain and subsequently epoxidized.956 The metabolism and degradation of various Y. Noma, Agric. Biol. Chem., 1980, 44, 807. M. Binder and A. Popp, Helv. Chim. Acta, 1980, 63, 2515. s35 J. M. Hunt, R. J. Miller, and J. K. Whelan, Nature, 1980, 288, 577. 836 A. H. Conner, B. A. Nogasampagi, and J. W. Rowe, Phytochemistry, 1980, 19, 1121. s37 E. Zavarin and K. Snajbark, J. Agric. Food Chem., 1980, 28, 829. g38 E. N. Smit, V. A. Khan, T. D. Drebyschak, Z. V. Dubovenko, E. P. Kemertelidze, and V. A. Pentegova, Khim. Prir. Soedin., 1981, 81, 665. 93s L. Gollob, Naturwissenschaften, 1980, 67,409. 940 A. Roedam, J. J. C. Scheffer, and A. B. Svendsen, J. Agric. Food. Chem., 1980, 28,862. g41 E. von Rudloff, L. Hogge, and M. Granat, Phytochemistry, 1980, 19, 1701. g42 R. P. Adams, E. von Rudloff, and L. Hogge, Lloydia, 1981, 44, 21. s43 R. P. Adams, M. M. Palma, and W. S. Moore, Phytochemistry, 1981, 20, 2501. s44 Y. Asakawa, R. Matsuda, and T. Takernoto, Phytochemistry, 1980, 19, 567. s45 Y. Asakawa, R. Matsuda, M. Toyota, S. Hattori, and G. Ourisson, Phytochemistry, 1981,20, @34
2187. 946
g47 s48 g4s s50
951 OSa
s53 s54
g55 g56
Y. Asakawa, M. Toyota, T. Takernoto, and R. Mues, Phytochemistry, 1981, 20, 2695. F. Bohlmann, H. Robinson, and R. M. King, Phytochemistry, 1980, 19, 2235. D. Corrigan, R. F. Tirnoney, and D. M. X. Donnelly, Phytochemistry, 1978, 17, 1131. K. A. Okamoto, B. 0. Ellison, and R. E. Kepner, J. Agric. Food Chem., 1981, 29, 324. J. Sakata and K. Koshimizu, Nippon Nogei Kagaku Kaishi, 1980, 54, 1037. D. E. Lincoln and M. J. Murray, Phytochemistry, 1978, 17, 1727. M. J. Murray, D. E. Lincoln, and F. W. Hefendehl, Phytochemistry, 1980, 19,2103. T. Ishida, Y.Asakawa, T. Takamoto, and T. Aratani, J. Pharm. Sci., 1979, 68,928. T. Ishida, Y. Asakawa, T. Takamoto, and T. Aratani, J. Pharm. Sci., 1981, 70,406. A. Ohlsson and I. Emanuelson, Acta Pharm. Suec., 1979, 16, 396, M. Binder and U. Barlage, Helv. Chim. Acta, 1980, 63, 255.
74
Terpenoids and Steroids
pyrethroids in insects has been fully worked out. 957 Chemical and ultrastructural investigation of a Pinus species implied that the monoterpenes and other resin components were terminal products of metabolism and were not degraded during normal growth or starvation conditions. 958 This appears to be in contradiction to previous studies on terpenoid metabolism. Several pairs of cannabinoid isomers were synthesized and tested for biological activity: two requirements were elucidated: (a) in the absence of other substituents, the equatorial stereochemistry of substituents at C-9 determined activity and (b) pairs of compounds with groups at C-9 and C-10, or C-8 and C-9, had the same activity if the configurations (a or p) at the appropriate carbons were the same.959 The antifungal activity of monoterpene aldehydesg60and the metabolism of monoterpenes in mammals leading to acute poisoning by pine oil have been described.961 The effects of light on pinene synthesis in Pinus s ~ p .chloroplast , ~ ~ ~ autonomy in the formation of acetyl coenzyme A and in terpenoid b i o s y n t h e ~ i sterpene , ~ ~ ~ formation by and the influence of metachlor on growth and terpenoid synthesis have been i r ~ v e s t i g a t e d . ~ ~ ~
We thank Dr. Margaret Banthorpe for much help with the preparation of this report.
*57 a58
959 g60
g61 g62
g64 866
L. 0. RUZO,L. C. Gaughan, and J. E. Casida, Pestic. Biochem. Physiol., 1981, 15, 137. J. Benayoun and R. Ikan, Ann. Bot., 1980, 45, 645. R. Mechoulam and seven others, J . Med. Chem., 1980, 23, 1068. N. Kurita, M. Miyaji, R. Kurane, Y. Takahara, and K. Ichimura, Agric. Biol. Chem., 1979,43, 2365. C. Koppel, J. Tenczer, U. Tonnesmann, T. Schikop, and K. Ibe, Arch. Toxicol., 1981, 49, 73. M. Gleizes, G. Pauly, C. Bernard-Dagan,and R. Jacques, Physiol. Plant., 1980, 50, 16. K. Grumbach and B. Forn, 2. Nuturforsch., Teil C, 1980, 35, 645. G. D. Prestwich, R. W. Sowes, and M. S. Collins, Insect Biochem., 1981, 11, 331. R. E. Wilkinson, Pestic. Biochem. Physiol., 1981, 16, 63.
2 Sesquiterpenoids BY J.
s. ROBERTS
1 Farnesane An investigation of the nudibranch, Chromodoris marislae, has led to the identification of marislin (la) together with the minor constituents (2a,b) and (3a,b).l Acid or heat treatment of marislin brings about its conversion into pleraplysillin-2 (1b), a sponge metabolite of Mediterranean origin. Pleraplysillin-2 (1b) has been synthesized by coupling 4-methyl-2-furyl-lithium with the bromo-geraniol derivative (4) followed by deprotection, oxidative esterification, hydrolysis, and final esterification with 3-f~rylmethanol.~ Further work on the constituents of Eremophila
Br
(4) rotundijdia has led to the isolation of ( 5 ) and 4-hydroxydendrolasin (6).3 The diene (5) can be obtained by cyclodehydration of the alcohols derived from reduction of dihydrophymaspermone (7). Other new farnesyl/nerolidyl sesquiterpenoids include vernopolyanthone (8) and vernopolyanthofuran (9) (from various Vernonia species),* 3E- and 2-semistriatin methyl ether (I 0),5 and 5-hydroxynerolidol (1 1) (together with its 5-a~etate).~ The stereoselective synthesis of P-sinensal (14) has been achieved by reaction of the x-allylnickel(1I) complex (12) (derived from brornomyrcene) with the chloroa a 4
6
6
J. E. Hochlowski and D. J. Faulkner, Tetrahedron Lett., 1981, 22, 271. D. W. Knight and D. C. Rustidge, J . Chem. Soc., Perkin Trans. 1, 1981, 679. E. Dimitriadis and R. A. Massy-Westropp, Aust. J. Chem., 1980, 33, 2729. F. Bohlmann, J. Jakupovic, R. K. Gupta, R. M. King, and H. Robinson, Phytochemistry, 1981, 20,473. F. Bohlmann, W.-R. Abraham, H. Robinson, and R. M. King, Phytochernistry, 1981,20,1639. F . Bohlmann, C. Zdero, R. M. King, and H. Robinson, Phytochernistry, 1981, 20, 1643.
75
76
Terpenoids and Steroids
cq..&& /
H
/
/ /
0
\
0
OMe OAng
(1 1)
acetal (13) followed by acid hydr~lysis.~ Full details of the synthesis of 7-hydroxymyoporone (15) have been published. In two important papers Poulter et al. have published their results on the compelling evidence for a stepwise mechanism for the 1 ’-4 condensation reaction between isopentenyl pyrophosphate and geranyl pyrophosphate to form farnesyl
(15)
pyrophosphate (Scheme 1). In the first paper9 evidence is presented for a geranyl cation-pyrophosphate ion pair which is enzyme bound, i.e. ionization of geranyl pyrophosphate and condensation with isopentenyl pyrophosphate are not concerted. In the second communication,1° ls0-labelling studies have shown that
’ K. Sato, S . Inoue, and K. Watanabe, J . Chem. SOC.,Perkin Trans, 1, 1981, 2411.
lo
H. J. Reich, S . K. Shah, P. M. Gold, and R. E. Olson, J . Am. Chem. SOC.,1981, 103, 3112. C. D. Poulter, P. L. Wiggins, and A. T. Le, J . Am. Chem. SOC.,1981, 103, 3926; see also M. Ladika, I. Bregovec, and D. E. Sunko, J . Am. Chem. SOC.,1981, 103, 1285, 7797; for an excellent review of prenyl transferases and isomerase, see C. D. Poulter and H. C. Rilling, ‘Biosynthesis of Isoprenoid Compounds’, Vol. 1, ed. J. W. Porter and S . L. Spurgeon, John Wiley, New York, 1981, p. 161. E. A. Mash, G. M. Gurria, and C . D. Poulter, J . Am. Chem. Soc., 1981, 103, 3927.
Sesquiterpenoids
77
Scheme 1 the geranyl cation-pyrophosphate ion pair has a rigid structure and does not scramble the bridging oxygen atom with the two non-bridging oxygen atoms in the pyrophosphate counter-ion. Four components of the trail pheromone of the red imported fire ant, Solenopsis invicta, have been identified as 2,E-a-farnesene (16)’ E,E-a-farnesene (17), and the two homofarnesenes (1 8) and (1 9).11 In a related study12all of the eight possible diastereoisomers of do-farnesene (20) have been synthesized. In this paper it is claimed that the E,Z,Z-isomer is identical to material isolated from the Dufour’s glands of S. invicta. Faranal (21) a trail pheromone of the pharaoh ant has been synthesized by small scale enzymatic condensation of 2-3-methylpent-3-enyl pyrophosphate (23) with homogeranyl pyrophosphate (22) to give the 4R-triene (24).13 Alkaline hydrolysis of the pyrophosphiite ester followed by manganese dioxide oxidation gave the corresponding a, P-unsaturated aldehyde. Reduction of this aldehyde with triethylsilane in the presence of (Ph3P),RhCl gave both the 3S,4R and 3R,4R diastereoisomers and it was shown by bioassay that the former (21) corresponds to the natural pheromone. Three other syntheses14-16of faranal using relatively straightforward synthetic procedures have been recorded ; one of these14 produces faranal in optically active form. An interesting review of the biosynthesis and transport of juvenile hormones iri insects has appeared.17The syntheses of the juvenile hormones JHI-JHIII (25)-
l1
l2
I4 l5
l6
R. K. Vander Meer, F. D. Williams, and C. S. Lofgren, Tetrahedron Lett., 1981, 22, 1651. H. J. Williams, M. R. Strand, and S. B. Vinson, Tetrahedron, 1981, 37, 2763. M. Kobayashi, T. Koyama, K. Ogura, S. Seto, F. J. Ritter, and I. E. M. Bruggemann-Rotgans, J. Am. Chem. SOC.,1980, 102,6602. K. Mori and H. Ueda, Tetrahedron Lett., 1981, 22,461. D. W. Knight and B. Ojhara, Tetrahedron Lett., 1981, 22, 5101. R. Baker, D. C. Billington, and N. Ekanayake, J . Chem. SOC.,Chem. Commun., 1981, 1234. S. J. Kramer and J. H. Law, Acc. Chem. Res., 1980, 13, 297.
Terpenoids and Steroids
78
(27) together with a number of analogues have been achieved by the use of vinylcuprates as key intermediates.18
1" (16) R (18) R
=
=
H Me
x (25) R' = R2 = Et (26) R1= Et, R2 = Me (27) R1 = R2 = Me
2 Mono- and Bi-cyclofarnesane The search for marine metabolites with biological activity continues to produce new and interesting compounds. These include siphonodictyal-A (28) and siphonodictyal-B (29) which have been isolated from the limestone-burrowing sponge, Siphonodictyon c~ralliphagurn.~~ The green alga, Caulerpa Jlexilis, has been shown to contain the two monocyclic sesquiterpenoids (30) and (31);20 their derivation from the acyclic precursor flexilin (32) which had previously been isolated from C. pexilis seems highly probable. Previous work on the red alga, Laurencia filiforrnis, has demonstrated the presence of laurane, eudesmane, and chamigrane sesquiterpenoids. In a study21of another variety of this alga from Western Australia, aplysistatin (33),22 previously obtained from the sea-hare Aplysia angasi, and
2o
21
22
H. KIeijn, H. Westmijze, and P. Vermeer, J . Roy. Netherlands Chem. SOC.,1981, 100, 249. B. Sullivan, P. Djura, D. E. McIntyre, and D. J . Faulkner, Tetrahedron, 1981, 37, 979. R. J. Capon, E. L. Ghisalberti, and P. R. Jefferies, Aust. J . Chem., 1981, 34, 1775. R. Capon, E. L. Ghisalberti, P. R. Jefferies, B. W. Skelton, and A. H. White, Tetrahedron, 1981,37, 1613. R. B. Von Dreele and J. P. Y . Kao, Acta Cryst., 1980, B36, 2695.
79
Sesquiterpenoids CHO
AcO
(30)
woAc (33) R (34) R
= =
H OH
6p-hydroxyaplysistatin (34)have been isolated and their structures determined by X-ray analysis. The digestive glands of the nudibranch, Dendrodoris limbata, contain sesquiterpenoids of the type (35) in which the R group is a saturated, mono-unsaturated, or di-unsaturated fatty-acid chain (c16 and C,, are the most abundant species).23Nakafuran-8 (37) and nakafuran-9 (38) are two novel sesquiterpenoids which have been isolated from three sources, namely the marine sponge Dysidea fragilis and its prey, the two nudibranchs, Hypselodorisgodefroyana and Chromodoris rnaridadil~s.~~ The biogenesis of these two compounds is considered to be in terms of derivation from the microcionins (36) as shown in Scheme 2. The bromonium ion-initiated cyclization of acyclic precursors as a biomimetic route to certain marine metabolites continues to be an attractive method of synthesizing such compounds. Thus, treatment of nerolidol with 2,4,4,6-tetrabromocyclohexa-2,5-dione gave in low yield a- and p-snyderols (39) and (40), together with the two 3p-bromocaparrapi oxides (41) (epimeric at C-8) of which the 8a-methyl isomer is the naturally occuring A higher yielding synthesis of a- and p-snyderols involves acid-catalysed cyclization of the terminal bromohydrin of homogeranonitrile (43)to give the isomeric nitriles (44).26Treatment of (44)with methyl-lithium followed by a Grignard reaction of the derived 23 24 25
26
G. Cimino, S. De Rosa, S. De Stefano, and G . Sodano, Tetrahedron Lett., 1981, 22, 1271. G. Schulte, P. J. Scheuer, and 0. J. McConnell, Helv. Chim. Acta, 1980, 63, 2159. T. Kato, K. Ishii, I. Ichinose, Y. Nakai, and T. Kumagai, J . Chem. SOC.,Chem. Commun., 1980, 1106. A. Murai, A. Abiko, K. Kato, and T. Masamune, Chem. Lett., 1981, 1125.
Terpenoids and Steroids
80
I
(37) Scheme 2
methylketones with vinylmagnesium bromide produced cr-(39) and p-snyderol(40). In a related experiment phenylselenium anion opening of the terrninal epoxide of neroiidol produced the P-hydroxy-selenide (45) which, on treatment with acid followed by deselenation with tri-n-butyltin hydride, gave the two caparrapi oxides (42) (epimeric at C-8).27A new sesquiterpenoid from the red alga Laurencia obtusa is obtusenol (46).2*This dibromide has been synthesized by reaction of trans,trans-farnesol acetate with aqueous NBS to give (47) as one of the
Br
Br
OH
OH (41) R (42) R
(39)
Br W N HO
Br (46) 2' 28 29
J;);""
Br
= =
Br H
PhSe
HO
Br (47)
T. Kametani, K . Fukumoto, H. Kurobe, and H . Nemoto, Tetrahedron Lett., 1981, 22, 3653. S. Imre, S. Islimyeli, A. OztunG, and R. H . Thornson, Phytochemistry, 1981,20,833. A. G . Gonzalez, J . D. Martin, C. Perez, M. A. Ramirez, and F. Ravelo, Tetrahedron Lett., 1981,22, 5071.
81
Sesquiterpenoids
(51)
(50)
This compound must arise from bromonium ion cyclization of the 6,7-bromohydrin of farnesol acetate. Hydrolysis of the acetate group in (47) and sequential treatment with phosphorus tribromide and water gave obtusenol (46). Other syntheses of marine sesquiterpenoids include those of pallescensin-E (48),30furoventalene (49),31 and dactyloxene-B (50) and -C(51).32 The last mentioned established the absolute configurations of the two dactyloxenes. A second synthesis of ancistrofuran (53) and its C-2epimer has been recorded starting from the lactone (52)which is derived from homogeranic acid (Scheme 3).33 Ph,PQ
0
w H
0
h i , iii
w02w0 H
H
0
(53) Reagents: i, Bu',AIH; ii, PhSeCI; iii, Ac0,H; iv, H 4
Scheme 3
The diverse biological activity (e.g. insect antifeeding, plant growth regulation, molluscicidal) of a number of drimane sesquiterpenoids has stimulated considerable interest in their synthesis and the year under review has seen many new developments and improvements. Much of the synthetic work has centred around the key bicyclic diester (54) derived from l-vinyl-2,6,6-trimethylcyclohexene and dimethyl acetylenedicarboxylate. In contrast to earlier Ley et ~ 2 1 . ~ ~ 30
31 32 33 34
35
R. Baker and R. J. Sims, Tetrahedron Lett., 1981, 22, 161. F. Kido, Y. Noda, T. Maruyama, C. Kabuto, and A. Yoshikoshi, J . Org. Chem., 1981,46,4264. B. Maurer, A. Hauser, and G. Ohloff, Helv. Chim. A d a , 1980, 63, 2503. T. R. Hoye and A. J. Caruso, J. Org. Chem., 1981,46, 1198. S. P. Tanis and K. Nakanishi, J . Am. Chem. SOC.,1979, 101, 4398. S. C. Howell, S. V. Ley, M. Mahon, and P. A. Worthington, J . Chem. SOC.,Chem. Commun., 1981, 507.
Terpenoids and Steroids
82
have shown that hydrogenation of (54) under isomerizing conditions (trace of HCl) gives the trans-fused decalin derivative (55). This finding has paved the way to short and efficient syntheses of cinnamolide (56), polygodial(57), and warburganal (58) (Scheme 4).36Lallemand and c o - w ~ r k e r shave ~ ~ also used the diester (54) as the starting material for the syntheses of polygodial (57) and drimenin (60). They found that deprotonation of (54) with LDA followed by kinetic protonation at low temperature gives the isomerized diester (59). Normal catalytic hydrogenation of (59) gives the key compound ( 5 5 ) which was converted into polygodial (57)
C0,Me
CO,Me C0,Me
,
ix, x
/;"
'
'
(jy H
(55)
qO,Me
/,vi
OAc (56)
OH ...
Vlll +
& HH
@ H
Ho
(58) Reagents: i, H,-Pd/C; ii, LiAlH,; iii, Ag,CO,-celite; iv, Me, SO-(COCl),, then NEt3; v, Ac,Opy; vi, SeO,; vii, K,CO,-MeOH; viii, Me,SO-TFAA, then NEt3; ix, Bu',AlH; x, PTSA; xi, LDA; xii, H + Scheme 4
36
S. V. Ley and M. Mahon, Tetrahedron Lett., 1981, 22, 3909. M. Jallali-Naini, G. Boussac, P. Lemaitre, M. Larcheveque, D. Guillerm, and J.-Y. Lallemand, Tetrahedron Lett., 1981, 22, 2995.
Sesquiterpenoids
a3
(OH
pH ...
Vlll
+
ix +
OH
&OACH O liv
&*Me
xi
f-
H O
#OACH O
.1
vii, xii, xiii
(63)
liv
(62)
Reagents: i, BH,-THF; ii, H,O,OH-; iii, MsC1-py; iv, DBU; v, LiAlH,, vi, H,-Pd/C; vii, Bu',AIH; viii, PCC; ix, Pb (OAc),; x, MCPBA; xi, MeOH-H+; xii, H 3 0 + ;xiii, Ac,O-pyDMAP Scheme 5
by an exactly parallel method to that described by Ley et aE. Selective reduction of (55) followed by lactonization gives drimenin (60) (Scheme 4). Burton and White3* have also used the diester (54) as the starting point for syntheses of isodrimenin (61), fragrolide (62), and cinnamodial(63) (Scheme 5). Euryfuran (65), valdiviolide (66), and confertifolin (67) have all been synthesized from the trans-decalone (64) (Scheme 6).39A rather different approach to the drimane sesquiterpenoids is seen in the synthesis of confertifolin (67) by an interesting degradation of the diterpene manool (68) (Scheme 7).40The key steps in this synthesis are the Norrish type I1 38
as 40
L. P. J. Burton and J. D. White, J. Am. Chem. SOC.,1981, 103, 3226. S. V. Ley and M. Mahon, Tetrahedron Lett., 1981, 22,4747. T. Nakano and M. A. Maillo, Synth. Commun., 1981, 11,463.
Terpenoids and Steroids
84
iiii
(66)
+
-
Reagents: i, HC0,Et-NaH; ii, BUSH-PTSA; iii, Me,S-CH,; eosin-2,6-lutidine; vi, Br,-MeOH; vii, H,O+
iv, A or HgS04; v, O&v-
Scheme 6
f--iii
~
H
H
(67) Reagents: i, KMnO,; ii, h v ; iii,
hv,
(70) 02-Rose Bengal
Scheme 7
Sesquiterpenoids
85
cleavage of the ketone (69) and the unusual photo-oxygenation of the diene (70) to give confertifolin (67) directly. Full details and further refinements of the syntheses of isodrimenin (6 I), confertifolin (67),41and warburganal (58)42 have been published. Norambreinolide (71) has been synthesized by stannic chloride-promoted cycliza-
tion of trans-P-monocyclohomofarnesic acid (72) which is derived from dihydro-pi ~ n o n eAnother . ~ ~ ambergris compound, a-ambrinol(73) can be obtained in a short synthesis from 3-methyl-2-cyclohexenone (Scheme 8).44 New drimane sesquiterpenoids include 6p-acetoxyisodrimenin (74), capsicodendrin, a partially characterized tetramer of cinnamodial (63),45 albicanyl 3,4-dihydroxycinnamate (75), albicanyl 2,4-dihydroxycinnamate (76) (both liverwort c ~ n s t i t u e n t s ) , and ~ ~ polyveoline (77), an indolo~esquiterpenoid.4~ Full details of the isolation and structural determination of pebrolide (78) and its congeners (79) and (80) have been published.48The biosynthesis of pebrolide
Jiv, v
n Reagents: i, MeMgI-CuI; ii, Me3SiC1; iii, v, H 3 0 +
(73) -TiC14-Ti(OPri)4; iv, Ph,P==CH,;
Scheme 8
42
4a 44 46
H. Akita, T. Naito, and T. Oishi, Chem. Pharm. Bull., 1980, 28, 2166. T. Nakata, H. Akita, T. Naito, and T. Oishi, Chem. Pharm. Bull., 1980, 28, 2172. A. Saito, H. Matsushita, Y. Tsujino, and H. Kaneko, Chem. Lett., 1981, 757. 0. Takazawa, H. Tamura, K. Kogami, and K. Hayashi, Chem. Lett., 1980, 1257. I. I. Mahmoud, A. D. Kinghorn, G. A. Cordell, and N. R. Farnsworth, J. Nat. Products, 1980, 43, 365.
1e 47
48
M. Toyota, Y. Asakawa, and T. Takemoto, Phytochemistry, 1981, 20, 2359. R. Hocquemiller, G. Dubois, M. Leboeuf, A. Cave, N. Kunesch, C. Riche, and A. Chiaroni, Tetrahedron Lett., 1981, 22, 5057. N. J. McCorkindale, C. H. Calzadilla, S. A. Hutchinson, D. H. Kitson, G. Ferguson, and I. M. Campbell, Tetrahedron, 1981, 37, 649.
4
86
Terpenoids and Steroids
& H OAc
(74)
(75) R1= H, R2 = OH (76) R’ = OH, R2 = H
@$ ’,. H
H
OCOPh
HO”
i 2
(77)
(78) R’ = OH, R2= OAC (79) R’ = R2 = OH (80) R’ = H, R2 = OAC
has also been investigated using [2-14C,2-3H2]mevalonicacid and degradative studies indicate the expected labelling pattern based on cyclization of farnesyl pyroph~sphate.~~ The antifungal mould metabolite siccanin (8 1) has been synthesized in nineteen The asymmetric intramolecular Diels-Alder reaction of the magnesium salt of the amide (82) gives a predominance of the tricyclic diastereoisomer (83) which can be converted into the enantiomer (84) of naturally occurring farnesiferol C.51 Some very interesting biosynthetic studies have been carried out by Simpson and co-workers on the meroterpenoids austin (86),52 terretonin (87),53anditomin
8WNqwp .
I
..._
fl (82)
H
HO
OOH (83)
(81)
(84) 48
61
b2 63
N. J. McCorkindale, C. H . Calzadilla, and R. L. Baxter, Tetrahedron, 1981, 37, 1991. M. Kato, K . Heima, Y . Matsumura, and A. Yoshikoshi, J . Am. Chem. SOC., 1981, 103, 2434. T. Mukaiyama and N. Iwasawa, Chem. Lett., 1981, 29. T. J. Simpson and D. J. StenzeI, J . Chem. SOC., Chem. Commun., 1981, 1042. C . H. McIntyre and T. J. Simpson, J . Chem. SOC.,Chem. Commun., 1981, 1043.
Sesguiterpenoids
87
(88)754v55and andilesin C (89).54 Incorporation of 13C-labels indicate that the biosyntheses of these compounds can be rationalized in terms of alkylation of farnesll pyrophosphate by a bis-C-methylated tetraketide-derived phenolic precursor to produce the key intermediate (85). Cyclization followed by a series of rearrangements and oxidative modifications leads to these interesting metabolites. The efficient incorporation of ethyl 2,4-dihydroxy-3,5,6-trimethylbenzoate (90) and
0 C02Me
(88)
6; C02Et
(90) R = OH (91) R = H (91) demonstrates that biological Cethyl 4-hydroxy-2,3,5-trimethylbenzoate methylation by methionine precedes aromatization of the tetraketide.56 Simpson
(92) R (93) R 54 65 56
=
H
=
OH
OH (94)
T. J. Simpson, Tetrahedron Lett., 1981, 22, 3785. T. J. Simpson and M. D. Walkinshaw, J . Chem. SOC.,Chem. Commun., 1981, 914. A. J. Bartlett, J . S. E. Holker, E. O’Brien, and T. J. Simpson, J . Chem. SOC.,Chem. Commun., 1981, 1198.
Terpenoids and Steroids
88
et uL5' have also found that a mutant of the andibenin producing strain of Aspergillus vuriecolor which lacks the polyketide-derived mycelial pigments produces the two drimane sesquiterpenoids astellolide A (92) and B (93) which are structurally close to the pebrolides (78)-(80). A very complete account has been published5* of the excellent labelling studies which have been carried out to elucidate cyclonerodiol (94) biosynthesis and the enzymatic conversion of farnesyl pyrophosphate into nerolidyl pyrophosphate (Vol. 10, pp. 5-7).
3 Bisabolane New bisabolane sesquiterpenoids from a variety of plant sources include (95)( 102).59-64E-y-Bisabolene-8,9-epoxide(1 03) has been isolated from the alga Laurenciu n i p p o n i ~ aThis . ~ ~ compound is possibly the precursor of various halogenated chamigranes which are abundant in Laurencia algae. Q $, . ,A @ ,n-
A
0
n
g
O
F Ang
pcH
0
0
(9359
(9Q5'
(97y0
P R
(98)''
I \ (99y2
(100)'3
(101)s4R (102) R
CH,OAc CHO
=
=
A low yield synthesis of p-bisabolene (104) has been achieved by reaction of (+)-limonene with acetic acid and acetic anhydride in the presence of manganese (111) acetate to give the acid (105) which could be converted into p-bisabolene in R. 0. Gould, T. J. Simpson, and M. D. Walkinshaw, Tetrahedron Lett., 1981, 22, 1047. D. E. Cane, R. Iyengar, and M.-S. Shiao, J . Am. Chem. Sac., 1981, 103,914; for an excellent review of the biosynthesis of sesquiterpenes see D. E. Cane, 'Biosynthesis of Isoprenoid Compounds', Vol. 1, ed. J. W. Porter and S . L. Spurgeon, John Wiley, New York, 1981, p. 283. 6 9 F. Bohlmann and J. Ziesche, Phytochemistry, 1981, 20, 469. Eo F. Bohlmann, M. Grenz, R. K. Gupta, A. K. Dhar, M . Ahmed, R. M . King, and H. Robinson, Phytochemistry, 1980 19, 2391. F. Bohlmann, A. Suwita, H. Robinson, and R. M. King, Phytochemistry, 1981, 20, 1887. 62 A. Rustaiyan, M. Dabiri, R. K. Gupta, and F. Bohlmann, Phytochemistry, 1981,20, 1429. Es F. Bohlmann, C. Zdero, H. Robinson, and R. M. King, Phytochemistry, 1981, 20, 2245. E4 F. Bohlmann, C. Zdero, R. M. King, and H. Robinson, Phytochemistry, 1981, 20, 2389. m T. Suzuki, H . Kikuchi, and E. Kurosawa, Chem. Lett., 1980, 1267. 67
68
89
Sesquiterpenoids
p Hpp R (108)
(109) R = CHO (1 10) R = CH20H
three steps.6sAnother synthesis of p-bisabolene involves the Carroll reaction of the keto-ester (106) with 2-methyl-3-buten-2-01 in the presence of aluminium isopropoxide to give the ketone (107) followed by methylenati~n.~' A simple synthesis of ( +)-a-bisabolol (108) and its C-8 epimer involves prenylation of ( +)-limonene with 2-methyl-3-buten-2-01in the presence of formic acid followed by hydrolysis of the derived formates.68A similar reaction with (-)-limonene gives the two enantiomeric bisabolols of which the (-)-a-isomer is a naturally occurring compound. Short syntheses of nuciferal(109)69and E-nuciferol(1 have also been recorded.
4 Sesquicamphane, Sesquipinane Two additional minor components of East Indian sandalwood oil have been identified as trans-p-santalol(ll1) (cf. Vol 11, ref. 48) and epi-cis-p-santalol(112).71 New syntheses in this area include those of cis-p-santalol (1 13) (Scheme 9),72
68
67
6s 70
72
N. Fukamiya, M. Oki, M. Okano, and T. Aratani, Chem. Ind., 1981, 96. T.-L. Ho, Synth. Commun., 1981, 11, 237. D. Babin, J.-D. Fourneron, and M. Julia, Tetrahedron, 1981, 37, Supplement No. 1, 1. L. Blanco, N. Slougui, G. Rousseau, and J. M. Conia, Tetrahedron Lett., 1981, 22, 645, J.-C.Depezay and Y. Le Merrer, Bull. Chim. SOC.France, 1981, 11-306. P.A. Christenson, N. Secord, and B. J. Willis, Phytochemistry, 1981, 20, 1139. K. Sato, 0. Miyamoto, S. Inoue, and K. Honda, Chem. Lett., 1981, 1183.
90
Terpenoids and Steroids
(1 13) Reagents: i, LDA; ii,
; iii, Bu',AlH; iv, PBr,; v, LiAIH,
Br TOAc
Scheme 9
1 vii
p, I
xii, v, vi
w
OSiMe,But
\viii,
ix
0
ii, xii
Aii-xv
.
Y*
xvii
+
(1 12) (115) (112) Reagents: i, A ; ii, H30+; iii, Ph,P=CMe,; iv, CrO,.py; v, NaNH,; vi, MeI; vii, Zn-TiC1,CH,Br,; viii, NMO-OSO,; ix, NaIO,; x, LiAlH,; xi, C1SiMe2Bu'-imidazole; xii, PCC; xiii, PPh,=CHMe; xiv, BuLi ; xv, CH,O ; xvi, (EtO),POC(Me)==CO,Et ; xvii, AlH,
Scheme 10
Sesquiterpenoids
+
0
CO2H 111I
& & + ii, iii
--L
I
'
91
C02H
OH Jiv
(116) Reagents: i, A; ii, Ra-Ni; iii, LiAlH,; iv, E u - H g ( O A c ) , , 135 "C;v, LiAlH,-AlCl,
Scheme 11
epi-p-santalene (1 14), epi-cis-p-santalol (1 12), epi-trans-P-santalol (1 15) (Scheme and p-santalene (1 16) (Scheme 1l).74A low yield synthesis of p-santalene (1 16) is realized in the final step of the last synthesis. The novel sesquiterpenoid, heterocurvistone (1 17) which belongs to the sesquicamphane group, has been isolated from the plant Heterotropa curvistigma.75
Its 2-oxabicyclo[2,2,2]octylskeleton bears a close resemblance to the monoterpene, cineole (118). The unique sesquiterpene albene (1 19) has been synthesized for a second time (Scheme 12).76 73
R. L. Snowden, P. Sonnay, and G. Ohloff, Helv. Chim. Acta, 1981, 64, 25
'' F.-M.Simmross and P. Weyerstahl, Liebigs Ann. Chem., 1981, 1089. 7s 76
M. Niwa, Y. Sugie, and S. Yamamura, Phytochemistry, 1981; 20, 11 37. J. E. Baldwin and T. C. Barden, J . Org. Chem., 1981, 46, 2442.
Terpenoids and Steroids
92
Reagents: i, MeLi; ii,
-PTSA; iii, Bu',AlH; iv, KOH; v, Ac,O-NaOAc; vi, Li-EtNH,
Scheme 12
5 Cuparane, Herbertane, Laurane, Trichothecane The direct geminal dimethylation of ketones using dimethyltitanium dichloride has provided an extremely simple synthesis of cuparene (120) from the ketone (l2l)." This efficient procedure should prove useful in other sesquiterpenoid syntheses in view of the fact that the gern-dimethyl group is a common feature in a number of such compounds. A new sesquiterpene, (-)-herbertene (122), has been
(120) (121) (122) isolated from the liverwort Herberta a d ~ n c aIn. ~view ~ o f the fact that (-)-cuparene is a known liverwort constituent, the genesis of herbertene by a 1,2-methyl migration of a cuparene-type precursor seems reasonable. Caraibical (123) has been isolated from the red algal species Laurencia caraibica and it is closely related to the bicyclic compound (124) found in the same alga.79 Intense interest in the trichothecane sesquiterpenoids has continued unabated on two fronts. The first concerns the conflicting reportsso of the possible use of mycotoxins of this class of sesquiterpenoid as fungal warfare agents ('yellow rain') in Kampuchea and Laos. The second area of research centres around the total synthesis of trichothecane sesquiterpenoids, although it should be pointed out that phase TI clinical trials with anguidine (125) as an antitumour drug appear to be disappointings1 thus possibly taking the edge off the synthetic impetus. 77
'I3 7s
8o
M. T. Reetz, J. Westermann, and R. Steinbach, J. Chem. Sac., Chem. Commun., 1981, 237. A. Matsuo, S. Yuki, M. Nakayama, and S. Hayashi, J. Chem. SOC.,Chem. Commun., 1981,864. R. R. Izac, J. S. Drage, and J. J. Sirns, Tetrahedron Lett., 1981, 22, 1799. Chem. Eng. News, 1981, Sept.21, p. 7; Oct. 26, p. 15; Nov. 16, p. 10; Dec. 14, p. 21. Chem. Eng. News, 1981, Nov. 30, p. 29.
93
Sesquiterpenoids
..-OH
(126) R (127) R
=0 = CH2
(128) R = 0 (129) R = CH,
Full details of the neat synthesis of the ketone (126) and its methylenation to give trichodiene (1 27) have been published.82 Unfortunately, sixteen attempts with different reagents to carry out a similar methylenation of the diastereoisomeric ketone (128) to give bazzanene (129) failed. A number of new and very interesting trichothecane sesquiterpenoids have been isolated from Myrothecium verrucuriu. These include trichodermadienediol A (130), trichoverrol A (1 3 I), and trichoverrin A (132) together with their B counterparts which are epimeric at C-7’.83 The trichoverrins are clearly biosynthetic intermediates of the more toxic macrocyclic
>OH
h
(130) R (131) R
= =
H OH
trichothecanes and indeed incubation of these two compounds gives rise to verrucarin A (133) and B (134) with smaller amounts of roridin A (135) and isororidin E (1 36). In these experiments each recovered trichoverrin is uncontaminated with its epimer, suggesting that each undergoes conversion into the macrocyclic compounds via a common intermediate. In an elegant piece of carbohydrate chemistry Tulshian and Fraser-Reida4 have synthesized the C-4 octadienic methyl esters derived by methanolysis of the six metabolites isolated by Jarvis et al.83 As shown in Scheme 13 S. C. Welch, A. S. C. Prakasa Rao, C. G. Gibbs, and R. Y. Wong, J . Org. Chem., 1980, 45,
84
4077. B. B. Jarvis, G. Pananasasivam, C. E. Lolmlund, T. DeSilva, G. P. Stahly, and E. P. Mazzola, J. Am. Chem. SOC.,1981,103,472. D. B. Tulshian and B. Fraser-Reid, J . Am. Chem. SOC.,1981, 103, 474.
Terpenoids and Steroids
94
HO---
Me’
CH ‘OH
Me’
CH ‘OH
__j
(137) liii
OH A c o y O j
AcO (139)
__3 __3
C0,Me (140)
H
C0,Me O -C (138)
Reagents: i , HgS0,-H,O+; ii, MeSiCH(Li)CO,Me; iii, NaOMe
Scheme 13
the syntheses start from the carbohydrate precursors (137) and (139). Whereas the glucal (137) gives the D-erythro-ester (138) identical in all respects with the compound derived from the B series of metabolites, the galactal (139) produces the D-threo-ester (140) which is enantiomeric with respect to the compound obtained from the A series of metabolites. Coupling of the THP ether of verrucarol(l41) with the acid (142) followed by deprotection and lactonization by the Corey-Mukaiyama procedure has produced the verrucarin A derivative (143).85 E.-A. Notegen, M . Tori, and C. Tamm, Helv. Chim. Acfu 1981, 64, 316.
Sesquiterpenoids
95
~ T H P
oq J.
vii
OMe
o%
OMe
hii-x
yy& qJ-& XI, XI1
OMe
OMe
(14) Reagents: i, NaBH,; ii, SOC1,-py; iii, Bu', AlH; iv, VO(acac),-Bu'OOH; v, MeI-NaH; + vi, Me,N--O; vii, H,O+; viii, MeLi; ix, Cr0,-py; x, POCl,-py; xi, Ph,P=CH,; xii, MCPBA
Scheme 14
96
Terpenoids and Steroids
C0,Me (145) Jii, iii
IV-VI
f--
Me0,C i
(146) (147) Reagents: i, A ; ii, (CH,OH),-PTSA; iii, Me,CuLi; iv, LDA; HC=CH; piii, Bu',AlH; ix, Ac,O-py; x, H,O+ Scheme 15
HO W
M
e
v, vi
V,
PhSeC1; vi, H,O,; vii hv-
O
~
+ I
*
Me0,C
I
Me0,C
j
.
i
bii,viii, i
(148)
(149)
Reagents: i, A ; ii, Me,CuLi; iii, Bu',AlH; iv, H,O+; v, MeOH-H+; vi, MeMgI, vii, H + ; viii, Ac,O-py
Scheme 16
H
Sesquiterpenoids
97
---+ OH
Me0,C
(145)
-@ -qo i v , vi
Qo
Ho
vii-ix
x, x i
0
OMe Me0,C
HO’
Me0,C
(150) Reagents: i, A; ii, Me,CuLi; iii, LDA; iv, MoO,*py.HMPA; v, NCS-Me,S; vi, Et,N; vii, NaH-Mel; viii, Bu’,AlH; ix, Et,SiH-BF,-Et,O; x, LiAlH,; xi, H +
Scheme 17
F
o
A
c
+
O + J
+ ii, iii
2 HO’
ButMe,SiO jiv, v
f--
CHO HO’
ButMe,SiO’
ButMe,SiO’
(151) Reagents: i, B(OAc),; ii, Bu‘Me,SiCI-imidazole; iii, K,C03-MeOH; iv, NCCH,COCl-py ; v, DBN; vi, Bu’,AIH; vii, Et,SiH-BF,*Et,O; viii, NaCIO,; ix, Et,N-ClC0,Et-NaN,; x,A-OH-; xi, Bu,NF Scheme 18
Ho :
R (152) R
(154) R
= =
H
Me
(153)
0
/
0 (155)
Pearson and Ongas have extended their route to trichothecane sesquiterpenoids via organoiron complexes by the synthesis of (144) (Scheme 14). The Diels-Alder approach to the construction of the cis-fused AB ring junction of the trichothecanes has been much in evidence. The use of methyl coumalate (145) as a 66
A. J. Pearson and C. W. Ong, J . Am. Chem. Soc., 1981.103,6686; Tetrahedron Lett., 1980,21, 4641.
Terp'enoids and Steroids
98
dienophile features in three independent ~ y n t h e s e s . * ~In- ~the ~ first of theses7 (Scheme 15) the subsequent addition of the C ring involves a novel cyclobutenylcarbinol-cyclopentenyl rearrangement, ( 146)+( 147). A second synthesisss using (145) (Scheme 16) achieves the conversion into (148) which has previously been transformed into (149). Finally, a third routesQinvolving (145) (Scheme 17) has been used to synthesize (1 50) which unfortunately has the endocyclic double bond in the wrong position. The desired isomer (1 5 1) can be synthesized by a different
*Q -
OPP
Diels-Alder-based strategy (Scheme 1Q g O An analogous route has also been explored by Miller et aLQ1who obtained the acetoxy-aldehyde (152) from the Diels-Alder reaction of 3-methylbuta- 1,3-dienyl acetate with 2-methylprop-2-enal. Cyclization of (1 52) with sodium hydride gave the coumarin derivative (1 53). Unfortunately, cyclization of the corresponding methyl ketone (154) yielded the chromanone derivative (155) and not the methyl analogue of (153). Cane et al.92have re-examined the biosynthesis of trichodiene (127) by incubation of tran~,trans[l-~H,,l2,1 3-14C]farnesylpyrophosphate (1 56) [3H/14Catom ratio 2 :21 with a cell-free extract of Trichotlzecium roseum. A crystalline derivative of the trans-diol derived from the endocyclic double bond of labelled trichodiene had a
\OPP
Scheme 19 J. D. White, T. Matsui, and J. A. Thomas, J . Org. Chem., 1981, 46, 3376. Y . Nakahara and T. Tatsuno, Chem. Pharm. Bull., 1980, 28, 1981. G. A. Kraus and K. Frazier, J . Org. Chem., 1980, 45,4820. G . A. Kraus and B. Roth, J . Org. Chem., 1980, 45,4825. 91 R. E. Banks, J. A. Miller, M. J. Nunn, P. Stanley, T. J. R . Weakley, and Z. Ullah, J . Chem. SOC.,Perkin Trans. 1, 1981, 1096. 82 D. E. Cane, S . Swanson, and P. P. N. Murthy, J . Am. Chem. SOC.,1981, 103, 2136. n7
nn
Sesquiterpenoids
99
(159) R (160) R
= =
OH H
3H/14C atom ratio of 1.8 :2 demonstrating that practically no loss of hydrogen from C-1 of the precursor had occurred. This result is at variance with an earlier result by Hanson and co-workers who claimed that loss of a C-1 hydrogen did occur in this biosynthesis. Furthermore degradation of the labelled trichodiene clearly established the position of the two tritium atoms as shown in (157). Cane's present evidence, together with other findings in monoterpene and sesquiterpene biosynthesis, strongly indicates that the biosynthesis of trichodiene (127) can be viewed as shown in Scheme 19 with the involvement of nerolidyl pyrophosphate (158).58 Full details of two of the elegant syntheses of gymnomitrol (159)93794 and gymnomitrene (160)94have been published.
6 Chamigrane, Widdrane Full details of an earlier synthesis of chamigrene (161) have been published.95 Further work on the components of the red alga Laurencia nipponica Yamada has resulted in the isolation and structural elucidation (by X-ray analysis) of the diol (162)96and spironippol (164).97The biogenesis of the latter compound can be viewed in terms of an intramolecular cyclization of the diol(l63) derivable from the naturally occurring epoxide of 1O-bromo-a-chamigrene.
(163) O4 O5
(164)
L. A. Paquette and Y.-K. Han, J. Am. Chem SOC.,1981, 103, 1831. S. C. Welch, S. Chayabunjonglerd, and A. S. C. Prakasa Rao, J. Org. Chem., 1980, 45,4086. J. D. White, J. F. Ruppert, M. A. Avery, S. Torii, and J. Nokami, J. Am. Chem. SOC.,1981,103, 1813.
O6
*'
K. Kurata, A. Furusaki, C. Katayama, H. Kikuchi, and T. Suzuki, Chem. Lett., 1981, 773. A. Fukuzawa, C. M. Shea, T. Masamune, A. Furusaki, C. Katayama, and T. Matsumoto, TetrahedronLett., 1981, 22, 4087.
Terpenoids and Steroids
100
An ingenious synthesis of widdrol (167) has been developedg8in which a key step is the Claisen rearrangement of the vinyl lactone enolate (165) to give the acid (166) (Scheme 20). This process proceeds via a boat-like transition state thus controlling the relative stereochemistries of the two quaternary methyl groups at C-4 and C-7.
b-vii
xiii, xi;
. O \i
0
A xv xvi
Lo
m
o
z
H
OSiMe,But
(165)
(166) Lrvii, xviii, ii
(1 67) Reagents : MeC(OEt),-EtC0,H; ii, LiAlH,; iii, MsC1-py; iv, NaI; v, NaH-CH,(CO,Me),; vi, MeOH-OH-; vii, A-py; viii, NBS; ix, MCPBA-TBP; x, Zn-MeOH; xi, OH-; xii, TFA; +xiii, LDA-MeI; xiv, LDA-Bu'Me,SiCl; xv, 110 "C; xvi, Bu,NF; xvii, SOCI,; xviii, MCPBA
Scheme 20
7 Acorane, Carotane, Cedrane, Zizaane Previously it had been shown that low temperature irradiation of the enone (168) gave the tricyclic ketone (169) as the major product. It has now been reportedgg that further photolysis of (169) at 0-5 "C promotes a Norrish type I1 process to give the ketone (170) which can be converted into oc-acoradiene (171). Epimerization of the isopropenyl group in (170) can be achieved by silver nitrate, thus paving the way for a synthesis of acorenone B (172). Pertinent to these results is the finding 98
S. Danishefsky and K. Tsuzuki, J . Am. Chem. SOC.,1980,102,6891. D. D. K. Manh, J. Ecoto, M. Fetizon, H. Colin, and J.-C. Diez-Masa, J . Chem. SOC.,Chem. Commun., 1981, 953.
Sesquiterpenoids
101
by Oppolzer et al.loOthat photocycloaddition of (173) gives (174) which then undergoes reductive ring-opening with lithium in liquid ammonia to produce the spiroketone (175). Full details of an alternative strategy for the synthesis of acorenone B (172) have been presented.95Another interesting approach to this class of sesquiterpenoid is that adopted by Ficini et al.lol in which the spiroannelation step is achieved by reaction of the enol lactone (176) with the ynamine (177) to give (178). Me
P p loo
lol
P
W. Oppolzer, L. Gorrichon, and T. G. C.Bird, Helv. Chim. Acra, 1981, 64, 186. J. Ficini, G. Revial, and J. P. GenCt, Tetrahedron Lett., 1981, 22, 629, 633.
Terpenoids and Steroids
102
The stereoselectivity of this reaction can be rationalized in terms of cyclization of the intermediate (179). A double Wittig reaction transforms (178) into (180). Hydrolysis of this enamine gives the enone (1 8 1) which can be isomerized by PTSA to produce (182). The synthesis of acoradiene I11 (183) was finally completed by reduction to the allylic alcohol followed by a further reduction of the derived diethyl phosphate. A full paper on the interesting rearrangement of carotol (184) with tluonyl chloride in pyridine to give the acoradienes (183) and (185) has been published.lo2Similar treatment of dihydrocarotol does not give rearranged products, thus indicating that the double bond in carotol is essential for migration to occur. It has been claimed that (186) is a new carotane derivative isolated from the Compositae species Inula ~rithrn0ides.l~~ There is little doubt, however, that this compound is in fact vaginatin, first reported in 1968.1°4 The first cedrene synthesis by Stork and Clarkelo5 over twenty years ago was achieved via the tricyclic dione (187). This compound has now been synthesized by
(1 87) Reagents: i, h v ; ii, Me,CuLi, iii, NaCI-H,O-DMSO; vi, H2-Pt; vii, Bu'OK Scheme 21
iv, H C r CLi; v, HC0,H-H2S0,;
L. H. Zalkow, M. G. Clover, Jr., M. M. Gordon, and L. T. Gelbaum, J . Nut. Products, 1980, 43, 382. 103 2. F. Mahmoud, N. A. Abdel Salam, T. M. Sarg, and F. Bohlmann, Phytochemisrry, 1981, 20, 735. lo4 K. Rajendran, S. K. Paknikar, G. K. Trivedi, and S. C. Bhattacharyya, Indian J. Chem., Sect. B, 1978,16,4; C. K. Mesta, S. K. Paknikar, and S. C. Bhattacharyya, Chem. Commun., 1968, 584. lo5 G. Stork and F. H. Clarke, Jr., J . Am. Chem. Soc., 1955, 77, 1072; 1961, 83, 31 14. lo2
Sesquiterpenoids
103
an entirely new route (Scheme 21).lo6A very ingenious short synthesis of cedrene (191) has been announced, which differs totally from previous syntheses in its conception (Scheme 22).Io7The success of this synthesis hinged upon a detailed
(191)
( 190)
t 189)
Reagents: i, Li-NH,-NH,CI; ii, h v ; iii, Br,; iv, Bun,SnH; v, NH,NH,-OH-
Scheme 22
mechanistic consideration of the intramolecular photochemical cycloaddition of the arene-alkene (188) in terms of regioselectivity and stereoselectivity. These considerations led Wender and Howbert to predict accurately the outcome of this reaction which produces two, (189) and (190), of the thirty-six possible cycloadducts. On thermolysis, perezone (192) undergoes a [4 +2] cycloaddition to produce equal amounts of the two pipitzols (193) and (194) i.e. there is no stereochemical induction by the chiral centre in (192). If, however, the reaction is carried at 0 "C in the presence of boron trifluoride etherate the cyclization becomes highly stereoselective producing largely a-pipitzol (193) and it has been shown that a stepwise mechanism ( 1 9 9 4196)+( 193) is operative in thls case.loS A previously uncharacterized sesquiterpene, a-duprezianene (197), has been isolated from Cupressus dupreziana and has been assigned this structure on the basis of spectral data together with its co-occurrence with ( +)-a-funebrene (198).Io9Scheme 23 illustrates a possible biogenetic relationship between these two hydrocarbons. (-)-Prezizanol(201) and ( -)-prezizaene (202) have been synthesized starting from the cyclopentanone derivative (199) which can be derived in three steps from ( +)-pulegone (Scheme 24).llo The drawback in this synthesis is that the diazo-ketone derived from (200) also gives an almost equal amount of an isomeric tricyclic ketone by insertion into the alternative methylene group. Recently the K. E. Stevens and P. Yates, J. Chem. SOC.,Chem. Commun., 1980, 990. P. A. Wender and J. J. Howbert, J . Am. Chem. SOC.,1981, 103,688. l o 8 I. H. Sanchez, R. Yaiiez, R. Enriquez, and P. Joseph-Nathan, J . Org. Chem., 1981, 46, 2818. l o B J. K. Kirtany and S. K. Paknikar, Indian J . Chem., Sect. B, 1981, 20, 506. 1 l 0 P. R. Vettel and R. M. Coates, J. Org. Chem., 1980, 45, 5430. log
lo7
Terpenoids and Steroids
104
0
P
a H
i
(??-
(-fJ H
(198)
(197) Scheme 23
prezizaene alcohol, jinkohol, has been ascribed the structure (2O3).l1l This is the same structure as that put forward for ( +)-allokhusiol,'12 although the Japanese workers seemed to be unaware of this. There is a very close similarity in the spectral data for the two compounds except for the optical rotations ([.ID of jinkohol claim that jinkohol (203) -6..l', [aID of allokhusiol +45'). Nakanishi et is not identical to the enantiomer of (201) ([aID -48.3') isolated by Carrol et al.l13 some years ago. Ganguly et also made the same claim about the non-identical *I2 113
T. Nakanishi, E. Yamagata, K. Yoneda, and 1. Miura, Phytochemistry, 1981, 20, 1597. R. N. Ganguly, G . K . Trivedi, and S. C. Bhattacharyya, Indian J. Chem., Sect. B, 1978, 16,20. P. J. Carrol, E. L. Ghisalberti, and D. E. Ralph, Phytochernistry, 1976, 15, 777.
Sesquiterpenoids
105
Jvi, vii, v
xi t
H
VIII-x
t
H
(20 1)
(202)
Reagents: i, MVK-Et,N; ii, Q - H O A c ; iii, H,-Pd/C; iv, (CH,OH),-H+; v, LiAlH,; H vi, MsCl-Et,N; vii, NaCN-Et,NCl; viii, PhCOCl; ix, H,O+; x, N,O,; xi, KOBu'; xii, KH-MeI; xiii, MeLi
Scheme 24
mirror image relationship of ( +)-allokhusiol and Carrol's alcohol, but considered (+)-allokhusiol to be the enantiomer of Tomita's alcohol ( [ Q ] ~4 6 . 2 " ) derived from solvolysis of the brosylate of allocedrol (2O4).ll4 Carrol et al., however, claimed that their alcohol was identical to Tomita's alcohol and thus there is some confusion in the literature concerning the structures of the four ( ?) tricyclic alcohols. Further work needs to be done with these compounds to clarify the situation. One of the original syntheses of zizaene (210) utilized the tricyclic ketone (209) as a key intermediate. A third synthesis of this compound has now been accomplished (Scheme 25)115 by an internal photochemical cycloaddition of (205) to give (206) as the major product. A subsequent Grob fragmentation of the P-alkoxide derived from (207) gave (208) from which the ketone (209) (together with its methyl epimer) could be derived by hydrogenation.
114 115
B. Tomita and Y . Hirose, Phytochemistry, 1973, 12, 1409. A. J. Barker and G . Pattenden, Tetrahedron Lett., 1981, 22, 2599.
Terpenoids and Steroids
106
AcO
c&
ii iii
+ 1
A
Reagents: i, h v ; ii, NaBH,; iii, MsC1-py; iv, NaOH; v, H,-Pd/C
Scheme 25
8 Cadinane, Cubebane, Oplopanane, Picrotoxane, Sativane, Copacamphane
A detailed n.m.r. investigation has provided further confirmation of the structures of torreyol (21 l), a-cadinol (212), T-muurolol (213), and T-cadinol (214).l16 New additions to this group of sesquiterpenoid include the ageraphorones (215)(219) (Ageratina adenophora)l17 and the muurolane-type acid (220) (Trichogonia grazielae).lls The phenolic cadinanes (221)-(224) have been isolated from Bombax malabaricum.llg The two hydroxy-cadalenes (225) and (226) have been detected in green and field-dried cotton bracts.120Autoxidation of these compounds leads to lacinilene C (227) and its methyl ether. The latter has been implicated in the chronic respiratory disease, byssinosis.
A.-K. Borg-Karlson, T. Norin, and A. Talvitie, Tetrahedron, 1981, 37, 425. F. Bohlmann and R. K. Gupta, Phytochemistry, 1981, 20, 1432. 118 F. Bohlmann, C. Zdero, J. Pickard, H. Robinson, and R. M. King, Phytochemistry, 1981, 20, 1323. 119 A. V. B. Sankaram; N. S. Reddy, and J. N. Shoolery, Phytochemistry, 1981, 20, 1877. no R. D. Stipanovic, G. A. Greenblatt, R. C. Beier, and A. A. Bell, Phytochemistry, 1981, 20,729. 11'
Sesquiterpenoids
107
H :
A
(215) R (216) R
=H = OH
(217) R (218) R
A
0 = P-OH, H =
OR1 CHO
CHO
R20q Hod Ho
HOaC
(221) R1= Me, R2 = H (222) R1= R2 = Me
\
/
\
A
/
A
(224)
(225) R (226) R
= =
(227)
H Me
The sesquiterpenoids (228)-(234), previously isolated from Heterotheca species, have all been synthesized.121 Further work on the photoadduct (235) derived from methyl cyclobutenecarboxylate and ( -)-piperitone has demonstrated the important synthetic utility of this compound.122Flash vacuum pyrolysis of (235) at 500 "Cgives (236)-(240). Additional thermolysis experiments showed that (237) and (238) are the precursors of (236) and that this compound undergoes a further
(228) R (229) R
= =
H Me
(231) R (232) R
\
lal
19z
CH20H CO,H
Hod \
A
= =
A
F. Bohlmann and W. Mailahn, Chem. Ber., 1981, 114, 1091. J. R. CIiIliams and 1. F. Callahan, J. Org. Chem., 1980, 45, 4479.
Terpenoids and Steroids
108
intramolecular ene reaction to form (240) which has been chemically converted into ( +)-isocalamendiol(241). The epimeric mixture of bicyclic enones (242) which have previously been converted into epizonarene (243) has been synthesized (Scheme 26).123A similar type of intramolecular Diels-Alder methodology has been used to
+
--+ Li+
A
l i i , iii
iv t--
(243)
(242)
Reagents: i, 180 "C;ii, RaNi; iii, Cr0,-H+; iv, PTSA
Scheme 26
convert the acyclic enone (244) into the octalone (245), which, on treatment with N-methylanilinium trifluoroacetate and paraformaldehyde, gave (246).lZ4This is 123
12'
S. R. Wilson and R. N. Misra, J . Org. Chem., 1980, 45, 5079. J.-L. Gras, J . Org. Chem., 1981, 46, 3738.
109
Sesquiterpenoids
0 (244)
(245) (246)
R R
= H2 = CH,
(247)
/
the structure originally assigned to chiloscyphone but since the synthetic and natural materials are not identical, the structure of natural chiloscyphone must be in error. Another variant of the intramolecular Diels-Alder reaction, this time using
Reagents: i, EtMgBr-DMF; ii, Me,SiCN-ZnI,; iii, Bu"Li; iv, MeCH=CHCO,Bu'; v, F-; vi, H,-Pd/C-HClO,; vii, PPE; viii, MeC(OAc)=CH,-H+; ix o-chloranil; x, NaBH,; xi, A ; xii, Me,SO,-OHScheme 27
110
Terpenoids and Steroids
a benzyne intermediate, has been devised for the synthesis of mansonone E (249).126 Thus, generation of the substituted benzyne (247) from the corresponding anthranilic acid spontaneously cyclizes to produce (248), which could be converted into mansonone E (249) by standard means. Gossypol(250) is a well known constituent of cottonseed pigment, and recently considerable interest has been generated in this compound because of the reported male contraceptive properties of its acetate and formate. A reasonably efficient synthesis of the nor-gossypol derivative (252) from the bromobenzene (25 1) has been recorded (Scheme 27).lZ6Attempts to synthesise the interesting cadinane sesquiterpenoid, arteannuin B (253), have been made
but the principal route used (Scheme 28) has only produced the stereoisomers (254)-(256) none of which is identical to the natural product.lZ7 A re-investigation of the brown alga Dictyopteris diuaricata has resulted in the identification of the new alcohol, epicubebol (257) together with the known
ii-iii
+
+ 0
0 ~\ 0 (254)
0
0 : \ 0 (255)
q H i
H i
0
(256)
Reagents: i, CH,=C(Li)C(OEt),; ii, H,O+; iii, Me$-NBS; iv, Zn/Cu; v, MCPBA
Scheme 28 lZ5 IZ6
12'
W. M. Best and D. Wege, Tetrahedron Lett., 1981, 22,4877. M. C. Venuti, J . Org. Chem., 1981, 46, 3124. 0. Goldberg, I. Deja, M . Rey, and A. S. Dreiding, Helv. Chim. Acta, 1980, 63, 2455.
111
Sesquiterpenoids
(258) A3*4 (259) A49I5
(257)
0
\
H
(26 1)
(262)
(263) compounds, ( -)-a-cubebene (258), ( -)-p-cubebene (259), epicubenol (260), cubenol (261), and ( +)-8-cadinene (262).12* Several new oplopanane sesquiterpenoids, exemplified by implexin (263), have been isolated from various Senecio s p e ~ i e s . ~ ~ Another ~ J ~ O synthesis of oplopanone (264) has been recorded (Scheme 29).131 In a continuation of his work on dendrobine synthesis, R o u s ~ Ihas ~ ~found that the intramolecular Diels-Alder reaction of the diene-ester (265) gives predominantly the bicyclic compound (266). This was an unexpected result because
viii-x
vi, vii
f--
0 (264) Reagents: i, Li-NH,-Bu'OH; ii, BunLi; iii, Me,C=CH(CH,),Br ; iv, HCl; v, Ac,O-HOAc+-
HC10,; vi, KOH-MeOH; vii, Me,SCH,; viii, LiAlH,; ix, 0,; x, KOBu' Scheme 29 M. Suzuki, N. Kowata, and E. Kurosawa, Bull. Chem. SOC.Jpn., 1981, 54, 2366. l Z 9F. Bohlmann, M. Ahmed, J. Jakupovic, and C. Jeffery,Phytochemistry, 1981, 20, 251. 130 F. Bohlmann, C. Zdero, and R. K. Gupta, Phytochemistry, 1981, 20, 2924. lS1 F.-H. Koster and H. Wolf, TetrahedronLett., 1981, 22, 3937. 132 W. R. Roush and H. R. Gillis, J. Org. Chem., 1980, 45,4283. 12*
Terpenoids and Steroids
112
the stereochemistry of the product indicates that a kinetically controlled e m addition has been favoured in this case. Hydrolysis of (266) gives the keto-ester (267) which has previously been used for the synthesis of dendrobine (268) (Vol. 11, p. 32).
vii
t-
MesSiO
C02Me h i i , ix, iv, x
A
i , xi, xii
c xiii
OSiMe2But
OSiMe,But
'
OSiMe,But
biv-xvi,
iv
(269) Reagents: i , LDA; i i , [ O F 1 ; iii, MeLi; iv, H,O+; v, (MeO),P(O)CHCO,Me; vi ZnC1,0 Me,SiCl-Et,N; vii, I10 "C; viii, (CH,OH),-H+; ix, LiAlH,; x, Bu'Me,SiCI; xi, Me3SiC1; xii, Zn/Cu-CH,I,; xiii, Feel,; xiv, H,-Pd/C; xv, Me,C=PPh,; xvi, H,-PtO, ; xvii, Bu3Pa0,NArSeCN-py; xviii, H,02 Scheme 30
Sesquiterpenoids
113
viii, ii, ix, v
S0,Ph %l
I
x-xiii
(270) Reagents: i, LiBr; ii, NaCN; iii, PhSCl; iv, Bu',AlH; v, H,O+; vi, LiBHEt,; vii, MCPBA; viii, MsCI-Et,N; ix, MeOH-H+; x, KN(SiMe,)2; xi, LiAlH,; xii, Li-EtNH,; xiii, CrO;py,; xiv, Ph,P=CHOMe; xv, K,CO,-MeOH; xvi, MeLi ; xvii, Ph,P=CH,; xviii, H2-(Ph,P),RhC1
Scheme 31
A very neat synthesis of sativene (269) has been reported by S n ~ w d e n(Scheme l~~ 30) which yet again illustrates the considerable synthetic advantages of the intramolecular [4 +21 cycloaddition. Heissler and RiehP3*have extended their methodology of homoconjugate addition of phenylsulphenyl chloride to methylenenorbornenes for the construction of tricyclene derivatives (Vol. 10, p. 18) to the synthesis of cyclosativene (270) (Scheme 31). They have also synthesised the
(274). laa
R. L. Snowden, Tetrahedron Lett., 1981, 22, 97, 101. D. Heissler and J.-J. Riehl, Tetrahedron Lett., 1980, 21, 4707
(275)
114
Terpenoids and Steroids
C,, hydrocarbon (271)135by a similar route but this compound is not identical to a tricyclic hydrocarbon isolated from East Indian sandalwood oil and reported to have this structure. (+)-Copacamphor (272) and ( +)-copaborneol(273) have been isolated from Espeltiupsis g u a c h a r a ~ aThe . ~ ~interesting ~ sinularene derivative (274) and the acetoxycyclosinularane (275) have been isolated from the marine source, Clavularia i n 3 ~ a t a .These l ~ ~ compounds, together with an aromadendrane derivative (see p. 18 1) are the first sesquiterpenoids from Octocorallia of the order Stolonifera. 9 Himachalane, Longifolane, Longipinane a- (278) and p-Himachalene (279) have been synthesized (Scheme 32).138 This route is not particularly attractive in view of the low yield (12%) at the isomerization step (276)+(277). The himachalenes can be converted into ar-himachalene (280) with 5 % palladium on carbon and various himachalenes with trans ring fusion can be prepared by treatment of the himachalenes with hydrochloric acid followed by base-induced dehydroch10rination.l~~ The lzlmachalanolide (281)
Me02C
Me0,C __+
H
a Jiv, v
~
2Et
vi
\
H
H
(278)
H
(279)
Reagents: j, SnCI,; ii, Et,SiH-(Ph,P),RhCI; iii, aq. K,CO,; iv, LiI-collidine; v, N,CHCO,EtBF,.Et,O; vi, PTSA; vii, MeLi; viii, POCI,-py
Scheme 32 135
136
13'
138 139
D. Heissler and J.-J. Riehl, Tetrahedron Lett., 1980, 21, 471 1. F. Bohlmann, H. Suding, J. Cuatrecasas, H. Robinson, and R. M. King, Phyruchemistry, 1980, 19, 2399. J. C. Braekman, D. Daloze, A. Dupont, B. Tursch, J. P. Declercq, G. Germain, and M. Van Meerssche, Tetrahedron, 1981, 37, 179. H.-J. Liu and E. N. C. Browne, Can. J. Chem., 1981, 59, 601. J. Daunis, R. Jacquier, H. Lopez, and P. Viallefont, J . Chem. Res. ( S ) , 1981,45; A. B. Harref, A. Bernardini, S. Fkih-Tetouani, R. Jacquier, and P. Viallefont, ibid., 1981,372.
Sesquiterpenoids
115
has been isolated from Acritopappus Z ~ n g i f o l i u s and ~ ~ ~ the seco-himachalane derivative, himasecolone (282), from Cedrus deodara.141 Over the past 25 years longifolene (283) has been the focus of many aspects of chemical research-synthesis, molecular rearrangements, transannular reactions, and biosynthesis. All these and other details of longifolene chemistry have been thoroughly reviewed by Sukh Dev142who himself has made many major contributions in this area of natural product chemistry. (+)-Longifolene can be converted into crystalline di10ngifolylborane.l~~ This chiral dialkylborane can
(280)
(28 1)
(282)
be used for the asymmetric hydroboration of cis-disubstituted, trisubstituted acyclic, and cyclic prochiral olefins to provide alcohols with optical purities in the range of 60-78% enantiomeric excess. In the cases studied to date the predominant alcohol is of the R-configuration. An X-ray analysis of rastevione, the main constituent of the roots of Stevia serrata and S . rhombifolia, has revealed it to have structure (284).144This definitive assignment calls into question the relative stereochemistry assigned to more than fifteen other longipinene and longipinane derivatives isolated from various plant sources (see Vol. 7, p. 75, Vol. 9, p. 110, Vol. 10, p. 34). The tiglate (285) has been isolated from Eupatoriadelphusp ~ r p u r e u s . ~ ~ ~
I
(283)
10 Caryophyllane, Humulane, and Related Sesquiterpenoids Force field calculations have been applied to caryophyllene and four basic conformers (286)-(289) have been identified of which (286) and (288) contribute 75 % and 2 1 % re~pective1y.l~~ The energy barrier to conformational interconversion at 35 "C F. Bohlmann, R. K. Gupta, H. Robinson, and R. M. King, Phytochemistry, 1981, 20, 275. P. K. Agarwal and R. P. Rastogi, Phytochemistry, 1981, 20, 1319. 14* S. Dev, Acc. Chem. Res., 1981, 14, 82; S. Dev in 'Progress in Chemistry of Organic Natural Products', ed. W. Herz, H. Grisebach, and G. W. Kirby, Springer-Verlag, Wein, 1981, Vol. 40 p. 49. 143 P. K. Jadhav and H. C. Brown, J . Org. Chem., 1981, 46,2988. lQ4L. U. Roman, R. E. del Rio, J. D. Hernindez, P. Joseph-Nathan, V. Zabel, and W. H. Watson, Tetrahedron, 1981, 37, 2769. lQ6 F. Bohlmann, M. &hmed, R. M. King, and H. Robinson, Phytochemistry, 1981,20, 2027. 146 H. Shirahama, E. Osawa, B. R. Chhabra, T. Shimokawa,T. Yokono, T. Kanaiwa, T. Amiya, and T. Matsumoto, Tetrahedron Lett., 1981, 22, 1527.
lQo lQ1
Terpenoids and Steroids
116
U (290)
Hd
n
jgco2H jf--J-.. H"
H'
(297) R (298) R
(300)151
= =
(299)
H150
OAcl5'
(301)152
has been calculated to be 16.25 kcal mol-1 based on a line shape analysis of certain peaks in the 13C n.m.r. spectrum. This leads to the conclusion that the two conformers (286) and (287) contribute 76% to the population equilibrium while conformers (288) and (289) contribute 24 %. The barriers to the interconversion of (286) and (287) and to (288) and (289) will be very small and it is interesting to note that earlier clearly indicated that conformer (287) leads to clovene (290) and conformer (288) to P-caryophyllene alcohol (29 1) on acid-catalysed rearrangement of caryophyllene. Various oxygenated caryophyllene derivatives (292)--(301)148-152 have been identified as constituents in a number of plant species. The number of sesquiterpenoids which can be formally derived from a caryophyllene-type precursor has risen quite dramatically in the last few years and includes the following structural types :147
148 149
l50 151
152
A. Nickon, F. Y. Edarnura, T. Iwadare, K . Matsuo, F. J. McGuire, and J. S. Roberts, J . Am. Chem. Soc., 1968,90,4196. F.Bohlmann, U.Fritz, R. M. Kinf, and H. Robinson, Phytochemistry, 1980, 19, 2655. F.Bohlmann and R. Bohlmann, Phytochemistry, 1980, 19, 2469. F. Bohlmann, C.Zdero, H. Robinson, and R. M. King, Phytochemistry, 1980, 19, 2381. F. Bohlrnann, A. K. Dhar, J. Jakupovic, R. M. King, and H. Robinson, Phytochemistry, 1981, 20, 1425. F. Bohlmann, L. Miiller, R. M. King, and H. Robinson, Phytochemistry, 1981, 20, 1149.
Sesquiterpenoids
117
Neoclovane
Panasinsane
Quadrane
Koraiane
Silphiperfolane
Presilphiperfolane
Isocomane
Modhephane
Senoxydane
Silphinane
Botrydiane
Senecrassiane
A new addition to this ever-growing group is senecrassidiol (302) which has been isolated from Senecio crassissirnus and it has been suggested that this compound with its unusual cis ring fusion may be formed from the co-metabolite (303) by transannular hydration.59Previously Bohlmann and Z d e r ~had l ~ identified ~ the rare epi-caryophyllene (304) in Euryops brevipapposus and converted it into
(303) by epoxidation. Another new skeleton is seen in the structure of 8-hydroxypresilphiperfolene (305), isolated from Eriophyllum staechadiJ~Ziurn.~~~ This interesting tricyclic alcohol is the missing link in the proposed biogenesis of the silphinane and silphiperfolane sesquiterpenoids from caryophyllene (Vol. 11, p. 50) The silphiperfolene derivative (306) has also been identified recently in Espeletiopsis g u ~ c h a r a c a . ~ ~ ~
153 154
F. Bohlmann and C. Zdero, Phytochernistry, 1978, 17, 1135. F. Bohlmann, C. Zdero, J. Jakupovic, H. Robinson, and R. M. King, Phytochernistry, 1981,20, 2239.
118
Terpenoids and Steroids
As mentioned in previous reports the structures of many of these metabolites which incorporate three angularly fused cyclopentane rings (triquinanes) have stimulated a flurry of synthetic interest with the result that four independent and imaginative syntheses of both isocomene (307) and modhephene (308) have been recorded so far. In addition to other sources these compounds co-occur in the roots of Otanthus r n a r i t i m ~ sIn . ~ the ~ ~ case of isocomene (307), full reports of the P a q ~ e t t e and l ~ ~P i ~ r u n g syntheses l~~ have appeared. The full Pirrung paper draws attention to the mechanistically interesting aspect of the final step in his isocomene synthesis. On the one hand, treatment of (309) with PTSA gives isocomene (307) exclusively, whereas similar treatment of the ketone (310) gives (31 1) and (312) in the ratio of 5 : 1. Further reaction of (311) with methyl-lithium gives a tertiary alcohol mixture, which on treatment with formic acid once again produces isocomene (307). Thus the rearrangement of (309) to give isocomene (307) could involve at least two pathways (or a mixture of both) (Scheme 33). The
Scheme 33
conversion of (310) into (309) with 13CH2=PPh3 could provide some insight into this mechanism since the fate of the labelled carbon is different for the two pathways. The latest synthesis of isocomene (Scheme 34)15* involves a classical construction of the triquinane nucleus terminating with the tricyclic ketone (3 13), which Paquette had already converted into isocomene in three steps. Turning now to the intriguing propellane sesquiterpene modhephene (308), Karpf and Dreidingls9 have provided full details of their original synthesis. Hot 155
J. de Pascual, A. San Feliciano, A. F. Barrero, M. Medarde, and F. TomC, Phytochemistry, 1981, 20, 166.
L. A. Paquette and Y.-K. Han, J . Am. Chem. SOC.,1981, 103, 1835. M. C. Pirrung, J. Am. Chem. SOC.,1981, 103, 82. W. G. Dauben and D. M. Walker, J . Org. Chem., 1981, 46, 1103. M. Karpf and A. S. Dreiding, Helv. Chim. Acta, 1981, 64, 1123.
*I6
157
lS8
Sesquiterpenoids
119
C0,Me
0
- /$
p
A
C0,Me
v , v i M e 0 2 C @ T e .CO,Me C0,Me
~
vii, vi
\co2Me
C0,Me
t +
Me0,C
mco2
0 0
C0,Me Ae
0 0
k i i , xiii, x
(313) Reagents: i, LDA; ii, Br(CH,), C0,Et; iii, NBS-aq. MeCN; iv, MeOH-pH 6.8; v, H,O+-A; vi, KF.2H20-MeI; vii, Me,C(CH,OH),-PTSA; viii, H 3 0 + ix, NH,NH2-KOH; x, PTSA; xi, Me1 ; xii, (CH,SH),-BF,.EtO,; xviii, Ph,P=CH,; xiv, MeI-CaC0,-aq. MeCN
Scheme 34
on the heels behind this synthesis have followed another three syntheses. The first of theselG0(Scheme 35) hinges upon the successful application of the acidcatalysed Cargill rearrangement of the strained [4,3,2]propellanes (315) and (319) to give (3 17) uniquely. The initial photo-addition of 1,Zdichloroethene to the enones (314) and (318) was surprisingly not stereospecific. In the case of (314) the desired isomer (315) was the minor one [ratio (315):(316) = 1 :2], while for (318) the required isomer was more abundant [ratio (319):(320) = 3:2]. The next synthesis of modhephene (308) (Scheme 36)la1 owes its success largely to the intramolecular ene reactions (321)+(322) and (323)+(324) originally developed by Conia. Unlike Smith's synthesis, this route achieves the stereocontrolled synthesis of 160
A. B. Smith, 111 and P. J. Jerris, J . Am. Chem. SOC.,1981, 103, 194. H. Schostarez and L. A. Paquette, J. Am. Chem. SOC.,1981, 103, 722.
120
Terpenoids and Steroids
0
@
Jviii, ix, v
. . I-IV
(318)
(319)
(320)
(308)
Reagents: i, hv-ClCH=CHCl; ii, (CH,OH),-H+; iii, Na-NH,; iv, H,O+; v, PTSA; vi, MeLi; vii, CrO,-H+; viii, Me,CuLi-BF,.EtO,; ix, CH,=PPh,
Scheme 35
~) -._
).$p
t vii,viii --
@) o
.
t
.
--.
-- . _ _
(324)
(323)
(325)
Reagents: i, Me,SiC = C(CH,),MgCl-CuI-BF,.Et,O ; ii, Bu,NF; iii, 360 "C; iv, Ph,P=CH,; v, MCPBA; vi, BF,.Et20; vii, I,; viii, K,C03-NH,NH,; ix, H,C=CH(CH,), MgBr-CuIBF,*Et,O
Scheme 36
Sesquiterpenoids
Reagents: i, CH,=CH(CH,),MgBr;
121
ii, H,O+; iii,[o>(CH,),MgBr
-CuBr.Me,S; iv, OH-;
v, MsC1-py; vi, DBN; vii, 250 "C; viii, H,-Pd/C; ix, LDA; x, PhSeBr; xi, H202; xii, MeMgICuBr.Me,S Scheme 37
both modhephene (308) and epimodhephene (325). Finally Oppolzer's approachlg2 to modhephene (Scheme 37) results in a stereoselective synthesis in which the crucial step is another intramolecular ene reaction (326)+(327) whose transition state ensures the correct orientation of the newly created secondary methyl group, The superb synthesis of quadrone (328) announced last year from Danishefsky's group has now been reported in A second synthesis of this complex fungal metabolite has been reported (Scheme 38).163bThe basic strategy of this latest synthesis parallels Danishefsky's approach in a number of points but overcomes the regiochemical difficulties of introducing the lactone ring of the natural product. A full account of the biosynthetic origin of dihydrobotrydial (331) from labelled acetate and mevalonate has been A number of the finer points in the biosynthesis of this class of sesquiterpenoid have also been established.lg5Jg6 Thus by a careful and detailed study of the 2H and 13Cn.m.r. spectra of appropriate metabolites after feeding the fungus Botrytis cinerea with [4JH2,4-13CJmevalonic acid, it was established that a 1,3-hydrideshift takes place (329)+(330) (Scheme 39). For example, the 2H n.m.r. spectrum of the ethyl acetal derivative of (331) showed a singlet for H-2 and doublets for H-1 and H-5. This result clearly distinguishes two consecutive 1,2-hydride shifts which would have produced an n.m.r. spectrum with two singlets and one doublet (for H-5). This observation was verified from the 13C n.m.r. spectrum. Furthermore the origin of the oxygen atom of the tertiary alcohol at C-9 has been traced to water since a study of the mass spectrum of the lea
W. Oppolzer and F. Marazza, Helv. Chim. Acta, 1981, 64, 1575.
163
(a) S. Danishefsky, K. Vaughan, R. Gadwood, and K. Tsuzuki, J . Am. Chem. SOC.,1981,103,
4136; (b) W. K. Bornack, S . S. Bhagwat, J. Ponton, and P. Helquist, J . Am. Chem. SOC.,1981, 103, 4647. 164 A. P. W. Bradshaw, J. R. Hanson, and R. Nyfeler, J. Chem. SOC.,Perkin Trans. 1 , 1981, 1469. le6 A. P. W. Bradshaw, J. R. Hanson, and R. Nyfeler, J . Chem. SOC.,Chem. Commun., 1981,649. lee A. P. W. Bradshaw, J. R. Hanson, and I. H. Sadler, J . Chem. SOC.,Chem. Commun., 1981,1169.
