A Specialist Periodical Report
Terpenoids and Steroids Volume 8
A Review of the Literature Published between Septembe...
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A Specialist Periodical Report
Terpenoids and Steroids Volume 8
A Review of the Literature Published between September 1976 and August 1977
Senior Reporter J. R. Hanson, School of Molecular Sciences, University of Sussex Reporters
G. Britton, University of Liverpool J. D. Connolly, University of Glasgow D.N. Kirk, Westfield College, London B. A. Marples, University of Technology, Loughborough T. Money, University of British Columbia, Vancouver, Canada R. B. b a t s , Bishop's University, Lennoxville, Quebec, Canada
The Chemical Society Burlington House, London, WIV OBN
ISBN 0-85186-326-4 ISSN 0300-5922 Library of Congress Catalog Card No. 74-615720
Copyright @ 1978 The Chemical Society All Rights Reserved No part of this book may be reproduced or transmitted in any form or by any means-graphic, electronic, including photocopying, recording, taping or information storage and retrieval systems-without written permission from The Chemical Society
Set in Times on Linotron and printed offset by J. W. Arrowsmith Ltd., Bristol, England Made in Great Britain
In trod uction During the year under review the number of known terpenoids has increased significantly, particularly amongst the sesqui- and di-terpenoids where a number of novel skeleta have been described. In a number of instances the novel diterpenoid skeleta are reminiscent of sesquiterpenoids. Marine organisms have provided the source of many new halogenated terpenoids. It is interesting to speculate o n the role of the halogen, particularly bromine, in the biosynthesis of these compounds. The sites of halogenation are in a number of instances those which would be expected if the halogen were playing a role in the cyclization of acyclic prenyl precursors. The format of these Reports has remained relatively constant from year t o year t o facilitate the location of subject matter. However, this year two changes have occurred. Firstly, as an experiment, the information on biosynthesis is contained within the chapters dealing with the individual group of terpenoids rather than as a separate chapter. Secondly, the steroid section has been recast t o minimize overlap. A report of the application of physical methods t o steroids forms o n e chapter whilst steroid reactions and partial syntheses are reported in the second. Total synthesis will be reviewed biennially.
J. R. HANSON
Contents Part I Terpenoids 3
Chapter 1 Monoterpenoids By R. 8.Yeats 1 Physical Measurements: Spectra etc.; Chirality
4
2 General Synthetic Reactions
9
3 Biogenesis, Occurrence, and Biological Activity
13
4 Acyclic Monoterpenoids 20 Terpenoid Synthesis from Isoprene 20 2,6-Dimethyloctanes 22 Halogenated Monoterpenoids 30 Artemisyl, Santolinyl, Lavandulyl, and Chrysanthemyl Derivatives 32 5 Monocyclic Monoterpenoids Cyclobutane Cyclopentanes, Iridoids p-Menthanes o-Menthanes m-Menthanes Tetramethy lcyclohexanes Dimethyleth ylcyclohexanes Cycloheptanes
35 35 35 39 46 46
6 Bicyclic Monoterpenoids Bicyclo[3,l,0]hexanes Bicyclo[2,2,l]heptanes Bicyclo[3,l ,l]heptanes Bicyclo[4,1,O]heptanes
48
7 Furanoid and Pyranoid Monoterpenoids
58
8 Cannabinoids and other Phenolic Monoterpenoids
61
46
47 48
48 49
53 56
V
Contents
vi
Chapter 2 Sesquiterpenoids By T. Money
64
1 Farnesane
64
2 Mono- and Bi-cyclofarnesane
66
3 Bisabolane
67
4 Sesquipinane, Sesquicamphane, Sesquifenchane
71
5 Cuparane, Trichothecane, Laurane
73
6 Acorane, Cedrane, Carotane
76
7 Chamigrane, Widdrane, Thujopsane
79
8 Cadinane, Amorphane, Copacamphane, etc
80
9 Himachalane, Longipinane, Longicamphane, etc.
86
10 Humulane, Caryophyllrrne
89
11 Germacrane
94
12 Eudesmane
99
13 Vetispirane, Elemane
106
14 Eremophilane, Bakkane (Fukinane), Ishwarane
111
15 Guaiane, Pseudoguaiane
118
16 Miscellaneous
121
Chapter 3 Diterpenoids By J. R. Hanson
123
1 Introduction
123
2 Bicyclic Diterpenoids Labdanes Clerodanes
123 123 127
3 Tricyclic Diterpenoids Naturally Occurring Substances Chemistry of the Tricyclic Diterpenoids
129 129 132
4 Tetracyclic Diterpenoids Naturally Occurring Substances Chemistry of the Tetracyclic Diterpenoids Gibberellins Grayanotoxins Diterpenoid Alkaloids
133 133 136 137 139 139
5 Macrocyclic Diterpenoids and their Cycliation Products
141
vii
Contents 6 Miscellaneous Diterpenoids
144
7 Diterpenoid Total Synthesis
147
Chapter 4 Triterpenoids By J. D. Connolly
150
1 Squalene Group
150
2 Fusidane-Lanostane Group
152
3 Dammarane-Euphane Group Tetranortriterpenoids Pentanortriterpenoids Quassinoids
160 163 165 167
4 Shionaae-Baccharane Group
168
5 Lupane Group
169
6 Oleanane Group
172
7 UFsaneGroup
178
0 Hopane Group
179
9 Stictane-Flavicane Group
180
Chapter 5 Carotenoids and Polyterpenoids By G. Britton
181
1 Introduction
181
2 Carotenoids New Structures Acyclic Carotenoids Monocyclic Carotenoids Bicyclic Carotenoids Apocarotenoids Carotenoid Glycosides Carotenoproteins Degraded Carotenoids Stereochemistry Synthesis and Reactions Carotenoids Retinol Derivatives Other Degraded Carotenoids Physical Methods and Physical Chemistry Separation and Assay Methods 13 C N.M.R. Spectroscopy Circular Dichroism
181 181 182 182 182 185 185 185 187 188 189 189 193 196 198 198 198 198
...
Contents
Vlll
Electronic Absorption Spectroscopy Resonance Raman Spectroscopy X-Ray Crystallography Miscellaneous Physical Chemistry Spectroscopy and Physical Chemistry of Retinal and Visual Pigments Biosynthesis and Metabolism Pathways and Reactions Enzyme Systems Regulation Carotenoid Metabolism and Metabolites
198 199 199 199 200 201 201 203 204 205
3 Polyprenols
206
4 Isoprenylated Quinones Chemistry Biosy nthesis Ubiquinone Menaquinone Other Quinones
206 207 208 208 208 208
Part lI Steroids Chapter 1 Physical Methods By 0.N. Kirk
211
1 Structure and Conformation
211
2 N.M.R. Spectroscopy 'H Spectra 3H Spectra 13 C Spectra
213 213 2 14 215
3 Chiroptical Phenomena
218
4 Mass Spectrometry
22 1
5 Miscellaneous Physical Properties
223
6 Analytical Methods Radioimmunoassay of Steroids Chromatography
224 224 225
Chapter 2 Steroid Reactions and Partial Syntheses By 8. A. Marples
227
Section A ; Steroid Reactions 1 Alcohols and their Derivatives, Halides, and Epoxides Substitution Oxidation and Reduction
227 227 229
ix
Contents
Epoxide formation and Ring-opening Ethers, Esters, and Related Derivatives of Alcohols 2 Unsaturated Compounds Electrophilic Addition Other Addition Reactions Other Reactions of Olefinic Steroids Aromatic Compounds
3 Carbonyl Compounds Reduction of Carbonyl Compounds and @-Unsaturated Carbonyl Compounds Nucleophilic Addition to Carbonyl Compounds and C Y-Unsaturated ~ Carbonyl Compounds Reaction involving Enols or Enolic Derivatives Oximes, Hydrazones, and Semicarbazones
23 1 233 234 234 236 237 238
239 241 243 244
4 Compounds of Nitrogen, Sulphur, and Selenium
245
5 Molecular Rearrangements Backbone Rearrangements Miscellaneous Rearrangements
247 247 249
6 Functionalization of Non-activated Positions
252
7 Photochemical Reactions
255
8 Miscellaneous
260
Section B : Partial Syntheses 9 Cholestane Derivatives and Analogues
260
10 Vitamin D and its Metabolites
266
11 Pregnanes
270
12 Androstanes
27 1
13.Cardenolides
272
14 Seco-steroids and Cyclo-steroids
274
15 Heterocyclic Steroids
275
16 Microbiological Oxidations and Reductions
279
17 Miscellaneous Syntheses
280
Errata
282
Author Index
283
Part I TERPENOIDS
1 Mon oterpeno ids BY R. B. YEATS
The format established in previous volumes is maintained, except that a consolidation this year brings all monoterpenoid biosynthetic work into this chapter; in keeping with previous practice, metabolic functionalization of monoterpenoids is reported in the relevant structural sections and not under Biogenesis. The number of monoterpenoid papers published this year appears to have increased,’ although a decline is noted for papers on essential o i k 2 Keeping abreast of this burgeoning literature, especially by means of alerting services and computer data bases, could be made easier if all authors and editors selected titles more judiciously and insisted upon the inclusion of keywords. For example, it is noted that, to the uninitiated, the title of Trost’s full paper3 on grandisol and fragranol synthesis (c$ Vol. 6, p. 21) gives too little clue of its content; the same is true of McMurry’s perillene ~ y n t h e s i sand , ~ even the author’s own abstract provides no clue of the inclusion of a yomogi alcohol synthesis in the paper by Wada et aL5 Such inadequacies result in an unnecessary shortfall in the number of monoterpenoid-related papers retrievable by the use of anticipatable keywords in alerting services such as Current Contents, Science Citation Index, and Index to Scientific Reviews when compared with this Reporter’s literature search.’ The inability to retrieve references to previous Reports o n monoterpenoids in this series by the use of Index to Scientific Reviews6 is, fortunately, not repeated in Lewis’s valuable index.’ The use of Chemical Abstracts as an alerting service again reveals some apparently inconsistent abstracting and misplaced abstracts. Examples include the unnecessary separation of abstracts referring to Volume 6,’ the classification of a
*
7
Approximately 1995 monoterpenoid-related papers were retrieved from the page-by-page search of 135 titles published since compiling the previous Report (Vol. 7, p. 3) to August 1977 and available to early November 1977; additional papers were retrieved via Current Abstracts of Chemistry and index Chemicus, and relevant sections of Current Contents, Physical and Chemical Sciences, and Chemical Abstracts. 1210 of these papers provided the core upon which this Report is based. Based upon computer-retrieved papers from the Essential Oils Section of Chemical Abstracts; September 1975 to August 1976,223 papers; September 1976 to August 1977, 144 papers. B. M. Trost, D. E. Keeley, H. C. Arndt, and M. J. Bogdanowicz, J. Amer. Chem. SOC.,1977,99,3088. J. E. McMurry and S. F. Donovan, Tetrahedron Letters, 1977, 2869. M. Wada, A. Fukui, H. Nakamura, and H. Takei, Chem. Letters, 1977, 557. Index to Scientific Reviews, Institute for Scientific Information, Philadelphia, 1975, 1976, and 1977 Semiannual. ‘ Index of Reviews in Organic Chemistry, Second Cumulative Volume 1976’. compiled by D. A. Lewis and P. Charnock, The Chemical Society, London, 1977. For example, see Chem. Abs., 1977,86, 72 919 for reference to the entire volume, Chem. Abs., 1976, 85, 192 902 for Monoterpenoids, and Chem. Abs., 1977,86,43 821 for Diterpenoids.