122
Terpenoids and Steroids
pi-xi
Jxvii
f.3
C0,Me
v, xviii,
v, xix
xx
’
_j
HO H02C $OAc
OX0 Reagents: i, CH,=CHMgBr-CuBr.Me,S ; ii, Me,SiCl-Et,N iii, MeLi ; iv, BrCH,C(OEt)= CHPO(OMe),; v, H,O+; vi, NaH; vii, PhSCHLiC0,Me; viii, CH,O; ix, aq- NH,Cl; x, NaBH,; xi, Me,C(CH,OH),-H+; xii, Li-NH,; xiii, 9-BBN; xiv, H,O,-OH-; xv, TsC1-py; xvi, NaI; xvii, LiN(SiMe,),; xviii, OH-; xix, Ac,O-py; xx, PCC; xxi, 200 “C
Scheme 38
from C-4 of mevalonic acid Scheme 39
Sesquiterpenoids
123
ethyl acetal of (331) obtained from B. cinerea grown on a H2 l8O medium clearly shows l80incorporation at C-9. These results are in accord with Scheme 39 which involves inversion of configuration at C-9 as a result of the 1,3-hydride shift.
(332)
(333) R (334) R (335) R
=
NO
(336)
= ONO, =
NO2
An examination of the products derived from humulene (332) on treatment with glacial acetic acid and sodium nitrite has revealed the formation of three major compounds (333)-(335),167 the first of which is the blue crystalline nitrosite prepared over eighty years ago by Chapman168and used as a means of distinguishing a-caryophyllene (now known as humulene) from p-caryophyllene. Further treatment of the nitrosite under the same conditions produced a plethora of diamagnetic and paramagnetic (nitroxides) products for which a number of structures have been proposed some of which are rather tentative. It is surprising that this paper makes no mention of the formation of the isohumulene (336) from the nitrosite", analogous to the formation of isocaryophyllene from caryophyllene nitrosite. Direct methods of converting humulene (332) into its 8,9-monoepoxide (337)t and into zerumbone (338) have proved to be very inefficient. Shirahama et al. have now brought about these conversions by indirect means. Thus, for the epoxide (337),169 humulene is first transformed to the acetate (339) by treatment with boron trifluoride etherate in glacial acetic acid followed by mono-epoxidation. Reduction of this acetate with LiAlH, followed by elimination with mesyl chloride in pyridine gives the epoxide (337). In the case of zerumbone (338),170 the readily
(337) 167
lE8 le0 1 ' 0
(338)
(339)
(340)
D. K. MacAlpine, A. L. Porte, and G. A. Sim, J . Chem. SOC.,Perkin Trans. I , 1981, 999. A. C. Chapman, J. Chem. SOC.,1895,67,54, 780. B. R. Chhabra, H. Shirahama, and T. Matsumoto, Chem. fnd., 1981, 539. H. Shirahama, B. R. Chhabra, and T. Matsumoto, Chem. Lett., 1981, 717.
*Recrystallization of humulene nitrosite from hot ethanol produces both humulene and isohumulene (336) (ca. 1 :1) together with the dinitro-cbmpound (334) and the nitrosite (333). I. Bryson and J. S . Roberts, unpublished results. ?We prefer the IUPAC numbering (see Editor's note in ref. 172) although we recognise the preference of Professor Matsumoto and others for humulene numbering based on its derivation from farnesyl pyrophosphate.
124
Terpenoids and Steroids
accessible humulene-epoxide (340) is treated with LDA to form the allylic alcohol (341) which is oxidized with Bu'OOH-VO(acac), to give predominantly (342). Collins oxidation of (342) gives the corresponding epoxy-ketone which on treatment with hydrazine hydrate and KOH undergoes a Wharton rearrangement to furnish zerumbol (343) which can be oxidized to zerumbone (338) with MnO,. As mentioned in previous reports the number of bicyclic and tricyclic sesquiterpenoids which can be derived from humulene (332) has continued to grow steadily over the past 10 years. Scheme 40 outlines briefly the 17 major structural types whose biogeneses have been proven or are thought to involve the intermediacy of humulene. The majority of these sesquiterpenoids have been isolated from fungal sources, particularly the Basidiomycetes and an excellent review of these fascinating metabolites has been written by Ayer and Browne.171 In addition to the challenging synthetic and biosynthetic problems that these metabolites have presented, another area of considerable interest is the biomimetic conversion of humulene and its derivatives into the novel skeletons which form the framework of these compounds. Of particular note is the work of Shirahama and Matsumoto who have gained considerable success in this area. A full publication from this group172 has now appeared which describes model studies which led to the successful conversion of the protoilludane epoxide (344) into the two hirsutane derivatives (345) and (346), the former of which was chemically transformed to hirsutene (347). It should be noted, however, that all evidence to date indicates that the hirsutanes are not derived from humulene via the protoilludyl cation but arise by a different pathway (see Scheme 40 and Vol. 1 1 , p. 39). One of the key compounds used in humulene biomimetic cyclizations is the 4,5-epoxide (348) which, under acidcatalysed conditions, is able to generate the all important humulen-4-yl cation. Shirahama and c o - w ~ r k e r have s~~~ subjected the epoxide (348) to two different sets of acid conditions. In one case, using trimethylsilyl trifluoromethanesulphonate, the products are the two africane-type alcohols (349) which had previously been obtained by reaction of the same epoxide with boron trifluoride e t h e ~ a t e . The '~~ tetrasubstituted isomer of (349) has been converted into africanol (350) in five steps. On the other hand, treatment of (348) with boron trifluoride etherate in acetic anhydride gave the bicyclohumulane derivative (35 1) which was converted into bicyclohumulenone (352), a naturally occurring compound, in seven steps. 171 172 173
17'
W. A. Ayer and L. M. Browne, Tetrahedron, 1981, 37, 2199. K. Hayano, Y . Ohfune, H. Shirahama, and T. Matsumoto, Helv. Chim. Acta, 1981, 64, 1347. H. Shirahama, K. Hayano, Y. Kanemoto, S. Misumi, T. Ohtsuka, N. Hashiba, A. Furusaki S. Murata, R. Noyori, and T. Matsumoto, Tetrahedron Lett., 1980, 21, 4835. J. A. Mlotkiewicz, J. Murray-Rust, P. Murray-Rust, W. Parker, F. G. Riddell, J. S. Roberts, and A. Sattar, Tetrahedron Lett., 1979, 3887.
Sesquiterpenoids
125
Y
-a cd
3
e
3
B
W
I
t
22 a
a
J. I
I
Terpenoids and Steroids
126
I
(344)
(346)
(345) HO
(347)
Y
H
-+ (349) R (356) R
(348)
H
=H = AC
H
(350)
/
(3 54)
? ..OAc
These two results demonstrate that cyclization of the epoxide (348) has proceeded from two different conformations of the epoxide, namely the CT conformer (353) in the absence of a nucleophile to produce (349) while the CC conformer (354) in the presence of the nucleophilic acetate proceeds to (351). In a subsequent paper175 it was shown that both conformers (353) and (354) react with boron trifluoride etherate in acetic acid to give (351) and (355)-(357), the first two arising from the CC conformer (354) and the second pair from the CT conformer (353).* Another significant result in this area is the biomimetic-type synthesis of pentalenic acid (360) from humulene (Scheme 41).176The design of this synthesis was based on earlier results (Vol. 10, p. 40) concerning the cyclization of the 5-deoxy analogue of (358) and the subsequent conversion of (358) into (359) in 20 % yield mimics the biosynthesis of the pentalenane sesquiterpenoids (see ref. 183). The latest result from the Japanese is the transformation of kumulene to sterpurene (364), one of the newest additions to the tricyclohumulane family, vide infra. In this case the results from a previous study (Vol. 10, p. 40) paved the way for the successful synthesis. Thus, treatment of (361), obtained from 176
177
H. Shirahama, K. Hayano, T. Ohtsuka, E. Osawa, and T. Matsumoto, Chem. Lett., 1981,351. K. Sakai, T. Ohtsuka, S. Misumi, H. Shirahama, and T. Matsumoto, Chem. Lett., 1981, 355. Y . Murata, T. Ohtsuka, H. Shirahama, and T. Matsumoto, Tetrahedron Lett., 1981, 22,4313.
*A similar result has been obtained when the epoxide (348) is allowed to react with boron trifluoride etherate in wet diethyl ether. In this case the diol corresponding to the diacetate (351) is formed exclusively. This diol reverts to the starting epoxide on treatment with PTSA. R. M. Carman, I. Bryson, and J. S. Roberts, unpublished results.
127
Sesquiterpeno ids
I
iii
Ho OH (358)
Ho
H
H
(360)
(359)
Reagents: i, aq. Hg(N03),; ii, KBr; iii, 0,-NaBH,; iv, Cr03-H+; v, NaBH,; vi, Ac,O-py; vii, PBr,; viii, Am'ONa; ix, Li-EtNH,; x, BF3.Et20;xi, SeO,; xii, Mn0,-KCN-MeOH; xiii, OH-; xiv, H 3 0 +
Scheme 41
humulene, with boron tribromide gave (362) and (363) both in yields of 20%. Further reaction of (362) with silver acetate in acetic acid gave sterpurene (364) in 61 % yield The sequence of rearrangements is interpreted in terms of Scheme 42 and this probably represents the actual biosynthetic pathway to the sterpuranes. As noted above this new class of sesquiterpenoid has emerged recently as a result of investigations by Ayer et al. on the metabolites of the fungus Stereum purpureum, the cause of the so-called silver leaf disease common to a number of fruit trees. In their first paper1'* Ayer et al. established the structures of sterpuric acid (365), the hydroxy-derivative (366), and the ethylidene acetal (367) by a combination of chemical and X-ray studies. Further on this fungus led to the isolation of sterepolide (368) and dihydrosterepolide (369) both of which are
a .cily, Br
.*
@ 0 I
-
H '. OMe (361) 178
H (362)
=*..
.
1
H : (363)
W. A. Ayer, M. H. Saeedi-Ghomi, D. Van Engen, B. Tagle, and J. Clardy, Tetrahedron, 1981,
37, 379. lTP W. A. Ayer and M. H. Saeedi-Ghomi, Tetrahedron Lett., 1981, 22,2071.
128
Terpenoids and Steroids
(364) Scheme 42
examples of the rare isolactarane group of which only one other member was known previously (Vol. 9, p. 116), although another example, merulidial (370), has been quoted recently.lso The co-occurrence of sterpurane and isolactarane sesquiterpenoids makes the biogenetic relationship shown briefly in Scheme 40 a distinct possibility. The neutral components of this fungus contain the trio1 (371) and very interestingly the parent hydrocarbon, sterpurene (364).ls1
(365) R (366) R
=H = OH
(367)
CHO (370)
W. Steglich, Pure Appl. Chem, 1981, 53, 1233. W. A. Ayer and M. H. Saeedi-Ghomi, Can.J , Chem., 1981, 59,2536.
lEo
lal
129
Sesquiterpenoids
Paquette et ~ 1 have . accomplished ~ ~ ~ a relatively short synthesis of the methyl ester of pentalenolactone E (372) (Scheme 43). Full details of the biosynthesis of pentalenolactone (373) from [ U-13C,J glucose and [6,6-2H2]glucose have been rep0rted.1~~ These substrates were used in view of the lack of incorporation of the more conventional acetate and mevalonate isoprenoid precursors. The stereochemical picture which has emerged from this study is that the pentalenane
H
H xi, v, xii
Reagents: i, (CH,OH),-PTSA; ii, Bu',AIH; iii, -CH,=CHOEt-Hg(OAc),; iv, 150 "C; v, H,O+; vi, OMe-; vii, NH,NH,-H,O-Et,N; viii, 1,-Et,N; ix, Ni(CO),-NaOMe; x, CrO,-H+; xi, MeOMgOCO, Me; xii, CH,O-Et,NH-AcOH
Scheme 43
skeleton is derived from the RSR-CT conformer of humulene (374) (Scheme 44) which results from attack on the si face of the distal double bond of farnesyl pyrophosphate. This pathway is consonant with the proven biosyntheses of fomannosin and the illudins. Cane et al. have further speculated about a possible enzyme receptor site for humulene formation and subsequent cyclization. In this work and elsewhere there is the tacit assumption that humulene retains the all-trans arrangement of the three double bonds prior to cyclization. Models indicate that this geometric imposition means that Lond formation between C-4 and C-8 may not be too facile and indeed there is no in vitro example of such bond formation in humulene chemistry. Examples of C-4-C-8 bond formation are only observed after 18s
L. A. Paquette, H. Schostarez, and G. D. Annis, J . Am. Chem. Soc., 1981, 103, 6526. D. E. Cane, T. Rossi, A. M. Tillman, and J. P. Pachlatko, J. Am. Chem. Soc., 1981, 103, 1838.
130
Terpenoids and Steroids H+
(374)
(373)
Scheme 44
C-1 and/or C-2 have been converted to sp3 geometry. One possible explanation for this apparent anomaly is to invoke a trans+cis isomerization in humulene prior to cyclization. This permits a more favourable interaction between a developing cationic centre at C-4 and the ABlg double bond. Thus the conformer (375) of isohumulene could serve as a precursor for the protoilludyl-derived metabolites while its enantiomer could proceed to the hirsutane sesquiterpenoids. A l p 2
(375) The biosynthetic relationship between illudol (379) and fomannosin (380) has inspired Semmelhack and c o - w o r k e r ~ ~to~ ~aJ ~beautifully ~ constructed synthesis of the two natural products via the common intermediate (378) (Schemes 45 and 46). This tricyclic compound (378) was obtained by a Diels-Alder reaction between (376) and the cyclobutene derivative (377). Another photochemically-based route (Scheme 47) has been used to obtain protoillud-7-ene (381) and several oxygenated derivatives.la6 Full reports on the syntheses of methyl isomarasmate (382) and the naturally occurring marasmic acid (383) have appeared.lB7Ja8A second imaginative synthesis of marasmic acid (383) has also been reported (Scheme 48).189Once again the power of the intramolecular Diels-Alder reaction has played a pivotal role in F. Semmelhack and S. Tomoda, J . Am. Chem. SOC.,1981, 103,2427. M. F. Semmelhack, S. Tomoda, and K. M. Hurst, J. Am. Chem. SOC.,1980,102,7567. H. Takeshita, I. Kouno, M. Iino, H. Iwabuchi, and D. Nomura, Bull. Chem. SOC.Jpn., 1980,
la4 M. la6
53, 3641. la' la8 189
W. J. Greenlee and R. B. Woodward, Tetrahedron, 1980, 36, 3361. W. J. Greenlee and R. B. Woodward, Tetrahedron, 1980, 36, 3367. R. K. Boeckman, Jr., and S. S. KO,J . Am. Chem. SOC.,1980, 102, 7146.
131
Sesquiterpenoids OSiMQ
OSiMe,
>o"
I
C0,Et
I
+
(376)
q OOEt E t
(377)
EtO OEt
qH qH v-viii
iii, iv
f---
H
EtO OEt
EtO OEt
Et0,C E t d OEt
.MP
H ' K EtO OEt
H EtO - uOEt
HY OH
(379) Reagents: i, A ; ii, 3A molecular sieves-MeOH; i i i , LiEt,BH; iv, NaH-PhCH,Br; v, LiAIH,; vi, BuLi-ClPO(NMe,),; vii, Li-EtNH,; viii, Cr0,-py; ix, LDA; x, CO,; xi, H + ; xii, CH,N,; xiii, PhSeC1; xiv, H,O,; xv, NaAl(OR),H,; xvi, Me,C=O-H+; xvii, H,O+ Scheme 45
-
the synthetic strategy. Thus, heating the triene (384) gave two tricyclic products (385) and (386) in the ratio of 1 : l . Compound (385) results from cyclization via an endo transition state whereas formation of (386) must occur by the usually disfavoured exo transition state. In the event both adducts could be converted into marasmic acid (383), Scheme 48 showing the sequence for (385). A similar set of transformations was effected on (386) and this gave the trans-isomer of (383) which was converted into the corresponding enol acetate which gave :-liarasmicacid (383) on hydrolysis. A full report on the structural determination of the seco-illudalane sesquiterpenoids, the cybrodins, has appeared.lgO These metabolites, which include cybrodol (387), isocybrodol (388), cybrodal (389), trisnorcybrodolide (390), and cybrodic acid (391), have been isolated from the bird's nest fungus Cyathus bulleri. In addition to these compounds, pterosin C (392), previously isolated from Pteridjum ferns, together with broderol (393) and nidulol (394) for which tentative structures have been put farward, have been isolated. The five compounds (387)l a 0 W.
A. Ayer and R. H. McCaskill, Can. J. Chem., 1981, 59, 2150.
132
Terpenoids and Steroids
i, ii
(378) --+
b,
vii
H
ButMe,SiOoH
MsO" (380) Reagents: i, LiAlH,; ii, 3A molecular sieves-MeOH; iii, MCPBA; iv, H,O+; v, Bu'Me,SiClimidazole; vi, NaBH,; vii, DHP-PTSA; viii, LDA; ix, CH,O; x, PhSeC1; xi, H + ;xii, H,O,; xiii, CH,=CHOEt-H+; xiv, MsCI-Et,N; xv, HF; xvi, Cr0,-py ; xvii, Bu,NF Scheme 46
qo
H
ii-iv i
4
:
H
/
H
H
M e 0 OMe
Q H
___, H (38 I )
Reagents: i, hv-CH,=C(OMe),; ii, MeMgI; iii, (CH,SH),-BF,; iv Ra-Ni
Scheme 47
---CHO
C0,Me
Sesquiterpenoids
133
Ijr
C0,Me
q; qoAc liv, v
J.
2-
(mOl2!7Q
Me0,C
C02Me
+
0
Vlll
d
Me02C
G xi
xii, ii
t---
Me02C Jxiii
CHO
4
fi
-*...;
Me0,C
OH
0
0 (3183) Reagents: Ph,P=CBrCO,Et ; ii, Bu',AlH; iii, Ni(CO),-NaOMe; iv, AcC1-py ; v, H 3 0 + ; vi, NaH; vii, 200 "C; viii, KOBu'; ix, PTSA-MeOH; x, MsC1-Et,N; xi, DBU; xii, PhSeBrMeOH; xiii, MCPBA: xiv, BBr,
Scheme 48
OH (387) R1= Me, R2 = CH20H (388) R1= CH,OH, R2 = Me (391) R1= Me, R2 = C02H
(389)
(390)
Terpenoids and Steroids
134
OH
'10' (392)
(394)
(393)
(39 1) have all been synthesized as reported earlier.lgl The seco-illudane, hypacrone (396) has been synthesized (Scheme 49) from the intermediate (395) previously used in illudin syntheses.lg2 I
so + i
P
0 0
a
+ ii a
0
0
0
U
(395)
H 0
0
0
U
iii, iJiv
Reagents: i, A ; ii, MeLi; iii, Me,CO-PTSA; iv, hv
Scheme 49
A number of new lactarane sesquiterpenoids have been identified from Lactarius scrobiculatus ; these include furoscrobiculin A (397), furanether A (398), furanether
lg1 lg2
W. A. Ayer and R. H. McCaskill, Can. J. Chem., 1981, 59, 2159. F. Sakan, Y. Minami, H. Shirahama, and T. Matsumoto, Bull. Chem. SOC.Jpn., 1981,9,2235.
135
Sesquiterpenoids
B (399), furoscrobiculin B (400), furoscrobiculin C (401), furoscrobiculin D (402), and lactaroscrobiculide B (4O3).lg3 Continued interest in the synthesis of hirsutane sesquiterpenoids has again been witnessed during the year under review. In this context, the previously reported synthesis of hirsutene (347) together with related model studies has been published in full.194Little and Mullerlg5have also achieved a synthesis of hirsutene (347) using their previously recorded strategy of intramolecular diyl trapping to construct the tricyclopentanoid ring system from (404) (Scheme 50) CO,Me
& A j i , iii
bi,
A
v, vii
(347) Reagents: i, A; ii, LiAlH,; iii, Bu'Me,SiCl-imidazole; iv, BH,; V, PCC; vi, Bu,NF; vii, (Ph,P), RhCl; viii, NaOMe-EtOCHO; ix, BuSH-PTSA; x, K0Bu'-MeI; xi, OH-; xii, Ph,P=CH2 Scheme 50
(see Vol. 11, p. 48). The latest synthesis of h i r s ~ t e n e l ~is~remarkable *'~~ (Scheme 51) and it is very unlikely that any computer-assisted retrosynthetic analysis would have come up with this route which involves a photochemical-thermal metathetic sequence. Thermolysis of the pentacyclic dione (405) gave the cis-syn-cis isomer (406) which at 310 "C produced an equilibrium mixture of (406)-(408) in the ratio of 14:49 :37. The requisite cis-anti-cis bisenone (408) was taken through to (409) which had previously been converted into hirsutene. ' Full details of the total synthesis of the more complex hirsutane sesquiterpenoids coriolin (410) and coriolin B (41 1) have been p ~ b 1 i s h e d .Another l~~ route to hirsutic R. Battaglia, M. De Bernardi, G . Fronza, G. Mellerio, G . Vidari, and P. Vita-Finsi, J . Nur. Products, 1980, 43, 319. lo4 T. Hudlicky, F. J. Koszyk, T. M. Kutchan, and J. P. Sheth, J. Org. Chem., 1980, 45, 5020. lS5 R. D . Little and G. W. Muller, J . Am. Chem. Soc., 1981, 103, 2744. lg6 G . Mehta and A. V. Reddy, J. Chem. SOC.,Chem. Commun., 1981, 756. I g 7 K. Taksuta, K. Akimoto, and M. Kinoshita, J . Am. Chem. SOC.,1979, 101, 6116. 19* S. Danishefsky, R. Zamboni, M. Kahn, and S. J. Etheredge, J . Am. Chem. Soc., 1981. 103, lg3
3460.
136
Terpenoids and Steroids
vii, viii ___, 1
0-7 Jix, x
f-xi
H..'
9 H:'
MeS,CO
0-7 OMe (409)
(347)
Reagents: i, A ; ii, hv; iii, 500 "C; iv, 310 "C; v, H2-Pd/C; vi, KOBut-MeI; vii, NaBH,; viii, MeOCH,C1-Pri2NEt; ix, LiAlH,; x, NaH-CS,-MeI; xi, Ref: 197
Scheme 51
H OH
H OH
.
"OH
(410) (411) acid (413) (Scheme 52) has been described;lg9this terminates at the keto-ester (412), have described a photoa key intermediate to hirsutic acid.200Pattenden et 2oo
M. Yamazaki, M. Shibasaki, and s. Ikegami, Chem. Lett., 1981, 1245. H. Hashimoto, K. Tsuzuki, F. Sakan, H. Shirahama, and T. Matsumoto, Tetrahedron Lett.,
201
J. S. H. Kueh, M. Mellor, and G. Pattenden, J. Chem. SOC.,Perkin Trans. I , 1981,1052.
lee
1974, 3745.
137
Sesquiterpenoids
H
kv H
H
(4 13) Reagents: i, TosNHNH,; ii, NaOMe; iii, F-; iv, DHP-H+; v, aq. NBS; vi, Bu,SnH; vii, PCC; viii, Ph,P=CH2; ix, MeOCH: ;x, H,O+; xi, HC1-MeOH; xii, CrO,H+; xiii, CH,N,; xiv, NaH-CH,=CHCH,Br ; xv, PdC1,-0,; xvi, KOBu'; xvii, Ref. 200
Scheme 52
chemically-based route to the tricyclopentanoid nucleus. Thus irradiation of the dicyclopent-1-enylmethane, (414) in methanol produced (416) through the intermediacy of the [2 + 21 addition product (415). Compound (416) has the cis-syn-cis stereochemistry which limits its synthetic potential for the hirsutane sesquiterpenoids. The precursor of the marine-derived capnellane sesquiterpenoids is precapnelladiene (417). The epimer (418) of this compound has been synthesized by a route (Scheme 53) which involves an intial intramolecular photocyclization
Terpenoids and Steroids
138 OMe
+ OCOPh
OCOPh pi,viii
@xii, xiii
t xi, iv
f-ix, x
b
0 (418)
0
Reagents: i, Li-NH3; ii, Bu'Li; iii, MeCH(I)(CH,),CH=CH,; iv, H,O+; v, PhCOC1-py; vi, hv; vii, LiN(SiMe,),-MeI; viii, OH-; ix, (CH,OH),H+; x, LiAlH,; xi, POCl,-py; xii, Ph,F'=CH,; xiii, RhCl3*3H20 Scheme 53
(420) Reagents: i, LiAlH,; ii, PCC; iii,
(419)
; iv, MeO,CN=NCO,Me;
v, KO,CN=NCO,KAcOH; vi, KOH; vii, K,Fe(CN),; viii, A ; ix, B2H,; x, H,O,-OH-, xi, PPh,=CH,
Scheme 54
followed by a retroaldolization to construct the bicyclo[6,3,0]undecane framework.202Two syntheses of A9$l2-capnellene (420) have been recorded. The first of 202
A. M. Birch and G. Pattenden, J . Chem. SOC.,Chem. Commun., 1980, 1195.
Sesquiterpenoids
139
these (Scheme 54)203is another nice example of the synthetic utility of intramolecular 1,3-diyl trapping reactions developed by Little. In this particular case the stereoselectivity of the ring closure of the intermediate cyclopenta-1,3-diyl (421) is not as great as in other examples and this may be the result of an unfavourable interaction between the hydrogen and the methyl group in (421). This interaction may be responsibfe for the significant formation of the cis-syn-isomer of (419). The second synthesis of (420) involves a stereocontrolled construction of the triquinane nucleus (Scheme 55). 204
I vi
(420) Reagents: i , CH,=CHMgBr; ii, MnO,; iii, P20,-MeS0,H; iv, Me,CuLi; v, LiC=CH; vi, HC0,H-H,SO,; vii, CH,=CHMgBr-Cul; viii, 0,; ix, Me,S; x, HC0,H; xi, KOH; xii, H,-Pt; xiii, PPh,=CH2 Scheme 55
p p...
HO-
0
(423) (424) (425) (426)
R’, R2= CH, R’ = R2= H R1= Me, R2= OH R’ = CH,OH, R2= H
Alliacolide (422) is a new fungal sesquiterpenoid with a unique carbon skeleton isolated from Marasmius alliaceus. Its absolute stereochemistry (422) has been determined by a series of circular dichroism measurements of degradation products 203 204
R. D. Little and G . L. Carroll, Tetrahedron Lett., 1981, 22, 4389. K. E. Stevens and L. A. Paquette, Tetrahedron Lett., 1981, 22, 4393.
140
p p --p Terpenoids and Steroids
0
0
(428)
(429)
(430)
in comparison with related Other metabolites from this fungus have been identified as alliacolide I1 (423), 12-hydroxydehydroalliacolide(427), 12noralliacolide (424), 1 1 - and 12-hydroxyalliacolide (425) and (426) respectively, and alliacide (428).206The biosynthesis of this unique group of sesquiterpenoids has been investigated207and as a result of feeding experiments with [1-13C]- and [1 ,2-13C,]-acetate and isolation of the labelled alliacolide, the pattern shown in (429) could be deduced from the 13C n.m.r. spectra. This means that the three isoprenoid fragments in the alliacane carbon framework can be dissected as shown in (430). Further feeding experiments208are under way to elucidate more details of the biosynthesis which may in fact indicate a cadinane-based route to the alliacanes. 11 Germacrane One of the most significant findings this year has been the isolation and identification of (-)-helminthogermacrene (431) from Helminthosporium s a t i v ~ m . ~ ~ ~
(434) Previously Arigoni2I0had put forward an elegant stereochemical argument for the co-occurrence of (-)-longifolene (432) and (-)-sativene (433) from this fungus, as summarized in Scheme 56. The detection of (431) in the mycelium adds substantial support to this proposal since it is the very ten-membered ring intermediate en route to (-)-sativene. The final verification of the structure of (431) was achieved by carbanionic cyclization of the cis,trans-farnesyl sulphide (434) followed by reductive removal of the sulphide group and dehydration of the derived tertiary alcohol. 6p-Hydroxygermacra- 1(1 0),4-diene (435) has been isolated from various Verbesina species as the corresponding coumaroyl and feruloyl esters.s0(-)-Mint205
206
207 208 208
210
A. P. W. Bradshaw, J. R. Hanson, D. N. Kirk, and P. M. Scopes, J. Chem. SOC.,Perkin Trans. 1, 1981, 1794. I. W. Farrell, T. G. Halsall, V. Thaller, A. P. W. Bradshaw, and J. R. Hanson, J . Chem. SOC.,Perkin Trans. 1 , 1981, 1790. A. P. W. Bradshaw, J. R. Hanson, and I. H. Sadler, J. Chem. SOC.,Chem. Commun., 1981,631. J. R. Hanson, Pure Appl. Chem., 1981,53, 1159. R. E. K. Winter, F. Dorn, and D. Arigoni, J. Org. Chem., 1980, 45, 4786. D. Arigoni, Pure Appl. Chem., 1975, 41, 219.
141
Sesquiterpenoids
(433)
sulphide (436), a novel sesquiterpenoid from peppermint oil, has been synthesized by irradiation of f -)-germacrene D (437) in the presence of sulphur.211Treatment of the methyl sulphonium salts of mintsulphide (438) and isomintsulphide (439) with LDA gives the homologous sulphides (440) and (441) respectively by way of a [2,3] sigmatropic rearrangement of the corresponding sulphonium ylides.212
(435)
211
z*a
(437)
K. Takahashi, S. Muraki, and T. Yoshida, Agric. Biol. Chem., 1981, 45, 129. T. Uyehara, T. Ohnuma, T. Saito, T. Kato, T. Yoshida, and K. Takahashi, J. Chem. SOC., Chem. Commun., 1981, 127.
Terpenoids and Steroids
142
On the other hand, reaction of (438)with methyl-lithium gives predominantly (442) and (443) via the diradical (444),whereas similar treatment of (439)gives largely
(445).
Reduction of the photo-adduct (446) derived from ( +)-isopiperitone and cyclobutene- 1-carboxylic acid with NaCNBH, gives the lactone (447).Thermolysis of this compound affords the 6ol-epimer of isoaristolactone (448)and the elemanolide (449).213 A novel approach to the synthesis of germacranes involves the thermal opening of a bridgehead cyclobutene which, in turn, is derived by an oxy-Cope rearrangement (Scheme 57).214
iiii
Reagents: i, hv-CH,=C=CH,;
ii, CH,=CHMgBr; iii, K H ; iv, 180 "C; v, h v
Scheme 57
In an effort to mimic the proposed cyclization of the gernacr-idienyl cation (450) to the cadinane skeleton, It8 et aL215have examined the fate of the four hedycaryol phenyl sulphides (451)-(454) on reaction with methyl iodide (cf. Vol. 10, p. 51). In all four cases the products derived (455)-(462) were eudesmane derivatives and this finding has been explained in terms of HI-induced cyclizations, the HI being generated from the initially formed sulphonium salts. De-
OH
213 214
216
G. L. Lange, S. So, M. Lautens, and K. Lohr, Tetrahedron Lett., 1981, 22, 311. S. L. Schreiber and C. Santini, Tetrahedron Lett., 1981, 22,4651. M. Kodama, K. Shimada, and S. It6, Tetrahedron Lett., 1981, 22, 1523.
Sesquiterpenoids
143
WH+ SPh
sulphurization of (459) gave the ether (463), a defence pheromone of Amitermes evuncifer. As an alternative approach to the cation (450),216the diol(464) has been obtained by a [2,3] sigmatropic shift of the sulphoxides (465) and (466) derived from (451) and (452) respectively. Treatment of the diol with various acids gave
o.-r
PhSO
*
(465)
(464)
(463)
4
qqq HO & (OH
PhSO
OH (466)
Rlp2
\
\
OH (467)
\
OH (468)
OH (469) X1= Me, R2= OH (470) R1= OH, R2= Me
varying yields of the cadinane-type compounds (467)-(470). In another interesting transannular cyclization study, the germacradiene (472), derived from (47 1) on thermolysis, has been subjected to treatment with acetic acid in thiophen01.~~~ ala
M. Kodama, K. Shimada, T. Takahashi, C. Kabuto, and S. It6, Tetrahedron Lett., 1981, 22, 427 1.
m7 J.
R. Williams, J. F. Callahan, and J. F. Blount, J . Org. Chern., 1981, 46,2665.
144
Terpenoids and Steroids
Me0,C (471)
PhS
PhS
m
Me0,C
(473) R1= H, R2 = C0,Me (474) R' = C0,Me; R2 = H
HO
A
(475)
(476)
Four products (473)-(476) resulted from this reaction, three of which are of the eudesmane class while the fourth has the cadinane skeleton. Treatment of the truns,truns-germacranolide, epitulipanolide (477) and two of its derivatives with selenium dioxide and t-butyl hydroperoxide gives the melampolidetype alcohol (478).21sA mechanism for this allylic oxidation with inversion of configuration at the AIJo double bond is proposed. It should be noted, however, that this is not the first report of such a process (cf Vol. 1 1 , p. 55).
(477) (478) The isolation and identification of germacrane lactones from a host of plant sources is an area of continuing interest particularly in the laboratories of Professors Herz and Bohlmann. The search for biologically active compounds and the chemotaxonomic classification of plant species are the two major driving forces for this research. The sub-division of these lactones into germacranolides (479)-
JV
q
0 (479)146Costunolide Derivative
218
Po ..--0
AcO
OAc
(480)219Artemisiifolin Diacetate
M. Haruna and K. Ito, J . Chem. SOC.,Chem. Commun., 1981, 483.
Sesquiterpenoids
145
(482)220Eupatolide Derivatives
(48 1)2m Tithifolin Derivatives
R
various R1and R2groups
w o ..--0
=
H and OAc
CH,OH
co-occurs with
OR2
R1O (483)221R1 =
Cc, R2
co
=H
CH20H (484)22’
etc.
Artemisiifolin Derivatives
(485)222R
= AC Ovatifolin (also R
=
H)
&-+(
QR
- .
mg;ws 0
0
-
0
(486)223Blainvilleolide Derivatives various R goups
and
1
0 (487)2234,5-cis-Acanthospermolide Derivative
&
)
0 (488)223Acanthospermolide
Derivative (also 1,lO-epoxide)
146
Terpenoids and Steroids
(524),14s9219-243heliangolides (525)-(563),5p6y118J509244-257 melampolides (564)(566),2589259and cis,&-germacranolides (567)--(580)2407260-264 is in most cases 21* 220
221 222
223
225
F. Bohlmann, C. Zdero, H. Robinson, and R. M. King, Phytochemistry, 1980, 19, 2473. F. Bohlmann, J. Ziesche, H. Robinson, and R. M. King, Phytochemistry, 1981. 20, 267. F. Bohlmann, J. Jakupovic, H. Robinson, and R. M. King, Phytochemistry, 1981, 20, 109. M. Hoeneisen, M. Sicva, and F. Bohlmann, Phytochemistry, 1980, 19,2765. F. Bohlmann, J. Ziesche, R. M. King, and H. Robinson, Phytochemistry, 1981, 20, 263. F. Bohlmann, P. Singh, N. Borthakur, and J. Jakupovic, Phytochemistry, 1981, 20, 2379. F. Bohlmann, A. Suwita, J. Jakupovic, R. W. King, and H. Robinson, Phytochemistry, 1981, 20, 1649.
228
228
229
W. Herz and N. Kumar, Phytochemistry, 1981, 20, 1339. W. Herz, S . V. Govindan, and N. Kumar, Phytochemistry, 1981, 20, 1343. F. Bohlmann, C. Zdero, R. M. King, and H. Robinson, Phytochemistry, 1981, 20, 1069. F. Bohlmann, A. K. Dhar, J. Jakupovic, R. M. King, and H. Robinson, Phytochemistry, 1981, 20, 1077.
F. Bohlmann, J. Jakupovic, R. M. King, and H. Robinson, Phytochemistry, 1981, 20, 1613. F. Bohlmann, J. Ziesche, R. M. King, and H. Robinson, Phytochemistry, 1981, 20, 1623. 232 W. Herz and S . V. Govindan, Phytochemistry, 1981, 20, 1740. 233 F. Bohlmann, C. Zdero, H. Robinson, and R. M. King, Phytochemistry, 1981, 20, 2029. 234 A. G. Gonzalez, J. Bermejo, F. Toledo, and L. R. Daza, Phytochemistry, 1981, 20, 1895. 235 U. Rychlewska, J . Chem. SOC., Perkin Trans. 2, 1981, 660. 236 M. J. Begley, L. Crombie, W. M. L. Crombie, A. K. Gatuma, and A. Maradufu, J . Chem. Soc., Perkin Trans. 1, 1981, 2702. 237 A. Rustaiyan, L. Nazarians, and F. Bohlmann, Phytochemistry, 1980, 19, 1230. 238 R. N. Baruah, R. P. Sharrna, G. Thyagarajan, W. Herz, S . V. Govindan, and J. F. Blount, J. Org. Chem., 1980, 45,4843. 239 B. A. Nagasampagi, U. G. Bhat, F. Bohlmann, and C. Zdero, Phytochemistry, 1981,20,2031. 240 F. Bohlmann, C. Zdero, H. Robinson, and R. M. King, Phytochemistry, 1981, 20, 1631. 241 F. Bohlmann, R. K. Gupta, J. Jakupovic, H. Robinson, and R. M. King, Phytochemistry, 1981. 20, 1609. 242 K. K. Purushothaman, S . Vasanth, P. J. Cox, J. A. Akinniyi, J. D. Connolly, D. S.Rycroft, and G. A. Sim, J . Chem. Res. ( S ) , 1981, 374. 243 K.-H. Lee, T. Ibuka, H. Furukawa, M. Kozuka, R.-Y. Wu, I. H. Hall, and H.-C. Huang, J. Pharm. Sci., 1980, 68, 1050. 244 W. Herz and N. Kumar, Phytochemistry, 1981, 20, 93. 245 0. Spring, K. Albert, and W. Gradrnann, Phytochemistry, 1981, 20, 1883. 240 F. Bohlmann and C. Zdero, Phytochemistry, 1981, 20, 2431. 247 F. Bohlmann, R. K. Gupta, J. Jakupovic, R. M. King, and H. Robinson, Phytochemistry, 1981, 20, 1635. 248 M. Hoeneisen, M. Kodama, and S . It8, Phytochemistry, 1981, 20, 1743. 249 W. Herz and N. Kumar, Phytochemistry, 1981, 20, 99. 250 F. Bohlmann, J. Jakupovic, M. Ahmed, M. Grenz, H. Suding, H. Robinson, and R. M. King, Phytochemistry, 198 1, 20, 113. 251 F. Bohlmann, C . Zdero, R. M. King, and H. Robinson, Phytochemistry, 1980, 19, 2663. .d52 C. Zdero, F. Bohlrnann, H. Robinson, and R . M. King, Phytochemistry, 1981, 20, 739. 263 F. Bohlmann, C. Zdero, H. Robinson, and R. M. King, Phytochemistry, 1981, 20, 731. 264 C. A. Bevelle, G. A. Handy, R. A. Segal, G. A. Cordell, and N. R. Farnsworth, Phytochemistry, 1981,20, 1605. stis P. K. Chowdhury, R. P. Sharma, G. Thyagarajan, W. Herz, and S . V. Govindan, J . Org. Chem., 1980, 45,4993. zs8 F. Bohlmann, U. Fritz, R. M. King, and H. Robinson, Phytochemistry, 1981, 20, 743. 267 F. Bohlmann, J. Jakupovic, A. K. Dhar, R. M. King, and H. Robinson, Phytochemistry, 1981, 20, 843. 258 X. A. Dominguez, R. Villarreal, R. Franco, and F. Bohlmann, Phytochemistry, 1981,20, 1431. 268 F. Bohlmann, J. Jakupovic, A. K. Dhar, R. M. King, and H. Robinson, Phytochemistry, 1981, 20, 1081. 280 W. Herz, S . V. Govindan, and J. F. Blount, J . Org. Chem., 1981, 46, 761. J. W. Klimash and N. H. Fischer, Phytochemistry, 1981, 20, 840. 262 P. L. Cowall, J. M. Cassady, C.-J. Chang, and J. F. Kozlowski, J. Org. Chem., 1981, 46, 1114. F. Bohlmann, C. Zdero, R. M. King, and H. Robinson, Phytochemistry, 1981, 20, 518. 264 F. Bohlmann, L. Miiller, R. K. Gupta, R. M. King, and H. Robinson, Phytochemistry, 1981, 20, 2233. 230
231
147
Sesquiterpenoids
W
i
A
c
0
bAC
(489)224Marginatin
(490)225Vautheriol Derivatives
Derivative
various R groups
HR o..;
q 9 3 O OH
HO'. 0 (491)226Eupaserrin
(492)2261 1 PH-Dihydrochamissonin
Derivative
(OAc
Q
' 04
0
0 (493)227Eupaserrin
(494)228Costunolide Derivatives
Derivative
various R groups
q : 0
0 = H and OH Acanthospermolide Derivatives
(495)22sR
(496)228Ovatifolin
(497)228Grazielia Acid
Derivative
QCAC 0 '0
(498)22s8~-Angeloyloxy-grazielolide (499)229Disyfolide
(and angelate epoxide)
(500)229 Disyhamifolide
Terpenoids and Steroids
148
R3 (501)230Costunolide Derivatives (various R1,R2,R3groups)
(502)231Haageanolide
Angelate
QH A
c
O
S
0
0 0 (503)231Zinangustolide (also 1 18, 13-dihydro derivative)
(504)232Scandenolide
AcO
HO (505)233Costunolide Derivative
(506)234Arbutifolin (and 11p, 13-dihydro derivative)
(507)235
(508)236Cordifene 48, I 5-oxide (cf. Ref. 237)
(509)236Cordifene
,, (5
Ineupatolide
Sesquiterpenoids
149
H
O
.
.
. ..-so R 0
0 AcO
R (512)238R (51
= MeBu, Ineupatorolide A = Ang, Ineupatorolide B
qp
0 ( 5 1 3)239
I;I
I;I
*fp
..-so
..--0
see also H --. ? - & y o
OAng (5 14)240Laurenobiolide Derivative
I:.:"'?:"
( 5 16)240
gQ I
OAc
T
0 (5 17)241Ereglomerulide
R
H-
OH (5 15)240Onoseriolide Derivatives
-
-
O 'OAng A c
HO
0 ( 5 18)2412,3-truns-Ereglomerulide
q
OAc
0 (51 9 y 1 Ereglomerulide Derivative
---OH
-
0
0 (520)242Vicolide B
(521)242Vicolide C
---OR
0 (522)243R (523)243R
= COC(Me)=CH,, Molephantin = Tig, Molephantinin
0 (524)243Phantomolin
Terpenoids and Steroids
150
a* OTig
HO
--.-
0 (525)5 3u- and 3P-H ydroxybejaranolide
OH
-
0
,OAc
co-occurs with
0 (526)5 Atripliciolide Derivative
gr:c OAc
'
04
0 (527)5 4,5-trans-Bejaranolide (R = H) (528)j 3u-Hydroxy-4,5-transbejaranolide (R = OH)
HO--. -
a
0 (529)6 1-epi-NiveusinC Acetate
HO
0
-
eacr
-
0 (531)11*Trichogoniolide
0 (530)11*Atripliciolide Derivatives (various R1 and R2groups)
"p::lt
0
-
eacr
-
0 (532)11*Isotrichogoniolide
?R'
O-S
0 (533)11*Trichosalviolide Derivatives (various R1 and R2 groups)
0 (534)11*Zexbrevanolide Derivative
151
Sesquiterpenoids
mo 0
-
OAng
pgJ OH
R--
-
-
\
(535)150 Lychnopholide
0 (536)244Niveusin C (= A n n ~ i t h r i n ~ ~ ~ )
R=OH =H
(537)244R
0
(538)244R1 = R2 = OH (539)244R1 = OH, R2 = H
-
AcOQ g -
(540)246
go% -
0
0 (542)24*
(541)247Heliangin 3-Acetate
(543)249Budlein Derivative
-
(544)249
0 (546)250Viguestenin Derivatives
(545)249Ovatifolin Derivative
152
Terpenoids and Steroids 0
Q(Tig) eacr ...-0
-
0
0
(547)251Eremantholanolide
Derivative (also 4,5-dihydro derivatives)
(548)251Goyazensolanolide Derivative
(549)251Zexbrevanolide Derivative
pp ...-o
-
(550)252Govazensolanolide
Deiivative
....0
OH
0 (55 1)252 Eremantholanolide Derivative
0
(552)253Goyazensolanolide
Derivative
'Q*
.OAng
'
OAc
HO
0
0 (5 53)253Zexbrevanolide Derivative
OAng
(554)253 Piptolepolide
HO bAng \ HO (555)254 Tsocentratherin
0
(556)255R
= CO(Me)CH,,
Calaxin = COCHMe,, Ciliarin
(557)255 R
0 ( 5 1 % ) ~R~ = ~ CO(Me)CH,, Zexbrevin B (559)255R = COCHMe,, Orizabin
Sesquiterpenoids
153
Q
0
0 (560)256 Atripliciolide
Derivatives (various R1 and R2 groups) (also I 1,13-epoxides)
(561)256 Atripliciolide Derivatives (various R groups)
Derivative
o:::Q&H
0 (563)257Punctatin Derivative
Qg
(562)256Atripliciolide
_.--
OAc
0 (564)25s1 1 p, 13-Dihydromelampodin
.OAng co-occurs with
HO 0 (565)259Acanthospermolide Derivative
(566)2594,5-cis-Acanthospermolide Derivative
CHO
OTig
n
0 (567)240Wunderolide
(568)260R (569)260R
= =
H, Rolandrolide Ac, Acetoxyrolandrolide
(570)226R = H, Isorolandrolide (571)260R = Et, Ethoxyisorolandrolide
Terpenoids and Steroids
154
HO
0 (572)261R1= Ac, R2 = CO(Me)=CH, (573) R1 = Ac, R2 = COCHMe, (574) R1= Ac, R2 = COCH(Me)Et (575) R1= COCH(Me)Et; R2= Ac
Melcanthin D Melcanthin E Melcanthin F Melcanthin G
(576)262Piptocarphins A-F
(various R1,R2,R3groups) HO.
qoA
TigO
I
OTig
OAc
co-occurs with AcO.’.
0
0
(577)263Hirsutinolide Derivative
(578)263Chrestanolide
.OAc
I~
WAC
‘O-X,
0
(579)264Hirsutinolide
(580)264Isohirsutinolide
Derivative
(58 l)2s5 Vernonallenolide
Derivative
(582)4
(583)4
Q;
155
Sesquiterpenoids
..OAc
A c o'0 * - ~ o A c
'0 0 (584)4
0 (585)
relatively straightforward but in other cases rather arbitrary.* The vast majority of the lactones listed are new, their structures having been deduced by spectral analysis. In view of the complexity of the structures of these compounds a heavy reliance on the interpretation of n.m.r. spectra may lead to erroneous conclusions and indeed some of the compounds listed appear as a result of structural revisions (particularly of stereochemistry) necessitated by X-ray studies and/or correlations with proven structures. The newest additions to this group of sesquiterpenoid lactones are the allenic germacranolides, the vernonallenolides (58 1)-(583), isolated from several Verrtonia specie^.^^^^^ They co-occur with a number of new compounds two of which are the glaucolide derivatives (584) and (585).
12 Elemane Additional examples of elemanolides from a variety of plant sources include disynaphiolide (586),229 a series of 8-epizinamultifluoride esters (587),231isoarbutifolin (588) and its I 1,13-dihydro derivative,234and (589 ; R = COC(CH,)Me or R = Tig).266 A full report on the preparation of the photo-adduct (590) from methylcyclobutene and (-)-piperitone and its thermal conversion into the various shyobunones (59 1) and related sesquiterpenoids has appeared.267Another synthesis of the cytotoxic compound ( +)-deoxyvernolepin (592) Starting from a-santonin has been recorded. 268
265
F. Bohlmann, R. K. Gupta, J. Jakupovic, R. M . King, and H. Robinson, Liebigs Ann. Chem., 1980, 1904.
266
e67
W. Herz and S. V. Govindan, Phytochemistry, 1981, 20, 2229. J. R. Williams and J. F. Callahan, J . Org. Chem., 1980, 45, 4475. M. Watanabe and A. Yoshikoshi, Chem. Lett., 1980, 1315.
*Occasionally co-metabolites are included in these structures for convenient referencing.
156
Terpenoids and Steroids
(589)
13 Eudesmane New additions to the eudesmane family of sesquiterpenoids include (593) and its 1 I, 12-dihydro deri~ative,~ 2-desoxyliguhodgonal (594),59and (595)-(601).60J48*269 Herz and Kurnar2'O have reported a compound from another Verbesina species which may well be identical to the coumarate ester (598). With good reason, however, they suggest a reversal of stereochemistry at C-4. The costic acid derivative (602) and its C-7 epimer co-occur with the reynosin derivative (603) in Lasiolaena s u n t ~ s i i .Huffman ~~~ and Pinder271have expressed some reservations about the identity of isointermedeol (604) (Vol. 10, p. 70). They have presented evidence to suggest that the material used may just have been an impure sample of ( +)-intermedeol (605). In an ongoing study of the constituents of the rare Guyanan tree DuZucia guianensis, Polonsky et al.272have identified by X-ray analysis the rather unusual
H?
(596) 26B L70
271 B7a
(597)
(598)
F. Bohlmann, M. Ahmed, R, M. King, and H. Robinson, Phytochemistry, 1981, 20, 1434. W. Herz and N. Kumar, Phytochemistry, 1981, 20, 247. J. W. Huffman and A. R. Pinder, Phytochemistry, 1980, 19, 2468. J. Polonsky, J. Varenne, T. Prange, C. Pascard, H. Jacquemin, and A. Fournet, J . Chem. Soc., Chem. Commun., 1981, 731.
Sesquit erpenoids
157
p y OAng
(599) R1= OCinn, R2 = H (600) R1= H, R2 = OCinn
(602)
P....(
HO,' H
sesquiterpenoid manicoline A (606). A plausible biogenesis of this a-aminotropone starting from eudesmol has been put forward. The mystery surrounding the structure of the marine metabolite, cyclaeudesmol, has finally been solved (see Vol. 10, p. 72) after all the combined efforts to synthesize the four stereoisomers of the claimed structure (607).273When the last remaining stereoisomer (608) had been and shown not to be identical to the- natural compound, a more fundamental structural modification was required. This came about by the isolation of a compound, originally referred to as isocycloeudesmol, from another marine source, Luurenciu n i p p ~ n i c aThis . ~ ~ compound was ultimately shown to be identical to cycloeudesmol from Chondriu oppositicladu and an X-ray analysis of a derivative was used to determine the structure as (609) which fits the original n.m.r. data much better.275
QoH
(608) 87s
274
276
(609)
R. A. Moss and E. Y . Chen, J. Org. Chem., 1981,46, 1466. M. Ando, S. Sayama, and K. Takase, Chem. Lett., 1981, 377. T. Suzuki, A. Furusaki, H. Kikuchi, E. Kurosawa, and C. Katayama, Tetrahedron Lett., 1981, 22, 3423.
158
Terpenoids and Steroids
New additions to the eudesmanolide family include (6 10)-(635).105J54922092229 The examination of liverwort species continues to reveal interesting new structures such as those of ( +)-P-frullanolide (636) and ( +)-brothenolide (637) from Frullania b r ~ t h e r and i ~ ~(~+)-crispatanolide (638) from Makinoa ~ r i s p a t a . ~ s ~ The last compound is unique in the eudesmane field having a 8-lactone attached between C-7 and C-14. 231p247p2499276-282
0
(61
(61O)lo3Inucrithmolide
Alantolactone Derivative
Q3$:
(Ac)HO*o
0
OH(AC) (6 I 3)154 Eridanolide Derivatives (various R groups)
(6 14)220Balchanin Derivative
qIg
A (Sen01 n
0
0 (615j2@Arhsculin
(612)lb4Ivangustin Derivative
0 (6 1 6)222Arturin
g
O
W
o
(617)231Ivangustin Derivative
Derivative 276
A. G . Gondlez, A. Galindo, H. Mansilla, and A. Gutibrrez, Phytochemistry, 1981, 20, 2367. 22,
277
278
27s 280
281
282
283 a84
X. A. Dominguez, R. Franco, G. Cano, R . Villarreal, M. Bapuji, and F. Bohlmann, Phyfochemistry, 1981, 20, 2297. F. Bohlmann, J. Jakupovic, and A. Schuster, Phytochemistry, 1981, 20, 1891. B. A. Nagasampagi, J. S. Sohoni, F. Bohlmann, and C . Zdero, Phytochmisfry,1981,20,2034. F. Bohlmann, J. Ziesche, R. M. King, and H. Robinson, Phytochemistry, 1981, 20, 1335. F. Bohlmann, A. K. Dhar, J. Jakupovic, R. M. King, and H. Robinson, Phytochemistry, 1981, 20, 838. F. Bohlmann, J. Ziesche, R. M. King, and H. Robinson, Phytochernistry, 1981, 20, 751. R. Takeda, Y. Ohta, and Y . Hirose, Chem. Lett., 1980, 1461. Y. Asakawa, M. Toyota, Z. Taira, T. Takemoto, M. Kido, and Y. Ichikawa, J . Chem. SOC., Chem. Commun., 1980, 1232.
Sesquiterpenoids
159
c":I.-
OTig
0
(618)247 Reynosin Derivative (619)247A's5 Arbusculin Derivative (620)247 Balchanin Derivative
(621)249Ivasperin Derivatives
A39',
..m
e
OH
-..o 0
H (622)249
__..
Po. Ho'
0
B
H
(624)277
(623)276Maritimin
OH
O q Z ? ? (625)277Ixtlixochilin Derivatives
(626)278
w o
Ho/
(627)278Asperilin Derivatives
q, 0-
(628)279Isoivangustin (629)280
R1 0'
*.. H
0
0 (630)280
I
0 "
0 (631)28'R1= R2= H Dimerostemmolide Derivatives (632) R1= OH, R2 = Ang (633) R1= OH, R2 = Mebu
160
Terpenoids and Steroids OAc OAc
q OR
(634)282Oxidoisotrilobolide Derivatives (various R groups)
(635)2s2Trilobolide Derivatives (various R groups)
The structure of cc-santonin chlorohydrin (639) has been revised as a result of an X-ray analysis.285 Further irradiation of photosantonin (640) produces neophotosantonin (641)286by a [1,5] antarafacial sigmatropic hydrogen migration. Syntheses of the following eudesmane sesquiterpenoids have been recorded : (642),2s7 (643),287 (644),287 ( +)-p-cyperone (645),28s P-costol (646),289 arctiol (647),289and vetiselinenol (648).290The photo-adduct (649), derived from I ,2bis(trimethylsi1oxy)cyclobutene and ( -)-piperitone, has been converted into the
q Eto2c20J Eto 6H 0
0
....
0
0
....
....
0
0
RO
0
R 2 R R l
(642) R' = OH, R2 = H (643) R' = R2 = H (644) R' = H, R2 = OH 285 288 287 288 288
2no
(645)
(646)
H. Takayanagi, H. Ogura, and T. B. H. McMurry, Bull. Chem. SOC.Jpn., 1981, 54,1259. A. W. Burgstahler, J. Org. Chem., 1981, 46, 1741. F. Bohlmann and H. Kassner, Chem. Ber., 1981, 114, 2415. J. P. Kutney, J. Balsevich, and P. Grice, Can. J. Chem., 1980, 58, 2641. S. Torii and T. Inokuchi, Bull. Chem. SOC.Jpn., 1980, 53, 2642. R. B. Miller and J. M. Frincke, J. Org. Chem., 1981, 46, 2972.
Sesquiterpenoids
161
p.. .,<
0
Q
0
eudesmane-type compound (650).291In an approach to the synthesis of polyhydroxyagarofurans, Huffman and Hillenbrand292have repeated the Robinson annelation of hydroxycarvone with ethyl vinyl ketone. In contrast to an earlier result, the major product of this reaction is the dione (651), the minor product being the C-10 epimer. Treatment of (651) with MCPBA, followed by LiAlH4reduction and Jones oxidation of the resultant stereoisomeric 3,9,11-trials gave 9-keto-a-agarofuran (652). A short synthesis of frullanolide (654) has been achieved, based on a newly developed nickel-promoted cyclization/carbonylation procedure for the one-step preparation of a-methylene-y-lactones (Scheme 58).293Both the E- and Z-isomers Br
+ 2-isomer (653)
(654)
Reagents: i , MeO,CC(Br)=PO(OEt),; ii, Bu',AlH ; iii, MsCl-Et,N; iv, Ni(CO),
Scheme 58
of (653) gave frullanolide on treatment with nickel carbonyl, presumably by reaction through a common allyl-nickel intermediate. A rather long but nonetheless interesting second synthesis of the seco-eudesmanolide eriolanin (656) has been accomplished (Scheme 59).294The stereocontrolled construction of the substituted cylohexenone (655) is reminiscent of Still's synthesis of trichodermol (Vol. 11, p. 18). 291
M. Van Audenhove, D . De Keukeleire, and M. Vandewalle, Bull. SOC.Chirn, Belg., 1981, 90, 255.
292
294
J. W. Huffman and G. F. Hillenbrand, Tetrahedron, 1981, 37, Suppl. No. 1, 269. M. F. Semmelhack and S. J. Brickner, J . Am. Chem. SOC.,1981, 103, 3945. M. R. Roberts and R. H. Schlessinger, J . Am. Chern. SOC.,1981, 103, 724.
Terpenoids and Steroids
162
MOMO OSiMe,But
x-xii
(655)
Jxiii-xvi
MOMOw S i M e z B u t
xvii-xx, ii, Jxxi, xxii
AcO
AcO
a OAc
pxV,
OAc
xxvi
HO
HO HO
0,
But Me,SiO >xviii, iv, xxvii, xix, xxix, xix
ButMe,SiO OSiMe,
II Reagents: i, ClCH,OMe-PhNMe,; ii, KOH; iii, Me,&,; iv, LDA; v, MeCH=CHCO,Me; vi, Br,; vii, NaBH,; viii, Zn-EtoH; ix, KOBu'; x, LiAlH(OBu'),; xi, Bu'Me, SiC1-imidazole; xii, aq. NBS-Na,CO,; xiii, Bu',AlH; xiv, MsCI-Et,N; xv, NaI; xvi (CH,=CH),CuLi ; xvii, Et3NHF; xviii, LiCH,CO,Li; xix , H + ; xx, 0,;xxi, Ac,O-py; xxii, (CH,SH)2-BF3Et20; xxiii, PCC; xxiv, PhSeCl ;xxv, K,CO,-MeOH ;xxvi, Bu'Me,SiCI-py-then Me3SiC1; xvii, CO,; xxviii, CH,O-Et,NH ; xxix, (CH,=CMeCO),O-py-DMAP
Scheme 59
Sesquiterpenoids
163
14 Vetispirane and Related Sesquiterpenoids A new pair of stereochemically different lubimins, 2-epi- and 15-dihydro-2epilubimin (657) and (658) respectively, have been identified as stress metabolites in potatoes inoculated with Alternaria s o l a ~ l i Another . ~ ~ ~ new phytoalexin from potatoes infected with Phytophthora infestans is rishitinone (659) whose structure is based on spectral data together with the correlation of its dihydro derivative with the identical compound synthesized from ( +)-nootkatone (660).296An investigation of the stress compounds from various Nicotiana species infected with tobacco mosaic virus and tobacco rattle virus has revealed the presence of six metabolites, solavetivone (661), 3-hydroxysolavetivone (662), solanascone (663), phytuberin (664), phytuberol (665) and glutinosone (666) in varying amounts.297 None of these compounds are present in the healthy tobacco leaves. By application of Nakanishi’s exciton chirality method to the dibenzoate of capsidiol, the absolute configuration of this stress compound has been shown to be (667) as anticipated on biogenetic grounds. 2 9 *
(657) R (658) R
= =
CHO CH20H
R Or&, (661) R = H (662) R = OH
(664) R = AC (665) R = H
HO
A. Stoessl and J. B. Stothers, Can. J. Chem., 1980, 58, 2069. N. Katsui, F. Yagihashi, A. Murai, and T. Masamune, Chem. Letr., 1980, 1455. 2 @ 7 R. Uegaki, T. Fujimori, S. Kubo, and K. Kato, Phytochemistry, 1981, 20, 1567. 2 9 8 M. J. Stillman, J. B. Stothers, and A. Stoessl, Can J. Chem., 1981, 59, 2303. IB6
164
Terpenoids and Steroids
(-)-Phytuberin (664) has been the synthetic target for three groups in the year under review. The first of these (Scheme 60) started from (-)-2-carone (668).299The second one (Scheme 61), commencing with (-)-carvone (669), is rather inadequately described.300 For instance, it is claimed that the lithium
i, ii
PhCH,O OQiii I
d
PhCH,O % 0 I
d
0
OCH2Ph
PhCH,?
H;q
PhCH20
&
t
OCHzPh
OAc
8
OCH,Ph
C / C0,Et
Reagents: i, LDA; ii, PhCH,OCH,Cl; iii, PhCH,OH-PTSA; iv, LiC rCC0,Et; v, Me,CuLi (-24 "C); vi, H,-Pd/C; vii, Bu',AlH; viii, OH-; ix, Ac,O-Et,N-DMAP Scheme 60
.1.;,
vii
0
0
(672) (67 1) Reagents: i, LDA; ii, CH,OH; iii, LiCECH; iv, Ac,O-py; v, HgS0,-aq. MeOH; vi, EtOC=CLi; vii, (CO,H),--MeOH; viii, MCPBA; ix, LiAIH,; x, 150 "C Scheme 61
aoo
D. Caine and T. L. Smith, Jr., J. Am. Chem. SOC.,1980, 102, 7570. J. A. Findlay, D. N. Desai, G. C. Lonergan, and P. S. White, Can. J . Chem., 1980, 58, 2827.
Sesquiterpenoids
165
enolate of (-)-camone reacts with formaldehyde to give (670) plus its C-10 epimer (do the authors mean dihydrocarvone?); no conditions are given for the conversion of (671) into (672); not a single optical rotation is recorded for any of the optically active compounds in the synthetic sequence. The final synthesis (Scheme 62) involves an interesting elaboration of elemol (673) to give the lactone (674) which had previously been converted into phytuberin (664).301
\\
0
piv,
ii
Reagents: i, O,-Me,S; ii, AcC1-PhNEt,; iii, NaI0,-OsO,; iv, OH-; v, 0,-NaH; vi, LiCH,CO,Li; vii, H,O+; viii, Os0,-py; ix, DBU; x, Pb(OAc),; xi, NaBH,; xii, TsC1-py; xiii, NaBH,CN; xiv, Li-NH,
Scheme 62
Solavetivone (661) has also been a synthetic objective with two new syntheses having been completed. The first of these (Scheme 63) achieved syntheses of both solavetivone (661) and the hydroxy derivative (675), whose glucoside has been identified in The second synthesis (Scheme 64) relied upon a Diels-Alder reaction to construct a bicyclo[2,2,2]octyl framework which was then cleaved by acid to release a prenyl-mesylate (679) for further acid-promoted 301 ao2
F. Kido, H. Kitahara, and A. Yoshikoshi, J. Chem. Soc., Chem. Commun., 1981, 1236. C. Iwata, T. Fusaka, T. Fujiwara, K. Tomita, and M. Yamada, J . Chem. SOC., Chem. Cornmun., 1981,463.
166
Terpenoids and Steroids "
O
s CHNz
--+ i
O
q
i
---+ i
OH
0 /,iii
CQ,
2=xcyq)toy& OMS
C0,Et j,x-xiii
OH
kii
Reagents: i, CuCI,; ii, LiAIH(OBu'),; iii, Li-NH,; iv, (CH,SH),-BF,.Et,O; v, MsC1-py ; vi, NaCH(CO,Et),; vii, OH-; viii, CH,O-Et,NH; ix, H+-A; x, Bu', AIH; xi, (CI,C),CO-Ph,P; xii, Zn-HOAc; xiii, Me1
Scheme 63
c y c l i ~ a t i o nIn . ~ ~the ~ event, conditions were found for the obtention of all four Diels-Alder a d d u c t ~ ,the ~ ~ syn-endo,exo ~ isomers (676) being transformed to hinesolone (680) and p-vetivone (68 l), while the anti-endo,exo isomers (677) were converted into solavetivone (661). In a subsequent communication the same devised an alternative method (Scheme 65) for the preparation of the anti-endo- and antfexo-adducts (682) and (683) corresponding to (678). A full paper on the synthesis of epihinesol (684) (ragarospirol) (see Vol. 2, p. 111) and the further elaboration of an intermediate to hinesol (685) has been published.306An interesting new spiro-annelation procedure has been developed which involves regiospecific intramolecular alkylation of enolates generated by non-hydrolytic decarboxylation of w-halo-p-keto-esters. Applying this method to the two ketoesters (686) and (687) (Scheme 66) provided a short route to p-vetivone (681) and p-vetispirene (688) (together with minor amounts of their C-4 e p i m e r ~ ) . ~ ~ '
303 ,04 305
306
307
A. Murai, S. Sato, and T. Masamune, Tetrahedron Lett., 1981, 22, 1033. A. Murai, S. Sato, and T. Masamune, Chem. Lett., 1981, 429. A. Murai, S. Sato, and T. Masamune, J . Chem. SOC.,Chem. Commun., 1981, 904. J. Lafontaine, M. Mongrain, M. Sergent-Guay, L. Ruest, and P. Deslongchamps, Can. J . Chem., 1980,58,2460. R. G. Eilerman and B. J. Willis, J . Chem. SOC.,Chem. Commun., 1981, 30.
Sesquiterpenoids
167
Reagents : i, Br2-Fe; ii, CH,=CHCH,MgBr ; iii, OsO,-NaIO,; iv, (CH,OH),-PTSA ; v, Li-NH,-EtOH; vi, 140°C; vii, CH,=CHCO,Me; viii, H,O+; ix, NaBH,; x, MeLi; xi, MsCl-Et,N; xii, HC0,H; xiii, aq. (CO,H),; xiv, Al,O,-py
Scheme 64
Terpenoids and Steroids
168
1
i-iii
Iv-vii
Hd
H6 (682)
(683)
; v, MeLi; vi, Bu',AlH;
Reagents: i, LDA; ii, ClCH,CN; iii, CH,PPh,; iv vii, NaBH,
0
Scheme 65
J,iiiv,
i, ii, v
(687)
(681)
Reagents: i, LiCl-HMPA; ii, MeLi; iii, PTSA; iv, PCC; v, H,O'
Scheme 66
Sesquiterpenoids
169
15 Eremophilane, Ishwarane
Recent additions to the eremophlane sesquiterpenoids include the petasol derivative (689),308 isofukinone (690),309 the noreremophilane (69 1),310 and the unique cyclopropenone derivative (692).311 This last compound also co-occurs
q&
qly 0
0
with its C-7 epimer and the eudesmane analogue (693). A variety of furanoeremophilanes, eremophilanolides, and cacalol derivatives (694)-(706)649312-314 have been isolated from various Senecio species. Noteworthy are the structures of the eremophilene derivative (699)312which has the same stereochemistry as capsidiol (667) and senaequidolide (705),313an oxidized cacalol derivative. An X-ray analysis of istanbulin-B has shown it to have structure (707).315A variety of seco-eremophi-
&
0 A
n
g
O
m
RO-*
(694)64various R groups
R
(695)64R (696) R
= H, =0
OH
(697)312
OH
HO
(698)312R 308 308
310 311
=
H or OH
***
(699)312
(700)313
F. Bohlmann, M. Ahmed, H. Robinson, and R. M. King, Phytochemistry, 1981, 20, 1157. F. Bohlmann and U. Fritz, Phytochemistry, 1980, 19, 2471. F. Bohlmann, W. Kramp, H. Robinson, and R. M. King, Phytochemistry, 1981, 20, 1739. F. Bohlmann, J. Jakupovic, L. Muller, and A. Schuster, Angew. Chem., Int. Ed. Engl., 1981,20, 292.
314
F. Bohlmann and J. Ziesche, Phytochemistry, 1980, 19, 2681. F. Bohlmann, J. Ziesche, R. M. King, and H. Robinson, Phytochemistry, 1980, 19, 2675. J. Jizba, V. LaudovA, Z . Samek, K. Ubik, and L. Novotny, CON.Czech. Chem. Commun., 1981,
315
46,1048. P. J. Cox, F. Hall, and G. A. Sim, Tetrahedron, 1980, 36, 3437.
313
.*
170
Terpenoids and Steroids
@&AngO...(y&
OMe
R‘. OH (701)313
\
OR (703)313various R groups
(702)313
OMe
0
HO
(705)313 Senaequidolide (706)314Nemosenin
(704)313
lanolides (708) have been identified in Senecio r n a ~ r o t i s .The ~ ~ ~conformational equilibria of a number of furanoeremophilanes have been studied by lH, 13Cn.m.r., and c.d. These compounds exist in ‘steroid-like’ conformations (709) and ‘non-steroid-like’ conformations (7 10) according to such factors as nature of substituents, nature of solvent, and concentration, etc.
mo (707)
OAc
( J OR Y k o (708)
A very neat method for the synthesis of furanoeremophilanes has been devised which incorporates a so-called bis-heteroannulation process.31sThis is achieved by an intramolecular Diels-Alder reaction between an oxazole and an acetylenic grouping and is nicely demonstrated by the synthesis of ligularone (711) and petasalbine (7 12) (Scheme 67).319 A number of straightforward syntheses of 316
317
s18 81B
F. Bohlmann, R. K. Gupta, J. Jakupovic, R.M. King, and H. Robinson, Phytochemistry, 1981, 20, 1155. M. Tada, T. Sato, T. Takahashi, K. Tori, I. Horibe and K. Kuriyama, J . Chem. SOC.,Perkin Trans. 1, 1981, 2695. P. A. Jacobi, D. G. Walker, and I. M. A . Odeh, J . Org. Chem., 1981, 46, 2065. P, A. Jacobi and D. G . Walker, J. Am. Chem. Soc., 1981, 103,461 1.
Sesquiterpenoids
171
(7 12) Reagents: i, MCPBA; ii, LiCH,NC; iii, Me,SO-(COCl),; iv, LiCzCMe; v, A
Scheme 67
R2
HO
(713) R1= R2 = H (714) R1= Ac, R2= H (715) R1= Bu', R2= H (716) R1= Pr; R2= OPr
J$Jq
0
0
(7 19)
Terpenoids and Steroids
172
eremophilane sesquiterpenoids include those of 6P-hydroxy-1,lO-dehydrofuranoeremophilan-9-one (7 13),320decompositin (714),320adenstylone (715),320 dihydrodecompositin (7 17),3203 ~,6~-dipropionyloxyeuryopsin-9-one (7 16),320eremofortin B (7 18),321 furanoeremophilan-3,6-dione (7 19),322and furanoeremophilan-6a, 14olide (720).322The unusual seco-furanoeremophilanes (72 1)323 and (722)324have also been synthesized. The biosynthesis of PR toxin (723), derived from Penicillium roqueforti, has been examined by incorporation of [ 1,2-13C2]acetateinto the fungus.325 The labelling pattern as observed from the I3C n.m.r. spectrum is completely in accord with the original Robinson proposal involving a C-10, C-5 methyl migration from a eudesmane-type precursor, as has been demonstrated before. A new type of seco-ishwarane alcohol (724) has been identified in the roots of A ristolochia i ~ d i c aThis . ~ ~compound, ~ which co-occurs with ( +)-led01 (725), has antifertility properties when tested on mice. Its structure was deduced on the basis of spectral analysis together w.ith its correlation with a derivative of ishwarane (726). A full report on the synthesis of ishwarone (727) has been presented.327
(723)
(726) R (727) R
= =
H2 0
16 Guaiane, Pseudoguaiane, Patchoulane, Seychellane The new guaiane alcohol (728) has been identified in the soft coral Nephthea ~ h a b r o l i i . The ~ ~ * vast majority of new guaiane sesquiterpenoids are guaian-6a, 12elides and these are listed in the Table.61,152,224,228,230,231,233,241,242,251,329-33 9 In 320
321 322 323 324 325
K. Yamakawa and T. Satoh, Heterocycles, 1981, 15, 337. K. Yamakawa, T. Mashiko, and T. Satoh, Chem. Lett., 1981, 929. M. Tada, Y. Sugimoto, and T. Takahashi, Bull. Chem. SOC.Jpn., 1980, 53, 2966. F. Bohlmann and G . Fritz, Tetrahedron Lett., 1981, 22, 4803. F. Bohlmann and G . Fritz, Tetrahedron Lett., 1981, 22, 95. S. Moreau, A. Lablache-Combier, and J. Biguet, Phytochemistry, 1981, 20, 2339; A. A. Chalmers, A. E. de Jesus, C. P. Gorst-Allman, and P. S . Steyn, J. Chem. SOC.,Perkin Trans. I, 1981, 2899.
S. C. Pakrashi, P. P. G. Dastidar, S. Chakrabarty, and B. Achari, J . Org. Chem., 1980,454765. 327 E. Piers and T.-W. Hall, Can. J. Chem., 1980, 58, 2613. 328 B. F. Bowden, J. C. Coil, and S. J. Mitchell, A m . J . Chem., 1980, 33, 1833. 328 F. Bohlmann, W. Kramp, R. K. Gupta, R. M. King, and H. Robinson, Phytochemistry, 1981, 20, 2375. 330 A. Rustaiyan, A. Niknejad, C . Zdero, and F. Bohlmann, Phytochemistry, 1981, 20, 2427. 331 E. Tsankova, U. J. Kempe, T. Norin, and 1. Ognyanov, Phytochemistry, 1981, 20, 1436. 332 F. Bohlmann, A. K. Dhar, R. M. King, and H. Robinson, Phytochemistry, 1981, 20, 1144. 333 A. Rustaiyan, L. Nazarians, and F. Bohlmann, Phytochemistry, 1981, 20, 1152. 334 A. Rustaiyan, A. Niknejad, F. Bohlmann, and A. Schuster, Phytochemistry, 1981, 20, 1154. 335 W. Herz and N. Kumar, Phytochemistry, 1980, 19, 2387. 336 A. F. Halim, A. M. Zaghloul, and F. Bohlmann, Phytochemistry, 1980, 19, 2767. 337 F. Bohlmann, C. Zdero, R. M. King, and H. Robinson, Phytochemistry, 1980, 19, 2669. 338 Y. Asakawa, M. Toyota, and T. Takemoto, Phytochemistry, 1981, 20, 257. 339 Y . Asakawa, Z . Taira, M . Toyota, T. Takemoto, W. Herz, and T. Sakai, J . Org. Chem., 1981, 326
46, 4602.
Sesquiterpenoidr
173
Table Guaian-6q12-olides (1 4 a H stereochemistry unless otherwise stated) Double bond position(s) 3,4; 11,13;10,14
Name
Substituents
Ref.
2P,8P-diOH ; 9P-0COC(CH2OAc)==CHMe Preeupatundin* 3,4;11,13;10,14 2P,9P-diOH ; 8P-OCOC(CHzOAc\-CHMe 3,4;11,13;10,14 Preeupatundin* 2P,9P-diOH ; 8P-OCOC(CHzOH+CHMe Agriantholide* 3,4;11,13 2/3,9a-diOH; 8P-OCOC(CH2OAc+CHMe ; 1Oa,14-epoxy 4,15;9,10 1 1a-Me Eremantholide* 4,15;11,13;10,14 3-keto; 8a-OH Zaluzanin C* 4,15 Zaluzanin C* 3P,8a-diOH; 4a, 11a-diMe 3,4;1,10;11,13 Guaiagrazielolide* 8P-OAng; 9,14-P-lactone Lasiolaenin*t 3,4;11,13;10,14 e.g. 8P-OTig; 9P-OH Dehydrocostus lactone" 4,15 ;11,13 ;10,14 9a-0MeBu Dehydrocostus lactone* 4,15;11,13;lo, 14 9a-Oval i Dehydrocostus lactone* 4,153 1,13;lo, 14 8cr-OAng Dehydrocostus lactone* 4,15;11,13;9,10 14-OAng Zaluzanin C* 3P-OAng; 1la-Me 4,15 ;lo, 14 Jaquilenin* 3,4;1,10 2-keto; 15-OAc; 11P-Me Estafiatin* 11,13 3a,4a-epoxy; 8a-OAng ; 10a-OH Vicolide A 3,4;11,13 2-keto; 8a-OH; 9P-OAng; IOP-Me Cumambranolide* 3,4;11,13 8a-OCOCHMe, ; 1 Ocr-OH 3,4;11,13;1,lO KauniolideG 3,4 ;11,13 ;10,14 Rupicolin* 2u-OH 3,4;11,13 Arbiglovin*0 2-keto; 10a-OH 1,10;11,13 2-Oxoludartin 2-keto ; 3u,4a-epoxy 10,14 Solstitidin* 3-keto ; 4a-Me ; 1 1or-OAc ; 1 3-OAc 2,3;11,13 la,4a-peroxy; 9a-OAc; 1Oa-OH Apressin 11,13;1,10 2-keto ; 3a,4a-epoxy ; %-OH ; Guevariolide 8P-OCOCH=CMez 4,159 1,13;10,14 2,3-diOH ; 8a-OCOC(Me)==CH Costus lactone* 11,13;10,14 3,4-diOH; 8a-OCOC(CH,0H)-CH2 Acrorepioli de 11,13;10,14 Repin* 3P,8P-diOH; 4p,15-epoxy 3,4;11,13 Spicatin*$ 2P-OH ; 8P-X ; 1Oa,14-epoxy 3,4;11,I3 Spicatin*$ 2P,lOa-diOH; 8P-X; 1 4 4 10,14 (no name) 3-keto; 4a,l la-diMe; 9p-OH 4,15;1 I , 13;9,10 Eremanthine* 8a-OCOCH2CHMe, 4,15; 1 1,13;10,14 8a-OCOCH,CHMe2 Costus lactone* 3,4;11,13 Cumambranolide* 8a-OCOC(Me)=CH 2 ; 1Oa-OH 3,4;11,13 Cumambranolide* 8or-OTig; 1Ou-OH 11,13;10,14 Estafiatin" 3a,4a-epoxy;8a-OCOC(Me)=CH 3,4;9,10 PorelladiolidelI 2P,14-y-lactone; 1 Icr-Me Eregoyazidin 9,lO 3-keto; 4a,l la-diMe Preeupatundin*
61 61 61 61 152 224 224 228 230 23 1 23 1 23 1 23 I 23 1 233 241 242 251 329 329 329 329 330 33 1 332 333 333 334 335 335 336 337 337 337 337 337 338 339
*Derivative of. ?Eight different compounds, four of which have 3a,4a-epoxide. $Also 11p,l3dihydro derivative. SX = 11 Also 3a,4a-epoxy derivative.
15 Q 3
11
0
13
0
174
Terpenoids and Steroids
addition to these are the more unusual or modified guaianolides (729)-(744).2309279f The new pseudoguaianolides are depicted by structures (745)-(758).345-350 3379340-344
(729)230R1= CHO, R2 = H, Lasiolaenolide Derivatives (730) R1= CH20H, R2 = H (731) R1= CH20H, R2 = OAC (732) R1= CHO, R2 = OAc (3a, 4a-epoxide)
R
(733)279
* IH
(734)337R = H, Elehirtanolide (735) R = OCOCH,CHMe,
0 (736)340R1 = CH,OH, R2 = Ac, Lactucin Derivatives (737) R1 = CHO, R2 = COC(Me)=CH,
(also I 1p, 13-dihydro analogues of (736) and (738)-Jaquinelin Derivatives)
343
F. Bohlmann, J. Jakupovic, W.-R. Abraham, and C. Zdero, Phytochemistry, 1981, 20, 2371. K. Ito and T. Iida, Phytochemistry, 1981, 20, 271. Z. Samek, T. VanEk, and M. Holub, Coll. Czech. Chem. Commun., 1981, 46, 941. J. F. Malone, M. Parves, A. Karim, M. A. McKervey, I. Ahmad, and M. K. Bhatty, J . Chem.
344
SOC., Perkin Trans. I , 1980, 1683. J. Beauhaire, J. L. Fourrey, J. Y.Lallemand, and M . Vuilhorgne, Tetrahedron Lett., 1981, 22,
340
s41 a4a
2269. 345
346 347
348
349
360
G . Willuhn, G. Pretzsch, and D Wendisch, Tetrahedron, 1981, 37, 773. W. Herz, N. Kumar, and J. F. Blount, J . Org. Chem., 1981, 46, 1356. Y. Imakura, K.-H. Lee, D. Sims, R.-W. Wu, I. H. Hall, H. Furukawa, M. Itoigawa, and K. Yonaha, J . Pharm. Sci., 1980, 69, 1044. W. Herz, D. Gage, and N. Kumar, Phytochemistry, 1981, 20, 1601. F. Bohlmann, J. Ziesche, H. Robinson, and R . M. King, Phytochemistry, 1981, 20, 1146. M. A. ElSohly, A. S . Sharma, and C . E. Turner, J . Nut. Products, 1981, 44, 617.
Sesquiterpenoids
175
(739)341Inuchinenolide B
(740) Inuchinenolide C
Go
and
OAc
, I
(741) Inuchinenolide A
Q.oAc
---0Ang
q.H 0
0 (742)342Acetylisomontanolide
(743)343Grilactone
0 (744)344Isoabsinthin
(745)345R = OH Chamissonolide (746) R = H
(747)346R1= R2 = H , R udmollin (748) R1= Ac, R2 = H Derivatives (749) R1 = H, R2 = AC
(750)34sRudmollitrin
(751)347Microhelenin A
Terpenoids and Steroids
176
(752)347R (753) R (754) R
= = =
H, Plenolin COCH(Me)Et, Microhelenin B Tig, Microhelenin C
aoQ ““;‘.Q (755)347Microlenin Acetate
0
0
0
0
-
0
(756)34s3-Hydroxyambrosin Damsinate
(757)349Kingiolide
(758)350Isoheleniamarin
Two stereochemically different sets of bourbonolides (759), (760),4 and (76 1)(763)224have been identified in various Vernonia species. Co-occurring with the last three is the guaianolide (764). A further examination of Trixis species has resulted in the isolation of the trixic acid derivative (765) and other examples of trixikingolides (766) together with the rotundene analogue (767).225Additional examples of xanthanolides are the tomentosin derivatives (768)-(770)27s and 2-epixanthanol (771).351It is interesting to note that it has been reported that xanthumin (772) and 8-epixanthatin (773) are potent insect development inhibitors. 352
0 (759) R (760) R asl
= Tig =
COC(Me)=CH,
F. Bohlmann and C . Zdero, Phytochernistry, 1981, 20, 2429. K. Kawazu, S . Nakajima, and M. Ariwa, Experientia, 1979, 35, 1294.
Sesquiterpenoids
177
---OR
co-occurs with
0
(761) R (762) R (763) R
= AC = Tig = COC(Me)=CH,
\
'0 (764)
(769) R' = H, OH; R2 = 0 (770) R' = 0; R2 = H, OH (771) R1= H, OAC; R2= H, OH
(772)
(773)
Some interesting new approaches to the synthesis of the hydroazulene skeleton found in guaiane and pseudoguaiane sesquiterpenoids have been reported. These include the synthesis of (774)353and the fluoride-induced fragmentation of the two silyl ethers (775) and (776) to give (777).354A carefully thought out potential synthesis of (778) by fragmentation and rearrangement of the alkoxide (779) unfortunately went awry because the A7ps-enolateof (778) formed in the reaction underwent a further intramolecular Michael reaction to produce (780).355Independent generation of this enolate also gave (780). Another product of the fragmentation reaction was the bicyclic ketone (781) whose structure could also be rationalized mechanistically from (779). Another interesting result was obtained from 363 s54
3bb
J. J. Christie, T. E. Varkey, and J. A. Whittle, J . Org. Chem., 1981, 46, 3590. L.-F. Tietze and U. Reichert, Angew. Chem., Int. Ed. Engl., 1980, 19, 830. C. M. Tice and C. H. Heathcock, J. Org. Chem., 1981, 46, 9.
178
Terpenoids and Steroids OMS
o+ H OSiMe,
(774)
(775 )
(776)
0 (777)
&0-
0
(778)
(779)
the thermolysis of compounds such as (782) which gave predominantly (783) and (784)356 before hydrolysis. A mechanistic rationale for the formation of these compounds which includes a trimethylsilyl from one oxygen to another has been given. A careful analysis of the thermally-induced tandem Cope-Claisen rearrangement of the vinyl ether (785) has shown that products (786) and (787) are formed in the ratio of 7:3."' The mechanistic implications of this are that the initial Cope rearrangement proceeds through a chairlike transition state preferentially, followed by a Claisen rearrangement of the intermediate (788). The synthetic interest in (786) and (787) is that they have been converted into a mixture of (789) and (790).
356
357
F. Audenaert and M. Vandewalle, Tetrahedron Lett., 1981, 22, 4521. F. E. Ziegler and J. J. Piwinski, J. Am. Chem. SOC.,1980, 102, 6576.
Sesquiterpenoids
179
i d
/
s
)
ii, iii + '1
0
Y-i
CHO
0 *.
I 0 -
HO
vii, viii
0 Jix-xii
kii-xv
v, vi
c-
HO
OH
\-xviii
(793)
(792) Reagents: i, CuI.(MeO),P-CH,=CHCH,Br; ii, 0,-Me,S; iii, H 3 0 + ; iv, OH-; v, P,05MeS0,H; vi, LiAlH,; vii, Me,NCMe(OMe),-K,C03; viii, I,; ix, Bun3 SnH; x, (Me,N), CHOMe; xi, Bu',AIH; xii, PCC; xiii, LDA; xiv, PhSeC1; xv, [ O ] ;xvi, DBN; xvii, H,-Pt02; xviii, Ac,O-py Scheme 68
In the area of total synthesis, a full description of aromaticin (791) has app e a ~ e d in , ~addition ~~ to newly announced syntheses of aromatin (792) and confertin (793) (Scheme 68),359compressanolide (794) (Scheme 69),360and carpesiolin (795) (Scheme 70).361 A full report on the short stereocontrolled synthesis of racemic patchouli alcohol has been the key steps of which are the Grignard addition of the magnesium derivative of the bromide (796) to the dienone (797) followed by an intramolecular Diels-Alder reaction. The preparation of the two enantiomers of 368 359 360
3s1 382
P. T. Lansbury and D . G. Hangauer, Jr., Tetrahedron, 1981, 37, Suppl. No. 1, 371. F. E. Ziegler and J.-M. Fang, J. Org. Chem., 1981, 46, 825. A. A. Devreese, P. J . De Clercq, and M. Vandewalle, Tetrahedron Lett., 1980, 21, 4767. K. Nagao, M. Chiba, I. Yoshimura, and S.-W. Kim, Chem. Pharm. Bull., 1981, 29,2733. F. Naf, R. Decorzant, W. Giersch, and G. Ohloff, Helv. Chim. Acta, 1981, 64, 1387.
Terpenoids and Steroids
180
P3 &
iii-v +
i, ii +
60
0
viii-x
iii, xi, viii
f---
t---
....
0
0 (794)
Reagents: i, (CH,OH),-PTSA; ii, cumylhydroperoxide-triton B; iii, LDA; iv, Me&= CHCH,Br; v, Li-NH,; vi, 0,-Me,S; vii, Cr0,-H+; viii, H,O+; ix, CH,=PPh,; X, Me,SiClEt,N-DMAP; xi, Me1 Scheme 69
i-iv
ButO
o +v-viii ButO
---OH ButO Jix, x
pii,
xix
(795) Reagents: i, H2-Pt02; ii, MeO-; iii, LDA-CH,Br,; iv, BuLi; v, LDA; vi, PhSeBr; vii, HzOz; viii, LiAlH,; ix, MCPBA; x, LiCH, CO,Li: xi, (CF,CO),O-py; xii, PTSA; xiii, DHP-H+; xiv, aq. K,CO,; xv, CH,O; xvi, MsC1-py; xvii, DBU; xviii, PCC; xix, H,O+
Scheme 70
Sesquiterpenoids
181
(796) from (-)- and (+)-a-pinene has permitted syntheses of both natural (-)patchouli alcohol (798) and its antipode. The olfactory properties of these two enantiomers are quite different, the natural isomer having the highly prized earthy camphoraceous aroma while the unnatural ( +)-enantiomer is rather nondescript and by no means reminiscent of patchouli oil, thus providing another example of odour differences between enantiomers. This detailed study should settle the long-standing claim that pure (-)-patchouli alcohol is odourless and that norpatchoulenol (799) is responsible for the typical note of the essential oil. It has now been shown that a very minor constituent of patchouli leaves is the diol (800), previously obtained from mammalian hydroxylation of patchouli alcohol.3s3 This diol may be the precursor of the norsesquiterpene (799) in the plant. Patchouli alcohol has been used as a test substance for a 13C n.m.r. technique which determines carbon connectivity by measurement and analysis of all one-bond 13C-13C coupling constants at natural abundance A limiting factor of this interesting technique for natural product structural elucidation is the relatively large sample required-3g of (798) in 0.3ml of C6D6. An earlier synthesis of seychellene (801) has been reported in full and improvements in some-key steps have been accomplished.365(Vol. 9, p. 155, Vol 11, p. 84).
(799) 17 Aromadendrane, Nardosinane, Neolemnane, Bicyclogermacrane In addition to the two sinularane derivatives isolated from the marine source CZavularia injluta (see p. 114), the aromadendrane derivative (802) has also been identified in the related species Clavularia k0e1likeri.l~’Another aromadendrane compound is the diol(803) obtained from the plant Senecio nemoren~is.~’~ An X-ray analysis of nardosinone has confirmed its structure as (804).366The soft coral Lemnalia africana is a rich source of sesquiterpenoids and recent investigations SO4
so5 866
E. Trifdieff, Phytochemistry, 1980, 19, 2467. A. Neszmelyi and G. Lukacs, J. Chem. Sac., Chern. Cornmun., 1981, 999. M.E. Jung, C. A. McCombs, Y.Takeda, and Y.-G. Pan, J. Am. Chern. SOC.,1981,103,6677. J. Friemann, G. Rucker, T. Frohlich, A. Kirfel, and G. Will, Liebigs Ann. Chem., 1981, 2057. 7
182
Terpenoids and Steroids
H o W ' * * ( ) A c
How.'.b H o W * , . IIo C ~
4OH
H+CHO (805)
A 0
0
(807) (806) have uncovered some more examples. These include the ent-nardosinane-type compounds (805)-(807).367 The metabolites from another sample of L. africana collected from the Western Caroline Islands have been identified as (808)-(810),
(808) R (809) R
=H = AC
d A
(819) 367
B. F. Bowden, J. C. Coll, S. J. Mitchell, B. W. Skelton, and A. H. White, Aust. J. Chem., 1980, 33, 2737.
Sesquiterpenoids
183
the first two of which have the novel neolemnane skeleton.368(-)-Spathulenol(8 1 1) and its C-4 epimer have been synthesized from (-)-p-pinene by an adaptation of the original Biichi synthesis of a r ~ r n a d e n d r e n e . ~ ~ ~ As noted in various places in this chapter, the identification of liverwort constituents has proved to be a very fruitful area of sesquiterpenoid chemistry. Several papers have been published on this subject; see for example the systematic screening of P l a g i o ~ h i l a ,F~r~~~l l a n i a ,R~ i~c~~ a r d i a ,P~a~l l~a ~ i c i n i a ,and ~ ~ ~ Conocephalum species.373A full paper has been published on the great variety of ent-2,3-secoalloaromadendranes and related sesquiterpenoids isolated from Plagiochila s e m i d e c ~ r r e n sMany . ~ ~ ~ of these compounds have plant growth-inhibitory properties. The latest additions to this group of sesquiterpenoids are (+)-9a-acetoxyovalifoliene (8 1 2)375and tridensenone (8 1 3).46 Some interesting, biologically active metabolites from the liverwort Lepidozia vitrea include (+)-vitrenal ( 8 14)376and ( -)-lepidozenal (8 1 5),37 the latter compound having the rare trans-fusion of the cyclopropane ring. Previously ( -)-isobicyclogermacrenal (8 16) had been isolated from this liverwort and there is a possible biogenetic link between it and ( +)-vitrenal via ring contraction of the ent-allo-aromadendryl cation (817) derived from cyclization of (816). A full paper on the photochemical synthesis of (818), a compound related to taylorione (819), has been 18 Pinguisane Some new pinguisane sesquiterpenoids have been isolated from liverwort species. These include dehydropinguisanin (820),dehydropinguisenol(821), and pinguisenal
@ 0
36 8 88 9 870
371
b
0 0
R. R. Izac, W. Fenical, B. Tagle, and J. Clardy, Tetrahedron, 1981, 37, 2569. H. Surburg and A. Mondon, Chem. Ber., 1981, 114, 118. Y. Asakawa, H. Inoue, M. Toyota, and T. Takemoto, Phytochemistry, 1980, 19,2623. Y . Asakawa, R. Matsuda, M . Toyota, S. Hattori, and G. Ourisson, Phytochemistry. 1981, 20, 2187.
3 7a
878
374
875
3 76
377 378
Y. Asakawa, M. Toyota, R. Takeda, C. Suire, and T. Takemoto, Phytochemistry, 1981, 20, 725. Y. Asakawa, R. Matsuda, and R. Takeda, Phytochemistry, 1981, 20, 1423. A. Matsuo, K. Atsumi, M. Nakayama, and S. Hayashi, J . Chem. SOC.,Perkin Trans. 1, 1981, 2816. A. Matsuo, K . Atsumi, K. Nadaya, M. Nakayama, and S. Hayashi, Phytochemistry, 1981,20, 1065. A. Matsuo, S. Uto, H. Nozaki, M. Nakayama, and S. Hayashi, J . Chem. SOC.,Chem. Commun. 1980, 1220. A. Matsuo, N. Kubota, M. Nakayama, and S. Hayashi, Chem. Lett., 1981, 1097. G . Pattenden and D. Whybrow, J . Chem. SOC.,Perkin Trans. 1 , 1981, 1046.
184
Terpenoids and Steroids
(822) from Trocholejeunea s a n d v i ~ e n s i s .The ~ ~ ~last compound, together with pinguisanin (823) and pinguisanolide (824) has been identified in Ptilidium pulcherr i r n ~ r nA . ~new ~ ~ type of pinguisane, ptychanolide (825), has been obtained from the liverwort Ptychanthus s t r i a t ~ sThe . ~ ~spiro-lactone ~ function in this compound is reminiscent of some of the fukinane sesquiterpenoids. In a synthetic study of the pinguisane compounds, Jommi et al. have converted the diene-dione (826) into 7-epipinguisone (827)382and pinguisone (828)383(Scheme 71).
i, iv t--
a5
0
(828) Reagents: i, Me,CuLi; ii, Br,-AcOH; iii, CaCO,; iv, CICH,COCI; v, 9-BBN; vi, Pr'SH; vii, NaIO,; viii, A-CaCO,
Scheme 71 19 Miscellaneous
The two epimeric sesquiterpenoids (829) have been synthesized and shown to be identical to minor constituents of Eumorphia p r ~ s t a t a Cantharidin .~~~ (832) has, 378 a80
381
382
383
a64
Y. Asakawa, M. Toyota, M. Kano, and T. Takernoto, Phytochemistry, 1980, 19, 2651. Y. Asakawa, R. Matsuda, and C. Suire, Phytochemistry, 1981, 20, 1427. R. Takeda, H. Naoki, T. Iwashita, and Y. Hirose, Tetrahedron Lett., 1981, 22, 5307. S. Bernasconi, M. Ferrari, P. Gariboldi, G. Jomrni, M. Sisti, and R. Destro, J. Chem. SOC., Perkin Trans. 1, 1981, 1994. S. Bernasconi, P. Gariboldi, G. Jommi, S. Montanari, and M. Sisti, J. Chem. Soc., Perkin Trans. 1, 1981, 2394. F. Bohlmann and L. Fiedler, Chem. Ber., 1981, 114, 227.
Sesquiterpenoids
185
at long last, succumbed to a straightforward synthesis by way of a high-pressure Diels-Alder reaction. 385 Thus, reaction of furan with the anhydride (830) in dichloromethane solution at 15 kbars gives predominantly the adduct (83 1). Treatment of this compound with Raney nickel produces cantharidin (832).
385
W. G . Dauben, C. R. Kessel, and K. H. Takemura, J. Am. Chem. SOC.,1980,102,6893.
3 Diterpenoids BY J. R. HANSON
1 Introduction
This review follows the pattern of previous Reports with sections based on the major skeletal types of diterpenoid. The literature that has been covered is that which was available to August, 1981. The useful Kyoto series of reviews has continued to appear.l An interesting number of new clerodanes have been obtained from the Labiateae, particularly Teucrium species, and the absolute stereochemistries of many of these have now been clarified. The extensive survey of the Compositae by Bohlmann has led to the description of many new diterpenoids although some of the structures which have been assigned purely on n.m.r. evidence require confirmation by chemical inter-relationships. The occurrence of particular diterpenoid skeleta may have taxonomic significance. The chemistry of the gibberellin plant hormones has attracted considerable attention during the year with a number of total and partial syntheses being recorded. Marine organisms have continued to yield many diverse types of diterpenoid skeleta. 2 Acyclic and Related Diterpenoids
20-Hydroxygeranylnerol has been obtained2 from Kingianthus paradoxus (Compositae). The biogenetic significance of a number of hydroxylated acyclic diterpenoids with internal cis double bonds [e.g. (l)], which were obtained from the resin of Eremophila exilijiolia and E. glutinosa, has been discussedSin relation to the cembrane and serrulatane diterpenoids which have been found in other Eremophila species. Marine organisms have been the source of a number of alicyclic diterpenoids. Some further acyclic diterpenoids [e.g. (2)] which are related to crinitol and eleganolone have been obtained4 from the brown alga, Cystoseira
H OH
*
E. Fujita, K. Fuji, Y.Nagao, and M. Ochiai, Bull. Znst. Chern. Res., Kyoto Univ., 1980,58,484. F. Bohlmann, J. Ziesche, H. Robinson, and R. M. King, Phytochemistry, 1981, 20, 1146. E. Ghisalberti, P. R. Jefferies, and G. M. Proudfoot, Aust. J . Chem., 1981,34, 1491. V. Amico, G. Oriente, M. Piatelli, G. Ruberto, and C. Tringali,Phytochemistry, 1981,20, 1085.
186
Diterpenoids
187
crinitu. The lactone (3), which may be derived by the internal hydrolysis of an epoxide, was amongst the terpenoids which were obtained from A canthospermurn uustrule.=
OH (3) 3 Bicyclic Diterpenoids Labdanes.-The 13C n.m.r. data for some labdanes related to andrographolide have been reported6and 13Cn.m.r. methods have been applied’ to the determination of the C-14 configuration of some 8,13-epoxylabdan-14-ols.The empirical correlation between structure and the optical rotation of the Cistus lubduniferus diterpenoids has been questioned.6 A number of labdane 13-0-glycosides have been obtained9 from Aster sputhulifolius (Compositae) and ent-3cr-hydroxy-13epimanool (4) has been obtained from Croton sublyrutus.1° Some labdane dialdehydes [e.g. ( 5 ) ] have been reportedll in Alpiniu species. In the course of a search
CH,OH
Br”-
G
P
O
H
for compounds with insect anti-feeding activity, the grindelane diterpenoid (6) and its succinate ester were isolated12from Crysothumnus nuuseosus (Compositae) (rabbitbrush). Various diacetates of the grindelane diterpenoid lagochilin have been F. Bohlmann,J. Jakupovic, A. K. Dhar, R. M. King, and H. Robinson, Phytochemistry, 1981, 20, 1081.
A. Patra, A. K. Mitra, S. Biswas, C. D. Gupta; A. Basak, and A. K. Barua, Org. Mugn. Reson., 1981, 16, 75. M. C. Garcia-Alvarez and B. Rodriguez, J. Org. Chem., 1981, 46, 1915. * V. A. Paldugin, Khim. Prir. Soedin., 1981, 169. * Y.Uchio, M. Nagasaki, S. E. Guchi, A. Matsuo, M. Nakayama, and S. Hayashi, Tetrahedron Lett., 1980,21, 3775. lo E. Kitazawa and A. Ogiso, Phytochemistry, 1981, 20, 287. l1 H. Itokawa, M. Morita, and S. Mihaashi, Chem. Pharm. Bull., 1980, 23, 3452. A. F. Rose, Phytochemistry, 1980, 19, 2689.
Terpenoids and Steroids
188
described.13 Some simple labdane acids are amongst14 the constituents of Morithamnus crassus and a number of labdanes and kolavenes were obtained15 from Acritopappus (Compositae) species. Chemical and spectroscopic data have been reported16for the structure of isoconcinndiol(7) which is a brominated diterpenoid from the red alga Laurencia snyderae. A series of andalusol derivatives (8) have been obtained1' from Sideritis foetens (Labiatae). 7a-Acetoxytranscommunic acid (9) was reportedla from Chrornoluenu collina. The acetate (10) and hemi-acetal (1 1) were describedlg as constituents of
(8) R' = H, R2 = OH, R3 = OAC R1 = H, R2 = OAC,R2 = OH R1 = OH, R2= H, R2 = OAC
(9)
(13) Schkuhria species. Some labdane derivatives [e.g. (12)] were obtained20 from Ageratium fastigiaturn. 7a-Hydroxylambertianic acid was isolated21from Gutierreziu dracunculoides. Dodonaea species have been a rich source of bicarbocyclic diterpenoids. The X-ray crystal structure of the acid (1 3), obtained from D . petioluris, has been reported.22 A further group of acetals has been prepared from m a n 0 0 1 ~for ~ structure-odour studies. Some lY5-diepoxidesin this group underwent rearrangement based on the intramolecular opening of 8@,9p-epo~ides.~~ (1 1)
(12)
R. Isiamov, U. N. Zainutdinov, and K. A. Aslanov, Khim..Prir. Soedin., 1981. 57. F. Bohlmann, J. Jakupovic, H. Robinson, and R. M. King., Phytochemistry, 1980, 19, 2769. I6 F. Bohlmann, C. Zdero, R. K. Gupta, R. M. King, and H. Robinson, Phytochemistry, 1980, 19, 2695. I@ B. M. Howard and W. Fenical, Phytochemistry, 1980, 19, 2774. M. C. Garcia-Alvarez and B. Rodriguez, Phytochemistry, 1980, 19, 2405. Is F. Bohlmann, C. Zdero, L. Fiedler, H. Robinson, and R. M. King, Phytochemistry, 1981, 20,
la
I4
1141. 2o
21 a2
*a 24
F. Bohlmann, J. Jakupovic, H. Robinson, and R. M. King, Phytochemistry, 1980, 19, 881. F. Bohlmann, M. Grenz, A. K. Dhar, and M. Goodman, Phytochemistry, 1981,20, 105. F. Bohlmann, M. Ahmed, R. M. King, and H. Robinson, Phytochemistry, 1981, 20, 1434. P. R. Jefferies, T. G. Payne, C. L. Raston, and A, H. White, Aust. J. Chem., 1981, 34, 1001. P. K. Grant and D. D. Rowan, Aust. J . Chem., 1981, 34, 1959. P. K. Grant and D. D. Rowan, Aust. J. Chem., 1981,34, 1975.
D iterpenoids
189
C1erodanes.-A number of bicyclic diterpenoids such as the labdane-lactone (14) and the epoxy-kolavane(1 5 ) are amongst the constituents of Hartwrightia J I ~ r i d a n a ~ ~ and some further clerodanes related to bacchotricuneatin B were obtainedz6from Baccharis species. Some kolavanes were reportedz7 as constituents of Liatris scariosa. A chemical correlation has been established2* between the cis- and trans-clerodane diterpenoids. A revision of the structures assigned to several solidagolactones (elongatolides) has been proposed.29A tricarbocyclic lactone (16),
w **.
H
:
which may be formed by the base-catalysed cyclization of a cis-clerodane, has been isolated30 from Solidago altissima. Its structure was established on the basis of its spectral data and an X-ray analysis of the corresponding triol. The X-ray structure of the diacetate of a transclerodane (17) isolated from Pityrodia Iepidota (Verbenaceae) has been reported.31 The structure (18) has been assigned32on the basis of n.m.r. evidence to a clerodane lactone from Bahianthus viscidus. A full paper has appeared33on the identification of the 5,lO-seco-clerodanesof Conyza stricta. Croton (Euphorbiaceae) species have afforded several types of diterpenoid. Penduliflaworosin (1 9), isolated34 from C. pendulzJ7orus, represents a structure a5
J. Jakupovic, A. K. Dhar, F. Bohlmann, R. M. King, and H. Robinson, Phytochemistry, 1981, 20, 843. F. Bohlmann, C. Zdero, M. Grenz, A. K. Dhar, H. Robinson, and R. M. King,Phytochemistry,
e7
F. Bohlmann, M. Ahmed, H. Robinson, and R. M. King, Phytachemistry, 1981, 20, 1439. I. Kitagawa, T. Kamigauchi, K. Yonetani, and M. Yoshihara, Chem. Pharm. Bull., 1980,28, 24-03. M. Niwa and S. Yamamura, Tetrahedron Lett., 1981, 22, 2789. S. Yamamura, M. Ito, M. Niwa, I. Hasegawa, S. Ohbao, and Y. Saito, Tetrahedron Lett., 1981, 22, 739. E. Ghisalberti, P. R. Jefferies, C. L. Raston, R. F. Toia, and A. H. White, Aust. J. Chem.,
1981, 20, 281.
ao a1
1981, 34, 1009. a2
a4
F. Bohlmann, R. K. Gupta, R. M. King, and H. Robinson, Phytochemistry, 1981, 20, 331. S. B. Mahato, A. K. Sen, P. C. Mazumdar, and K. Yamasaki, Phytochemistry, 1981, 20, 850. K. A. Adesogan, J. Chem. Sac., Perkin Trans. I , 1981, 1151.
190
Terpenoids and Steroids
intermediate between the labdane and clerodane series. A similar feature is revealed35 by the 19-epimeric hemi-acetals, mallotucins C and D (20), which are constituents of Mallotus repandus (Euphorbiaceae). Sonderianin (21) is a clerodane which was
from Croton sonderianus, and the diacetate (22) has been reported37 as a constituent of C . pyramidalis. The structure (23) of croverin, which was obtained from C . verreauxii, was determined3* by X-ray analysis.
Although the absolute configuration of these clerodanes from Croton species was not determined, the absolute stereochemistry of a number of clerodanes from Teucrium (Labiatae) species has been clarified.39 19-Acetylgnaphalin and isofruticolone were shown to belong to the neoclerodane series. Teuflin (24) has been obtained40 from Teucrium viscidum and details of an X-ray structure have been published.41The structure (25), without absolute configuration, was assigned42to 35
86
T. Nakatsu, S. Ito, and T. Kawashima, Heterocycles, 1981, 15, 241. A. A, Craveiro, E. R. Silveira, R. F. Braz, and I. P. Mascarenhas, Phytochemistry, 1981, 20, 852.
s7
38
ag
40
48
L. Rodriguez-Hahn, A. Valencia, R. Saucedo, E. Diaz, and G . Negron, Rev. Latinoam. Quim., 1981, 12, 16 (Chem. Abstr., 1981, 94, 205 402). E. Fujita, M. Node, K. Nishida, M. Sai, K. Fuji, A. T. McPhail, and J. A. Lamberton, J . Chem. Sac., Chem. Commun., 1980, 920. M. Martinez-Ripoll, J. Fayos, B. Rodriguez, M. C . Garcia-Alvarez, G. Savona, F. Piozzi, M. Paternostro, and J. R. Hanson, J. Chem. SOC.,Perkin Trans. I , 1981, 1186; for a review see F. Piozzi, Heterocycles, 1981, 15, 1489. M. Node, M. Sai, and E. Fujita, Phytochemistry, 1981, 20, 757. M. Node, M. Sai, E. Fujita, and A. T. McPhail, J. Chem. Res. (S), 1981, 32. G. Papanov, P. Malakov, and F. Bohlmann, Phytochemistry, 1981, 20, 170.
Diterpenoids
191
J \
O0
OAc
(27)
(28)
(29)
teuscordinon from T. scordium. The structures of capitatin (26)43and lolin (27)44' obtained from T. capitatum were determined by X-ray analysis. Teucapitatin (28), obtained from the same source, was related to picropolin. The structure of auropolin (29), from T.polium subsp. aureum, was deduced45from an X-ray analysis of the
0
OAc
43
44
46
I
OAc
C. Marquez, R. M. Rabanal, S. Valverde, L. Eguren, A. Perales, and J. Fayos, Tetrahedron Lett., 1980, 21, 5039. C. Marquez, R. M. Rabanal, S. Valverde, L. Eguren, A. Peralse, and J. Fayos, Tetrahedron Lett., 1981, 22, 2823. L. Eguren, A. Peralse, J. Fayos, G. Savona, M. Paternostro, F. Piozzi, and B. Rodriguez, J. Org. Chem., 1981,46, 3364.
192
Terpenoids and Steroids
corresponding lactone. The clerodanes obtained from Ajuga (Labiatae) species have attracted attention because of their insect anti-feedant activity. The structures of some further clerodanes, ajugareptansone A (30) (ajugareptansone B is the A2-elimination from A . reptans and ajugamarin (31)47 from A . nipponensis, were established by X-ray analysis. 4 Tricyclic Diterpenoids
Naturally Occurring Substances.-The I3C n.m.r. data for isopimara 15,16-diols and the corresponding sandaracopimara- 15,16-diols have been correlated48 with their structures and the 13C n.m.r. spectra of some ent-rosane diterpenoids have been assigned.49 19-Norisopirnara-7,15-dien-3-one has been isolated50 from the fungus Acrernoniurn luzulae. The pimarane diterpenoid (32) has been isolated5’ from a Vellozia species and the trio1 (33) has been reported52 as a constituent of
SMe
0
(35) (36) (37) Prernna latifolia. The structure of the unusual ether (34), obtained from Acacia Zeucophloea,was established by X-ray analysis.53Micrandrol C (35) and micrandrol D (36) are constituents of Micrandropsis ~ c l e r o x y l o nUrbalactone .~~ (37) is another 49
F. Camps, J. C. Coll, and A. Cortel, Chem. Lett., 1981, 1093.
48
E. Wenkert, T. D. J. Halls, P. Ceccherelli, M. Curini, and R. Pellicciari, J . Org. Chem., 1981,
(’H. Shimomura, Y. Sashida, K. Ogawa, and Y. Litaka, Tetrahedron Lett., 1981, 22, 1367. O8
Lo
6a 63
64
46, 3135. M. C. Garcia-Alvarez, B. Rodriguez, S. Valverde, B. M. Fraga, and A. G. Gonzalez, Phytochemistry, 1981, 20, 167. N. Cagnoli, P. Ceccherelli, M. Curini, N. Spagnoli, and M. Ribaldi, J . Chem. Res. (S), 1980, 276. A. C. Pinto, L. M. Valente, R. S. Da Silva, W. S . Garzez, and P. P. Queirez, An. Acad. Bras. Cienc., 1981, 53, 73 (Chem. Abstr., 1981, 95, 98 071). B. C. Rao, K. Suseela, and E. K. S. Vijayakumar, Indian. J. Chem., Sect. B, 1981, 20, 175. A. Perales, M. Martinez-Ripoll, J. Fayos, R. K. Bansal, K. C. Joshi, R. Patni, and B. Rodriguez, Tetrahedron Lett., 1980, 21, 2843. M. A. De Alvarenga, J. J. Da Silva, H. E. Gottlieb, and 0. R. Gottlieb, Phytochemistry, 1981, 20, 1159.
193
Diterpenoids
member of the podolactone series which have been isolated from Podocarpus ~ r b a n i iA . ~ ~further report has appeared56 on the caesalpin from Caesalpinia bonducella. Diterpenoid quinones have been isolated from a number of the Labiatae. An o-quinone, ethiopinone (38), has been described as a c o n ~ t i t u e nof t ~ the ~ roots of Salvia aethiopis (Labiatae) and the known quinones horminone and 7cc-acetoxyroyleanone have been isolated58from S. lanata. The dehydroabietic acid derivative (39) was obtained59from S. tomentosa. The partial synthesis of the epimeric ring B
C0,Me (39)
(40)
(41)
mono- and di-hydroxyroyleanones has been reported60 and coleon U has been synthesized61from a podocarpic acid derivative. Some unusual rearranged tricyclic diterpenoids with a cis- A/B ring fusion have been isolated62 from Rondeletia panamensis (Rubiaceae). Panamensin has the structure (40) whereas its dihydro-derivative, rondeletin, has the 2-keto structure (41). Chemistry of the Tricyclic Diterpenoids.-The addition of chlorosulphonyl isocyanate to the methyl esters of levopimaric and neoabietic acids with the formation of C-12 carboxyamides has been described.63 The well documented aromatic substitution reactions of dehydroabietic acid continue to be examined,64together 65
5 .'
6B
Eo
Ea 63
6*
B. Dasgupta, B. A. Burke, and K. L. Stuart, Phytochemistry, 1981, 20, 153. K. K. Purushothaman, K. Kalyani, K. Subramanian, and S . Shanmuganathan, Indian J. Chem., Sect. B, 1981, 20, 625. M. T. Boya and S. Valverde, Phytochemistry, 1981, 20, 1367. K. S . Mukherjee, P. K. Ghosh, and S . Badruddoza, Phytochemistry, 1981, 20, 1441. A. Ulubelen, M. Miski, and T. J. Mabry, J . Nat. Products, 1981, 44, 119. H. Meier, P. Rueedi, and C. H. Eugster, Helv. Chim. Acta, 1981, 64, 630. S. Savard, M. Neron Desbiens, and R. H. Burnell, Synth. Commun., 1981, 11, 399. K. Koike, G. A. Cordell, N . R. Farnsworth, A. A. Freer, C. J. Gilmore, and G. A. Sim, Tetrahedron, 1980, 36, 1167. G. Mehta, D. N. Dhar, S. C. Suri, M. M. Bhadbhade, and K. Venkatesan, Indian J. Chem., Sect. B, 1981, 20, 193. H. Akita and T. Oishi, Chem. Pharm. Bull., 1981, 29, 1567.
Terpenoids and Steroids
194
with the cleavage65of the aromatic ring to form drimane sesquiterpenoids. The preparation of shonanol from dehydroabietic acid has also been reported.66 An improved route for the synthesis of methyl vouacapenate from podocarpic acid has been de~cribed.~' The photo-oxygenation of pimara-8-enes and isopimara-8-enes to afford the As(14)-9-alcohols has been described.6s The preparation and cleavage of some isopimarane-7,8-epoxides,with the formation of (11 )-dienes, has been examStudies on the rearrangement of some 8a,9a-epoxypodocarpanes with boron trifluoride etherate have been directed 70 at inducing a backbone rearrangement to afford the rimuene skeleton. The structure of an unusual pentacyclic ether (43), prepared by the action of boron trifluoride etherate on the epoxypimarane (42), A799
CH202CPh (42)
(43)
(44) (45) was established'l by X-ray analysis. The acid (45)was formed72by carbonylation of dihydroabietic acid (44)in the presence of carbon monoxide. The cyclization of methyl copalate to the tricyclic analogue of isoagathic acid has been followed75 by the conversion of the product into the enantiomer of the marine diterpenoid spongiadien- 12-01. The stereochemistry of the S,i cyclization in the biosynthesis of ent-sandaraco~ i m a r a d i e n eand ~ ~ virescenol B 75 has been studied using stereospecifically as O6
67
H. Akita and T. Oishi, Chem. Pharm. Bull., 1981, 29, 1580. T. Matsumoto, S. Irnai, H. Kawashima, and M. Mitsuki, Bull. Chem. SOC.Jpn., 1981,54,2099. G. Jommi, S. Bernasconi, P. Gariboldi, M. Sisti, and P. Tavecchia, J. Org. Chem., 1981, 46, 3719.
69
'O 71
74 7s
P. Ceccherelli, M. Curini, and R. Pellicciari, J . Chem. Res. ( S ) , 1981, 77. M. Curini, P. Ceccherelli, R. Pellicciari, and E. Sisani, Gazz. Chim. Ztaf., 1980, 110, 621. T. Nakano, A. Haces, A. Martin, and A. Rojas, J. Chem. SOC.,Perkin Trans. I , 1981, 2075. J. W. Blunt, E. J. Ditzel, M. P. Hartshorn, L. H. Sieng, M. H. G. Munro, and W. T. Robinson, Tetrahedron Lett., 1981, 22, 1923. B. E. Cross and M. R. Firth, J. Chem. Res. (S), 1981, 216. D. S. De Miranda, G. Brendolan, P. M. Imamura, M. Gonzalez Sierra, A. J. Marsaidi, and E. A. Ruveda, J. Org. Chem., 1981,46,4851. K. A. Drengler and R. M. Coates, J. Chem. SOC.,Chem. Commun., 1980, 856. D. E. Cane, H. Hasler, J. Materna, N. Cagnoli-Bellavita, P. Ceccherelli, G. F. Madruua, and J. Polonsky, J. Chem. SOC.,Chem. Commun., 1981, 280.
Diterpenoids
195
deuteriated substrates. The cyclization has been shown to proceed with the antistereochemistry . 5 Tetracyclic Diterpenoids
Kaurenoid Diterpenoids.-The 13C n.m.r. spectra of some 18-hydroxykaur-16-enes have been assigned.76The application of these results to the determination of the stereochemistry of substituents at C-4 has been discussed. Authentic phyllocladan16p-01 has been prepared77from phyllocladene. It differs from the ‘phyllocladan16p-01’ which was previously reported to occur naturally. The latter had very similar physical constants to phyllocladanol (the 16a-epimer). ent-Kauran-l6a, 17-diol has been from Aristolochia eleguns. Derivatives of ent-l5ahydroxykaurenoic acid are quite common. The cinnamic acid ester has been isolated79from Wedeliu gluucu (Compositae) and some other esters have been obtaineds0from Ichthyothere (Compositae) species. Crystallographic studies have establisheds1 the structure (46) for pterokaurene L,, which was isolated from Pteris longipes, and (47) for pteroatisene P,, which was isolated from P.purpureorachis.
:*
H CO,H
(48)
CO,H
(49)
The synthesis of some 18-norkaurene-15-carboxylic acids from 4p, 18-norkaurene3-one has been describeds2 as has the synthesis of 15-carbo~ykaurene.~~ The preparation of a series of fluorinated kaurenoids, including 16,16-difluoro-17norkauran- 19-oic acid from xylopic acid, has been described. 84 Ruboside, from
7~
A. G . Gonzalez, B. M. Fraga, M. G . Hernandez, and J. R. Hanson, Phytochemistry. 1981,20, 846.
’’ R. M. Carman, Aust. J . Chem., 1981, 34,923.
83
M. A. A. Habib and N. A. El-Sebakhy, Pharmazie, 1981,36,291. J. C. Oberti, A. B. Pomilio, and E. G . Gros, Phytochemistry, 1980, 19, 2051. F. Bohlmann, C. Zdeto, H. Robinson, and R. M. King, Phytochemistry, 1981,20, 522. T. Murakami, N. Tanaka, H. Iida, and Y . Iitaka, Chem. Pharm. Bull., 1981, 29, 773. A. L. Cossey, L. N. Mander, and J. V. Turner, Aust. J. Chem., 1980, 33, 2061. D. P. Popa, G . S. Pasechnik, A. M. Reinbol’d, and M. V. Atimoshone, Khim. Prir. Soedin.,
84
B. E. Cross, A. Erasmuson, and P. Filippone, J . Chem. SOC.,Perkin Trans. I , 1981, 1293.
78 79
82
1981,217.
196
Terpenoids and Steroids
Rubus chingii (Rosaceae), is a close relative of stevioside and is the p-D-glucosyl ester of 13-O-~-~-glucosylstevio1.~~ Some 12-oxygenated ent-Ag(11)J6-kauradienes have been obtaineds6from Vellozia caput-ardeae and the ,Ag(11)-dehydro-derivatives of trachylobanic and stachenic acids were isolateds7 from Viguiera species. The unusual 9(10)-secokaurene structure (48) has been proposedss for a lactone obtained from Gnaphalium undulatum (Compositae). Some tumour-inhibitory phyllocladene-based diterpenoids including (49) have been obtainedsg from Bromel ia pinguin . Although a number of Isodon species have been reclassified as Rabdosia (Labiatae) species, their similarity is revealed by the highly hydroxylated kaurenoids which they contain. Effusin, which was isolated from R. eflusus and shown to inhibit insect growth, possessesg0the unusual spiro-secokaurene structure (50). A
(50) R (51) R
= =
H OH
& '3.H
HO
R2H2C OH (54) (55) (56) (57)
R' = H, R2 = OAC R' = OH, R2 = OAC R1= OACR2 = H R' = OAC,R2 = OAC
similar structure (5 1) for trichorabdal B, another diterpenoid from the same plant, was establishedg1 by X-ray analysis. On treatment with sodium hydroxide this compound underwent a retro-Claisen and aldol condensation to afford (52). Excisanin A (53) and B (the 12-acetate) are hydroxylated kaurenoids which were T. Tanaka, H. Kohda, 0.Tanaka, F. H. Chen, W. H. Chou, and J. L. Leu, Agric. Biol. Chem., 1981,45,2165.
A. C. Pinto, S. K. Do Prado, and R. Pinchin, Phytochernistry, 1981, 20, 520. F. Bohlmann, J. Jakupovic, M. Ahmed, M . Grenz, H. Suding, H. Robinson, and R. M. King, Phytochemistry, 1981, 20, 113.
F. Bohlmann, J. Ziesche, R. M. King, and H. Robinson, Phytochemistry, 1981, 20, 751. R. Raffauf, M. D. Menarchy, P. W. LeQuesne, E. V. Arnold, and J. Clardy, J. Org. Chem., 1981,46, 1094. O0
I. Kubo. T. Kamikawa, T. Isobe, and T. Kubota, J . Chem. SOC.,Chem. Commun., 1980, 1206 E. Fujita, K . Fuji, M. Sai, M . Node, W. H. Watson, and V. Zabel, J . Chem. Soc., Chem, Commun., 1981,899.
Diterpenoids
197
obtainedg2from R . excisa, and the longikaurins C, D, E, and F (54)-(57) are a group of antibacterial diterpenoids from R . Zongituba.93 The structures of the leukamenins I-VI (58)-(63), which were isolated from R. umbrosia, were establishedg4by spectral studies and a series of chemical correlations. The glycosides shikokiasides A (64) and B (65), from R. shikokiana, have a similar oxygenation pattern. 95
R 3
= R3 = R4 = OH, R2 = OAC (59) R' = R2 = OAC,R3 = R4 = OH (60)R' = R2 = R4= OAC,R3 = OH (61) R' = R2 = R3 = OAC,R4 = OH (62) R1 = H, R2 = OAC, R3 = R4 = OH
(58) R'
(64) R (65) R
= OH =H
Gibberellins.-Considerable effort has been directed at the study of the gibberellin plant hormones. A useful procedure for the g.c.-m.s. identification of permethylated gibberellins has been described.96 The separation of some gibberellins by adsorption and reversed-phase partition h.p.1.c. has been reported. 97 Evidence (66), and a range of has been presentedg8 for the structure of gibberellin gibberellins, including the 1-hydroxygibberellinsA,, and A,, which were previously obtained from G .fujikuroi, have been obtained from developing wheat grain.gg Several aspects of the chemistry of gibberellic acid have been studied. The 3-hydroxy-group has been shownlo0to participate in the rearrangement of Al (2)gibberellin 19-10-lactones to the isomeric Al (l0)-gibbere1lin19-2-lactone (67).
g9
H.-D. Sun, X.-C. Sun, Z.-W. Lin, Y.-L. Xu, Y. Minami, T. Marunaka, and T. Fujita, Chem. Lett., 1981, 753. T. Fujita, Y. Takeda, and T. Shingu, Heterocycles, 1981, 16, 227. Y. Takeda, T. Fujita, and A. Ueno, Chem. Left., 1981, 1229. T. Isobe, Y. Noda, K. Shibata, and T. Kubota, Chem. Lett., 1981, 1225. L. Rivier, P. Gaskin, K. Y . S. Albone, and J. MacMillan, Phytochemistry, 1981, 20, 687. J. T. Lin and E. Heftmann, J. Chromatogr., 1981, 213, 507. T. Yokota and N. Takahashi, Agric. Biol. Chem., 1981, 45, 1251. P. Gaskin, P. S. Kirkwood, J. R. Lenton, J. MacMillan, and M. E. Radley, Agric. Biof. Chem.,
loo
P. S. Kirkwood, J. MacMillan, and M. L. Sinnott, J . Chem. Soc., Perkin Trans. I , 1980, 2117.
O8
93 94 86
96 O7 88
1980,44, 1589.
198
Terpenoids and Steroids
(68) R = Hal (69) R = H Several groups have reported lo1-lo3the isomerization of h1( 2 )-3-hydroxygibberellins to A2 ( 3 )- 1-chlorogibberellins (68) on treatment with various halogenating agents. Hydrogenolysis of the 1-halides provides a convenient route for the preparation of gibberellin A, (69). The hydrogenolysis of 13-chlorogibberellins by tributyltin hydride has also been reported. The partial synthesis of gibberellins A7,104A,, and A2t05from gibberellic acid has been described together with routes for the preparation of labelled gibberellins A29and A51.106 The unsaturated ketone (70) is a catabolite of gibberellin A29. It has been preparedlo7 from gibberellic acid. The 2-position of gibberellins is metabolically reactive and consequently the biological activity of a number of 2-substituted
derivatives of gibberellin A, including the 2-methyl compounds have been examined.108~10g The rates of glucosylation of the 3- and 13-hydroxy-groups have been examinedllo in the light of the occurrence of a number of gibberellins as their glucosides. The photodimerization of 3-dehydrogibberellins occurs across the 1,2-double bond. Since this can occur in the crystalline state, the crystal structure of 3-dehydrogibberellin A3 methyl ester has been determinedlll in this context. The corresponding reactions of dimethyl 3-dehydrogibberellenate have also been examined.l12 The transformation of some gibberellin A, derivatives with palladium acetate catalysis has been r e p 0 r t ~ d .A l ~full ~ paper has appeared on the preparation of 7-deoxygibberellin A number of improved procedures for the degradation B. E.Cross and I. C. Simpson, J . Chem. SOC.,Perkin Trans. I , 1981, 98. J. R. Bearder, P. S. Kirkwood, and J. MacMillan, J . Chem. SOC.,Perkin Trans. I , 1981, 672. lo3 J. R.Hanson, British Plant Growth Regulator Group Monograph, 1980, 5, 5 . lop M. H.Beale and J. MacMillan, J . Chem. Res. ( S ) , 1980, 289. lo5 Z. J. Duri, B. M. Fraga, and J. R. Hanson, J. Chem. SOC.,Perkin Trans. I , 1981, 161. lo* M. H. Beale and J. MacMillan, J . Chem. SOC., Perkin Trans. I , 1981, 394. 10' P. Gaskin, P. S . Kirkwood, and J. MacMillan, J . Chem. SOC.,Perkin Trans. I , 1981, 1083. lo8 M. H. Beale and J. MacMillan, Phytochemistry, 1981, 20, 693. log G. V. Hoad, B. 0. Phinney, V. M. Sponsel, and J. MacMillan, Phytochemistry, 1981, 20, 703. 11* G.Schneider, Tetrahedron, 1981, 37, 545. L. Kutschabsky, G. Reck, E. Hoehne, B. Voigt, and G. Adam, Tetrahedron, 1980, 36, 3421. H. K. Al-Ekabi, G. A. W. Derwish, G. Adam, and K. Schreiber, Tetrahedron, 1981, 37, 1735, lol
Io2
1741. 113 114
E.P.Serebryakov, Izv. Akad. Nauk SSSR, Ser. Khim., 1980, 2596. M.Lischewski and G. Adam, Tetrahedron, 1980, 36, 1237.
Diterpenoids
199
of gibberellin A, have been noted115and a method for introducing a 15-carboxygroup has been described.l16 Methanolysis of' a C-20' mixed anhydride of gibberellin A,, gave the unusual 19-ortho-ester, the structure (71) of which was established by X-ray a n a 1 ~ s i s .The l~~ formation of this compound and the corresponding 19-epimeric 20-tl9-lactols by sodium borohydride reduction of the mixed anhydrides reveals the facile participation of the 19-estersin the reactions of C-20. This feature may be of biosynthetic significance. A number of metabolic studies have been reported in connection with gibberellin biosynthesis. ent-Kaur-6,16-dien-19-oic acid has been described as a key intermediate in the biosynthesis of the kaurenolides in Cucurbita maxima.l18 The production of 16,16-difluoro- derivatives of gibberellin A, and 7-hydroxykaurenolide using 16,16-difluoro-17-norkauranoic acid as a substrate with G. fujikuroi has been reported,l19 and ent-15p-fluorokaurenoic acid has been shown to give rise to a group of 15-fluorinated gibberellins.lZ0Some 7-fluorogibberellins may act as gibberellin biosynthesis inhibitors.lZ1The production of 12p-hydroxygibberellins by incubation of the corresponding ent- 12a-hydroxykaurene with Gibberella fujikuroi has also been described.122 Graymotoxins.-The X-ray crystal structures for grayanotoxins XVI-XIX have been r e p ~ r t e d . ~Routes ~ ~ - ~to~1,5-secograyanotoxins ~ (grayanol) derivatives have been d e ~ c r i b e d . ~ ~ ~ ~ ~ ~ ~ Atiserenes.-The 1 1a,16,17-trihydroxyatiserene structure has been proposedlZ8 for atisideritol, obtained from Sideritis pusilla (Labiatae), on the basis of chemical and spectroscopic evidence. 6 Macrocyclic Diterpenoids Marine organisms, particularly corals, have continued to be a source of novel diterpenoids. Cembrenene (72) and mayol (73) are two new cembranoid diterpenoids from the soft coral Sinularia mayi.129The cembrene alcohol (74) has been 116
L. Lombardo, L. N. Mander, and J. V. Turner, Aust. J. Chem., 1981,34, 745.
116
L.N . Mander, J. V. Turner, and B. Twitchin, Tetrahedron Lett., 1981, 22, 3017.
11'
118 119
B. M. Fraga, A. G. Gonzalez, M. G. Hernandez, F. G. Tellado, J. R. Hanson, and P. B. Hitchcock, J. Chem. SOC.,Perkin Trans. I , 1981, 2740. P.Hedden and J. E. Graebe, Phytochemistry, 1981,20, 1011. B. E.Cross and P. Filippone, J . Chem. SOC.,Chem. Commun., 1980, 1097; J . Chem. Res. ( S ) , 1981, 166.
B. E. Cross and A. Erasmuson, J . Chem. SOC.,Perkin Trans. I , 1981, 1918. 131 K.Boulton and B. E. Cross, J . Chem. SOC., Perkin Trans. I , 1981, 427. 1z2 K.Wada, T. Imai, H. Yamashita, Agric. Biol. Chem., 1981, 45, 1833. A. Furusaki, S. Gasa, R. Ikeda, and T. Matsumoto, Bull. Chem. SOC.Jpn., 1981, 54,49. A. Furusaki, S. Gasa, R. Ikeda, T. Matsumoto, N. Yasuoka, and Y. Matsuura, Bull. Chem. SOC.Jpn., 1981, 54, 657. 135 A. Furasaki, S. Gasa, R. Ikeda, T. Matsumoto, N. Yasuoka, and Y. Matsuura, Bull. Chem. SOC.Jpn., 1981, 54, 1622. T. Terai, H. Meguri, N . Hamanaka, T. Matsuzaki, A. Furusaki, T. Kato, and T. Matsumoto, Chem. Lett., 1980, 1111. le7 T. Kaiya, N . Shirai, and J . Sakakibara, J . Chem. SOC.,Chem. Commun., 1981, 22. lZ8 A. Garcia-Granados, A. Parra, A. Pena, A. Saenz de Buruaga, J. M. Saenz de Buruaga, and S. Valverde, Tetrahedron Lett., 1980, 21, 361 1. la* Y.Uchio, H. Nabeya, M. Nakayama, S. Hayashi, and T. Hasa, Tetrahedron Lett., 1981, 22, Iso
1689.
200
Terpenoids and Steroids
(75)
(76)
obtained130from S.facile and cembrene C, sarcophytol B, flaccidoxide (75) were isolated131from the Red Sea coral, Alcyoniumflaccidurn. The constituents of samples of the coral Lobophytum crassum vary with the site of collection. Evidence has been for the structure (76) for decaryiol, which was isolated along with 3,4-epoxynephthenol from Sarcophyton decanyi. A full paper giving X-ray crystallographic evidence has been presented133for the structure for emblide, a cembranolide from Sarcophyton glaucum, and a number of minor constituents of this coral have also been r e p 0 ~ t e d . lThe ~ ~ stereochemistry of the 13-membered ring cembranolide diterpenoids from the coral Lobophytum pauciflorum has been elucidated.135 The X-ray crystal structure of the triepoxide of cembrene has been reported,136revealing a remarkable stereoselectivity in its formation. The Euphorbiaceae are the source of a number of diterpenoids derived by the cyclization of macrocylic systems. Chemical, spectral, and X-ray crystallographic evidence has been presentedl3' for the structure (77) for crotonitenone, a casbene diterpenoid obtained from Crotoiz nitens. A group o f irritant esters with the daphnane and tigliane skeleta have been reported13*from the roots of Stillingia sylvatica. Linifolins A (78) and B (79) are piscicidal constituents of Pimilea species.139 Some aspects of the chemistry of ingenol have been reported.l*O 130
131 132
B. F. Bowden, J. C. Coll, S. J. Mitchell, and R. Kazlauskas, Aust. J . Chem., 1981, 34, 1551. Y. Kashman, S. Carmely, and A. Groweiss, J . Org. Chem., 1981, 46,3592. S . Carmely, A. Groweiss, and Y. Kashman, J . Org. Chem., 1981, 46, 4279. J. A. Toth, B. J. Burreson, P. J. Scheur, J. Finer-Moore, and J . Clardy, Tetrahedron, 1980, 36, 1307.
134
136
13e
la' I38
lP0
T. Nakagawa, M. Kobayashi, K. Hayashi, and H. Mitsuhashi, Chem. Pharm. Bull., 1981, 29, Y . Yamada, S. Suzuki, K. Iguchi, €I. Kikuchi, Y. Tsukitani, H. Horiai, and F. Shibayama, Tetrahedron Lett., 1980, 21,3911. V. A. Paldugin, N. I. Yaroshenko, and Y . V. Gatilov, Khim. Prir. Soedin., 1981, 174. B. A. Burke, W. R. Chan, K. 0. Pascoe, J. F. Blount, and P. S. Manchand, J . Chem. SOC., Perkin Trans. 1, 1981, 2666. W. Adolf and E. Hecker, Tetrahedron Left., 1980, 21,2887. M. I. Tyler and M. E. H. Howden, Tetrahedron Lett., 1981, 22,689. H. J. Opferkuch, W. Adolf, B. Sorg, S. Kusumoto, and E. Hecker, 2.Naturforsch., Teil B, 1981, 36, 878.
Diterpenoids
20 1
(78) R = OAC (79) R = H
7 Miscellaneous Diterpenoids Taonianone (80) is an unusual furan obtained141from Taonia australasica. A full paper has appeared142on the structures of the diterpenoids based on the dolabellane skeleton which were obtained from Dictyota dichotoma. 18-Hydroxydollabella3,7-diene (81) is another member of this group of compounds obtained from the same source. A number of tricyclic relatives with the dolastane ring system, including (82), were isolated144from Dictyota divaricata. Spectral and chemical evidence has been for the structure (83) of linearol, obtained from
a HO
(84) 141 148
143
lP4 145
(85)
P.T. Murphy, G. March, and R. J. Wells, Tetrahedron Left.,1981, 22, 1555. V. Amico, G. Oriente, M. Piattelli, C. Tringali, E. Fattorusso, S. Magno, and L. Mayol, Tetrahedron, 1980,36, 1409. V. Amico, R. Currenti, G. Oriente, M. Piattelli, and C. Tringali, Phytochemistry, 1981,20,848. H. H. Sun,0.J. McConnell, W. Fenical, K. Hirotsu, and J. Clardy, Tetrahedron, 1981,37,1237. M. Ochi, I. Miura, and T. Tokoroyama, J. Chem. SOC.,Chem. Commun., 1981, 100.
202
Terpenoids and Steroids
Dictyota linearis. This name has been used previously for another diterpenoid. The unusual tricyclic structure (84) has been proposed for the spatane diterpenoids, which were from the alga Stoechospermum marginatum (Dictyotaceae). A diterpenoid (85) related to cladiellin has been isolated147from a Pacific soft coral, and a further member of the asbestinin series, asbestinin epoxide, was obtained14s from the Caribbean gorgonian, Briareum asbestinum. Full papers have appeared on the and absolute configuration150 of the decipiene diterpenoids. The structure (86) was assigned151to a new member of this series on the basis of X-ray evidence. The defensive secretions of termites have afforded an unusual group of diterpenoids. Spectral and X-ray crystallographic evidence has been presented for the structure (87) assigned to a secotrinervitane which was from Nasutitermes princeps. X-Ray crystallographic studies have also led to the structures of
some esters of the trinervitane alcohol (88) which were from Nasutitermes havilandii. A methyl migration occurs during the formation of the tetracyclic diterpenoid 3a-hydroxyrippert- 15-ene (89) by Nasutitermes rippertii. The structure was elucidated154by an X-ray analysis of the corresponding epoxyfrom the acetate. An unrearranged tetracyclic diterpenoid (90) was Malaysian nasute termite, Bulbitermes singaporensis. Cleomeolide (9 1) is an unusual bicyclic diterpenoid from Cleome viscosa (Capparaceae). The Basidiomycetes contain a number of unusual terpenoid metabolites such as the cyathins. These have now been thoroughly W. H. Gerwick, W. Fenical, and M. U. S. Sultanbawa, J. Org. Chem., 1981, 46, 2233. J. E.Hochlowski and D. J. Faulkner, Tetrahedron Lett., 1980, 21, 4055. 148 S. J. Selover, P. Crews, B. Tagle, and J. Clardy, J. Org. Chem., 1981, 46, 964. lilQ E.L.Ghisalberti, P. R. Jefferies, and P. N. Sheppard, Tetrahedron, 1980,36, 3253. 150' K. D. Croft, E. L. Ghisalberti, P. R. Jefferies, and A. D Stuart, Tetrahedron, 1981, 37, 383. 151 K. D. Croft, E. L. Ghisalberti, P. R. Jefferies, D. G. Marshall, C. L. Raston, and A. H. White, Aust. J. Chem., 1980, 33, 1529. 161 J. C. Braekman, D. Daloze, A. Dupont, J. Pasteels, B. Tursch, J. P. Declercq, G. Cermain, and M. Van Meerssche, Tetrahedron Lett., 1980, 21, 2761; A. Dupont, J. C. Braekman, D. Daloze, J. M. Pasteels, and B. Tursch, Bull. SOC.Chim. Belg., 1981, 90, 485. 153 G. D. Prestwich, S. G. Spanton, S. H. Goh, and Y. P. Tho, Tefrahedron Lett., 1981,22, 1563. 154 G. D. Prestwich, S. G. Spanton, J. W. Lauher, and J. Vrkoc, J. Am. Chem. SOC.,1980, 102, 146
147
6825 156 168
G. D. Prestwich, S. H. Goh, and Y. P. Tho, Experientia, 1981, 37, 11. B. A. Burke, W. R. Chan, V. A. Honkan, J. F. Blount, and P. S. Manchand, Tefrahedron, 1980,36, 3489.
157
W. A. Ayer and L. M. Browne, Tetrahedron, 1981, 37, 2199.
203
Diterpenoids
Some aspects of the chemistry of lauren-1-ene, including the remote functionalization of other rings based on the I,-Pb(OAc), oxidation of laurenan-2-ols, have been described.158 X-Ray crystallographic evidence has been presented for the structure (92) of cinncassiol D,a pentacyclic diterpenoid from the dried bark of Cinnamomum cassia possessing anti-complement activity.159
8 Diterpenoid Total Synthesis Biomimetic cyclization of polyenes as routes to diterpenoids continues to be explored. The brominative cyclization of geranyl-linalool afforded160the 3-bromomanoyl oxide and the boron trifluoride-catalysed cyclization of the diepoxide of p-homogeranylanisole gave 13-methoxy-~-homo-4a-oxopodocarpatrienol Some further synthetic studies of anhydroverticillol have been reported.162 A number of bicyclic diterpenoids have insect anti-feedant properties and consequently the synthesis of intermediates such as (93) in this series has attracted
CHO
OAc (93) 158
i6@ l80
(94)
N. K. Nathu and R. T. Weavers, Aust. J. Chem., 1980, 33, 1589. T. Nohara, Y. Kashiwada, T. Tomimatsu, M. Kido, N. Tokubuchi, and I. Nishioka, Tetrahedron Lett., 1980, 21, 2641. T. Kato, K. Ishi, I. Ichinose, Y . Nakai, and T. Kumagai, J . Chem. Soc., Chem. Commun.,1980, 1106.
D. Nasipuri and A. K. Samaddar, Indian J . Chem., Sect. B, 1981, 20, 261. m T. Kumagai, F. Ise, T. Uyehara, and T. Kato, Chem. Lett., 1981, 25. 181
(95)
204
Terpenoids and Steroids
attenti0n.1~~3-l~~ The total synthesis of dihydro-8-epiacrostalidic acid has been reported.166 The synthesis of perhydrophenanthrenes related to tri- and tetra-cyclic diterpenoids has continued to be an active area.167Compound (94) has been synthesized as a possible intermediate for the synthesis of cafestanone.168A synthetic approach to diterpenoids with an abnormal trans-syn AB ring junction [e.g. (95)] has been described.169The syntheses of 13-methoxypodocarpatrien- 19,20-dioic acid170 and the 1l-hydroxyabieta-2,8,11, I3-tetraen- 1-one,l" isomeric with shonanol, have been described.
AH (97)
A '
---CH,SiMe3
(99)
The biological activity of the diterpenoids of the aphidicolin-stemodin series makes these compounds attractive targets. The total synthesis of stemodin (96) has been described.172The key spiro-centre at C-9 was constructed by the internal aldol condensation of the keto-aldehyde (97) to afford (98). Several stereoselective syntheses of aphidicolin have been reported with different solutions to the problem
J. M. Luteijn, M. Van Doorn, and A. De Groot, Tetrahedron Lett., 1980, 21, 4127; J. M. Luteijn and A. D e Groot, ibid., p. 4129 ltt4 J. M. Luteijn and A. D e Groot, Tetrahedron Lett., 1981, 22, 789. le6 J. M. Luteijn and A. D e Groot, J . Org. Chem., 1981, 46, 3448. I. H. Sanchez and J. C. Aranda, Tetrahedron Lett., 1980, 3655. 167 R. V. Venkateswaran, D. Mukherjee. and P. C. Dutta, J . Chem. Soc., Perkin Trans. I, 1981, 1603.
K. S. Maji, S. K. Mukhopadhyaya, D. Mukherjee, and P. C. Dutta, J . Chem. SOC.,Perkin Tram. I, 1980, 2511. l 8 9 F. Orsini and F. Pelizzoni, Gazz. Chim. Ital., 1980, 110, 499. 170 A. K. Banerjee and H. E. Hurtado, Heterocycles, 1981, 16, 613. 171 T.Matsumoto, S. Imai, and S. Yuki, Bull. Chem. SOC. Jpn., 1981, 54, 1448. 172 E. J. Corey, M. A. Tius, and J. Das, J . Am. Chem. SOC.,1980, 102, 7612. 168
205
Diterpenoids
of creating the spiro-centre at C-9.173-175One procedure utilized the Claisen rearrangement of the vinyl ether (99) to afford The gibberellin plant hormones continue to attract synthetic attention. The total synthesis of gibberellin A4 (101) by a more efficient route has been and a major achievement has been the total synthesis of gibberellin A, (102) and
0
(101) (102)
R R
=H = OH
0
gibberellic The general strategy was based on a retrosynthetic analysis which utilized the construction of the C-3-C-4 bond by an Aldol process (103), the C-4-4-5 bond by a Michael process (104), and the C-I-C-10 bond by the addition of a nucleophile to the enone (105). The latter was prepared from 1,7dimethoxynaphthalene (1 07) via (106). 173
l74 175
176
17?
R. E. Ireland, J. D . Godfrey, and S. Thaisrivongs, J . Am. Chem. SOC.,1981, 103, 2446. R. L. Cargill, D . F. Bushey, J. R. Dalton, R. S. Prasad, R. D. Dyer, and J. Bordner, J . Org. Chem., 1981,46,3389. J. E. McMurry, A. Andrus, G. M. Ksander, J. H. Musser, and M. A. Johnson, Tetrahedron Suppl., 1981, 9, 319. A. L. Cossey, L. Lombardo, and L. N. Mander, Tetrahedron Lett., 1980, 21, 4383. L. Lombardo, L. N. Mander, and J. V. Turner, J . Am. Chem. Sac., 1980,102,6626.
206
Terpenoids and Steroids
Several reports have appeared on the elaboration of other intermediates for gibberellin synthesis.l 78J The novel decipiadiene diterpenoid (1 08) has been synthesizedlS0and a report has appeared on the synthesis of cubitene,lsl a monocyclic constituent of the termite Cubitermes umratus.
G. Stork, W. C. Still, J. Singh, and S. Takei, Tetrahedron Lett., 1980, 21, 4051. S. Takane, C. Kasahara, and K. Ogasawara, J . Chem. SOC.,Chem. Commun., 1981, 635. 180 M. L. Greenlee, J . Am. Chem. SOC.,1981,103,2425. 0.P.Vig. S.S. Bari, I. R. Teehan. and R. Vig, ZndianJ. Chem., Sect. B, 1980, 19, 446. 178
17*
4 Triterpenoids BY R. B. BOAR
1 Introduction This chapter follows the pattern of last year’s Report with the addition of a section on Triterpenoid Saponins. The highlight of this year’s Report is undoubtedly the total synthesis of dl-quassin by Grieco and his co-workers? Reviews have appeared on the occurrence of triterpenoid saponins and sapogenins,2 the mass spectra of pentacyclic triterpenoids,s and the possible role of triterpenoids as membrane component^.^ The plenary lectures from the 12th IUPAC Symposium on the Chemistry of Natural Products have been p~blished.~ 2 Squalene Group and Triterpenoid Biosynthesis The biosynthesis of triterpenoids is discussed at some length in a new book.8 The bacterium Acetobacter pasteurianum forms hopanoids such as diploptene (1) by
(1) R = H, (4) R = H, (5) R = H,a-OH (2) R = H,a-OH (3) R = H,B-OH (6) R ==H,P-OH cyclization of squalene. When a cell-free system was fed with the unnatural substrate (3RS)-squalene 2,3-epoxide, hop-22(29)-en-3a-ol (2) and -3p-01 (3) were formed. Appropriate experiments established that the 3a-hydroxy-compound (2) is derived from the (3R)-epoxide and the 3P-hydroxy-compound (3) from the (3S)-epoxide. Similarly, a cell-free system from the protozoon Tetrahyrnena pyriformis was shown to convert squalene into tetrahymanol (4) and (3R)- and P. A. Grieco, S. Ferrino, and G. Vidari, J. Am. Chem. SOC.,1980, 102, 7586. * R. S.Chandel and R. P. Rastogi, Phytochemistry, 1980, 19, 1889. L. Ogunkoya, Phytochemistry, 1981, 20, 121. W. D. Nes and E. Heftmann, J. Nat. Prod., 1981, 44, 377. Pure Appl. Chem., 1981, 53, No. 6. C. P. Manitto, ‘Biosynthesis of Natural Products’, Ellis Horwood Ltd., Chichester, 1981. ’ M. Rohmer, C. Anding, and G. Ourisson, Eur. J. Biochem., 1980, 112, 541.
207
Terpenoids and Steroids
208
(3s)-squalene 2,3-epoxides into gammacerane-3a,2la-diol (5) and -3p,2la-diol (6) respectively.8 The single cyclase present in each of the above systems is clearly rather primitive as regards substrate specificity. The stereospecifically labelled squalene (7) and (3RS)-squalene 2,3-epoxide (8) were synthesized and fed to the cell-free system from T. pyriforrnis. Examination of the IH n.m.r. spectra of the derived triterpenoids (4), (9,and (6) showed that (4) and (6) arise via cyclization of an all-chair conformation of squalene (7) and (3s)-epoxide (8) respectively (4a
and 228 methyls labelled in each case), but that (5) arises from the (3R)-epoxide (8) with a boat-chair-chair-chair-chair folding (4p and 22p methyls labelled) (Scheme 1).8
HO
The bacterium Methylococcus capsulatus is unique among prokaryotes in that it produces not only hopanoids but also lanosterol derivatives. Evidence for the
' P. Bouvier, Y . Berger, M. Rohmer, and G. Ourisson, Eur. J . Biochem., 1980,112, 549.
Trit erpenoids
209
(9) R = H2 (10) R = H,P-OH (11) R = H,a-OH presence of two separate cyclases has now been obtained. A cell-free preparation from M . capsulatus converted squalene into diploptene (1) [but not into 5a-lanosta8,24-diene (9)], (3S)-squalene 2,3-epoxide into hop-22(29)-en-3p-ol (3) and lanosterol (lo), and (3R)-squalene 2,3-epoxide into hop-22(29)-en-3a-o1 (2) and 3-epilanosterol(ll). In that it does not reject the (3R)-epoxide, the squalene epoxide cyclase is less specific than that present in typical e~karyotes.~ Details have been published of the biosynthesis of olean-12-ene and urs- 12-ene type triterpenoids in tissue cultures of Isodon japonicus (Labiatae).lo The results are fully in accord with the original biogenetic postulates of Ruzicka and his colleagues.11 By using [5-13C, 5-2H2]MVAas substrate it was shown that, as expected, both squalene 2,3-epoxides [part structures (12) and (13)] are involved in the biosynthesis of 2a-hydroxyursolic acid (14), 3-epimaslinic acid (13, and p-sitosterol in I. japonicus. The 13C n.m.r. spectra of (14) and (15) suggested
Jvu
Jvu
(14) (15) additionally that in the olean-12-ene series the double bond is formed by elimination of the 12a-H, but that in the urs-12-ene series it is the 12p-H that is lost.12 It has been shown that the hydrogen migration from C-24 to C-25 that occurs during the biosynthesis o f isofucosterol in Pinus pinea (Pinaceae) occurs such that lo
l2
M. Rohmer, P. Bouvier, and G. Ourisson, Eur. J . Biochem., 1980, 112, 557. S. Seo, Y. Tomita, and K. Tori, J. Am. Chem. SOC.,1981,103,2075. A. Eschenmoser, L. Ruzicka, 0. Jeger, and D. Arigoni, Hefv. Chim. Acra, 1955, 38, 1890. S. Seo, Y. Tomita, K. Tori, and Y. Yoshimura, J . Chem. SOC.,Chem. Commun., 1980, 1275.
210
Terpenoids and Steroids
(16)
(17)
the pro-E methyl group of the precursor (16) becomes the pro-R methyl group of isofucosterol [as (1 7)].13 24-Methyl-25-azacycloartanol (1 8) has been synthesized. It acts as a potent inhibitor of C-24 methyltransferase in higher plant cells.14 It is more potent than 25-azacycloartanol (1 9).15 The effects of various triterpenoids on the growth of the fungus Phytophthora cactorum have been investigated.16.The enzymic preparation of [14C]-labelled squalene from [2-14C]MVA has been described.l
(18) R = Me (19) R = H
3 Fusidane-Lanostane Group The bark of Pinus monticolu (Pinaceae) contains many triterpenoids of the lanostane and serratane groups. Of these, the lanost-9(1 I)-enes (20)-(27) are new natural products (see also Section 9).lS The sea cucumber Stichopus chloronotus affords a series of antifungal oligoglycosides which on enzymatic hydrolysis yield the genuine sapogenins stichlorogenol(28) and 25,26-dehydrostichlorogenol(29).The structure and stereochemistry of (28) were confirmed by X-ray analysis. Acid hydrolysis of the saponins gave artefact sapogenins containing the 8-ene or 9( I 1)-ene system.lg Other sea cucumbers contain oligoglycosides based on the sa?ogenins (30) and (31) (Bohadschia bivittata)20 and (32) (Actinopyga echinites).21Two further 27-nortril3
l4 l6
l8 l7 l8
l9
21
F. Nicotra, F. Ronchetti, G. Russo, G. Lugaro, and M. Casellato, J. Chem. SOC.,Perkin Trans. I , 1981, 498. A. S. Narula, A. Rahier, P. Benveniste, and F. Schuber, J. Am. Chem. SOC.,1981, 103, 2408. P. Schmitt, A. S. Narula, P. Benveniste, and A. Rahier, Phytochemistry, 1981, 20, 197. W. D. Nes and G. W. Patterson, J. Nut. Prod., 1981, 44, 215. G. Sandmann, W. Hilgenberg, and P. Boeger, Z. Naturforsch., Teil C,1980, 35, 927. J. P. Kutney, G. Eigendorf, B. R. Worth, J. W. Rowe, A. H. Conner, and B. A. Nagasampagi, Helv. Chim. Acta, 1981, 64, 1183. I. Kitagawa, M. Kobayashi, T. Inamoto, T. Yasuzawa, Y. Kyogoku, and M. Kido, Chem. Pharm. Bull., 1981, 29, 1189. I. Kitagawa, M. Kobayashi, M. Hori, and Y. Kyogoku, Chem. Pharm. Bull., 1981, 29, 282. I. Kitagawa, T. Inamoto, M. Fuchida, S. Okada, M. Kobayashi, T. Nishino, and Y . Kyogoku, Chem. Pharm. Bull., 1980,28,1651.
21 1
Trit erpenoids
RO
(22) R (23) R
(20) R = Me (21) R = H
As (20)
=
=
Me H
{p
(26) OH at C-22 or C-23 (24) R (25) R
= Me (24s) = H (24Q
(28) (29) 25,26-dehydro
terpenoids from Muscari comosum (Liliaceae) have the interesting structures (33) and (34).22 Polyporenic acid D (35) is a new natural product from Polyporus oficinalis (P~lyporaceae).~~ The cytotoxicity of various lanosterol derivatives isolated from the fungus Poria cocos (Polyporaceae) has been inve~tigated.~~ 5cc-Lanost-S-en-24-one [as (36)] has been converted into 5a-lanost-S-en-23-one [as (37)J in 21 % overall yield (Scheme 2). A similar sequence was successfully applied to 29-nor-5a-lanost-9( 1l)-en-24-0ne.~~A series of 9,ll -epoxy-7-ketolanostane derivatives with degraded side chains has been synthesised,26as has a range of side-chain modified lanosterol analogue^.^' Details have been reported 21
M. Parrilli, R. Lanzetta, M. Adinolfi, and L. Mangoni, Tetrahedron, 1980,36, 3591. See also, M. Parrilli, R. Lanzetta, V. Dovinola, M. Adinolfi, and L. Mangoni, Can. J . Chem., 1981, 59, 2261.
2s 2p
25 86
27
R. K. Thappa, S. G. Agarwal, K. L. Dhar, and C. K. Atal, Phytochemistry, 1981, 20, 1746. J. Valisolalao, L. Bang, J.-P. Beck, and G. Ourisson, BUN.SOC.Chim. Fr., 1980, 473. M. Namikawa, T. Murae, and T. Takahashi, Chem. Lett., 1981, 733. Z. Paryzek and R. Wydra, Monatsh. Chem., 1980, 111, 1427. Y . Sat0 and Y . Sonoda, Chem. Pharm. Bull., 1981,29, 356.
212
Terpenoids and Steroids
HO (30) R1 = R2= H (31) R1= OH, R2= H (32) R' = R2= OH
0
(33) R = H,P-OH (34) R = 0
0
0
+ & ~
v, vi
Me0
(37) Reagents: i, LDA; ii, Ph,S,; iii, Pb(OAc),; iv, MeOH-I,; v, LiAlH,; vi, HCI; vii, Ac,O; viii, Ca-liq. NH,
Scheme 2
Triterpenoids
213
of the efficient dehydrogenation of steroidal and triterpenoid ketones using benzeneseleninic anhydride.28 The absolute configurations at C-24 of the 24,25dibromides A and B derived from 5a-lanosta-8,24-dien-3p-yl acetate have been reversed.29
Further new natural products are (38) from the toxic micro-organism Fusarium triphyllol (41) from Adenosporotrichioides 92Z,30(39) and (40) from olive and cyclonervilol (42) and cyclohomonervilol phora triphyh (Campan~laceae),~~ (43) from Nerviliapurpurea (Orchidaceae). The structure of (43)was supported by its conversion into cycloeucalenol.33Two new xylosides from Cimicifuga japonica (Ranunculaceae) are based on the genuine sapogenins (44) and (45). Treatment of
(43)
OH
(47)
(45) R = OH (46) R = H
30 31
s2
83
D. H. R. Barton, D. J. Lester, and S. V. Ley, J . Chem. SOC.,Perkin Trans. 1, 1980, 2209. R. M. Carman and B. N . Venzke, Aust. J . Chem., 1981,34,679. B. Yagen, P. Horn, A. Z . Joffe, and R. H. Cox, J. Chem. SOC.,Perkin Trans. I , 1980, 2914. T. Itoh, K. Yoshida, T. Yatsu, T. Tamura, T. Matsumoto, and G. F. Spencer, J. Am. Oil Chem. SOC.,1981,58, 545. C. Konno, T. Saito, Y. Oshima, H. Hikino, and C. Kabuto, Plunta Med., 1981, 42, 268. T. Kikuchi, S. Kadota, H. Suehara, and T. Namba, Tetrahedron Lett., 1981, 22, 465.