3
4
Terpenoids and Steroids
paper on cis-3,4-A1-THC under alkaloids,' and the inclusion of the non-terpenoid C1 compound pestalotin under Terpenoids," especially when neither Cavill's
characterization of the cyclopentane monoterpenoid dolichodial and related compounds'' nor the identification of new limonene metabolites12 is even crossreferenced. Papers on the characterization of iridoids are rarely found under T e r p e n ~ i d s , 'and ~ cross-referencing to and between carbohydrate^'^ and Plant Biochemistry," where papers seem to be located at random, is poor. It would also be helpful to translate more than a title for abstracts based upon Referativnyi Zhurnal, Khimiya.16 The prompt compilation of future Reports will be helped substantially if monoterpenoid chemists would be willing automatically to send reprints of papers, particularly of articles published in less accessible journals, directly to this Reporter. 1 Physical Measurements: Spectra etc.; Chirality A review of 'H n.m.r. spectra of cyclic alkenes points out the need to re-examine car-2-ene and car-3-ene conformations (cf. Vol. 5, p. 41).17Further 'H n.m.r. data on methyl-substituted norborneols in the presence of [Eu(dpm),] shift reagent have been reported." Attempts to correlate calculated and experimental lanthanideinduced shift data could not distinguish between diastereomeric esters of transmyrtanoic acid," gave poor results with the 4-arninoborneols,'' and, although readily distinguishing between cis- and trans -pinocarveol, could not distinguish between proposed conformations with certainty.20 The use of [Eu(fod),] with Mosher's reagent esters of diastereomeric secondary alcohols (e.g. borneol/isoborneol, cis-carveolltrans-carveol, isopinocampheol/neoisopinocampheol) allows configurational assignments at the carbinol centre by observing the magnitude of methoxy lanthanide-induced shifts and should be valuable in assigning stereochemistry in diastereoselective reductions of ketones.21 The absolute configuration of chiral thiols can be determined from the 'H n.m.r. spectra of the diastereomeric hydratropic thioesters.22 The observation that the well known iridoid aucubin is R. M. Smith and K. D. Kempfert, Phytochernistry, 1977,16, 1088 (Chem.Abs., 1977,87,98 815). Chem. Abs., 1977,86,90 039. G. W. K. Cavill, E. Houghton, F. J. McDonald, and P. J. Williams, Insect Biochem., 1976, 6, 483 (Chem.Abs., 1977,86,1399). I' R. Kodama, T. Yano, K. Furukawa, K. Noda, and H. Ide, Xenobiotica, 1976,6,377. l3 For xylomollin (145) see I. Kubo, I. Miura, and K. Nakanishi, J. Amer. Chem. SOC.,1976, 98, 6704 (Chem. Abs., 1977,86, 16 795). l4 For bartsioside (121; X = H , R=@-Glu) see A. Bianco, M. Guiso, C. Iavarone, and C. Trogolo, Gazzetta, 1976,106, 725 (Chem.Abs., 1977, 86, 106 984). " For example, vogeloside (Vol. 7, p. 27, ref. 265) is abstracted under Plant Biochemistry (Chem. Abs., 1976, 85, 74 898) and is not cross-referenced from Carbohydrates or Terpenoids, whereas the related centapicrin (Vol. 7, p. 27, ref. 266) is similarly located (Chem. Abs., 1976, 85, 74968) but is cross-referenced from Carbohydrates. l6 For example, see 'Stereochemistry of some new rearrangements of bicyclic terpenes', T. F. Gavrilova, I. S. Aul'chenko, and L.A. Kheifits, Voprosy StereokhirniiResp. Mezhved. Nauch. Sb., 1976,77 (Chem. Abs., 1977,86, 121 534). " H. Giinther and G. Jikeli, Chem. Rev., 1977, 7 7 , 599. " K.-T. Liu,J. Chinese Chem. SOC.(Taiwan), 1976,23, 1; cf. Vol. 4, p. 3. '9 G. R. Sullivan, J. Amer. Chem. Sac., 1976,98, 7162. 2o C. C. Hinckley and W. C. Brumley, J. Magn. Resonance, 1976, 24, 239. S. Yamaguchi and F. Yasuhara, Tetrahedron Letters, 1977, 89. " G. Helmchen and R. Schmierer, Angew. Chem. Znternar. Edn., 1976,15,703. 'O
Monoterpenoids
5
readily identified in an intact seed of Aucuba japonica may signal a useful monitoring role of I3cn.m.r. spectroscopy in plants.23 The bathochromic-hypochromic shift in the U.V. spectra of umbellulone and verbenone has been interpreted as being due to extension of the ap-unsaturated carbonyl c h r ~ m o p h o r e .U.V. ~ ~ and c.d. data into the vacuum region have been recorded in the vapour phase and in solution for a- and p-pinene, camphene, bornene, fenchylidenefenchane, and bornylidenebornane; the major c.d. bands were assigned." Whilst calculated rotatory strengths of cisoid dienes of fixed conformation are in good agreement with experimental results, calculations on the conformationally flexible a -phellandrene fail to give good agreement.2hThe value and limitations of using n-propylammonium (+)-camphor-10-sulphonate as a standard for c.d. and 0.r.d. calibration have been discussed f ~ r t h e r . ~Variations ' in the rotivities of (-)-a-pinene and (+)-limonene with temperature and solvent are reported.** The discussion of a series displacement index for classifying mass spectra and for correlation with structural stability includes some monoterpenoids (e.g. myrcene limonene, ~ a n t e n e ) . ~ ~ Rate constants are reported for the reactions of a - and 0-pinene and of (+)limonene with OH radicals so that comparison is now possible with those from reaction with O ( 3 P )(see Vol. 7, p. 6) and with ozone (see Vol. 6, p. 8); results are consistent with those calculated from the data of Grimsrud et aE. (Vol. 6, p. 8) from which further rate constants for the reaction of nine other monoterpenoid hydrocarbons with OH radicals have been ~ a l c u l a t e d . ~In ' the oxidation of sterically unhindered alcohols (e.g. borneol, the pinocampheols, the nopinols), the reaction rate correlates with the strain difference between the alcohols and the derived ketones, suggesting that the properties of the carbonyl group are reflected in the oxidation transition state.31 A second paper reports Sicher correlations for the chromic acid oxidation of epimeric alcohols (e.g. the i s o ~ e r b a n o l s ) .Attempts ~~ have been made to calculate the proportions of epimeric alcohols formed on complex metal hydride reduction of cyclic ketones by considering steric congestion and torsional effects, interpreting the results in favour of a mechanism involving initial complexation between the ketone and the reagent followed by rate-determining nucleophile transfer. Camphor and isopinocamphone calculations bear out known epimeric alcohol proportions but agreement for the hindered fenchone and for chrysanthenone is not good. In chrysanthenone reduction the major predicted product is not in keeping with that which is observed;33the authors suggest that the 23 24
z5
26 27
29
30
31
32 33
M. Kainosho, Tetrahedron Letters, 1976, 4279. A. Y. Meyer, R. Pasternak, J. Sterling, N. Lander, and R. Mechoulam, Tetrahedron, 1976,32, 2805. A. F. Drake and S. F. Mason, Tetrahedron, 1977, 33, 937. J. S. Rosenfield and E. Charney, J. Amer. Chem. Soc., 1977, 99, 3209. Y. Nakagawa, M. F. Gillen, and R. E. Williams, Cunad. J. Chem., 1976,54, 3200; see M. F. Gillen and R. E. Williams, ibid., 1975, 53, 2351 for the earlier unreported c.d. calibration. R. Lauricella, J. Kechayan, and H. Bodot, J. Phys. Chem., 1977,81, 542. R. G . Dromey, Analyt. Chem., 1976.48, 1464. A. M. Winer, A. C. Lloyd, K. R. Darnall, and J. N. Pitts, J. Phys. Chem., 1976,80, 1635. P. Miiller and J.-C. Perlberger, J. Amer. Chem. SOE.,1976,98,8407; see also P. Miiller, Chimia (Swirz.), 1977.31, 209. P. Miiller and J.-C. Perlberger, Helv. Chim. Acta, 1976.59, 2335. W. T. Wipke and P. Gund, J. Amer. Chem. Soc., 1976,98, 8107.
6
Terpenoids and Steroids
original assignment of product stereochemistry may be in error,34without reference to recent Another approach for substituted cyclohexanone reduction by NaBH, in propan-2-01, which is based upon free-energy increments for non-polar substituent groups, gives good agreement between theory and experiment for menth~ne.~~ The adsorption of (+)-camphor-10-sulphonate ions on a mercury electrode is a two-dimensional associative adsorption of ions as micelles in equilibrium with free adsorbed ions (cf. camphor and borneol, Vol. 5, p. 4).37 The factors affecting asymmetric electrochemical reduction of (-)-menthy1 phenylglyoxylate have been examined.38 Asymmetric homogeneous catalytic hydrogenation of substituted cinnamic acids (in up to 70% enantiomeric excess) with [Rh(~od)C1]~-(-)-menthylmethylphenylphosphine catalyst is probably more influenced by the chirality at phosphorus than that at carbon, with results similar to those obtained with a (-)-neomenthyldiphenylphosphine ligand39 which is also reported to yield 95% of (3R)-(+)-dihydrogeranic acid from geranic acid ( E : Z/9: l).40Much useful asymmetric synthetic work has centred on boron reagents. Lithium B-isopinocampheyl-9-borabicyclo[3,3,l]nonylhydride reduces ketones to R-alcohols in up to 37% enantiomeric excess;41 the reagent is readily available from B-isopinocampheyl-9-borabicyclo[3,3,l]nonane, the product of oxidation of hydroboration of (+)-a-pinene with 9-borabicyc10[3,3,1]nonane;~~~~ B-isopinocampheyl-9-borabicyclo[3,3,l]nonane yields isopinocampheol(1; 99.9% optical and it can also be used for the highly enantioselective reduction of
(1)
aldehydes (e.g. [c~-~H]benzaldehyde to the corresponding S-alcohol in 90% enantiomeric excess; a modification yields the R-alcohol) with the promise of chemoselectivity Monoisopin~campheylborane,~~ which is readily available from the corresponding triethylamine c o r n p l e ~hydroborates ~~ trisubstituted alkenes leading to alcohols of S-configuration in up to 72% enantiomeric excess;44 useful asymmetric reductions of ketones with di-isopinocampheylborane of high 34
35 36
37
38 39 40 41
42 43
44
"
J. J. Hurst and G. H. Whitham, J. Chep. SOC.,1960, 2864. See Vol. 6, p. 42, refs. 312, 313, and Vol. 7, p. 43, ref. 430. D. C. Wigfield, Canad. J. Chem., 1977, 55, 646. A. C. Ramamurthy and S . Sathyanarayana, J. Electroanalyt. Chem. Interfacial Electrochem., 1976, 73, 253. M. Jubault, E. Raoult, and D. Peltier, Electrochim. Acta, 1977, 22, 67. C. Fisher and H. S . Mosher, Tetrahedron Letters, 1977, 2487. F. Hoffmann-La Roche und Co., Dutch P. 12 729/1975 (Chem. Abs., 1977,86,55 597). S. Krishnamurthy, F. Vogel, and H. C. Brown, J. Org. Chem., 1977, 42, 2534; 173rd A.C.S. Meeting, New Orleans, March 1977, Abstracts ORGN, No. 17. H. C. Brown, R. Liotta, and L. Brener, J. Amer. Chem. SOC.,1977,99, 3427; see also ref. 47. M. M. Midland, A. Tramontano, and S. A. Zderic, J. Amer. Chem. SOC.,1977,99,5211; 174th A.C.k. Meeting, Chicago, August 1977, Abstracts ORGN, No. 28. H. C. Brown and N. M. Yoon, J. Amer. Chem. SOC.,1977,99,5514. H. C. Brown, N. M. Yoon, and A. K. Mandal, J. Organometallic Chem., 1977, 135,C10.