8
214
Terpenoids and Steroids
(44) with sulphuric acid in aqueous methanol gave cimigenol (46).34 Cyclosadol (47) from Zea mays (Gramineae) has been shown by n.m.r. spectroscopy to have the 23E c ~ n f i g u r a t i o n3.1-Norcycloswietenol(48) ~~ has been isolated from Swietenia mahagoni (Meliaceae) heartwood.36 The assigned structure is supported by 13C n.m.r. spectral data.37The ketone (49), itself readily available from cycloartenol, has been converted into the Buxus alkaloid, cyclobuxophylline-M (50).38
The seed oil of Cucumissativus (Cucurbitaceae) contains (51) and (52) in addition Momordicosides A-E from the seeds to other known 4a-methyl of Mornordica charantia (Cucurbitaceae) are based on the sapogenins (53)-(56). The structure and stereochemistry of compound (53) were established by X-ray analysis.4oThese cucurbitacins are notable for the absence of an oxygen function
(51) R (52) R
=
=
Me, 8,9-ene H, 7,8-ene
OH
OH
H = ..* ~ v n
As (53)
As (53)
(54) 34
35
36
37
38
39
I0
OH
yCHO As (53)
(55)
(56)
N. Sakurai, 0. Kimura, T. Inoue, and M. Nagai, Chem. Pharm. Bull., 1981, 29, 955. T. Itoh, N. Shimizu, T. Tamura, and T. Matsumoto, Phytochemistry, 1981, 20, 1353. A. S. R. Anjaneyulu, V. Lakshminarayana, Y. L. N. Murty, and L. R. Row, Indian J . Chem., 1979,17B, 423. V. Lakshminarayana, Y . L. N. Murty, and L. R. Row, Org. Magn. Reson., 1981, 17, 77. M. C . Desai, J. Singh, H. P. S . Chawla, and S . Dev, Tetrahedron, 1981, 37, 2935. T. Itoh, Y. Kikuchi, N. Shimizu, T. Tamura, and T. Matsumoto, Phytochemistry, 1981, 20, 1929. H. Okabe, Y. Miyahara, T. Yamauchi, K. Miyahara, and T. Kawasaki, Chem. Pharm. Bull., 1980,28,2753; Y. Miyahara, H. Okabe, and T. Yamauchi, ibid., 1981,29, 1561.
215
Triterpenoids
at C-1 1, as is lOa-cucurbita-5,24-dien-3P-o1 which has now been isolated from seedlings of Bryonia dioica (Cu~urbitaceae).~' The biogenesis of the cucurbitacins has been discussed.*l
4 Dammarane-Euphane Group The bark of Rhus javanica (Anacardiaceae) contains rhuslactone (57), a novel dammarane-type triterpenoid with an a-oriented side chain. The structure followed
@ p
HO
HO=* (58)
(57)
(59) 24,25-dihydro
OH
(61)
(62) 24,25-dihydro from X-ray analysis of the derived tri01.~~ Acid hydrolysis of the saponin of Emmenospermum pancherianum (Rhamnaceae) affords ebelin lactone (58) together with 24,25-dihydroebelin lactone (59) and the novel D-homo aromatic triterpenoid (60). All three compounds are artefacts since Smith-de Mayo degradation of the saponin affords the genuine, acid-labile, sapogenins jujubogenin (6 1) and dihydrojujubogenin (62).43The saponins of Zizyphus jujuba (Rhamnaceae) are also based on j ~ j u b o g e n i n Other . ~ ~ dammaranes reported this year are vellozone [(20R)-20hydroxy-24-methylenedammar-3-one]from VeZlozia stipitata (Vell~ziaceae),~~ 41
42
44
45
L. Cattel, G. Balliano, 0. Caputo, and F. Viola, Planta Med., 1981, 41, 328. C.-K. Sung, T. Akiyama, U. Sankawa, Y. Iitaka, and D.-S. Han, J. Chem. Soc., Chem. Commun., 1980,909. G. V. Baddeley, J. J. H. Simes, and T.-H. Ai, Aust. J. Chem., 1980, 33, 2071. N. Okamura, T. Nohara, A. Yagi, and I. Nishioka, Chem. Pharm. Bull., 1981, 29, 676. A. C. Pinto, P. M. Baker, B. Gilbert, R. Pinchin, F. A. M. Reis, M. S. Waineraich, and D. H. T. Zocher, Phytochemistry, 1980, 19, 2486.
216
Terpenoids and Steroids
(20S)-damrnar-24-ene-20(,3p, 12p,20-tetraol from Gynostemma pentaphyllum (Cucurb i t a ~ e a e ) ,(20S724S)-20,24-dihydroxydammar-25-en-3-one ~~ from Betula mandschurica (Bet~laceae),~' the (20S724R)-20,24-ethers (63)-(66) from B. lanata,48 and (20S)-dammar-24-ene-3a,17a,20-triol plus the ethers (67)-(69) from various HO
6 R'
(63) (64) (65) (66)
R1= H,a-OH, R2= Ac R1= H,a-OAc, R2= H R1= 0, R2 = H R1= H,a-OH, R2 = H
(67) R' = H,a-OH, R2= H,, R3= H,P-OH, R4= OH (68) R' = H,B-OH, R2= H,P-OAc, R3= Hz, R4= H (69) R' = R2 = H,P-OH, R3= HQ,R4= H
Betula species.49The efficient conversion of (20S,24R)-20,24-epoxydammarane-3a, 12$,25-triolinto the 25-O-p-~-glucosidehas been reported.50The seed oil of Cacalia atriplicifolia (Compositae) is a rich source of esters of dammarenediol II.61 New tirucallane triterpenoids are adenophorate (70) (X-ray analysis) from Adenophora triphylla (Campan~laceae),~~ and the ring A seco derivatives (71) and (72) from Guarea cedrata (Melia~eae].~~ Treatment of the 7a-hydroxy- or 7-ketoapotirucall- 14-enes (73)-(75) with monoperphthalic acid affords the corresponding 14a,15a-epo~ides.~~
(70) 46
47
48
48
50
51 52
53
(71) R (72) R
=H = Me
M. Nagai, K. Izawa, S. Nagumo, N. Sakurai, and T. Inoue, Chem. Pharm. Bull., 1981,29,779. G. V. Malinovskaya, V. L. Novikov, V. A. Denisenko, and N . 1. Uvarova, Khim. Prir. Soedin., 1980, 346; English translation, Chem. Nat. Compoundr, 1980,16, 257. N. D. Pokhilo, G . V. Malinovskaya, V. V. Makhan'kov, V. F. Anufriev, and N. I. Uvarova, Khim. Prir. Soedin., 1980, 513; English translation, Chem. Nat. Compounds, 1980, 16, 368. G. V. Malinovskaya, N. D. Pokhilo, V. V. Isakov, and N. I. Uvarova, Chem. Abstr., 1980, 93, 220 945. L. N. Atopkina and N.I. Uvarova, Khim. Prir. Soedin., 1980,205; English translation, Chem. Nut. Compounds, 1980, 16, 159. G. F. Spencer, J . Nat. Prod., 1981, 44, 166. J. A. Akinniyi, J. D. Connolly, D. S. Rycroft, B. L. Sondengam, and N. P. Ifeadike, Can. J . Chem., 1980,58, 1865. A . Merrien, B. Meunier, C. Pascard, and J. Polonsky, Tetrahedron, 1981, 37, 2303.
217
Triterpenoids
(73)R1 = H,@-OAc,R2= H,a-OH (74) R1 = 0,R2= H,a-OH (75)R1= R2= 0 Tetranortriterpen0ids.-The cytotoxic or insect antifeedant activity shown by various tetranortriterpenoids ensures that the isolation and structure determination of these often complex molecules continue to attract attention. A detailed examination of the seeds of Azadirachta indica (Meliaceae) has yielded the further tetranortriterpenoids (76)-(8 1). The stereochemistry of 7-acetylneotrichilenone (78)
‘“OAc
a ‘“OAc
(77)
21 8
Terpenoids and Steroids
was confirmed by X-ray analysis.54 Seed oil of A . indica gave three compounds with insect antifeedant activity-3-deacetylsalannin (82), salannol (83), and the known 1,3-diacetylvilasinin (see Vol. 10, p. 145).55The fruit of Melia azedarach (Meliaceae) contains ohchinolides A and B (see Vol. 11, p. 117), nimbolidins A
(82) R (83) R
(84) R = COPh (85) R = tiglate
= tiglate = COCH,CHMe,
~o AcO"'
"OTig
'*,a (86) R = AC (87) R = H, (12R)
(84) and B (85), nimbolinin B (86), and 1-deacetylnimbolinin (87).56 Trichilins A-D, insect antifeedants from the root bark of Trichilia roka (Meliaceae), have structures (88)-(91) respectively. This paper provides a fine example of the potential of modern chromatographic and spectroscopic (particularly n.m.r.) techniques. In the presence of traces of acid, trichilin A (88) rearranges to C (90). Treatment
AcO-..
As (88)
"OH
0 (88) R (89) R (91) R 64 56 58
1
= = =
H,P-OH H,a-OH H2
W. Kraus, R. Cramer, and G. Sawitzki, Phytochernistry, 1981, 20, 117 W. Kraus and R. Cramer, Liebigs Ann. Chern., 1981, 181. W. Kraus and M. Bokel, Chern. Ber., 1981,114,267.
Triterpenoids
219
AcO"'
OAc
0 I
(94)
(95) R1= Me, R2= Ac (96) R1= CH,OH, R2= COCHOHCHMe,
of trichilin B (89) with zinc borohydride induced an unexpected acetyl migration which resulted in the formation of aphanastatin (92).57 The X-ray structural analyses of aphanastatin (92) and related compounds from Aphanamixis grandifolia (Meliaceae) have now been reported.58Seeds of T . dregeana contain dregeanas 1-5 for which the structures (93)-(97) respectively have been deduced.59Continued investigation of T. hispida has resulted in the elucidation of structures (98)-(100) for the cytotoxic hispidins A-C respectively.60Hispidin C (100) is thus identical to the compound previously isolated from Aphanamixis polystacha (see Vol. 10, p. 150). 2'-Hydroxyrohitukin has been isolated from Guarea cedrata.52 The bark of Toona ciliata (Meliaceae) has yielded two further ring B seco tetranortriterpenoids (101) and (102) which have insect antifeedant activity.61 57 68 69 6o
M. Nakatani, J. C. James, and K. Nakanishi, J . Am. Chem. SOC.,1981, 103, 1228. B. Arnoux and C. Pascard, Acta Crystallogr., Sect. B, 1980, 36, 2709. D. A. Mulholland and D. A. H. Taylor, Phytochemistry, 1980, 19, 2421. S. D. Jolad, J. J. Hoffmann, K. H. Schram, J. R. Cole, M. S. Tempesta, and R. B. Bates, J . Org. Chem., 1981, 46, 641. W. Kraus and W. Grimminger, N o w . J . Chem., 1980, 4, 651.
Terpenoids and Steroids
220
(99) R = tiglate (100) R = A c
fi0
H *cO
.
b: OH
w
0
0
H
0 "OH
7 p "=/p
HO
Triterpenoids
22 1
H
0
2
C
e
0
0 H
I‘
C0,Me
h1
?H
As (111)
(113)
(111) R (112) R
=
C(OH)Me,
=H
Further new natural limonoids are tecleanin (103), 7-deacetylproceranone (104), and 7-deacetylazadirone (105) from Teclea grandifolia (Rutaceae),62 7a,ll pdiacetoxydihydronomilin (1 06) from Cedrela mexicana (Melia~eae),~~ proceranolide (107y4 and proceranone (108y5 from Carapa procera (Meliaceae), isolimonic acid (109) from Citrus aurantium (Rutaceae),66and methyl deacetylnomilinate (1lo), calamin (1 1l), retrocalamin (1 12), cyclocalamin (1 13), and methyl isoobacunoate diosphenol (114) from C. reti~ulata.~’ Chromatography of calamin (111) on a silica gel column induced the formation of retrocalamin (1 12) via a retro-Aldol rea~tion.~ Investigation of the possible synthesis of limonin from a steroidal starting material has led to the preparation of the model compound (115).se
62
83 84 85
J . F. Ayafor, B. L. Sondengam, J. D. Connolly, D. S. Rycroft, and J. I. Okogun, J . Chem. Soc., Perkin Trans. 1, 1981, 1750. G. B. Marcelle and B. S. Mootoo, Tetrahedron Left., 1981, 22, 505. B. L. Sondengam, C. S. Kamga, and J. D. Connolly, Phytochemistry, 1980,19, 2488. B. L. Sondengam, C. S. Kamga, S. F. Kimbu, and J. D. Connolly, Phytochemistry, 1981, 20, 173.
86
68
R. D. Bennett and S. Hasegawa, Phytochemistry, 1980, 19, 2417. R. D. Bennett and S. Hasegawa, Tetrahedron, 1981, 37, 17. G. Emmer and W. Graf, Helv. Chim. Acta, 1981, 64, 1398.
222
Terpenoids and Steroids
0 ' 0 OH
Pentanortriterpenoids.-Azadirachta indica, a rich source of tetranortriterpenoids, has now afforded the pentanor-compounds nimbinene (1 16), 6-deacetylnimbinene (1 17), nimbandiol (1 1S), and 6-O-acetylnimbandiol (1 19).69
(116) R = A c (117) R = H
(118) R
=
H
(119) R = A c
Quassinoids.-Soulamea muelleri (Simaroubaceae) has yielded soulameanone (1 20), 1,12-di-O-acetylsoulameanone(121), and A2-picrasin B (122). The structure of (120) was established by X-ray analysis. Treatment of (122) with diazomethane afforded quassin. 70 Other new quassinoid natural products reported this year are ~~ soularubinone (123), an antileukaemic compound from S . t o m e n t o ~ a ,13,18OMe
0 H
\
H
. H
H
(120) R = H (121) R = AC
W. Kraus and R. Cramer, Chem. Ber., 1981, 114, 2375. J. Polonsky, M. Van Tri, T. Prange, C. Pascard, T. Sevenet, and J. Pusset, Tetrahedron, 1980, 36, 2983. 71 M . Van Tri, J. Polonsky, C. Merienne, and T. Sevenet, J . Nat. Prod., 1981, 44, 279.
6B 'O
Triterpen oids
223
dehydroexcelsin (124) from Ailanthus excelsa (Simaroubaceae),72 and dehydrobruceine A (125) and dihydrobruceine A (I 26) from Brucea javanica (Simaroubaceae).73 Grieco and his co-workers have completed a most notable total synthesis of dl-quassin (130) (Scheme 3).l The synthesis of the hydroxy-lactone (127) was outlined last year (see Vol. 1 1 , p. 121). The conditions developed for the conversion of the bis-(cc-hydroxy-ketone) (1 28) into the bis-(O-methyldiosphenol)(1 29) also achieved the crucial inversion of configuration at C-9.74The close proximity of the C-7 oxygen atom to the C-11 carbon atom in the 9-epiquassin skeleton is evident from a series of reactions in which intramolecular participation occurs. Thus, for example, treatment of the epoxide (131) with lithium aluminium hydride gave the ether (132) whose structure and stereochemistry were established by X-ray analysis.75Synthesis of the tetracyclic (133), a possible intermediate for quassinoid synthesis, involved the intramolecular cycloaddition of a quinonedimethane as the key step.76 Various workers have attempted the chemical 77-80 or microbiologica181 modification of quassinoids in the search for compounds with potent antileukaemic activity.
73 74 75
7e 77
78 78
S . A. Khan and K. M. Shamsuddin, Phytochemistry, 1980, 19, 2484. J. D. Phillipson and F. A. Darwish, Planta Med., 1981, 41, 209. P. A. Grieco, S . Ferrino, G. Vidari, and J. C. Huffman, J . Org. Chem., 1981, 46, 1022. P. A. Grieco, S . Ferrino, G . Vidari, J. C . Huffman, and E. Williams, Tetrahedron Lett., 1981, 22, 1071. T. Kametani, M. Chihiro, T. Honda, and K. Fukumoto, Chem. Pharm. Bull., 1980, 28, 2468. T. Murae and T. Takahashi, Bull. Chem. SOC.Jpn., 1981, 54, 941. N. Khoi and J. Polonsky, Helv. Chim. Acta, 1981, 64, 1540. C . G. Casinovi, G. Fardella, G. Grandolini, and C . Burinato, Farmaco, Ed. Sci., 1981,36, 116. M. Okano and K.-H. Lee, J . Org. Chem., 1981,46, 1138. M. M. Chien and J. P. Rosazza, J . Chem. Sac., Perkin Trans. I , 1981, 1352.
224
Terpenoids and Steroids
1
viii, ix
& OMe
H
Me0
! H
OMe
x,xi
H
MeO&o
~
H
0
OMe
j H
Reagents: i, Bu',AIH; ii, MeOH-H+; iii, B2H,; iv, H,O,-OH-; v, Collins reagent; vi, LDA; vii, Moo,-pyridine-HMPA ; viii, MeOH-MeO--DMSO; ix, MeI; x, aq. HOAc; xi, Fetizon's reagent
Scheme 3
Me0
OMe
H
H
OMe
Me
H
225
Triterpenoids 5 Lupane Group
X-Ray analysis of the new triterpenoid ( 1 34) from Emmenospermum pancherianum (Rhamnaceae) indicated that the isopropenyl group has the unusual P-configura t i ~ n Subsequent .~~ reinvestigation of emmolactones2 by X-ray analysis showed that it also has a p-isopropenyl group, and its structure is therefore revised to (135).43 Other lupane natural products reported this year are lupa-5,20(29)-diennepeticin (lup-20(29)-ene3p-01 from Holarrhena antidysenterica (Apo~ynaceae),~~ 3p, 11a-diol) from Nepeta hindostana (Labiatae),84 3p-hydroxylup-20(29)-en-30-al
-OH
HY,
8 J.
Me0,C Me0,C (136) R = H,P-OH (137) R = H,p-OAc (138) R = 0
from Lychnophora unij7ora ( C o m p ~ s i t a e ) ,lup-20(29)-ene-3p, ~~ 16p,28-triol from Stenocereus thurberi (Cactaceae),86 and compounds (1 36)-( 138) from Salvia phzomoides (Labiatae). 8 7 Methyl 3,4-secolup-20(29)-en-3-oate(139), reported last year as a component of certain .sedirnentsys8has now been found in Caralluma buchardii (Asclepiadaceae).8 9 Neolupenyl acetate (1 40) and tarolupenyl acetate (141) and the corresponding alcohols have been isolated from the dried roots of Taraxacum japonicum (Compositae). R. A. Eade, J. Ellis, and J . J. H. Simes, Aust. J . Chem., 1967, 20, 2737. C. R. Narayanan and D. G. Naik, Indian J . Chem., Sect. B, 1981, 20, 62. 1 3 ~V. U. Abmad, S. Bano, W. Voelter, and W. Fuchs, Tetrahedron Leu., 1981, 22, 1715. 85 F. Bohlmann, L. Muller, R. M. King, and H. Robinson, Phytochemistry, 1981, 20, 1149. B6 H. W. Kircher, Phytochemistry, 1980, 19, 2707. 8 7 M. C. Garcia-Alvarez,G. Savona, and B. Rodriguez, Phytochemistry, 1981, 20, 481. 8 8 B. Corbet, P. Albrecht, and G. Ourisson, J . Am. Chem. SOC.,1980, 102, 1171. 8 9 V. A. Castro, C. Garcia, A. G. Gonzalez, R. Hernandez, and E. Suarez, Phytochemistry, 1980, 82 83
19, 2210.
H. Ageta, K. Shiojima, K. Masuda, and T. Lin, Tetrahedron Lett., 1981, 22, 2289.
Terpenoids and Steroids
226
(14) (141) Details have appeared of the synthesiss1 and rearrangements2 of 3a,4a- and 3P,4p-epoxy-~:A-friedo-l8P,19cr-H-lupanes (see Vol. 1 1, p. 123). Wagner-Meenvein type rearrangements of some lupane derivatives have been The I3C n.m.r. spectra of some lupanes have been reported. s4
6 Oleanane Group The confusingly named periandric acid I1 (142) and periandric acid IV (143) are the aglycones of periandrins 11 and IV respectively, sweet glycosides from Periundra dulcis (Leguminosae).s5 Other new olean- 12-ene natural products are 16p-hydroxy3-0x0-olean-12-en-28-oicacid and 16~-hydroxy-3-oxo-oleana1,12-dien-28-0icacid from grape peel, 96 canthic acid (3p,7p-dihydroxyolean-12-en-28-oic acid) from Canthiurn dicoccum (Rubia~eae),~' and bartogenic acid (2a,3p, 19a-trihydroxyolean12-ene-24,28-dioic acid) from Burringtoniu speciosa (Lecythadaceae).D8 Napoleogenol (see Vol. 11, p. 126) is now considered to be identical to aescigenin (16cc,2l0c-epoxyolean-12-ene-3~,24,28-tri01).~~ The unusual structure (144) has been proposed for salviolide from Sulviu rnexicunu (Labiatae).lo0 X-Ray analysis of methyl morolate acetate (145) has been reported.lof The friedelanes (146)-( 148) have been isolated from Cutha cussinoides (Celastraceae). The structure and stereochemistry of (147) were proved unambiguously by X-ray analysis of the corresponding acetate.lo2Structure (147) had previously been assigned to octandronal (see Vol. 4, p. 214), a compound with different 91
O2
O3
Y. Yokoyama, Y.Moriyama, T. Tsuyuki, T. Takahashi, A. Itai, and Y. Iitaka, Bull. Chem. SOC.Jpn., 1980, 53, 2971. Y . Yokoyama, Y. Moriyama, T. Tsuyuki, and T . Takahashi, Bull. Chem. Soc. Jpn., 1981, 54, 234. A. S. R. Anjaneyulu, M. N. Rao, A. Sree, and V. S . Murty, Indian J. Chem., Sect. B, 1980, 19, 735.
O4
R. C. Carpenter, S . Sotheeswaran, M. U. S. Sultanbawa, and B. Ternai, Org. Mugn. Reson.,
1980, 14, 462. Y . Hashimoto, H. Ishizone, and M. Ogura, Phytochemistry, 1980,19,2411. g* C. H. Brieskorn and G. Blosczyk, Z . Lebensm.-Unters.Forsch., 1981, 172, 201. $' T. K. Chatterjee, A. Basak, A. K. Barua, K. Mukherjee, and L. N. Roy, Trans. Bose Res. Inst. (Calcutta), 1979, 42, 85. O 8 G. S. R. Subba Rao, S . Prasanna, V. P. S. Kumar, and G. R. Mallavarapu, Phytochemistry, 1981, 20, 333. M. Kapundu, R. Warin, C. Delaude, and R. Huls, Bull. SOC.Chim. Belg., 1980, 89, 1001. loo 0. Collera, E. Gomora, and F. G. Jimenez, Rev. Latinoum. Quim., 1980, 11, 60. lol J. R. Cannon, B. W. Metcalf, C . L. Raston, and A. H. White, Aust. J. Chem., 1981, 34, 1135. lo2 C. Betancor, R. Freire, A. G . Gonzalez, J. A. Salazar, C. Pascard, and T. Prange, Phytochemistry, 1980, 19, 1989. 95
227
Triterpenoids
HO (142) R (143) R
(147) R (148) R
=
= CHO = CH,OH
CH20H
= CO,H
(149) R = H, (150) R = 0
physical and spectral properties. It follows that the structures of octandronal and the related octandronic acid require revision. Other new friedelanes include kokzeylanol (149) and kokzeylanonol (150) from Kokoona zeylanica (Celastraceae),lo3 lp-hydroxyfriedel-6-en-3-onefrom Momordica foetida (Cucurbitaceae),lo4and 3 p-hydroxyfriedelan-7-onefrom Pergularia extensa (As~lepiadaceae).~~~ Following the X-ray analysis of compound T, the structures of triterpenoids Q, T, and U from Sulacia prinoides (Hippocrateaceae) have been revised to (151)-( 153) respective1y.lo6The X-ray analysis of salaspermic acid has been p~b1ished.l~~ Io3
A. A, L. Gunatilaka, N. P. D. Nanayakkara, and M . U. S . Sultanbawa, Tetrahedron Lett., 1981,22, 1425.
Io5
A. A. Olaniyi, Planta Med., 1980, 40, 303. B. Talapatra, A. Basak, S.Goswami, and S . K. Talapatra, Indian J . Chem., Sect. B, 1981, 20,
lo6
D. Rogers, F. L. Phillips, B. S. Joshi, and N . Viswanathan, J . Chem. SOC.,Chem. Commun.,
lo'
D. Rogers, K. A. Woode, N. Viswanathan, and B. S . Joshi, J . Chem. SOC.,Chem. Commun.,
lo*
249 1980, 1048. 1980, 1049.
Terpenoids and Steroids
228
1
(151) R (152) R (153) R
= CHO = CH,OH = COzH
Zeylasterone (154) is a novel phenolic 24-norfriedelane from K. zeylanica.los Isoiquesterin (1 55) from Sulaciamadugus~ariensis~~~ and (156) from S . macrosperma are new quinone methides.l1° The biogenesis of triterpenoid quinone methides has been discussed.lll Isomultiflorenol (157) co-occurs with cucurbitacins in seedlings of Bryonia d i o i ~ aThe . ~ ~derivatives (158) and (159), both of which show diuretic activity in rats, occur in Antidesma menusu (Euphorbiaceae).l123cr-Hydroxymultiflora-7,9(11)dien-29-oicacid occurs in the roots of B. dioica as the p-hydroxycinnamateester.l13 The compounds (160),114 (161),115 and (162)116 have been prepared as possible intermediates for pentacyclic triterpenoid synthesis. Treatment of oleana-l2,15diene-3p,28-diol 3-acetate with toluene-p-sulphonyl chloride in pyridine affords the ~(16a)-homocompound (163). The mechanisms of this and related reactions are discussed.l172a,3p-Diacetoxy-28-noroleana12,17-diene has been synthesized.lls lo8
loQ 110 ll1
112 113 11*
115 ll6
11' 118
G.M.K.B. Gunaherath, A. A. L. Gunatilaka, M . U. S. Sultanbawa, and M. I. M. Wazeer, Tetrahedron Lett., 1980, 21, 4749. A. T. Sneden, J . Nut. Prod., 1981, 44,503. G. C. S. Reddy, K. N. N. Ayengar, and S . Rangaswami, Indian J . Chem., Sect. B , 1981,20,197. J. P. Kutney, M. H. Beale, P. J. Salisbury, K. L. Stuart, B. R. Worth, P. M. Townsley, W. T. Chalmers, K, Nilsson, and G . G. Jacoli, Phytochemistry, 1981, 20, 653. S. H. Rizvi, A. Shoeb, R. S. Kapil, and S. P. Popli, Phytochemistry, 1980, 19, 2409. P. J. Hylands, E.-S. S. Mansour, and M. T. Oskoui, J . Chem. Soc., Perkin Trans. I , 1980,2933. J. W. ApSimon, A. M. Greaves, N.-D. Tho, and C. P. Huber, Tetrahedron, 1981, Supplement No. 9, 117. J. W. ApSimon, D. Moir, and K. Yamasaki, Can. J . Chem., 1981, 59, 1010. J. M. Coisne, J. Pecher, J. P. Declercq, G. Germain, and M. Van Meerssche, Bull. SOC.Chim. Belg., 1980, 89, 551. 0.D. Hensens, K. G. Lewis, and D. J. Tucker, Aust. J . Chem., 1980, 33, 2517. A. Goswami and H. N. Khastgir, Indian J . Chem., Sect. B, 1980, 19, 315.
Triterpenoids
229
(157) R1= H,P-OH, R2= H, (158) R' = 0, RZ = H,a-OH (159) R1= H,P-OH, R2 0 1
09
0
(165) 13,18-ene (166) 12,13-ene, 18a-H
The selective oxidation of oleanane triterpenoids by a Cr0,-py-BunOH-H,Oderived reagent has been studied.llgSome reactions of glycyrrhetic acid have been
llQ
Y.Kobayashi, M. Ogawa, and Y. Ogihara, J. Chem. SOC.,Perkin Trans. I , 1981, 2277.
230
Terpenoids and Steroids
des~ribed.l~O-l~~ Reaction of 16-oxofriedel-3-ene with zinc chloride in acetic acid affords the rearranged products (164) and (165) in addition to the previously described (1 66).124The enol acetylation of friedel-3-en-2-one has been Rearrangements of friedelaneslZsand of the epoxide (1 67) have been studied.12' The lH 128 and 13ClZ9 n.m.r. spectra of some friedelanes have been assigned, olean-18-enes,131 hederas have the 13C n.m.r. spectra of some 0lean-l2-enes,1~~ agenin g l y c o ~ i d e sand , ~ ~taraxeranes. ~ 94 The mass spectra of some bryonolic acid derivatives133and some f r i e d e l a n e ~have l ~ ~ been discussed.
7 Ursane Group New natural products include ursonic aldehyde (3-oxours- 12-en-28-al) from Dragon's Blood, a resin from Daemonorops draco (Palmae),135dulcioic acid (168) from Scoparia dulcis (Scr~phulariaceae),~~~ rubifolic acid (169) from Rubia cordifolia (Rubiaceae),13' esculentic acid (2a,3a,23-trihydroxyurs-12-en-28-oic acid)
(168) R1= C02H, R2 = Me (169) R' = CH20H, R2 = C02H 12*
121
lZ3
124
lZ5 126
lZ7 128
lZ9
130
131
132
133
13*
135 136
137
H.-0. Kim, M. P. Irismetov, R. Kh. Garyanov, M. I. Goryaev, and Kh. A. Alibaeva, Zzv. &ad. Nauk Kaz. SSR, Ser. Khim., 1980, 61. H.-8. Kim, R. Kh. Garyanov, M . P. Irismetov, and M. I. Goryaev, Izv. Akad. Nauk Kaz. SSR, Ser. Khim., 1980, 85. M. Kanaoka, S. Yano, H. Kato, and N. Nakano, Chem. Pharm. Bull., 1981, 29, 1533. K. Takahashi, S. Shibata, S. Yano, M. Harada, H. Saito, Y. Tamura, and A. Kumagai, Chern. Pharm. Bull., 1980, 28, 3449. T. Kikuchi, M. Niwa, M. Takayama, T. Yokoi, and T. Shingu, Chern. Pharm. Bull., 1980, 28, 1999. Y. P. Gupta and J. L. Courtney, Indian J . Chem , Sect. B, 1981, 20, 65. A. S. R. Anjaneyulu and M. N. Rao, Indian J . Chern., Sect. B, 1980, 19, 634, P. Sengupta, M. Sen, and S. N. Maiti, J . Indian Chem. SOC.,1980, 57, 1181. T. Kikuchi, T. Yokoi, M. Niwa, and T. Shingu, Chem. Pharm. Bull., 1980, 28, 2014. A. A. L. Gunatilaka, N. P. D. Nanayakkara, M. U. S. Sultanbawa, and M. I. M . Wazeer, Org. Magn. Reson., 1980, 14, 415. A. Patra, A. K. Mitra, S. Ghosh, A. Ghosh, and A. K. Barua, Org. Magn. Reson., 1981, 15, 399. A. G. Gonzalez, B. M. Fraga, P. Gonzalez, M. G. Hernandez, and A. G. Ravelo, Phytochemistry, 1981, 20, 1919. A. I. Kalinovskii and N . 1. Chetyrina, Khirn. Prir. Soedin., 1980, 359; English translation, Chem. Nut. Compounds, 1980, 16, 269. A. G . Panosyan, G . M. Avetisyan, V . A. Mnatsakanyan, and B. V. Rozynov, Bioorg. Khim., 1980, 6 , 1094. J. Schmidt, S. Huneck, and W. Ihn, J . Prakt. Chem., 1980, 322, 695. G . Nasini and F. Piozzi, Phytochemistry, 1981, 20, 514. S. B. Mahato, M . C . Das, and N. P. Sahu, Phytochemistry, 1981, 20, 171. S. K. Talapatra, A. C. Sarkar, and B. Talapatra, Phytochemistry, 1981, 20, 1923.
Triterpenoids
23 1
(172) R1 = Ac, R2= H (173) R1 = H,R2 = AC from the fern DipZazium esculentum (Athyriaceae),13*polemoniogenin ( 1 70) from PoZemonium coeruZeum (Polemonia~eae),1~~ a lactone, probably (1 71), from Pieris japonica (Ericaceae),lQ0and the acetates (1 72) and (1 73) from Myrianthus arboreus (Urti~aceae).~~~ Degradation of ursolic acid gave the triester (174) which was required to correlate the stereochemistry of a key intermediate in the synthesis of (-)-(S)-2-hydroxyP-ionone.142 Rearrangement of the epoxide (1 75) has been
Fe @ C0,Me
AcO AcO ( 174)
(175)
The 13C n.m.r. spectra of some urs-12-enes130 and the mass spectra of 18x,19pH-ursane ring E lactoneslQ4have been reported.
8 Hopane Group
3P-Hydroxy-17-methylhopane(1 76) and 29-hydroxy-3,17-dimethylhopane(1 77) have been isolated from the photosynthetic bacterium Rhodomicrobium vannielii. The origin of the 3P-oxygen atom of (176) poses an interesting biogenetic question since the bacterium was grown under strictly anaerobic conditions.145Examination of some recent sediments has shown the presence of unaltered bacteriohopanoids 138 13$
140
141 142 143
144
145
R. Tandon, G. K. Jain, R. Pal, and N. M. Khanna, Indian J . Chem., Sect. B, 1980, 19, 819. R. Tandon, G. K. Jain, R. Pal, and N. M. Khanna, Indian J . Chem., Sect. B. 1981. 20. 46 M. Katai, T. Terai, and H. Meguri, Chem. Pharm. Bull., 1981, 29,261. C. M. Ojinnaka, J. I. Okogun, and D. A. Okorie, Phytochemistry, 1980, 19, 2482. S. Escher, W. Giersch, and G. Ohloff, Helv. Chim. A d a , 1981, 64, 943. A. K. Sil, J. K. Ganguly, K. P. Dhara, C. P. Dutta, and D. N. Roy, IndianJ. Chem., Sect. B, 1981, 20, 201. J. Protiva, E. Klinotova, H. Skorkovska, and A. Vystrcil, Collect. Czech. Chem. Commun., 1981, 46, 1023. D. L. Howard and D. J. Chapman, J . Chem. Soc., Chem. Commun., 1981, 468.
Terpenoids and Steroids
232
( 180)
such as diploptene (1) together with many modified hopanoids typical of sedimentary rocks. This supports the hypothesis that the former are precursors of the latter.146 The trisnormoretane (1 78) is the major saturated hydrocarbon of a The structure of thysanolactone (179), a novel ring A seco moreJurassic tane from Thysanospermum dzflusum (Rubiaceae) was established by X-ray analysis.148The X-ray crystal and molecular structure of 9(11)-fernene (180) has been r e ~ 0 r t e d . l ~ ~
9 Miscellaneous The stereochemistries of the three isomeric onoceranediol diacetates have been assigned.150Wightianol-A ( 1 8 I ) and -B (1 82) from Lycapodium wightianum (Lycopodiaceae)151 and 3a-hydroxy- 14-serraten-21-one (1 83)152 and the novel norserratene (1 84)153from Pinus monticola (Pinaceae) are new natural products. The lA6
M . Rohmer, M . Dastillung, and G. Ourisson, Naturwissenschaften, 1980, 67, 456; see also.
R. C. Barrick and J . I. Hedges, Geochim. Cosmochitn. Acta, 1981, 45, 381. 147 148
149
IS0
151 lS2 153
M. Bjoroy and J. Rullkotter, Chem. Geol., 1980, 30, 27. N. Aimi, K. Yamaguchi, M . Takahashi, M . Iwata, S. Sakai, J. Haginiwa, and Y.Iitaka, Tetrahedron, 1981, 37, 983. H. W. Schmalle, 0. H. Jarchow, and B. M . Hausen, Acta Crystalfogr., Sect. B, 1980, 36, 2450. Y. Tsuda and T. Sano, Chem. Pharm. Bull., 1980,28, 3134. Y. Tsuda, Y. Tabata, and Y . Ichinohe, Chem. Pharm. Bull., 1980, 28, 3275. A. H. Conner, B. A. Nagasampagi, and J. W. Rowe, Phytochemistry, 1980, 19, 1121. A. H. Conner, T. P. Haromy, and M . Sundaralingam, J . Org. Chem., 1981, 46, 2987.
233
Triterpenoids OH
(181) 14,15-dihydro,14P-OH (1 82)
fl-(cH2 0 . (185)
(186) (187)
0
R R
=0
= H,P-OAc
234
Terpenoids and Steroids
rearrangement of 3$,4p-epoxyshionane (1 85) has been The sponge Jaspis stellifera is a novel source of the malabaricane type triterpenoids (186)(1 88).155 Another sponge, Siphonochalina siphonella, contains sipholenol (1 89), whose structure was established by X-ray analysis of the derived 4-acetate. The name sipholane has been proposed for this new squalene-derived ~ k e 1 e t o n . l ~ ~ Terretonin (see Vol. 11, p. 132) has been shown to be of mixed polyketideterpenoid origin .15 10 Triterpenoid Saponins
The interesting biological properties shown by many saponins, coupled with improvements in spectroscopic methods of structure determination have led to the increased study of this class of compound. The following papers deal with saponins and prosapogenins which are based on known triterpenoids of the following groups : d a m m a r a n e - e ~ p h a n e ,l ~~~p~a n e ,o1eanane,l6O l~~ and ursane.lG1 Desorption/chemical ionization mass spectrometry is a useful technique for the investigation of underivatized polar and involatile compounds such as triterpenoid saponins.162The cleavage of saponins by anodic oxidation has been investigated,163 as has the glycosidation of triterpenoids.164
L. Cattel, L. Delprino, and A. Dietsch, Gazz. Chim. Ital., 1979, 109, 705. B. N. Ravi, R. J. Wells, and K. D. Croft, J . Urg. Chem., 1981, 46, 1998. 156 U. Shmueli, S . Carmely, A. Groweiss, and Y. Kashman, Tetrahedron Lett., 1981, 22, 709. 15' C. R. McIntyre and T. J. Simpson, J . Chem. Soc., Chem. Commun., 1981, 1043. 15* Y. Kimura, Y. Kobayashi, T. Takeda, and Y . Ogihara, J . Chem. Soc., Perkin Trans. I , 1981, 1923; M. Ikram, Y. Ogihara, and K. Yamasaki, J . Nar. Prod., 1981,44,91; M. Okano, K.-H. Lee, I. H . Hall, and F. E. Boettner, ibid., p. 470; S . E. Chen, E. J . Staba, S. Taniyasu, R. Kasai, and 0. Tanaka, Planta Med., 1981, 42, 406. 15B P. K. Minocha and K. P. Tiwari, Phytochernistry, 1981, 20, 135; D. Mandloi and P. G. Sant, ibid., p. 1687. H. Ishii, M. Nakamura, S.,Seo, K. Tori, T. Tozyo, and Y. Yoshimura, Chem. Pharm. Bull., 1980, 28, 2367; H. Kizu and T. Tomimori, ibid., pp. 2827, 3555; T. Konoshima, H. Inui, K. Sato, M. Yonezawa, and T. Sawada, ibid., p. 3473; S. Takabe, T. Takeda, Y. Ogihara, and K. Yamasaki, J . Chem. Res. ( S ) , 1981, 16; H. Ishii, K. Tori, T. Tozyo, and Y. Yoshimura, J . Chem. Soc., Perkin Trans. I , 1981, 1928; P. N . Singh and S . B. Singh, Phyrochemistry, 1980, 19, 2056; R. D. Tripathi and K. P. Tiwari, ibid., p. 2163; T. Konoshima, H. Fukushima, H. Inui, K. Sato, and T. Sawada, ibid., 1981, 20, 139; M. Moreno and V. M. Rodriguez, ibid., p. 1446; M. Masood, P. K. Minocha, K. P. Tiwari, and K. C. Srivastava, ibid., p. 1675; T. Aoki, K. Shido, Y . Takahashi, and T. Suga, ibid., p. 1681; P. Forgacs and J. Provost, ibid., p. 1689; R. Encarnacion, L. Kenne, G . Samuelsson, and F. Sandberg, ibid.. p. 1939; Y. Okada, K. Koyama, K. Takahashi, T. Okuyama, and S. Shibata, Planta Med., 1980,40,185; S . Ghosal, A. K. Srivastava, R. S . Srivastava, S. Chattopadhyay, and M. Maitra, ibid., 1981, 42, 279; H. Ishii, I. Kitagawa, K. Matsushita, K. Shirakawa, K. Tori, T. Tozyo, M. Yoshikawa, and Y. Yoshimura, Tetrahedron Lett., 1981, 22, 1529. P. K. Minocha and R. N. Tandon, Phytochemistry, 1980, 19, 2053. 162 K. Hostettmann, J. Doumas, and M. Hardy, Helv. Chim. Acta, 1981, 64, 297. 163 I. Kitagawa, T. Kamigauchi, H. Ohmori, and M. Yoshikawa, Chem. Pharm. Bull., 1980, 28, 3078. 164 A. A. Akimaliev, N. Sh. Pal'yants, P. K. Alimbaeva, and N. K. Abubakirov, Khim. Prir. Soedin., 1979, 668; W. Janiszowska, B. Wilkomirski, and Z. Kasprzyk, Pol. J . Chem., 1980, 54, 2147; see also ref. 50. l5*
155
5 Carotenoids and Polyterpenoids BY G.BRITTON
1 Carotenoids Introduction.-This Report covers the literature published up to approximately the end of September, 1981. Few new carotenoid structures have been reported. The main advances in carotenoid chemistry have been in the stereospecific synthesis of carotenoids with chiral end-groups. Current interest in the possible use of retinoids in cancer chemotherapy has prompted the preparation of a considerable number of retinoic acid analogues. There has been no major new development in the use of physical methods but h.p.1.c. becomes more and more the method of choice for carotenoid separation, purification, and assay, and the increasing number of papers on resonance Raman spectroscopy emphasizes the potential value of this technique in the carotenoid field. Reviews.-The major new publication is Volume 1 of the completely rewritten second edition of Goodwin's book1 'The Biochemistry of the Carotenoids'. This volume gives an introduction to carotenoid chemistry and a comprehensive survey of the distribution, biosynthesis, and functions of carotenoids in plants and microorganisms. The biochemistry of plant carotenoids is also dealt with in an extensive review by Spurgeon and Porter.2 The second edition of Czygan's book3 'Pigments in Plants' includes chapters on carotenoid bio~ynthesis,~" xanthophyll interconversion^,^^ photoregulation of carotenoid bio~ynthesis,~" and carotenoids in algal c h e r n o t a ~ o n o m yElsewhere, .~~ reviews have been published on the use of carotenoids as food c o l o u r ~ , the * ~ ~metabolic and nutritional significance of carotenoids,6 carotenoids in green and purple photosynthetic bacteria, and carotenoid biosynthesis in plants, especially enzymic aspects.a The retinoid field is surveyed in
*
T. W. Goodwin, 'The Biochemistry of the Carotenoids', Vol. 1, 2nd Edn., Chapman and Hall, London, 1980,432 pp. S. L. Spurgeon and J. W. Porter, in 'Biochemistry of Plants,' ed. P. K. Stumpf, Academic Press, New York, 1980, Vol. 4, p. 419. 'Pigments in Plants', 2nd Edn., ed. F.-C. Czygan, Gustav Fischer, Stuttgart and New York, 1980; (a) B. H. Davies, p. 31; (b) A. Hager, p. 57; (c) W. Rau, p. 80; (d) A. Weber and M. Wettern, p. 104. J. N. Counsell, Dev. Food Colours, 1980, 1, 151. H. Klaui, in 'Natural Colours in Food and other Uses, International Symposium 1979', ed. J. N. Counsell, Applied Science Publishers, London, 1981, p. 91. K. L. Simpson and C. 0. Chichester, Ann. Rev. Nutrition, 1981, 1, 351. T. W. Goodwin, J. Sci. lad. Res., 1980, 39, 682. J. W. Porter, S. L. Spurgeon, and D. Pan, Dev. Plant Biol., 1980, 6, 321.
235
Terpenoids and Steroids
236
two extensive b o o k ~ , ~ and J ~two collections of Symposium proceedings deal with light-energy transduction mechanisms in visual cellsll and HaIohacterium halobium12 respectively. New Structures and Stere0chemistry.-Carotenoids. Of the few new carotenoid structures that have been reported, all but one are from marine animals. Lactucaxanthin, a major xanthophyll in chloroplasts of lettuce (Lactuca saliva) and
OH
&--,
a
C
b
-=.
e
d
(1) R1 = R2 = a
(2) R1 = b, R2 = c (3) R1= d, R2 = c (4) R1= e, R2 = f ( 5 ) R1 = g, R2 = h (6) R1 = c, R2 = i
\
f
(7) R1 = R2 = j (8) R1 = R2 = d (9) R1 = d, R2 = k (10) R1 = R2 = k (11) R1 = k, Ra = i
‘Retinoids : Advances in Basic Research and Therapy’, ed.-C. E. Orfanos, 0. Braun-Falco, E. M. Farber, C. Grupper, M. K. Polano, and R. Schuppli, Springer, Berlin, 1981, 527 pp. lo ‘Modulation of Cellular Interactions by Vitamin A and Derivatives (Retinoids),’ ed. L. M. DeLuca and S. S. Shapiro, N. Y. Acad. Sci., 1981,430 pp (also published as Ann. N.Y. Acad. Sci., Vol. 359). l1 Phofochem. Photobiol, 1980,32, 423. Photochem. Photobiol, 1981,33,417. @
Carotenoids and Polyterpenoids
237
related species, has been identified13by n.m.r. and c.d. correlation as (3R,6R,3’R, h’R)-~,~-carotene-3,3’-diol (I), the sixth of the ten possible chiral isomers of this diol to be found in Nature. 7‘8’-Didehydro-p,p-carotene-3,4,3’-triol (2) has been obtained from a number of she1lfish.l4-l6The structure was confirmed by NaBH, reduction of pectenolone (3,3’-dihydroxy-7’,8’-didehydro-p,p-caroten-4-one (3). The 3,4-cis-vic-diol thus formed was identical to the new carotenoid. Three new pigments from the sponge Microciona prolifera have been characterized by their spectroscopic properties1’ as 3,4(or 2,3)-didehydro-y,~-carotene (4),3-hydroxy-x,~carotene-6,8-dione [‘trikentriophidin’ (5)], and 7,8-didehydro-p,p-caroten-3-01 [‘allobetaxanthin’ (6)]. The occurrence of free actinioerythrol [3,3’-dihydroxy-2, 2’-dinor-p,p-carotene-4,4’-dione (7)] and its monoester in the sea anemones Actinia equina and A . tenebrosa has been reported for the first time.18 The fatty acid composition of the (7) diester, actinioerythrin, the main pigment of these animals, has been describedlg along with those of astaxanthin [3,3‘-dihydroxy-p, p-carotene-4,4’-dione (S)] esters from Haematococcus pluvialis and Panadalus borealis. The preparation of ( -)-camphanate diesters followed by h.p.1.c. separation is a good method for determining the isomeric composition of samples of (8) and adonirubin [3-hydroxy-p,p-carotene-4,4’-dione (9)].20The astaxanthin of the shrimp Pandalus borealis21and of salmon22contained the (3R,3‘R)-, (3R,3’S)-, and (3S,3’S)-isomers. The absolute configuration of mimulaxanthin [6,7,6’,7’-tetradehydro-5,6,5‘,6’-tetrahydro-p,p-carotene-3,5,3‘5’-tetrol (12)] from Lamium montanum has been determined23 as (3S,SR,sR,3’S,S’R,6’R) by degradation and
R2
a
b
C
(12) R1 = R2 = a (X = H) (13) R1 = a (X = H), R2 = b (Y = CH=CH) (14) R1= a (X = H), R2= c (15) R1= a (X = Ac), R2= b (Y = CH2CO) D. Siefermann-Harms, S. Hertzberg, G. Borch, and S . Liaaen-Jensen, Phytochemistry, 1981, 20, 85. l4 T. Matsuno, T. Maoka, and K. Hiraoka, Bull. Jpn. SOC. Sci. Fisheries, 1981,47, 143. 16 T.Matsuno and T. Maoka, Bull. Jpn. SOC.Sci. Fisheries, 1981,47, 377, 495. l8 T. Matsuno, K. Hiraoka, and T. Maoka, Bull. Jpn. SOC.Sci. Fisheries, 1981,47, 385, 501. C. Litchfield and S . Liaaen-Jensen, Comp. Biochem. Physiol., 1980,6 W ,359. J. D. Tauber, A. Fiksdahl, and S. Liaaen-Jensen, Biochem. Syst. Ecol., 1980,8,437. l 8 B. Renstrcam and S. Liaaen-Jensen, Comp. Biochem. Physiol., 1981,69B,625. 8o R. K. Muller, K. Bernhard, H. Mayer, A. Ruttimann, and M. Vecchi, Helv. Chim. Acta, 1980, 63,1654. *l B. Renstrram, G. Borch, and S. Liaaen-Jensen, Comp. Biochem. Physiol., 1981,69B,621. 88 K.Schiedt, F. J. Leuenberger, and M. Vecchi, Helv. Chim. Acta, 1981,64, 449. R. Buchecker and C. H. Eugster, Helv. Chim. Acta, 1980,63,2531. la
238
Terpenoids and Steroids
spectroscopic and c.d. comparison with neoxanthin [(3S,SR,SR,3’S,S’R,6’S)-5’, 6’-epoxy-6,7-didehydro-5,6,5’,6’-tetrahydro-p, p-carotene-3,5,3’-triol (1 3)]. Similarly, desepoxyneoxanthin has been shown to be (3S,5R,6R,3’R)-6,7-didehydro-5, 6-dihydro-p,p-carotene-3,5,3’-triol (14). For these correlations, the difficult desepoxidation of neoxanthin was achieved with BuLi-FeC1, after silylation. Chiroptical correlation of its hexa-acetate with (2S,2’S)-bacterioruberin [2,2’-bis(3-hydroxy-3-methylbutyl)-3,4,3’,4’-tetradehydo1,2,1’2’-tetrahydro-+,+-carotene1, 1’-diol (1 6)] and plectaniaxanthin [3’,4’-didehydro-1’,2’-dihydro-p,+-carotene1 ’, 2‘-diol ( 17)] p-D-glucoside supported the assignment of the (2R,2’R)configuration for oscillaxanthin [ 1,2,1’2’-tetrahydro-+,+-carotene1,2,1’,2’-tetrol 2,2’-rhamnoside (1 S)].24
OH
b
a
C
(16) R1= R2= a R1= b, R2= c (X = H) (18) R1= R2= c (X = rhamnosyl) (17)
New NaturalProducts Related to Carotenoids. New compounds which have norcarotenoid-like structures include ambliol A (19), dehydroambliol A (20), and ambliolide (21), diterpenoids from the sponge Dysidea a m b l i ~ deoxyabscisic ,~~ acid (22), a precursor to abscisic acid (23) in Cercospora rosicolaYz6and two tobacco products, 3-hydroxy-5,6-epoxy-p-ionyl-~-~-glucopyranoside (24)27 and 8,9-dihydroxy-8,9dihydromegastigmatrienone (25).28 The absolute configuration of (-)-(S)-2hydroxy-p-ionone (26) has been determined by correlation with ursolic acid and ( -)-trans-verbenol. 29 Carotenoid-Protein Complexes. Three new purple-blue carotenoprotein complexes from invertebrate animals have been described. That from the carapace of Orconectes Iimosus (Amax 335, 460, 675 nm) has astaxanthin (8) and canthaxanthin and that from the fly Rhyn[p,p-carotene-4,4’-dione(lo)] as prosthetic chosciara americana (Amax 465,545 nm) has one canthaxanthin and one echinenone [p,p-caroten-4-one (1 l)] per mole of protein.31 The sponge Suberites domuncula H. Ranneberg, P. FOSS, T. Ramdahl, G. Borch, 0. M. Skulberg, and S. Liaaen-Jensen, Phyrochemistry, 1980, 19, 2167. 25 R. P. Walker and D. J. Faulkner, J . Urg. Chem., 1981, 46, 1098. 28 S. J. Neill, R. Horgan, T. S. Lee, and D. C. Walton, FEBS Lett., 1981, 128, 30. 2 7 H. Kodama, T. Fujimori, and K. Kato, Agric. Biol. Chem., 1981, 45, 941. 2 8 Y . Takagi, T, Fujimori, H. Kaneko, and K. Kato, Agric. Biol. Chem., 1981,45, 787. 2 g S . Escher, W. Giersch, and G. Ohloff, Helv. Chim. Acta, 1981, 64, 943. 30 B. Czeczuga and S. Krywuta, Comp. Biochem. Physiol., 1981, 68B, 339. 31 W. R. Terra, C. Ferreira, A. G. De Bianchi, and K. Zinner, Comp. Biochem. Physiol., 1981, 68B, 89. Z4
239
Carotenoids and Polyterpenoids
6.X
0
b* Me OH
(19) X = a-Me, P-OH (20) X = CH2
OMe (21)
@
-Glucose
0W
C
(22) X (23) X
0
2
H
HO
=H = OH
(24)
yielded a blue carotenoprotein (31 000 dalton) in which the carotenoid was not identified but described as similar to a monohydroxymonoepoxycarotene.32A new fucoxanthin [5,6-epoxy-3,3’,5’-trihydroxy-6’,7’-didehydro-5,6,7,8,5’,6’-hexahydroP,P-caroten-8-one 3’-acetate (1 5)]-chlorophyll a-protein complex from brown algae and diatoms has been described.33
Synthesis and Reactions.-Curotenoids. Two review a r t i c l e ~ ~devoted * - ~ ~ to synthetic methods in the isoprenoid field contain information that is, or may be, useful for carotenoid synthesis. Methods have been reported for the synthesis of a ..OH
HO
w c M e 2 O M e x&H20H Y
(28)
x
p
h
h
(31) X (32) X
= OH,
3 Br-
Y
(29) X =OH, Y = H (30) X = H, Y = OH
= H,
Y =H Y = OH
L. Cariello and L. Zanetti, Mar. Biol. (Berlin), 1981, 62, 151. 33
R. S. Alberte, A. L. Friedman, D: L. Gustafson, M. S. Rudnick, and H. Lyman, Biochim.
36
Biophys. Acta, 1981, 635, 304 M. Julia, in ‘Organic Synthesis Today and Tomorrow,’ Proc.IUPAC Symp. Org. Synth., 3rd 1980, ed. B. M. Trost and C. R. Hutchinson, Pergamon, Oxford, 1981, p. 231. G. Cainelli and G. Cardillo, Acc. Chem. Res., 1981, 14, 89.
240
Terpenoids and Steroids
(33)
(34)
number of carotenoids with chiral end-groups. The (3R,3’R)-, (3S,3’S)-, and (3R,3‘S, meso)-isomers of zeaxanthin [P, P-carotene-3,3’-diol (27)] have been prepared by a route which utilizes asymmetric hydroboration as the key reaction.36 Thus safranol isopropenylmethyl ether (28), on hydroboration with ( +)- or (-)-di-isopinocamphenylborane gave the optically pure (R)-and (S)-diols (29) and (30) respectively. Chain elongation and conversion into the C15 Wittig salts (31) and (32) followed by reaction with the appropriate aldehyde (33) or (34) afforded the (27) isomers. The synthesis of (3R,3’R,6’R)-lutein [P,~-carotene-3,3’diol (35)] was achieved from (R)-4-hydroxy-2,6,6-trimethylcyclohex-2-en1-one (36) as a readily available key intermediate.37 This was used to prepare the C,,
&
HO
p i c1-+ HO”
Wittig salt (37) for reaction with (34) to give lutein. The synthesis of all-trans(3S,3’S)-7,8,7’,8’-tetradehydroastaxanthin [3,3’-dihydroxy-7,8,7’,8‘-tetradehydrop, p-carotene-4,4’-dione (3S)] and all-trans-(3S,3‘S)-7,8-didehydroastaxanthn[3,3’dihydroxy-7,8-didehydro-P,p-carotene-4,4’-dione (39)], the two components of ‘asterinic acid’, and of their 9-cis- and 9,9’-di-cis-isomers from (4‘S)-(2E)-5-(4’hydroxy-2’,6’,6’-trimethy1-3’-oxocyclohex1’-eny1)-3-methylpent-2-en-4-ynal(40) as starting material in a CI5 + C,, + C15Wittig scheme.38The (3R,3’R)-, (3S,3’S)-, and (3R,3’S)-isomers of astaxanthin (8) can be obtained from a synthetic racemate by separation of the diastereomeric di-( -)-~amphanates.~~ The preparation of (3R)+-citraurin [3-hydroxy-8’-apo-P-caroten-8’-al (41)], (3R)-P-citraurol [8’-apoP-carotene-3,8’-diol (42)], and (3R)-p-citraurinene [8‘-apo-P-caroten-3-01 (43)] from the C,, Wittig salt (31) has been reported.40 36 37
38 38
A. Riittimann and H. Mayer, Helv. Chim. Acta, 1980, 63,1456,
H.Mayer and A. Ruttimann, Helv. Chim. Acta, 1980, 63,1451. K.Bernhard, F. Kienzle, H. Mayer, and R. K. Muller, Helv. Chim. Acta, 1980, 63,1473. R.K. Muller, K. Bernhard, H. Mayer, A. Riittimann, and M. Vecchi, Helv. Chim. Acta, 1980, 63, 1654. H.Pfander, A. Lachenmeier, and M. Hadorn, Helv. Chim. Acta, 1980, 63,1377.
Carotenoids and Polyterpenoids
0
24 1
(38) X = Y = C E C (39) X = C E C , Y = CH=CH
HO (41) R = CHO (42) R = CH20H (43) R = Me
0 (4.0)
Tedanin [P,~-carotene-3,4-dione (44)], tethyatene [3,4-didehydro-(3 ,X-carotene (45)], and agelaxanthin A [PYcp-caroten-3-ol(46)] have been prepared from (41) acetate.41MnOz oxidation of (45) gave renieratene [cp,X-carotene (47)] in low yield.
0 a
b
(44) R1= a, R2 = b (45) R1= C, R2= b
C
d
e
(46) R1= d, R2= e (47) R1= e, R2= b
Further syntheses of zeaxanthin (27) and rhodoxanthin [4’,5’-didehydro-4,5’retro-p,p-carotene-3,3’dione(48)] have been described.42In a simplification of a previous procedure, the acetylenic trio1 (49) was reduced (LiAlH,) to the allenic diol (50), which with PPh,Br underwent rearrangement to the 3-hydroxy-p-ring 41
A. Shimada, Y. Ezaki, J. Inanaga, T. Katsuki, and M. Yamaguchi, Tetrahedron Lett., 1981,22, 773.
P. R. Ellis, A. E. Faruk, G . P. Moss, and B. C. L. Weedon, Helv. Chim. Acta, 1981, 64, 1092.
Terpenoids and Steroids
242
Wittig salt (51). Wittig reaction with the C,, dialdehyde (52) gave racemic (27). The 3-hydroxy-p-ring system was also obtained from a-ionone (53). Oxidation with t-butyl chromate gave the ketone (54), which with ethanediol underwent double-bond migration to give (55), which was hydrolysed in the presence of
(
y
o
(53)
o
p
o
z
(54)
cyanoborohydride to the intermediate (56) en route to (27). 3-Keto-cx-ionone (57) gave the diacetal (58), mild hydrolysis of which afforded (59), the key intermediate in a synthesis of (48). The C,, epoxy Wittig salt (60) has been used to synthesize lycopene 1 ,Zepoxide [lY2-epoxy-1,2-dihydro-#,#-carotene(61)] and 1,2 :1‘,2’-
w
0
(57)
Carotenoids and Polyterpenoids
243
(62)],43 and the diepoxide [ 1,2:1’,2’-diepoxy-I,2,1’,2’-tetrahydro-~,+-~arotene 1’,2’-epoxides of y- and %carotenes [ 1’,2’-epoxy-1 ’,2’-dihydro-p,$-carotene(63)
a
b
(61) (62) (63) (64) (65)
I
k
1
R1= a, R2= b R1= R2= a R1= c, R2= a R1 = d, R2= a R1= e, R2= b
(66) (67) (68) (69) (70)
d
C
R1= R2= e R3= f, R2= b R1= R2= f R1= R2= g R1= R2= h
(71) (72) (73) (74) (75)
R1= R2= i R1= R2= j R’ = R2= k R1= R2= 1 R1= R2= c
and 1’,2’-epoxy-l’,2’-dihydro-~,$-carotene (64)].44The acetonides (65) and (66) of the 1,2-diol(67) and 1,2,1‘,2’-tetrol (68) were also prepared.43Synthetic carotenoid analogues with 2- and 3-pyridyl, 2- and 3-furyl, and 2- and 3-thienyl end-groups, (69)-(74), have been made from the corresponding Wittig salts and the C,, crocetindial (76).45 A novel carotenoporphyrin ester (77) has been prepared and used as a model in light-energy transfer s t ~ d i e s . ~An ~ - ~unusual * 1,6-methano[lO]annulene homologue (78) of P-carotene [P,P-carotene (75)]has been synthesized by a Wittig reaction between the retinol derivative (79) and the cyclic dialdehyde Treatment of zeaxanthin (27) with chlorsulphonic acid followed by base gave the disulphate salt (8 l).50 Lycoxanthin ($,$-caroten- 16-01) monosulphate (82) 43 44
45
H. Pfander, M. Kamber, and Y . Battegay-Nussbaumer, Helv. Chim. Acta, 1980, 63, 1367.
H.Pfander and M. Kamber, Helv. Chim. Acta, 1980, 63, 1792. H.R. Brahmana, K. Katsuyama, J. Inanaga, T. Katsuki, and M. Yamaguchi, TetrahedronLett., 1981,22, 1695.
46
47 48
4s 6o
G . Dirks, A. L. Moore, T. A. Moore, and D. Gust, Photochem. Photobiol., 1980, 32, 277. A. L. Moore, G . Dirks, D. Gust, and T. A. Moore, Photochem. Photobiol., 1980, 32, 691. R. V. Bensasson, E. J. Land, A. L. Moore, R. L. Crouch, G . Dirks, T. A. Moore, and D. Gust, Nature, 1981, 290, 329. R. Neidlein and H. Zeiner, Arch. Pharm. (Weinheim, Ger.), 1980, 313, 970. T.Ramdahl and S. Liaaen-Jensen, Acta Chem. Scand., Ser. B, 1980, 34,773.
244
Terpenoids and Steroids
HO
0 d
C
(81) R1= R2 = a
(82) R1= b, R2= c
(83) R1= R2 = d
245
Carotenoids and Polyterpenoids 0 OH
0
(84)
0
.
HO
0 0 OH
HO
was prepared similarly. Epoxidation of astacene [3,3'-dihydrox~-2,3,2',3'-tetradehydro-@,@-carotene-4,4'-dione(83)] with perbenzoic acid gave the 9,lO-, 11,12and 9,12-epoxides (84)-(86).51 Astacene has been to form complexes with Al, Cr"', Cd*, Fe'I', and Hg" salts, including a stable 1 : 1 complex with Fe(NO,),. Cleavage of 8'-apo-p-carotenylidene oxazolone (87) with aqueous or methanolic NaOH, piperidine, or morpholine gave the 7'-benzoylamino-@-apo-6'-carotenoic acid derivatives (88) (R = OH, OMe, piperidinyl, or m o r p h ~ l i n o ) Mono.~~ and di-anions of p-carotene have been formed by reaction with a Na mirror in THF.54 The oxidation of @-carotenewith nitroxyl radical compounds has been The pyrolysis of p-carotene under various conditions afforded a range of methylbenzenes, methylnaphthalenes and p h e n a n t h r e n e ~ Kinetic . ~ ~ ~ ~ studies ~ have been reported of reactions of @-caroteneand retinyl acetate (89) with various radicals58 and with peroxide oxygen and dicyclohexyl peroxydicarb~nate.~~ 61
6s 64
bb
66
b7 O8
D. Osianu, E. Nicoara, and C. Bodea, Rev. Roum. Chim., 1980, 25, 261. J. Zsako and T. Laszlo, Rev. Roum. Chim., 1981, 26, 237. V. Ciurdaru, V. Tamas, and K. L. Simpson, Rev. Roum. Chim., 1980, 25, 571. G. N. Sinyakov, Zh. Prikl. Spektrosk., 1981, 35, 487. 0. T. Kasaikina, T. V. Lobanova, A. B. Gagarina, and N. M. Emanuel, Dokl. Akad. Nauk SSSR, 1980, 255, 1407. M. Ishiwatari, J. Anal. Appl. Pyrolysis, 1980, 2, 153. M. Ishiwatari, J . Anal. Appl. Pyrolysis, 1981, 2, 339. 0. T. Kasaikina, Z. S. Kartasheva, and A. B. Gagarina, Zzv. Akad. N a u ~SSSR,Ser. Khim., 1981, 536. Z. S. Kartasheva, 0. T. Kasaikina, and A. B. Gagarina, Izv. Akad. Nauk SSSR, Ser. Khim., 1981, 541.
9
246
Terpenoids and Steroids
NHCOPh (87) X
=
NY Ph
(88) X
=
'.*?
COR
(89) R = CH20Ac (90) R = CHO (91) R = CH20H (92) R = C02H Retinoids. The 9,ll-di-cis-isomer of retinaldehyde (90) has been prepared in six steps from the C15 aldehyde (93) and used to form a 9,ll-di-cis-rhodopsin with cattle opsin.60The 9,ll-di-cis-isomer was also one of four di-cis forms obtained by irradiation of all-trans-retinaldehyde in acetonitrile.61The sterically hindered 7-cis- and 7,13-di-cis-isomers of vitamin A [retinol (91)] have been prepared via the 7-cis photoisomerization product of the sulphone (94).62Several isotopically labelled species of retinaldehyde and derivatives have been synthesized, including 11-cis-[18-2H3]retinaldehyde(95) and 11-cis-[19-2H,]retinaldehyde,63(96), the alltrans-, 9-cis-, 1 1-cis-, and 13-cis-isomers of [ 10-2Hl]-, [ 1l-2Hl]-, [ 12-2Hl]-, and [l 1, 12-2H,]-retinaldehyde,64 all-trans-[ 13,14-14C2]- and [ 1 l-3H,]-retinoic acid (92),65-67 trans-[11-3H,]-5,6-epoxyretinoic acid (97),66 and trans-[1 1-3Hl]retinyl acetate (89).67
(93)
R'
~
6O
62
63
64
6B 13'
(94)
\
(95) R1= CD,, R2= CH, CHO (96) R1= CH,, R2 = CD,
(97)
A. Kini, H. Matsumoto, and R. S. H. Liu, Bioorg. Chem., 1980, 9, 406. M. Denny, M. Chun, and R. S. H. Liu, Photochem. Phofobiol., 1981, 33, 267. D. Miller, M. Tramell, A. Kini, and R. S. H. Liu, Tetrahedron Lett., 1981, 22, 409. M. R. Fransen, I. Palings, J. Lugtenburg, P. A. A. Jansen, and G. W. T. Groenendijk, Recl. Trav. Chim. Pays-Bas, 1980, 99, 384. A. D. Broek and J. Lugtenburg, Recl. Trav. Chim. Pays-Bas, 1980,99, 363. H. Kaegi, E. Chew, and P.-L. Chien, J . Labelled Compd. Radiopharm., 1980, 17, 745. P.-L. Chien and B. Amin, J . Labelled Compd. Hadiopharm., 1980, 17, 759. H. H. Kaegi and J. I. Degraw, J. Labelled Compd. Radiopharm., 1981, 18, 1099.
247
Carotenoids and Polyterpenoids
Many retinaldehyde, retinol, and retinoic acid derivatives and analogues have been synthesized. The (3R)-3-hydroxy-derivatives (98), (99), and (100) were prepared from the optically active C,, Wittig salt (3 1).689-Bromoretinaldehyde (101 ; trans and 9-cis), 13-bromoretinaldehyde (102; trans and 11-cis), ‘phenylretinaldehyde’ (103; trans and 9-cis), and ‘p-dimethylarninophenylretinaldehyde’ (104; trans) have been prepared and used to make bacteriorhodopsin analogue^.^^ 5,6-Dihydroretinaldehyde(105) and its desmethyl analogue (106) also formed
(98) R = CH,OH (99) R = CHO (100) R = COzH
10
(103) R = H (104) R=NMe,
(1 05)
(106)
bacteriorhodopsin analogues, 70 as did a number of synthetic arylretinaldehyde derivatives containing 1-5 conjugated double bonds. 71 The synthetic vitamin A analogues (107) (R = Ac, Me, or H) have been prepared from (108) by a Wittig scheme,72The many retinoic analogues to have been synthesized include a range of aromatic fluorine derivatives (109)-( 1 13),73the cyclopropane derivatives (114) and (1 15),74 and the bicyclic compounds (1 16) (R = H or Et), (1 17) (R = CO,H or OH), and (1 18) (R = C0,H or OH).75The cyclopentane retinoid (1 19), obtainable from retinoic acid, underwent thermal reactions to give bicyclic derivatives ( 120)-( 125).76
** OS
H. Mayer and J. M. Santer, Helv. Cylim. Acta, 1980, 63, 1467. M. G . Motto, M. SheJres, K. Tsujimoto, V. Balogh-Nair, and K. Nakanishi,J. Am. Chem. Soc., 1980,102,7947.
70
71 72
73 74 76
B. Mao, R. Govindjee, T. G. Ebrey, M. Amaboldi, V. Balogh-Nair, K . Nakanishi, and R. Crouch, Biochemistry, 1981, 20, 428. A. M. Shkrob, A. V. Rodionov, and Y. A. Ovchinnikov, Bioorg. Khim., 1981, 7 , 1169. I. M. Yakovleva, L. A. Vakulova, T. M. Filippova, A. R. Bekker, and G. I. Samokhvalov, Zh. Org. Khim., 1980, 16, 2289. K.-K. Chan, A. C. Specian, and B. A. Pawson, J . Med. Chem., 1981,24, 101. M. I. Dawson, P. D . Hobbs, R.L. S. Chan, and W.-R. Chao, J . Med. Chem., 1981,24, 1214. M. I. Dawson, P. D . Hobbs, R. L. S. Chan, W.-R. Chao, and V. A. Fung, J . Med. Chem., 1981, 24, 583.
70
P. Loliger and H. Mayer, Helv. Chim. Acta, 1980, 63, 1604.
248
Terpenoids and Steroids
R3+R5
F
iP (109) (110) (111) (112) (113)
R' = R2= R5= Me, R3 = OMe, R4= H R1= Cl, R2= H, R3 = OMe, R4 = R5= Me R1= C1, R2= R5= Me, R3 = OMe, R4= H R1= R5= C1, R2= H, R3 = OMe, R4= Me R' = R3 = R5= Me, R2= C1, R4 = H
Carotenoids and Polyterpenoids
249
(123) X = 0 (124) X = H,OH
(125)
A procedure for the preparation of 1-bromoacetylenes and conjugated enynes” has been used to make the retinaldehyde derivative (126). Retro-aldol reaction of the retinylidenedimedone (127) with MeNH, gave all-trans-retinaldehyde in 90 % yield.’* Oxidation of (127) gave the 5,6- and 5,8-epoxides (128) and (130).79The 4-acetoxy-, 4-hydroxy-, and 4-keto-derivatives (131) (X = H,OH, H,OAc, and 0 respectively) and the seco-compound (1 33) were also prepared. Compounds (128), (130; X = 0), and (131) underwent retro-aldol reaction to give the aldehydes
0
(128) R
=
(129) R
=
(132) R 77
78
H. J. Bestmann and H. Frey, Liebigs Ann. Chem., 1980, 2061. N. Acton and A. Brossi, Helv. Chim. Ada, 1980, 63, 1396. N. Acton and A. Brossi, Helv. Chim. Ada, 1980, 63, 1391.
CHO
=
CHO
250
Terpenoidr and Steroids
(129), (132), and (134). The synthesis of D-glucuronic acid conjugates of N(4hydroxypheny1)- and N-(2-hydroxyethyl)-retinamide (135) (X = p-C,H, or CH,
NH /
0 (133) R
=
HO (134) R
=
OH
CHO
(135)
CH2) from trans-retinoyl chloride has been reported.8o Retinyl phosphate (136) has been prepareda1in 40-60 % yield from retinol and POCI,. Thermal sigmatropic rearrangement of the allenic retinoids (138) (R = H or SiMe,CMe,) gave the 12,14-retroretinol compounds (139) as a mixture of geometrical isomers.82 The preparation of a water-soluble retinaldehyde-dextran complex has been described. Two-electron electrochemical reduction of N-retinylidene-n-butylamine(I 37) gave the 5,6-dihydro-derivative.84
(136) R (137) R
= CH20POgH2 =
CH=NBu"
(141)
(142)
A study of solvent effects on the photoisomerization of retinaldehyde and the C&, aldehyde (140) and G8ketone (141) has been The kinetics of formation and decay of radical anions of all-trans-retinaldehyde and derivatives B1
83 84 86
M. I. Dawson and P. D . Hobbs, Carbohydr. Res., 1980, 85, 121. S. P. Poznyakov and A. A. Dmitrovskii, Biokhim. Metody, 1980, 70. J. Sueiras and W. H. Okamura, J . Am. Chem. SOC.,1980,102, 6255. J. Pitha, S. Zawadzki, F. Chytil, D. Lotan, and R. Lotan, J . Natl. Cancer Inst., 1980, 65, 101 1. K. J. Stutts, L. A. Powell, and R. M. Wightman, J . Electrochem. Soc., 1981, 128, 1248. V. Ramamurthy, M . Denny, and R. S . H. Liu, Tetrahedron Lett., 1981, 22, 2463.
Carotenoids and Polyterpenoids
25 1
have been studied.86 The mechanisni of electrodimerization of retinaldehyde has been elucidated. Kinetic studies of liquid-phase oxidation of retinyl acetate and retinoic acid have been d e s ~ r i b e d . ~Hydrophobic ~-~~ bond energies of 11-cisretinaldehyde and P-ionone (142) have been calculated.a1 Carotenoid-like Compounds. Synthetic procedures for construction of the rings of ionones and other substances structurally related to carotenoids, and other procedures for the preparation and transformations of such compounds, may be useful in the carotenoid field. Thus reaction between the phenyl sulphide (143) and the ClJLSPh
+J-
S0,Ph
+M,,,
R (143)
R
(1.44)
(1 46)
(145)
(147)
(148)
Grignard reagent (144) (R = H or Me) followed by oxidation gave the sulphone (145) which with ally1 bromide afforded the acyclic C,, compound (146).Q2This gave rise to P-ionone (142) or a- and p-irones (147) and (148), cyclization being achieved with H,P04. p-Cyclogeranyl phenyl sulphide (149) has been prepared
(149) R = CH,SPh (150) R = CHO
Ph*f%zAc &Ho \
from (151) by sequential cyclization, reaction with ClCO,Et, and photochemical addition of PhSH.Q3Selenium-assisted cyclization of (152) over BF,-Et,O, SnCl,, CF3C02H,or HC0,H gave the cyclic compound (153), which was used in the B6
88
O1
93
N. V. Raghavan, P. K. Das, and K. Bobrowski, J . Am. Chem. Soc., 1981, 103,4569. L. A. Powell and R. M. Wightman, J . Electroanal. Chem. Interfacial Electrochem., 1981, 117, 321. E. I. Finkel'shtein, N. A. Mednikova, and E. I. Kozlov, Zh. Org. Khim., 1981, 17, 929. E. I. Finkel'shtein, N. A. Mednikova, I. S. Panasenko, and E. I. Kozlov, Zh. Org. Khim., 1981, 17, 933. E. I. Finkel'shtein, Y. M. Rubchinskaya, and E. I. Kozlov, Zh. Org. Khim., 1981, 17, 936. T. Kakitani, H. Kakitani, and S. Yomosa, Biophys. Struct. Mech., 1980, 7, 101. T. Mandai, K. Nishikawa, H. Yamaguchi, M. Kawada, and J. Otera, Chem. Lett., 1981, 473. K. Takabe, T. Yamada, and T. Katagiri, Chem. Znd. (London), 1980, 540.
252
Terpenoids and Steroids
t 157)
(158) R = H (160) (159) R = OH preparation of safranal(154). 94 Cyclization of 2-geranylthiophen and its 5-carboxyderivative (155) (R = H or C02H)gave products including (156) and (157).95New syntheses have been reported for p-damascone (158) from P-cyclocitral( 150)9sand 3-hydroxy-P-damascone (159) in four steps from the keto-ester (160).9 7 a-Ionone (161) was the starting material in new syntheses of dihydroedulans (163) and theaspiranes, e.g. (1 64),98 and of the theaspirones (165). gg (&)-(166) has been
“.o” Me
(161) R = 0 (162) R = H,OH
R
m (165) R = 0 (166) R = H,
(171) 84
95
O7
WH
(172)
T. Kametani, K. Suzuki, H. Kurobe, and H. Nemoto, Chem. Pharm. Bull., 1981, 29, 105. A. V. Semenovskii and M. M. Emel’yanov, Izv. Akad. Nauk SSSR, Ser. Khim., 1980, 2578. R. Pellicciari, E. Sisani, and R. Fringuelli, Tetrahedran Lett., 1980, 21, 4039. Y . Tsujino, M. Shibagaki, H. Matsushita, K. Kato, and H. Kaneko, Agric. Biol. Chem., 1981, 45, 1731.
H. Etoh, K. Ina, and M. Iguchi, Agric. B i d . Chem., 1980, 44, 2871. W. M. B. Koenst, W. Appeldoorn, and H. Boelens, Synrh. Commun., 1980,10,899.
Carotenoids and Polyterpenoids
253
prepared from dihydro-a-ionol (167) by sequential electrochemical chlorination, dehydrochlorination, and cyclization.looA five-step route to the vitispirane diastereomers (168) used dehydro-p-ionone (169).lo1Diastereomers of dihydrololiolide (170) were obtained, along with the dehydration product (171) from the cyclohexanone (172),lo2An efficient three-step preparation of all-trans-p-ionylidene-
pN
P
/
(173)
(174) R (175) R
= CH=CH
C
H
O
(176)
= CHO
0
OH (180)
acetaldehyde (140) from p-ionone (142) via the nitrile (173) has been described.lo3 Mild acid dehydration of a-ionol (162) gave products including megastigma-4, 7(E),Ptriene (1 74), which was oxidized to the aldehyde (175).lo4Other natural products with carotenoid-like rings for which syntheses have been reported include Latiu luciferin ( 176)lo5and mokupalide (177)?05J06( +)-farnesiferol C (178),107 trans-y-monocyclofarnesol (179),lo8and the glucoside picrocrocin (18O).lo9 S. Torii, K. Uneyama, T. Nakai, and T. Yasuda, Tetrahedron Lett., 1981, 22, 2291. T.Kato and H. Kondo, Bull. Chem. Soc. Jpn., 1981, 54, 1573. lo2 S. Shibata, H. Matsushita, K. Kato, H. Kaneko, M. Noguchi, M. Saburi, and S. Yoshikawa, Agric. Biol. Chem., 1981, 45, 315. lo3 R.W.Dugger and C. H. Heathcock, Synth. Commun., 1980,10, 509. lo4 B.-H. Song, D.L. Davis, and C. M. Song, J . Agric. Food Chem., 1980, 28, 997. lo6 F.W. Sum and L. Weiter, Tetrahedron,Suppl. 1981, 303. lo6 M. Kobayashi and E. Negishi, J . Org. Chem., 1980, 45, 5223. lo' T. Mukaiyama and N . Iwasawa, Chem. Lett., 1981, 29. lo* 0. P.Vig, M. L. Sharma, N. Trehan, and N. K. Verma, IndianJ . Chern., Sect. B, 1980,19,450. loo H. Mayer and J. M. Santer, Helv. Chim. A d a , 1980, 63, 1463. loo
lol
254
Terpenoids and Steroids
The I , 1-didesmethyl analogue (1 8 1) of abscisic acid (23) has been prepared.l1° The cis-trans photoisomerization of (23) has been studied.’l1 A convenient procedure has been developed for the catalytic hydrogenation of p-ionone (142) to the cis-5,6dihydroionone (182).l12 On treatment with Me2S+CH;, P-ionone gave the epoxide (183), which with MgBr, afforded the aldehyde ( 1 84) without halohydrin formatio n .l13 The photochemical reactions of ionones and related compounds have been studied extensively and in most cases large numbers of products have been characterized. Compounds whose behaviour on irradiation have been investigated include
@R (188) R (189) R
111
02Me
p \
@d OR
= H, = CH,
(190) R = 0 (191) R = CH,
(192)
E. Nagano, T. Oritani, and K. Yamashita, Agric. Biol. Chem., 1980, 44, 2095. D. E. Brabham and R. H. Biggs, Photochem. Photobiol., 1981, 34, 3 3 . C. N. Filer, J. C. Pugliese, J. C. Morrison, and D. G . Ahern, Org. Prep. Proced, Znt., 1981, 13, 140.
113
M. Rosenberger, W. Jackson, and G . Saucy, Helv. Chim. Acta, 1980, 63, 1665.
Carotenoids and Polyterpenoids
255
(E)- and (2)-p-ionone and the bicyclic compound (185)>14(E)- and (Z)-a-i~none,”~ (E)-p-ionone oxime ethyl ether (186)>16 the cyclopropane derivative (187);17 the epoxy-esters(188)llSand (189),119and the epoxides (19Oy2O (192) (R = H or Ac),121 (191), and (193).122The catalytic hydrogenation of compounds including p-ionone with K,[Co(CN),H] in aqueous solution with phase-transfer reagents has been described.12, The mechanisms of hydrogenation of 13-ionong~~ and pseudoionone (1 94)125have been studied. Physical Methods.-Separation and Assay. A range of isomers of astaxanthin (8) diacetate (9-cis, I3-cis, 15-cis, 9,9’-di-cis, 9,13-di-cis, 9,13’-di-cis, 13,13’-di-cis, 13,15-di-cis), prepared by thermal and iodine-catalysed isomerization of rrans-(8) have been separated by h.p.l.c.126A procedure has been developed for separation of bean leaf etioplast pigments, including c a r ~ t e n o i d s ,by ~ ~h.p.1.c. ~ H.p.1.c. separations of esters of all-trans-, 9-cis-, 11-cis-, and 1 3 - ~ i ~ - r e t i n o l , l ~and *-~~~ determinations of retinol in retinol and 13-cis-retinoic and the aromatic retinoid (195)13,in plasma have been described. A reversed-phaseion-pair
h.p.1.c. method has been used for analysis of plant hormones including abscisic acid.ls4T.1.c. methods have been described for the separation of green plant135and phyt~planktonl~~ carotenoids, and paper chromatography of chloroplast pigments 114 116 116 117 118
H. Cerfontain and J. A. J. Geenevasen, Tetrahedron, 1981, 37, 1571. C. P.Visser and H. Cerfontain, Recl. Trav. Chim. Pays-Bas, 1981, 100, 153. P.Baas, H. Cerfontain, and P. C. M. Van Noort, Tetrahedron, 1981, 37, 1583. K.Ishii, H. R. Wolf, and 0. Jeger, Helv. Chim. Acta, €980, 63, 1520. A. P. Alder, H. R. Wolf, and 0. Jeger, Helv. Chim. Acta, 1980, 63, 1833. K. Murato, B. Frei, W. B. Schweizer, H. R. Wolf, and 0. Jeger, Helv. Chim. Acra, 1980, 63, 1856.
lZo lal
K. Murato, H. R. Wolf, and 0. Jeger, Helv. Chim. Acta, 1980, 63, 2212. N. Nakamura, W. B. Schweitzer, B. Frei, H. R. Wolf, and 0. Jeger, Helv. Chim. Acta, 1980, 63,2230.
12z lZ3 lZ4 lZ5
126
lZ8 lZ0
132 133
la4 lS5 136
A. P. Alder, H. R. Wolf, and 0. Jeger, Helv. Chim. Acta, 1981, 64, 198.
D.L.Reger, M. M. Habib, and D. J. Fauth, J. Org. Chem., 1980, 45, 3860. D.V. Sokol’skii, T. 0. Omarkulov, U. Suyunbaev, 0. V. Vyaznikovtseva, and E. M. Mekeev, Zzv. Akad. Nauk Kaz. SSR, Ser. Khim., 198 I , 13. E. M. Sul’man, 0. B. Sannikov, 0. S. Popov, T. V. Ankudinova, M. K. Shakhova, and G. I. Samokhvalov, Khim.-Farm. Zh., 1980, 14, 94. G.Englert and M. Vecchi, Helv. Chim. Acta, 1980, 63, 1711. K. Eskins and L. Harris, Photochem. Photobiol., 1981, 33, 131. R. A. Alvarez, C. D. B. Bridges, and S.-L. Fong, Invest. Ophthalmol. Visual Sci., 1981, 20, 304. H.Stuerle, J. Chromatogr., 1981, 206, 319. A. C. Ross, Anal. Biochem., 1981,115, 324. M. Leclercq and M. Bourgeay-Causse, Rev. Inst. Pasteur Lyon, 1981, 14, 475. J. G. Besner, R. Leclaire, and P. R. Band, J. Chromatogr., 1980, 183, 346. G. Palmskog, J. Chromatogr., 1980, 221, 345. D.M. A. Mousdale, J. Chromatogr., 1981, 209,489. D.R.Janero and R. Barnett, Anal. Biochem., 1981, 111, 283. S. W. Jeffrey, Limnol. Oceanogr., 1981, 26, 191.
256
Terpenoids and Steroids
has been reviewed.137A study of different adsorbents for column chromatography of p-carotene, canthaxanthin, lutein, zeaxanthin, isozeaxanthin, and astaxanthin esters revealed that decomposition occurred most extensively on silica gel, but could be prevented by pretreatment of the silica with edta.13*Recovery of retinyl phosphates from silicic acid increased from 15 ”/, to 85 % in the presence of 0.5 % trieth~1amine.l~~ A fluorimetric method for the determination of all-trans-retinol in serum has been described.140Radioimmunoassay procedures for the determination of retinol in serum are as sensitive as h.p.l.c.,lgl and can be used for determining retinol a n a l 0 g ~ e s . lAn ~ ~ immunoassay procedure has also been developed for abscisic which can also be determined by g.1.c. of its methyl ester.144 N.M.R. Spectroscopy. High-resolution n.m.r. has proved to be a very powerful method for studying and determining the configurations of cis-isomeric carotenoids. The full IH n.m.r. characterization of nine mono-cis- and di-cis-isomers of astaxanthin diacetate has been published.126Details of a 13C n.m.r. study of the 9-cis-, 13-cis-, 9’-cis-, and 13’-cis-isomers of lutein (35) and capsanthin [3,3’-dihydroxy-p, x-caroten-6’-one (196)] have been The conformation and energytransfer properties of the carotenoporphyrin ester (77) have been studied by n.m.r.146Samples of bacteriorhodopsin obtained by enrichment with [ 14-l3C1]and [ 15-13C,]-retinaldehydehave been investigated by 13C n.m.r.lg7 Circular Dichroism. The normally achiral carotenoids echinenone (1 1) and canthaxanthin (10) exhibit c.d. when bound as the chromophore of the violet carotenoprotein of the fly Rhynchosciara a m e r i ~ a n aInteraction .~~ of lutein (35) with ovalbumin and related proteins gave a ‘complex’with a changed absorption spectrum and strong c.d. at around 384 nm suggesting aggregation of the lutein in a chiral form.148 P-Cryptoxanthin (1 97) behaved similarly, but canthaxanthin and ethyl 8’-apo-pcaroten-8’-oate (1 98) showed no c.d. bands, even though they formed complexes.149 C.d. analysis has also been used to investigate the organization of carotenoids in phospholipid vesicles and membranes.lso The c.d. spectrum of sodium cholatesolubilized rhodopsin has been determined.151
13’
138
139 140 141 142 143
144 145
146
14’ 148
149
lS0 161
Z . Sestak, Photosynthetica, 1980, 14, 239. Y. Tanaka, T. Katayama, K. L. Simpson, and C. 0. Chichester, Bull. Jpn. SOC.Sci. Fisheries, 1981, 47, 799. J. Frot-Coutaz, R. Letoublon, B. Gautier, and R. Got, Anal. Lett., 1981, 14, 69. S.-C. Wu, A. C. Capomacchia, and J. C. Price, J . Pharm. Sci., 1981, 70, 685. S. S. Westfall and G. H. Wirtz, Experientia, 1980, 36, 1351. G. H. Wirtz and S. S. Westfall, J . Lipid Res., 1981, 22, 869. S. M. Sircar, P. K. Sircar, P. K. Nagar, R. I. Iyer, and K. Chattopadhyay, Plant Biochem. J., 1980, 7, 83. K. A. Karavaeva, A. A. Bezzubov, and N. P. Korableva, Biokhim. Melody, 1980, 185. M. Baranyai, P. Molnar, J. Szabolcs, L. Radics, and M. Kajtar-Peredy, Tetrahedron, 1981,37, 203. A. L. Moore, G. Dirks, D. Gust, and T. A. Moore, Photochem. Photobiol., 1980, 32, 691. A. Yamaguchi, T. Unemoto, and A. Ikegami, Photochem. Photobiol., 1981, 33, 511. S. Takagi, M. Shiroishi, and T. Takagi, Agric. Biol. Chem., 1980, 44, 2111. S. Takagi, M. Shiroishi, and T. Takagi, Agric. Biol. Chem., 1981, 45, 1159. M. Cheron and J. Bolard, C.R. Hebd. Seances Acad. Sci.,Ser. 3, 1981, 292, 1125. J. Wagner, E. Smith, and M. A. Cusanovich, Photochem. Photobiol., 1981, 33, 929.
Carotenoids and Polyterpenoids
257
Raman and Infrared Spectroscopy. Two reviews deal with resonance Raman spectroscopy of carotenoid-containing biomolecules and rnicro-organism~~~~ and of carotenoids and chlorophylls in photosynthetic bacteria.153 The resonance Raman excitation profile of lycopene in acetone has been determined.154Calculations previously used for p-carotene do not explain the lycopene data. Several papers report detailed studies of the time-resolved resonance Raman spectra of
a
C
b
(196) R1= a, R2= b (197) R1= a, R2 = c (198) R1= C, R2 = C02Et
(199) R1= C, R2 = CHO (200) R1= R2= CH=CHCO,Me (201) R1= R2 = b
the lowest excited triplet states of all trans-p-carotene, all-trans-retinaldehyde,and all-trans-~anthaxanthin.~~~-~~~ A coherent anti-Stokes lineshape analysis has been performed for P-carotene.160The de-excitation lifetime of P-carotene, singlet state, has been deterrnined161as < 1 ps. Changes in the molecular geometry of P-carotene on electronic excitation have been determined by high-resolution resonance Raman spectroscopy.162A model has been applied to the excitation profile of 8carotene to explain Raman line-br0adeni11g.l~~ The Raman and i.r. bands of retinaldehyde were markedly affected in the presence of water, owing to hydrogenb0nding.1~~ The authors conclude that these results cast doubt on the ability of the resonance Raman technique alone to detect the chemical state of the chromophore in rhodopsin cyclic intermediates. Carotenoid-phycocyanin interactions in Anacystis nidulans have been investigated by carotenoid resonance Raman spectro-
W. H. Nelson, Am. Lab., 1981, 13, 94. M. Tasumi, Kagaku Sosetsu, 1980, 28, 249. L. C. Hoskins, J. Chem. Phys., 1981, 74, 882. R. Wilbrandt, N.-H. Jensen, P. Pagsberg, A. H. Sillesen, and K. B. Hansen, C.R. Conf. Int. Spectrosc. Raman, 7th, ed. W. F. Murphy, N.R.C.C., Ottawa, 1980, p. 632. N.-H. Jensen, R. Wilbrandt, P. B. Pagsberg, A. H. Sillesen, and K. B. Hansen, J . Am. Chem.
lba
lS3 lS4 ls5
lS6
SOC.,1980, 102, 7441. 16' 158
lS0 160
16a
16s 164
R. Wilbrandt and N.-H. Jensen, Eer. Bunsenges. Phys. Chem., 1981, 85, 508. R. Wilbrandt and N.-H. Jensen, J . Am. Chem. SOC.,1981,103, 1036. G. H. Atkinson, J. B. Pallix, T. B. Freedman, D. A. Gilmore, and R. Wilbrandt, J . Am. Chem. SOC.,1981, 103, 5069. P. K. Dutta, R. Dallinger, and T. G . Spiro, J . Chem. Phys., 1980, 73, 3580. R. F. Dallinger, W. H. Woodruff, and M. A. J. Rodgers, Photochem. Photobid., 1981,33, 275. A. V. Lukashin and M. D. Frank-Kamenetsky, Chem. Phys. Lett., 1981, 80, 119. K. Kodama and A. D. Bandrauk, Chem. Phys. Lett., 1981, 80, 248. A. E. Allan and A. Cooper, FEBS Lett., 1980, 119, 238. 4
258
Terpenoids and Steroids
~ c 0 p y .A l ~detailed ~ resonance Raman study of invertebrate astaxanthin-proteins has been published.166 Many papers report resonance Raman studies of the retinaldehyde-protein visual pigments and bacteriorhodopsin. A Symposium proceedings contains several, including review article^.^^^-^^* Papers published elsewhere deal with resonance Raman spectroscopic studies of rhodopsin and intermediates in the visual including deuterium-labelled ana10gues.l~~ Resonance Raman studies on bacteriorhodopsinare covered in a review174and a number of p a p e r ~ . l ~ ~ - l ~ l Hydrogen-bonding between the trans-N-retinylidene-butylamine Schiff base and phenols has been studied by i.r. spectroscopy.ls2 Electronic Absorption Spectroscopy. The pressure dependence of the absorption spectrum of p-carotene in pentane-isopentane, up to 60 kbar, has been studied.ls3 A large red shift and broadening of vibronic peaks was observed. The absorption spectra of charge-transfer complexes of trans-p-carotene, 8’-apo-p-caroten-8’-al (1 99), astacene (83), and methylbixin(200) have been determined.ls4The orientation of P-carotene and retinaldehyde in lipid bilayers has been investigated.ls5Agreement was found between the theory of elastic light scattering accompanying light absorption and the blue part (but not the red part) of the absorption bands of three carotenoids.ls6 U.V.spectra have been reported for the 9 4 s - and all-trans-G, and -C1,, and the all-trans-C,, and -CZ4homologues of retin01.l~~ Several retinaldehyde isomers in iso-octane solution with [Eu(fod),] gave a new characteristic absorption band.les
B. Szalontai and M. Van de Ven, FEBS Lett. , 1981, 131, 155. R. J. H. Clark, N. R. D’Urso, and P. F. Zagalsky, J. Am. Chem. SOC.,1980, 102, 6693. 167 C.R. Conf. Int. Spectrosc. Raman, 7th, ed. W. F. Murphy, N.R.C.C., Ottawa, 1980. lB8 M. A. El-Sayed, in Ref. 167, p. 542. lBD A. Warshel and R. M. Weiss, in Ref. 167, p. 552. 170 A. Lewis, in Ref. 167, p. 556. 171 D. Narva and R. H. Callender, Photochem. Photobiol., 1980, 32, 273. G. Hayward, W. CarIsen, A. Siegman, and L. Stryer, Science, 1981, 211, 942. 173 R. Mathies, G. Eyring, B. Curry, A. Broek, I. Palings, R. Fransen, and J. Lugtenburg, in Ref. 167, p. 546. 174 M. A, El-Sayed, Springer Ser Opt. Sci., 1981, 26, 295. 17b A. G. Doukas, A. Pande, T. Suzuki, R. H. Callender, B. Honig, and M. Ottolenghi, Biophys. J., 1981, 33, 275. 176 M. Braiman and R. Mathies, Biochemistry, 1980, 19, 5421. B. Ehrenberg, A. T. Lemley, A. Lewis, M. Von Zastrow, and H. L. Crespi, Biochim. Biophys. Acta, 1980, 593, 441. 178 P. V. Argade, K. J. Rothschild, A. H. Kawamoto, J. Herzfeld, and W. C. Herlihy, Proc. Natl. Acad. Sci. USA, 1981, 78, 1643. 178 B. Szalontai, Biochem. Biophys. Res. Commun., 1981, 100, 1126. 180 C.-L. Hsieh, M. Nagumo, M. Nicol, and M. A. El-Sayed, J. Phys. Chem., 1981, 85, 2714. lS1 T. Alshuth and M. Stockburger, Ber. Bunsenges. Phys. Chem., 1981, 85, 484. lB2 P. P. Rastogi and G. Zundel, Biochem. Biophys. Res. Commun., 1981,99, 804. ls3 Z. Z. Ho, T. A. Moore, S. H. Lin, and R. C. Hanson, J. Chem. Phys., 1981, 74, 873. lS4 B. Mallik, K. M. Jain, and T. N. Misra, Biochem. J., 1980, 189, 547. l E 6 L. B. A. Johansson, G. Lindblom, A. Wieslander, and G. Arvidson, FEBSLett., 1981, 128,97. I. Z. Steinberg and J. Anglister, Ann. N. Y. Acad. Sci., 1981, 336, 125. l E 7 P. K. Das and R. S. Becker, Photochem. Photobiol., 1980, 32, 739. la8A. B. Ellis, R. Schreiner, and R. A. Ulkus, Proc. Natl. Acad. Sci. USA, 1981, 78, 3993. lBb
lB6
Carotenoids and Polyterpenoids
259
Irradiation into this band caused photoisomerization, appreciable quantities of the 11-cis-isomer being formed. Several papers18g-191report calculations related to the spectroscopicproperties of retinylidene Schiffbases. The principal absorption axes of rhodopsin and prelumirhodopsin have been determined.lg2 Photoacoustic Spectroscopy. The photoacoustic spectra of visual pigments have been reported.lg3 Miscellaneous Physical Chemistry. The naphthalene-sensitized formation of triplet @-carotenehas been studied.lg4The lifetime of the excited singlet state of P-carotene has been discussed in relation to photosynthetic light harvesting.lg5Laser flash photolysis of the haematoporphyrin-P-carotene and the photoconductivity of carotenoid-containing bilayer lipid membraneslg7have been reported. Ground-state dipole moments of all-trans- and 9-cis-retinaldehyde have been determined from solution dielectric constant rneasurement~.~~~ Hydrophobic bond energies of 1l-cis-retinaldehyde and P-ionone have been The production of transient radical anions in the pulse radiolysis of retinyl polyenes has been studied.200 Photoreceptor Pigments. Light-energy transduction mechanisms in visual cells11 and the bacteriorhodopsin system of Halobacteriuml2 are the subjects of two Symposium proceedings. Several other r e v i e w ~ ~deal ~ l -with ~ ~ ~aspects of the same topics. Of the very many original papers on visual pigments, some report aspects of the chemistry and spectroscopic properties of the retinaldehyde chromophore of r h o d o p ~ i n ~and ~ ~ rhodopsin -~l~ a n a l o g ~ e s . ~The ~ ~ -chemistry, ~~' photochemistry,
K. Ishikawa, T. Yoshihara, and H. Suzuki, J. Phys. SOC.Jpn., 1980, 49, 1505. J. M. Leclercq and C. Sandorfy, Photochem. Photobiol., 1981, 33, 361. K. Nakachi, K. Ishikawa, and H. Suzuki, J. Phys. SOC.Jpn., 1981, 50, 617. lg2 B. D. Gupta, Biophys. Struct. Mech., 1980,7, 97. Ig3 F. Boucher and R. M. Leblanc, Biochem. Biophys. Res. Commun., 1981, 100, 385. 19* N.-H. Jensen, R. Wilbrandt, and P. B. Pagsberg, Photochem. Photobiol., 1980, 32, 719. lg5 R. F. Dallinger, W. H. Woodruff, and M. A. J. Rodgers, Photochem. Phorobiol., 1981,33, 275. lQ6A. Poletti, S. M. Murgia, and S. Cannistraro, Photobiochem. Photobiophys., 1981, 2, 167. lg7 J. Kutnik and Z . Lojewska, Stud. Biophys., 1981, 82, 127. lgE A. B. Myers and R. R. Birge, J. Am. Chem. SOC.,1981,103, 1881. lg0 T, Kakitani, H. Kakitani, and S. Yomosa, Biophys. Struct. Mech., 1980, 7, 101. mo N. V. Raghavan, P. K. Das, and K. Bobrowski, J. Am. Chem. SOC.,1981,103,4569. 201 R. R. Birge, Ann. Rev. Biophys. Bioeng., 1981, 10, 315. B. Honig, Ann. N.Y. Acad. Sci., 1981, 367, 269. 803 P. M. Rentzepis and P. F. Barbara, Adv. Chem. Phys., 1981, 47, 627. 204 S. P. Balashov and F. F. Litvin, Biojizika, 1981, 26, 557. zo6 W. Stoeckenius, Acc. Chem. Res., 1980, 13, 337. 208 A. E. Allan and A. Cooper, FEBS Lerr., 1980,119, 238. 207 N. Bennett, Biochem. Biophys. Res. Commun., 1980, 96, 1695. 208 R. R. Birge and L. M. Hubbard, Biophys. J., 1981, 34, 517. 2oQ A. G. Doukas, P. Y. Lu, and R. R. Alfano, Biophys. J., 1981, 35, 547. alo G. Hayward, Science, 1981,211, 942. 211 M. Nanasawa and H. Kamogawa, Bull. Chem. SOC. Jpn., 1981, 51, 1104. 81z T. Suzuki and R. H. Callender, Biophys. J., 1981, 34, 261. T. Suzuki and M. Makino, Biochem. Biophys. Acta, 1981, 636, 27. a14 M. R. Fransen, I. Palings, and J. Lugtenburg, Recl. Trav. Chim. Pays-Bas, 1980, 99,384. a16 B. Mao, M. Tsuda, T. G. Ebrey, H. Akita, V. Balogh-Nair, and K. Nakanishi, Biophys. J., IEg
IDO
1981, 35, 543. 116
217
Y . Shichida, A. Kropf, and T. Yoshizawa, Biochemistry, 1981, 20, 1962. P. Towner, W. Gaertner, B. Walckhoff, and D. Oesterhelt, Eur. J. Biochem., 1981, 117, 353.
Terpenoids and Steroids
260
and spectroscopy of the chromophore of b a c t e r i o r h o d o p ~ i n ~and ~ ~ -analogues ~~~ prepared from retinaldehyde analogues 224-229 are also the subject of several papers.
Biosynthesis and Metabolism.--Biosynthesis. Carotenoid biosynthesis is dealt with extensively in the book by Goodwinl and the chapter by Spurgeon and Porter,2
b
a
(202) R1= a, R2= b (203) R1= R2= a and is the subject of other more specific review^.^^^^ Several papers report studies of carotenoid biosynthesis and transformations in cell-free systems. The capsanthin-synthesizing activity of Capsicum annuum chromoplasts has been studied extensively. The incorporation of labelled acetate, mevalonate, and isopentenyl pyrophosphate into capsanthin (1 96) and capsorubin [3,3’-dihydroxy-x,x-carotene6,6’-dione (201)]has been demonstrated,231and the incorporation of antheraxanthin [5,6-epoxy-5,6-dihydro-p,p-carotene-3,3’-diol (202)J into capsanthin and of violaxanthin [5,6,5’,6’-diepoxy-5,6,5’,6’-tetrahydro-p,p-carotene-3,3’-diol (203)] into capsorubin are r e p ~ r t e d . Labelling ~ ~ ~ * ~ studies ~~ with isopentenyl pyrophosphate suggest that, in Capsicum, cis-trans isomerization occurs at the level of phyto(204) Isolated chromoplasts of fluene [7,8,11,12,7’,8’-hexahydro-$,$-carotene Narcissus pseudonarcissus synthesize phytoene [7,8,11,12,7’,8’11’,12’-octahydro-+, 21 a 21 8 220 221 222 2 23
224
S. P. Balashov and F. F. Litvin, Photobiochem. Photobiophys., 1981, 2, 111. T. Iwasa, F. Tokunaga, and T. Yoshizawa, Biophys. Struct. Mech., 1980, 6, 253. 0. Kalisky, M. Ottolenghi, B. Honig, and R. Korenstein, Biochemistry, 1981, 20, 649. T, Kouyama, Y. Kimura, K. Kinosita, and A. Ikegami, FEBS Lett., 1981, 124, 100. W. Maentele, F. Siebert, and W. Kreutz, FEBSLett., 1981, 128, 249. P. C. Mowery and W. Stoeckenius, Biochemistry, 1981, 20, 2302. H. Bayley, R. Radhakrishnan, K.-S. Huang, and H. G. Khorana, J . Biol. Chem., 1981, 258, 3797.
225
226
B. Mao, R. Govindjee, T. G. Ebrey, M. Arnaboldi, V. Balogh-Nair, K. Nakanishi, and R. Crouch, Biochemistry, 1981, 20, 428. K. Nakanishi, V. Balogh-Nair, M. Amaboldi, K. Tsujimoto, and B. Honig, J . Am. Chem. SOC.,1980, 102, 7945
227
22 8 229
P. G. Kryukov, Y. A. Lazarev, Y. A. Matveets, E. ‘L. Terpugov, L. N. Chekulaeva, and A. V. Sharkov, Stud. Biophys., 1981, 82, 101. F. Tokunaga, T. G . Ebrey, and R. Crouch, Photochem. Photobiol., 1981, 33, 495. P. Towner, W. Gaertner, B. Walckhoff, D. Oesterhelt, and H. Hopf, FEBS Lett., 1980, 117, 367.
230 231 232
a33
B. Camara and J. Brangeon, Pfanta, 1981, 151, 359. B. Camara and R. Moneger, Dev. Plant Biol., 1980, 6, 363. B. Camara and R. Monkger, Biochem. Biophys. Res. Commun., 1981, 99, 1117. B. Camara, C. Payan, A. Escoffier, and R. Moneger, C.R. Hebd. Seances Acad. Sci., Ser. D., 1980, 291, 303.
Car0tenoids and Poly terpeno ids
26 1
e
(204) R1= a, R2= b (205) R1= R2= b (206) R1= R2= c (207) R1= d, R2= a
(208) R1= d, R2= c
(209) R1= R2= a (210) R1= e, R2= c
+-carotene (205)] and p-carotene from isopentenyl p y r o p h ~ s p h a t eDesaturation .~~~ was inhibited by SAN 6706, but nicotine did not cause lycopene [$,$-carotene (206)] to accumulate. A cell-free system from Phycomyces blakesleeanus incorporated mevalonate into p h y t ~ e n e In . ~ Neurospora ~ ~ ~ ~ ~ ~crassa, the ability to synthesize phytoene from mevalonate was located in the plasma and endoplasmic reticulum membrane fractions.237 The use of inhibitors in studies of carotenoid biosynthesis continues. In Micrococcus roseus, canthaxanthin synthesis is .inhibited by nicotine (P-zeacarotene [7’,8‘-dihydro-p,+-carotene(207)] accumulates), piperonyl butoxide (phytoene accumulates), and CPTA (p-zeacarotene, y-carotene [P,Jr-carotene (208)], and their hydroxy-derivatives accumulate).238It was suggested that cyclization occurs at the <-carotene [7,8,7’,8’-tetrahydro-+,$-carotene (209)] stage, and hydroxylation at the p-zeacarotene stage. The conversion of pools of lycopene, accumulated in the presence of nicotine, into chlorobactene [cp,+-carotene (210)] by Chlorobium Nicotine also inhibits p-carotene formation in limicola has been Leptosphaeria michotii, and lycopene accumulates.24oThe influence of compounds structurally related to trisporic acid (2 11) on carotenogenesis in BZakeslea trispora has been 234
235
238 237 238 230 240 241
P. Beyer, K. Kreuz, and H. Kleinig, Planta, 1980, 150, 435. G. Sandmann, W. Hilgenberg, and P. Boger, Z . Naturforsch., Teil C, 1980, 35, 927. G. Sandmann, P. M. Bramley, and P. Boger, Pesticide Biochem. Physiol., 1980, 14, 185. U. Mitzka-Schnabel and W. Rau, Phytochemistry, 1981, 20, 63. J. J. Cooney and R. A. Berry, Can. J. Microbiol., 1981, 27, 421. L. S. Leutwiler and D. J. Chapman, Plant CellPhysiol., 1981, 22, 781. S. Jerebzoff-Quintin and S. Jerebzoff, Protoplasma, 1980, 104, 43. I. M. Yakovleva, L. A. Vakulova, E. P. Feofilova, M. N. Bekhtereva, and G. I. Samokhvalov, Mikrobiologiya, 1980, 49, 199.
262
Terpenoids and Steroids
Three reviews discuss the photoregulation of carotenoid biosynthesis in microo r g a n i s m ~ . ~Other ~ - ~papers ~ ~ + report ~ ~ ~ various aspects of the photoinduction and photoregulation of biosynthesis in the fungi Neurospora crassa244-249 and Phycomyces b l a k e s l e e a n ~ sand ~ ~ in ~ *Brevibacterium ~~~ s u I f u r e ~ mand ~ ~Mycobacterium ~ ~ m e g m a t i s Genetic . ~ ~ ~ studies with Phycomyces have led to the suggestion of an important genetically controlled transfer of substrate (lycopene) to the cyclizing The involvement of cyclic AMP as mediator of trisporic acid biosynthesis in B. trispora has been reported.256 Metabolism. The Japanese catfish Parasilurus asotus metabolizes zeaxanthin (27) into parasiloxanthin [7,8-dihydro-P,P-carotene-3,3’-diol (212)] and 7’,8’-dihydro(213)].257Lutein (35) parasiloxanthin [7,8,7’,8’-tetrahydro-P,P-carotene-3,3’-diol
R2 X 2 ’
HO
A- &. HO
a
HO
b
0 C
(212) (213) (214) (215) (216) 842 243
844
245 246 241
*48
248
a60 851 a62
263 864
R1= R2 = a, X1 = CH2CH2,X2 = CH=CH R1= R2 = a, X1 = X2 = CH,CH2 R1= a, R2 = b, X1 = CH2CH2,X2 = CH=CH X2 = CH=CH R1= c, R2 = a, R1= C, R2 = b, X2 = CH=CH
W. Rau, in ‘Blue Light Syndrome’, ed. H. Senger, Springer, Berlin, 1980, p. 283. W. Rau, in ‘Pigments in Plants’, 2nd Edn., ed. F.-C. Czygan, Gustav Fischer, Stuttgart and New York, 1980, 1981, p. 80. E. L. Schrott, in ‘Blue Light Syndrome’, ed. H. Senger, Springer, Berlin, 1980, p. 309. E. L. Schrott, Planta, 1980, 150, 174. E. L. Schrott, Planta, 1981, 151, 371. M. S. Kritsky and E. K. Chernysheva, Dokl. Akad. Nauk SSSR, 1980,255,228. M. S. Kritsky, V. Y. Sokolovsky, T. A. Belozerskaya, and E. K. Chernysheva, Dokl. Akad. Nauk SSSR, 1981, 258, 759. R. W. Harding and R. V. Turner, Plant Physiol., 1981,68, 745. B. D. Whitaker and W. Shropshire, jun., Exp. Mycol., 1981, 5, 243. I. Lopez-Diaz and E. Cerda-Olmedo, Planta, 1980, 150, 134. Y. Koyama, Y. Yazawa, K. Kato, and S . Yamagishi, Chem. Pharm. Bull., 1981, 29, 176. F. Kato, Y. Koyama, S. Muto, and S. Yamagishi, Chem. Pharm. Bull., 1981, 29, 1674. S. Torres-Martinez, F. J. Murillo, and E. Cerda-Olmedo, Genet. Res., 1980, 36, 299. F. J. Murillo, S. Torres-Martinez, C. M. G. Aragon, and E. Cerda-Olmedo, Eur. J. Biochem., 1981,119, 511.
*66
N. S. Govind and V. V. Modi, Indian J. Exp. Biol., 1981, 19, 544. T. Matsuno and S . Nagata, Bull. Jpn. SOC.Sci. Fisheries, 1980, 46, 1191.
263
Curotenoids and Po iy terpen oids
was converted only into 7,8-dihydrolutein (214).a58In goldfish, Curussius uurutus, lutein and zeaxanthin were metabolized to keto-derivative~.~~~ Thus zeaxanthin gave p-doradexanthin (2 15) and astaxanthin, whereas lutein gave or-doradexanthin (216). The incorporation of [ 15,l5’-3H2]-P-caroteneinto astaxanthin and other ketocarotenoids by the crab Clibunarius erythropus has been demonstrated.Z60 In the intestines of the fishes Heteropneustesfossilis and Channa striatus, lutein underwent cleavage to 3-dehydroretinol [vitamin A2(217)].2s1
(217)
(218)
The conversion of trans-retinyl acetate into retinoic acid in hamster organ culture,262and of cis- and trans-retinoic acid into the 5,6-epoxy- and 4-0x0derivatives and their glucuronides has been d e m o n ~ t r a t e d . ~ ~ ~ ~ ~ ~ ~ Strains of Aspergillus niger metabolize ionones and related compounds to oxygenated derivatives, some of which may be useful intermediates for carotenoid synthesis. The asymmetric oxidation of P-ionone to (2S,6R77R)-2,7-epoxydihydroa-ionone (218) has been (R)-4-Hydroxy-p-ionone(219 ; X = OH)
(219) R
=
(-!5J* x
(222) R
=
6. &* (223) R
0
=
\
(224) R
=
@‘ 0
T. Matsuno and S. Nagata, Bull. Jpn. SOC.Sci. Fisheries, 1980, 46, 1363. T. Matsuno, H. Matsutaka, and S. Nagata, Bull. Jpn. SOC.Sci. Fisheries, 1981, 47, 605. m0 R. Castillo, Comp. Biochem. Physiol., 1980, MA, 695. 261 U. C. Goswami and A. B. Barua, Zndian J. Biochem. Biophys., 1981,18, 88. C. A. Frolik, L. L. Dart, and M. B. Sporn, Biochim. Biophys. Acta, 1981, 663, 329. s63 H. F. DeLuca, M. Zile, and W. K. Sietsema, Ann. N . Y. Acad. Sci., 1981, 359, 25. s64 C. A. Frolik, B. N. Swanson, L. L. Dart, and M. B. Sporn, Arch. Biochem. Biophys. 1981,208, s68 a59
344. s65
Y . Mikami, Y . Fukunaga, T. Hieda, Y . Obi, and T. Kisaki, Agric. Biol. Chem., 1981, 45, 331.
Terpenoids and Steroids
264
and (S)-2-hydroxy-p-ionone (220; X = OH) were the major products formed from P-ionone by another A . niger strain, with 2-oxo-P-ionone (22 l), 4-oxo-pionone (222), 3,4-didehydro-p-ionone (223), 2,3-didehydro-4-oxo-(3-ionone (224), 3,4-didehydro-2-oxo-p-ionone (225), (S)-2-acetoxy-p-ionone (220; X = OAc), (R)4-acetoxy-p-ionine ( 2 I9 ; X = OAc), 5,6-epoxy-p-ionone (226), and the aryl derivative (227) as minor products.266Isophorone gave the trimethylcyclohexanone derivatives (228)-(23 l).267
2 Polyterpenoids and Quinones
Po1yterpenoids.-The cleomeprenols from Cleorne ~ p i n o s a and * ~ ~the malloprenols from MaZlotzrsj a p o n i c ~each s ~ ~consist ~ of a mixture of cis-trans C4o-C55 isoprenoid alcohols (232), formed by addition of cis-isoprene units from isopentenyl pyrophosphate to all-trans-geranylgeranylpyrophosphate. The C55component, referred to as moraprenol, has been converted chemically into the diphosphate-sugar derivative.27013C N.m.r. relaxation times have been used to identify the cis- and trans-methyl groups of terminal isoprene residues in isoprenoids :271 the cis-methyl group has the longer Tl. A method has been developed for the preparation of stereochemically pure 1,5-dienes by coupling allylic p-tolylsulphones with an allylic bromide.272Thus reaction of trans-bromogeranyl acetate (233) with the sulphone
(232) n = 3-6
(233) X = Br, R = OAc (234) X = H, R = S0,PhMe
0
(236) X (237) X 266 267 268 269
270
272
= OMe,
= Me,
n
n
= =9
1-10 or 10
Y . Mikami, Y . Fukunaga, M. Arita, and T. Kisaki, Appl. Environ. Microbiol., 1981, 41, 610. Y. Mikami, Y. Fukunaga, M. Arita, Y. Obi, and T. Kisaki, Agric. Biol. Chem., 1981,45, 791. T. Suga and T. Shishibori, J . Chem. SOC.,Perkin Trans. 1, 1980, 2098. T. Suga, T. Shishibori, and K. Nakaya, Phytochemistry, 1980, 19,2327. L. L. Danilov, D. Mal’tsev, V. N. Shibaev, and N. K. Kochetkov, Caubohydr. Res., 1981, 88, 203. A. Okubo, H. Kawai, T. Matsunaga, T. Chuman, S. Yamazaki, and S . Toda, Tetrahedron Lett., 1980, 21, 4095. K. Sato, S. Inoue, A. Onishi, N. Uchida, and N. Minowa. J . Cfiem.SOC.,Perkin Trans. I , 1981, 761.
265
Carotenoids ctnd Polyterpenoids
(234) followed by reductive elimination gave all-trans-geranylgeraniol (235). Higher analogues (C45and C5Jwere prepared by the same route. Isoprenylated Quinones.-A review has been published on the chemistry and biochemistry of ubiquinone (236) and plastoquinone (237) in plants.273 Chemistry. Methods have been presented for the preparation of sulphone-functionalized prenylhydroquinone~.~~~ Thus the ubiquinol (238), plastoquinol (239), and OMe
OMe
X
S0,Ph
OMe
(238) X = Me0 (239) X = Me OMe
OMe
X
OMe (241) X = Me0 (242) X = Me
OMe
(243)
naphthoquinol ethers (240) were obtained by reaction of the corresponding bromides (241), (242), and (243) with magnesium and the sulphone (244). The regio- and stereo-selective synthesis of ubiquinones-2-10 (236 ; n = 2-10), phylloquinone (245), and related polyprenylquinones has been described.27s Chemical model
studies for the mechanism of vitamin K [phylloquinone or menaquinone (246)] epoxide reductase have been The mechanism of photo-oxidation of menaquinone-1 (246; n = 1) to the hydroperoxide (247) has been investigated.277
274
276 277
H. K. Lichtenthaler, Dev. Plant Biol.,1980, 6, 299. Y . Fujita, M. Ishiguro, T. Onishi, and T. Nishida, Synthesis, 1981, 469. Y . Naruta, J. Org. Chem., 1980, 45, 4097. R. B. Silverman, J . Am. Chem. SOC.,1981, 103, 5939. D. Creed, H. Werbin, and T. Daniel, Tetrahedron Lett., 1981, 22, 2039.
Terpenoids and Steroids
266
Physical Methods. H.p.1.c. procedures for the separation and assay of ubiquinone and h o m o l o g ~ e s ~and ~ ~of- ~menaquinone ~~ cis- and trans-isomers, 2,3-epoxides, and chain-length homo10guesZ81~282 have been described. A lH n.m.r. study has been reported2B3of the location and motion of ubiquinones in perdeuteriated phosphatidylcholine bilayers. Other aspects of the interaction of ubiquinone with phospholipid monolayers have been Biosynthesis. An alternative pathway has been proposed for the early stages of the biosynthesis of the isoprenoid side-chain of ubiquinone in bacteria, via acetolactate acid (248)286and rather than a c e t o a ~ e t a t e 3,4-Dihydroxy-5-hexaprenylbenzoic .~~~
(248) R = H (249) R = Me
3-methoxy-4-hydroxy-5-hexaprenylbenzoic acid (249)287have been identified as intermediates in the biosynthesis of ubiquinone-6 in Saccharomyces cerevisiae. In Escherichia coli, an enzyme-complex-bound pool of 2-octaprenylphenol (250) accumulated under anaerobic conditions, and was rapidly converted into ubiquinone-8 in air.288The enzymic synthesis of o-succinylbenzoate,z89the conversion of this into its coenzyme A thioester, and the cyclization of this to 1,4-dihydroxy2-naphthoic acid (25 1)290 have been demonstrated with bacterial cell-free preparations. Micrococcus luteus membrane fractions catalysed the prenylation of (251) by C15-C4, prenyl pyrophosphates en route to m e n a q u i n ~ n e The . ~ ~ chloroplast ~ envelope has been reported as the site of (25 1) prenylation by phytyl pyrophosphate in phylloquinone b i o s y n t h e s i ~Several . ~ ~ ~ genetic studies of bacterial menaquinone biosynthesis have been d e ~ c r i b e d . ~Two ~ ~ -papers ~ ~ ~ report the formation of plastoquinone (237) in spinachzg6and lettucesg7chloroplasts, G. Katsui, Bitamin, 1981, 55, 305. M. D. Collins and D. Jones, J . Appl. Bacteriol., 1981, 51, 129. 2no S. Ikenoya, M. Takada, T. Yuzuriha, K. Abe, and K. Katayama, Chem. Pharm. Bull., 1981, 29, 158. 281 Y . Haroon, M. J. Shearer, and P. Barkhan, J . Chromatogr., 1980, 200, 293. 282 Y . Haroon, M. J. Shearer, and P. Barkhan, J . Chromatogr., 1981, 206, 333. 283 P. B. Kingsley and G . W. Feigenson, Biochim. Biophys. Acra, 1981, 635, 602. 284 P. J. Quinn, Biochem. hr., 1980, 1, 77. 2n5 S. Pandian, S. Saengchjan, and T. S . Raman, Biochem. J . , 1981, 196, 675. z86 R. R. Goewert, C . J. Sippel, and R. E. Olson, Biochemistry, 1981, 20, 4217. 287 R. R. GoewFrt, C . J. Sippel, M. F. Grimm, and R. E. Olson, Biochemistry, 1981, 20, 5611. H. E. Knoll, FEMS Microbial. Lett., 1981, 10, 59, 63. 28B R. Meganathan, J . Biol. Chem., 1981, 256, 9386. L. Heide and E. Leistner, FEBS Lett., 1981, 128, 201. *B1 Y . Saito and K. Ogura, J . Biochem. Tokyo, 1981, 89, 1445. 2s2 G. Schultz, B. H. Ellerbrock, and J. Soll, Eur. J . Biochem., 1981, 117, 329. J. R. Guest and D. J. Shaw, Mol. Gen. Genet., 1981, 181, 379. zB4 R. Meganathan, R. Bentley, and H. Taber, J . Bacteriol., 1981, 145, 328. 28s H. W. Taber, E. A. Dellers, and L. R. Lombardo, J . Bacteriol., 1981, 145, 321. 8B6 J. Soll, M. Kemmerling, and G . Schultz, Arch. Biochem. Biophys., 1980, 204, 544. 2B7 K. G . Hutson and D. R. Threlfall, Biochim. Biophys. Acta, 1980, 632, 630. 278 278
Part II STEROIDS
1 Physical Methods BY D. N. KIRK
1 Structure and Conformation
The Table beginning on p. 271 lists steroids whch have been the subject of X-ray crystallographic studies during the year. Comment on the conclusions is limited to only a few of the compounds. X-Ray crystallographic study of synthetic (23S)-cholest-5-ene-3p,23,25-triol, and comparison of the derived 23,25-dihydroxycholecalciferol(1) with a new natural metabolite of vitamin D has established the configuration of the latter compound.l Syntheses of the (25s)- and (25R)-isomers of 25,26-dihydroxycholecalciferol, using C 5precursors of known configuration to elaborate the sidechain, have established the configuration of the natural compound as (25s). The configuration was confirmed by X-ray crystallographic analysis of the intermediate compound (2).2
OAc 1
(4)
(3) N. Ikekawa, T. Eguchi, Y.Hirano, Y.Tanaka, H. F. DeLuca, A. Itai, and Y.Iitaka, J . Chern. SOC.,Chem. Commun., 1981, 1157. R. Barner, J. Hubscher, J. J. Daly, and P. Schonholzer, Helv. Chim. A d a , 1981, 84, 915.
269
270
Terpenoids and Steroids
The use of X-ray diffraction to assign structures to unusual steroid derivatives has been briefly r e ~ i e w e d .It~ includes reference to brassinolide (3), a steroidal plant growth hormone. Another unusual product assigned its structure by the X-ray method is the spiro-lactone (4), derived by thallium triacetate oxidation of
5a-~holestane-3,4-dione.~ The C- 17 configurations of the epimeric 17-ethynyl-14p-androstane- 14,17-diols ( 5 ) and (6) have been established by X-ray crystallographic s t ~ d y They . ~ were formed stereospecificallyby use of either LiC = CH or BrMgC = CMgBr (Scheme 1).
OH /
0
CH 111
Scheme 1 (&)-17p-Hydroxy-8a-androst-4-en-3-0ne crystallizes with molecules in two conformationally distinct forms.6 Ring A has the la-sofa conformation, but rings B exist in two conformations, each deviating somewhat from the ideal twist and characterized by small negative and positive torsion angles, respectively, about the C-9-C-10 bond. Two polymorphic forms of 17~-acetoxy-6p-bromoandrost-4-en3-one exhibit markedly different crystal packings and solid-state i.r. spectra although the conformations of individual molecules show only slight variation. One polymorph comprises two conformers in I : 1 ratio, whereas the other contains only a single conformer. It is concluded that in this case crystal packing has little effect on molecular conformation, while causing changes in carbonyl stretching frequencies. Crystalline cholesterol, with a bilayer structure, has hydrophilic regions with parallel chains of hydrogen bonds. Side-chains exist in two distinct conformations.8 The crystal habit of anhydrous cholesterol varies with solvent
J. Karle, Lipids, 1980, 15, 793. A. M. Maione, A. Romeo, S. Cerrinc, W. Fedeli, and F. Mazza, Tetrahedron, 1981, 37, 1407. J.-C. Beloeil, M. Bertranne, M. Fetizon, and T. Prange, J. Chem. SOC.,Chem. Commun.,1981, 363.
P. Chakrabarti, D . K. Banerjee, and K. Venkatesan, Steroids, 1981, 37, 269. W. L. Duax, M. Numazawa, Y . Osawa, P. D. Strong, and C. M. Weeks,J. Org. Chem., 1981, 46, 2650. H.-S. Shieh, L. G. Hoard, and C. E. Nordman, Acta Crystallogr., Ser. B, 1981,37,1538.
27 1
Physical Methods
and the degree of supersaturation of ~olution.~ The high-melting polymorph1° of 3a,7a-dihydroxy-5p-cholan-24-oicacid (chenodeoxycholic acid) has pairs of molecules, with different conformations of their 17@-side-chains,forming an asymmetric unit.ll Insight into the photochemical reactions between deoxycholic or apocholic acid (‘choleic acids’) and guest molecules in crystalline inclusion complexes has been obtained by X-ray studies. The choleic acids form channels with wall structures determined by the nature of the guest molecule. Guest ketones of various types react photochemically by addition to the choleic acid at a site determined by the orientation of the ketone molecule in relation to the host (e.g. deoxycholic acid reacts at C-5 or C-6 with linear aliphatic ketones, but at C- 16with cyclohexanone).12
Table Steroids studied by X-ray crystdogrdphy (Compounds with references 1-12 are mentioned also in the text.) Compound
Ref.
Oestranes 17P-Acetoxyoestr-4-en-3-one 2a-Fluoro-17 p-hydroxyoestr-4-en-3-one 17p-Hydroxy- 17a-methyloestra-4,9,1 l-trien-3-one
17~-Hydroxy-8a,l0a-oestr-4-en-3-one dl-3-Methoxy-8a,l4p-oestra-l,3,5( 10),9(ll)-tetraene-l4,17a-diolmonohydrate 17a-Ethynyl-l7~-hydroxyoestranes : see pregn-20-ynes, below
13 14 15 16 17
Androstanes
17p-Acetoxy-6 P-bromoandrost-4-en-3-one 17p-Hydroxy-7 a-methylandrost-5-en-3-one dZ-17/3-Hydroxy-8a-androst-4-en-3-one (8-isotestosterone) 17-Methoxy-16,17-seco-8a,13a-androsta-4,9(1 l)-diene-3,15,17-trione 17@-(5-Methyltetrazol-1-yl)-7a-aza-~-homoandrost-5-eno[7a,7-d]tetrazol-3 p-yl acetate
6 18
6, 16 19
20
17a-Ethynyl-l7~-hydroxyandrostanes: see pregn-20-ynes, below Pregnanes 16a,l7a-Cyclopropanopregn-4-ene-3,20-dione 16a,l7a-Cyclobutanopregn-4-ene-3,20-dione
lo
I1
21 22
N. Garti, L. Karpuj, and S. Sarig, Cryst. Res. Techno[., 1981, 16, 1111. M. C. Attwell, T. F. Massiah, R. A. Vergottini, and P. Ziegler, Belg. Pat. 879 844 1980, P. F. Lindley, M. M. Mahmoud, F. E. Watson, and W. A. Jones, Acta Crystullogr. Ser. B, 1980,36, 1893.
R. Popovitz-Biro, H. C. Chang, C. P. Tang, N. R. Shochet, M. Lahav, and L. Leiserowitz, Pure Appl. Chem., 1980,52, 2693. la G. Precigoux, C. Courseille, and F. Leroy, Cryst. Struct. Commun., 1980, 9, 1005. I4 D. C. Swenson, P. D. Strong, and W. L. Duax, Cryst. Strucr. Commun.,1981,10, 659. G. Precigoux, B. Busetta, and S . Geoffre, Actu Crystullogr., Ser. B, 1981, 37,291. M.M. Bhadbhade, P. Chakrabarti, D. K. Banerjee, and K. Venkatesan, Proc. Natl. Acud. Sci. India, Sect. A, 1981, 47, 100. l7 A. N. Chekhlov and S . P. Ionov, Bioorg. Khim., 1981, 7,436. l 8 P. J. Cox, G. J. Mkandawire, and P. R. Mallinson, Actu Crystallogr., Ser. B, 1981, 37,727. l9 D. C. N. Swindells, P. S. White, and 2.Valenta, Acta Crystullogr., Ser. B, 1981, 37, 263. 2o J. Husain, R. A. Palmer, H. Singh, T. R. Bhardwaj, and D. Paul, Actu Crystallogr. Ser. B, l2
1981, 37, 205. *l
V. M. Tseikinskii, V. B. Rybakov, V. I. Simonov, A. V. Kamernitskii, V. N. Ignatov, and I. S. Levina, Bioorg. Khim., 1980, 6, 752. V. M. Tseikinskii, V. B. Rybakov, V. I. Simonov, A. V. Kamernitskii, V. N. Ignatov, and I. S . Levina, Bioorg. Khim., 1980, 6, 1872.
272
Terpenoids and Steroids
Compound Ref 6a-Methyl-16 u , 17a-cyclohexanopregn-4-ene-3,20-dione 23 1 1 p,17a,21-Trihydroxypregn-4-ene-3,20-dione (Cortisol) 24 1 1 ~,17a-Dihydroxy-21-iodopregn-4-ene-3,20-dione 24 21-Chloro-9a-fluoro-ll~-hydroxy-l6u,l7u-isopropylidenedioxypregn-4-ene3,20-dione 25 5a,14P-Pregn-20-yne-14,17a-diol 5 5a,14p,17P(H)-Pregn-20-yne-l4,17P-diol 5 18-Methyl-1l-methylene-19-nor-l7~(H)-pregn-4-en-20-yn-l7~-ol 26 17P-Hydroxy-l l ~-methoxy-l8-methyl-19-nor-17~(H)-pregna-4,9-dien-20-yn-3-one 27 17~-Hydroxy-l2-methyl-l7(3(H)-pregna-4,9,1 l-trien-20-yn-3-one 28 21-Bromo-9a-fluoro-1 1 p, 17aa-dihydroxy16P-methoxy-~-homo17-oxapregna39 1,4-diene-3,20-dione
Sterols and bile acids
Cholesterol Cholesteryl hexanoate Cholesteryl p-bromobenzoate Cholest-5-ene-3 p,23(S),25-triol 2,4,6-Tribromocholest-4-en-3-one (Z)-3~-Hydroxy-5(10)-secocholest-l( lO)-en-5-one 3-p-bromobenzoate 3 ~,22(S),25(S),26-Tetrahydroxycholest-5-en-7-one 3,22,26-triacetate(2) Brassinolide (3) Spiro-lactone(4)(see text) 3a,7a-Dihydroxy-5 P-cholan-24-oicacid (chenodeoxycholic acid; high m.p.) Deoxycholic acid-norbornadiene (2: 1) complex ‘Choleicacid’inclusion complexes (see text)
8, 9
30 31
1 32 33 2 3 4 11 34 12
Cardenolides
3p, 14-Dihydroxy-12P-acetoxy-5P, 14P-card-20(22)-enolide 3a,14-Dihydroxy-5p, 14P-card-20(22)-enolide p, 14p-card-20(22)-enolide 3P-Acetoxy-14-hydroxy-5 3p,16P-Acetoxy-(21R)-14,21-epoxy-5p,14P-card-20(22)-enolide 3~-Bromoacetoxy-l4-hydroxy-5p,14P-card-20(22)-enolide 3p,l6P-Diacetoxy-14-hydroxy-5P,14P-card-20(22)-enolide 3P,1 6$-Diacetoxy-l4-hydroxy-(21 R)-2 1-bromo-5P, 14P-card-20(22)-enolide 23
24
e6 26 27
28
30
s1
32
33
34
36
36
35 36 37 38 39 40 41
V. M. Tseikinskii, V. B. Rybakov, V. I. Simonov, A. V. Kamernitskii, L. E. Kulikova, and I. S. Levina, Bioorg. Khim., 1980, 6, 1409. E. E. Castellano, P. Main, and E. Westbrook, Acta Crystallogr., Ser. B, 1980, 36, 3063. R. Ceolin, R. Julien, and N. Rodier, Acta Crystallogr., Ser. B, 1981, 37, 148. F. J. Zeelen, Red. Trav. Chim. Pays-Bas, 1980, 99, 323. J. Delettre, G. Lepicard, E. Surcouf, and J. P. Mornon, Acta Crysfallogr., Ser. B, 1981, 37, 1712. G. Precigoux, F. Leroy, and S. Geoffre, Acta Crystallogr., Ser. B, 1980, 36, 3123. C. M. Cimarusti, P. G. Grabowich, B. K. Toeplitz, and R.K. Varma,J. Urg. Chern., 1981,46, 803. Y . Ja. Park and B. M. Craven, Taehan Hwahakhoe Chi., 1981, 25, 131. A. P. Polishchuk, M. Y. Antipin, R. G. Gerr, V. I. Kulishov, Y. T. Struchkov, and V. G. Tishchenko, Cryst. Struct. Commun., 1981, 10, 312. B. V. Prelesnik, R. M. Herak, I. Micovic, and B. Jelenkovic, Acra Crystallogr., Ser. B, 1981, 37, 1793. H. Fuhrer, L. Lorenc, V. PavloviC, G. Rihs, G. Rist, J. Kalvoda, and M. Lj. Mihailovid, Helv. Chim. Acta, 1981, 64, 703. A. D’Andrea, W. Fedeli, E. Giglio, F. Mazza, and N. V. Pavel, Acta Crystallogr., Ser. B, 1981, 37, 368. A. Messerschmidt, E. Hoehne, and B. Streckenbach, Cryst. Struct. Commun., 1981, 10, 141. A. Messerschmidt, E. Hoehne, and R. Megges, Cryst. Struct. Commun., 1981, 10, 149.
Physical Methods
273
2 N.M.R. Spectroscopy
lH Spectra.-The total analysis of the IH n.m.r. spectrum of 11p-hydroxyprogesterone, reported briefly last year,42has now been described in full.43This is a further illustration of the value of computer-controlled use of a 400 MHz spectrometer to obtain two-dimensional J spectra, and n.0.e. difference and decoupling difference spectra, which provided all the lH chemical shifts and virtually all geminal and vicinal coupling constants. Comparisons with the previously reported findingP for 1-dehydrotestosterone acetate represent the first step in a correlation of detailed n.m.r. and structural parameters which promises to have widespread application in future studies on steroidal and terpenoid compounds. 220 MHz spectra permit quantitative estimation of C-24 epimeric mixtures of 24-alkyl A combination of procedures using IH n.m.r. allowed assignment of configurations to a series of 15,16,17-trisubstituted oestra- 1,3,5(lO)-triene~.~~ Coupling constants between ring D protons were not alone sufficient, but were augmented by chemical shift data, including the downfield shifts of methine proton signals on reaction of hydroxy-groups with trichloroacetyl isocyanate. Spectra of protonated forms of androst-4-en-3-ones, androsta-4,6-dien-3-one, and 17,17-dimethy1-18norandrosta-4,6,8(14)-trien-3-one in 80 % H2S04 indicate the presence of the 0-protonated species. The trienone was the only one of the compounds to undergo vinyl proton exchange in 80% D2S04.46The presence of a 5-hydroxy or particularly a 5-acetoxy substituent in either 5a- or 5p-steroids causes deshielding effects on neighbouring protons (at C-4 and 6a) which can be useful in structural assignments.4 Although aldosterone exists in the crystalline state in the 1 1p, 18: 18,2O-diepoxy20-hydroxy form (7), and in solution as a mixture containing both the diepoxy form (7) and the 11p, 18-hemiacetal-20-0x0 form (8) in substantial proportions, n.m.r. and i.r. data show that 21-deoxy-3a,5p-tetrahydroaldosteroneexists in solution essentially in the 11p, 18-hemiacetal-20-0x0form (9), with two epimers at C-18 in the ratio 5 : 1.48 3a,5P-Tetrahydroaldosterone itself, however, is similar to aldosterone in solution, where the n.m.r. spectrum indicates the presence of forms (10) and (1 1) in ca. 1 : 1 ratio.49
s7
s8 38
A. Messerschmidt, E. Hoehne, and R. Megges, Cryst. Struct. Commun., 1981, 10, 157. A. Messerschmidt, E. Hoehne, and R. Megges, Cryst. Struct. Commun., 1981, 10, 399. E. Hoehne, A. Messerschmidt, B. Streckenbach, and I. Seidel, Cryst. Struct. Commun., 1981, 10,415.
40
41
4s 44
47
48
G. Reck, A. Messerschmidt, and R. Megges, Cryst. Struct. Commun., 1981, 10, 637. E. Hoehne, A. Messerschmidt, R. Megges, and I. Seidel, Cryst. Struct. Commun., 1981,10,407. ‘Terpenoids and Steroids’, ed. J. R. Hanson (Specialist Periodical Reports), Royal Society of Chemistry, London, 1981, Vol. 11, p. 173. L. D. Hall and J. K. M. Sanders, J. Org. Chem., 1981,46, 1132. P. L. Chiu and G. W. Patterson, Lipids, 1981, 16, 203. B. Schonecker, D. Tresselt, G. Schubert, and K. Ponsold, J . Prakt. Chem., 1981, 323, 207. H. Takagi, M. Kokuryo, T. Miura, and M. Kimura, Bunseki Kugaku, 1981,30, 191. M. Lj. MihailoviC, L. Lorenc,V. PavloviC, and H. Fuhrer, Helv. Chim. Actu, 1981, 64, 1032. D. R. Crump, D. N. Kirk, and B. W. Miller, J. Chem. Soc., Perkin Trans. 1, 1980, 2597. D. N. Kirk and B. W. Miller, J. Chem. SOC.,Perkin Trans. 1. 1980. 2818.
274
Terpenoids and Steroids
OH P
(9) R (10) R
=H = OH
(11)
R
=
OH
The effect of the lanthanoid shift reagent [Ho(fod),] on spectra of sterol 3acetates is unusual. Induced shifts with this reagent are normally upfield, and the C-19 and C-18 proton signals conform, although only weakly in the latter case. The peculiarities lie in downfield shifts of the signals of side-chain methyl protons. Moreover the C-26 and C-27 methyls are rendered non-equivalent by [Ho(fod)J, and (24R)- and (24S)-24-methyl sterols are easily distinguished by the methyl shifts.5oLanthanoid-induced shifts of methyl signals are reported for a series of sterols with various ring and side-chain structures and substituents.61Jj2 13C Spectra.-An n.m.r. technique53 for studying 13C-13C spin-spin coupling at natural abundance offers a remarkable way of establishing the carbon-carbon connectivities within an organic framework. Based upon the principle of doublequantum coherence, it suppresses the strong signals from isolated 13C nuclei and reveals the weak 13C satellite spectrum. A complex pulse sequence (at 50 MHz) and a two-dimensional Fourier transformation affords a spectrum with the 13C satellite lines in the F, dimension and the corresponding double-quantum frequencies in the Fl dimension. Directly coupled 13C resonances generate the same double-quantum frequency, and so can be recognized. Application of the technique to 5a-androstane shows that it is capable of detecting even the complex connectivities within this four-ring system.63 Pulse sequences used to induce lH-13C polarization transfer (PT), with suitably chosen delays (A) before data acquisition, provide a simple and reliable way of separating 13C resonances according to the number of attached In an illustration for cholesterol, the seven CH carbons are displayed with A = (U)-l bo 61 6s
6a
b4
T. Iida, T. Ishikawa, T. Tamura, and T. Matsumoto, Yukagaku, 1980, 29, 683. T. Iida, Nihon Daigaku Kogakubu Kiyo Bunrui A, 1980,21, 227. I. Takashi, Nihon Daigaku Kogakabu Kiyo Bunrui A , 1980, 21, 233. A. Bax, R. Freeman, and T. A. Frenkiel, J. Am. Chem. SOC.,1981,103,2102. D. M. Doddrell and D. T. Pegg, J . Am. Chem. SOC.,1980,102, 6388.
Physical Methods
275
= 3.8 ms. When A = 3(4J)-l = 5.7 ms, CH and CH3 signals appear in-phase and CH2 signals 180" out-of-phase (inverted). Spin-echo Fourier transform (SEFT) experiments which simplify 13C n.m.r. spectra to singlets offer another method for distinguishing methyl, methylene, methine, and quaternary carbons which is superior to off-resonance decoupling for complex molecules, illustrated by application to cholester01.~~ Cholesteryl acetate has been used as a model to demonstrate the indirect measurement of proton relaxation rates by 'INEPT' polarization transfer to directly bonded 13C nuclei;56direct measurement of proton Tl values is impractical except for those few signals which are well separated from the crowded methylene envelope. Steroidal and other rigid alcohols have been used to derive a four-parameter equation for the calculation of 13C chemical shifts due to substitution by the OH Calculated 13C chemical shifts for all the likely saturated sterol sidechains with from seven to eleven carbon atoms have been tabulated and compared, where possible, with published data.58 Good agreement is found in most cases, with standard deviations of ca. 1 p.p.m. Only C-20, attached to the steroid nucleus, showed serious deviations (ca. + 5 p.p.m.) from calculated values. The results will be useful in future structural assignments of new sterols. The aromatic ring of oestradiol or oestrone methyl ether readily forms a tricarbonyl chromium (0) complex in which the 13C signals from the aromatic ring are shifted strongly upfield (by ca. 14-34 p.p.m.). Smaller upfield shifts for other carbon atoms close to the aromatic ring (e.g. 2 p.p.m. for C-6) have been used to settle uncertainties in the earlier literature concerning the assignments of individual 13C resonance^.^^ 13CN.m.r. spectra discriminate between A4- and A5-isomers of spiro-3-steroidal ketone derivatives; thiazolidine formation results only in the (3R)-isomer (12), whereas hemithioacetals are mixtures of the (3R)- and (3s)forms.60
R
(12) R = H or C0,Et lSCN.m.r. data for a series of A5- and saturated 4,4-dimethyl-3-oxo-steroids and related compounds reveal the distorting effect of A5-unsaturation on rings A and B, and the effects of compression between the 4p- and C-19 methyl groups.61Longstanding uncertaintiess2 about the regioselectivity of the Beckmann, Schmidt, and Baeyer-Villiger reactions of 3-keto-steroids and their derivatives have at last been resolved by a 13C n.m.r. study of the reaction products and of the pure lactams or sK s7 68
IJO
D. W. Brown, T. T. Nakashima, and D. L. Rabenstein, J . Magn. Reson., 1981, 45, 302. G. A. Morris, J. Magn. Reson., 1980, 41, 185. V. Wray, Tetrahedron, 1981, 37, 777. A. Kelecom, Bull. SOC.Chim. Belg., 1980, 89;343. G. Pouskouleli, I. S. Butler, and J. P. Hickey, J. Znorg. Nucl. Chem., 1980, 42, 1659. K. B. Sloan, N. Bodor, and R. J. Little, Tetrahedron, 1981,37, 3467. S . Q. A. Rizvi and J. R. Williams, J . Org. Chem., 1981, 46, 1127. Ref. 42, 1980, Vol. 10, p. 204.
276
Terpenoids and Steroids
lactones (5a- and 5 It is now clear that both possible migration products are formed in varying proportions in each reaction. 13C N.m.r. spectra have been assigned to a series of backbone-rearranged cholestanes (‘diacholestanes’) by a combination of SFORD, partially relaxed, and lanthanoid-shifted Assignments for the 13(17)-ene (1 3) disagree with an earlier published set but seem more reliably based. A combination of ‘H two-dimensional J spectroscopy with 2H and 13Cn.m.r. has established the .2Hlabel distribution in the backbonerearranged isoholamine (14), which results from the reaction of holamine with D,SO,, and has shown the rearrangement to occur mainly via a series of protonation-deprotonation steps.ss
(13)
(14) *Sites of 2H-labelling
Assignments are proposed for the 13C n.m.r. spectra of some natural and synthetic hormonal steroids, including the acetates of cortisone, cortisol, prednisone, prednisolone and some of its derivatives [6a-Me; 9a-F, 16a-Me (dexamethasone) ; 9a-F, 16p-Me (betamethasone) ; 6a-F, 16a-Me (paramethasone)], and a few miscellaneous compounds.6613C N.m.r. assignments have been revised for p-sitosterol and its 3 - g l u ~ u r o n i d eand ~ ~ ~a reassignment of signals from ring F is reported for (25S)-spiro~tans.~~ ‘H and 13Cn.m.r., with n.0.e. experiments, have established the structures (1 5 ) and (1 6) for gomphoside and afroside;69 other related cardenolide glycosides have also been studied. 70
(15) R (16) R
=
=
H OH
V. Dave, J. B. Stothers, and E. W. Warnhoff, Can. J . Chem., 1980, 58, 2666. D. M. Tal, H. E. Gottlieb, C. Ben-Ari, and Y. Mazur, Tetrahedron, 1981, 37, 4331. F. Frappier, W. E. Hull, and G. Lukacs, J . Org. Chem., 1981, 46, 4314. M J. P. Hickey, I. S. Butler, and G. Pouskouleli, J. Magn. Reson., 1980, 38, 501. O 7 1.-M. Chang, H. S . Yun, and K. Yamasaki, Saengyak Hukhoe Chi, 1981,12, 12. an K. Tori, S . Seo, Y . Terui, J. Nishikawa, and F. Yasuda, Tetrahedron Lett., 1981, 22, 2405. H. T. A. Cheung and T. R. Watson, J . Chem. SOC.,Perkin Trans. I , 1980,2162. ‘O H. T. A. Cheung, T. R. Watson, J. N . Seiber, and C. Nelson, J . Chem. SOC., Perkin Trans. 1, Is O4
1980, 2169.
Physical Methods
277
phytosterols 24-methylenecholesterol, lSCN.m.r. data are reported for the A24(2s) fucosterol, isofucosterol, and cycloeucalenol acetate, 71 for hecogenin acetate, 11-oxotigogenin, 6-methyldiosgenin acetate, botogenin, and other s a p o g e n i n ~ , ~ ~ for a series of 6,23-dihydroxylated sapogenins [e.g.solaspigenin (17), as triacetate],75 and for 29 withanolides and other polar c z s steroids.74 19F and 2H Spectra.-Substituent effects are reported on the lSF n.m.r. of sterol trifluoroacetates.75 2HN.m.r. has been used to study the state of labelled cholesterol in multibilayers of egg yolk lecithin containing digitonin. 78
3 Chiroptical Phenomena
The frequent observation of apparently bisignate character in the n+x* c.d. bands in the region 300--400nm for steroidal 4-en-3-ones has generally been ignored, but a new and detailed study now indicates that there are probably two electronic transitions, singlet-triplet and singlet-singlet n+x*, respectively, which sometimes result in overlapping but not coincident c.d. bands of opposite sign, giving rise to the observed curve profile.77C.d. curves for (25R)- and (25S)-26hydroxycholesterol 3-acetate 26-p-bromobenzoates both show positive Cotton effects at 240-244 nm due to the aromatic chromophore.78The chirality at C-25 cannot therefore be distinguished by this method. However, lanthanoid-induced c.d., employing [Eu(fod)J, has been observed for the 25,26-diol system in 25,26dihydroxycholecalciferols,with signs corresponding to the configurations at C-25 [(25S), negative above 300 nm, positive below 300 nm; (25R) showed reversed sign^].^ The exciton coupling principle has been extended to benzoates of allylic alcohols, which show coupled transitions at ca. 230 nm (benzoate, Tc-+x*) and ca. 195 nm (olefin). The sign of the 230 nm c.d. band correlates with absolute configuration in the sense of Figure 1, confirmed by study of a series of steroidal compounds belonging to this class.79 Negative
3 %OF-
O
H
(-) c.d. at ca. 230 nm Figure 1 C.d. of allylic benzoates
pa
Positive
+Yo H O (+)c.d. at ca. 230 nm
C.d. curves for the imines (Schiff bases) formed from some keto-steroids and 2-phenylethylamine, tyramine, or hexanamine show n+x* bands generally of the same sign as those of the corresponding ketones, but near 235 nm.80Additional A. G. McInnes, J. A. Walter, and J. L. C. Wright, Org. Mugn. Reson., 1980, 13, 302. M. H. A. Elgamal, M. S. Bedour, and H. Duddeck, Indian J. Chem., Sect. B, 1980,19, 549. A. K. Chakravarty, S. C. Pakrashi, and J. Uzawa, Cun. J. Chem., 1981,59, 1328. '* H. E. Gottlieb and I. Kirson, Org. Mugn. Reson., 1981, 16, 20. 76 T. Iida, T. Tamura, and T. Matsumoto, Nihon Duiguku Kogukuba Kiyo Bunrui A , 1980,21,223. T . Akiyama, S. Takagi, U. Sankawa, S. Inari, and H. Saito, Biochemistry, 1980, 19, 1904. 'I7 A. F. Beecham and D. C. Collins, Aust. J. Chem., 1980,33, 2189. 7 8 C.-Y. Byon, M. Gut, and V. Toome, J. Org. Chem., 1981, 46, 3901. N. Haroda, J. Iwabuchi, Y. Yokota, and H. Uda, J . Am. Chem. SOC.,1981,103, 5590. H. C. Price, D. G. Sawutz, T. E. Wagner, and C. Shewmaker, Tetrahedron, 1981, 37, 1679. 71
10
Terpenoids and Steroids
278
bands at 218-219 nm are attributed to the aromatic lLa transition for derivatives of imines containing an aromatic group. Imines derived from testosterone or oestrone showed additional c.d. features associated with the ap-unsaturation and the aromatic ring A, respectively. 3 p-Acetoxyeti-5-enic esters have been used to resolve enantiomers of perhydroanthracenol (1 8)s1 and perhydrophenanthren-4-01( 19y2 as tricyclic systems for study of the c.d. characteristics of the corresponding ketones.
(18)
(19)
C.d. and u.v.-visible spectra are reported for solutions of the antitumour triterpenoid tingenone in aqueous sodium deoxy~holate,~~ and c.d. curves have been recorded for morphine and related alkaloids in cholesteric liquid crystals.84
4 Infrared Spectroscopy Rather little attention is normally paid to the intensities of i.r. absorption bands of steroids, but two papers now detail interesting variations in v(C=O) for primary, secondary, and tertiary acetoxy-gro~ps,~~ and in v(C=O) and v(C=C) for variously substituted progesterone derivatives.s5p861.r. absorption intensities of progesterone derivatives have been studied with a Fourier-transform ~pectrometer.~~
5 Mass Spectrometry and Gas Chromatography-Mass Spectrometry In a continued study of the mass spectrometric fragmentations of key classes of steroids, 4,6-dien-3-ones and 1,4,6-trien-3-0nes have been shownss to undergo characteristic rupture of ring B (Figure 2), accompanied in the case of 4,6-dienones
-2H
Figure 2 Mass spectral fragmentations of 4,6-dien-3-onesand 1,4,6-trien-3-ones
8a
8a
84
87
B. Alcaide and F. Fernandez, An. Quim., 1980, C76, 41. B. Alcaide and F. Fernandez, J. Chem. SOC.,Perkin Trans. 1, 1980, 2250. A. R. Campanelli, M. D’Alagni, G. B. Marini Bettolo, and E. Giglio, Farmaco, Ed. Prat., 1981, 36, 30. J. M. Bowen, T. A. Crone, A. 0. Hermann, and N. Purdie, Anal. Chem., 1980,52, 2436. G . Aruldhas, G. Jalsovszky, and S. Holly, Acta Chim. Acad. Sci. Hung., 1980, 104. 117. S. Holly, G. Jalsovszky, and 0. Egyed, J. Mol. Struct., 1980, 60, 131. G. Jalsovszky and 0. Egyed, Kem. Kod., 1980,54, 385. F. J. Brown and C. Djerassi, J. Org. Chem., 1981, 46, 954.
Physical Methods
279
by the other cleavages illustrated. Hydrogen transfers during such processes have been determined by specificdeuterium labelling. The very unusual loss of 44 mass units from the 4,6-dienone involves expulsion of C2H40instead of the usual keten, through a complex rearrangement which transfers the hydrogen atoms from C-4 and C-9 to the eliminated fragment. 5a-Androstane-7,17-dionesundergo a major and very strange mass spectral fragmentation to give an ion with m/z = M - 47, irrespective of substitution in ~ ~ measurements indicate loss of CH302,and preliminary ring A . High-resolution experiments with deuteriated material (at 6, 6, 8P, 16, 16) indicate loss of CHD,02. The nature of the fragmentation is as yet unknown. Trienes of the vitamin D series show competition between two fragmentations with very similar energy requirements. 5,7,10(19)-Trienes (20), irrespective of configuration, favour rupture of the 7,8-bond, whereas 5(10),6,8-trienes(21) break preferentially across ring c.
(20) (21) In each case the resulting ions may fragment further. This very detailed study includes measurements of appearance energies of ions and ionization energies of derivatives and isomers of vitamin D.90 Cleavage of side-chain trimethylsilyl ethers in the pregnane series is complicated by Me,& exchange between oxygen atoms at C-17 and C-20.91Mass spectral data are reportedg2for derivatives of 5?-pregnane-3a,17a,20a-trioI silylated selectively at the 3- and 20-positions with either t-butyldimethylchlorosilane or t-butyltetramethylenechlorosilane and fully silylated by vigorous treatment with trimethylsilylimidazole. The mass spectral fragmentations of 3-methoxyoestra-l,3, 5(10)-trienes with hydroxy substitution at C-14, -15, -16, or -17 show distinctive patterns, although the configuration of the hydroxy-group matters only at C-14 or C-15,O3 Ions resulting from loss of water in the mass spectra of spirostan-3-01s isomeric at C-3 and C-5 show characteristic relative intensities which can be helpful in assigning configurations.94 The mass spectral fragmentation of 3a,5srcyclo-6-0x0-steroidsand other cyclopropyl ketones is a complex process.95 Selective deuterium IabeIIing has shown that the [M - H20]+ ion from 3a,5-cyclo-5acholestan-6-one is derived from hydrogen atoms located at the 2P- and 9a-positions; Bo OS
J. E. Gurst and A. K. Schrock, J . Org. Chem., 1980,45, 4062. Z. V. I. Zaretskii, Adv. MassSpectrom., 1980, 8, 590. P. Vouros and D. J. Harvey, Biomed. Mass Spectrom., 1980, 7 , 217. M. A. Quilliam and J. B. Westmore, Eur. J . Mass Spectrom. Biochem., Med. Environ. Res., 1980, 1, 53.
oI g6
W. Schade, W. Ihn, J. Vokoun, B. Schonecker, and G.Schubert, Steroid, 1980,36, 547. G . Blunden, J. A. Jaffer, K. Jewers, and J. M. Robinson, Steroids, 1980, 36, 299. A. Kasal and A. Trka, Collect. Czech. Chem. Commun., 1980, 45, 2985.
280
Terpenoids and Steroids
the detailed mechanism is not yet clear. Characteristic fragmentations are reported for other 3,5-cyclocholestanyl derivatives (@-OH, -OMe, -OEt, -OBU'),~~ for the corresponding cholesteryl and for the ring B-hydroxylated 3P-acetoxy~-homo-5a-cholestanes.97 An interactive system of computer programs for the elucidation of structures from mass spectral data is illustrated with reference to some marine sterols. 98 The program generates all structural isomers compatible with the data, and evaluates them in terms of biological plausibility. Chemical Ionization Mass Spectrometry (CIMS).-Monohydroxylated cholesterols are differentiated by h.p.1.c. and CIMS, with ammonia as reagent gas. Trimethylsilyl ethers of side-chain hydroxylated cholesterols fragment in CI mass spectra with methane to give [C,H,,OSiMe,]+ ions characteristic of the site of hydroxyl a t i ~ nCIMS . ~ ~ with ammonia as the reagent gas proved highly efficient for producing [ M + NH,]+ ions as base peaks from a series of methyl ester-acetate derivatives of bile acids. Minor peaks permitted selective detection of 3-keto or unsaturated bile acids.looAnother paper lol describes the application of CIMS to the identification of side-chain hydroxylated cholesterols, sterol esters, bile acids, and even underivatized steroid glycosides, and a CIMS study of (20s)-protopanaxadiol (22) and (20s)-protopanaxatriol (23) is reported.lo2
(22) R = H (23) R = a-OH Further of the application of negative ion CIMS to steroids have shown that use of Freon 12 (CF,Cl,) as reagent gas provides very satisfactory [A4 + Cl]- ions, even from polyfunctional compounds like prednisolone which are prone to fragmentation. Bile acid chlorides, with CH, as reagent gas, gave [ M + OH]- peaks (doublets, containing chlorine).lo4Negative ion CI (with OH-) provides mass spectra of underivatized steroid glucuronides (RO-gluc), showing abundant [ M - HI- and [ROI- ions. lo5 Gas Chromatography-Mass Spectrometry (g.c.-m.s.).-Syntheses of twenty different steroids (oestrogens, androgens, progesterone, and corticosteroids and their metabolites) with from two to four deuterium atoms per molecule have F. J. Brown, I. J. Massey, and C. Djerassi, Can. J. Chem., 1980, 58, 2592. F. Turecek and L. Kohout, Collect. Czech. Chem. Commun., 1980, 45, 2433. N. A. B. Gray, A. Buchs, D. H. Smith, and C. Djerassi, Helv.Chim. Acta, 1981, 64, 458. Y.Y.Lin, C.-E. Low, and L. L. Smith, J . Steroid Biochem., 1981, 14, 563. loo B. R. DeMark and P. D. Klein, J . Lipid Res., 1981, 22, 166. lol Y . Y . Lin, Lipids, 1980, 15, 756. Ioa M. Desage, M. Becchi, M. Trouilloud, and J. Raymaud, Planta Med., 1980, 39, 189. Io3 H. Fujiwara and A. K. Bose, Pract. Spectrosc., 1980, 3, 329. lo4 H. Fujiwara and A. K. Bose, Pract. Spectrosc., 1980, 3, 373. Io6 A. P. Bruins, Biomed. Mass Spectrom., 1981, 8, 31. O7
Physical Methods
28 1
provided internal standards for isotope-dilution g.c.-m.s. studies. The labelled steroids were isotopically stable to the conditions of derivatizationfor g.c. purposes and to incubation in plasma. It was noted that more than four deuterium atoms may result in decreased g.c. retention times, sufficient to broaden or even to split peaks.loGBile acids are efficiently analysed (g.c.-m.s.) as their hexafluoroisopropyl ester trifluoroacetates, which are superior to heptafluorobutyrates.lo7 Selective oxidation of 3 p-hydroxy-5a- and 3 p-hydroxy-A5-steroIds by cholesterol oxidase has been adapted as a method for improving the analysis of steroid mixtures by g.c.-m.s., when g.c. peaks happen to overlap.1os Characteristic retention increments are quoted for a series of sterol-keto-steroid pairs. Some further applications of the formation of cyclic methylboronates from diols (20,21 - and 20,22-) are also described.losA further paperlog has appeared on the identification of sterols and bile acids by computerized g.c.-m.s., using fragment ion current chromatograms.l10 Biomedical applications of g.c.-m.s. to the study of steroid hormones have been reviewed (208 references).ll* 6 High-performance Liquid Chromatography (h.p.1.c.) and other Chromatographic Methods
A review of h.p.1.c. of steroid hormones traces the history of the subject, and describes methods for h.p.1.c. analyses of the main classes of steroids in biological fluids and pharmaceuticals.112 H.p.1.c. of adrenal 18-hydroxy-steroids (e.g. 18-hydroxycorticosterone, which exists as the 18+20-hemiacetal) is complicated by their labile nature. Normal handling, without special precautions, may result in the formation of 20-alkoxyderivatives, dehydration products, or dimers. Procedures are now described113for the extraction and reversed-phase h.p.1.c. of these compounds from biological sources without the appearance of artefacts. H.p.1.c. separations of aldosterone and its metabolites from biological sources have distinguished between known derivatives and some unidentified reduced and polar metabolites, which may have physiological significance.l14 H.p.1.c. separations and retention data are reported for all the isomeric reduced metabolites of progesterone, where combinations of normal and reversed-phase columns can resolve complex mixtures of biological origix~,l~~*ll~ and for the steroid hormones in adrenal and testicular An extensive review (155 references) of the separation and determination of D vitamins by h.p.1.c. includes discussion of the problem of instability, and a detailed lo6
L.Dehennin, A. Reiffsteck, and R. Scholler, Biomed. Muss Spectrom., 1980, 7 , 493.