Monoterpenoids
7
optical purity,46 two syntheses of which have been r e ~ o r t e d , ~as ~ ,well ~ ' as nearly complete asymmetric induction in the hydroboration-oxidation of c i s - b ~ t - 2 - e n e ~ ~ have been discussed. The full paper on the asymmetric reduction of acetophenone with monoterpenoid glycol-lithium aluminium hydride complexes (Vol. 7, p. 5 ; cf. Vol. 4, p. S)49 has been published as well as further synthetic work on S-(+)-2,2,2trifluoro-l-phenylethanol (Vol. 7, p. 4)50and on its resolution as (-)-o-camphanic acid esters;51 the latterS1 is one of a number of examples in which resolution via (-)-w-camphanic esters is monitored by 'H n.m.r. in the presence of [ E u ( f ~ d ) ~ ] ~ l , ~ ~ or [ E ~ ( d p m )[see ~ ] ~Vol. ~ 4, p. 4; formula (4) should have the alkoxycarbonyl group attached to the bridgehead position]. In an extension of previous work (Vol. 6, p. 6), the asymmetric reduction of ethyl benzoylformate with the NAD(P)H model system (2kmagnesium perchlorate is best when X=NH;54 the inability of horse liver alcohol dehydrogenase to reduce fenchone and camphor is consistent with the diamond lattice section model of the active and accounts for the HLADHcatalysed oxidation of (f)-(3) to the 'unnatural' (-)-cis-tetrahydroactinidiolide
(258) (p. 60) in 14% optical purity.56 Such reactions must be interpreted with care in view of the observation that N-benzyl-1,4-dihydronicotinamideacts as an electron donor in the reduction of 2-exo-brom0-2-endo-nitrobornane.~~ The synthesis and use of peroxycamphoric acid as an asymmetric oxidizing agent has been r e - e ~ a l u a t e d . ~ ~ Other interesting examples of asymmetric syntheses involving chiral monoterpenoids include the Claisen reaction between (-)-menthy1 phenylacetate and benzaldehyde (optical purity is confirmed by micr~calorimetry),~~ a highly enanand the crossed aldol tioselective carbenoid cyclopropanation catalysed by (4),60 H. C. Brown and A. K. Mandal, J. Org. Chem., 1977,42, 2996. H. C. Brown and N. M. Yoon, Israel J. Chem., 1976/1977,15, 12. H. C. Brown, A. K. Mandal, and S. U. Kulkarni, J. Org. Chem., 1977.42, 1392. 49 E. D. Lund and P. E. Shaw, J. Org. Chem., 1977,42,2073. 5 0 D. Nasipuri and P. K. Bhattacharya, J.C.S. Perkin I, 1977,576. 5 1 J. Jurczak, A. Konowal, and Z. Krawczyk, Synthesis, 1977, 258. '' A. Konowal, J. Jurczak, and A. Zamojski, Tetrahedron, 1976, 32, 2957 [formula (7) lacks a carbonyl group]; C. Belzecki and I. Panfil, J.C.S. Chern. Comrn., 1977,303 [in Table 2 footnote e, [o]$:g should be -236" and not -23.6", ref. 4 should be to Synthesis 1975 and not 1976, and in Current Abstracts of Chemistry, Abstract Number 258 347 [formula (X) is completely incorrect]. 53 W. L. F. Armarego, B. A. Milloy, and W. Pendergast, J.C.S. Perkin I, 1976,2229; E. Caspi and C. R. Eck, J. Org. Chem., 1977, 42, 767. s4 A. Ohno, H. Yamamoto, T. Kimura, S. Oka, and Y. Ohnishi, Tetrahedron Letters, 1976, 4585. 5 5 A. J. Irwin and J. B. Jones, J. Amer. Chem. SOC.,1976,98, 8476. 56 J. B. Jones and H. B. Goodbrand, Canad. J. Chem., 1977,55,2685. " R. J. Kill and D. A. Widdowson, J.C.S. Chem. Comrn., 1976, 755. 5 8 W. H. Pirkle and P. L. Rinaldi, J. Org. Chem., 1977, 42, 2080. 59 N. A. Kirtchev, N. D. Berova, C. G. Kratchanov, and B. J. Kurtev, Compt. rend. Acad. bulg. Sci.,1976, 29, 849. 60 A. Nakamura, A. Konishi, R. Tsujitani, and S. Otsuka, 172nd A.C.S. Meeting, San Francisco, August-September 1976, Abstracts ORGN, No. 144. 46
47
48
8
Terpenoids and Steroids
addition of silyl enol ethers6' as well as the addition of allyltrimethylsilane62 to (-)-menthy1 keto-esters; in the latter case the product stereochemistry was tentatively assigned according to the Prelog g e n e r a l i ~ a t i o nwhich , ~ ~ is not applicable to ~~ Reformatsky reactions of (-)-menthy1 and (+)-bornyl p y r ~ v a t e s .Applications involving chiral centres other than carbon include organosilane synthesis,65 the reaction of (-)-menthy1 (-)-(S)-toluene-p-sulphinate with Grignard66.67 and organocopper-lithium and selenonium ylide formation.68 Asymmetric hydrolysis of (*)-menthy1 acetate by Rhodotorula rnuciluginosa is reported.69 A method for determining optical purities of less than one percent for secondary alcohols has been p ~ b l i s h e d , ~and ' Mislow has observed a partial resolution which may serve to distinguish between a rneso and a racemic host product when a derived inclusion compound is recrystallized from an enantiomerically enriched guest solvent . 7 1 G.1.c. papers of interest include the classification of 22 acyclic monoterpenoid alcohols according to retention indexes,72 resolution of cyclic ketones [e.g. (+)menthone, (&)-isomenthone] as diethyl (+)-tartrate a ~ e t a l s ,and ~ ~ the use of lanthanide shift reagents to resolve non-terpenoid racemic e p o x i d e ~ .The ~ ~ occurrence and prevention of monoterpenoid hydrocarbon isomerization during silica gel chromatography has been examined75 and the separation of monoterpenoids and sesquiterpenoids by gel permeation chromatography is reported.76 Monoterpenoid hydrocarbons have been selectively extracted from essential oils using dirnethyl~ilicone.~~
61
" 63 64 65
67
69
70 71 72
73 74 75
76 77
I. Ojima, K. Yoshida, and S.-I. Inaba, Chem. Letters, 1977, 429. I. Ojima, Y. Miyazawa, and M. Kumagai, J.C.S. Chem. Comm., 1976,927. V. Prelog, Helv. Chim. Acta, 1953, 36, 308; Bull. SOC.chim. France, 1956, 987. S. Brandange, S. Josephson, and S . VallCn, Acta Chem. Scand., 1977, B31, 179. R. J. P. Corriu and J. J. E. Moreau, Nouv. J. Chim., 1977, 1, 71; J. Organometallic Chem., 1976, 120, 337. M. Cinquini, S . Colonna, F. Cozzi, and C. J. M. Stirling, J.C.S. Perkin I, 1976, 2061. D. N. Harpp, S. M. Vines, J. P. Montillier, and T. H. Chan, J. Org. Chem., 1976,41, 3987. K. Sakaki and S . Oae, Tetrahedron Letters, 1976, 3703. Y. Yamaguchi, A. Komatsu, and T. Moroe, Nippon Nogei Kagaku Kaishi, 1977,51,411. A. Schoofs and A. Horeau, Tetrahedron, 1977, 33, 245. K. S. Hayes, W. D. Hounshell, P. Finocchiaro, and K. Mislow, J. Amer. Chem. SOC., 1977,99,4152. R. ter Heide, J. Chromatog., 1976, 129, 143. J. Irurre-Perez and M. Sanz-Burata, Anales de Quim., 1977,73, 254. B. T. Golding, P. J. Sellars, and A. K. Wong, J.C.S. Chem. Comm., 1977, 570. J. J. C. Scheffer, A. Koedam, and A. Baerheim Svendsen, Chromarographia, 1976,9,425. N. Hayashi, Y. Yamamura, and H. Komae, Chem. and Znd., 1977, 34. M, Yoshikura, H. Kobayashi, and Y. Nakayama, Jap. P. 29 500/1975 (Chem. Abs., 1976,85,99 028).
Monoterpenoids
9
2 General Synthetic Reactions Some useful reviews which discuss applications from, or are of value to, monoterpenoid chemistry include applications of diborane reduction^,^^^^' transition metals in organic synthesis," 0-silylated enolates,'l the Barbier reaction," selenium dioxide ~ x i d a t i o n , 'Birch ~ reduction of a@-unsaturatedcarbonyl compounds,84and homogeneous hydrogenation catalyst^.'^ A broad overview of organoboranes has been published.86 Kagan has reviewed the use of graphite insertion corn pound^.^^ Less substituted @-unsaturated cycloalkenones rearrange by double-bond migration around the ring to the more substituted @-unsaturated cycloalkenones in high yield, catalysed by RhC1,,3H2O; non-conjugated double bonds also migrate into the ring system to become conjugated; e.g., dihydrocarvone rearranges efficiently to [ ( 5 ) :(6)/7 : 11." The thermodynamically favoured isomerization of
(5)
(6)
alkenes (e.g. P-pinene to a-pinene) in sulphur dioxide has been interpreted as a reversible ene reaction;" an earlier Report (Vol. 1, p. 43) erroneously alludes to the reaction of P-pinene with sulphur dioxide to form the corresponding cyclic sulphite. Relatively rapid racemization of p-menth- 1-ene is also observed in sulphur d i o ~ i d e . ' ~The rearrangement of a-ethylenic and a-acetylenic alcohols (e.g. 1,2-dehydrolinalool to citral, cf. Vol. 7, p. 17) via vanadate esters has been discussed.90 Methods for oxidative transformations continue to receive attention. Nickel peroxide on graphite oxidizes geraniol to citral in 89% yield." Three groups r e p ~ r t ~the * - oxidative ~~ rearrangement of tertiary vinyl carbinols. Linalool is conC. F. Lane, Chem. Rev., 1976, 76, 773; Aldrichimica Acta, 1977, 10,41. A. Pelter, Chem. and Ind., 1976, 888. A. P. Kozikowski and H. F. Wetter, Synthesis, 1976, 561. 8 1 J. K. Rasmussen, Synthesis, 1977, 91. 82 C. Blomberg and F. A. Hartog, Synthesis, 1977, 18. 83 N. Rabjohn, Org. Reactions, 1976, 24, 261. 84 D. Caine, Org. Reactions, 1976, 23, 1. 85 A. J. Birch and D. H. Williamson, Org. Reactions, 1976, 24, 1. 86 H. C. Brown, Pure Appl. Chern., 1976,47,49. '' (a)H. B. Kagan, Pure Appl. Chem., 1976,46, 177; ( b ) Chem. TechnoL, 1976,6,510. 88 P. A. Grieco, M. Nishizawa, N. Marinovic, and W. J. Ehmann, J. Amer. Chem. SOC.,1976,98,7102. M. M. RogiC and D. Masilamani, J. Amer. Chem. SOC.,1977, 99, 5219; the entry in Table I under 2,4,4-trimethyl-2-pentene is in error. 90 P. Chabardes, E. Kuntz, and J. Varagnat, Tetrahedron, 1977,33, 1775; see also T. Hosogai, T. Nishida, and K. Itoi, Jap. P. 48 608/1976 (Chem. A h . , 1976,85, 142 638). Last year's Report questioned that only E-citral was formed (Vol. 7, p. 17, ref. 190); the English translation of the full paper clarifies that E :2 ratios vary during the course of the reaction. y1 J. D. Surmatis, U.S.P. 4 005 031 (Chem. Abs., 1977.86, 140 297). See Vol. 4,p. 6 for chromic oxide on graphite oxidations. 92 J. H. Babler and M. J. Coghlan, Synrh. Comm., 1976,6, 469. 93 W. G. Dauben and D. M. Michno, J. Org. Chem., 1977,42,682. 94 P.Sundararaman and W. Herz, J. Org. Chem., 1977,42,813; formula (13)should have a hydrogen atom and not a methyl group at C-2 and the formula for linalool has a misplaced double bond. 78
79
10
Terpenoids and Steroids
verted smoothly into a 1 : 1 mixture of E - and 2-citral using pyridinium chlorochromate (cf.Vol. 6 , p. 8; Vol. 7, p. 30); oxidation of linalool with Collins reagent yields only 10% of E- and 2-citral with the epoxides (7) pred~minating.’~By analogy with nerolidol, chromous chloride would be expected to convert (7) into Eand Z - ~ i t r a l . ’Alkylative ~ enone transposition is achieved by the l ,4-addition of trialkylstannyl-lithium-THFto ap-unsaturated ketones (in contrast the reagent gives 1,2-addition in ether as solvent) followed by alkylation, oxidative destannylation with Collins reagent, and dehydration; (*)-piperitone (8; X = H)is readily synthesized from 4-isopropylcyclohex-2-enone.95Applications of polymeric oxidizing agents include the efficient oxidation of alcohols ( e.g. geraniol, menth01)’~ and allylic halides (e.g. geranyl b r ~ m i d e ) ~to’ aldehydes and ketones with chromic acid on anion-exchange resin, and sensitized oxidation of the enamino-ketone (9)
(7)
(81
(9)
in the presence of polymer-bound Rose Bengal yields buchucamphor (8; X = OH) in 81% overall yield from menthone.” Selenium dioxide allylic oxidation may be effected much more cleanly than with selenium dioxide alone by using t-butyl hydroperoxide in the presence of a catalytic amount of selenium dioxide; e.g., geranyl acetate is oxidized to (E,E)-8-acetoxy-2,6-dimethylocta-2,6-dien-1-01 (48%) and the corresponding aldehyde (7’/0).~’Some further details of the photochemical cleavage of pyruvate esters (Vol. 7, p. 6 ) have been published;’00when so much of these two papers-results, references, and actual paragraphs-are virtually identical, there seems little need for separate publication. An improved method (high to quantitative yields) for oxidizing alcohols, uia dimethylalkoxysulphonium salt, using DMSO-TFAA followed by base at very low temperatures, works well with sterically hindered alcohols; isoborneol yields camphor at low temperature (>go%) but camphene (>85%), by rearrangement-elimination, when the base treatment is at room temperature.”’ Other oxidation papers of interest include alkali hypochlorite oxidation catalysed by RuOz (chrysanthemyl alcohol to chrysanthemaldehyde),lo2 the full paper which extends earlier observations (Vol. 4, p. 6 ) on the oxidation of saturated secondary alcohols with 2,3-dichloro-5,6-dicyano95 96
97
98 99
lo’
W. C. Still, J. Amer. Chem. SOC.,1977,99, 4836. G. Cainelli, G. Cardillo, M. Orena, and S. Sandri, J. Amer. Chem. SOC.,1976,98,6737. For a review of polymers as chemical reagents see ‘Encyclopaedia of Polymer Science and Technology’, Supplement Vol. 1, ed. H. F. Mark and N. B. Bikales, Wiley-Interscience, New York, 1976, p. 468. G. Cardillo, M. Orena, and S. Sandri, Tetrahedron Letters, 1976, 3985; cf Vol. 7, p. 6, ref. 53. H. H. Wasserman and J. L. Ives, J. Amer. Chem. SOC., 1976,98, 7868. M. A. Umbreit and K. B. Sharpless, J. Amer. Chem. Soc., 1977,99,5526. R. W. Binkley, J. Org. Chem., 1976, 41, 3030. S. L. Huang, K. Omura, and D. Swern, J. Org. Chem., 1976.41, 3329. For earlier applications of this reagent see K. Omura, A. K. Sharma, and D. Swern, ibid., 1976, 41,957. A. I. Dalton, H. J. Doran, and R. D. H. Murray, Ger. Offen. 2 642 671 (Chem. Abs., 1977,87,6228).