R. Edenharder and J. Slemr, J. Chromutogr., 1981, 222, 1. C. J. W.Brooks, W. J. Cole, H. B. Mclntyre, and A. G. Smith, Lipids,1980,15,745. loo W.H.Elliott, Lipids, 1980, 15, 764. Ref. 42, 1981, Vol. 11, p. 183. n1 H. Adlercreutz, Adv. Muss Spectrom., 1980, 8B, 1165. F. A. Fitzpatrick, Adv. Chromutogr., 1978, 16, 37. 113 M. J. O’Hare, E. C. Nice, and M. Capp, J. Chromutogr,, 1980, 198, 23. D. J. Morris and R. Rsai, Adv. Chromutogr., 1981, 19, 261; D. J. Morris, Endocrine Rev., 1981,2,234. 116 J.-T. Lin, E. Heftmann, and I. R. Hunter, J. Chromutogr., 1980, 190, 169. R. H. Purdy, C. K. Durocher, P. H. Moore, and R. N. Rao, Chromatogr. Sci., 1981, 16, 81. 11’ M. J. O’Hare and E. C. Nice, in ‘Steroid Analysis by H.p.l.c.’, ed. M. P. Kautsky, Dekker, New York, 1981, pp. 277-321. lo8
282
Terpenoids and Steroids
account of chromatographic systems for the separation of vitamins D, and D,, their precursors, isomers, and metabolites.ll8 The sensitivity of U.V. detection of the vitamins D (20) and their metabolites during h.p.1.c. is improved two-fold by prior HC1-catalysed isomerization to their isotachysterol derivatives (24).lls Ternary solvent systems are recommended for the h.p.1.c. resolution of hydroxylated metabolites of vitamins Dz and D3,lZ0and in general for the separation of polar steroid hormones on reversed-phase h.p.1.c. systems when binary solvent mixtures prove unsatisfactory.lZ1
NMe, (25) R = O-steroid (24) (26) R = CN Practical problems of chemical reaction detection following elution from h.p.1.c. columns have been examined with particular reference to the formation of fluorescent derivatives of corticosteroids. Steroidal 4-en-3-ones are allowed to react, for example, with isonicotinoylhydrazide, in an air-segmented tubular flow system to minimize eluate mixing or band-broadening. Following de-aeration, the solution then passes through a fluxescence detector, giving a system sensitive to ca. 100 ng samples.122Dansyl derivatives have been used for h.p.1.c. of equine oestrogens, with fluorescence detection ; the 17-keto-oestrogens were separated after reduction with bor01iydride.l~~ 4-Dimethylaminonaphthalene-1-carboxylates (25), prepared from steroidal alcohols by reaction with the acyl cyanide (26), may be used for h.p.1.c. with absorbance and fluorescence detectors.lZ4 H.p.1.c. procedures are described for the separation of cardiac glycosides,125 metabolites of ecdysone,126and solanum and veratrum alka10ids.l~~ Sterol intermediates in cholesterol biosynthesis have been resolved by a threestep chromatographic procedure.128A detailed study of reversed-phase thin-layer chromatography of a wide variety of steroids (on silanized silica gel) includes a correlation of ARM values of substituents with hydrophobicity R.Vanhaelen-Fastre and M. Vanhaelen, Chromatogr. Sci., 1981, 16, 173. D.A. Seamark, D. J. H. Trafford, P. G. Hiscocks, and H. L. J. Makin, J . Chromatogr., 1980,
Ile
llB
197,271. G.Jones, J . Chromatogr., 1980, 221, 27. 121 G. J.-L. Lee, R. M. K. Carlson, and S. Kushinsky, J . Chromatogr., 1981, 212, 108. 12% E. Reh and G. Schwedt, Fresenius' 2. Anal. Chem., 1980,303, 117; G. Schwedt and E. Reh, 120
Chromatographia, 1981, 14, 249, 317.
R. W. Roos and T. Medwick, J . Chromatogr. Sci., 1980, 18, 626. 12* J. Goto, S. Komatsu, N. Goto, and T. Nambara, Chem. Pharm. Bull., 1981, 29,899. lZ5 V. Y. Davydov, M. Elizalde Gonzalez, and A. V. Kiselev, J. Chromatogr., 1981, 204, 293. lZ8 R.Lafont, P.Beydon, G . Somme-Martin, and C. Blais, Steroids, 1980, 36, 185. 12' I. R. Hunter, M. K. Walden, and E. Heftmann, J . Chromatogr., 1980, 198,363. lZ8 E.Hansbury and T. J. Scallen, J . Lipid. Res, 1980, 21, 921. 12@ J. Draffehn, B. Schonecker, and K. Ponsold, J . Chromatogr., 1981, 205, 113. 123
Physical Methods
283
Centrifugal thin-layer chromatography is claimed to provide a fast and efficient separation of ginsenosides and other natural products.13*Olefinic insect pheromones are separated efficiently on glass capillary columns coated with the correct film thickness of cholesteryl cinnamate in the liquid crystalline phase.131 Methoxyamine has a catalytic effect in the silylation of the hindered hydroxy-group of 17phydroxy- 17a-methylandrosta-1,4-dien-3-one with common silylating reagents.132
7 Immunoassays Those immunoassays which depend upon a tracer attached by a ‘bridge’ to the steroid have a potentially serious disadvantage compared with the use of the tritium-labelled steroid as tracer. Antibodies produced in response to a steroidprotein complex (antigen) may recognize not only the steroid but also the bridge by which the steroid-protein linkage is achieved. If the same bridging group links the steroid to the moiety which ultimately acts as tracer, competition between the natural steroid and the steroid-tracer complex for antibody binding may excessively favour the tracer if the antibody recognizes the bridge as well as the steroid. The resulting preferential binding of the tracer complex by the antibody reduces the sensitivity of the immunoassay. Bridge recognition has proved to be a problem when the tracer is the y-emitting p251]iodotyrosinelinked to the steroid via a succinoyl bridge. For a [lZ5I]-based assay of androstenedione, using an antibody to the ester-linked 19-succinoyl-BSA complex (27), bridge recognition has been reduced to produce a sensitive assay by employing an ether-linked bridge from C-19 to tyramine as the iodinated label (28)?% NH-BSA
(27) (28) The principle of bridge heterology has been applied also to cortisol enzymeimmunoassay, by linking !3-galactosidase through a variety of bridges to C-4 (29).134A shorter bridge than that used for the antigen gave improved sensitivity, but a longer bridge gave no advantage. Antibodies with high specificity for 4-hydroxy-oestrogens have been obtained by use of a 17-(O-carboxymethyl)oxime-BSA conjugate as antigen; the same hapten combined with [1251]iodohistaminewas employed as radioactive tracer.135Antisera K. Hostettmann, K. M. Hostettmann, and 0. Sticher, J. Chromatogr., 1980, 202, 154. R. R. Heath, J. R. Jordan, and P. E. Sonnet, J . High Resolut. Chromatogr. Chromatogr. Commun., 1981, 4, 328. 13a A. B. Benko and V. Mann, Anal. Lett., 1980, 13, 735. G. D. Nordblom, R. Webb, R. E. Counsell, and B. G. England, Steroids, 1981,38, 161. 13* H. Hosoda, N. Kawamura, and T. Nambara, Chem. Pharm. Bull., 1981, 29, 1969. lab D. Berg and E. Kuss, 2. Physiol. Chem., 1980, 361, 1743.
13*
284
Terpenoids and Steroids CH,OH
I
@
---OH
0
R
(29) R = SCH,CO,H, or SCH,CH,CO,H, or SCH,CH,0COCH,CH,C02H, or OCOCH,CH,CO,H
for testosterone and 17P-hydroxy-5a-androstan-3-one(DHT) having low crossreactivities have been obtained by pretreatment of mice with the cross-reacting steroid coupled via a 15~-carboxymethylmercapto bridge to a copolymer of Dglutamic acid and D-lysine, before immunization with testosterone-protein or DHT-protein complex in the usual Radioimmunoassay of solasodine and related plant alkaloids is rep0~ted.l~’ New enzyme-immunoassays include use of the P-galactosidase conjugate of 1 1a-hemisuccinoyloxyprogesteroneas tracer for a sensitive assay of progesterone in bovine milk,13*one for the synthetic anti-inflammatory steroid ‘betamethasone’, using the 3-(O-carboxymethyl)oxime-~-~-galactosidase conjugate as ‘labelled antigen’ and 4-methylumbelliferyl-~-D-galactoside as a fluorescent tracer,139 and a method for the quantification of d i g o ~ i n . l ~ ~ A fluorescence-quenching immunoassay for cortisol, based upon the use of a tracer comprising fluorescein linked to the steroid via a 21-amino-group, claims a good correlation with radioimmunoassay results. Separation of free and bound fractions is unnecessary with this Chemiluminescence-labelling has been applied to the immunoassay of oestriol 16a-glucuronide by synthesis of the N-aminobutyl-N-ethylisoluminolderivative (30), which emits light when oxidized with H,O,-microperoxidase. Binding of the conjugate (30) to an antibody for the steroid enhances light emission. Competitive
K. Tateishi, T. Hamaoka, C. Hayashi, J. Goto, S. Ikegawa, and T. Nambara, Steroids, 1980, 36, 283. 13’ E. W. Weiler, H. Krueger, and M. H. Zenk, Planta Med., 1980, 39, 112. M. J . Sauer, J. A. Foulkes, and A. D. Cookson, Steroids, 1981, 38, 45. 13@ G. Kominami, A. Yamauchi, S. Ishihara, and M. Kono, Steroids, 1981, 37, 303. 140 N. Monji, H. Ali, and A. Castro, Experientiu, 1980, 36, 1141. lol Y. Kobayashi, N. Tsubota, K. Miyai, and F. Watanabe, Steroids, 1980, 36, 177.
13’
Physical Methods
285
binding of oestriol 16a-glucuronide itself by the antibody inhibits the enhancement of emission, providing the basis of a very sensitive assay.142 A direct chemiluminescence assay for urinary pregnanediol 3-glucuronide employs the isoluminol conjugate (3 1) as tracer, with monoclonal antibodies. Specificity is excellent, the assay being sensitive to 30 pg.lP3A solid-phase chemiluminescence assay for plasma progesterone uses as tracer the isoluminol conjugate (32) derived from 1 1a-hydroxyproge~terone.~~~ \)...OH
(32) Hydroxy-steroid dehydrogenases co-immobilized on Sepharose 4B with NADH : FMN oxidoreductase and luciferase provide light-emission assays for picomole levels of androsterone or testo~terone.'~~
8 Miscellaneous The nitroxide (33) closely resembles cholesterol in its physical and biological properties, and has been used as a spin-labelled analogue of cholesterol to investigate cholesterol-protein interactions in human high-density 1ip0protein.l~~ The fluorescent cholesterol analogue N-(7-nitrobenz-2-oxa-1,3-diazole)-22-amino-23, 24-dinorchol-5-en-3p-01(34) has been used as a substrate for lecithin : cholesterol F. Kohen, J. B. Kim, G. Barnard, and H. R. Lindner, Steroids, 1980, 36, 405. Z. Eshhar, J. B. Kim, G. Barnard, W. P. Collins, S. Gilad, H. R. Lindner, and F. Kohen, Steroids, 1981, 38, 89. 14* F. Kohen, J. B. Kim, H. R. Lindner, and W. P. Collins, Steroids, 1981, 38, 73. J. Ford and M. DeLuca, Anal. Biochem., 1981, 110, 43. u6 J. F. W. Keana, T. Tamura, D. A. McMillen, and P. C. Jost, J . Am. Chem. SOC.,1981, 103, lQB
4904.
286
Terpenoids and Steroids
(33)
(34)
acyltransferase, and as its linoleate ester was incorporated into low-density lipop r o t e i n ~ .A ~ ~fluorimetric ' assay for ecdysteroids is sensitive to 10-l' rn01e.l~~ Esters of oestradiol and other steroids with ferrocenecarboxylic acid149have been converted into [103R~]ruthenocenecarboxylatesby exchange with [lo3Ru]RuC13,150 for use as y-emitting tracers in organ-affinity s t ~ d i e s . l ~ ~ Improved J~l yields were subsequently obtained by esterifying the steroid with [103R~]ruthenocenecarboxylic acid chloride obtained via metal exchange in o-chlorobenzoylferr0~ene.I~~ lo3Ruprovides a useful alternative to 1251as a y-radioactive tracer. The use of tetrazolium salts in the analysis of corticosteroids and other pharmaceuticals has been reviewed.153Polarographic study of cholesterol, 7-dehydrocholesterol, Vitamin D3,and related compounds has revealed differences in oxidation potentials which were correlated with molecular shape.154The measured dipole moment of cholesterol in toluene (1.55 D at 40 "C) increases at lower temperatures owing to molecular aggregati~n.'~~ Equilibration of the diastereoisomers of cholestane (Pt-C at 600 "C) has shown the most stable to be (20R)and (20S)-5a,14p, 17P-ch01estanes.l~~ A review of the use of torsion angle notation to describe stereochemical processes in cyclic molecules includes some steroid exam~1es.l~~ An interactive computer programme (SCRIPT) which can provide conformers and their relative energies has been applied to steroid molecules by drawing their formulae on a cathode ray tube.15* The relationship between crystal packing and liquid crystalline ordering has been discussed for cholesteryl n-alkanoates with between two and eighteen carbon atoms in the acyl group.159The mesomorphic transition temperatures of cholesteryl oleate, linoleate, and linolenate are pressure-dependent.160The thermal stabilities 147
14*
lSo 151 15a
153
150
168
I. F. Craig, D. P. Via, W. W. Mantulin, H. J. Pownall, A. M. Gott, jun., and L. C . Smith, J . Lipid Res., 1981, 22, 687. J. Koolman, Insect Biochem., 1980, 10, 381. K. Hoffmann, B. Riesselmann, and M. Wenzel, Liebigs Ann. Chem., 1980, 8, 1181. B. Riesselmann and M. Wenzel, Hoppe-Seyler's Z . Physiol. Chem., 1977, 358, 1353. M. Wenzel and K. Hoffmann, Naturwissenschaften, 1979, 66, 313. K. Hoffmann, B. Riesselmann, and M. Wenzel, J . Labelled Compd. Radiopharm., 1980, 17, 421. G. E. Veeman, Pharm. Weekbl., 1981, 116, 109. M. Wilk and K . Schmitt, Z . Naturforsch., Teil B, 1980, 35, 1496. L. L. Burshtein, T. P. Stepanova, and A. V. Purkina, Zh. Fiz. Khim., 1980, 54, 1493. S . D. Pustil'nikova, N. N. Abryutina, G . P. Kayukova, and A. A. Petrov, Neftekhirniya, 1980, 20, 26.
lS7
E. Toromanoff, Tetrahedron, 1980, 36, 2809. N. C. Cohen, P. Colin, and G . Lemoine, Tetrahedron, 1981, 37, 1711. P. Sawzik and B. M. Craven, Liq. Cryst. Proc. Znt. Cunf., Pittsburgh, U.S.A., 1979 (Pub]. 1980), 171.
ld0 M.
Nakahara, K. Maeda, and J. Osugi, Bull. Chem. Sac. Jpn., 1980, 53, 2499.
Physical Methods
287
of the cholesteric mesophase of esters of cholesterol with a series of m- and p substituted benzoic acids (PhXC6H,C02H) depend upon the nature of the linkage (X), and decrease in the order CO > 0 > S > CH2.161A further study has been reported16aon the ‘blue phases’163of cholesteryl nonanoate and myristate. A bibliography, ‘Fifty years of oestrogen analysis’, is available in rni~rofiche.16~
la’
M. Koden, S. Takenaka, and S. Kusabayashi, Chem. Lett., 1980, 5,471.
m2
S. Meiboom and M. Sammon, Phys. Rev. A, 1981, 24,468.
le3
Ref. 42, 1980, Vol. 10, p. 211; 1981, Vol. 11, p. 185. R. W. A. Oliver, C. T. Brooks, and J. E. Sugden, Biological Materials Analysis Unit, University of Salford M5 4WT, U.K., 1980.
le4
2 Steroid Reactions and Partial Syntheses BY 6. A. MARPLES
SECTION A: Steroid Reactions
1 General
Reviews on the use of DMSO in synthesis,l functionalized polymers as heterogeneous reagents,2 methods of fl~orination,~ and the application of the torsion angle notation in 5-, 6 ,and 7-membered rings4 all contain steroidal examples. 2 Alcohols and Carboxylic Acids and their Derivatives, Halides, and Epoxides Solvolysis, Substitution, Elimination, and Reduction.-Studies on the solvolysis of 3~-tosyloxy-5,10-secocholest-l( lO)-en-5-ones have been reported5 and are complementary to those reported earlier6 on similar compounds. Considerable double bond participation was observed for the 2-3a-compound (I), the E-3a-compound (2),
&
TsO
0
A. J. Mancuso and D. Swern, Synthesis, 1981, 165. A. Akelah, Synthesis, 1981, 413. M. R. C, Gerstenberger and A. Haas, Angew. Chem., Int. Ed. Engl., 1981, 20, 647. E. Toromanoff, Tetrahedron, 1980, 36,2809. L. Lorenc, M. J. GBsiC, I. JuraniC, M. Dabovib, and M. Lj. Mihailovib, J. Chem. SOC., Perkin Trans. 2, 1980, 1356. See 'Terpenoids and Steroids', ed. J. R. Hanson (Specialist Periodical Reports) The Royal Society of Chemistry, London, 1982, Vol. 11, p. 187.
288
Steroid Reactions and Partial Syntheses
289
and the E-3p-compound (3) but not for the 2-3p-compound (4). A study' of the conformations of esters of 2-3E-hydroxy-5,lO-secocholest1(lO)-en5-ones and the related 3,5-diketone is also relevant to this work. Diethylazodicarboxylate-Ph,P mediated reactions have been reviewed and steroid substitution reactions were included.* Reactions of 3-O-acetyldigitoxigenin with SF4-KF gave the 14~-fluoro-derivative. Sa-Cholestan-3p-01 was converted into 3a-cyano-cholestanol by treatment with NaCN-Me3SiCI (2 equivalents) and NaI (catalyst) in DMF-MeCN.1° Acetolyses of 4-, 6a-, and 6p-bromocholest-4-en3-ones catalysed by AgOAc gave the 6-acetoxy-compounds in contrast to similar reactions with KOAc where 2- and 4-acetoxy-compounds may result.ll In those cases where the S,l mechanism operated the attack on the mesomeric cation at C-6 was largely stereoelectronically controlled 6p. Controlled alkaline hydrolysis of 16a-bromo- 17-keto-steroids with NaOH in aqueous pyridine gave the 16a-hydroxy17-keto-compounds and no rearranged ketols.12J3 Studies with l8O-1abelled base suggested that epimerization of the 16~-bromineis followed by its direct displacement,12 21-Mesyloxy-20-keto-17-hydroxy-compounds were reported to react smoothly with thiolate anions [e.g. thiolacetate and O-ethylxanthate] in contrast with other nitrogen and oxygen nu~leophiles.~~ The 17-hydroxy-group appeared to catalyse the reactions. Calculations suggested that the preferred elimination of 3-substituted androstanes to give A2- rather than A3-compounds could not be explained alone by differences in calculated heats of formation. Differences in the energies of the respective transition states appeared to be irn~0rtant.l~ Dehydration of the cyclobutanol (5) gave largely the exo-alkene (7) but the tetradeuterio-compound (6)
(9) H. Fuhrer, L. Lorenc, V. PavloviC, G . Rihs, G. Rist, J. Kalvoda, and M. Lj. MihailoviC, Helv. Chim. Acta, 1981, 64, 703. 0. Mitsunobo, Synthesis, 1981, 1. A. Haas and D. Kortmann, Chem. Ber., 1981,114,1176. l o R. Davis and K. G. Untch, J. Org. Chem., 1981, 46, 2985. l1 T. Koga and Y . Nogami, Tetrahedron Lett., 1981, 22, 3075. l2 M. Numazawa and Y . Osawa, J. Am. Chem. SOC.,1980,102, 5403. l3 M. Numazawa and Y . Osawa, Steroidr, 1981,38, 149. l4 S. S. Simons, M. Pons, and D. F. Johnson, J . Org. Chem., 1980, 45, 3084. l5 W. Gschwendtner, V. Hoppen, and H. J. Schneider, J. Chem. Res. (S), 1981, 96.
290
Terpenoids and Steroids
gavel6 a greater proportion of the endo-alkene (8) which was used to prepare 18oxoprogesterone (9). Hydrogenolysis of 3- and 24-fluoro-compounds was effected with potassium and dicyclohexyl-18-crown-6 in toluene or dig1yme.l' Epoxide Ring 0pening.-A detailed study has been reported for the Li-NH3 reductions of la,2a-epo~y-h~~~-3-keto-steroids.~~ Reproducible and optimum yields of the 1a,3~-dihydroxy-A5-compounds were obtained by using an initial reduction with a stoicheiometric quantity of Li-NH, followed by protonation with NH4Cl and repeated alternating treatment with NH4C1 and Li. Diaxial chlorohydrins were formed from the reactions of 5,6-epoxy-cholestaneswith trimethylsilyl ch10ride.l~The participation of 19-substituents in the HBr- and HC104- catalysed cleavages of 5a,6a-epoxycholestanes was compared20with similar reactions of the 3 P-acetoxy-derivati~es,~~ The absence of the 3P-acetoxy-group was significant in that in the reaction of the 19-acetoxy-5a,6a-epoxide(10) with HBr, the participation
(10) R
=
AC
(11) R = Me
of the 19-acetoxy-group was only partially rather than fully suppressed. In the reaction of the 19-methoxy-5a,6a-epoxide(1 1) with HBr, no participation of the methoxy-group was observed and only the normal bromohydrin was formed. A study of similar reactions of 3cc,4a- and 4a,5a-epoxycholestanes was reported.22 The effects of a-acetoxy- and cc-hydroxy-groups on the aqueous HCIO,-catalysed ring opening were reported for the l-oxo-4,5-epoxycholest-2-enes(12) and the
(12) R'=
R'
R' R' R'
= = = =
R2= H OH, R2= H H, R2= OH OAC, R2= H
(13) R
=
H, Me, or Ac
H, R2= OAC 3p,6p-disubstituted-4,5-epoxycholestanes(1 3).23 In the former, it was suggested that the polar group repulsions in the transition state were important and it was M. Mujano, J. Org. Chem., 1981, 46, 1854. T. Ohsawa, T. Takagaki, A. Haneda, and T. Oishi, Tetrahedron Lett., 1981, 22, 2583. A. Fiirst, L. Labler, and W. Meier, Helv. Chim. Actu, 1981, 64, 1870. l o M. Husain and N. H. Khan, Synth. Commun., 1981, 11, 185. 2o P. KoEovsky and V. Cerny, Collect. Czech. Chem. Commun., 1980, 45, 3190. 21 See 'Terpenoids and Steroids' ed. J. R. Hanson (Specialist Periodical Reports), The Royal Society of Chemistry, London, 1981, Vol. 10, p. 216. 22 P. KoEovsky and V. terny, Collect. Czech. Chem. Commun., 1980, 45, 3199. M. Ishiguro, H. Saito, Y. Hirano, and N. Ikekawa, f. Chem. Soc., Perkin Trans. I , 1980,2503. l6
l7
Steroid Reactions and Partial Syntheses
29 1
observed that the 6p-acetoxy-group prevented cleavage of the 4a,5a- and 4p,5pepoxides, while in the latter, the participation of the 3p- or 6p-acetoxy-groups in the ring opening process was of particular importance and it was noted that the 4p,5@-epoxideswere unreactive. Esters, Carboxylic Acids, and Ethers.-The rates of hydrolysis of 38- and 68acetoxy-4E,5E-epoxides and la-acetoxy-2p,3P-epoxides were observed to be accelerated relative to those acetates not containing a neighbouring epoxide Bile acid methyl esters were readily prepared from the carboxylic acids by reaction with methanol in the presence of toluene-p-sulphonic Bile acids were readily converted into the amino-amides (14) by successive reaction with BulN-
Bu'OCOCl and 1,2-diamin0ethane.~~ A number of side chain keto-steroids were obtained by reactions of the carboxylic acid chlorides with organomanganous iodides and the reactions are exemplified by the conversion of the acid chloride (15) into the 24-keto-compound (16) using isobutylmanganous iodide.27The 16a,1 7 ~ (alkoxymethy1enedioxy)-steroids (18) were prepared from the 16a-formyloxy-17ahydroxy-compounds (17) with acetals and P205.28The major product of thermal decarboxylation of the 3,17-dioxo-4p,5p-epoxyandrostan-19-oic acid (19) was the hydroxy-enone (20). Digitoxigenin 3-alkyl ethers were prepared by BF,.Et,O-catalysed alkylation of digitoxigenin with diazoalkanes, AgBF,-assisted solvolysis of 3-desoxy-3a-iododigitoxigenin, and MCPBA-induced oxidative solvolytic displacement on the 3-desoxy-3a-iodo-compound in alcohols.30
M. Ishiguro, H. Saito, and N. Ikekawa, J. Chem. SOC.Perkin Trans. 1 , 1980, 2507. B. Dayal, J. Speek, E. Bagan, G. S. Tint, and G. Salen, Sferoids, 1981, 37, 239. A. Hill, P. E. Ross, and I. A. D. Bouchier, Steroids, 1981, 37, 393. G. Cahiez, Tetrahedron Lett., 1981, 22, 1239. J.-C. Hilscher, Chem. Ber., 1981, 114, 389. 2B H. Mastalerz and P. Morand, J. Org. Chem., 1981, 46, 1206. 30 R.Greenhouse and J. M. Muchowski, Can. J. Chem., 1981,59, 1025.
25
292
Terpenoids and Steroids
OR
{gH
OR
---0COH
(18) n
=
1 or 3
Treatment of oestrone with tetraphenylbismuth monotrifluoroacetate gave oestrone phenyl ether and exemplified, in part, a new procedure for aryl ether f ~ r m a t i o nA . ~ detailed ~ study was reported of the formation of benzyl ethers by sequential reaction of alcohols with chloro(phenylmethy1ene)dimethylammonium chloride and sodium hydrogen telluride.32 Steroidal alcohols, inter alia, were converted into hydrolytically stable silyl ethers by reaction with Bu'Me,SiI or Bu'PhJ which were generated in situ from the selenosilane and iodine.33 The 5cc-hydroxycholestane (2 1) was protected in this way.
3 Unsaturated Compounds
Electrophilic Addition.-Reactions of androsta-3,5-dienes with MCPBA gave complex mixtures the composition of which was dependent upon the level of peracid used (1 or 2 equivalents). Diepoxides were isolated in low yield only when 2 equivalents were used and in general products were derived from epoxide ring opening.34 In a study of the structures of withanolides G,H,I,J,K, and U which were all shown to possess the 14a-hydroxy-group, it was demonstrated that the 14a-hydroxy-group influenced the epoxidation of the 5,6-double bond.35Incorporation of ozonizable dyes as internal standards facilitated selective ozonization of 31
52
D. H. R. Barton, J.-C. Blazejewski,B. Charpiot, and W. B. Motherwell,J. Chem. SOC.,Chem. Commun., 1981, 503. A. G . M. Barrett, R. W. Read, and D. H. R. Barton, J. Chem. SOC.,Perkin Trans. I , 1980, 2184.
a3 34
35
M. R. Detty and M.D . Seidler, J . Org. Chem., 1981, 46, 1283. R. C. Cambie, C. M. Read, P. S. Rutledge, G . J. Walker, P. D. Woodgate, and J. R. Hanson, J. Chem. SOC.,Perkin Trans. I , 1980, 2581. I. Kirson and H. E. Gottlieb, J . Chem. Res. (S)., 1980, 338.
293
Steroid Reactions and Partial Syntheses
alkenes and 3-oxostigmasta-4,22-diene gave the aldehyde (22) in high yield using solvent Red 23.36 Ozonolysis of hl6-20-oxopregnanes in CH2C12-lower alkanol followed by reductive work-up with Me,S gave the novel 16P-alkoxy-17aahydroxy-D-homo-17-oxapregnanes (23).37
dcHo
o
o&OR /
/
(22)
(23) X = AcO, C1 or Br
Addition of HOBr to the 3p-acetoxy-oestr-4-ene (24) gave the 4p-acetoxy-5~bromo-3 p-hydroxy-compound (25) resulting from participation of the neighbouring acetoxy-group.38 Equilibration of the major product (25) or its 3p-acetoxy-4phydroxy-isomer (26) led to a mixture containing largely the latter (ca. 85%). Participation of 19-substituents in the additions of HOBr to A5-cholesteneswas compared39 with that in the similar reactions of the 3p-a~etoxy-analogues~~ and the
AAJ
AcO
(25) R1= H, R2 = AC (26) R1= Ac, R2 = H
(24)
AcO
&
HO
ir
(28)
@ Ho OR
(29) R (30) R 36
s8 39 *O
=H = AC
OH (31)
(32)
T. Veysoglu, L. A. Mitscher, and J. K. Swayze, Synthesis, 1980, 807. C. M. Cimarusti, P. G. Grabovitch, B. K. Toeplitz, R. K. Varma, and J. Z. Gougoutas, J. Org. Chem., 1981,46,803. D. F. Covey and V. D. Parikh, Steroids, 1980, 36, 451. P. K&ovskY and V. Cernf, Collect. Czech. Chem. Commun., 1980, 45, 3023. See reference 21, p. 218.
294
Terpenoids and Steroids
study was complementary to that reported for the 5a,6a-epo~ides.~~ The expected 6(0)n9nparticipation was observed for the 19-acetoxy-derivative(27) but in contrast to the reaction in the 3p-acetoxy-series the 'abnormal' bromohydrin (28) was the exclusive product. The formation of the bromohydrin (28) is a key step in the synthesis of 19-functionalized-A4- and A3-cholestenes,41and the reactions of these with HOBr were also reported to show participation of the 19-s~bstituents.~~ In similar studies, it was observed that addition of HOBr to thelop-vinylcholestanediol(29) gave the epimeric bromopyrans (3 1) whereas the 6@-acetoxy-analogue(30) under similar conditions gave the spiro-ketone (32) in addition and in approximately equal yield.43 Other Addition Reactions.-A review of singlet oxygen used in organic synthesis contained some steroidal examples.44Ergosteryl acetate was reported to react with NOCN which was cleanly generated by thermolysis of the cycloadduct of 9,lOdimethylanthracene and NOCN. Both regioisomers (33) and (34) were 0btained.4~
CN
(33)
(34)
A number of hindered steroidal alkenes were successfully hydrogenated using [Ir(cod)py(PCy,)]PF, as homogeneous catalyst.46Ketones, C-halogen bonds, and cyclopropane rings were unreactive. Platinum-catalysed hydrogenations of the 12-oxo-5@-chol-9( 11)-enates (35) have been studied and deoxygenation at C-12 and
(35) R = a-OH, H R = a-OAc, H R=0
R=
H 2
R = @-OH,H
at C-3 (for the 3-0x0-derivative) was noted particularly in those reactions in which significant saturation of the double bond was a~hieved.~' Other Reactions of Unsaturated Steroids.-Allylic alkylations catalysed by palladium have been reviewed and steroid examples are i n c o r p ~ r a t e d .The ~ ~ full 41 42
43 44
45
46 47 4B
P. KoEovsky, Collect. Czech. Chem. Commun., 1980, 45, 3008. P. KoCovsky and V. cerny, Collect. Czech. Chem. Commun., 1980,45, 3030. P. KoEovsky and F. TureEek, Tetrahedron Lett., 1981, 22,2699. H. H. Wasserman and J. L. Ives, Tetrahedron, 1981, 37, 1825. P. Horsewood, G . W. Kirby, R. P. Sharma, and J. G. Sweeney, J. Chem. SOC. Perkin Trans. I , 1981, 1802. J. W. Suggs, S. D. Cox, R. H. Crabtree, and J. M. Quirk, Tetrahedron Lett., 1981, 22, 303. A. Kasal, Collect. Czech. Chem. Commun., 1981, 46, 1839, B. M. Trost, Acc. Chem. Rex, 1980, 13, 385.
Steroid Reactions and Partial Syntheses
295
paper was reported49 for the mechanistic of the stereochemistry of a(4-6q)-PdCl complexes from A4-3-0x0-steroidsconfirming the initial preferential loss of the 6p-H in the enolization, which is catalysed by the Lewis acids Pd'ICl, or PdC1,2-, followed by intramolecular a-face transfer of the Pd from oxygen to carbon. Oxidation with pyridine chlorochrornate in Fyridine and acetylation with acetic anhydride in pyridine of the 17-hydroxy-group of the a-(4--6q)-PdCl complex (36) proceeded normally although the products were largely obtained as
x-ally1 pyridine cornplexe~.~~ Oxidation of x-ally1 palladium complexes with Crv' in DMF-ether containing a trace of sulphuric acid was reported to give the corresponding a,p-unsaturated ketones and is exemplified by the conversion of the complex (37) into 5a-cholest-2-en-1-one and Sa-cholest-l-en-3-0ne.~~ Reaction of Fe(CO), with the epoxy-vinylcholestane (38) gave the complexes (39) and (40) which were oxidized with Ce'" ammonium nitrate, the former giving a mixture of the lactones (41) and (42) and the latter giving only the 8-lactone (42).53
f
(39)
Aromatic Compounds.-Regioselective mercuration at position 2 was reported for oestradiyl 3-methyl ether 17-acetate with Hg(OAc)2-CH,CN and allowed the preparation of the 2-chloro-, -bromo-, and -iodo-deri~atives.~~ The major product (41 %) of the reaction between oestrone and Ph5Bi was reported to be the 2,448 50
61 52 5s
54
D. J. Collins, W. R. Jackson, and R. N. Timms, Aust. J . Chem., 1980,33,2663. See Reference 6, p. 193. D. J. Collins, W. R. Jackson, and R. N. Timms, Aust. J. Chem., 1980, 33,2761. J. Y . Satoh and C. A. Horiuchi, Bull. Chem. Sac. Jpn., 1981, 54, 625. G. D. Annis, S. V. Ley, C. R. Self, and R. Sivaramakrishnan,J. Chern. SOC., Perkin Trans. I , 1981,270. E. Santaniello and P. Ferraboschi, J. Chem. SOC.,Chem., Cornrnun. 1981, 217.
296
Terpenoids and Steroids
diphenyl derivative and the minor product (18 %) was the 4-phenyl derivative.55 Oestradiol reacted in a similar manner but oxidation of the 17-hydroxy-group also occurred. 4 Carbonyl Compounds
Reduction.-Further were reported on the use of poly(N-isopropyliminoalane) as a selective reducing agent for steroidal dicarbonyl compounds and selective reduction of the 6-0x0-group was reported for 3a,5-cyclo-5a-androstane6,17-dione and 3cr,5-cyc10-5a-pregnane-6,20-dione.~~ A reinvestigation of the Clemmensen reduction of tigogenin established that the major products were tetrahydrotigogenin (43) and furostan (44) both of which were relatively Reductive cyclizations of the acetylenic-5-ox0-5,6-secocholestanes(45) and the
(43)
R = H or Me, n R=H.n=2
(45) R
=
1
olefinic analogue (46) (inter a h ) using Na-NH,THF and Na-THF were compared with those reported earlier for C,oH,Na-THF.59 The presence of ammonia in the reducing medium allowed reduction to the secondary alcohol to compete with the reductive cyclization and from a study60 of these competing reactions it was concluded that alkali metal-ammonia reductions of enolizable or a,&unsaturated ketones proceeds through the vicinal dianion. Reduction of A4-3-0x0-steroidsto the 3-0x0-compounds was achieved by treatment of the pyrrolidinium salts with 1,4-dihydropyridine derivatives.61 D. H. R. Barton, J.-C. Blazejewski, B. Charpiot, D. J. Lester, W. B. Motherwell, and M. T. Barros Papoula, J . Chem. SOC.,Chem. Commun., 1980, 827. 56 See ‘Terpenoids and Steroids’ ed. J. R. Hanson (Specialist Periodical Reports), The Chemical Society, London, 1978, Vol. 8, p. 240. 5 7 M. P. Paradisi and G . P. Zecchini, Tetrahedron, 1981, 37, 971. 5 8 M. Zachis and J. A. Rabi, Tetrahedron Lett., 1980, 21, 3135. 5 9 S. K. Pradhan, S . R. Kadam, J . N. Kolhe, T. V. Radhakrishnan, S. V. Sohani, and V. B. Thacker, J . Org. Chem., 1981, 46, 2622. 6D S . K. Pradhan, S . R. Kadam, and J. N. Kolhe, J . Org. Chem., 1981,46, 2633. R. A. Gase and U. K. Pandit, Red. Trav. Chim. Pay-Bas, 1980, 99, 334. 55
297
Steroid Reactions and Partial Syntheses
Other Reactions.-A review on the preparative methods of acetal formation contains steroidal examples.62Periodic acid was reported to be useful for regeneration of ketones from t h i o a c e t a l ~The . ~ ~ reaction of lithium acetylide with the 14p-hydroxy17-ketone (47) gave stereospecifically the 17p-hydroxy-compound (48)whereas the
& H
{I3 OH
"(48) (49)
(47)
R' R'
= =
Me,Si
& ' H
CECH, R2 = OH OH, R2 = C E C H
(50)
w \ ( 5 5 ) 12a and 12p
(54)
z
OAc (57) (56)
epimer (49) was obtained from the reaction with the equivalent acetylenic Grignard reagent.64Scr-Cholestanewas converted into 3,3-dimethyl-5cr-cholestane by sequential treatment with MeMgX, ZnC1,-HCI, and ZnMe2-TiC1,.65 A new method for 1,2-transposition of ketones was appliedaa to 5cc-cholestan-3-one. The initially formed vinyl silane (50)67was oxidized with MCPBA to the epoxide (51) which on 62
63 64
65
66
F. A. J. Meskens, Synthesis, 1981, 501. J. Cairns and R. T. Logan, J. Chem. SOC.,Chem. Commun.,1980, 886. J.-C. Beloeil, M. Bertranne, M. Fetizon, and T. Prangk,J . Chem. SOC.,Chem. Commun., 1981, 363, M. T, Reetz, J. Westermann, and R. Steinbach, Angew. Chem., Znt. Ed. Engl., 1980, 19, 900. W. E. Fristad, T. R. Bailey, and L. A. Paquette, J. Org. Chem., 1980, 45, 3028. L. A. Paquette, W. E. Fristad. D. S. Dime, and T. R. Bailey, J . Org. Chem., 1980, 45, 3017.
Terpenoids and Steroids
298
reduction with LiAlH, gave the hydroxy-silanes (52) and (53). Final oxidation with chromic acid gave a mixture of the 2- and 3-ketones. The Prins reaction of lumihecogenin acetate (54) was reported to give the 14-hydroxy-compounds (55).68 A novel base-catalysed cleavage of steroids containing the 17-dihydroxyacetone group was reported to yield 1 7 - 0 x o - ~ t e r o i dAttempted ~.~~ acetylation of the novel marine sterol (56) was reported7* to give the retro-aldol product (57). of hydrocyanation of 3-oxo-Al-steroids and analogues were The full reported, 73 and a full account was available for the acid- and base-catalysed additions of thiols to 3-OXO-A'- and related s t e r o i d ~and , ~ thiourea ~ ~ ~ ~ was observed to react with androst-l-en-3-ones to give the adduct (58). Reaction of 2-bromo-Al729
(59) R (60) R
(61) R = C02Et
= C0,Et = CN
(62) R
=
CN
and - A 1 ~ 4 ~ 6 - ~ t with e r ~ i malonic d~ ester and tetramethylguanidine gave the cyclopropanes (59) and (61) respectively as expected. 76 However, the cyano-derivatives
Me,N (Me,N),C=O
+
(60)
f-
Scheme 1 68
Be 70
71 72
73 14 76 76
P. Welzel, B. Janssen, and H. Duddeck, Annalen, 1981, 546. S . S. Simons Jr., M. J. Merchlinsky, and D. F. Johnson, Steroids, 1981, 37, 281. G. Cimino, S. De Rosa, S. De Stefano, G. Scognamiglio, and G . Sodano, Tetrahedron Lett., 1981,22,3013. See Reference 6, p. 195. C. Agami, M. Fadlallah, and J. Levisalles, Tetrahedron, 1981, 37,903. C. Agami, M. Fadlallah, and J. Levisalles, Tetrahedron, 1981, 37, 909. See Reference 21, p. 225. M. M. Campbell, V. B. Jigajinni, and R. H. Wightman, J. Chem. Res. (S)., 1981, 185. M. Kocor, W. Kroszczyiiski, and J. Pietrzak, Synthesis, 1980, 742.
Steroid Reactions and Partial Syntheses
299
(60) and (62) were also isolated and the suggested mechanism from the initial Michael adduct from the 2-bromo-Al-compound is outlined in Scheme 1. Reactions Involving Enols or Enolic Derivatives.-The full account was reported for the dehydrogenation of ketones using benzene seleninic anhydride. 77 Further studies were reported on catalysts specific for the isomerization of A5-cholestenone to A4-cholestenone.78 8a-Methylation of the 7-OXO-1 3,17-seco-steroid (63) was reported79with MeIAmtOK and efficient2 1-methylation of 20-oxo-pregnanes was achieved with MeILDA and led to the synthesis of 16a,17cc,21-trimethylpregnanes. 8o a-Thiocyanation
THPO&OTHP
(63) of ketones was reported using copper(I1) thiocyanatesl and 21-hydroxylation of pregnenolone exemplified a general procedure of a-hydroxylation of ketones involving oxidation of the silyl enol ethers with OsO,-N-methyl morpho1ine-Noxide.82 6a-Methylation of the 3-oxo-androst-4-ene(64) was achieved by allowing the silyl dienol ether (65) to react with dithienium fluoroborate and treatment of the resultant substituted enone (66) with Raney nickel.83 The enol triflate (67) was
(66) D. H. R. Barton, D. J. Lester, and S. V. Ley, J. Chem. SOC.,Perkin Trans. 1, 1980, 2209. 7 8 A. Fauve and A. Kergomard, Tetrahedron, 1981,37, 1697. 79 H.-R. Schlatter and W. Graf, Helv. Chim. Acta, 1980, 63, 1554. 80 J. Cairns, R. T. Logan, G. McGarry, R. G. Roy, D. F. M. Stephenson, and G. F. Woods, J. Chem. SOC.,Perkin Trans. 1, 1981, 2306. S. M. Ali, D. Clarke, G. R. Cliff, and G. A. Morrison, J. Chem. Res. ( S ) , 1981, 234. J. P. McCormick, W. Tomasik, and M. W. Johnson, Tetrahedron Lett., 1981, 22, 607. 8a I. Paterson and L. G. Price, Tetrahedron Lett., 1981, 22, 2833. 77
Terpenoids and Steroids
300
coupled with lithium dimethyl cuprate and with lithium diphenyl cuprate to give 3-methylcholest-2-ene and 3-phenylcholest-2-ene respectively.s4 Ketones or their derived enol acetates were converted into the cc-iodo-ketones with iodine and copper(r1) acetate. 85 0ximes.-Treatment of ketoximes with acetyl chloride-acetic anhydride-tertiary amine followed by hydrolysis gave the a-acetoxy-ketones and was exemplified by the conversion of 5cc-cholestan-3-one oxime to the 2a-acetoxy-3-oxo-derivative.~6 An investigation of the mechanism of the Moffatt fragmentation of oximes suggested that the bond which breaks is antiperiplanar to the h y d r o x y - g r ~ u pAccor.~~ dingly, the Z-isomers (68) gave the 13,17-seco-nitrile (70) through the intermediate (69) where as the E-isomers (71) gave the 16,17-seco-nitrile (73) through the intermediate (72). Reaction of 6-oximino-steroids with trimethylsilyl chloride was reported to give the cc-chloro-derivatives.19
(71) 16a or 16p
+O
(73)
5 Compounds of Nitrogen, Selenium, Sulphur, and Tellurium
A review on the acid promoted decomposition of a-diazoketones contains some steroidal examples.88 The full account was reported of the conversion of cc-azidoketones into cyano-carboxylic acids promoted by bromine in acetic a ~ i d . 8A~ general review on new reagents in natural product chemistry included the deamination of amines via the isonitriles, isothiocyanates, and isoselenocyanates reported 84
85 B6
87 88
J. E. McMurray and W. J. Scott, Tetrahedron Lett., 1980, 21, 4313. C. A. Horuichi and J. Y. Satoh, Synthesis, 1981, 312. G. S. Reddy and M. V. Bhatt, Synthesis, 1981, 223. J. Pfenninger and W. Graf, Helv. Chim. Acra, 1980, 63, 2338. A. B. Smith and R. K. Dieter, Tetrahedron, 1981, 37, 2407. T. T. Takahashi and J. Y. Satoh, J. Chem. SOC.,Perkin. Trans. I , 1980, 1916.
Steroid Reactions and Partial Syntheses
301
earlier. Reaction of cc, p-epoxy-O-thiocarbonylimidazolederivatives of steroidal alcohols were reported to react with AIBN-Bu,SnH to give the allylic alkoxy radical which was converted into the allylic alcohol or a rearranged product dependent on the mode of addition of the B U , S ~ HFor . ~ ~example, the cholestane derivative (74) with AIBN when added to excess Bu,SnH (inverse addition) gave the allylic alcohol (75) and a small amount of the A-nor-B-homo-ketone (76). However, the latter compound became the major product if Bu,SnH was added to a mixture of the cholestane derivative (74) with AIBN. This reaction, in the inverse addition mode, provides an alternative to the Wharton reaction and the pregnane epoxy-O-thiocarbonylimidazole(77) was converted into the allylic alcohol (78).
&--OH
(77) Steroidal alcohols were reported to be deoxygenated by conversion into the selenocarbonates and reduction with Bu,SnH-AIBN. Carboxylic acids were similarly converted into the selenoesters which on treatment with Bu,SnH-AIBN gave mainly the aldehyde or the nor-alkane depending whether xylene or benzene was used as solvent. 92 Deoxygenation was reportedg3in full for N,N-dialkylaminothiocarbonyloxyalkanes by treatment with potassium in t-butylamine containing 18-crown-6.
(79)
x =0
(80) X
So
S1 92
s3
=
H2
(82) R' = SCN, R2= I (83) R1= NCS, R2 = I (84) R' = I, R2= NCS
D. H. R. Barton and W. B. Motherwell, Pure Appl. Chem., 1981,53, 1081. D. H. R. Barton, R. S. Hay Motherwell, and W. B. Motherwell, J . Chem. Soc., Perkin Trans. I , 1981, 2363. J. Pfenninger, C. Heuberger, and W. Graf, Helv. Chim.Acta, 1980, 63, 2328. A. G. M. Barrett, P. A. Prokopiou, and D. H. R. Barton, J. Chem. SOC.,Perkin Trans. I , 1981, 1510.
302
Terpenoids and Steroids
Treatment of 3~-t-butyltellurocarbonyloxy-5a-cholestane with benzene seleninic anhydride gave the cholestanyl ester (79) whereas with sodium hydrogen telluride the ethers (80) and (81) were ~ b t a i n e d . ~ Reaction * of the vic-iodothiocyanate (82) and the iodoisothiocyanates (83) and (84) with BuLi at room temperature gave a n d r o ~ t - 2 - e n eit; ~was ~ observed that the diaxial nature of the substituents was responsible for the elimination. It was reported that the reaction of the aminomesylate (85) with basic reagents gave Wagner-Meenvein rearrangement products OMS
(85) R = H
(86) R
=
MS
(87) R (88) R
=
=
H MS
(89) 16P917P (90) 16a,17a
SCH2CH,N3
H (94) . , (95)
whereas the isomer (87) was converted into the 16a-amino-17P-hydroxy-compound and the 16a,I7a-aziridine. 96 The N-mesylaziridines (89) and (90) were smoothly obtained by reaction of the 16,17-trans-mesylamidomesyloxy-compounds (86) and (88) respectively with Bu'OK-DMSO. Further studies on the dehydrogenation of lactams were reported with benzene seleninic anhydride. 9 7 Heating the azidocholestenone (91) in xylene was reportedg8to give the cyclic enamide (92). Hydrozirconation of the thioketone (93) followed by reaction with a variety of electrophiles led to a variety of sulphur compounds and exemplified quite a general reaction sequence.99Thus, for example, sequential treatment of (93) with Cp,ZrHCl and MeCOCH=CH, gave the 0x0-thioether (94). A comparative study was g4 85
A. G. M. Barrett, R. W. Read, and D. H. R. Barton, J . Chem. SOC.,Perkin Trans. I , 1980,2191. R. C. Cambie, D. Chambers, P. S. Rutledge, and P. D. Woodgate, J . Chern. Soc., Perkin
Trans.I, 1981, 40. 86 g7
gg
B. Schoenecker and K. Ponsold, J. Prakt. Chem., 1981, 323, 223. T. G. Back, J . Org. Chem., 1981, 46, 1442. A. G. Schultz and R. Ravichandran, J. Org. Chem., 1980, 45, 5008. D. E. Laycock and H. Alper, J . Org. Chem., 1981,46,289.
Steroid Reactions and Partial Syntheses
303
reported of the action of H202and p-nitroperbenzoic acid on the pyrroline (95) and the derived oxaziridine and nitrone .loo 6 Molecular Rearrangements
The previously observed backbone rearrangement of cholest-5-ene to cholest13(17)-ene in acetic acid-toluene-p-sulphonicacid and the subsequent slow epimerization at C-20 were shown by a deuterium incorporation study to involve a series of carbo-cation-olefin equilibria.lo1The full account was reported for the BC1,-catalysed backbone rearrangement of 4,4-dimethyl-6,20-epoxy-5a-androstane.lo2The oxetane (96) was reportedlo, to react with RCN-HBF, to give the
@
~@HI3F4
{j$F (99)
AcO (96) 16P917P (97) 16a,17a
(98)
hydro-oxazine salts (98) while its 16,17-epimer (97) underwent rearrangement to the A13-l7-methyl compound (99). The 17a-propynyl-17P-hydroxy-11B-hydroxyandrostadienone (100) was observed to give a high yield of the A13-17-methyl derivative (101) when treated with BF,-Et,O in acetic acid or a~etonitri1e.l~~ However, in benzene, chloroform, or carbon tetrachloride participation of the propynyl group was favoured and the major product was the 13a-propynyl-118,I7B-epoxide H. Dadoun, J.-P. Alazard, and X . Lusinchi, Tetrahedron, 1981, 37, 1525. D. E. Akporiaye, R. D. Farrant, and D. N. Kirk, J. Chem. Res. ( S ) , 1980, 210. lo8 M. Fetizon and G. Sozzi, Tetrahedron, 1981, 37, 61. lo3 G. Schneider, L.Hackler, and P. Sohhr, Tetrahedron Lett., 1981,22, 341. lo4 G. Teutsch, C. Lang, R. Smolik, J. P. Mornon, and J. Delettrk, Tetrahedron Lett., 1981, 22, loo
lol
327.
304
Terpenoids and Steroids
(102). Further rearrangement of the 11P, 17p-epoxide (102) with SnC1, in acetic anhydride gave cyclobutene (103). A convenient method for the introduction of the isopropenyl group into a$-unsaturated ketones involved the BF,*Et,O-catalysed cleavage of the allene-enone photo-adducts.lo5 Thus, for example photo-adduct (104) gave the 4-isopropenyl-A4-3-oxo-compound (105). The BF,-Et,O-catalysed
(104) (105) rearrangement of the 3,19-epoxy-androstane (106) to the 10-formyl-compound (108) was shown106 to involve a reversible 1,5-hydride ion shift which was highly stereoselective for the H, and involved the intermediate (107). Whereas-the 19-hydroxy-5p76p-epoxides (109) underwent cleavage of the 10,19-bond with BF,
-
(109) R (110) R
=
H
=
AC
BF3
(1 12) gas in benzene to give the dienes (1 1 I), the equivalent 19-acetoxy-compounds (1 10) (1 12):lo7A study of the acid-catalysed rearranged to the 5-formy~-~-n0r-~0mpounds reactions of 3p-acetoxy-5-hydroxy-5ct-cholestan-6-one and the 3p-tosylate was lo5 lo6 '07
D. K. M. Duc, M. Fetizon, I. Hanna, and S. Lazare, Synthesis, 1981, 139. G. Acklin and W. Graf, Helv. Chim. Acta, 1980, 63, 2343. H. Mastalerz and P. Morand, J. Chem. SOC.Perkin Trans. 1, 1981, 154.
Steroid Reactions and Partial Syntheses
305
(1 17) (1 18) reported.lo8Aromatic ~-ring-6-oxo-compounds were the major products from the former with CC1,CO2H, ClCH2C02H,or CBr,C02H whereas the latter gave mainly the dienone (113) and the diketone (114) with KHS04 and HBr respectively. Reaction of the 1cc,2cc-rnethyleneandrost-4-en-3-one (1 15) and the 2a73a-methyleneandrost-6-en-4-one (1 17) with HBr gave the simple bromomethyl derivatives (1 16) and (1 18) respectively and no dienone-phenol rearrangement was reported.lo9
*p;
BzO-
(124) lop (125) 10a lo*
(126) R’ = Bz, R2 = AC (127) R’ = Ac, R2= BZ
RIO
(128) R1= Bz, R2= Ac; 3a,lOa (129) R‘ = Ac, R2= Bz; 3f3,lOp
J, J. Jagodzifiski, J. Gumulka, and W. J. Szczepek, Tetrahedron,1981, 37, 1015. J. R. Hanson and S. G . Knights, J. Chem. SOC.,Perkin Trans. I , 1981, 25.
loB
0r2
306
Terpenoids and Steroids
The full account was reported for the study of the intramolecular ene reactions of the enols of 5-vinyl-3-oxo-steroidsand an examination of the photolysis of the bridged bicyclic ketone (1 19) was incorporated.110A by-product of the reaction of 3p-tosyloxy-5,6p-dihydroxy-5~-cholestane (120) with ButOK-Bu'OH was reportedlll to be the A-nor-compound (123) which arose from an ene reaction of the enol(l22) of the fragmentation product (121). Buffered acetolysis of the tosylate (124) gave the A-homo-compounds (125) and (126) while the tosylate (127) gave the related A-homo-compounds (128) and (129).lI2 Thermally and photochemically induced fragmentations of the hypoiodites of 3-methylcholest-5-en-3-01,1~~ 4,4-dimethylcholest-5-en-3p-01,~~~ cholesterol, epicholesterol, and 3a,4,4-trimethyl-cholest-5-en3p-o1115which were generated in situ from the parent alcohols were reported to give a variety of products all derived from the oxyl radicals (130).
(130)
Oxidation of cholestane-2,3-dione with thallium(m) acetate gave the A-nor-pketo-ester (131) whereas a low yield of the keto-lactones (132) was obtained from 3,4-diketo-steroids.l16
(131)
(1 32)
An investigation into the migratory aptitudes of C-2 versus C-4 in Beckmann, Schmidt, and Baeyer-Villiger reactions employed 13C n.m.r. spectroscopy and demonstrated that all reactions proceeded with migration of both C-2 and C-4 0
OOH
(135) R = 0 (136) R = p-Cl, H P.Yates and F. M. Winnik, Can. J. Chem., 1981, 59, 1641. D.S.Brown, R . W. G. Foster, B. A. Marples, and K. G. Mason, Tetrahedron Lett., 1980, 21, (133)
l10 ll1
5057.
115
J. M. Gerder, A. W. Norman, and W. H. Okamura, J. Org. Chem., 1981, 46, 599. H Suginome and N Maeda, Bull. Chem. SOC.Jpn., 1980, 53,2621. H.Suginome and N. Maeda, Bull. Chem. SOC.Jpn., 1980, 53, 2626. H. Suginome, A. Furusaki, K. Kato, H. Maeda, and F. Yonebayashi, J. Chem. SOC.,Perkin
116
A. M.Maione, A. Romeo, S. Cerrini, W. Fedeli, and F. Mazza, Tetrahedron, 1981,37, 1407.
112 113 114
Trans. 1 , 1981, 236.
Steroid Reactions and Partial Syntheses
307
notwithstanding earlier reports to the ~0ntrary.l~' Acetylation of the 5-hydroperoxide (133) gave the ~-homo-6-oxa-compound (134) demonstrating the preferred alkenyl versus alkyl migration for this Criegee rearrangement.ll* Baeyer-Villiger oxidation of the 5P-methylcholest-9-enedione (135) gave a variety of products and interestingly the related chloro-ketone (136) gave the 5a-methyl-lactone (137).l19 Reaction of the A14-17-0x0-androstsne (138) with alkaline hydrogen peroxide led to three novel ring D-cleaved products (139), (140), and (141) which were isolated 0
(138) from the acidic fraction of the product after methyl ester formation and acetylation.lS0 Oxidation of cholest-4-ene-3,6-dione with excess perbenzoic acid in the presence of toluene-p-sulphonic acid gave the oxetalactones (142) and (143).121
The a-azido-sulphide (145), which was generated in situ from the thioacetal (144), was reported122to undergo SnC1,-catalysed rearrangement to the cyclic iminothiomethyl ethers (146) and (1 47).
MeS
&
MeS
H
Mes@NS (145)
(144)
(144) 11' 11* lln 121 122
(147)
V. Dave, J. B. Stothers, and E. W. Warnhoff, Can. J. Chem., 1980, 58, 2666. J. A. M.Peters, N. P. van Vliet, and F. J. Zeelen, Red. Truv. Chim. Pays-Bas, 1981, 100,226. Shafiullah, M. A. Ghaffari, and H. Ali, Tetrahedron, 1980, 36, 2263. M. Bialer, Tetrahedron Lett., 1981, 22, 2683. M.S.Ahmad, I. A. Khan, and N. K. Pillai, Tetrahedron, 1980, 36, 2341. B. M. Trost, M. Vaultier, and M. L. Santiago, J . Am. Chem. SOC.,1980, 102, 7929.
Terpenoids and Steroids
308 7 Functionalization of Non-activated Positions
Reaction of 6p-hydroxy-steroids with ceric ammonium nitrate was reported to give the 6p, 19-epoxide~,1~~ and fragmentation of 5- and 19-hydroxy-compounds were also reported. A detailed investigation of the hypoiodite reaction and the related Pb(OAc), oxidation of a 5a-bromo-6p-hydroxy-compoundindicated that for the former a halocarbon solvent promotes 6p, 19-epoxide formation.lz4Photolysis of the 17a-iodobenzoate (148) with PhICI, gave the 9a-chloro-derivative (149) which on thermolysis gave a good yield of the 9(11),16-diene (150).125 Photolysis of
(150)
nitroamines wth I,-Pb(OAc)4 or I,-HgO was reported to generate the nitroamine radicals which led to functionalization of non-activated positions.12s Thus the 6p-nitro-aminocholestanes (I 5 1) gave the N-nitropyrrolidines (152) and the
(151) R
=
H or OAc
(152)
R
=
H or OAc
(153) lZ3 lz4
lZ5
126
V. Balasubramanian and C. H. Robinson, Tetrahedron Lett., 1981, 22, 501. B. H. Jennings and L. M. Yelle, Sreroidr, 1981, 37, 7 . U. Kerb, M. Stahnke, P.-E. Schulze, and R. Wiechert, Angew. Chem., Int. Ed. Engl., 1981,20, 88. R. Hernhndez, A. Rivera, J. A. Salazar, and E. Suhrez, J. Chem. Soc., Chem. Commun., 1980, 958.
Steroid Reactions and Partial Syntheses
309
nitroamine (153) after the photolysis and reaction with AgOAc gave the similar 18-functionalized derivative (154). Jervine was reportedla' to be transformed into the 18-functionalized c/D-trans-D-homo-c-nor-compound (153, the 1l-oxofunction of which was readily removed by Wolff-Kishner reduction.
8 Photochemical Reactions Aspects of photosensitization in organic synthesis were reviewed12* and stereospecific and regiospecific photoreactions inside the channels of choleic acids were r e ~ 0 r t e d . lIrradiation ~~ of saturated acids or esters was reportedlsO to lead to Norrish type I1 reaction or a 1,Zelimination and was exemplified by conversion of cholanic acid or its ethyl ester into the A20(22)-compound (156). Photolysis of the PAC
(157) enol ester (157) gave131the P-diketone (158) through a photo-Fries type rearrangein methanol saturated with ment. Irradiation of 3a,5-cyclo-5a-cholestan-7-one oxygen was reported132to give the 7-oxa-compound (159) along with the 7,S-seco-
(159) (160) H. Suginome, H. Ono, and T . Masamune, Bull. Chem. SOC.Jpn., 1981, 54, 852. l Z 8A. Albini, Synthesis, 1981, 249. 12@ R. Popovitz-Biro, H. C. Chang, C. P. Tang, N. R. Shochet, M. Lahav, and L. Leiserowitz, Pure. Appl. Chem., 1980,52,2693. l3O G.Wolff and G. Ourisson, Tetrahedron Lett., 1981, 22, 1441. 131 D.Veierov, Y.Mazur, and E. Fischer, J. Chem. SOC.,Perkin Trans. 2, 1980, 1659. lS2 H. Suginome and C.-M. Shea, Bull. Chem. SOC. Jpn., 1980, 53, 3387.
lZ7
3 10
Terpenoids and Steroids
ester (160). The a,@-unsaturated8-lactone (161) was converted into the aldehydeSimilar photolyses in methanol of the ester (162) by irradiation in rnethan01.l~~
(161) (162) analogous %lactones (163) gave the 5,l O-seco-derivatives (164) whereas the isomeric &lactones (165) led to the 1,lo-seco-derivatives (166).13* A further study was reported135 of the photochemical reactivity of 3-oxo-h5(lo)-steroids. Photolysis of
(163) , a aR M = H or Me
(164) R
=H
& or Me
R-N
0 (166) R
9 & =H
0'
or Me
(167)
C8H1,
AcO
a
(168)
(1 69) the related A-homo-enone (167) in benzene was shown to give the spiro-ketone (168), probably via a singlet or short-lived triplet excited A triplet-sensitized photo-equilibrium may be established between vitamin D, and trans-vitamin D, in which the equilibrium position depends on the energy of the triplet sensitizer. In the presence of oxygen selective photo-oxygenation of the trans-isomer was re~0rted.l~' As would be predicted from steric considerations, the photo-adduct (169) derived from allene and 3 ~-acetoxycholest-8-en-7-one has the 8a,9a-configuration. However, since the isomeric As-1 l-oxo-compound did not react, it is 133
l3*
A. Canovas and J.-J. Bonet, Helv. Chim. Acta, 1980, 63, 2390. A. CCmovas, J. Fonrodona, J.-J. Bonet, M. C. Brianso, and J. L. Brians6, Helv. Chim. Actu, 1980, 63,2381.
J. R. Williams and A. Abdel-Magid, Tetrahedron,1981,37,1675. 136 J. R. Williams and G. M. Sarkisian, . I Org. . Chem., 1980, 45, 5088. n7 J. W. J. Gielen, R. B. Koolstra, H. J. C. Jacobs, and E. Havinga, Recl. Trav. Chim. Pays-Bas., 99,306.
la6
31 1
Steroid Reactions und Partial Syntheses
confirmed that not only steric considerations operate and that the configuration of the adducts may be predicted assuming an intermediate species which is trigonal in the a-position and pyramidal in the p-position.13* Photo-Beckmann rearrangement of 4,4-dimethylcholest-5-en-3-oneoxime and 4,4,6-trimethylcholest-5-en-3-one oxime gave essentially the predicted lactams and little or no nitrile in contrast to the SOC1,-induced Beckmann rea~rangernent.~~~ It is inferred that ionic or radical species derived by cleavage of the 3,4-bond are not involved in the photo-Beckmann rearrangements. The photo-Beckmann rearrangement of ~-nor-Sa-androstan-l6one oxime gave140,inter alia, a 13a-lactam. A similar inversion had previously been reported for a 17-ketoximeand in both cases some form of open-chain intermediate is implied. The photo-Beckmann rearrangement of 3a,5-cyclo-5a-cholestan-7-one oxime was u n e ~ c e p t i o n a l .The ~ ~ ~photolysis of ~-nor-Sa-androstan16-one acetyl hydrazone in the presence of oxygen gave the expected142lactams and some inversion at C-13 SECTION B: Partial Syntheses 9 Cbolestane Derivatives and Analogues Recent studies in marine sterols were reviewed144and related to this is a review of sterol biosynthesis and metabolism in marine invertebrate^.^^^ Mutasterol (171), a
I
ii, iii
(171) Reagents: i, LDA-MeCOCMe,Et; ii, H,-Pd/C; iii, BuLi-Ph,P+MeBr-; iv, H30+
Scheme 2 J. F. Blount, G. D. Gray, K. S. Atwal, T. Y. R. Tsai, and K. Wiesner, Tetrahedron Lett., 1980, 21,4413. 139 H. Suginome, N. Maeda, Y.Takahashi, and N. Miyata, Bull. Chem. SOC. Jpn., 1981,54,846. loo H. Suginome and T. Uchida, Bull. Chem. SOC.Jpn., 1980, 53, 2292. 1 4 1 H. Suginome and C.-M. Shea, J. Chem. SOC. Perkin Trans. 1, 1980, 2268. 14e See Reference 6, p. 209. 143 H. Suginome, T. Uchida, K. Kizuka, and T. Masamune, Bull. Chem. SOC. Jpn., 1980,53,2285. 144 C. Djerassi, Pure Appl. Chem., 1981,53,873. 14s L. J. Goad, Pure Appl, Chem., 1981, 53, 837. 138
3 12
Terpenoids and Steroids
novel sponge sterol alkylated at C-25, was synthesized from the stigmasterolderived 3,5-cyclo-aldehyde (170) as indicated in Scheme 2.14sA synthesis was reported for 22-methylenecholestero1147 which along with (22S), (23S)methylene~ h o I e ~ t e r o 1 , 1observed ~ ~ ~ a ~to be a novel marine sterol. The key step in the synthesis of stellasterol (173) involved the reaction of the allylic alcohol (172) with triethyl-
(172) (173) o r t h o a ~ e t a t e The l ~ ~ ene reaction product (174) of ergosteryl acetate and diethyl azodicarboxylate was reduced with Li-EtNH, to afford lichasterol (175).150 ca17
I
AcO&02Et
HN, C0,Et
J& (175)
( 1 74)
Xestospongesterol(l76) and isoxestospongesterol(l77), examples of marine sterols with q2side chains, were synthesized according to Scheme 3.151 The oxidation of 5p-cholestane-3a,7a,12a,26-tetrol with Ag,CO,-celite gave 3cr,7cc, 12a-trihydroxy-5p-cholestan-26-a1, 7a, 12~,26-trihydroxy-5 p-cholestan-3-one, and 7a, 12%-dihydroxy-3-oxo-5p-chole~tan-26-al.~~~ A new route to chenodeoxycholic acid163 and a novel synthesis of 25-a~acoprostanel~~ from lithocholic acid were reported. Partial synthesisof halosterols epimeric at C-20 established that the natural material (178) had the 20R-~0nfiguration.l~~ A number of stereocontrolled syntheses of the steroidal side chain were r e p ~ r t e d . l ~ ~Reaction - l ~ ~ of Z- 17(20)-pregnenes (179) L. N. Li, U . Sjostrand, and C . Djerassi, J. Am. Chem. SOC.,1981, 103, 115. J. Zielinski, H. Li, T. S. Milkova, S. Popov, N. L. Marekov, and C. Djerassi, TetrahedronLett., 1981, 22,2345. 148 P. A. Blanc and C . Djerassi, J. Am. Chem. Soc., 1980, 102, 7113. 148 M. Anastasia and A. Fiecchi, J. Org. Chem., 1981, 46, 1726. 150 M. Anastasia and A. Fiecchi, J . Chem. SOC., Perkin Trans. 1, 1981, 2125. 151 L. N. Li and C. Djerassi, J . Am. Chem. SOC.,1981, 103, 3606. 152 B. Dayal, G. S. Tint, A. K. Bhatta, S. Shefer, and G. Salen, Steroids, 1981, 37, 205. lS3 T. Ida and F. C. Chang, J . Org. Chem., 1981,46,2786. 154 T. W. Gibson, Synthesis, 1980, 995. 156 J. M. Joseph and W. R. Nes, J. Chem. SOC.,Chem. Commun., 1981, 367. 156 W. G. Dauben and T. Brookhart, J. Am. Chem. SOC.,1981,103,237. 15’ A. D. Bateho, D. E. Berger, M. R. Uskokovid, and B. B. Snider, J. Am. Chem. SOC., 1981,103, 1293. 158 M. M. Midland and Y. C. Kwon, J . Org. Chem., 1981,46,229. 158 J. S. Temple and J. Schwartz, J. Am. Chem. SOC.,1980, 102, 7381. J. P. Marino and H. Abe, J. Am. Chem. Sac., 1981, 103,2907. 146
14’
313
Steroid Reactions and Partial Syntheses
I OMe
--\
’
b i , iii
f
v,
v1
I
(176) 252 (177) 25E Reagents: i, LDA-Me,CHCO,Me; ii, EtMgBr; iii, SOC1,-pyridine; iv, H,O+; v, MCPBA; vi, Me,Si-SiMe3-KOMe-HMPA
Scheme 3
(178) with diethylaluminium chloride and methyl p r ~ p i o l a t e or l ~ with ~ ethylaluminium dichloride and methyl p r ~ p i o l a t gave e ~ ~ the ~ A15p22-dieneesters (180) which had the natural configuration at C-20 and which could be hydrogenated to give the 17pconfiguration. Hydroboration of 2-1 7(20)-pregnenes (179)with9-borabicyclo[3.3.1Jnonane and subsequent reaction with chloroacetonitrile and base led to the 21-cyano-compounds (181).158 Reaction of the x-ally1 palladium complex (182) with isohexenyl zirconium gave the diene (1 83) with the natural configuration at C-20.159 The 15p,16p-epoxy-Z- 17(20)-pregnene (184) was allowed to react with lithium isohexylcyanocuprate to give the 15~-hydroxy-A16-compound (185) which could be modified to give cholesterol.lG0
314
Terpenoids and Steroids
Syntheses were reportedlsl for the 20-epimers of 21-nor-5a-cholane-20,24-diol (1 87) from the methyl ester (186). Cholest-4-en-3-one was convertedls2 into 24-hydroxychol-4-en-3-one in one step by treatment with CF,C0,H-H2S04 at
(186) 0 "C. A key step in the stereoselective synthesis of 24,25- and 25,26-dihydroxycholesterol is the asymmetric reduction of the A25-24-oxo-compound(188) using a complex of LiAlH, and optically active 2,2'-dihydroxy-1,l'-binaphthyl. Thus, the reduction of (188) with the R-( +)-dihydroxybinaphthyl gave largely the alcohol (1 89) which was converted into the diols (190) and (19 1) as indicated in Scheme 4.1s3 A Claisen rearrangement, effected by treatment of the deuteriated substrate (192) with ethyl orthopropionate led to the 24-deuterio-ester (1 93) which was converted A novel synthetic approach to the into [24R-2H]-25-hydroxyprovitamin ecdysone side chain was demonstratedls5 with pregnenolone acetate, which was reported to react with 2-lithio-5-methylfuran to give, after reacetylation, the AZ0-
162
laa 164 165
V. Pouzar and M. Havel, Collect. Czech. Chem. Commun., 1980, 45, 2443. R. P. Manley, K. W. Curry, N. C. Dens, and M. D. Meyer, J. Org. Chem., 1980,45,4385. M . Ishiguro, N. Koizurni, M. Yasuda, and N. Ikekawa, J. Chem. Soc., Chem. Commun., 1981, 115. J. D. Meadows and D. H. Williams, Tetrahedron Lett., 1980, 21, 4373. T. Kametani, M. Tsubuki, and H. Nemoto, Tetrahedron Lett., 1981, 22, 2373.
Steroid Reactions and Partial Syntheses
315
ji
iiii
?H
(191) (190) Reagents : i, VO(acac),-Bu'OOH ; ii, K,CO,-PrOH ; iii, LiAIHo
Scheme 4
(192)
furanoid (194). This compound, on hydrogenation, gave the 20s-furanoid (195). Acid-catalysedcleavage of the furan ring followed by reacetylation gave the diketone (196) which was converted into the 22,25-diols with the cholestane side chain. A novel route was reported166for the conversion of diosgenin into a-ecdysone and material labelled with tritium at positions 15 and 16 was prepared. Two independent
188
Y.-W.Lee, E. Lee, and K. Nakanishi, Tetrahedron Lett., 1980, 21, 4323.
316
Terpenoids and Steroids
( I 94)
syntheses of brassinolide (198) were r e p ~ r t e d ~and ~ ~the J ~essential ~ steps for the construction of the side chain from the aldehydes (170)16' and (197)168are shown in
i
Reagents : i, [BuMe,AlCH=CMePr']Li; ii, MCPBA; iii, LiBH,-BH,
Scheme 5
1
iii, iv
v, vi
Reagents: i, Me,CH-C = CLi ; ii, Lindlar catalyst-H2; iii, Bu'OOH-VO(acac),; iv, Ac,Opyridine; v, HCN-Et3A1; vi, KOH
Scheme 6 16' 168
S. Fung and J. B. Siddall, J. Am. Chem. Soc., 1980, 102, 6580. M. Ishiguro, S. Takaksuto, M. Morisaki, and N. Ikekawa, J . Chem. SOC.,Chem. Commun., 1980,962.
317
Steroid Reactions and Partial Syntheses
Schemes 5 and 6 respectively.Reformatsky reaction of 3@,21-diacetoxy-pregn-5-en20-one (199) was reported169to give the 20-acetoxy- and 20-hydroxy-lactones(200) which were converted into 3@,23-diacetoxy-24-norchol-5-ene via hydrogenation of the A20-compound(201) allowing incorporation of isotopic label at C-20 and C-21. OAc
&
AcO
(200) R
=H
or Ac
@-' & iii, iv
0 R
H
(203) Reagents: i, R-C
=CMgBr; ii, POC1,-pyridine;
iii, MPA; iv, HC0,H-H20
Scheme 7 169
A. M. Seldes, C. R. Anding, and E. G. Gros, Steroids, 1980, 36, 575.
318
Terpenoids and Steroids
Ruscogenin was converted into 1p-hydroxy- and 1a-hydroxy-cholesterol derivat i v e ~3~,6~-Dihydroxy-5a-cholest-7-ene ,~~~ and the 6a-epimer were prepared from comparison with the aglycone (202) of sepositoside A.171Preparation of 7-dehydrocholesteryl acetate free of the A4v6-dienewas accomplished by heating the A5-7@phenylsulphoxide which was obtained by oxidation of the sulphide which was in turn prepared, in admixture with a small amount of the 7a-epimer, by sequential treatment of cholesteryl acetate with dibromantin-NaHCO,, LiBr, and Et,NPhSH.1723-Acyl-2-oxo-5cc-cholestanes(203) were reported173to be prepared from 5a-cholestan-3-one by the sequence shown in Scheme 7 and 3-alkyl-2-oxo-Sacholestanes were obtained by direct alkylation of the 2-oxo-compound.174Syntheses were reported175for [6a-2H]- and [6p-2H]cholest-4-en-3-onesusing slight modifications of existing procedures. Full characterization of 5-chloro-5p-cholestane was r e ~ 0 r t e d . The l ~ ~ synthesis of 9a-fluoro-3P-hydroxy-Sa-cholest-8( 14)-en-15-one involved the reaction with HF of the equivalent 9a-hydroxy-compound (205) which was synthesized by reaction of the ethyl dienol ether (204) with MCPBA-NaHC0,THF-H,O followed by hydr01ysis.l~~ All four possible 7-hydroxy-5,6-methylenecholestanes were synthesized from cholest-5-en-7-0ne.l~~The cc-methylene-ybutyrolactone (206) was to be the major epimer of the mixture obtained from the Reformatsky reaction of 5a-cholestan-3-one and ethyl bromomethacryldte.
10 Vitamin D, Its Metabolites, and Related Compounds Totally synthetic approaches to vitamin D and its relatives are presented in the Simonsen 1ecture.lB0Two syntheses of 25,26-dihydroxycholecalciferolhave been reported and establish the 25s-configuration for the natural metabolite,181~182 and the 25R-configurationlB2for the previously synthesized 25,26-dihydroxycholesterol, l70 171
172 173 174 176 176
177
178 178
180 181
M. Noam, I. Tamir, E. Breuer, and R. Mechoulam, Tetrahedron, 1981, 37, 597. F. De Simone, A. Dini, E. Finamore, L. Minale, C. Pizza, R. Riccio, and F. Zollo, J. Chem. SOC.,Perkin Trans. 1, 1981, 1855. P. N. Confalone, I. D. Kulesha, and M. R. UskokoviC, J. Org. Chem., 1981, 46, 1030. H. Berbalk, K. Eichinger, and R. Schuster, Synthesis, 1981, 613. C. A. Horiuchi and J. Y. Satoh, Can. J. Chem., 1981, 59,2382. D. J. Collins, W. R. Jackson, and R. N. Timms, Aust. J. Chem., 1980, 33, 2767. C. W. Snoppee, R. J. Hart, and M. E. H. Howden, J. Chem. SOC.,Perkin Trans. I , 1980, 1904. E. J. Parish and G. J. Schroepfer Jr., J. Org. Chem., 1980, 45, 4035. L. Kohout, Collect. Czech. Chem. Commun., 1981, 46, 1828. G. Schlewer, J.-L. Stampf, and C. Benezva, J. Med. Chem., 1980, 23, 1031. B. Lythgoe, Chem. Suc. Rev., 1980, 9, 449. R. Barner, J. Hubscher, J. J. Daly, and P. Schonholzer, Helv. Chim. Acta, 1981, 64, 915. J. J. Partridge, S.-J. Shiuey, N. K. Chadha, E. G. Baggiolini, J. F. Blount, and M. R. UskokoviC, J. Am. Chem. SOC.,1981,103,1253.