Monoterpenoids
11
1 , 4 - b e n ~ o q u i n o n e , 'halothiation ~~ as a method for oxidizing primary halides and terminal alkenes (e.g. 0-pinene; low yield) to aldehydes,lo4 and the oxidation of secondary alcohols by trichloroacetaldehyde on alumina (e.g. menthol to menthone, plus some i~omenthone);'~'homogeneous catalytic oxidation of secondary alcohols with 0,-PdC1,-NaOAc fails in the presence of alkenes (e.g. p-menth8-en-3-01). lo6 Benzeneseleninic acid and hydrogen peroxide epoxidizes alkenes [e.g. citronel101, (-)-isopdlegol (10; R = H), E-3,7-dimethyloct-5-en-l-ol and the corresponding acetate]; (11; X=O) and (12; X = 0)are obtained from geraniol (the structure is incorrect in the paper) and linalool respectively by predominant epoxidation distant from the hydroxy-group,Io7 in contrast to epoxidation with t-butyl hydroperoxide-vanadium or -molybdenum complexes (Vol. 5 , p. 6). In the presence of the chiral acetylacetonato-[(-)-N-alkylephedrinato]dioxomolybdenum(~~), cumene hydroperoxide converts nerol into (13) in 33% enantiomeric excess.Io8 Sharpless finds t-butyl hydroperoxide more efficient than cumene hydroperoxide in asymmetric epoxidation in the presence of N-phenylcampholylhydroxamic acid: VO(acac),/S : 1;lo9geraniol yields a 30% enantiomeric excess of (14),'09 the enantiomer of that produced from geraniol by the Japanese group.lo8
Selective catalytic hydrogenation with chromium-promoted Raney nickel is reported (e.g. citral and citronella1 to citronellol);l10 NaHCr2(CO)lo and KHFe(CO), reduction of ap-unsaturated ketones (e.g. citral to citronellal) has been described (cf. Vol. 7, p. 7).l11 The full paper on selective carbonyl reductions on alumina (Vol. 7, p. 7) has been published.'12 Dehydrogenation of monoterpenoid alcohols over liquid-metal catalysts gives aldehydes and ketones in useful ~ i e 1 d s . l ' ~ Sensitized photo-oxidation of substituted cyclohexanone silyl enol ethers yields substituted ~ y c l o h e x - 2 - e n o n e s .For ~ ~ ~example, menthone may yield (8; X = H ) or (15)'14 depending upon the direction of enoli~ation;"~ the corresponding hydroxyJ.-I. Iwamura, Nippon Kagaku Kaishi, 1977, 10U3. L. A. Paquette, W. D. Klobucar, and R. A. Snow, Synth. Comm., 1976,6,575. G. H. Posner, R. B. Perfetti, and A. W. Runquist, Tetrahedron Letters, 1976, 3499. T. F. Blackburn and J. Schwartz, J.C.S. Chem. Comm., 1977, 157. 107 P. A. Grieco, Y. Yokoyama, S. Gilman, and M. Nishizawa, J. Org. Chem., 1977, 42, 2034. lo* S.-I. Yamada, T. Mashiko, and S . Terashima, J. Amer. Chem. SOC.,1977,99, 1988. R. C . Michaelson, R. E. Palermo, and K. B. Sharpless, J. Amer. Chem. SOC.,1977,99, 1990. P. S. Gradeff and G . Formica, Tetrahedron Letters, 1976, 4681; cf. Vol. 4, p. 17. G. P. Boldrini, A. Umani-Ronchi, and M. Panunzio, Synthesis, 1976, 596. G. H. Posner, A. W. Runquist, and M. J. Chapdelaine, J. Org. Chem., 1977,42, 1202. Y. Saito and Y. Ogino, Nippon Kagaku Kaishi, 1976, 1018. E. Friedrich and W. Lutz, Angew. Chem. Internat. Edn., 1977,16,413. "'For a recent discussion of regiospecific synthesis of trimethylsilyl enol ethers see G . M. Rubottorn, R. C. Mott, and D. S . Krueger, Synth. Comm., 1977,7, 327. lo3
Terpenoids and Steroids
12
ketones (16) and (17; major product) are also reported (with no supporting data) from respective competing ene reacti~ns.''~a-Nitro-ketones (e.g. 3-nitrocamphor) are formed by treating trimethylsilyl enol ethers with nitronium tetrafluoroborate.ll6 a-Epoxysilanes are readily formed by what is essentially reductive nucleophilic acylation of a carbonyl group from a-chloro-a-trimethylsilyl carbanion; nopinone yields (18),'17 from which one should obtain myrtanal in good yield.
Q
o (15)
Q: 90 (16)
(17)
(18)
Azides [e.g. (+)-neomenthyl azide; no physical data reported] are formed efficiently''' by inversion, from the corresponding alcohols and diphenylphosphoryl azide, in the presence of triphenylphosphine and diethyl azodicarboxylate [which has also been used for esterification with inversion (Vol. 5 , p. 334); for a related esterification of (-)-menthol see ref. 1191; a conceptually similar synthesis also yields (+)-neomenthyl azide.'" Cyanoselenenylation of a1dehydesl2l and of alcohols122has been reported; thus treatment of geraniol with o-nitrophenyl selenocyanide-Bun3P-THF yields the selenide (19) which can be converted into the
(19)
known (Vol. 4, p. 6, ref. 27) linalool epoxide (12; X=O) with 30% hydrogen peroxide-pyridine-CH2Clz.'22 Further papers of interest report regeneration of ketones from oximes using NOCl,123 synthesis of acetamides from alcohols with SOzC12,124alkylation of
'19
'" 12'
I. Sh. Shvarts, V. N. Yarovenko, M. M. Krayushkin, S. S. Novikov, and V. V. Sevost'yanova, Bull. Acad. Sci.,U.S.S.R.,Div. Chem. Sci., 1976, 25, 1589. C. Burford, F. Cooke, E. Ehlinger, and P. Magnus, J. Amer. Chem. Soc., 1977,99,4536. B. Lal, B. N. Pramanik, M. S. Manhas, and A. K. Bose, Tehahedron Letters, 1977, 1977; the presumed (+)-neomenthyl azide is named (+)-menthy1 azide in this paper. 0. Achmatowicz and G. Grynkiewicz, Tetrahedron Letters, 1977, 3179. Y. Chapleur, B. Castro, and B. Gross, Synth. Comm., 1977, 7, 143; the azide is poorly named and based upon an incorrect structure for (-)-menthol. P. A. Grieco and Y. Yokoyama, J. Amer. Chem. SOC.,1977,99,5210. T. Kametani, H. Nemoto, and K. Fukumoto, Heterocycles, 1977, 6 , 1365; see also P. A. Grieco, S. Gilman, and M. Nishizawa, J. Org. Chem., 1976,41, 1485. C. R. Narayanan, P. S. Ramaswamy, and M. S. Wadia, Chem. and Znd., 1977,454. K. Takeuchi, M. Nojima, and N. Tokura, J.C.S. Perkin Z, 1976, 2205.
Monoterpenoids
13
ketones with a dianion of ethyl a - m e r c a p t ~ a c e t a t e , 'the ~ ~ addition of l-lithiocyclopropyl phenyl sulphide to saturated and @-unsaturated ketones,'26 thio-. cyanate and selenocyanate formation,127and the formation of a-chloro-ketones via dichloromet hyl -lit hium. '28
3 Biogenesis, Occurrence, and Biological Activity Last year's Report propagated an error in Chemical abstract^;"^ Opdyke has published further monographs on fragrance raw materials, including data on legal status and toxi~ology.'~"Two useful books on perfume technology have a ~ p e a r e d ' ~ ~and . ' ~ 'the industrial importance of monoterpenoids and essential oils has been reviewed.'33 The biennial review of essential oils by Guenther et and a collection of 6 4 essential oil analyses (emphasizing g.c. and m.s. data, with references to 1974 in some cases)13s have been published. The well known problems of essential oil composition studies have been reviewed. 13' The biosynthesis of monoterpenoids is included in a book devoted largely to unfortunately some formulae have been drawn carelessly [e.g. menthol (p. 282)' loganin (p. 284), presqualene pyrophosphate (p. 209)]. Other reviews in this section cover monoterpenoid and sesquiterpenoid b i o s y n t h e s i ~biogenetic-type ,~~~ rearrangements of monoterpenoids and related model the biosynthesis of loganin-derived alkaloids,'40 and monoterpenoid alkaloid chemistry.14' Microbial transformations of monoterpenoids have been reviewed with a literature coverage to 1973/74.14'" 125 K. Tanaka, N. Yamagishi, R. Tanikaga, and A. Kaji, Chem. Leffers,1977, 471. B. M. Trost, D. E. Keeley, H. C. Arndt, J. H. Rigby, and M. J. Bogdanowicz, J. Amer. Chem. SOC., 1977, 99, 3080; see also ref. 3. lZ7 A. Arase and Y. Masuda, Chem. Letters, 1976, 1115. 128 H. Taguchi, H.Yamamoto, and H. Nozaki, Bull. Chem. SOC. Japan, 1977, 50, 1592. Ref. 84 in Vol. 7, p. 8 should read D. L. J. Opdyke, Food and Cosmetics Toxicol., 1975, 13 suppl., 681 (Special Issue 11; Monographs on Fragrance Raw Materials); for the first special issue in this series, see D. L. J. Opdyke, ibid., 1974, 12 suppl., 807. 13* D. L. J. Opdyke, Food and Cosmefics Toxicol., 1976, 1 4 suppl., 659 (Special Issue 111; Monographs on Fragrance Raw Materials); additional monographs have been published periodical!y by D. L. J. Opdyke, beginning ibid., 1973, 11, 95. For recent monographs see D. L. J. Opdyke, ibid., 1976, 14, 197, 307,443,601. 131 M. Billot and F. V. Wells, 'Perfumery Technology. Art: Science: Industry', Ellis Horwood, Chichester, England, 1975. 13* R. W. James, 'Fragrance Technology. Synthetic and Natural Perfumes', Noyes Data Corporation, Park Ridge, New Jersey, 1975; this useful review covers the US. Patent literature from January 1964 (U.S. P. 3 117 982) until mid-1974 (U.S. P. 3 819 737). 133 R. E. Erickson, Lloydia, 1976, 39, 8. For an earlier review of industrial syntheses which was inadvertently omitted from these Reports, see W. Hoffmann, Seifen-Ole Ferte- Wachse, 1975, 101, 89. 134 E. Guenther, G. Gilbertson, and R. T. Koenig, Analyt. Chem., 1977, 49, 83R; these biennial reviews (see also Vol. 6, p. 10, ref. 70) are particularly important since the limited space available for these Reports allows little detailed coverage of this field. 135 Y. Masada, 'Analysis of Essential Oils by Gas Chromatography and Mass Spectrometry', Wiley, 1976. 136 J. Garnero, Parfums, Cosmet., Aromes, 1977, 14, 31. 137 W. R. Nes and M. L. McKean, 'Biochemistry of Steroids and other Isopentenoids', University Park Press, Baltimore, 1977, pp. 271-284. 13' M. Gleizes, Annie BioL, 1976,15, 101. 139 R. M. Coates, Fortschr. Chem. org. Naturstoffe, 1976, 33, 73. D. S . Bhakuni, J. Sci. Ind. Res., India, 1976, 35, 449; see also A. I. Scott, Recent A d v . Phytochem., 1975, 9, 189. 141 V. Snieckus, in 'Alkaloids', ed. K. Wiesner, MTP International Review of Science, Organic Chemistry, Series Two, Vol. 9, Butterworth, London, 1976; Chapter 7, pp. 191-263. 1410 K. Kieslich, 'Microbial Transformations of Non-Steroid Cyclic Compounds', Wiley, New York, 1976; pp. 56-70. lZ6
'''
14
Terpenoids and Steroids
The number of computer-generated monoterpenoid carbon skeletons exceeds those which are presently HLADH oxidation of 3-methylpentane-1,3,S-triolyields, after silver oxide oxidation, (3s)-(+)-mevalonolactone of 14% optical p ~ r i t y . ’ ~ ’The synthesis of [4,5-13C2]MVA using known procedures was omitted from last year’s Report,144 and another synthesis of (*)-mevalonolactone has been rep~rted.’~’ There have been significant advances in our knowledge of monoterpenoid biosynthesis this year, particularly with the painstaking work of Banthorpe’s group in examining partially purified enzyme systems and stereochemical implications; 146-150 further papers from Poulter’s group on biosynthetic model s t ~ d i e s , ’ ~which ~ - ’ ~ may ~ be usefully read in conjunction with some of Banthorpe’s work on the irregular m ~ n ~ t e t - p e n ~ iare d ~reviewed , ~ ~ ~ ”in~the ~ ~Artemisyl, ~ ~ ~ Santolinyl, Lavandulyl, Chrysanthemyl section. In one of them,’51Poulter proposes a simple numerical method for describing the various linkings of isoprene units and suggests that it will overcome the confusion caused by some workers (including Poulter) who describe ‘the tail of isoprene as its head’.lS4 Monoterpenoid biosynthesis in excised epidermis of Majorana hortensis has been examined’55 and Banthorpe has made the interesting observation that the highest rates of incorporation of biosynthetic precursors with Tanacetum vulgare occur in uivo during the plant’s dormant phase (75-fold increase over the growing phase).I4’ The incorporation of [2-14C]MVA into monoterpenoids (e.g. geraniol) in a microbial system (Ceratocystismoniliformis)results in a symmetrical distribution between the IPP- and DMAPP-derived moieties of the monoterpenoid ske1et0n.l~~ Feeding experiments with [2-’4C,S-3H2]MVA and Citrus natsudaidai, Perilla frutescens, and Cinnamomum camphora have shown that (+)-limonene, (-)-perillaldehyde, and (+)-camphor respectively are biosynthesized with retention of all four tritium atoms, indicating symmetrical distribution between IPP and DMAPP derivation; the results are also consistent with a biosynthetic pathway involving geranyl pyrophosphate (GPP) neryl pyrophosphate (NPP) isomerization via a non-oxidative pathway.ls7 An alternative suggestion, which has
+
143
D. H. Smith and R.’ E. Carhart, Tetrahedron, 1976,32,2513. A. J. Irwin and J. B. Jones, J. Amer. Chem. SOC.,1977,99, 556.
144
J. R. Hanson and R. Nyfeler, J.C.S. Chem. Comm., 1976, 72; see Vol. 6, p. 10, ref. 73.
14*
145 146
14’
H. Omichi, H. Machida, T. Miyakoshi, and S. Saito, Nippon Kugaku Kaishi, 1977, 1021. K. G. Allen, D. V. Banthorpe, B. V. Charlwood, and C. M. Voller, Phytochemistry, 1977,16,79; tho numbering of formulae (1)and (3) in this paper should be reversed. D. V. Banthorpe, S. Doonan, and J. A. Gutowski, Phytochemistry, 1977, 16, 8 5 ; the reference to
3,3-dimenthylallyl alcohol in the Experimental is obviously a typographical error and formula (2) in figure 3 should be formula (12). 14’ D. V. Banthorpe, G. A. Bucknall, J. A. Gutowski, and M. G. Rowan, Phytochemistry, 1977,16, 355. 149 D. V. Banthorpe, J. Mann, and I. Poots, Phytochemistry, 1977,16, 547. 150 D. V. Banthorpe, B. V. Charlwood, G. M. Greaves, and C. M. Voller, Phyrochemistry, 1977,16, 1387. 15’ C. D. Poulter, L. L. Marsh, J. M. Hughes, J. C. Argyle, D. M. Satterwhite, R. J. Goodfellow, and S. G. Moesinger. J. Amer. Chem. SOC., 1977,99, 3816. lS2 C. D. Poulter and J. M. Hughes, J. Amer. Chem. SOC.,1977, 99, 3824. lS3 C. D. Poulter and J. M. Hughes, J. Amer. Chem. SOC.,1977,99,3830; corrigendum, ibid., p. 7400. lS4 See, for example, I. L. Finar, ‘Organic Chemistry’, Vol. 2, 5th Edn., Longman, London, 1975, p. 3551 155 R. Croteau, PluntPhysiol., 1977, 59, 519. E. Lanza and J. K. Palmer, Phytochemistry, 1977, 16, 1555; for a review of some earlier work on volatile odorous materials (including monoterpenoids) produced by micro-organisms see R. P. Collins, Lloydia, 1976, 39, 20. T. Suga, T. Shishibori, and T. Hirata, Chem. Letters, 1977, 937. For previous discussion of these two pathways see Vol. 4, p. 255 and VoI. 7, pp. 181, 186.
Monoterpenoids
15
been made to account for results with soluble enzymes from Citrus limonum where a substrate isomerization is not observed,lT8is that both GPP and NPP produce enzyme-bound carbocations, whose conformations on species-specific cyclases determine their direct incorporation into monoterpenoids; the low in vitro incorporation of substrates into limonene with these soluble enzymes1ss may be consistent with Banthorpe's similar o b s e r v a t i ~ n with ' ~ ~ cell-free extracts of Tuna cetum vulgare, Artemisia annua, and Santolina chamaecyparissus, which is attributed to seasonally dependent enzymes converting IPP, DMAPP, GPP, and NPP into water-soluble products, possibly as a salvage system regulating the nonphysiological levels of monoterpenoid precursors. For example, the epoxide (1 1; X = 0)and the corresponding trans,trans-3,7-dimethylocta-2,5-diene-l,7-diol are major products from GPP substrate, with minor products involving C-2-C-3 epoxidation; it is suggested that the decomposition of such salvage products may account for difficulties encountered in the purification of monoterpenoids biosynthesized from radioactive exogenous The full paper on Banthorpe's previously reported (Vol. 2, pp. 13, 202) work on the biosynthesis of artemisia ketone (20; X=O) in Artemisia annua and Santolina chamaecyparissus includes some new findings, namely the non-incorporation of dimethylvinylcarbinol (DMVC) and the cis- and trans -chrysanthemic acids and alcohols in uivo, and the asymmetry of labelling of artemisia ketone (20; X=O) derived from IPP and DMAPP in S. chamaecyparissus via the 'two pool hypothesis' (see Vol. 7, p. 184). (+)-trans-Chrysanthemyl alcohol (21) is also reported to serve as an excellent precursor of the pyrethrins in Chrysanthemum cinerariaefolium (see Vol. 6 , p. 1l).146To overcome difficulties of substrate incorporation due to possible compartmentation, a second paper'47 reports biosynthesis using cell-free extracts in vitro. IPP, DMAPP, and particularly DMVC (cf.Vol. 7 , p. 185; difficulties encountered in purifying DMVC pyrophosphate did not allow its comparison with IPP and DMAPP) were effective precursors of artemisia alcohol (20; X = H,OH), artemisia ketone (20; X = 0),trans-chrysanthemyl alcohol (21) (whose interconversions were also catalysed), and lavandulol (22); interestingly, neither (21) nor (22) has been detected in the essential oils of A. annua or S. chamaecyparissus. Whereas cis-chrysanthemyl alcohol and its pyrophosphate are effectively converted into (20; X=O) and (20; X=H,OH) also, little effective incorporation of GPP, NPP, and linaloyl pyrophosphate was observed. Artemisia ketone (20; X = 0)and trans-chrysanthemyl alcohol (21) were effectively formed from [Me-14C]DMVC pyrophosphate with the now well established asymmetry of labelling (cf. Vol. 7, p. 184), raising the question of an obligatory role of DMVC in monoterpenoid biosynthesis and its relation to a metabolic pool of protein-bound DMAPP. Other important observations from this most important paper are the involvement of sulphydryl groups in the metabolic pathway and of a dehydrogenase system in the formation of artemisia ketone (20; X=O) rather than a mixedfunction oxidase system dependent upon cytochrome P450. A tentative biosynthetic scheme has been proposed (Scheme 1; alcohol intermediates are shown for clarity) to accommodate these observations in which artemisyl and chrysanthemyl compounds are now suggested to be on divergent pathways (for earlier obserL. Chayet, C. Rojas, E. Cardemil, A. M. Jabalquinto, R. Vicuna, and 0. Cori, Arch. Biochem. Biophys., 1977,180, 318; for earlier work see Vol. 4, p. 255.
16
Terpenoids and Steroids
Scheme 1
vations see Vol. 2, p. 13; Vol. 7, p. 185) beginning with the ylide form of the protein-bound pool of DMAPP [e.g. (23)]. The paper also reports reliable methods A comparison for the purification of pyrophosphate esters of substrate of the incorporation of [2-14C]- and [4-I4C]-geraniol and -nerol into the cooccurring regular (borneol, trans-thujan-3-one, and pinocamphone) and irregular [artemisia ketone (20; X=O)] monoterpenoids in A. annua is consistent with intact incorporation of Clo precursors into the regular monoterpenoids, but extensive degradation must occur in artemisia ketone (20; X = 0)biosynthesis to account for the extensive scrambling of the label from [2-I4C]geraniol over all ten carbon atoms.1s0 Oxidative degradation, via the epoxide (11; X=O),14' to yield a C s fragment which is incorporated intact into artemisia ketone (20; X = 0),along with a second Cs moiety which may arise from simpler precursors, provides a plausible explanation of these result^.'^' It is not possible to evaluate the significance of thiamine in artemisyl biosynthesis at present.159 Some progress has been made towards understanding the conversion of MVA, via 1 0-hydroxygeraniol (24),I6O into iridoids and secoiridoids; the suggestion that two distinct biosynthetic pathways may exist, depending upon whether iridoid glucosides, containing a highly oxidized cyclopentane ring, or secoiridoids (and indole alkaloids) are being formed (Vol. 7, p. 22, ref. 230), has received additional support. Whereas the secoiridoid and indole alkaloid pathway usually involves the If('
160
G. E. Risinger, K. Karimian, S. Jungk, and R. L. Bell, 174th A.C.S. Meeting, Chicago, August 1977, Abstracts ORGN, No. 140. The paper by K. M. Madyastha, T. D. Meehan, and C. J. Coscia, Biochemistry, 1976, 15, 1097, which was inadvertently omitted from last year's Report, discusses a cytochrome P450-dependent hydroxylase involved in biosynthesis of (24).