Steroid Reactions and Partial Syntheses
319
which was believed to have the 25s-configuration. A key step in the synthesis of (24R)-24,25-dihydroxycholecalciferolwas the reaction of the epoxide (208) with the
(210) sulphone (209), which led to the diol sulphone (210). The epoxide(208) was obtained from the tosylate (207) which was synthesizedfrom D-glyCeriC acid.ls3A synthesis of calcitroic acid (21 1) involved184the previously reported direct hydroxylation procedure of vitamin D and related compounds which was also reported in full.lS5JS6
HO'
(213) R = SiMe,But (214) R = MeOCH, Three syntheses were r e p ~ r t e d l ~ for~ -25-hydroxycholecalciferol-26,23-lactone ~~~ (216) which was assigned1E8~1Eg the 23R,25S-configuration. The most stereoselective of these syntheseslsginvolves the LDA-catalysed reaction of the sulphone (212) with the aldehyde (213) to give the hydroxy-sulphone (215) which was modified as in Scheme 8 to give the required side chain. The sulphone (212) was derived from S-citramalic acid. Reaction of the trideuterio-Grignard reagent (217), which was derived from S-lactic acid, with the aldehyde (214) led to 25R-[26-2H,]las 18*
H. Takayama, M. Ohmori, and S. Yamada, Tetrahedron Lett., 1980, 21, 5027. R. P. Esvelt, M. A. Fivizzani, H. E. Paaren, H. K. Schnoes, and H. F. DeLuca, J . Org. Chem., 1981,46,456.
H. E. Paaren, H. F. DeLuca, and H. K. Schnoes, J . Org. Chem., 1980,45,3253. See Reference 21, p. 253. la7 J. K. Wichmann, H. E. Paaren, M. A. Fivizzmi, H. K. Schnoes, and H. F. DeLuca, Tetruhedron Lett., 1980, 21,4667. la8D. S . Morris, D . H. Williams, and A. F. Norris, J . Chem. SOC., Chem. Commun.,1981, 424. lagS. Yamada, K. Nakayama, and H. Takayama, Tetrahedron Lett., 1981, 22, 2591. IE5
320
Terpenoids and Steroids
b,
(215)
iii, iv
Reagents: i, Na-Hg ;ii, TsOH-H,O; iii, Ac,O-pyridine; iv, EtOH-PPTS; v, DMSO-pyridineSO3-Et3N; vi, 1,KOH; vii, 1,MeCN; viii, Bu,SnH
Scheme 8
cholecalciferol.190Methylation of the SO2 adducts of cholecalciferol with NaH occurred regioselectively at C-6 whereas with lithium tetramethylpiperidide the reaction was directed to C-19.1g1Extrusion of SO, (NaHC0,-EtOH-90 "C)from
the 6-methyl-derivatives was reported to give mainly the 6-methyl-previtamin whereas the reaction with the 19-methyl-derivatives gave mainly the 19-methyl-5,6trans-vitamin. Irradiation and heating of 19-acetoxy-7-dehydrocholesterylacetate and the 19-methoxy-analogue led to the E-vitamin D, analogues (218) and (219) respectively,la2 whereas 19-hydroxy-7-dehydrocholesterylfragmented to give 19-n0r-A~(lO)?~-diene (221) via a 1,7-hydrogen shift as indicated in (220). The full account was reportedlg3 for the vinyl allene approach to 3-deoxy-1-hydroxyM.R.Lindley and D. H. Williams, Tetrahedron Lett., 1980, 21,4377. S. Yamada, T.Suzuki, and H. Takayama, Tetrahedron Lett., 1981, 22, 3085. l s a R. M. Moriarty and H. E. Paaren, J. Org. Chem., 1981, 46, 970. l B 3 P. Condran Jr., M. L. Hammond, A. Mourifio, and W. H. Okamura, J. Am. Chem. SOC., 1980,102,6259. lgo lgl
Steroid Reactions and Partial Syntheses
321
cholecalciferol and the study was extendedlg4to include the synthesis of 3-deoxy3,3-dimethyl- l-hydroxycholecalciferolsfrom the thermolysis of the vinyl allenes (222) and (223).
-
Act (218) R = AC (219) R = Me
(222) R1= OH, R2= H
(223) R'
=
H, R2= OH
11 Pregnanes Three new approaches to the construction of the dihydroxyacetone side chain were rep~rted.~ Pregenolone ~ ~ J ~ ~ was oxidized with PhIO-KOH-MeOH to the hydroxyacetal(224) which, after acetylation and heating in xylene with toluene-p-sulphonic acid, gave the acetoxy-enol ether (225). Oxidation (MCPBA) and hydrolysis gave the required compound (266).lg5The other two routes which started with 17-oxosteroids are outlined, in part, in Schemes 9lQ6and Tetrazolium salts were
(224)
(225)
(226)
reported to be oxidizing agents suitable for the conversion of 21-hydroxy-20-0~0steroids into the 20-hydroxy- or 20-oxo-21-oic a ~ i d s . 1 ~ A~synthesis was reportedlg9 (Scheme 11) of 1l-deoxyaldosterone from the exo-epoxide mixture (227) which was ls4
A. Mourifio, S. Lewicka-Piekut, A. W. Norman, and W. H. Okamura, J . Org. Chem., 1980, 45,4015.
R. M. Moriarty, L. S . John, and P. C. Du, J. Chem. SOC.,Chem. Commun., 1981, 641. D. H. R. Barton, W. B. Motherwell, and S. Z. Zard, J. Chem. SOC., Chem. Commun., 1981, 774. 1 @ 7 L. Nkdelec, V. Torelli, and M. Hardy, J. Chem. SOC., Chem. Commun., 1981, 775. 198 M. A. Smoczkiewicz qnd J. Jasiczak, Synthesis, 1980, 739. lSs M. Miyano, J. Org. Chem., 1981, 46, 1846. lS5
196
322
Terpenoids and Steroids
Reagents : i, (EtO),POCH(NC)Me-KH ; ii, HCO,H ; iii, Pb(OAc),; iv, pyridinium bromide perbromide; v, H,O+; vi, KOAc
Scheme 9
{go OAc
___, ii, iii
d iv
{
~
A
c
Reagents: i, CNCH2C02Et-Bu'OK; ii, LiAIH,; iii, Pb(OAc),; iv, H,O+
Scheme 10
&
($
CH20H ii,iii
i +
-
?OH2.-
p,
0
v
(227)
1 1-deoxyaldosterone
Reagents: i, LiNEt2-THF; ii, , Ac,O-pyridine ; iii, N-methylmorpholine N-oxide-Os0,Bu'OH-THF-H,O; iv, NaIO,; v, K,CO,
Scheme 11
obtained from the methylene cyclobutane (7).16 The hypoiodite reaction of 20hydroxy-pregnaneswas a key step in the synthesesof 1 8-hydroxycorticosterone200~201 and in the syntheses of 21-deoxy-3a,5~-tetrahydroaldosterone (228)202and 3a,5p-
2*1 202
D, N. Kiik and C. J. Slade, J . Chem. SOC.,Perkin Trans. 1, 1980, 2591. D. N. Kirk and C. J. Slade, J. Chem. SOC.,Perkin Trans. I , 1981, 703. D. R.Crump, D. N. Kirk, and B. W. Miller, J. Chem. SOC.,Perkin Trans. I , 1980, 2597.
323
Steroid Reactions and Partial Syntheses
tetrahydroaldosterone (229).?-03 The 21-hydroxy-compound (229) was obtained from deprotection of the derivative (231) which was in turn obtained from (230) by the sequence shown in Scheme 12.
& &[g Meo
\ OSiMe,
5 (231)
RO-=
(228) (229) (230) (231)
R1= Rz= R3= H R1= R2= H, R3 = OH R1= THP, Rz= Me, R3 = H R1= THP, R2= Me, R3 = OH
Reagents: i, LDA-TMSCI; ii, MCPBA
Scheme 12
The hydroxy-lactone (233) was obtainedzo4by treatment of the 16,17-epoxy-200x0-21-acetate (232) with KOBut. The trifluoroacetoxypregnan-20-ones(234) were converted into the spirofuranones (235) with DBU in benzene.205The conversion
(232) of 15a-hydroxy-l l-oxo-progesterone to 3p, 1 1a, 15p-trihydroxypregn-5-en-20-one has been reported.20s The synthesis of (20R)-5ct-pregn-9(11)-ene-3p,6a,20-triol, a minor starfish sterol, was reported from ll-oxoprogesterone.zo7A key step in the synthesis of 10P-ethenyl-hydrocortisoneacetate is the addition of LiC 3 CH to the 5,lO-epoxide (236).208Syntheses of 10-norprogesterone and 19-nordeoxycortiA series costerone have been reported from 19-norandrost-4-ene-3,17-dione.z09 of hormonally active D-homopregnanes has been synthesized210 and c-homo20a 204
D. N. Kirk and B. W. Miller, J. Chem. Soc., Peikin Trans. I , 1980, 2818. K. AMen, H. Hofmeister, H. Laurent, K. Petzdolt, A. Seeger, and R. Wiechert, Chem. Ber., 1980,113,3827.
G. Ortar and E. Morera, J. Org. Chem., 1981, 46,452. G. R. Weihe and T. C. McMorris, Steroids, 1981,37,291. 207 J. W. ApSimon, S. Badripersaud, J. A. Buccini, J. Eenkhoorn, and M. W. Gilgan, Can. J. Chem., 1980,58,2703. 208 G. Teutsch and C. Richard, J. Chem. Res. (S), 1981, 87. 209 C.-Y. Byon and M. Gut, J. Org. Chem., 1980, 45,4403. 210 M. Muller, L. Alig, P. Keller, A. Furst, U. Kerb, and R. Wiechert, Web. Chim. Actu, 1980,63,
206 20*
1867.
324
Terpenoids and Steroids
(236)
compounds were obtained from hecogenin, the ring expansion being achieved by a Demjanov reaction on the 12-aminomethyl-12-hydro~y-derivative.~~~
12 Androstanes and Oestranes The Claisen rearrangement of the A5-vinyl ether (237) provided the aldehyde (238) which was modified to give the ethynyl derivative (239) and the allene (241) was prepared from the acetoxy-ethynyl derivative (240) through a mixed cuprate-
B
e o
hP
0
mediated reductive elimination.212Further studies were reported in the preparation of D-nor-androstanes from p,y-unsaturated diazoketones in the d i t e r p e n e ~ A .~~~ number of 4,5-seco- and ~-nor-3,5-seco-androstanes were ~ynthesized.~l* An extension was reported215of the preparation of 11p-substituted compounds (242) through reaction of A9 (11)-5,10-epoxides with lithium organocuprates.216A 212
G. Haffer, U. Eder, G. Neef, G. Sauer, and R. Wiechert, Annulen, 1981, 425. B. W. Metcalf, C. L. Wright, J. P. Burkhart, and J. 0.Johnston, J. Am. Chem. SOC.,1981,103,
213
P. Ceccherelli, M. Curini, M. Tingoli, and R. Pellicciari, J. Chem. SOC.,Perkin Trans. 1, 1980,
211
3221. 1924. 214 216
A. Kasal, Collect. Czech. Chem. Commun., 1980, 45, 2541. A. Belanger, D. Philibert, and G. Teutsch, Steroids, 1981, 37, 361.
325
Steroid Reactions and Partial Syntheses
synthesis of 16a-hydroxy-~-nor-5a-oestran-2-one involved regioselective hydroboration of a AIG-derivativewith di-isoamylborane.216 The synthesesof 1l-hydroxy9a- and -9p-oestrones were reported217and an investigation into stereoselective routes to 14,15,17-trisubstituted oestra-l,3,5(10)-trienes from the A14-compounds demonstrated that both the 17@-acetoxy-14a,l5a-epoxideand its 14@,15@-epimer gave largely the 14p-15-oxo-compound.218 Oestriol 16-glucuronidewas synthesized through reaction of 2,4-dibromo-16a-hydroxyoestrone with methyl l-bromo-ldeoxy-2,3,~-tri-~-acety~-a-~-pyranosuronate.~~~ 13 Cardenolides
Further studies in the synthesis of 14-deoxy-14a-strophanthidinwere reported.220v221 A new synthesis of 15-hydroxy-cardenolidesinvolved the addition of 2-methoxy-4fury1 lithium to A 1 5 - 1 7 - ~ ~ ~ - ~ ~asmap key ~~n step.222 d ~ A novel approach to cardenolides from 17-0x0-steroids is outlined223in Scheme 13. Anhydroxysmalo-
+ vi
vii, viii
Reagents: i, NCCH,CO,Et-base; ii, NaBH,; i i i , vii, SOC1,-pyridine; viii, Li,CO,-DMF
8
I -H+; iv Bu',AlH; v, HCN; vi, HCI;
Scheme 13
genin was from the A5~14-diene-20-oxo-compound (244) which was obtained from the enone (243). An improved synthesis225of 14p-hydroxy-cardenolides from the A 1 4 - ~ ~ m pinvolved ~~nd~ sequential reaction with NBA and Bu3SnH. Syntheses of the saturated lactones (245)226and their a,@-unsaturatedanalogues227 21@
21*
$lQ
220 221
222
233 224
aa6
J. Canceill and J. Jacques, Bull. SOC.Chim. Fr., 1980, 468. R. B. Gabbard, L. F. Hamer, and A. Segaloff, Steroid, 1981,37,243. J. R. Bull and J. Floor, J. Chem. SOC.,Perkin Trans. I , 1981, 437. M. Numazawa, M. Nagaoka, M. Tsuji, and Y .Osawa, J. Chem. SOC.,Chem. Commun., 1981, 383. P. KoEovskg, Collect. Czech. Chem. Commun., 1980, 45,2998. See Reference 6, p. 222. R. Marini-Bettolo, P. Flecker, T. Y. R. Tsai, and K. Wiesner, Can.J. Chem., 1981, 59, 1403. A. Kurek, M. Gumulka, and J. Wicha, J. Chem. SOC.,Chem. Commun., 1981, 25. P. KoEovskY and V. Cerny, Collect. Czech. Chem. Commun., 1981,46,446. C. R. Engel and D. Mukherjee, Steroid, 1981, 37, 73. V. Pouzar and M. Havel, Collect. Czech. Chem. Commun., 1981,46, 107. V. Pouzar and M. Havel, Collect. Czech. Chem. Commun., 1981, 46, 917.
12
326
Terpenoids and Steroids
and of the methylene lactones (246)226were reported. Methylation of digitoxigenin led228to the cardenolides (247)-(250) and the syntheses of the y-steroidyl buten-
0
6'.
{ (247) (248) (249) (250)
OH
R1= H, R2= p-Me R1 = H, R2= a-Me R1 = Me, R2 = H R1 = Me, R2 = Me
(251) (252) (253) (254)
R' = R2 = H, 20p-H R1 = R2 = H, 20a-H R1 = Me, R2 = H R1 = H, R2 = Me, 203-H
olides (25 1)-(254) were reported.229The p-steroidyl crotonate methyl esters (255) and (256) were synthesized from the 14~-hydroxy-20-oxo-compound.230 kCHC02Me 3-OAc
220
230
\ ,.CHCO,
@
C. Lindig and K. Kepke, J. Prakt. Chem., 1980, 322,991. F. Theil, C. Lindig, and K. Repke, J. Prakt. Chem., 1980, 322, 1003. F. Theil, C. Lindig, and K. Repke, J. Prakt. Chem., 1980, 322, 1012.
327
Steroid Reactions and Partial Syntheses 14 Heterocyclic Steroids
Reaction of 2a,3a-epoxy-5a-androstanewith CF3C02H and the thiazolidine-2thione (257) gave 2@,3f~epithio-Sa-androstane.~~~ The reactions of 2-aminobenz-
U k S NH -.
1
(257)
(258)
imadazole with 2-hydroxymethylene-3-oxo-androstanes were reported232to give the pyrimidobenzimidazoles (258). The reaction between 2-mercaptoimidazole and 2a-bromo-5a-cholestan-3-one in ethanol gave the imidazothiazole (259) and the ethanol adduct (260) and similar reactions were observed with 2-mercaptobenzimidazole and 3-rnercapt0-1,2,4-triazole.~~~ Similar reactions occurred between
(259) (260) 16a-bromo-oestrone methyl ether and 3-mercapto-1,2,4-triazole and its 5-methyl derivative, but with 2-mercaptoimidazole simple displacement of the bromine was observed. In NaHC0,-DMSO, 16a-aminomethyl- and 16a-benzyIarninomethy13-methoxy-17~-tosyloxyoestra-l,3,5(10)-trieneunderwent cyclization to the tetrahydro-oxazin-2-ones(26 1) and (262) respectively.234Tomatidine was converted into the (22S,25S)-N-methyl-derivative stereospecifically,whereas solasodine led to and the (22S,25R)-N-methyl-deriva mixture of the (22RY25R)-N-methyl-derivative a t i ~ e .Treatment ~~~ of 17p-acetoxy-17a-ethynyl-steroids with NOF-NOBF, gave236the diacylfuroxans (263) which on thermolysis gave the acylnitrile oxides (264) which could be trapped with suitable d i p o l a r o p h l e ~ A , ~ ~synthesis ~ of 26-(3-methylindol-l-yl)cholesterolwas Hexachlorotriphosphazene was to react with a variety of steroidal alcohol sodium salts to give the substituted derivatives (265). Organopalladium complex-catalysed coupling of acetylenic organozincs with 5-iodo-3’,5’-0-bis(trimethylsilyl)deoxyuridinegave 5-alkynyl-2’-deoxyuridinesand was exemplified by the preparation of the steroidal example (266).240 R. C. Cambie, G. D. Mayer, P. S. Rutledge, and P. D. Woodgate, J. Chem. SOC.,Perkin Trans. 1, 1981, 52. 232 J. S.Bajwa and P. J. Sykes, J. Chem. SOC., Perkin Trans. 1, 1980, 1859. 2S3 J. S. Bajwa and P. J. Sykes, J . Chem. SOC.,Perkin Trans. 1, 1980, 2146. 234 G. Schneider, L. Hackler, and G. Dombi, J. Chem. SOC.,Chem. Commun., 1980, 891. 235 H. E. Gottleib, I. Belic, R. Komel, and M. Mervic, J. Chem. SOC., Perkin Trans. I , 1981, 1888. 236 D.R.Britteli and G. A. Boswell Jr., J. Org. Chem., 1981, 46, 312. 237 D.R.Britteli and G. A. Boswell Jr., J . Org. Chem., 1981, 46, 316. 2s8 T. Arunachalam, P. J. MacKouI, N. M. Green, and E. Caspi, J. Org. Chem., 1981, 46,2966. 239 H.R.Allcock, T. J. Fuller, and K. Matsumura, J. Org. Chem., 1981,46, 13. 240 P. Vincent, J.-P. Beaucourt, and L. Pichet, Tetrahedron Lett., 1981, 22,945. 231
328
Terpenoids and Steroids
(261) R
=
H
(262) R
=
CH,Ph
C1 O-Steroid
deoxyribose I CI-P,
/ N ‘’
c1
P-Cl Me0
15 Microbiological Reactions
Further studies were r e p ~ r t e d ~on ~ lthe ? ~degradation ~~ of deoxycholic acid with Pseudoinonas species. Side chain-degraded products, for example the hydroxydiene-dione (267), appeared to be important. Digoxin was reported as the main degradation product from Streptomyces mediated modification o f d i g i t o ~ i n . ~ 4 ~
Other products were 7p-hydroxydigitoxin and 7P-hydroxydigoxin. .Microbial transformation of [ 16~-~H]-precursors gave [16~-~H]androstenedione and [16ce3H]o e ~ t r a d i o lIt. ~was ~ ~reported that Tenebrio molitor was able to convert the 24R,28Sisofucosterol epoxide into cholesterol more readily than the 24S,28R-isomer, whereas no significant difference was observed for the reactivities of the 24,213fucosterol e p o x i d ~ sIncubation .~~~ of phytosterol mixtures with a mutant strain of Mycobacterium fortuiticrn resulted246in the accumulation of novel 24-oxo-steroids L41 242 243
?44
245
246
R. A. Leppik, Tetrahedron, 1981, 37, 1747. R. F. Bilton, A. N. Mason, and M. E. Tenneson, Tetrahedron, 1981,37, 2509. Z. Szeleczky, M. Soti, G . Horvith, and K. Albrecht, Steroids, 1981,38, 11. R. Cantineau, P. Kremers, J. De Graeve, A. Cornelis, P. Laszlo, J. E. Gielen, and R. Lambotte, Steroids, 1981, 37, 177. F. Nicotra, P. Pizzi, F. Ronchetti, G. Russo, and L. Toma,J. Chem. Soc., Perkin Trans.I, 1981, 480 J. C. Knight and M. G. Wovcha, Steroids, 1980, 36, 723.
Steroid Reactions and Partial Syntheses
329
for example (268) (269). An aerobic, concentration dependent, reduction of A4-3-oxo-androstanes and -pregnanes to the 5 P-3-oxo-analogues was reported with Clostridium paraputrifactum. 247 The thermophilic bacterium Caldariella acidophila was reported to convert progesterone into a number of 6-oxygenated derivati~es.~4* Hydroxylation of B-nortestosterone and related compounds with Rhizopus arrhizus ATCC11145 gave a product range which suggested that the stereochemistry of oxidation at C-6 was controlled by stereoelectronic effects in the substrate.249 [3-180]Testosterone was reported to be transformed to oestradiol by human placental microsomes and to the 68- and I 1P-hydroxy-derivatives by Rhizopus arrhizus without significant loss of the oxygen label, suggesting that neither process involves reversible Schiff base formation at C-3.250The major products from incubation of androst-4-enes and androst-5-enes with Cunninghamella elegans arose from allylic and those from Sa-androstan- 17-oneswere reported252 to arise from 1 p,7-dihydroxylation or 7-hydroxylation. Under similar conditions, 17a-aza-~-horno-5a-androstan17-ones underwent monohydroxylation at positions 6p-, 7a-, or 9a- dependent upon substituents at C-3.252
24i
248 240 250
251 2j2
A. Fauve and A. Kergomard, Tetrahedron, 1981, 37, 899. M. De Rosa, A. Gambacorta, G . Sodano, and A. Trabucco, Experientia, 1981, 37, 541. H. L. Holland, Can. J. Chem., 1981, 59, 1651. H. L. Holland and G . J. Taylor, Can. J . Chem., 1980, 58, 2326. T. A. Crabb, P. J. Dawson, and R. 0. Williams, J . Chem. SOC.,Perkin Trans. I , 1980, 2535. T. A. Crabb, J. A. Saul, and R. 0. Williams, J. Chem. SOC,Perkin Trans. I , 1981, 1041.
Author Index Abdel-Magid, A., 310 Abdel Salam, N. A,, 102 Abe, F., 59 Abe, H., 312 Abe, K., 266 Abiko, A., 29, 79 Abraham, W.-R., 75, 174 Abryutina, N. N., 286 Abubakirov, N. K., 234 Accrombessi, G., 39 Achari, B., 172 Acharya, S. P., 6 Achenbach, H., 58 Acklin, G., 304 Acton, N., 249 Adam, G., 198 Adam, W., 38 Adams, R. P., 73 Addae-Mensah, I., 58 Adesogan, E. K., 59, 60 Adesogan, K. A., 189 Adinolfi, M., 21 1 Adlercreutz, H., 281 Adolf, W., 200 Adriani, C., 59 Afifi-Yazar, F. U., 5, 59 Agami, C., 298 Agarwal, P. K., 115 Agarwal, S. G., 211 Ager, D. J., 34 Ageta, H., 225 Aggarwal, R. C., 39 Agosta, W. C., 25 Agurell, S., 66 Ahem, D. G., 254 Ahmad, I., 174 Ahmad, M. S., 307 Ahmad, V. U., 225 Ahmed, M., 88, 111, 115, 146,156,169,188,189,196 Ahmeij, M., 66 Ahn, B. Z., 59 Ai, T.-H., 215 Aimi, N., 232 Akelah, A., 288 Akhila, A., 39, 68 Akhmetov, L. I., 12, 48 Akimaliev, A. A., 234 Akimoto, K., 135 Akinniyi, J . A., 146, 216 Akita, H., 85, 193, 194, 259 Akiyama, T., 60, 61, 215, 277 Akporiaye, D. E., 303 Akutogawa, S., 42
Alazard, J.-P., 303 Albert, K., 146 Alberte, R. S., 239 Alberti, A., 7 Alberts, V., 38 Albone, K. Y. S., 197 Albrecht, K., 328 Albrecht, P., 225 Albini, A., 309 Alcaide, B., 278 Alder, A. P., 255 Alderice, M., 31 Al-Ekabi, H. K., 198 Alfano, R. R., 259 Ali, H., 284, 307 Ali, S. M., 299 Alibaeva, Kh. A., 230 Alig, L., 323 Alimbaeva, P. K., 234 Allan, A. E., 257, 259 Allcock, H. R., 327 Allen, M. S., 45, 48 Alper, H., 46, 302 Alshuth, T., 258 Alvarez, R. A., 255 Amico, V., 186, 201 Amin, B., 246 Amiya, T., 115 Amouroux, A., 27 Anandaraman, S., 42 Anastasia, M., 312 Andenaert, F., 39 Anding, C., 207 Anding, C. R., 317 Ando, M., 157 Andreetti, G. D., 61 Andreis, P., 45 Andrews, G. C., 45 Andrianov, V. G., 6 Andrieu, C. G., 4, 5 Andrus, A., 205 Anglister, J., 258 Anjaneyulu, A. S. R., 214, 226,230 Ankudinova, T. V., 255 Annen, K., 323 Annis, G. D., 129,295 Ansell, M. F., 52 Antbarjanam, T. G. B., 18 Antipin, M. Ya., 272 Antkowiak, R., 45 Antkowiak, W., 45 Anufriev, V. F., 216 Aoki, S., 19, 62 Aoki, T., 72, 234
w.,
252 Appeldoorn, ApSimon, J. W., 228, 323 Aragon, C. M. G., 262 Aranda, J. C., 204 Arata, K., 37,42, 51 Aratani, T., 40, 89 Arbuzov, B. A., 43, 5 5 , 56, 57 Argade, P. V., 258 Argyriadou, N., 44 Arigoni, D., 140, 209 Arita, M., 31, 264 Ariwa, M., 176 Arlt, D., 61 Amaboldi, M., 247, 260 Arnold, E. V., 196 Arnoux, B., 219 Arora, A. K., 14 Aruldhas, G., 278 Arunachalam, T., 327 Arvidson, G., 258 Asakawa, Y., 73, 8 5 , 158, 172, 183, 184 Asano, S.,62 Ashref, M., 31 Aslanov, K. A., 188 Atal, C. K., 15, 33, 211 Atimoshone, M. V., 195 Atkinson, G. H., 257 Atopkina, L. N., 216 Atsumi, K., 183 Attwell, M. C., 271 Atwal, K. S., 3 11 Audenaert, F., 178 Aulchenko, I. S., 20, 34 Avery, M. A., 60, 99 Avetisyan, G. M., 230 Aviv, D., 72 Ayafor, J. F., 221 Ayengar, K. N. N., 228 Ayer, W. A., 124, 127, 128, 131, 134, 202 Baas, P., 255 Babin, D., 16, 39, 64, 89 Babler, J. H., 25, 64 Bachner, J., 47 Back, T. G., 302 Baddeley, G. V., 21 5 Badripersaud, S., 323 Badruddoza, S., 193 Bagan, E., 291 Baggiolini, E. G., 318 Bailey, T. R., 42, 297
33 1
Author Index Bailleul, F., 58, 59 Baines, D. A., 55 Bajwa, J. S., 327 Baker, P. M., 215 Baker, R., 23, 77, 81 Bakunin, V. N., 49, 51 Bakuzis, M. L. F., 43 Bakuzis, P., 43 Bal, B. S., 24, 36, 38 Balashov, S. P., 259, 260 Balasubramanian, V., 308 Balci, M., 32 Baldwin, J. E., 91 Baldwin, S. W., 60 Balliano, G., 215 Balogh-Nair, V., 247, 259, 260 Balsevich, J., 54, 160 Bambagiotti, A. M., 5 Band, P. R., 255 Bandrauk, A. D., 257 Banerjee, A. K., 204 Banerjee, D. K., 270, 271 Bang, L., 21 1 Banks, R. E., 98 Bano, S., 225 Banou, T., 14 Bansal, R. K., 192 Banthorpe, D. V., 4, 13, 39, 63,68 Bapuji, M., 158 Baragliu, A., 37 Barany, F., 25 Baranyai, M., 256 Barba, R., 45 Barbara, P. F., 259 Barden, T. C., 91 Bardyshev, I. I., 45, 5 5 Barer, D. G., 42 Bari, S. S., 18, 206 Barker, A. J., 105 Barkhan, P., 266 Barnard, G., 285 Barner, R., 269, 318 Barnett, R., 255 Barnette, W. E., 43 Barrero, A. F., 48, 118 Barrett, A. G. M., 292, 301, 302 Barrick, R. C., 232 Barron, L. D., 5 Barros Papoula, M. T., 296 Barrow, S. E., 13 Barth, G., 51, 52 Bartlett, A. J., 87 Bartlett, P. A., 27, 34 Barton, D. H. R., 35,37,213, 292, 296, 299, 301, 302, 321 Barua, A. B., 263 Barua, A. K., 187,226, 230 Baruah, R. N., 146 Basak, A., 187, 227 Bateho, A. D., 312
Bates, P., 15 Bates, R. B., 219 Battaglia, R., 135 Battalova, S., 49 Battegay-Nussbaumer, Y ., 243 Battersby, A. R., 70 Bax, A., 274 Baxter, R. L., 86 Bayley, H., 260 Bazylchik, V. V., 13, 33 Beal, J. L., 4 Beale, M. H., 198, 228 Bearder, J. R., 198 Beaucourt, J.-P., 327 BeauLaire, J., 174 Beaulieu, P., 21 Beaupin, C., 60 Becchi, M., 280 Beck, J.-P., 211 Becker, J. J., 51 Becker, R. S., 258 Bedi, A. L., 21, 39 Bedour, M. S., 277 Beecham, A. F., 277 Begley, M. J., 146 Begue: J. P., 9 Beier, R. C., 106 Bekhtereva, M. N., 261 Bekker, A. R., 247 Belanger, A., 324 Belanova, E. P., 33 Beletskaya, I. P., 49, 51 Belic, I., 327 Bell, A. A., 106 Bell, K. H., 46 Bellesia, F., 61 Bellido, I. S., 32 Bellus, D., 64 Beloeil, J.-C., 270, 297 Belousova, L. I., 46 Below, P., 33 Belozerskaya, T. A., 262 Belyaeva, M. E., 55 Ben-Ari, C., 276 Benayoun, J., 74 Bendall, M. R., 58, 60 Benezva, C., 318 Benko, A. B., 283 Bennett, N., 259 Bennett, R. D., 221 Bensasson, R. V., 243 Bensel, N., 11 Bentley, R., 266 Benveniste, P., 210 Ben-Zvi, Z., 66 Berbalk, H., 318 Berg, D., 283 Berger, D. E., 312 Berger, Y., 208 Bermejo, J., 146 Bernard-Dagan, C., 4, 74 Bernardini, A., 114 Bernasconi, S., 184, 194
Bernays, E., 57 Bernhard, K., 237, 240 Berry, R. A., 261 Berti, C., 52 Bertran, J. F., 5 Bertrand, C., 42 Bertranne, M., 270, 297 Besai, D. N., 39 Besner, J. G., 255 Bessiere, Y., 3 Best, W. M., 110 Bestmann, H. J., 249 Betancor, C., 226 Bettolo, R. M., 61 Bevelle, C. A., 146 Beydon, P., 282 Beyer, P., 261 Bezzubov, A. A., 256 Bhadbhade, M. M., 193,271 Bhagwat, S. S., 121 Bhardwaj, T. R., 271 Bhat, N. E., 55 Bhat, N. G., 57, 64 Bhat, U. G., 146 Bhatt, M. V., 300 Bhatta, A. K., 312 Bhattacharyya, S. C., 65, 66 102, 104 Bhatty, M. K., 31, 174 Bialer, M., 307 Bianco, A., 5, 58, 59, 60, 61 Biedrzycki, H., 10 Bierl-Leonhardt, B. A., 7,63 Biggs, R. H., 254 Biguet, J., 172 Bikbulatova, G. S., 56, 57 Billington, D. C., 77 Bilton, R. F., 328 Binder, M., 65, 73 Biran, C., 10 Birch, A. J., 6, 44 Birch, A. M., 138 Bird, T. G. C., 101 Birge, R. R., 259 Bishop, R. D., 12 Biswas, S., 187 Bjoroy, M., 232 Black, B., 47 Blackwell, D. S. L., 53 Blais, C., 282 Blanc, P. A., 312 Blanco, L., 63, 88 Blazejewski, J.-C., 292, 296 Bledsoe, J. O., 38 Blinova, V. A., 6 Blosczyk, G., 226 Blount, J. F., 143, 146, 174, 200, 202,311, 318 Blum, M. S., 60 Blunden, G., 279 Blunt, J. W., 194 Blunt, R. W., 15 Bluthe, N., 50 Bobrowski, K., 251, 259
Author Index
332 Boccalotte, A., 69 Bocelli, G., 61 Bodea, C., 245 Bodor, N., 275 Boeckman, R. K., jun., 130 Boger, P., 210, 260 Boelens, H., 252 Boeren, E. E., 65 Boettner, F. E., 234 Bohlmann, F., 32,62,66,73, 75, 88, 102, 106, 107, 111, 114, 115, 116, 117, 146, 155, 156, 158, 160, 169, 170, 172, 174, 176, 184, 186, 187, 188, 189, 190, 195,196,225 Bohlmann, R., 67, 116 Bokel, M., 218 Bolard, J., 256 Bolli, D., 58, 59 Bond, F. T., 46 Bondavalli, F., 43, 46 Bonet, J.-J., 310 Bonnet-Delpon, D., 9 Bonini, C., 5 , 59 Borch, G., 237, 238 Borden, W. T., 50 Bordner, J., 205 Borg-Karlson, A.-K., 106 Bori, S. S., 37 Bornack, W. K., 121 Borowiecki, L., 46 Borschberg, H. J., 45 Borthakur, N., 146 Bose, A. K., 60, 280 Bosshardt, M., 35 Boswell, G. A., jun., 327 Botten, J. A., 28 Boucher, F., 259 Bouchier, I. A. D., 291 Bouchisic, B., 51 Boulton, K., 199 Bourgeay-Causse, M., 255 Boussac, G., 31, 82 Bouvier, P., 208, 209 Bowden, B. F., 172,182,200 Bowen, J. M., 278 Boya, M. T., 193 Boyd, J. D., 38 Boyd, R. K., 5 Boyer, J., 40 Brabham, D. E., 254 Bradshaw, A. P. W., 140 Braekman, J. C., 114, 202 Brahmana, H. R., 243 Braiman, M., 258 Bramley, P. M., 261 Branca, S. J., 63 Brand, J. M., 60 Brand, M., 41 Brandange, S., 8 Brangeon, J., 260 Braz Filho, R., 190 Bregovec, I., 76
Brendolan, G., 194 Breuer, A., 62 Breuer, E., 3 18 Brianso, J. L., 310 Brianso, M. C., 310 Brich, Z., 44 Brickner, S. J., 161 Bricout, J., 72 Bridges, C. D. B., 255 Brieger, E., 42 Brieskorn, C. H., 54, 226 Brion, F., 63 Britteli, D. R., 327 Brocksom, T. J., 36, 37 Broek, A., 258 Broek, A. D., 246 Bronneke, A., 40 Brooks, C. J. W., 281 Brooks, C. T., 287 Brookhart, T., 312 Brosche, T., 54 Brossi, A., 249 Brown, D. S., 306 Brown, D. W., 275 Brown, F. J., 278, 280 Brown, H. C., 51, 52, 115 Brown, J. D., 67 Brown, K. H., 38 Browne, E. N. C., 114 Browne, L. E., 70 Browne, L. M., 124, 202 Briiggemann-Rotgans, I. E. M., 77 Bruins, A. P., 280 Brun, P., 5 Buccini, J. A., 323 Buchbauer, G., 47, 48 Buchecker, R., 237 Buchectar, C. D., 64 Buchs, A., 280 Budai, D., 61 Budzikiewicz, H., 44,59,62 Biichi, G., 23, 39, 46 Buinova, E. F., 55 Bull, J. R., 325 Bunton, C. A., 28 Burak, K., 49 Burbott, A. J., 72 Burger, U., 14 Burgstahler, A. W., 160 Burinato, C., 223 Burke, B. A., 193, 200, 202 Burke, M. C., 45 Burkhart, J. P., 324 Burlage, U., 73 Burnell, R. H., 193 Burreson, B. J., 200 Burshtein, L. L., 286 Burton, L. P. J., 83 Busetta, B., 271 Bushey, D. F., 205 Butler, I. S., 275, 276 Byon, C.-Y., 277, 323
Caballero, E., 48 Cagnoli-Bellavita, N., 192, 194 Cahiez, G., 29 Caine, D., 164 Cainelli, G., 3, 239 Cairns, J., 297 Calas, R., 10, 25, 51 Cole, W. J., 281 Callahan, J. F., 107,143, 155 Callant, P., 61 Callender, R. H., 258, 259 Calzadilla, C. H., 85, 86 Camara, B., 260 Cambie, R. C., 292,302,327 Campanelli, A. R., 278 Campbell, I. M.,85 Campbell, M. M., 298 Camps, F., 192 Canceill, J., 325 Cane, D. E., 70, 88, 98, 129, 194 Cane, O., 4 Cano, G., 158 Cannistraro, S., 259 Cannon, J. R., 226 Canoras, A., 310 Cantineau, R., 328 Capdevielle, P., 49 Capomacchia, A. C., 256 Capon, R. J., 15, 17 Caporusso, A. M., 13 Capp, M., 281 Caputo, O., 215 Cardenas, C. G., 38, 45 Cardillo, G., 3, 239 Cariello, L., 239 Cargill, R. L., 205 Carlsen, P. H. J., 27 Carlsen, W., 258 Carlson, R. M. K., 282 Carman, R. M., 38, 41, 46, 47,195,213 Carmely, S., 200,234 Carpenter, R. C., 226 Carr, D., 28 Carr, R. V. C., 21, 36 Carroll, G. L., 139 Carrol, P. J., 104 Caruso, A. J., 81 Casanova, J., 5 Casellato, M., 210 Casida, J. E., 64, 74 Casinos, I., 40 Casinovi, C. G., 37, 223 Caspi, E., 327 Cassady, J. M., 146 Castanet, Y.,48 Castellani, G., 6 Castellano, E. E., 272 Castillo, R., 263 Castognino, E., 31 Castro, A., 284 Castro, V. A., 225
Author Index Caton, M. P. L., 52 Cattel, L., 215, 234 Cazes, B., 64 Cave, A., 85 Ceccherelli, P., 192, 194,324 Ceolin, R., 272 Cerda-Olmedo, E., 262 Cerfontain, H., 255 Cerny, N. H., 290 Cerny, V., 293, 294, 325 Cerrini, S., 270, 306 Ceskis, B., 16 Chabudzinski, Z., 10,37,40, 49, 50,51 Chadha, N. K., 318 Chakrabarti, P., 270, 271 Chakrabarty, S., 172 Chakravarty, A. K., 277 Chalmers, A. A., 172 Chalmers, W. T., 228 Chambers, D., 302 Chan, D. M. T., 60 Chan, K.-K., 247 Chan, R. L. S., 247 Chan, W. H., 46 Chan, W. R., 200, 202 Chandel, R. S., 207 Chandrasekharan, V., 65,66 Chang, C.-J., 146 Chang, F. C., 312 Chang, H. C., 271, 309 Chang, I.-M., 276 Chang, T. C. T., 35 Chao, P. D. L., 59 Chao, W.-R., 247 Chapman, A. C., 123 Chapman, D. J., 231,261 Charlwood, B. V., 4 Charpentier-Morize, M., 9 Charpiot, B., 292,296 Chastrette, F., 27 Chastrette, M., 27 Chatterjee, S., 23 Chatterjee, T. K., 226 Chattopadhyay, K., 256 Chattopadhyay, S., 234 Chaudhuri, R. K., 5, 7, 58, 59, 60 Chawla, H. P. S., 47, 214 Chayabunjonglercl, S., 99 Chekhlov, A. N., 271 Chekulaeva, L. N., 260 Chen, C. C., 49 Chen, E. Y., 157 Chen, F. H., 196 Chen, S. E., 234 Cheng, Y. S., 35 Chernysheva, E. K., 262 Cheron, M., 256 Chetyrina, N. I., 230 Cheung, H. T. A., 276 Chew, E. 246 Chhabra, B. R., 123 Chiaroni, A., 85
333 Chiba, M., 179 Chichester, C. O., 235, 256 Chien, M. M., 223 Chien, P.-L., 246 Chihiro, M., 223 Childers, W. E., 24, 36 Childs, R. F., 47 Chiu, P. L., 273 Chou, W. H., 196 Choudhury, M. K., 55 Chowdhury, P. K., 146 Chriki, G., 54 Christenson, P. A., 48, 89 Christi, N. H., 31 Christie, J. J., 177 Christou, P. N., 63 Chuiko, V. A., 62 Chuman, T., 264 Chun, M., 246 Chung, S. G., 59 Chytil, F., 250 Cimarusti, C. M., 272, 293 Cimino, G., 79, 298 Ciurdaru, V., 245 Clardy, J., 60, 127, 183, 196, 200, 201, 202 Clark, B. C., 36, 57 Clark, B. P., 5 Clark, R. D., 63 Clark, R. J. H., 258 Clarke, D., 299 Clarke, F. H., jun., 102 Clegg, W., 66 Cliff, G. R., 299 Clive, D. L. J., 21, 38 Clover, M. G., jun., 102 Coates, R. M., 103, 194 Cocker, W., 41, 55 Cohen, N. C., 286 Cohen, T., 39 Coisne, J. M., 228 Cole, J. R., 60, 219 Coleman, J. B., 45 Colin, H., 100 Colin, P., 286 Coll, J. C., 172,182, 192,200 Collera, O., 226 Collins, D. C., 277 Collins, D. J., 295, 318 Collins, M. D., 266 Collins, M. S., 74 Collins, W. P., 285 Comins, D. L., 67 Condran, P., jun., 320 Confalone, P. N., 3 18 Conia, J. M., 63, 89 Conn, R. S. E., 21,48 Conner, A. H., 73, 210, 232 Connolly, J. D., 146, 216, 221 Cooke, R. S., 54 Cookson, A. D., 284 Cookson, R. C., 29, 62 Cooney, J. J., 261
Cooper, A., 257,259 Coran, S. A., 5 Corbet, B., 225 Corde, J. P., 4 Cordell, G. A., 85, 146, 193 Corey, E. J., 25, 53, 204 Cori, O., 4, 28 Cornelis, A., 328 Corrigan, D., 73 Corriu, R. J. P., 40 Corsano, S., 31 Cortel, A., 192 Cortese, N. A., 35 Cossey, A. L., 195, 205 Couffignal, R., 14 Counsell, J. N., 235 Counsell, R. E., 283 Courseille, C., 271 Courtney, J. L., 230 Covey, D. F., 293 Cowall, P. L., 146 Cox, P. J., 146, 169, 271 Cox, R. H., 213 Cox, S. D., 39, 294 Crabb, T. A., 329 Crabtree, R. H., 39, 294 Craig, I. F., 286 Cramer, R., 218, 222 Craveiro, A. A., 190 Craven, B. M., 272,286 Crawford, T. C., 45 Creed, D., 265 Crespi, H. L., 258 Crews, P., 202 Crimmins, M. T., 60 Crist, B. V., 5 Croft, K. D., 202, 234 Crombie, W. M. L., 146 Crombie, L., 10, 22, 64, 146 Crump, D. R., 273 Crone, T. A., 278 Cross, B. E., 194, 195, 198, 199 Croteau, R.,4,35,70,71,72 Crouch, R., 247, 260 Crouch, R. L., 243 Crowley, K. J., 41 Cuatrecasas, J., 114 Cunat, P., 15, 32 Curini, M., 192, 194, 324 Currenti, R., 201 Curry, B., 258 Curry, K. W., 314 Cusanovich, M. A., 256 Czeczuga, B., 238 Dabiri, M., 88 Dabovic, M., 288 Dadoun, H., 303 Dahmen, J., 66 D’Alagni, M., 278 Dallinger, R., 257, 259 Daloze, D., 114, 202
Author Index
334 Dalton, J. R., 205 Daly, J. J., 269, 318 Dalzell, H. C., 65, 66 Damtoft, S., 5, 57, 70 Damodaran, N. P., 26 D'Andrea, A., 272 Daniel, T., 265 Danilov, L. L., 264 Danishefsky, S., 100, 121, 135 Dantes, A., 72 Darby, N., 45, 48 Dart, L. L., 263 Darwish, F. A., 223 Das, J., 204 Das, M. C., 230 Das, P. K., 251, 258, 259 Dasgupta, EL, 193 DaSilva, R. S., 19% DaSilva, J. J., 192 Dastidar, P. P. G., 172 Dastillung, M., 232 Dauben, W. G., 118, 185, 312 Daunis, J., 114 Dauzonne, D., 4 Davydov, V. Y., 282 Dave, V., 276, 307 David, S., 5 Davini, E., 58 Davis, D. L., 253 Davis, R., 289 Dawson, M. I., 247, 250 Dawson, P. J., 329 Day, R. O., 53 Dayal, B., 291, 312 Daza, L. R., 146 De Alvarenga, M. A., 192 De Bernardi, M., 135 De Bianchi, A. G., 238 Declercq, J. P., 6, 114, 202, 228 De Clercq, P. J., 179 De Graeve, J., 328 Degraw, J. I., 246 De Groot, A., 204 Dehennin, L., 281 Deja, I., 110 de Jesus, A. E., 172 Decorzant, R., 23, 179 De Keukeleire, D., 39, 161 Delaris, G., 62 Delaude, C., 226 Delaveau, P., 58, 59 Delay, F., 37 Deleris, G., 10, 51 Delettre, J., 272, 303 Dellers, E. A., 266 Delpech, B., 42 Delprino, L., 234 del Rio, R. E., 115 Deluca, C., 57 DeLuca, H. F., 263,269,319 DeLuca, M., 285
Demailly, G., 34 De Mark, €3. R., 280 Demath, M., 61 de Mayo, P., 53 Dernbitski, A. D., 48, 62 De Miranda, D. S., 194 Demole, E., 23 Denisenko, V. A., 216 Denny, M., 246,250 Dens, N. C., 314 De Pascual Teresa, J., 32,48, 118 Depezay, J.-C., 89 De Rosa, M., 329 De Rosa, S., 79, 298 Derwish, G. A. W., 198 Desage, M., 280 Desai, D. N., 40, 164 Desai, M. C., 214 Descesare, J.-M., 55 Deshchits, G. V., 55 Deshmukh, A. R. A. S., 57, 67 DeSilva, T., 93 De Simone, F., 318 Deslongchamps, P., 45, 166 De Stefano, S., 79, 298 Destro, R., 184 Detty, M. R., 292 Dev, S., 26, 41, 47, 115, 214 Devilbiss, E. D., 7 De Vos, M. J., 64 Devreese, A. A., 179 Dewey, W. L., 66 Dhar, A. K., 88, 116, 146, 158, 172, 187, 188, 189 Dhar, D. N., 193 Dhar, K. L., 15, 33,211 Dhara, K. P., 231 Dhekne, V. V., 67 Diaz, E., 190 Diem, M., 5 Dieter, R. K., 63, 300 Dietsch, A., 234 Diez-Masa, J.-C., 100 Dike, S. Y., 21 Dikstein, S., 51 Dime, D. S., 297 Dimitriadis, E., 75 Din, Z. U., 33, 64 Dinge, A. S., 67 Dini, A., 318 Dinogues, J., 5 1 Dipietro, R. A,, 46 Dirks, G., 243, 256 Ditzel, E. J., 194 Dixon, J., 47 Djerassi, C., 51,52,278,280, 311, 312 Djura, P., 78 Dmitrovskii, A. A., 250 Doddrell, D. M., 274 Doehner, R. F., 41 Doi, E., 34
Dolhyj, S. R., 35 Dombi, G., 327 Dominguez, X. A., 146, 158 Donnelly, D. M. X., 73 Donskova, A. I., 56 Doolittle, R. E., 38 Do Prado, S. K., 196 Dorn, F., 140 Doskotch, R. W., 58 Dougall, D. K., 4 Doukas, A. G., 258,259 Doumas, J., 234 Dovinola, V., 21 1 Draffehn, J., 282 Drage, J. S., 92 Drawert, F., 33 Drebyschak, T. D., 73 Dreiding, A. S., 110, 118 Drengler, K. A., 194 Drief, A., 64 Driessen, R. A., 66 Du, P. C., 321 Duax, W. L., 270, 271 Dubois, G., 85 Dubovenko, Z. V., 73 DUC,D. K. M., 33, 43, 304 Duddeck, H., 277, 298 Duffield, R. M., 60 Duffley, R. P., 65 Dugger, R. W., 253 Duncia, J. V., 61 Dung, J. S., 40 Dunlop, R. W., 15 Dunogues, J., 10, 25, 51 Dupont, A., 114,202 Du Preez, H. E., 62 Durocher, C. K., 281 Duri, Z. J., 198 D'Urso, N. R., 258 Dutta, C. P., 231 Dutta, P. C., 204 Dutta, P. K., 257 Dworan, E., 47 Dyakonova, R. R., 56 Dyer, R. D., 205 Eade, R. A., 225 Ebrey, T. G., 247, 259, 260 Ecoto, J., 50, 100 Ecoto, S. L., 51 Edamura, F. Y., 116 Edenharder, R., 281 Edeny, H., 66 Eder, U., 324 Edgar, M. T., 52 Edwards, 0. E., 47 Eenkhoorn, J., 323 Egger, J. C., 32 Eguchi, T., 269 Eguren, L., 191 Egyed, O., 278 Ehrenberg, B., 258 Eichinger, K., 318
335
Author Index 3gendorf, G., 210 Zilerman, R. G., 166 Zkanayake, N., 77 Zlder, J. W., 47 3lgama1, M. H. A., 277 Zliel, E. L., 44 Zlizalde Gonzalez, M., 282 Zllerbrock, B. H., 266 Zlliott, W. H., 281 Zllis, A. B., 258 Sllis, J., 225 Zllis, P. R., 241 Zllison, B. O., 73 Zl-Naggar, L. J., 4 Slnaggar, S. R., 58 3-Sayed, M. A., 258 Zl-Sebakhv. N. A.. 195 Elsohly, M: A., 65, 66, 70, 174 Elvidge, J. A., 15 Emanuel, N. M., 245 Emanuelson, I., 73 Emelyanov, M. M., 33, 252 Emmer, G., 221 Encarnacion, R., 234 Endo, T., 32, 59 Engel, C. R., 325 Engel, L., 14 Enggist, P., 23 England, B. G., 283 Englert, G., 255 Enriquez, R., 103 Ensley, H. E., 36 Epstein, W. W., 62 Erasmuson, A., 195, 199 Erickson, E. W., 44 Eridente, A., 69 Erm, A., 15 Erman, M. B., 20, 34 Ernst, L., 48 Eschenmoser, A., 209 Escher, S., 32, 51, 231, 238 Escoffier, A., 260 Eshhar, Z., 285 Eskins, K., 255 Esposito, P., 58 Esvelt, R. P., 319 Etheredge, S. J., 135 Etoh, H., 14, 252 Eugster, C. H., 193, 237 Eyring, G., 258 Ezaki, Y., 241
-
Fadlallah, M., 298 Fales, H. M., 60 Fang, J.-M., 179 Fardella, G., 223 Fargerlund, J., 63 Farina, V., 21 Farnsworth, N. R., 85, 146 193 Farrant, R. D., 303 Farrell, I. W., 140
Faruk, A. E., 241 Fatturusso, E., 201 Faulkner, D. J., 75, 78, 202, 238 Faust, Y., 42 Fauth, D. J., 38, 255 Fauve, A., 299, 329 Fayos, J., 190, 191, 192 Fedeli, W., 270, 272, 306 Fedorov, P. I., 13, 33 Feigenson, G. W., 266 Felton, M., 71 Fenical, W., 31, 183, 188, 201,202 Feofilova, E. P., 261 Ferber, G. J., 28 Ferguson, G., 85 Fernandez, F., 278 Ferraboschi, P., 295 Ferrari, M., 184 Ferreira, C., 238 Ferreira, J. T. B., 36, 37 Ferrino, S., 207, 223 Fetizon, M., 33,50, 100,270, 297,303,304 Feuerstein, I., 62 Feuillerat, G., 6 Fiand, J. C., 11, 43 Ficini, J., 64, 101 Fiecchi, A,, 312 Fiedler, L., 184, 188 Fielden, R., 46 Fields, K. W., 45 Fiksdahl, A., 237 Filer, C. N., 254 Filippone, P., 195, 199 Filippova, T. M., 247 Finamore, E., 318 Findlay, J. A., 39, 164 Findlay, J. N., 40 Finer-Moore, J., 200 Finkel’shtein, E. I., 251 Finner, E., 5, 59 Firth, M. R., 194 Fischer, E., 309 Fischer, N. H., 146 Fischli, A., 13 Fish, R. H., 70 Fitch, F. M., 12 Fitzpatrick, F. A., 281 Fitzsimmons, B. J., 64 Firizzani, M. A., 319 Fkih-Tetouani, S., 114 Flecker, P., 325 Fleming, I., 19, 34 Fleming, M. P., 5 Floor, J., 325 Folefoc, G., 27 Fong, S.-L., 255 Fonrodona, J., 310 Foote, C. S., 38 Ford, C. W., 58, 60 Ford, J., 285 Ford, T. M., 51
Forgacs, P., 234 Forn, B., 74 Forni, A., 5 Forster, R. W. G., 306 Foss, P., 238 Fouchet, B., 44 Foulkes, J. A., 284 Fourneron, J.-D., 16,39,64, 89 Fournet, A., 156 Fourrey, J. L., 174 Fox, M. A., 49 Fraga, B. M., 192, 195, 198, 199,230 Francesconi, A., 60 Francke, W., 28 Franck-Neumann, M., 63, 64 Franco, R., 146, 158 Frank, A. W., 31 Franke, C. S., 53 Franke, I., 65 Frank-Kamenetsky, M. D., 257 Fransen, M. R., 246, 258, 259 Frappier, F., 276 Fraser-Reid, B., 64, 93 Frater, G., 42 Frazier, K., 98 Frazier, R. H., 40 Freedman, T. B., 257 Freeman, R., 274 Freer, A. A., 193 Frei, B., 255 Freire, R., 226 Frenkiel, T. A., 274 Frey, H., 249 Friedman, A. L., 239 Friedman, L., 37 Friedrich, E., 36 Friedrich, K., 52 Friemann. J., 181 Friguelli, R., 31, 252 Frimer, A. A., 64 Frincke, J. M., 160 Fristad, W. E., 42, 297 Fritz, G., 172 Fritz, U., 62, 116, 146, 169 Frohlich, T., 181 Frolik, C. A., 263 Fronza, G., 135 Frost, D. C., 7 Frot-Coutaz, J., 256 Fry, A. J., 49 Fry, J. L., 53 Fuchida, M., 210 Fuchs, W., 225 Furst, A., 290, 323 Fuhrer, H., 272, 273, 289 Fuji, K., 186, 190, 196 Fujihara, Y., 24, 35, 42, 51 Fujimori, T., 163, 238 Fujisawa, T., 9, 39
Author Index
336 Fujita, E., 186, 190, 196 Fujita, T., 11, 21, 60, 197 Fujita, Y., 265 Fujiwara, H., 60, 280 Fujiwara, T., 165 Fukamija, N., 40, 89 Fukumoto, K., 27, 80, 223 Fukunaga, Y., 31, 263, 264 Fukungaga, T., 41 Fukushima, H., 234 Fukuzawa, A., 99 Fuller, T. J., 327 Fung, S., 316 Fung, V. A., 247 Furukawa, H., 146, 174 Furusaki, A., 99, 124, 157, 199,306 Fusaka, T., 165 Fusitani, M., 33 Gabbard, R. B., 325 Gabke, S. Y., 45 Gadwood, R., 121 Gaertner, W., 259, 260 Gagarina, A. B,, 245 Gage, D., 174 Gal, C., 42 Galdecki, Z., 55 Galindo, A,, 158 Galum, E., 72 Gambacorta, A., 329 Gambliel, H., 71 Ganguly, J. K., 231 Ganguly, R. N., 104 Cannon, M., 50 Garbers, C. F., 62 Garcia, C., 225 Garcia, G. A., 15 Garcia-Alvarez, M. C., 187, 188, 190, 192, 225 Garcia-Fraile, A., 47 Garcia-Granados, A., 199 Garcia-Martinez, A., 47 Garcia-Rodriguez, M. J., 72 Gardlik, J. M., 46 Gariboldi, P., 184, 194 Garnero, J., 31 Garti, N., 271 Garyanov, R. Kh., 230 Garzez, W. S., 192 Gasa, S., 199 Gase, R. A., 296 Gasic, M. J., 288 Gaskin, P., 197, 198 Gatilov, Y. V., 200 Gatuma, A. K., 146 Gaudioso, L. A., 62 Gaughan, L. C., 64, 74 Gaughan, R. G., 63 Gautier, B., 256 Geenevasen, J. A. J., 255 Gelbaum, L,. T., 102 Gemal, A. L., 13
Gendin, D. V., 46 Geneste, P., 39 Gen&t,J. P., 64, 101 Geoffre, S., 271, 272 Gerder, J. M., 306 Germain, G., 6, 114, 202, 228 Geroghty, N. W. A., 55 Gerr, R. G., 272 Gerstenberger, M. R. C., 288 Gerval, J., 10 Gerwick, W. H., 202 Ghaffiari, M. A., 307 Ghisalberti, E. L., 15, 78, 104, 186, 189, 202 Ghosal, S., 234 Ghosh, A,, 230 Ghosh, P. K., 193 Ghosh, S., 40, 230 Giacomelli, G., 13 Giannellini, V., 5 Gibbs, C. G., 93 Gibson, T., 47 Gibson, T. W., 312 Giddings, R. M., 52 Giebfried, J., 28 Gielen, J. E., 328 Gielen, J. W. J., 310 Giersch, W., 23, 38, 51, 179, 231, 238 Giglio, E., 272, 278 Giguere, R. J., 40 Gilad, S., 285 Gilbert, B., 215 Cilgan, M. W., 323 Gillick, S. G., 13 Gillis, H. R., 111 Gilrnore, C. J., 193 Gilmore, D. A., 257 Ginsburg, G. S., 49 Ginzburg, M. A,, 25 Girard, J. P., 60 Giumanini, A. G., 45 Gleizes, M., 4, 74 Glowka, M. L., 55 Glusenkamp, K.-H., 5, 6, 70 Glushko, L. P., 23 Goad, L. J., 311 Goadscloue, N., 4 Godfrey, J. D., 205 Goewert, R. R., 266 Goh, S. H., 202 Gold, P. M., 76 Goldberg, O., 110 Gollob, L., 73 Gomora, E., 226 Gonzalez, A. G., 80, 146, 158, 192, 195, 199, 225, 226, 230, Gonzalez, D., 40 Gonzalez, P., 230 Gonzalez Sierra, M., 194 Goodman, M., 188 Goodwin, T. W., 235
Gopalkrishnan, B., 39 Gora, J., 55 Gordon, A. G., 41 Gordon, M. H., 102 Gore, K. G., 55, 56, 57, 64 Gorrichon, L., 101 Gorst-Allman, C. P., 172 Goryaev, M. I., 48, 62, 230 Goswami, A., 32,228 Goswami, S., 227 Goswami, U. C., 263 Got, R., 256 Goto, J., 282, 284 Goto, N., 282 Goto, T., 45 Gott, A. M., jun., 286 Gottlieb, H. E., 192, 276, 277, 292, 327 Gottlieb, 0. R., 192 Gougoutas, J. Z., 293 Gould, R. O., 88 Govind, N. S., 262 Govindan, S. V., 146, 155 Govindjee, R., 247, 260 Grabowich, P. G., 272, 293 Gradmann, W., 146 Graebe, J. E., 199 Graf, W., 221,299,300,301, 304 Graham, M. R., 4 Granat, M., 73 Grande, M., 32 Grandi, R., 61 Grandolini, G., 37, 223 Grant, H. G., 59 Grant, P. K., 188 Gras, J.-L., 108 Gray, G. D., 31 1 Gray, N. A. B., 280 Grayson, D. A., 55 Greaves, A. M., 228 Green, M. B., 64 Green, N. M., 327 Green, S., 8 Greenblatt, G. A., 106 Greenhouse, R., 291 Greenlee, M. L., 206 Greenlee, W. J., 130 Grenz, M., 88, 146,188,189, 196 Greuter, H., 64 Grice, P., 54, 160 Grieco, P. A., 61, 207, 223 Grignon-Dubois, M., 51 Grillasia, Y., 15 Grimm, M. F., 266 Grimminger, W., 219 Grishin, Y. K., 51 Groenendijk, G. W. T., 246 Gros, E. G., 195, 317 Groweiss, A., 200, 234 Grumbach, K., 74 Gschwendtner, W., 289 Guchi, S. E., 187
337
Author Index Gudova, V. N., 55 Guelz, P. G., 44 Guerra, M., 7 Guest, J. R., 266 Guillerm, D., 82 Guirado, A., 45 Guiso, M., 5, 58, 59, 61 Guittet, E., 17 Gujval, V. K., 58 Gullerm, D., 31 Gumulka, J., 305 Gumulka, M., 325 Gunaherath, G. M. K. B., 228 Gunatilaka, A. A. L., 227, 228, 230 Gunn, B. P., 34 Gupta, B. D., 259 Gupta, C. D., 187 Gupta, R., 14 Gupta, R. K., 75, 88, 106, 111, 115, 146, 155, 170, 172, 188, 189 Gupta, S. R., 58 Gupta, Y. P., 230 Gurria, G. M., 76 Gurst, J. E., 279 Gurudutt, K. N., 42 Gust, D., 243, 256 Gustafson, D. L., 239 Gut, M., 277 Gutierrez, A., 158 Gutman, A., 46 Gutwillinger, H., 33 Guziec, F. S., 53 Haas, A,, 288, 289 Habib, H. A. A., 195 Habib, M. M., 38, 255 Haces, A., 194 Hachey, D., 28 Hackler, L., 303, 327 Hadorn, M., 240 Haffer, G., 324 Haf-Muller, R., 62 Haginiwa, J., 232 Hahn, W. E., 46 Halim, A. F., 172 Hall, F., 169 Hall, I. H., 146, 174, 234 Hall, L. D., 273 Hall, T.-W., 172 Halls, T. D. J., 192 Halsall, T. G., 140 Hamada, Y., 19 Hamanaka, N., 199 Hamaoka, T., 284 Hamelin, J., 44 Hamer, L. F., 325 Hammerschimdt, F. J., 15 Hammond, M. L., 320 Han, D.-S., 215 Han, Y.-K., 99, 118
Hana, G. W., 47 Handley, J. R., 36 Handrick, G. R., 65, 66 Handy, G. A., 146 Haneda, A., 290 Hangauer, D. G., 179 Hanko, R., 40 Hanna, I., 33, 43, 304 Hansbury, E., 282 Hansen, K. B., 257 Hanson, J. R., 121,140,190, 195, 198, 199,292, 305 Hanson, R. C., 258 Harada, M., 230 Harada, N., 5 Harada, T., 21 Harborne, J. B., 4 Harderstein, R., 12 Harding, R. W., 262 Hardy, M., 234, 321 Harlow, R. L., 40 Harms, K., 66 Haroda, N., 277 Haromy, T. P., 232 Haroon, Y., 266 Harref, A. B., 114 Harris, D., 5 Harris, L., 255 Hart, R. J., 318 Hartley, G. S., 64 Hartshorn, M. P., 15, 194 Haruna, M., 144 Harvey, D. J., 5 , 279 Harwood, L. M., 49, 64 Hasa, T., 199 Hasegawa, I., 189 Hasegawa, S., 54, 221 Hashiba, N., 124 Hashimoto, H., 136 Hashimoto, K., 12, 33, 63 Hashimoto, T., 59 Hashimoto, Y., 226 Haslanger, M. F., 45 Hasler, H., 194 Hassam, S. B., 61 Hatem, J., 5 Hattori, H., 49 Hattori, S., 73, 183 Hausen, B. M., 232 Hauser, A., 81 Havel, M., 314, 325 Havinga, E., 310 Hayano, K., 49, 124, 126 Hayashi, C., 284 Hayashi, K., 8 5 , 200 Hayashi, S., 92,183,187,199 Hay Motherwell, R. S., 301 Hayward, G., 258, 259 Heath, R. R., 38,283 Heathcock, C. H., 177, 253 Heck, R. F., 35 Hecker, E., 200 Hedden, P., 199 Hedges, J. I., 232
Hefendehl, F. W., 73 Heftmann, E., 197, 207, 281, 282 Hegde, S. G., 12, 27, 31, 42 Hegedus, L. S., 11 Heide, L., 266 Heikes, J., 45 Heima, K., 86 Heindze, I., 33 Heinvali, M., 15 Heissler, D., 113, 114 Helbling, S. M., 61 Helquist, P., 121 Hendry, L. B., 70 Henke, S., 61 Hensens, 0.D., 228 Herak, R. M.; 272 Herbert, R. B., 4 Herlihy, W. C., 258 Hermann, A. O., 278 Hernandez, J. D., 115 Hernandez, M. G., 195,199, 230 Hernandez, R., 225, 308 Herold, T., 8 Herout, V., 4 Herz, W., 146, 155, 156, 172, 174 Herzfeld, J., 258 Hertzberg, S., 237 Hesse, M., 58 Hethelyi, E., 54 Heuberger, C., 301 Heywood, V. H., 4 Hibino, S., 12 Hickey, J. P., 275, 276 Hieda, T., 263 Hielsen, B. J., 60 Higo, M., 54 Hikino, H., 213 Hilgenberg, W., 210,261 Hill, A., 291 Hillenbrand, G. F., 161 Hilscher, J.-C., 29 1 Hiltunen, R., 5 Hirano, H., 66 Hirano, Y.,72, 269, 290 Hiraoka, K., 237 Hirata, T., 69, 72 Hiroi, K., 61 Hirose, Y., 54, 105, 158, 184 Hirotsu, K., 201 Hirschy, L. M., 41 Hirsl-Starcevic, S., 42 Hiscocks, P. G., 282 Hitchcock, P. B., 199 Hiyama, T., 10, 37, 42 Hixson, S. S., 53 Ho, T. L., 33, 64, 89 Ho, Z. Z., 258 Hoad, G. V., 198 Hoard, L. G., 270 Hobbs, P. D., 247,250 Hochlowski, J. E., 75, 202
Author Index
338 Hocquemiller, R., 85 Hoehne, E., 198, 272, 273 Hoeneisen, M., 146 Hoffmann, H. M. R., 40,47 Hoffmann, J. J., 60, 219 Hoffmann, K., 286 Hoffmann, R. V., 12 Hoffmann, R. W., 8 Hofmeister, H., 323 Hogge, L., 73 Hohn, J., 11 Holker, J. S. E., 87 Holland, D., 64 Holland, H. L., 329 Holly, S., 278 Holub, M., 174 Honda, K., 89 Honda, T., 223 Honig, B., 258,259,260 Honkan, V. A., 202 Hooper, C. L., 71 Hopf, H., 260 Hoppe, D., 40 Hoppen, V., 289 Horgan, R., 238 Hori, M., 210 Hori, T., 50 Horiai, H., 200 Horibe, I., 170 Horinaka, A., 35 Horiuchi, C. A.,295,360,318 Horn, P., 213 Horsewood, P., 294 Horunka, A., 37 Horvath, G., 328 Hosakawa, H., 52 Hoshino, Y . , 13 Hoskins, L. C., 257 Hosoda, H., 283 Hosomi, A., 16 Hostettmann, K., 7,234,283 Hostettmann-Kaldas, M., 7 Howard, B. M., 188 Howard, D. L., 231 Howbert, J. J., 103 Howden, M. E. H., 200, 318 Howell, S. C., 81 Hoye, T. R., 81 Hsieh, C.-L., 258 Huang, H.-C., 146 Huang, J. T., 58 Huang, K.-S., 260 Hubbard, L. M., 259 Nuber, C . P., 228 Huber, U., 47 Hubscher, J., 269, 318 Huchette, D., 33 Hudlicky, T., 63, 135 Huffman, J. C., 39, 223 Huffman, J. W., 156, 161 Hull, W. E., 276 Huls, R., 226 Huneck, S., 230 Hung, H. K., 31
Hunt, J. M., 73 Hunter, G . L. K., 57 Hunter, I. R., 281, 282 Hurst, K. M., 130 Hurtado, H. E., 204 Husain, J., 271 Husain, M., 290 Hutchinson, C. R., 60, 61 Hutchinson, S. A., 85 Hutson, K. G., 266 Hwang, K.-J., 38 Hylands, P. J., 228 Iacobucci, L. A., 36 Iavarone, C., 5, 58, 59, 61 Ibe, K., 74 Ibragimova, N. D., 55, 56 Ibuka, T., 146 Ichikawa, Y . , 158 Ichimoto, I., 33 Ichimura, K., 74 Ichinohe, Y . , 232 Ichinose, I., 20, 79, 203 Ida, T., 312 Ifeodike, N. P., 216 Ignatov, V. N., 271 Iguchi, K., 29, 60, 200 Iguchi, M., 14, 252 Ihm, H., 54 Ihn, W., 230, 279 Iida, H., 195 Iida, T., 174, 274, 277 Iijima, S., 44 Iino, M., 130 Iitaka, Y., 32, 59, 195, 215, 226, 232, 269,
Ikan, R., 74 Ikawa, I., 22 Ikeda, R., 199 Ikegami, A., 256, 260 Ikegami, S., 136 Ikegawa, S., 284 Ikekawa, N., 269, 290, 291, 314, 316
Ikenoya, S., 266 Ikram, M., 234 Imagawa, D. K., 38 Imagawa, T., 60, 61 Imai, S., 194, 204 Imai, T., 199 Imakura, Y., 58, 174 Imamura, P. M., 194 Imre, S., 80 h a , K., 14, 252 Inamoto, T., 210 Inanaga, J., 241, 243 Inari, S., 277 Inokuchi, T., 160 Inomata, K., 22 Inoue, H., 183 Inoue, K., 13, 61, 70 Inoue, S., 76, 89, 264 Inoue, T., 214, 216
Inouye, H., 57, 59, 61, 70 Inouye, J., 4 Inui, H., 234 Inui, S., 52 Invergo, B. J., 25, 64 Ionov, S. P., 271 Ionora, E. I., 33 Ireland, R. E., 205 Irie, H., 36 Irismeto,v M. P., 230 Isae, S., 60 Tsaera, Z. G., 43, 5 5 , 56, 57 Isakov, V. V., 216 Ise, F., 20, 203 Ishi, K., 203 Ishida, T., 73 Ishiguro, M., 265, 290, 291, 314, 316
Ishihara, M., 59 Ishihara, S., 284 Ishii, H., 234 Ishii, K., 26, 79, 255 Ishikawa, H., 18, 25 Ishikawa, K., 12, 16, 259 Ishikawa, T., 274 Ishiwatari, M., 245 Ishiwari, H., 60 Ishizone, H., 226 Islamov, R., 188 Islimyeli, S., 80 Ismail, J., 47 Isobe, T., 196, 197 Itai, A., 226, 269 Ito, I., 46, 72 Ito, K., 144, 174 Ito, M., 43, 189 Ito, S., 13, 28, 142, 143, 146, 190
Itoh, A., 29, 37, 42, 63 Itoh, T., 213, 214 Itoi, K., 62 Itoigawa, M., 174 Itokawa, H., 187 Ives, J. L., 294 Iwabuchi, H., 130 Iwabuchi, J., 5, 277 Iwadare, T., 116 Iwai, M., 14, 72 Iwamoto, M., 33, 51 Iwamura, H., 32 Iwasa, T., 260 Iwasawa, N., 31, 86, 253 Iwashita, T., 184 Iwata, C., 165 Iwata, I., 34, 50 Iwata, M., 232 Iyengar, R., 52, 70, 88 Iyer, R. I., 256 Izawa, K., 216 Izac, R. R., 92, 183 Izotova, L. V., 55 Jackson, W., 254
339
Author Index Jackson, W. K., 295, 318 Jacobi, P. A., 170 Jacobs, H., 5 5 Jacobs, H. J. C., 310 Jacoli, G. G., 228 Jacquemin, H., 59, 156 Jacques, J., 325 Jacques, R., 74 Jacquier, R., 114 Jadhav, P. K., 115 Jaffer, J. A., 279 Jagodzinski, J. J., 305 Jahodar, L., 58 Jain, G. K., 231 Jain, K. M., 258 Jakobsen, P., 46 Jakupovic, J., 66, 75, 111, 116, 117, 146, 155, 158, 169, 170, 174, 187, 188, 189, 196 Jallali-Naini, M., 82 Jalsovszky, G., 278 James, J. C., 219 Janero, D. R., 255 Janiszo wska , W., 234 Janitschke, L., 48 Jansen, P. A. A., 246 Janssen, B., 298 Janus, J., 50 Jarchow, 0. H., 232 Jarvis, B. B., 93 Jasiczak, J., 321 Jautelat, M., 61 Jefferies, P. R., 15, 78, 186, 188, 189, 202 Jeffery, C., 111 Jeffrey, S. W., 255 Jeger, O., 209, 255 Jelenkovic, B., 272 Jennings, B. H., 308 Jensen, N.-H., 257, 259 Jensen, S. R., 57, 58, 59, 60, 70 Jensen, U., 21 Jerebzoff, S., 261 Jerebzoff-Quintin, S., 261 Jerris, P. J., 119 Jewers, K., 279 Jigajinni, V. B., 298 Jimenez, F. G., 226 Jizba, J., 169 Joffe, A. Z., 213 Johansson, L. B. A., 258 John, L. S., 321 Johne, S., 58 Johnson, D. F., 289, 298 Johnson, K. K., 13 Johnson, M., 72 Johnson, M. A., 5,205 Johnson, M. W., 299 Johnston, J. O., 324 Jolad, S. D., 60, 219 Jommi, G., 184, 194 Jones, A. J., 15
Jones, B. B., 36 Jones, D., 266 Jones, G., 282 Jones, T. H., 60 Jones, W. A., 271 Jonkers, F. L., 34 Jordan, J. R., 283 Joseph, J. M., 312 Joseph-Nathan, P., 103, 115 Joshi, B. C., 4 Joshi, B. S., 227 Joshi, G. D., 5 5 , 56, 64 Joshi, K. C., 192 Joshi, R. S., 56 Jost, P. C., 285 Joucla, M., 44 Joulain, D., 31 Julia, M., 16, 39, 49, 62, 64, 89, 239 Julia, S., 17, 64 Julien, R., 272 Jung, M. E., 181 Jungk, S., 69 Junior, P., 59 Juranic I., 288 Kabore, I., 42 Kabuto, C., 81, 143, 213 Kad, G. L., 21 Kadam, S. R., 296 Kadota, S., 213 Kaegi, H., 246 Kagan, H. B., 4 Kahn, M., 135 Kaiya, T., 199 Kaji, K., 12, 20, 33, 63 Kajihara, Y., 12, 16 Kajtar-Peredy, M., 256 Kakitani, H., 251, 259 Kakitani, T., 251, 259 Kalikhman, I. D., 46 Kalinovskii, A. I., 230 Kalisky, O., 260 Kalkoff, H., 50 Kalvoda, J., 272, 289 Kalyani, K., 193 Kamber, M., 243 Kameoka, H., 70 Kametani, T., 27, 28, 29, 34, 80,223, 252, 314 Kamernitskii, A. V., 271,272 Kamga, C. S., 221 Kamigauchi, T., 189,234 Kamikawa, T., 196 Kamogawa, H., 259 Kanaiwa, T., 115 Kanakura, A., 10 Kanaoka, M., 230 Kane, B. J., 14, 41, 45, 50 Kaneko, H., 85, 238, 252, 253 Kanemoto, Y., 124 Kano, S., 12