Monoterpenoids
17
equal labelling o f C-3 and C-11 from [2-I4C]MVA (see Vol. 1, p. 229*), similar feeding experiments with [2-l4C]MVA and Lamium amplexicaule, Deutzia crenata, and Galium spurium have established that the radioactive label essentially resides only at C-3 (as well as C-7) for deutzioside (25; X = H), scabroside (25; X = OH), lamioside (26), asperuloside (27), lamiide (28; X = OH, R = H), and ipolamiide (28; R=X=H).16' In these cases, this result may be interpreted in terms of cyclization of a precursor such as 10-hydroxygeraniol (24) to a methylcyclopentane intermediate without eqivalence of the carbon atoms which give rise to C-3 and C-11 [this is not so with verbenalin (Vol. 1, p. 231)'62" and plumieride;16*' with the latter randomization has been observed]. Formation of the C-11 oxygenated iridoids (27), (28; R = X = H), and (28; X = OH, R = H) seems to involve the sequence CH3 -+ C H 2 0 H + CO,R after the initial cyclization (see also on deutzioside [whose stereochemistry is Vol. 3, p. 254). In a second pape? now confirmed as (25; X = H)] biosynthesis in Deutzia crenata, Inouye et al. provide evidence in favour of the biosynthetic sequence 10-hydroxygeraniol (24) -+ iridodial (29; R = H) -+ iridodialglucoside (29; R = P-Glu) -+ deutzioside (25; X=H). It is suggested that this pathway may also apply to the biosynthesis of lamioside (26), ipolamiide (28; R = X = H ) , lamiide (28; X = O H , R = H ) , and
' ~ ~ cell-free asperuloside (27)163as discussed in the earlier paper. 16' C r ~ t e a u ,using preparations from Salvia officinalis, has shown that NPP independently forms a-terpineol, limonene, and 1 , 8 - ~ i n e o l e , with ' ~ ~ no evidence for any free inter16' 16'
163 164
16'
H.Inouye, S. Ueda, and s. Uesato, Tetrahedron Letters, 1977, 709. ( a )J. E.S. Hueni, H. Hiltebrand, H. Schmid, D. Groeger, S. Johne, and K. Mothes, Experientia, 1966, 22,656; ( b ) D. A. Yeowell and H. Schmid, ibid., 1964.20, 250. H . Inouye, S. Ueda, and S. Uesato, Tetrahedron Letters, 1977, 713. R. Croteau and W. D. Loomis, Znternat. Flavours Food Additives, 1975,6,292; this excellent review of monoterpenoids was omitted from Vol. 7. R. Croteau and F. Karp, Arch. Biochem. Biophys., 1976, 176, 734; this is another example of a monoterpenoid paper which is not recorded in the Terpenoids section of Chemical Abstracts (see also refs. 164, 166, 167).
* The numbering system used for the iridoids in this Report conforms to that used in earlier recent Monoterpenoid Reports; in the Vol. 1 references, however, a different numbering system was used.
Terpenoids a n d Steroids
18
mediates between NPP and 1 , 8 - ~ i n e o l e ; the ' ~ ~ cyclase activity may involve enzyme thiol-bound intermediates.'66 An enzyme preparation, containing both cyclase and dehydrogenase, also converts NPP into borneol and camphor.167 The recent observation (Vol. 7, p. 18.5) that a-terpineol is a more effective precursor of (+)-thuj-3-one (30) (see Vol. 6, p. 11) than p-menth-l-en-4-01 in cell-free extracts of Tanacetum vulgare is now supported by in uivo feeding experiments with (3RS)-[2-'4CC,2-3Hz]MVA,(3RS,2R)-[2-'4C,2-3Hl]MVA, (3RS,2S)-[2-'4C,2-3Hl]MVA, and [9-'4C,4-3H1,10-3H,]-a-terpineol and considered to be consistent with the biosynthetic mechanism (Scheme 2) which involves the stereospecific migration of the pro-(2S) hydrogen of MVA in one of the two 1,2-shifts proposed in forming (+)-thuj-3-one (30) via the corresponding neothujan-3-01 (31).14'
Scheme 2
Cantharidin (Vol. 1, p. 228; Vol. 5, p. 42) is biosynthesized from farnesol by degradation but not from geraniol.16' Attempts to investigate boll weevil (Anthonornus grandis) pheromone biosynthesis have identified isomerization, dehydration, and oxidation of the pheromone alcohols, and anticipated allylic oxidation of myrcene and limonene, but no evidence for the cyclization of acyclic precursors. 16' The aggregation pheromones of bark beetles have been r e ~ i e w e d . ' ~Ips ' calligraphus responds to ipsdienol only in the presence of the cis-verbenol (32); large additional concentrations of the enantiomer (lR,4R,jR)-(32) reduce beetle r e ~ p 0 n s e . lS-(-)-Ipsenol, ~~ the pheromone of Ips grandicollis, increases the response of I. avulsus to its own pheromone ip~dienol.'~' I
(32) 166
167
170
17'
17'
R, Croteau and F. Karp, Arch. Biochem. Biophys., 1977, 179, 257; for an earlier uncited paper on 1,8-cineole biosynthesis in Rosmarinus officinalis, see B. Achiiladelis and J. R. Hanson, Phytochemistry, 1968,7, 1317. R. Croteau and F. Karp, Biochem. Biophys. Res. Comm.,1976,72.440. M. G . Peter, W.-D. Woggon, C. Schlatter, and H. Schmid, Helu. Chim. Acta, 1977,60, 844, 1262. P. A. Hedin, J. Chem. Ecol., 1917, 3 , 279. J. P. VitC and W. Francke, Naturwiss., 1976,63, 550; the absolute configuration of (+)-trans-verbenol in figure 5 is incorrect (see Vol. 7, p. 41). J. P. VitB, D. Klirnetzek, G. Loskant, R. Heddon, and K. Mori, Naturwiss., 1976,63,582; see ref. 485 for the synthesis of these enantiomers. R. Heddon, J. P. VitC, and K. Mori, Nature, 1976, 261, 696.
Monoterpenoids
19
The limited space available for this Report allows for little discussion of essential papers of chemotaxonomic importance from this year's literature will be discussed in next year's Report (i.e. biennially). Apparatus for isolating trace volatile component^'^^ and also for undergraduate laboratory essential oils extract i ~ n has ' ~ been ~ described. Methods of analysis of 1,8-cineole in essential oils have been ~ u b 1 i s h e d . lEssential ~~ oil composition studies of interest are of Tagetes lunulafa (tagetone, dehydrotagetone, and d i h y d r ~ t a g e t o n e ) , 'Eucalyptus ~~ species (cis-piperitol, cis-p-menth-2-en-1-01, and frans-p-menth-Z-en-l-~I),'~~ Chaerophyllum hursutum (fenchyl acetate),'78 Piper nigrum (further oxygenated menthadienol~),"~Hyssopus officinalis [no reference is made to the earlier communication by the same author (Vol. 7, p. 9); myrtenol methyl ether is an additional component],180Arfemisia pontica (artemisia ketone and not isoartemisia ketone as stated),'" and Sanfolina virens and S. chamaecyparissus.18*The surprising feature of the last paper is the claim to have isolated a-santolinenone,lR2which is generally believed not to exist;lR3incredibly the claim is not substantiated by spectral data and recent analytical work on these species is not cited. The bacteriostatic behaviour of six chemotypes of Thymus vulgaris has been examined.lR4 Papers from the symposium on the chemistry, biochemistry, and insecticidal action of natural and synthetic pyrethroids (Helsinki 1974, Third I.U.P.A.C. International Congress on Pesticide Chemistry)'8' and the proceedings of a symposium on synthetic pyrethroids held at the 172nd A.C.S. Meeting (San Francisco, 1976)186 have been published. Other pyrethroid papers of interest include 13Cn.m.r. spectra of synthetic pyrethroids (cf. Vol. 7, p. 20),lE7g.1.c. analysis of permethrin"* and b i ~ r e s m e t h r i nfurther , ~ ~ ~ work (Vol. 7, p. 10) on permethrin metabolism in rats'" R. A. Flath and R. R. Forrey, J. Agric. Food Chem., 1977, 25, 103; T. H. Schultz, R. A. Flath, T. R. Mon, S.B. Eggling, and R. Teranishi, ibid., 1977, 25, 446; S. S. Chang, F. M. Vallese, L. S. Hwang, 0. A. L. Hsieh, and D. B. S. Min, ibid., 1977, 25, 450. 174 A. A. Craveiro, F. J. A. Matos, and J. W. de Alencar, J. Chem. Educ., 1976,53, 652. ''' ( a ) A. M. Humphrey, J. H. Greaves, B. E. Kent, W. S. Matthews, D. A. Moyler, R. G. Perry, J. Ridlington, R. A. Stocks, and G. Watson, Analyst, 1977,102,607; C. L. Goodwin and A. E. Squillace, Phytochemistry, 1976,15,1771; (b)C. H. Brieskorn and W. Schlicht, Pharm. Actu Helu., 1976,51,133. 176 J. Calderon, J. L. Munoz, L. Quijano, and T. Rios, Rev. Latinoamer. Quim., 1976,7, 114 (Chem. Abs., 1977,86,47 204). 177 E. V. Lassak, 10th I.U.P.A.C. International Symposium on the Chemistry of Natural Products, Dunedin, New Zealand, 1976, Abstract D27. 17' F. W. Kudrzycka-Bieloszabska and K. Glowniak, Actu Polon. Pharm., 1976, 33, 395. 17' J. Debrauwere and M. Verzele, J. Sci. Food Agric., 1975, 26, 1887; cf. Vol. 6, p. 13. D. Joulain, Riuista Ital. Essenze-Profumi, Piante Ofic., Aromi, Suponi, Cosmet., Aerosol., 1976, 58, 479. M. Hurabielle, F. Tillequin, and M. Paris, P l u m Med., 1977, 31, 97. 182 V. A. Ushakov, D. A. Murav'eva, and L. A. Bakina, Chem. Natural Compounds, 1976,12,597. 183 L. H. Zalkow, D. R. Brannon, and J. W. Uecke, J. Org. Chem., 1964.29,2786; A. F. Thomas and B. Willhalm, Tetrahedron Letters, 1964, 3775. 184 M. S. de Bouchberg, J. Allegrini, C. Bessiere, M. Attisso, J. Passet, and R. Granger, Riuistu Ital. Essenze-Profumi, Piante Ofic., Aromi, Saponi, Cosmet., Aerosol., 1976, 58, 527. lS5 Pesticide Science, 1976,7, issue 3. la6 'Synthetic Pyrethroids', ed. M. Elliot, ACS Symposium Series, Volume 42, Washington, American Chemical Society, 1977. N. F. Janes, J.C.S. Perkin I, 1977, 1878. M. Horiba, A. Kobayashi, and A. Murano, Agric. and Biol. Chem. (Japan), 1977, 41, 581. I. Camoni, E. Chiacchierini, A. di Domenico, R. Iachetta, and A. L. Magri, Ann. Chim. (Italy), 1976, 66,439. 190 L. C. Gaughan, T. Unai, and J. E. Casida, J. Agric. Food Chem., 1977, 25, 9. 170
20
Terpenoids and Steroids
and lactating goats,”’ the asymmetric synthesis of R-(-)-allethr~lone,”~and the synthesis and insecticidal properties of some [2-(5-aryl)furyl]methyl chrysanthernate~.’~~ Many papers from the patent literature on pyrethroids and juvenile hormones cannot be included in this Report. Papers have reported the synthesis and activity of monoterpenoid juvenoids, including geranyl pyridyl ether^''^ and geranyl alkyl ethers and amines and their e p o ~ i d e s . ~ ~ Further ’ , ~ ’ ~ papers in this section include a report of the potent lung toxicity of perillaket~ne,”~ the observation that the malodorous water contaminant 2-methylisoborneol has the 1-R -ex0 configuration,19*and that fenchyl methyl L-aspartylaminomalonate is 2 X lo4 times sweeter than sucrose.199 4 Acyclic Monoterpenoids
Terpenoid Synthesis from Isoprene.-Syntheses of the useful synthons (33) and (34) have been reported.”’ The vinyl-oxygen bond of diketen is selectively cleaved by Me,SiCH,MgCl-NiCl, to yield the synthon (35)”* which is readily converted into the dicopper dienolate (Vol. 7, p. 14) and prenylated to yield (36; X = CO,H) after hydrolytic work-up and desilylation; (36; X = C 0 2 H ) yields
(33)
(34)
(35)
(36)
geranic acid (E:Z/91: 9) on treatment with strong base (see Vol. 5 , p. 12).202 Prenylation of a previously reported phenylsulphoxide synthon [Vol. 7, p. 10, formula (9)] yields, after desulphurization, linalool in 78% yield.“, Much of the telomerization work this year is either closely related or similar to work reported previously. This includes tail-to-tail isoprene dimerization [Pd(PEt),-CO,] to (37) which is extensively isomerized on prolonged reaction,204 191 192
19‘ 195
‘91
19’ 19* 199
’On 201
2n2
203 204
L. M. Hunt and B. N. Gilbert, J. Agric. Food Chem., 1977,25,673. M. Kitamoto, K. Kameo, S. Terashima, and S.-I. Yamada, Chem. and Pharm. Bull. (Japan), 1977,25, 1273. Y. P. Volkov, I. I. Zavedeeva, P. I. Zimov, G. M. Zubova, and A. F. Oleinik, Khim. Farm. Zhur., 1976, 10, 26. H. Solli, H. B. Madsen, P. L. Holst, and P. D. Klemmensen, Pesticide Science, 1976, 7 , 503. R. S. Deshpande, H. P. Tipnis, and V. M. Kulkarni, Indian J. G e m . , 1976,14B, 979. J. W. Patterson and M. Schwarz, J. Insect. Physiol., 1977, 23, 121. B. J. Wilson, J. E. Garst, R. D. Linnabary, and R. B. Channell, Science, 1977, 197, 573. N. F. Wood and V. L. Snoeyink, J. Chromatog., 1977, 132, 405. M. Fujino, M. Wakimasu, M. Mano, K. Tanaka, N. Nakajima, and H. Aoki, Chem. and Pharm. Bull. (Japan), 1976,24,2112. J. Paust, W. Reif, and H. Schumacher, Annalen, 1976, 2194, K. Itoh, T. Yogo, and Y. Ishii, Chem. Letters, 1977, 103. K. Itoh, M. Fukui, and Y.Kurachi, J.C.S. Chem. Comm., 1977, 500; reference 3 of this paper should refer to p. 4925 and not p. 492. P. J. R. Nederlof, M. J. Moolenaar, E. R. de Waard, and H. 0. Huisman, Tetrahedron, 1977, 33, 579. A. Musco, J. Mol. Catalysis, 1975/1976,1, 443.
Monoterpenoids
21
dimerization .to (37) in up to 90% yield and/or to 2,7-dimethylo.cta-2,7-dien-l-ol and 2,7-dimethylocta-l,7-dien-3-ol, or to various acetates depending upon the palladium catalyst/water/acetic acid/C02 . ratio,205 dimerization to (37)
exclusively or with accompanying 8-alkoxy-2,7-dimethylocta- 1,6-diene and 3alkoxy-2,7-dimethylocta- 1,7-diene (palladium catalysts-alcohols) (cf. Vol. 6, p. 15, ref. 115),206and considerable product variation is reported (palladium catalystsalcohols) in another paper (cf. Vol. 6, p. 15, ref. 116);207thus the head-to-tail and E-8-methoxy-3,7-dimethylocta1,6dimers E-2,6-dimethylocta-l,3,7-triene diene and the tail-to-tail dimer 2,7-dimethylocta- 1,7-diene may each be formed in high yield.207 Further reports of myrcene formation by telomerization of isoprene using sodium and amines (cf. Vol. 6, p. 15)'08 or using palladium catalystsalkoxides or -phenoxides, with accompanying ocimene formation (see Vol. 7, p. 12),209have been published. The catalytic activity of [Ni(PPh3)2C12]-NaBH4-amine in isoprene dimerization is enhanced to a maximum by water with little effect on product distribution (see Vol. 7, p. 11).210 The influence of triorganophosphine-palladium salts on the reductive dimerization of isoprene in the presence of formic acid and triethylamine has been investigated mechanistically and synthetically; the head-to-tail dimers 2,6-dimethylocta-1,7-dieneand 3,7-dimethylocta-1,6-diene,the former usually predominating, may be formed in up to 79% yield; preferential hydrochlorination allowed separation from tail-to-tail dimers and elaboration into citronellol and its double-bond isomer and into linalool.*" Another synthesis of citronellol (50% overall yield) involves dimerization of isoprene [(Et0)4Zr-Et2A1C1-Ph3P] to 3E,6Z-2,6-dimethylocta-1,3,6-triene,selective 1,4hydrogenation [Cr(CO),PhC02Me-H2], hydrozirconation, and oxidation.212 Sodamide in ethylenediamine isomerizes the well known telomer N-(3,7-dimethylocta-2,6-dienyl)dialkylamineto N-(3,7-dimethylocta-1,3-dienyl)dialkylamine,which is hydrolysed to dihydrocitral in good yield,213in contrast to elimination in the absence of solvent (Vol. 7, p. 12), where metallation occurs at the &position. Further syntheses with isoprene units are discussed in the next section. 205
206
207 208
209 210
L. I. Zakharkin, S. A. Babich, and I. V. Pisareva, Bull. Acad. Sci., U.S.S.R., Div. Chem. Sci., 1976,25, 1531. L. I. Zakharkin and S. A. Babich, Bull. Acad. Sci., U.S.S.R.,Div. Chem. Sci., 1976, 25, 1967. H. Yagi, E. Tanaka, H. Ishiwatari, M. Hidai, and Y. Uchida, Synthesis, 1977,334. K. Takabe, A. Agata, T. Katagiri, and J. Tanaka, Synthesis, 1977, 307; A. Murata, S. Tsuchiya, A. Konno, J. Tanaka, and K. Takabe, Ger. Offen. 2 542 798 (Chem. A h . , 1976,85,94 544). S . Akutagawa, Jap. P. 70 70511976 (Chem. Abs., 1976,85, 143 332). I. Mochida, K. Kitagawa, H. Fujitsu, and K. Takeshita, Chem. Letters, 1977,417. J. P. Neilan, R. M. Laine, N. Cortese, and R. F. Heck, J. Org. Chem., 1976, 41,3455. H. Yagi, M. Shirado, M. Hidai, and Y. Uchida, Yukagaku, 1977, 26, 232. M. Tanaka and G. Hata, Chem. and Ind., 1977,202.
'"
22
Terpenoids and Steroids
2,6-Dimethyloctanes.-McQuillin has reviewed the functionalization of alkenes and alkanes using homogeneous catalysis, emphasizing his own work with acyclic m o n o t e r p e n ~ i d s . ' ~Linalool ~ P-~-O-glucoside-3,4-diangelicate has been isolated from Syneilesis a~onitifolia,~'~ and the dehydronerol esters (38; R = Ac) and (38; R = COHCMe2) from Schkuhria senecioides; (38; R = COCHMe2) is also present in S. pinnata.216The essential oil of Artemisia absinthium is reported to contain up to 57% of the epoxides (39),217and further analysis (cf.Vol. 4, p. 12)of lavender oil has revealed the presence of (40) and (41))in addition to related oxidation and reduction uroducts.218
OAC
(38) (39) (40) (41) C N.m.r. relaxation of linalool has been analy~ed.''~The use of myrcene as an indicating quencher to distinguish between singlet and triplet excited-state photodecarboxylation of phenylacetic acid has been reported.'" R -(+)-a-Methyl-pnitrobenzylamide derivatives of chiral dihydro- and tetrahydro-geranic acids have been used for liquid chromatographic and the g.c. analysis of geraniol oxidation products using a graphite porous-layer open-tubular column has been reported twice.222 There has been considerable activity in this area of monoterpenoid synthesis. Syntheses of [7-'4C]-,223[7',8-14C]-, and [7',8-3H]-geraniol have been reported.'68 The ocimene (42; X=H) has been synthesized again by Vig et al., this time from trans-6,6-ethylenedioxy-2-methylhept-2-en-1-01via Wittig reactions.224 Both (4E)- and (42)-(6S)-2,6-dirnethyloct-4-ene have been synthesized by known The addition of organohomocuprates (e.g. routes from S-3-methylpent-l-yne.225 13
F. J. McQhillin, Chem. andInd., 1976, 941. F. Bohlmann and M. Grenz, Phytochemistry, 1977, 16,1057; formulae (3) and (9) erroneously depict B-L-glucoside derivatives. 2*6 F. Bohlmann and C. Zdero, Phytochemistry, 1977, 16,780; the keyword index refers in addition to a new dehydrocinnarnyl alcohol derivative. It should refer to a dihydrocinnamyl alcohol derivative: 21' F. Chialva, G. Doglia, G. Gabri, S. Aime, and L. Milone, Riuisfa Ztal., Essenze-Profirmi, Pianre W c . , Aromi, Saponi,Cosmet., Aerosol, 1976, 58, 522. 218 R. Kaiser and D. Lamparsky, Tetrahedron Letters, 1977, 665; formula (3) should have a 3,4-double bond. 'I9 A. Olivson and E. Lippmaa, in 'Magnetic Resonance and Related Phenomena, Proceedings of the 19th Ampere Congress', ed. H. Brunner, K. H. Hawser, and D. Schweitzer, Group Ampere, Heidelberg, 1976; p, 325 (Chem. Abs., 1977,87,23524). 220 G. A. Epling and A. Lopes, J. Amer. Chem. Soc., 1977,99, 2700. zzl c . G. Scott, M. J. Petrin, and T. McCorkle, J. Chromatog., 1976, 125, 157; see refs. 248-250 for related synthetic work. This method was previously applied to citronellic acid, see Vol. 7, p. 12, ref. 154. 222 C. Vidal-Madjar, S. BtkBssy, M. F. Gonnord, P. Arpino, and G. Guiochon, Analyt. Chem., 1977, 49, 768; P. Arpino, C. Vidal-Madjar, G. Guiochon, and S . BBkLssy, J. Chromatog., 1977, 138,173. 223 An earlier synthesis, H. D. Durst and E. Leete, J. Labelled Compounds, 1971,7, 52, was omitted from these Reports. 224 0. P. Vig, S. D. Sharma, M. L. Sharma, and K. C. Gupta, Indian J. Chem., 1977, 15B,25. '" A. M. Caporusso, G. Giacomelli, and L. Lardicci, Gazzetta, 1976, 106,879.