Kano, M., 184 Kantor, E. A., 16 Kao, J. P. Y., 78 Kao, L. C., 35 Kapadia, G. J., 60 Kapil, R. S., 228 Kapundu, M., 226 Karaseva, A. N., 56, 57 Karavaeva, K. A,, 256 Karim, A., 174 Karimian, K., 69 Karle, J., 270 Karlin, V. V., 56 Karp, F., 70, 71 Karpf, M., 118 Karpuj, L., 271 Karras, M., 28 Kartasheva, Z. S., 245 Kartashov, V. R., 46 Kartonozhkina, 0. I., 25 Kasahara, C., 206 Kasahara, K., 11 Kasai, R., 234 Kasaikina, 0. T., 245 Kasal, A,, 279, 294, 324 Kashin, A. N., 49, 51 Kashiwada, Y., 203 Kashman, Y.,200, 234 Kasprzyk, Z., 234 Kassner, H., 160 Katagiri, T., 30, 251 Katai, M., 231 Katakawa, J., 36 Katayama, C., 99, 157 Katayama, K., 266 Katayama, T., 256 Kating, H., 66 Kato, F., 262 Kato, H., 230 Kato, K., 29, 79, 163, 238, 252,253, 262, 306 Kato, M., 86 Kato, T., 20, 79, 141, 199, 203, 253 Katsui, G., 266 Katsui, N., 163 Katsuki, T., 23, 27, 241, 243 Katsuyama, K., 243 Katzenellenbogen, J. A., 17 Kavara, T., 9 Kaverin, V. V., 50 Kawada, M., 19,251 Kawaguchi, A., 4 Kawaguchi, T., 62 Kawai, H., 264 Kawakami, S., 64 Kawamoto, A. H., 258 Kawamura, N., 283 Kawanisi, M., 60, 61 Kawano, Y., 64 Kawara, T., 39 Kawasaki, T., 214 Kawashima, H., 194 Kawashima, K., 33
340 Kawashima, T., 190 Kawazu, K., 176 Kayukova, G. P., 286 Kazi, M. A., 58 Kazlauskas, R., 200 Keana, J. F. W., 285 Keiderling, T. A., 6 Keim, W., 12 Kelecom, A., 275 Keller, P., 323 Keller, U., 32 Kemertelidze, E. P., 73 Kemmerling, M., 266 Kempe, U. J., 172 Kenne, L., 234 Kepner, R. E., 73 Kerb, U., 308, 323 Kergomard, A., 299, 329 Kern, M., 48 Kerr, K., 66 Kessel, C. R., 185 Khan, I. A., 307 Khan, N. H., 290 Khan, S. A., 223 Khan, V. A., 73 Khanna, N. M., 46, 231 Khanna, R. N., 67 Khanra, A. S., 57 Khatri, L. M., 58 Khastgir, H. N., 228 Khoi, N., 223 Kholi, J. C., 14 Khorana, H. G., 260 Khuong-Huu, Q., 42 Khrostik, G. M., 48 Kido, F., 81, 165 Kido, M., 158, 203, 210 Kienzle, F., 240 Kikuchi, H., 88, 99, 157, 200 Kikuchi, M., 15 Kikuchi, T., 213, 230 Kikuchi, Y . , 214 Killinger, T. A., 61 Kim, H.-O., 230 Kim, J. B., 285 Kim, S.-W., 179 Kimbu, S. F., 221 Kimmel, Y., 66 Kimura, K., 34 Kimura, M., 273 Kimura, O., 214 Kirnura, Y., 21, 234, 260 King, A. O., 18 King, R. M., 62, 66, 73, 75, 88, 106, 114, 115, 116, 117, 146, 155, 156, 158, 169, 170, 172, 174, 186, 187, 188, 189, 195, 196, 225 Kinghorn, A. D., 85 Kingsley, P. B., 266 Kini, A,, 246 Kinoshita, M., 135 Kinosita, K., 260 Kinting, A., 42
Author Index Kirby, G. W., 294 Kircher, H. W., 225 Kirfel, A., 181 Kirk, D. N., 140, 273, 303, 322, 323 Kirkwood, P. S., 197, 198 Kirmse, W., 53 Kirson, I., 277, 292 Kirtany, J. K., 67, 103 Kisaki, T., 31, 263, 264 Kise, N., 64 Kiselev, A. V., 282 Kisiel, Z., 6 Kitagawa, I., 31, 46, 48, 189, 210,234 Kitahara, H., 165 Kitahara, T., 15 Kitazawa, E., 187 Kitchin, J. P., 35 Kitson, D. H., 85 Kim, H., 234 Kizuka, K., 3 11 Kjonaas, R., 71 Klaui, H., 235 Kleijn, H., 19, 78 Klein, E., 33 Klein, P. D., 280 Kleinig, H., 260 Klemmenson, P. D., 64 Klimash, J. W., 146 Klimetzet, D., 28 Klina, W. L., 18 Klinotova, E., 231 Klyner, Y. P., 41 Kneen, G., 64 Knight, D. W., 21, 75, 76 Knight, J. C., 328 Knights, S. G., 305 Knipser, W., 14 Knoblauch, K., 54 Knoll, H. E., 266 Knoll, F. M., 22 KO, S. S., 130 Kobayashi, K., 57 Kobayashi, M., 77,200,210, 229, 253 Kobayashi, S., 58 Kobayashi, Y., 234, 284 Koch, H., 47 Koch, M., 58, 59 Kochetkov, N. K., 264 Kochhar, K. S., 36 Kocienski, P. J., 24 Koco'r, M., 298 Koc'orsky', P., 290, 293, 294, 325 Kodama, H., 238 Kodama, K., 257 Kodama, M., 28, 142, 143, 146 Koden, M., 287 Koedam, A., 44 Koenst, W. M. B., 252 KGster, F.-H., 111
Koga, T., 289 Kogami, K., 85 Kohda, A., 36 Kohda, H., 196 Kohen, F., 285 Kohout, L., 280, 318 Koike, K., 193 Koizumi, N., 314 Kojo, K., 33, 51 Kokuryo, M., 273 Kolhe, J. N., 296 Kolind-Andersen, H., 64 Kott, J. R., 47 Komatsu, S., 282 Komel, R., 327 Kominami, G., 284 Kon, K., 60 Kondo, H., 253 Konno, C., 213 Kono, M., 284 Konopelski, J. P., 51, 52 Konoshima, T., 234 Konuspaev, S. R., 25 Koolman, J., 286 Koolstra, R. B., 310 Koppel, C., 74 Korableva, N. P., 256 Korenstein, R., 260 Korobkova, 0. I., 46 Kortmann, D., 289 Koshimizu, K., 32, 73 Kosugi, H., 63 Koszyk, F. J., 135 Kotake, H., 22 Kotsuji, K., 61 Kouno, I., 130 Kouyama, T., 260 Kowalski, C. J., 40, 45 Kowata, N., 111 Koyama, K., 15,234 Koyama, T., 77 Koyama, Y., 262 Kozlov, E. I., 251 Kozlov, N. G., 45 Kozlowska, M., 57 Kozlowskagramsz, E., 46 Kozlowski, J. F., 146 Kozuka, M., 146 Kraus, G. A., 98 Kraus, W., 218, 219, 222 Krause, H. W., 42 Kramer, S. J., 77 Kramp, W., 169, 172 Kreiser, W., 33, 48 Kremers, P., 328 Kreutz, W., 260 Kreuz, K., 261 Krishendhar, A., 66 Krishna Rao, G. S., 67 Krishnasamy, V., 56 Kritskaya, I. I., 6, 48 Kritsky, M. S., 262 Krochmal, E., 72 Kropf, A., 259
Author Index Kroszczynski, W., 298 Krow, G. R., 46 Krueger, H., 284 Kruglaya, 0.A,, 46 Kruppa, G., 46 Krgukov, P. G., 260 Krywuta, S., 238 Ksander, G. M., 205 Kubo, I., 196 Kubo, S., 163 Kubota, N., 183 Kubota, T., 196, 197 Kucaba, W., 59 Kuchin, A. V., 12, 48 Kuczynski, H., 43 Kudryavtseva, M. I., 37 Kueh, J. S. H., 136 Kula, J., 38 Kulesha, I. D., 318 Kulikova, K. E., 272 Kulishov, V. I., 272 Kulkarni, G. H., 55, 56, 57, 64 Kulshreshtha, M. J., 46 Kumagai, A., 230 Kumagai, T., 20, 79, 203 Kumagi, M., 11 Kumar, N., 146, 156, 172, 174 Kumar, S., 4 Kumar, V. P. S., 226 Kumobayashi, H., 42 Kunesch, N., 85 Kurane, R., 74 Kurata, K., 99 Kurata, T., 51, 67 Kurek, A,, 325 Kurihara, T., 15 Kurita, N., 74 Kuriyama, K., 170 Kurobe, H., 28, 29, 34, 80, 252 Kurosawa, E., 88, 111, 157 Kurusu, Y., 13 Kusabayashi, S., 287 Kushinsky, S., 282 KUSS,E., 283 Kusumoto, S., 200 Kutchan, T. M., 63, 135 Kutney, J. P., 54, 55, 160, 210,228 Kutnik, J., 259 Kutschabsky, L., 198 Kuwajima, I., 46 Kuwata, M., 41 Kuzmichkin, P. V., 62 Kuznetsova, R. E., 25 Kwon, Y. C., 312 Kyogoku, Y., 210 Kyonaas, R., 72 Laats, K., 15 Lablache-Combier, A., 172
341 Labler, L., 290 Lachenmeier, A,, 240 Ladika, M., 76 Ladner, W., 8 Ladwa, P. H., 55 Lafont, R., 282 Lafontaine, J., 166 Laguerre, M., 51 Lahav, M., 271, 309 Lakshminarayana, V., 214 Lal, M., 37 Lalande, J., 31 Lallemand, J.-Y., 31,82, 174 Lamatkin, A. I., 41 Lamazouene, A. M., 52 Lamb, N., 48 Lambert, G., 65 Lamberton J. A,, 190 Lambotte, R., 328 Lammel, G., 60 Lamparsky, D., 32 Land, E. J., 243 Lander, N., 51, 66 Lang, C., 303 Lange, G. L., 42, 142 Lansbury, P. T., 179 Lanteri, S., 43 Lantzsch, R., 61 Lanzetta, R., 211 Lapalme, R., 45 Larcheveque, M., 82 Lardicci, L., 13 Laszlo, P., 328 Laszlo, T., 245 Laudova, V., 169 Lauer, M., 44 Lauher, J. W., 202 Laurent, H., 323 Lautens, M., 142 Law, J. H., 77 Lawrence, R. F., 10 Laycock, D. E., 302 Lazare, S., 33, 50, 304 Lazarev, Y. A., 260 Le, A. T., 76 Leander, K., 66 Leblanc, R. M., 259 Leboeuf, M., 85 Leclaire, R., 255 Leclercq, J. M., 259 Leclercq, M., 255 Lee, E., 315 Lee, G. J.-L., 282 Lee, J. G., 50 Lee,K. H., 53, 146, 174, 223, 234 Lee, T. S., 238 Lee, Y.-W., 315 Legon, A. C., 6 Lehmann, D., 59 Leiserowitz, L., 271, 309 Leistner, E., 266 Lemaitre, P., 3 1, 82 Le Merrer, Y., 89
Lemley, A. T., 258 Lemoine, G., 286 Lenton, J. R., 197 Lepicard, G., 272 Leppik, R. A,, 328 LeQuesne, D. W., 196 Leresche, J. P., 28 Leroy, E., 33 Leroy, F., 271, 272 Lesage, M., 47 Lester, D. J., 35, 213, 296, 299 Lethuillier, G., 62 Letoublon, R., 256 Leu, J. L., 196 Leuenberger, F. J., 237 Leutwiler, L. S., 261 Levina, I. S., 271, 272 Levine, S. G., 39 Levisalles, J., 298 Levy, S., 66 Lewicka-Piekut, S., 321 Lewis, A., 258 Lewis, K. G., 228 Lewis, N. J., 45 Ley, S. V., 81, 82, 83, 213, 295,299 Li, H., 312 Li, L. N., 312 Liaaen-Jensen, S., 237, 238, 243 Liang-Liu, W., 35 Lichtenberg, F., 40 Lichtenthaler, H. K., 265 Liefertova, I., 58 Lightner, D. A., 5, 33 Lin, J. T., 197, 281 Lin, S. H., 258 Lin, T., 225 Lin, Y. Y., 280 Lin, Z.-W., 197 Lincoln, D. E., 73 Lindblom, G., 258 Ljndig, C.,326 Lmdley, M. R., 320 Lindley, P. F., 271 Lindner, H. R., 285 Lipnicka, U., 50 Lisa, M.; 58 Lischewski, M., 198 Litaka, Y., 192 Litchfield, C., 237 Little, R. D., 135, 139 Little, R. J., 275 Lituyakova, E. N., 25 Litvin, F. F., 259, 260 Liu, C., 17 Liu, H. J., 31, 46, 114 Liu, R. S. H., 246, 250 Lloyd, H. A., 60 Lobanova, T. V., 245 Lochynski, S., 56 Loliger, P., 247 Lofgren, C. S., 77
342 Logan, R. T., 297, 299 Lohmann, J. J., 64 Lohr, K., 142 Lojewska, Z., 259 Lok Ho, T., 39 Lolmlund, C. E., 93 Lombardo, L., 199, 205 Lombardo, L. R., 266 Lonergan, G. C., 164 Lonergan, G. T., 39 Loomis, W. D., 4, 72 Lopez-Diaz, I., 262 Lopez, H., 114 Lorenc, L., 272,273,288,289 Lotan, D., 250 Lotan, R., 250 LOW,C.-E., 280 Lu, P. Y., 259 Luche, J. L., 13 Luckner, M., 4 Luft, R., 41 Lugaro, G., 210 Lugtenburg, J., 246,258,259 Lukacs, G., 4, 181, 276 Lukashin, A. V., 257 Lusinchi, X., 303 Luteijn. J. M., 65, 204 Lutz, W., 36 Lyman, H., 239 Lynch, J. E., 44 Lyon, G. D., 54 Lyse-Petersen, S. E., 59 Lythgoe, B., 318 Lyuts, A. E., 48, 62 Mabry, T. J., 193 MacAlpine, D. K., 123 Macaulay, J. B., 40 McCaskill, R. H., 131, 134 McCombs, C. A., 181 McConnell, 0. J., 31, 79,201 McCorkindale, N. J., 85, 86 McCormick, J. P., 299 Macdonald, J. E., 10 McDonard, J. T., 6 McElhinney, R. S., 50 McGarry, G., 299 McGrath, M. J., 55 McGuire, F. J., 116 McInnes, A. G., 277 McIntyre, C. R., 86, 234 McIntyre, D. E., 78 McIntyre, H. B., 281 Mackae, I. C., 38 McKervey, M. A., 174 MacKinnon, S., 5 MacKoul, P. J., 327 MacMillan, J., 197, 198 McMillen, D. A., 285 McMorris, T. C., 323 McMurry, J. E., 205, 300 McMurry, T. B. H., 160 McPhail, A. T., 190
Author Index Maddocks., P. J., 10 Madruzza, G. F., 194 Maeda, K, 286 Maeda, N., 306, 3 11 Maemoto, K., 36 Maentele, W., 260 Magasuna, K., 16 Magno, S., 201 Magnus, P., 20 Magnus, P. D., 52 Mahato, S. B., 189, 230 Mahmoud, I. I., 85 Mahmoud, M. M., 271 Mahmoud, Z. F., 102 Mahon, M., 81, 82, 83 Mailahn, W., 107 Maillo, M. A., 83 Main, P., 272 Maione, A. M., 270, 306 Maiti, S. N., 230 Maitra, M., 234 Majerski, Z., 42 Majewski, M., 17, 63 Maji, K. S., 204 Makhan’kov, V. V., 216 Makin, H. L. J., 282 Makino, M., 259 Makowski, B., 46 Malakov, P., 190 Maldonado, L. A., 15 Malingre, T. M., 60 Malinovskaya, G. V., 216 Malinovskii, M. S., 23 Mallavarapu, G. R., 226 Malleron, J. L., 11, 43 Mallik, B., 258 Mallinson, P. R., 271 Malone, J. F., 174 Mal’tsev, D., 264 Manchand, P. S., 200, 202 Mancuso, A. J., 288 Mandai, T., 19, 251 Mander, L. N. 195, 199, 205 Mandloi, D., 234 Mane, B. M., 56, 57 Mangoni, L., 211 Manh, D. D. K., 100 Manitto, P., 207 Manley, R. P., 314 Mann, V., 283 Mannschreck, A., 7 Mansilla, H., 158 Mansour, E . 4 . S., 228 Mantulin, W. W., 286 Manukov, E. M., 62 Mao, B., 247,259, 260 Maoka, T., 237 Maradufu, A., 146 Marazza, F., 121 Marcelin, G., 50 Marcelle, G. B., 221 March, G., 201 Marchand, B., 46 Marekov, N. L., 312
Marini Bettolo, G. B., 278 Marini-Bettolo, R., 325 Markowicz, S. W., 51, 52 Marples, B. A., 306 Marquez, C., 191 Marsaidi, A. J., 194 Marschall, H., 11 Marshall, D. G., 202 Martin, A., 194 Martin, B. R., 66 Martin, J. D., 80 Martin, P., 64 Martin, V. S., 27 Martha, D., 63 Martinez-Ripoll, M., 190, 192 Martinkus, C., 72 Martinkus-Taylor, C., 72 Martino, J. P., 312 Marunaka, T., 197 Maruyama, T., 81 Marx, P., 5, 6 Masaki, Y., 12,20,33,63 Masamune, T., 29, 79, 99, 163, 166, 309, 311 Mascarenhas, I. P., 190 Mash, E. A., 76 Mashiko, T., 172 Mashima, K., 16 Mason, A. N., 328 Mason, K. G., 306 Masood, M., 234 Massey, I. J., 280 Massiah, T. F., 271 Massy-Westropp, R. A., 75 Mastalerz, H., 291, 304 Masuda, H., 59 Masuda, K., 38,225 Masuda, S., 21 Masuyama, Y., 13 Matawowski, A,, 14 Materna, J., 194 Mathew, K. K., 18 Mathew, P. C., 41 Mathews, R. S., 61 Mathies, R., 258 Matsubara, Y., 24,35,41,42, 50, 51, 53 Matsuda, R., 73, 183, 184 Matsui, M., 15 Matsui, T., 98 Matsuki, Y., 28 Matsumato, M., 13 Matsumoto, H., 246 Matsumoto, T., 49, 99, 115, 123, 124, 126, 134, 136, 194, 199, 204, 213, 214, 274, 277 Matsumura, C., 60 Matsumura, K., 327 Matsumura, Y., 86 Matsunaga, T., 264 Matsunami, S., 24 Matsuno, T., 237, 262, 263
343
Author Index Matsuo, A., 92, 183, 187 Matsuo, K., 116 Matsuo, N., 64 Matsuo, T., 19 Matsushita, H., 23, 85, 253 Matsushita, K., 234 Matsuura, Y., 199 Matsuzaki, T., 199 Matteson, D. S., 50 Matveets, Y. A., 260 Matz, J. R., 39 Maumy, M., 49 Maurer, B., 81 May, E. L., 66 Mayer, G. D., 327 Mayer, H., 237, 240, 247, 253 Maynard, J. K. L., 41 Mayol, L., 201 Mazumdar, P. C., 189 Mazumder, A., 52 Mazur, Y., 276, 309 Mazza, F., 270, 272, 306 Mazzola, E. P., 93 Meadows, J. D., 314 Mechoulam, R., 51, 66, 74, 318 Medarde, M., 48, 118 Mednikova, N. A., 251 Medwick, T., 282 Meganathan, R., 266 Megges, R., 272,273 Meguri, H., 199,231 Mehrotra, A. K., 52 Mehta, G., 39, 135, 193 Meiboom, S., 287 Meier, B., 59 Meier, H., 193 Meier, W., 290 Meijer, E. W., 53 Meijer, J., 19 Mekeev, E. M., 255 Mellerio, G., 135 Mellor, M., 136 Meltzer, P. C., 65, 66 Menarchy, M. D., 196 Merchant, J. R., 21 Merchlinsky, M. J., 298 Merienne, C., 222 Merrien, A., 216 Mervic, M., 327 Meskens, F. A. J., 297 Messerschmidt, A., 272, 273 Mesta, C. K., 102 Mestres, R., 37, 40 Metcalf, B. W., 226, 324 Metge, C., 42 Meunier, B., 48, 216 Meyer, M. D., 314 Meyers, A. I., 44 Mhehe, G. L., 31 Michon, J., 53 Micovic, I., 272 Midgley, J. M., 47
Midland, M. M., 8, 312 Mielczarek, I., 63 Mihaashi, S., 187 Mihailovic, M. Lj., 272,273, 288,289 Mikami, Y., 31, 263, 264 Mikkelsen, C. B., 58, 60 Milkova, T. S., 312 Miller, B. W., 273, 322, 323 Miller, D., 246 Miller, J. A., 98 Miller, J. G., 37 Miller, R. B., 160 Miller, R. J., 73 Milner, D. J., 64 Mimura, T., 9, 21 Minachev, K. M., 33 Minale, L., 3, 318 Minami, Y., 134, 197 Minkiewicz, J. V., 35 Minocha, P. K., 234 Minowa, N., 264 Minton, M. A., 61 Mirek, J., 39 Mirza, N. A., 62 Miski, M., 193 Misra, A. N., 41 Misra, L. N., 55, 56 Misra, R. N., 108 Misra, T. N., 258 Misumi, S., 124, 126 Mitchell, S. J., 172, 182, 200 Mitra, A. K., 187, 230 Mitra, R. B., 57, 64 Mitscher, L. A., 19, 293 Mitsuhashi, H., 200 Mitsuki, M., 194 Mitsunobo, O., 289 Mitzka-Schnabel, U., 261 Miura, H., 61 Miura, I., 104, 201 Miura, T., 273 Miyahara, K., 214 Miyahara, Y., 214 Miyai, K., 284 Miyaji, M., 74 Miyamoto, T., 64 Miyamoto, O., 89 Miyanke, T., 18 Miyano, M., 321 Miyashita, M., 52 Miyata, N., 3 11 Miyawaki, H., 38, 50 Miyazaki, S., 38 Mizuno, A., 19 Mizuno, Y., 36 Mkandawire, G. J., 271 Mlotkiewicz, J. A., 124 Mnatsakanyan, V. A., 230 Mpango, G. B., 17, 63 Modi, V. V., 262 Modsen, H. B., 64 Moir, D., 228 Moiseenkov, A. M., 16
Molls, U., 38, 43 Molnar, P.,256 Mondon, A., 183 Monbger, R., 260 Moneti, G., 5 Money, T., 45, 48 Mongrain, M., 166 Monji, N., 284 Monroe, B. M., 36 Montanari, S., 184 Moore, A. L., 243, 256 Moore, P. H., 281 Moore, T. A., 243, 256, 258 Moore, W. S., 73 Mootoo, B. S., 221 Morah, F. N., 60 Morand, P., 291, 304 Morch, L., 8 Moreau, J. L., 14 Moreau, S., 172 Moreno, D. S., 63 Moreno, M., 234 Morera, E., 323 Moretti, I., 5 Morgans, D. J., 20 Mori, K., 19, 21, 38, 62, 63, 77 Mori, O., 35 Moriarty, R. M., 320, 321 Morin, L., 5 Morinaka, H., 68 Morisaki, M., 316 Morita, M., 187 Morita, K., 60 Moriyama, Y., 226 Mornon, J. P., 272, 303 Moroe, M., 54 Morris, D. J., 281 Morris, D. S., 319 Morris, G. A., 275 Morrison, J. C., 254 Morrison, G. A., 299 Morton, R. S., 36 Mortreux, A., 33 Moss, G. P., 241 Moss, R. A., 157 Motherwell, R. S. H., 37 Motherwell, W. B., 35, 37, 292, 296, 307, 321 Motto, M. G., 247 Mourino, A., 320, 321 Mousdale, D. M. A., 255 Mowery, P. C., 260 Mrozinska, P., 37, 43 Muccino, R. R., 18 Muchowski, J. M., 291 Muller, L., 116,146, 169,225 Mueller, R. H., 13 Muller, R. K., 237, 240 Mues, R., 73 Mujano, M., 290 Mukaiyama, T., 21, 31, 86, 283 Mukharnedova, L. A., 37
Author Index
344 Mukherjee, D., 204, 325 Mukherjee, K., 226 Mukherjee, K. S., 193 Mukhopadhyaya, S. K., 204 Mukitanova, T. R., 49 Mulholland, D. A., 219 Muller, B. L., 23 Muller, G. W., 135 Muller, P. M., 13 Muneyuki, R., 50 Munro, M. H. G., 15, 194 Murae, T., 21 1, 223 Murahashi, S. I., 28, 52 Murai, A., 29, 79, 163, 166 Murai, F., 58, 59, 60 Murai, N., 61 Murakami, T., 195 Muraki, S., 32, 141 Muramatsu, T., 57 Murata, S., 124 Murata, Y., 126 Murato, K., 255 Murgia, S. M., 259 Murillo, F. J., 262 Muro-Oka, Y., 22 Murphy, C. J., 53 Murphy, P. T., 15, 201 Murphy, R., 29 Murray, M. J., 73 Murray-Rust, J., 124 Murray-Rust, P., 124 Murthi, G. S. S., 52 Murthy, P. P. N., 98 Murty, V. S., 226 Murty, Y. L. N., 214 Musavirov, R. S., 16 Musiani, M. M., 45 Musser, J. H., 205 Muto, S., 262 Mutsushita, S., 38 Muzart, J., 11, 13 Myers, A. B., 259 Myshenkova, T. N., 40 Myskewnora, T. N., 14 Nabeya, H., 199 Nadaya, K., 183 Naf, F., 21, 179 Nafie, L. A., 5 Nagai, K., 40 Nagai, M., 214, 216 Nagai, S., 46 Nagai, Y., 13 Nagajima, K., 59 Nagakura, A., 54 Nagano, E., 254 Nagao, K., 179 Nagao, Y., 186 Nagaoka, M., 325 Nagar, P. K., 256 Nagasaki, M., 187 Nagasampagi, B. A., 146, 158, 210,232 Nagata, S., 262, 263
Nagumo, M., 258 Nagumo, S., 216 Nahrstedt, A., 15 Naik, D. G., 225 Naik, V. G., 50, 56 Nair, A. G. R., 32 Naito, T., 85 Nakachi, K., 259 Nakagama, H., 21 Nakagawa, K., 62 Nakagawa, T., 200 Nakahara, M., 286 Nakahara, Y., 98 Nakai, J., 45 Nakai, T., 9, 14, 21, 253 Nakai, Y., 79, 203 Nakajima, K., 59 Nakajima, S., 176 Nakamo, S., 64 Nakamura, A., 16 Nakamura, M., 234 Nakamura, N., 27, 255 Nakane, M., 60 Nakanishi, K., 81, 219, 247, 259, 260 Nakanishi, T., 104 Nakano, T., 83, 194 Nakao, Y., 69 Nakashima, T. T., 275 Nakata, T., 85 Nakatani, M., 219 Nakatsu, T., 190 Nakaya, K., 264 Nakayama, K., 319 Nakayama, M., 40, 92, 183, 187, 199 Nakayama, N., 48 Nakenishi, K., 315 Namamura, A., 12 Namanishi, O., 33 Namba, T., 213 Nambara, T., 282, 283, 284 Namikawa, M., 21 1 Nanasawa, M., 259 Nanayakkara, N. P. D., 227, 230 Naoki, H., 70, 184 Narasaka, K., 31 Narayanan, C. R., 225 Narula, A. S., 210 Naruse, N., 61 Naruta, Y., 265 Naruto, M., 61 Narva, D., 258 Nasini, G., 230 Nasipuri, D., 203 Nasybullina, F. G., 37 Natakani, Y., 33 Natalie, K. J., Natarajan, C. P., 42 Nathu, N. K., 203 Natu, A. A., 66 Naya, K., 35, 37 Nayak, U. R., 47
Nazarians, L., 146, 172 NCdelec, L., 321 Neef, G., 324 Negishi, E., 18, 23, 253 Negishi, T., 62 Negron, G., 190 Neidlein, R., 243 Neill, S. J., 238 Nelson, C., 276 Nelson, W. H., 257 Nemoto, H., 27, 28, 29, 34, 80, 252, 314 Neron Desbiens, M., 193 Nes, W. D., 207, 210 Nes, W. R., 312 Nesmeyanov, A. N., 48 Neszmelyi, A., 4, 181 Nice, E. C., 281 Nick, H., 45 Nickon, A., 116 Nicoara, E., 245 Nicol, M., 258 Nicolaou, K. C., 43 Nicotra, F., 210, 328 Nielsen, B. J., 5, 57, 58, 59, 70 Niemeyer, U., 5 , 6 Nigarn, M. C., 32, 55, 56 Niknejad, A., 172 Nikolaev, V. F., 6 Nilsson, K., 228 Nishida, K., 190 Nishida, T., 265 Nishida, Y., 54 Nishihama, Y., 59 Nishikawa, J., 276 Nishikawa, K., 19, 251 Nishimura, H., 34, 61 Nishimura, T., 33, 51 Nishino, C., 5 , 50, 51 Nishino, T., 210 Nishioka, I., 66, 203, 215 Nishizawa, A., 9 Nishizawa, M., 24 Niwa, M., 91, 189, 230 Noam, M., 318 Noda, Y., 81, 197 Node, H., 190, 196 Nogami, Y., 289 Nogasampagi, B. A., 73 Noguchi, M., 253 Nokami, J., 60, 99 NoLara, T., 203, 215 Noma, Y., 73 Nomura, D., 130 Nomura, M., 24, 35, 42, 51 Nordblom, G. D., 283 Nordman, C. E., 270 Norin, T., 106, 172 Norman, A. W., 306, 321 Norris, A. F., 319 Notegen, E.-A., 94 Novikov, V. L., 216 Novotny, L., 169
345
Author Index Noyori, R., 24, 44, 124 Nozaki, H., 25, 29, 37, 42, 63, 183 Nozaki, K., 15 Nozaki, N., 12 Nozari, H., 10 Nozoe, S., 4 Numazawa, M., 270, 289 325 Nunn, M. J., 98 Nyfeler, R., 121 Obermann, H., 33 Oberti, J. C., 195 Obi, Y.,31, 263, 264 O’Brien, E., 87 Ochi, M., 201 Ochiai, M., 186 Oda, N., 46 Odeh, I. M. A., 170 O’Dowd, M. L., 45 Oesterhelt, D., 259, 260 Offermann, W., 7 Ogasawara, K., 38, 206 Ogawa, K., 192 Ogawa, M., 229 Ogihara, Y., 229, 234 Ogiso, A., 187 Ognyanov, I., 172 Ogunkoya, L., 207 Ogura, H., 160 Ogura, K., 77 Ogura, M., 226 Oguri, K., 66,266 O’Hare, M. J., 281 Ohashu, K., 39 Ohbao, S., 189 Ohfune, Y., 124 Ohloff,G.,23,37,38,51,81, 91,179,231,238 Ohlsson, A., 66, 73 Ohmizu, H., 64 Ohmori, H., 234 Ohmori, M., 319 Ohnishi, R., 49 Ohno, A., 45 Ohno, K., 61 Ohnuma, T., 141 Ohsawa, T., 290 Ohta, Y., 158 Ohtsuka, T., 124, 126 Oikawa, T., 25 Oishi, T., 8 5 , 193, 194,290 Ojhara, B., 77 Ojima, I., 11 Ojinnaka, C. M., 231 Oka, S., 45 Okabe, H., 214 Okada, S., 210 Okada, Y., 15,234 Okamoto, K. A., 73 Okamura, N., 215 Okamura, S., 14
Okamura, W. H., 250, 306, 320, 321 Okano, M., 40, 89, 223, 234 Okawara, M., 19, 42, 62 Oki, M., 40,89 Okita, H., 69 Okogun, J. I., 221, 231 Okorie, D. A., 231 Okubo, A., 264 Okukado, N., 18 Okumura, S., 72 Okuyama, T., 15,234 Olaniyi, A. A., 227 Olesker, A., 43 OlivC, J. L., 39 Oliver, R. W. A., 287 Olson, R. E., 76, 266 Oniarkulov, T. O., 255 Omura, Y., 62 Ong, C. W., 97 Ongena, R., 61 Onishi, A., 264 Onishi, T., 265 Ono, H., 309 Ono, M., 14, 24 Oontento, M., 25 Opferkuch, H. J., 200 Oppolzer, W., 101, 121 Orchinnikov, Y. A., 247 O’Regan, P. J., 59 Oriente, G., 186, 201 Oritani, T., 14, 72, 254 Ors, J. A., 38 Orsini, F., 68, 204 Orszanska, H., 37, 40 Ortar, G., 323 Osawa, E., 115, 126 Osawa, Y., 270,289, 325 Oshima, K., 29, 37, 42, 63 Oshima, Y., 213 Osianu, D., 245 Oskoui, M. T., 228 Osugi, J., 286 Otera, J., 19, 251 Ottolenghi, M., 258, 260 Ourisson, G., 73, 183, 207, 208, 209, 211, 225, 232, 309,407 Overman, L. E., 22 Ozaki, Y., 58 Ozawa, S., 42 Oztunc, A., 80 Paaren, H. E., 319, 320 Pachaly, P., 59 Pachlatko, J. P., 129 Pagnoni, U. M., 61 Pagsberg, P. B., 257, 259 Pai, P. P., 55, 56 Pailer, M., 33 Paine, A. J., 46 Pak, A. M., 25 Pak, N. D., 49
Paknikar, S. K., 62, 67, 102, 103 Pakrashi, S. C., 172, 277 Pal, R., 231 Paldugin, V. A., 187, 200 Pale, P., 13 Palfreymer, M. N., 52 Palings, I., 246, 258, 259 Pallix, J. B., 257 Palma, M. M., 73 Palmer, R. A., 271 Palmskog, G., 255 Pal’yants, N. Sh., 234 Pamingle, H., 23 Pan, D., 235 Pan, Y.-G.,181 Panasenko, I. S., 251 Panorazi, A,, 42 Pande, A., 258 Pandian, S., 266 Pandit, U. K., 296 Pandy-Szekeres, D., 10 Panosyan, A. G., 230 Papagorgiou, V. P., 44 Papanov, G., 190 Papoula, M. T. B., 35 Paquer, D., 4, 5 Paquette, L. A., 21, 41, 42, 46, 99, 118, 119, 129, 139, 297 Paradisi, M. P., 296 Pardo, R., 40, 42 Parikh, V. D., 293 Parish, E. J., 318 Park, 0. S., 15 Park, R. J., 59 Park, Y. Ja, 272 Parker, W., 124 Parra, A., 199 Parrilli, M., 21 1 Partridge, J. J., 318 Parves, M., 174 Paryzek, Z., 211 Pascard, C., 43,48,156,216, 219, 226 Pascoe, K. O., 200 Pasechnik, G. S., 195 Passacantilli, P., 58, 59, 60, 61 Passet, J., 60 Pasteels, J., 202 Patel, B. A., 35 Patel, D. P. J., 22 Patel, S. K., 34 Paternostro, M., 190, 191 Paterson, I., 19, 299 Pathak, V. P., 67 Patil, D. G., 47 Patni, R., 192 Patra, A., 187, 230 Pattenden, G., 10, 64, 105, 136,138,183 Patterson, G. W., 210,273 Patterson, W., 18
346 Paul, D., 271 Paul, V. J., 31 Pauly, G., 74 Pauptit, R. A., 6 Paupurdin, C., 72 Pavanasasivam, G., 93 Pavel, N. V., 272 Pavia, A. A., 39 Pavlin, M. S., 49 Pavlovic, V., 272, 273, 289 Pawson, B. A., 247 Payan, C., 260 Payne, T. G., 188 Pearce, A., 19 Pearson, A. J., 97 Pecher, J., 228 Pedulli, G. F., 7 Pegg, D. T., 274 Pelister, Y.,39 Pelizzoni, F., 68, 204 Pelliciari, R., 31, 192, 194, 252, 324 Pena, A., 199 Pentegova, V. A., 73 Peppard, T. L., 15 Perales, A., 191, 192 Pereira, V. A., 42 Perez, C., 62, 80 Peries, R., 31 Perkins, M. J., 52 Pernold, W., 47 Perz, R., 40 Pete, J. O., 11, 13 Peters, J. A. M., 307 Petiaud, R., 33 Petit, F., 33, 48 Petrasiunas, G. L. P., 53 Petrov, A. A., 286 Petzdolt, K., 323 Pfander, H., 240, 243 Pfenninger, J., 300, 301 Pham, C. C., 4 Philibert, D., 324 Phillips, F. L., 227 Phillips, L. R., 35, 39 Phillipson, J. D., 223 Phinney, B. O., 198 Piatkowski, K., 35, 37, 43 Piattelli, M., 186, 201 Piau, F., 64 Picard, J. P., 10 Pichet, L., 327 Pickard, J., 106 Pickenhagen, W., 62 Pierce, T. E., 36 Piers, E., 172 Pietrzak, J., 298 Pillai, N. K., 307 Pillot, J.-P., 10, 25, 51, 62 Pinchin, R., 196, 215 Pinder, A. R., 156 Pinnick, H. W., 24, 36, 38 Pinto, A. C., 192, 196, 215 Piozzi, F., 190, 191, 230
Author Index Pirozhkov, S. D., 14, 40 Pirrung, M. C., 118 Pitha, J., 250 Pitt, C. G., 65, 66 Piwinski, J. J., 178 Pizza, C., 318 Pizzi, P., 328 Pizzo, C. F., 34 Platzer, N., 4 Plimmer, J. R., 63 Plummer, T. L., 180 Poddubnaya, S. S., 14, 40 Podlejski, J., 38 Pokhilo, N. D., 216 Pol, A. V., 50, 56 Polavarapu, P. L., 5 Poldidon, G., 59 Poletti, A., 259 Polishchuk, A. P., 272 Polo, M. C., 37 Polonsky, J., 156, 194, 216, 222,223 Polunin, E. V., 16 Pomilio, A. B., 195 Pons, M., 289 Ponsold, K., 273, 282, 302 Ponton, J., 121 Poots, I., 68 Popa, D. P., 195 Popli, S. P., 228 Popov, A. A., 49 Popov, 0. S., 255 Popov, S., 312 Popovitz-Biro, R., 271, 309 Popp, A., 73 Popplestone, R. J., 23 Porath, G., 66 Porte, A. L., 123 Porter, J. W., 235 Postlewhite, A., 50 Potlier, E., 40 Poulose, A. J., 35, 71 Poulter, C. D., 20, 63, 76 Pouskouleli, G., 275, 276 Pouzar, V., 314, 325 Povelikina, L. N., 46 Povodyreva, I. P., 5 5 , 56 Powell, L. A., 250, 251 Pownall, H. J., 286 Poznyakov, S. P., 250 Pradhan, S. K., 296 Prager, R. H., 29 Prakasa Rao, A. S. C., 93,99 Prange, T., 43,156,226,270, 297 Prasad, R. S., 205 Prasanna, S., 226 Precigoux, G., 271, 272 Prelesnik, B. V., 272 Prestwich, G. D., 74, 202 Pretzsch, G., 174 Pribytkova, I. M., 20, 34 Price, H. C., 277 Price, J. C., 256
Price, L. G., 299 Priester, W., 13 Prokopiou, P. A., 301 Proksch, P., 44 Protiva, J., 231 Proudfoot, G. H., 186 Provost, J., 234 Pugliese, J. C., 254 Purdie, N., 278 Purdy, R. H., 281 Puritskii, K. V., 40 Purkina, A. V., 286 Purushothaman, K. K., 146, 193 Pusil'nikova, S. D., 286 Puzitski, N. V., 14 Queirez, P. P., 192 Quilliam, M. A., 279 Quinn, P. J., 266 Quirk, J. M., 39, 294 Raasch, M. S., 51 Rabanal, R. M., 191 Rabaron, A., 59 Rabenstein, D. L., 275 Rabi, J. A., 296 Radhakrishnan, R., 260 Radhakrishnan, T. V., 296 Radics, L., 256 Radley, M. E., 197 Raffauf, R., 196 Raffelsberger, B., 58 Raghavan, N. V., 251, 259 Rahier, A., 210 Raisanen, S., 5 Rajendran, K., 102 Rakhmankulov, D. L., 16 Ralph, D. E., 104 Ramachandra Rao, V., 53 Ramamurthy, V., 250 Raman, P. S., 18 Raman, T. S., 266 Ramdahl, T., 238, 243 Ramdazzo, G., 69 Ramirez, M. A., 80 Ramise, A., 46 Ranganathan, D., 52 Ranganathan, S., 52 Rangaswami, S., 228 Ranise, A., 43 Rapp, A., 14 Rao, A. S., 38, 67 Rao, B. C., 192 Rao, C. B., 52, 60 Rao, M. N., 226, 230 Rao, R. N., 281 Rassat, A., 53 Rassl, D., 37 Rastogi, R. P., 115, 207, 258 Raston, C. L., 188, 189,202, 226
347
Author Index Ratner, V. V., 43, 55 Rau, W., 261, 262 Raucher, S., 10, 38 Rautenstrauch, V., 12, 14 Ravelo, A. G., 230 Ravelo, F., 80 Raverty, W. D., 44 Ravi, B. N., 234 Ravichandran, R., 302 Ravindranath, B., 42, 67 Ray, R., 50 Rayer, R. C., 62 Raymaud, J., 280 Razdan, R. K., 65, 66 Read, C. M., 292 Read, R. W., 292, 302 Reck, G., 198, 273 Recti, M. T., 8 Reddy, A. V., 39, 135 Reddy, G. C. S., 228 Reddy, G. S., 300 Reddy, N. S., 106 Redshaw, S. D., 22 Rees, J. C., 6, 54 Reetz, M. T., 92, 297 Reger, D. L., 255 Reh, E., 282 Reich, H. J., 76 Reichert, U., 177 Reiffsteck, A., 281 Reinbol’d, A. M., 195 Reis, F. A. M., 215 Renstrom, B., 237 Rentzepis, P. M., 259 Repke, K., 326 Rettig, M. F., 64 Reutov, 0. A., 49, 51 Reverdy, G., 53 Revial, G., 101 Rey, M., 110 Reye, C., 40 Ribaldi, M., 192 Riccio, R., 318 Richard, C., 323 Riche, C., 85 Rickards, R. W., 37 Riddell, F. G., 124 Riechst, R. A. K., 38 Rieger, D. L., 38 Riehl, J.-J., 113, 114 Riesselmann, B., 286 Rihs, G., 272, 289 Rilling, H. C., 76 Rimpler, H., 59, 60 Risinger, G. E., 69 Rist, G., 272, 289 Ritter, F. J., 77 Rivera, A., 308 Rivier, L., 197 Rizvi, S. H., 228 Rizvi, S. Q. A., 275 Roberts, J. S., 116, 124 Roberts, M. R., 161 Robinson, C. H., 308
Robinson, H., 62,66,73, 75, 88, 106, 114, 115, 116, 117, 146, 155, 156, 158, 169, 170, 172, 174, 187, 188, 189, 195, 196, 225 Robinson, J. M., 279 Robinson, T., 4 Robinson, W. T., 15, 194 Rodgers, M. A. J., 257, 259 Rodier, N., 272 Rodini, D. J., 9, 21, 40, 48, 63 Rodionov, A. V., 247 Rodriguez, B., 187, 188, 190, 191,192,225 Rodriguez, M., 5 Rodriguez, V. M., 234 Rodriguez-Hahn, L., 190 Roedam, A., 73 Rogers, D., 227 Rogerson, C. V., 47 Rogues, R., 6 Rohmer, M., 207, 208, 209, 232 Rohner, H. C., 53 Rojas, A., 194 Romdn, L. U., 115 Romanov, N. A., 16 Romeo, A., 270, 306 Ronald, R. C., 71 Ronchetti, F., 210, 328 RBnneberg, H., 238 Roobeck, C. F., 33 ROOS,R. W., 282 Roper, M., 12 Rosazza, J. P., 223 Rose, A. F., 187 Rosenberger, M., 254 Rosenblum, M., 35 Ross, A. C., 255 Ross, P. E., 291 Rossi, C., 37, 69 Rossi, J. C., 60 Rossi, T., 129 Roth, B., 98 Rothschild, K. J., 258 Rouessac, F., 31 Roush, D. M., 40, 61 Roush, W. R., 111 Rousseau, G., 63, 89 Rouwette, P. H. F. M., 44 Row, L. R., 214 Rowan, D. D., 188 Rowan, M. G., 68 Rowe, J. W., 73, 210, 232 Roy, D. N., 231 Roy, G., 20 Roy, L. N., 226 Roy, R. G., 299 Rozen, S., 41,42 Rozynov, B. V., 230 Rsai, R., 281 Rubchinskaya, Y. M., 251 Ruberto, G., 186
Rubin, M. B., 46 Rubinova, N. R., 5 5 Rucker, E., 43 Rudnick, M. S., 239 Rucker, G., 38, 181 Rueedi, P., 193 Ruel, O., 64 Ruest, L., 166 Riittimann, A., 237, 240 Ruhdorfer, J., 59 Rulko, F., 63 Rullkotter, J., 232 Ruppert, J. F., 60, 99 RUSSO, G., 210, 328 Rustaiyan, A., 88, 146, 172 Rustidge, D. C., 75 Rutledge, P. S., 292,302,327 Ruveda, E. A., 194 Ruzicka, L., 209 RUZO,L. O., 64,74 Ryabora, K. C., 40 Ryabushkina, N. M., 33 Rybakov, V. B., 271,272 Rychlewska, U., 146 Rychnovsky, S. D., 27 Rycroft, D. S., 146, 216, 221 Rykowski, Z., 41, 49, 50, 51 Ryoshentseva, M. A., 33 Saburi, M., 253 Sadasivan, V., 41 Sadler, I. H., 121, 140 Sadowska, H., 55 Saeedi-Ghomi, M. H., 127, 128 Saengchjan, S., 266 Saenz de Buruaga, A., 199 Saga, H., 54 Sahu, N. P., 230 Sahui, R., 26 Sai, H., 190, 196 Sainton, J., 48 Sainty, D., 59 Saito, A., 85 Saito, H., 230,277,290,291 Saito, M., 16 Saito, T., 29, 141, 213 Saito, Y., 189, 266 Sakai, K., 126 Sakai, S., 232 Sakai, T., 59, 60, 70, 172 Sakakibara, J., 199 Sakan, F., 134, 136 Sakan, T., 59 Sakata, I., 32 Sakata, J., 73 Sakdarat, S., 29 Sakina, K., 59 Sakuma, K., 20, 33, 63 Sakurai, H., 16 Sakurai, N., 214,216 Salama, O., 7,, 58, 60 Salazar, J. A., 226, 308
348 Salemink, C. A., 67 Salen, G., 291, 312 Salisbury, P., 45, 48 Salisbury, P. J., 228 Salomon, R. G., 40 Sam, F. W., 31 Samaddar, A. K., 203 Samek, Z., 169, 174 Sammon, M., 287 Samokhvalov, G. I., 247, 255,261 Samsonova, V. N., 23 Samuel, O., 44 Samuelsson, G., 234 Sanchez, I. H., 103, 204 Sandberg, F., 234 Sanders, J. K. M., 273 Sandmann, G., 210, 261 Sandorfy, C., 259 Sandra, J. M., 15 San Feliciano, A., 118 Sangaiah, R., 67 Sanghui, Y. S., 67 Sanjoh, H., 29, 60 Sankaram, A. V. B., 106 Sankawa, U., 215, 277 Sannikov, 0. B., 255 Sano, H., 19,42 Sano, T., 232 Sansoulet, J., 9 Sant, P. G., 234 Santaniella, E., 295 Santelli, M., 40, 42 Santer, J. M., 247, 253 Santiago, M. L., 307 Santini, C., 142 Saplay, K. M., 26 Sarel, S., 54 Sarg, T. M., 102 Sarig, S., 271 Sarkar, A. C., 230 Sarkisian, G. M., 310 Sarma, M. R., 41 Sasaki, H., 32, 59 Sasaki, M., 63 Sasaki, S., 37, 42 Sashida, Y., 192 Sastre, B. A., 32 Sato, F., 18, 25, 44 Sato, K., 76, 89, 234, 264 Sato, M., 18, 25, 44 Sato, S., 61, 166 Sato, T., 9,30,33,36,39, 170 Sato, Y., 211 Satoh, J. Y., 295, 300, 318 Satoh, T., 172 Sattar, A., 31, 124 Saucedo, R.,190 Saucy, G., 13, 254 Sauer, G., 324 Sauer, M. J., 284 Saul, J. A., 329 Saussay, R., 72 Saussine, L., 62
Author Index Savard, S., 193 Saverwein, P., 28 Savoia, D., 25 Savona, G., 190, 191, 225 Savu, P. M., 17 Sawada, T., 234 Sawitzki, G., 218 Sawutz, D. G., 277 Sawzik, P., 286 Sayama, S., 157 Sayed, Y., 65 Scallen, T. J., 282 Scarborough, R. M., 43 Schade, W., 279 Schafer, H.-J., 21 Schaffner, K., 61 Scharf, H. D., 50 Scheffer, J. J. C., 44, 73 Scheidl, O., 33 Schene, A. L., 42 Schenk, H. P., 32 Schenone, P., 43, 46 Scheuer, P. J., 79, 200 Schiedt, K., 237 Schikop, T., 74 Schlatter, H.-R., 299 Schlessinger, R. H,, 161 Schlewer, G., 318 Schlosser, M., 35 Schmalle, H. W., 232 Schmidt, G., 25 Schmidt, J., 230 Schmitt, K., 286 Schmitt, P., 210 Schmuff, N. R., 43 Schneider, G., 198,303,327 Schneider, H. J., 50, 289 Schnelle, G., 8 Schnoes, H. K., 319 Schonecker, B., 273, 279, 282, 302 Schonholzer, P., 269, 318 Scholler, R., 281 Schostarez, H., 119, 129 Schouwey, M., 32 Schram, K. H., 219 Schreiber, K., 198 Schreiber, S. L., 38, 142 Schreier, P., 33 Schreiner, R., 258 Schrock, A. K., 279 Schroepfer, G. J., jun., 318 Schrott, E. L., 262 Schrott, U., 8 Schuber, F., 210 Schubert, G., 273,279 Schuelte, H. R., 4 Schulte, G., 79 Schulte-Elte, K. H., 12, 23, 28 Schulze, P.-E., 308 Schultz, A. G., 302 Schultz, G., 266 Schurig. V.,8
Schuster, A., 158, 169, 172 Schuster, R., 318 Schwack, W., 54 Schwartz, J., 312 Schwarz, M., 63 Schwedt, G., 282 Schweizer, W. B., 255 Schwenen, L., 5 Schwier, J. R., 52 Schwindeman, J. A., 52 Scognamiglio, G., 298 Scopes, P. M., 140 Scordamaglia, R., 6 Scott, W. J., 300 Scriven, F. M., 15 Sealfon, S., 21, 48 Seamark, D. A,, 282 Secord, N., 89 Seeger, A., 323 Segal, R., 62 Segal, R. A., 146 Segaloff, A., 325 Segura, M. L., 45 Seiber, J. N., 276 Seidel, I., 273 Seidler, M. D., 292 Seldes, A. M., 317 Self, C. R., 295 Selover, S. J., 202 Seltzman, H. H., 65, 66 Selva, A., 5 Semenovski, A. V., 16, 33, 252 Semmelhack, M. F., 130,161 Sen, A. K., 189 Sen, M., 230 Sendra, J. M., 32 Sengupta, P., 230 Sensen, S. R., 5 Seo, S., 209, 234, 276 Sepiol, J., 39 Sepulveda, J., 37 Serebryakov, E. P., 198 Sergent-Guay, M., 166 Sestak, Z., 256 Sethi, A. S., 39 Sethi, M. L., 15 Seto, S., 77 Setzer, S. R., 66 Sevenet, T., 222 Sgarabotto, P., 61 Shaden, G., 66 Shafiullah, 307 Shah, G. D., 65, 66 Shah, J. N., 52 Shah, S. K., 76 Shakhova, M. K., 255 Shamsuddin, K. M., 223 Shankaran, K., 38 Shanmuganathan, S., 193 Sharkov, A. V., 260 Sharma, A. S., 174 Sharma, M. L., 39, 253 Sharma, R. P., 146, 294
Author Index Sharma, S. P., 37, 39 Sharpless, K. B., 20, 23, 27, 50 Shaw, D. J., 266 Shaw, I. M., 38,47 Shchirina-Eingoru, I. V., 48 Shea, C. M., 99, 309, 311 Shearer, M. J., 266 Shefer, S., 312 Sheldrick, G., 66 Sheldrick, W. S., 48 Sheppard, P. N., 202 Sheth, J. P., 135 Sheves, M., 247 Shewmaker, C., 277 Shiao, M. S., 70, 88 Shibaev, V. N., 264 Shibagaki, M., 252 Shibasaki, M., 136 Shibata, K., 197 Shibata, S., 15,230,234,253 Shibayama, F., 200 Shichida, Y., 259 Shido, K., 234 Shieh, H.-S., 270 Shiga, M., 59 Shimada, A., 241 Shimada, K., 142, 143 Shimizu, M., 46, 48 Shimizu, N., 63, 214 Shimokawa, T., 115 Shimomura, H., 192 Shimozuma, K., 33 Shimpo, T., 54 Shingu, T., 58, 197, 230 Shioiri, T., 19 Shiojima, K., 225 Shiota, H., 59 Shirahama, H., 49, 115, 123, 124, 126, 134, 136 Shirai, N., 199 Shirakawa, K., 234 Shiroishi, M., 256 Shishibori, T., 68, 264 Shiuey, S.-J., 318 Shkrob, A. M., 247 Shmelev, L. V., 20, 34 Shmitz, R., 66 Shmueli, U., 234 Shochet, N. R., 271, 309 Shoda, S., 21 Shoeb, A., 228 Shono, T., 64 Shoolery, J. N., 63, 106 Shoppee, C. W., 318 Shoyama, Y., 66 Shropshire, W., jun., 262 Shukla, Y. N., 60 Sicva, M., 146 Siddall, J. B., 316 Siebert, F., 260 Siefermann-Harms, D., 237 Siegman, A., 258 Siemienink, A., 43
349 Sieng, L. H., 194 Sietsema, W. K., 263 Sigurdson, E. P., 45 Sil, A. K., 231 Sillesen, A. H., 257 Silveira, A., 18 Silveira, E. R., 190 Silverman, R. B., 265 Silverstein, R. M., 36 Sim, G. A., 123, 146, 169, 193 Simes, J. J. H., 215, 225 Simmross, F. M., 44, 91 Simonov, V. I., 271, 272 Simons, S. S., 289, 298 Simpson, I. C., 198 Simpson, J. B., 69 Simpson, K. L., 235, 245, 256 Simpson, T. J., 86, 87, 88, 234 Sims, D., 174 Sims, J. J., 15, 92 Sims, R. J., 81 Singaram, B., 52 Singh, A. K., 5 , 55 Singh, H., 271 Singh, J., 206, 214 Singh, P., 146 Singh, P. N., 234 Singh, R. D., 6 Singh, S. B., 32,234 Sinnott, M. L., 197 Sinyakov, G. N., 245 Sippel, C. J., 266 Sircar, P. K., 256 Sircar, S. M., 256 Sisani, E., 194, 252 Sisti, M., 184, 194 Sivaramakrishnan, R., 295 Sjostrand, U., 312 Skattebol, L., 20 Skatovski, E. D., 33 Skeiton, B. W., 78, 182 Skorkovska, H., 231 Skorobogatova, E. V., 46 Skripiuk, 0. B., 56 Skulberg, 0. M., 238 Slack, D. A,, 22 Slade, C. J., 322, 323 Slemt, J., 281 Sloan, K. B., 275 Slougui, N., 63, 89 Smit, E. N., 73 Smith, A. B., 43,63,119,300 Smith, A. G., 281 Smith, D. H., 280 Smith, E., 256 Smith, I. H., 64 Smith, L. C., 286 Smith, L. L., 280 Smith, T. L., 164 Smoczkiewicz, M. A., 321 Smolik, R., 303
Snajbark, K., 73 Sneden, A. T., 228 Snider, B. B., 9, 21, 28, 40, 48, 61, 63, 312 Snieckus, S., 17 Snieckus, V., 63 Snowden, R. L., 91, 113 So, S., 142 Soai, K., 44 Sobotka, W., 57 Sodano, G., 79, 298, 329 Soderlund, D. M., 64 Sohani, S. V., 296 Sohar, P., 303 Sohoni, J. S., 158 Sokoloski, E. A., 60 Sokolovsky, V. Y., 262 Sokolov, V. N., 48 Sokolskii, D. V., 25, 255 Soler, A., 45 Soll, J., 266 Solladie, G., 34 Soman, R., 41 Someya, T., 32 SommC-Martin, G., 282 Sonawane, H. R., 50, 56 Sondengam, B. L., 216,221 Song, B.-H., 253 Song, C. M., 253 Sonnay, P., 91 Sonnet, P. E., 38, 283 Sonobe, T , 6 0 Sonoda, Y., 211 Sood, G. R., 58 Sorg, B., 200 Sotheeswaran, S., 226 Soti, M., 328 Sotiropoulos, J., 6, 52 Soucy, P., 45 Soulen, R. L., 39 Southwick, E. W., 63 Sowes, R. W., 74 Sozzi, G., 303 Spagnoli, N., 192 Spaleck, N., 53 Spanton, S. G., 202 Specian, A. C., 247 Speek, J., 291 Spencer, G. F.. 213, 216 Spindell, D., 40 Spiridonova, M. E., 46 Spiro, T. G., 257 Sponsel, V. M., 198 Sporn, M. B., 263 Spring, O., 146 Spronck, H. J. W., 65 Spurgeon, S. L., 235 Sree, A., 226 Srinivas, P., 67 Srinivasan, C. V., 61 Srinivasan, R., 38 Srivastava, A. K., 234 Srivastava, K. C., 234 Srivastava, R. S., 234
Author Index
350 Staba, E. J., 234 Stahle, M., 35 Stahly, G. P., 93 Stahnke, M., 308 Stampf, J.-L., 318 Stanley, P., 98 Starzemska, H., 35 Steenkamp, J. A., 62 Steglich, W., 128 Steinbach, R., 8, 92, 297 Steinberg, 1. Z., 258 Steinbuch, K., 8 Steiner, E., 64 Stenstrou, Y., 20 Stenzel, D. J., 86 Stepanova, T. P., 286 Stephenson, D. F. M., 299 Stephenson, G. R., 44 Sterligova, G. I., 46 Stevens, E. S., 6 Stevens, K. E., 103, 139 Steyn, P. S., 172 Sticher, O., 5, 7, 58, 59, 60, 283 Stierle, D. B., 15 Still, W. C., 206 Stillman, M. J., 163 Stipanovic, R. D., 106 Stockburger, M., 258 Stockis, A,, 28 Stoeckenius, W., 259, 26) Stoessl, A., 163 Stork, G., 102, 206 Stothers, J. B., 163, 276, 307 Strand, M. R., 77 Straws, C. R., 14, 15, 27 Streckenbach, B., 272,273 Stribel, M. P., 4 Strong, P. D., 270, 271 Struchkov, Yu. T., 6, 272 Struchkova, M. I., 16 Stryer, L., 258 Stuart, A. D., 202 Stuart, K. L., 193, 228 Stuerle, H., 255 Stuttle, K. A. J., 52 Stutts, K. J., 250 Suarez, E., 225, 308 Subbarao, G. S. R., 39, 226 Subramanian, K., 193 Suda, M., 21 Suding, H., 114, 146, 196 Sudo, A., 60 Suehara, H., 21 3 Sueiras, J., 250 Suemitsu, R., 38 Suga, K., 11,21 Suga, T., 68,69,72,234,264 Sugden, J. E., 287 Suggs, J. W., 39, 294 Sugie, Y., 91 Sugimoto, Y., 172 Suginome, H., 306, 309, 3 11 Suguro, T., 21
Suhr, H., 46 Suire, C., 183, 184 Sullivan, B., 78 Sullman, E. M., 255 Sultanbawa, M. U. S., 202, 226, 227, 228, 230 Sum, F. W., 253 Sun, H.-D., 197 Sun, H. H., 201 Sun, R. C., 13 Sun, X.-C., 197 Sundar, N. S., 39 Sundaralingam, M., 232 Sunderaraman, P., 51 Sung, C.-K., 215 Sunko, D. E., 42, 76 Sunyawanshi, S. N., 47 Surburg, H., 183 Surcouf, E., 272 Suri, S. C., 193 Suseela, K., 192 Suterjadi, A., 60 Sutherland, M. D., 59 Suwita, A., 67, 88, 146 Suyunbaev, U., 255 Suzukamo, G., 46 Suzuki, H., 22, 259 Suzuki, K., 29, 54, 252 Suzuki, M., 111 Suzuki, S., 200 Suzuki, T., 21, 88, 99, 157, 258,259, 320 Svendsen, A. B., 44, 64, 73 Svovoda, G. H., 59 Swanson, B. N., 263 Swanson, S., 98 Swayze, J. K., 293 Sweeney, J. G., 294 Swenson, D. C., 271 Swern, D., 288 Swiatek, L., 59 Swiger, A. A., 36 Swindells, D. C. N., 271 Sykes, P. J., 327 Szabolcs, J., 256 Szalontai, B., 258 Szczepanski, A., 46 Szczepek, W. J., 305 Szeleczky, Z., 328 Taarit, Y. B., 33 Tabata, T., 232 Taber, D. F., 34 Taber, H. W., 266 Tada, M., 33, 170, 172 Tagawa, M., 58, 59, 60 Tagle, B., 127, 183, 202 Taguchi, H., 32, 59 Taira, Z., 158, 172 Takabe, K., 30,251 Takabe, S., 234 Takada, M., 266 Takagaki, T., 290
Takagi, H., 273 Takagi, K., 33, 51 Takagi, S., 59, 256, 277 Takagi, T., 256 Takagi, Y., 15, 238 Takahara, Y., 74 Takahashi, H., 43 Takahashi, K., 15, 32, 41, 141,230,234 Takahashi, M., 22, 232 Takahashi, N., 197 Takahashi, T., 33, 143, 170, 172, 211, 223, 226 Takahashi, T. T., 300 Takahashi, Y., 311 Takaki, K., 70 Takaksuto, S., 316 Takami, M., 62 Takane, S., 206 Takano, S., 38 Takase, K., 157 Takashi, I., 274 Takayama, H., 319, 320 Takayama, M., 230 Takayanagi, H., 5, 50, 51, 160 Takazawa, O., 85 Takeda, A,, 33, 38, 60 Takeda, R., 158, 183, 184 Takeda, T., 234 Takeda, Y., 59, 60, 61, 70, 181,197 Takei, S., 206 Takemoto, T., 73, 85, 158, 172,183,184 Takemura, K. H., 185 Takenaka, S., 287 Takeo, T., 15 Takeshita, H., 130 Taketomi, H., 42 Taki, M., 59 Takigawa, T., 19 Taksuta, K., 135 Tal, D. M., 276 Talapatra, B., 227, 230 Talapatra, S. K., 227, 230 Talvitie, A., 106 Tamaru, Y., 12 Tamas, V., 245 Tamm, C., 94 Tamir, I., 66, 318 Tamura, H., 85 Tamura, M., 46 Tamura, T., 213, 214, 230, 274, 277,285 Tanabe, K., 37,42, 49, 51 Tanahashi, T., 70 Tanaka, K., 41 Tanaka, M., 46 Tanaka, N., 195 Tanaka, O., 196,234 Tanaka, S., 12, 25 Tanaka, T., 196 Tanaka, Y., 12, 256, 269
Author Index Tandon, R., 231 Tandon, R. N., 234 Taneja, S. C., 15, 33 Tang, C. P., 271, 309 Tange, K., 69 Tani, T., 48 Tanida, K., 38 Tanis, S. P., 81 Taniyasu, S., 234 Tasumi, M., 257 Tateishi, K., 284 Tatsuno, T., 98 Tauber, J. D., 237 Tavecchia, P., 194 Taylor, D. A. H., 219 Taylor, G. J., 329 Taylor, W. G., 64 Tazawa, H., 24 Teehan, I. R., 206 Tellado, F. G., 199 Tempesta, M. S., 219 Temple, J. S., 312 Tenczer, J., 74 Tenneson, M. E., 328 Terai, T., 199, 231 Ternai, B., 226 Terpugov, E. L., 260 Terra, W. R., 238 Terui, Y., 276 Teutsch, G., 303, 323, 324 Texter, J., 6 Thacker, V. B., 296 Thaisrivongs, S., 205 Thakur, R. S., 32 Thaller, V., 140 Thappa, R. K., 211 Theil, F., 326 Thies, P. W., 5 , 59 Tho, N.-D., 228 Tho, Y. P., 202 Thomas, A. F., 3, 32 Thomas, D. M., 60 Thomas, H., 59, 62 Thomas, J. A., 98 Thomas, M. T., 17, 63 Thommen, W., 14 Thompson, M., 70 Thomson, R. H., 80 Threlfall, D. R., 266 Thyagarajan, G., 146 Tice, C. H., 177 Tietze, L.-F., 5,6,61,66,70, 177 Tilchourova, L. A., 46 Tillman, A. M., 129 Timms, R. N., 295, 318 Timoney, R. T., 73 Timoshina, T. N., 56 Tingoli, M., 324 Tint, G. S., 291, 312 Tishchenko, V. G., 272 Tius, M. A,, 53, 204 Tiwari, K. P., 234 Toda, H., 52
351 Toda, S., 264 Toder, B. H., 63 Toeplitz, B. K., 272, 293 Toia, R. F., 189 Tokoroyama, T., 201 Tokubuchi, N., 203 Tokunaga, F., 260 Toledo, F., 146 Tolstikov, G. A., 12, 48 Toma, L., 328 Tomasik, W., 299 Tomb, F., 118 Tome, G., 5 Tomimatsu, T., 203 Tomimori, T., 234 Tomita, B., 105 Tomita, K., 165 Tomita, M., 36 Tomita, Y., 209 Tomoda, S., 130 Tomosue, K., 48 Tomuro, Y., 25 Tonnesmann, U., 74 Toome, V., 277 Torelli, V., 321 Tori, K., 50, 170, 209, 234, 276 Tori, M., 94 Torii, S., 14, 24, 60, 99, 160, 253 Toromanoff, E., 286,288 Torres, C., 32 Torres-Martinez, S., 262 Tosi, C., 6 Toth, J. A., 200 Toth, K., 13 Towner, P., 259, 260 Townsley, P. M., 228 Toyota, M., 73,85, 158, 172, 183, 184 Tozyo, T., 234 Trabucco, A., 329 Trafford, D. J. H., 282 Traldi, P., 5 Tramell, M., 246 Tramontano, A., 8 Tran-Viet, D., 61 Trave, R., 61 Traynor, S. G., 14, 20, 33, 41, 44, 45, 50 Trehan, I. R., 18, 21 Trehan, N., 253 Treppendahl, S., 46 Tresselt, D., 273 Trifilieff, E., 181 Tringali, C., 186, 201 Tripathi, R. D., 234 Trius, A., 12 Trivedi, G. K., 102, 104 Trivino, A., 12 Trka, A., 279 Troffer, J., 6 Trogolo, C., 5 , 58, 59, 61 Trombini, C., 25
Trost, B. M., 23,43, 60, 294, 307 Trouilloud, M., 280 Tsai, T. Y. R., 311, 325 Tsankova, E., 172 Tseikinskii, V. M., 271, 272 Tskhovrebachvili, T., 10 Tsuboi, S., 33, 60 Tsubota, N., 284 Tsubuki, M., 314 Tsuda, M., 259 Tsuda, Y., 232 Tsuhako, A., 13 Tsuji, J., 22 Tsuji, M., 325 Tsuji, T., 31 Tsujimoto, K., 247, 260 Tsujino, Y., 85, 252 Tsujisaka, Y., 14, 72 Tsukitani, Y., 200 Tsunaga, K., 48 Tsuneyawa, T., 59 Tsuno, Y., 63 Tsuruta, H., 54 Tsutsumi, K., 63 Tsuyuki, T., 226 Tsuzuki, K., 100, 121, 136 Tucker, D. J., 228 Tulshian, D. B., 93 Tumlinson, J. H., 38 Turecek, F., 280,294 Turganbaeva, S. M., 25 Turner, B. L., 4 Turner, C. E., 65,66,70, 174 Turner, J. V., 195, 199, 205 Turner, R. V., 262 Tursch, B., 114, 202 Twine, C. E., 65 Twitchin, B., 199 Tyler, M. I., 200 Ubik, K., 169 Uchida, M., 62 Uchida, N., 264 Uchida, T., 311 Uchio, Y., 48, 187, 199 Uda, H., 5, 63, 277 Ueda, H., 33,77 Ueda, S., 57 Uegaki, R., 163 Ueno, A., 197 Ueno, Y., 19,42, 62 Uesato, S., 59 Uijttewaal, A. P., 34 Uliss, D. B., 65, 66 Ulkus, R. A., 258 Ullah, Z., 98 Ulubelen, A., 193 Umani-Ronchi, A., 25 Unemoto, T., 256 Uneyama, K., 14,24, 253 Unnikrishnan, P., 65, 66 Uno, T., 52
Author Index
352 Untch, K. G., 289 Uobe, K., 59 Urata, M., 41 Urbanovich, T. R., 55 Ushminder, K., 14 Uskokovic, M. R., 312, 318 Utaka, M., 38 Uto, S., 183 Uvarova, N. I., 216 Uyehara, I., 20 Uyehara, T., 141, 203 Uzar, H. C., 61 Uzarewicz, A., 49 Uzarewicz, I., 35, 49 Uzawa, J., 277 Vakhrameeva, A. A., 55 Vakulova, L. A., 247, 261 Valasinsky, V. F., 6 Valencia, A., 190 Valenta, Z., 271 Valente, L. M., 192 Valentine, D., 13 Valero, M. J., 37, 40 Valimae, T., 15 Valisolalao, J., 21 1 Vallen, S., 8 Valverde, S., 191, 192, 193, 199 van Audenhove, M., 39, 161 van der Gen, A., 34 Vander Meer, R. K., 77 Van de Ven, M., 258 Vandewalle, M., 39, 61, 161, 178, 179 Van Doorn, M., 204 Vanek, T., 174 van Engen, D., 60, 127 Vanhaelen, M., 282 Vanhaelen-Fastre, R., 282 van Leeuwen, P. W. N. M., 33 van Leusen, A. M., 44 van Leusen, D., 44 Van Meerssche, M., 114, 202, 228 Van Noort, P. C. M., 255 van Os, F. H. L., 60 van Straten, J., 63 Van Tri, M,, 222 van Vliet, N. P., 307 Varaprath, S., 11 Varenne, J., 156 Varkey, T. E., 177 Varma, R. K., 272, 293 Vasanth, S., 146 Vasilyuk, S. M., 62 Vathke-Ernst, H., 40 Vaughan, K., 121 Vaultier, M., 307 Vazeux, M., 4, 5 Vecchi, M., 237, 240, 255 Veeman, G. E., 286
Veeravalli, J., 62 Veierov, D., 309 Velenyi, L. J., 35 Venkatesan, K., 193, 270, 27 1 Venkateswaran, R. V., 204 Venuti, M. C., 110 Venzke, B. N., 213 Vereshchagin, A. N., 56 Verghese, J., 4, 32, 41, 55 Vergottini, R. A., 271 Verhoeven, T. R., 23 Verma, K., 58 Verma, N. K., 253 Verma, 0. P., 4 Verma, S. M., 5 Vermeer, P., 19, 78 Vettel, P. R., 103 Vetter, U., 15 Veysoglu, T., 19, 293 Via, D. P., 286 Vial, M. V., 72 Viallefont, P., 114 Vickery, B., 4 Vickery, M., 4 Vidal, J. P., 60 Vidari, G., 135, 207, 223 Vig, 0. P., 18,21,37,39,206, 253 Vig, R., 18,206 Vignudelli, E., 5 Vijayakumar, E. K. S., 60, 192 Vijayalakshmi, K. U., 60 Vile, J. P., 28 Vilkas, E., 48 Vilkas, M., 48 Villarreal, R., 146, 158 Vincent, P., 327 Vincien, F. F., 5 Vinogradov, L. I., 33 Vinson, S. B., 77 Viola, F., 215 Virgili, A., 12 Visser, C . P., 255 Viswanathan, N., 227 Vita-Finsi, P., 135 Voelter, W., 225 Vogel, M. K., 12 Voight, S., 4 Voigt, B., 198 Vokoun, J., 279 von der Eltz, H., 61 Von Dreele, R. B., 78 von Kiedrowski, G., 66 von Rudloff, E., 73 von Schantz, M., 5 Von Zastrow, M., 258 Voss, W., 48 Vostrowsky, O., 54 Vouros, P., 279 Vrbancich, J., 5 Vrkoc, J., 202 Vuilhorgne, M., 174
Vulfson, S. G., 6, 56 Vyazankin, N. S., 46 Vyaznikovtseva, 0. V., 25, 255 Vyrdov, V. A., 49 Vystrcil, A., 231 Wada, K., 199 Waegell, B., 5 Wagner, J., 256 Wagner, T. E., 277 Waibel, R., 58 Waineraich, M. S., 215 Waki, T., 48. Walckhoff, B., 259, 260 Walde, A,, 35 Walden, M. K., 282 Walker, D. G., 170 Walker, D. M., 118 Walker, G. J., 292 Walker, R. P., 238 Walkinshaw, M. D., 87, 88 Walkowicz, C., 56 Walkowicz, M., 56 Wallace, J. B., 60 Walter, J. A., 277 Walton, D. C., 238 Warin, R., 226 Warkentin, J., 46 Warnhog, E. W., 276,307 Warshel, A., 258 Wasiowich, C. A., 18 Wasserman, H. H., 294 Wasylishen, R., 4 Watanabe, A., 50 Watanabe, F., 284 Watanabe, H., 18 Watanabe, K., 66, 76 Watanabe, M., 155 Watanabe, S . , 11, 21 Watson, F. E., 271 Watson, S. W., 42 Watson, T. R., 276 Watson, W. H., 115, 196 Watson, W. P., 37 Wazeer, M. I. M., 228, 230 Weakley, T. J. R., 98 Weavers, R. T., 203 Webb, R., 283 Webster, M., 290 Weedle, M., 42 Weedon, B. C. L., 241 Weeks, C. M., 270 Wege, D., 110 Wegerstahl, P., 44 Weigand, E. F., 50 Weihe, G. R., 323 Weiler, E. W., 284 Weiler, L., 31 Weinberg, M. L. D., 31 Weinges, K., 61 Weiss, R. M., 258 Weissberger, E., 28
Author Index Weiter, L., 253 Welch, S. C., 93, 99 Wells, R. J., 15, 201, 234 Welmak, M., 46 Welniak, M., 46 Wender, P. A., 103 Wenderoth, B., 8 Wendisch, D., 174 Wenkert, E., 192 Wenzel, M., 286 Werbin, H., 265 Werstiuk, N. H., 7, 45 West, J. W., 53 West, T. F., 64 Westbrook, E., 272 Westermann, J., 8, 92, 297 Westfall, S. S., 256 Westmijze, H., 19, 78 Westmore, J. B., 279 Westwood, N. P. C., 7 Weyerstahl, P., 11, 91 Whelan, J. K., 73 Whitaker, B. D., 262 White, A. H., 78, 182, 188, 189,202,226 White, J. D., 60, 83,98,99 White, L. S., 38 White, P. S., 39, 164, 271 Whitesell, J. K., 61 Whiting, D. A,, 22 Whittaker, D., 6, 52, 54 Whittle, J. A., 177 Whybrow, D., 64, 183 Wicha, J., 325 Wichmann, J. K., 319 Wiechert, R., 308, 323, 324 Wieslander, A., 258 Wiesner, K., 311, 325 Wiggins, P. L., 20, 76 Wightman, R. M., 250, 251, 298 Wilbrandt, R., 257, 259 Wilk, M., 286 Wilkinson, R. E., 74 Wilkomirski, B., 234 Will, G., 181 Willhalm, B., 14, 32, 62 Williams, D. H., 314, 319, 320 Williams, D. L., 65, 66 Williams, E., 223 Williams, F. D., 77 Williams, H. J., 77 Williams, J. L., 64 Williams, J. R., 17, 107, 143, 155, 275, 310 Williams, P. J., 14, 15, 27 Williams, R. O., 329 Willis, B. J., 48, 89, 166 Wills, R. B. H., 15 Willuhn, G., 174 Wilson, B., 14, 15, 27 Wilson, R. S., 66 Wilson, S. R., 35, 39, 108
353 Wing, R. M., 15 Winkler, T., 5 , 58, 64 Winnik, F. M., 306 Winter, R. E. K., 140 Wirtz, G. H., 256 Witkiewicz, K., 10, 37, 40 Wodzki, W., 46 Wolf, H., 111 Wold, H. R., 26, 63, 255 Wolff, G., 309 Wolff, S., 25 Wolinsky, J., 31, 42 Wollenberg, R. H., 31 Wong, R. Y., 93 Wood, D. L., 70 Woode, K. A., 227 Woodgate, P. D., 292, 302, 327 Woodruff, W. H., 257, 259 Woods, G. F., 299 Woodward, R. B., 130 Worth, B. R., 55, 210,228 Worthington, P. A., 81 Wovcha, M. G., 328 Wray, V., 275 Wright, C. L., 324 Wright, J. L. C., 277 Wrzesien, J., 41, 49, 50 Wu, A., 17, 63 WU, R.-W., 174 WU, R.-Y., 146 WU, S.-C., 256 Wuest, H., 39, 46 Wydra, R., 211 Wynberg, H., 53 XU, Y.-L., 197 Yagen, B., 213 Yagi, A., 215 Yagihashi, F., 163 Yakovleva, I. M., 247, 261 Yamada, M., 165 Yamada, T., 30, 251 Yamada, S., 319, 320 Yamada, Y., 13,29, 60, 200 Yamahara, Y., 58 Yamagata, E., 104 Yamagishi, S., 262 Yamagiwa, S., 63 Yamaguchi, A., 256 Yamaguchi, H., 19, 251 Yamaguchi, K., 232 Yamaguchi, M., 241, 243 Yamakawa, K., 172 Yamakawa, T., 22 Yamaki, M., 59 Yamamoto, I., 64 Yamamoto, H., 10, 12, 22, 25, 37, 42, 63 Yamamura, A., 48 Yamamura, S., 91, 189
Yamasaki, K., 189,228,234, 276 Yamashita, H., 38, 199 Yamashita, K., 72, 254 Yamashita, M., 14, 38 Yamato, T., 27 Y amauchi, A., 284 Yamauchi, T., 59, 214 Yamazaki, M., 136 Yamazaki, S., 264 Yanagihara, K., 64 Yanami, T., 52 Yanez, R., 103 Yano, S., 230 Yano, T., 28, 64 Yanovskaya, L. A., 23 Yaremchenko, N. G., 55 Yaroshenko, N. I., 200 Yasuda, A., 12,25, 37 Yasuda, F., 276 Yasuda, H., 12, 16 Yasuda, M., 314 Yasuda, T., 14 Yasuoka, N., 199 Yasuzawa, T., 210, 253 Yates, P., 103, 306 Yatsu, T., 213 Yazawa, Y., 262 Yehia, A. A. I., 64 Yelle, L. M., 308 Yo, E., 35 Yokoi, K., 50, 53 Yokoi, T., 230 Yokono, T., 115 Yokota, T., 197 Yokota, Y., 5 , 277 Yokoyama, Y., 226 Yomosa, S., 251,259 Yonaha, K., 174 Yonebayashi, F., 306 Yoneda, K., 104 Yonetani, K., 189 Yonezawa, M., 234 Yorke, S. C., 15 Yoshida, K., 213 Yoshida, H., 64 Yoshida, T., 32, 54, 141 Yoshida, Z., 13 Yoshihara, H., 189 Yoshihara, T., 259 Yoshikawa, M., 48, 234 Yoshikawa, S., 253 Yoshikoshi, A., 33, 51, 52, 81, 86, 155, 165 Yoshimura, H., 66 Yoshimura, I., 179 Yoshimura, Y., 50, 209, 234 Yoshioka, M., 26 Yoshizawa, T., 259, 260 Yosioka, I., 32, 59 Young, S. D., 50 Young, R. N., 5 5 Yuki, S., 92, 204 Yun, H. S., 276
Author Index
354 Yurev, V. P., 12, 48 Yurina, R. A., 48, 62 Yuzuriha, T., 266 Zabel, V., 115, 196 Zachis, M., 296 Zagalsky, P. F., 258 Zaghloul, A. M., 172 Zahra, J.-P., 40 Zahrar, J. P., 5 Zainutdinov, U. N., 188 Zalkow, L. H., 102 Zamarlik, H., 31
Zamboni, R., 135 Zamkovnei, M., 52 Zanetti, L., 239 Zard, S. Z., 321 Zaretskii, 2. V. I., 279 Zavarin, E., 73 Zawadzki, S., 250 Zderic, S. A., 8 Zdero, C., 32,62,75,88,106, 111, 116, 117, 146, 158, 172, 174, 176, 188, 189, 195 Zecchini, G. P., 296 Zeelen, F. J., 272, 307
Zeiner, H., 243 Zenk, M. H., 284 Ziegler, F. E., 178, 179 Ziegler, P., 271 Zielinski, J., 312 Ziesche, J.,88,146, 158, 169, 174, 186, 196 Zile, M., 263 Zinner, K., 238 Zintl, R., 54 Zocher, D. H. T., 215 Zollo, F., 318 Zsako, J., 245 Zundel, G., 258