'I4
215
23
Monoterpenoids
R2CuMgCl) to the triple bond of conjugated enynes to yield vinylic cuprates has been used in a one-step synthesis of myrcene (43; X=H, 96% pure in 90% yield).226 Reaction of myrcene (43; X = H ) with magnesium in THF yields an enediyl metal species which may be hydrolysed to a mixture of (36; X = Me, 87%) and 3,7-dimethylocta- 1,6-diene (13%), or treated with acetone to yield 3-methyl(36; X = CMe20H),227an isomer of which is reported by the same author via the telomerization of isoprene in the presence of acetone and nickel-ligand catalyst.229 Cuprous iodide-catalysed a-coupling of prenylmagnesium chloride with E-4chloro-3-methylbut-2-en-1-01 yields pure gerani01.’’~ Syntheses of geraniol isomers have been reported. y-Geraniol [(36; X = CH20H); it is named isogeraniol in the paper] is obtained in 72% yield (see Vol. 6, p. 33, ref. 252 for earlier syntheses) from myrcene (43; X = H) via BF3,Et20-peroxide treatment of the derived enediyl species,227and Vig et al. report a straightforward second synthesis.231Borohydride reduction of citral enol acetate yields the E-A’-isomer of geraniol (Vol. 7, p. 16; line 4 should refer to this same A3-isomer and not to a A2-isomer); methylation yields the corresponding methyl ether which is one of four products (44) obtained after
(42)
(43)
(44)
dehydrochlorination of the products of the two-step TiC14-catalysed addition of methoxymethyl chloride to isoprene followed by product addition to 2-methylpropene (cf. Vol. 7, p. 17, which should have referred to a-isogeranyl methyl ether).’’’ Geranyl esters can be prepared from myrcene (43; X = H ) via NNdiethylgeranylamine.233 2-Fluorogeraniol and its 2-isomer are obtained via the corresponding aldehydes which result from the easy solvolytic cleavage of the chlorofluoromethoxycyclopropane obtained by addition of chlorofluorocarbene to l-methoxy-2,6-dimethylhepta-1,5-diene; l-methoxy-2,6-dimethylhept-l-ene correspondingly produces the dihydro-2-fluorogeraniols in better yield, as expected 226 227
”*229
230 231 232
233
H. Westmijze, H. Kleijn, J. Meijer, and P. Vermeer, Tetrahedron Letters, 1977, 869. S. Akutagawa and S. Otsuka, J. Amer. Chem. SOC.,1976,98, 7420; the formula for isogeraniol lacks the 6,7-double bond and the diene minor product is named incorrectly. No experimental details are given for the hydrolysis of this myrcene-magnesium complex but the results contradict those reported by Cookson et al. who have extensively investigated its reactions with carbonyl compounds, epoxides, carbon dioxide, and acetonitrile.228 R. Baker, R. C. Cookson, and A. D. Saunders, J.C.S. Perkin I, 1976, 1809, 1815. S. Akutagawa, Bull. Chem. SOC.Japan, 1976, 49 3646; formula ( 1 ) of this paper has a double bond omitted. Earlier uncited reports of this work22i*229 have appeared in the patent literature; e.g. T. Moroe, A. Komatsu, S. Akutagawa, T. Sakaguchi, and H. Matsuyama, Jap. P. 3770/1971 (Chem. Abs., 1971, 75, 20 583); T. Sakaguchi, S. Akutagma, and A. Komasu (sic), Jap. P. 15 941/1972 (Chem. Abs., 1972,77, 48 616). F. Derguini-Boumechal, R. Lorne, and G. Linstrumelle, Tetrahedron Letters, 1977, 1181. 0. P. Vig, S. D. Sharma, S. S. Bari, and S. D. Kumar, Indian J. Chem., 1977, 15B,93. B. V. Burger, C. F. Garbers, and F. Scott, J. S. African Chem. Inst., 1976, 29, 143; the preliminary communication (Vol. 6, p. 14, ref. 111) was only available as the Chemical Abstract, which gives no information on the work reported here, nor is any of the work in the abstract reported in this paper. K. Suga, T. Fujita, S. Watanabe, and R. Takiguchi, Yukagaku, 1976,25, 494.
Terpenoids and Steroids
24
when there is only one site of chlorofluorocarbene addition. Similarly, isopropenyl methyl ether readily yields 3-fluorobut-3-en-2-01 which undergoes Grignard addition to yield 2-fluorolinaloo1.234Poulter et al. have also synthesized 2-fluorogeraniol, which is readily separable from accompanying 2-fluoronerol, using the known addition of 1,2,2-trifluoroethenyl-lithium to ketones as the key step; using 2fluorogeranyl pyrophosphate, further evidence is provided for prenyltransferasecatalysed head-to-tail coupling in terpenoid biosynthesis occurring tiia an ionization-condensation-elimination mechanism (see Vol. 7, p. 1 The full paper (cfi Vol. 7, p. 15) on the synthesis of E-3,7-dimethyloct-2-ene-1,8-diol from the The chiral ipsdienols, RMonarch butterfly by Kossanyi et al. has been and S-(43; X = OH) have been synthesized elegantly. NaH-THF deconjugation of the (+)-enone (45) to (46) and reduction yields the (+)-alcohol (47) which is pyrolysed to R-(-)-ipsdienol (43; X = R-OH, 90% optical purity); (-)-verbenone [(45); enantiomer] similarly yields S-(+)-ipsdienol (43; X = S-OH) via the corresponding alcohol [(47); enantiomer] which is also obtained by LiAlH, reduction of the enol acetate (48) of (-)-verbenone. Lithium-ammonia reduction of the ketone (46) and its enantiomer yields inter alia th_ecorresponding trans-alcohols [e.g.(49)]; (49) is also pyrolysed to R-(-)-ipsdienol (43; X = R-OH) as expected.237 These
OH (45)
(46)
(47)
OH
OAc
(48)
(49)
results suggest an optical purity of 75% for the natural S-(+)-ipsdienol (43; X = S-OH), which would mean that Mori's syntheticsample of R-(-)-ipsdienol (Vol. 7, p. 15) had an optical purity of 38% and not 50% as claimed.237 Reaction of 2-buta-1,3-dienylmagnesium chloride with 4-methyl- lY2-epoxypentane yields ipsenol [2,3-dihydro-(43; X = OH)] and with 4-methylpent-4-ena1, (50) is 3-Methylpentadienyl-lithium reacts with methacrolein to yield (42; X = OH), a component of Ledum palustre essential oil (Vol. 4, p. 12), together with a minor amount of the exclusively E-lY4-adduct(51; R = vinyl); in the presence of cuprous iodide the yield of (5 1;R = vinyl) increases to 30% and a similar amount of the 1,2-adduct (52; R=vinyI) at the C-3 position of 3-methylpentadiene is formed!239 The lithium salt of (52; R = vinyl) readily undergoes exclusive [3;3] sigmatropic rearrangement to (51 ; R = vinyl) rather than the [1,3] sigmatropic rearrangement required for (42; X = OH) formation.240 Hotrienol (53) has been synthesized in one step from 2-methylpentadienyl-lithium and methyl vinyl ketone,239and also uia a straightforward Grignard-Wittig reaction sequence from 234
235
236
237 238 239 240
Y. Bessitre, D. N.-H. Savary, and M. Schlosser, Helu. Chim.Acta, 1977, 60, 1739. C. D. Poulter, J. C. Argyle, and E. A . Mash, J. Amer. Chem. Soc., 1977,99, 957. G. Bidan, J. Kossanyi, V. Meyer, and J.-P. Morizur, Tetrahedron, 1977, 33, 2193; formulae (2) and (7A) on p. 2194 both lack a methyl group. G. Ohloff and W. Giersch, Helv. Chim.Acra, 1977,60, 1496. K. Kondo, S. Dobashi, and M. Matsumoto, Chem. Letters, 1976, 1077. S. R. Wilson, K. M. Jernberg, and D . T. Mao, J. Urg. Chem., 1976,41, 3209. S. R. Wilson, D. T. Mao, K. M. Jernberg, and S. T. Ezmirly, Tetrahedron Letters, 1977, 2559. In contrast (52; R = ethynyl) undergoes [3,3] sigmatropic rearrangement in refluxing diglyme to a 45 : 55 mixture of (51; R=ethynyl) and the corresponding Z-isomer; M. L. Roumestant, P. Place, and J. Gore, Tetrahedron, 1977, 33, 1283.
Monoterpenoids
25
4,4-dirnethoxybutan-2-0ne.~~’ Citral has been synthesized by [3,3] sigmatropic rearrangement of a linalool thionocarbamate (cf. Vol. 4, p. 17, and Trost’s [2,3] sigmatropic rearrangement of allylic sulphoxides-Vol. 7, p. 5),242and by pyrolysis (cf.Vol. 7, p. 15).243The of prenol and 3-methyl-l-trimethylsilyloxybuta-1,3-diene favoured terminal Vilsmeier formylation of 2,6-dimethylhepta-l,3,5-triene (presumably a mixture of E- and 2-isomers) yields the four dehydrocitrals [ratio ~ ~ ~hydrounspecified; ambrosial (Vol. 6, p. 15) was not ~ h a r a c t e r i z e d ]and formylation has been used in a straightforward synthesis of h y d r o ~ y c i t r o n e l l a l . ~ ~ ~ Pyrolysis of the di-isoamyl acetal of 3-methylbut-3-enal is reported to yield 3,7d i m e t h y l o ~ t - 2 - e n a l .The ~ ~ ~ocimenones (54; E: Z/4:1) have been prepared from the kinetic enolate of mesityl oxide and methyl vinyl ketone; similar aldol condensation using the kinetic enolate from methyl isobutyl ketone yields tagetonol which is
(50)
(52)
(51)
(53)
(54)
likewise dehydrated to the tagetones [2,3-dihydro-(54; E: 2 / 7 :3)].247 Tagetonol has also been synthesized from 4,4-dimethoxybutan-2-oneby Grignard reaction^.^^' In attempted syntheses of chiral a-tocopherol a number of chiral monoterpenoid acids and other derivatives have been ~ y n t h e s i z e d ~ ~and ~ - ~shownzz1 ” to have high optical purity. Addition of propynylmagnesium bromide to isovaleraldehyde gave, after resolution, two acetylenic carbinols one of which was reduced to (55) and the other to (56); both (55) and (56), as vinyl ethers or other derivatives, undergo [3,3] sigmatropic rearrangement with almost 100°/~chiral transmission to yield, after work-up, S-(+)-E-3,7-dimethyloct-4-enoicacid which is reduced without racemization, using Raney nickel, to R-(+)-3,7-dimethyloctanoicacid (57; X = C02H, 90.8% optical Another approach to (+)-(57; X = C02H) and (+)-(57; X = CHzOH)of almost 100% optical purity uses the bacterial oxidation product S-(+)-3hydroxy-2-methylpropanoic acid to yield (57; X = Bu‘O) by treating the derived
w a xu \
(55) 241 242
243 244
24s
246 247 248 249 250
(56)
(57)
0.P. Vig, S. D. Sharma, S. S. Rana, and S. S. Bari, Indian J. Chem., 1976, 14B, 562. T. Nakai, T. Mimura, and A. Ari-Izumi, Tetrahedron Letters, 1977, 2425. P. Chabardes, Ger. Offen. 2 632 220 (Chem. Abs., 1977,87,38 877). P. C. Traas, H. J. Takken, and H. Boelens, Tetrahedron Letters, 1977, 2129. R. Van Helden and A. J. De Jong, Ger. Offen. 2 652 202 (Chem. Abs., 1977,87,67 845; the abstract has an obvious formula misprint). Y. Ichikawa, M. Yamamoto, and T. Yamaji, Jap. P. 75 015/1976 (Chem. Abs., 1976,85, 177 693). 0. S. Park, Y. Grillasca, G. A. Garcia, and L. A. Maldonado, Synrh. Cumm., 1977,7, 345. K.-K.Chan, N. Cohen, J. P. DeNoble, A. C. Specian, jun., and G . Saucy,J. Org. Chem., 1976,41,3497. N. Cohen, W. F. Eichel, R. J. Lopresti, C. Neukom, and G. Saucy, J. Org. Chem., 1976,41,3505. N. Cohen, W. F. Eichel, R. J. Lopresti, C. Neukom, and G. Saucy, J. Org. Chem., 1976,41, 3512.
26
Terpenoids and Steroids
3-t-butoxy-2-methylpropan-1-01 tosylate with 3-methyl-1-butylmagnesium bromide in the presence of dilithium tetrachlorocuprate; further elaboration is s t r a i g h t f o r ~ a r dA . ~combination ~~ of these two appro ache^^^^.^^' has been used to synthesize ethyl (3R,7R)-(E)-8-t-butoxy-3,7-dimethyloct-4-enoate having an 8789% ( 3 R ) and >99% ( 7 R ) enantiomeric composition.250 R-(+)-Citronello1 (98% optical purity) is prepared by reduction of the chiral citronellal obtained via the 1,4-Grignard addition to the aldimine formed from (2E)-butenal and D-t-leucine t-butyl ester of high optical (+)-Methyl citronellate upon epoxidation, rearrangement, and hydrolysis, yields the (+)-enantiomer of (-)-(5 8), a new constituent of Pelargonium graveolens essential Other synthetic work of interest is an improved synthesis of geranyl chloride (cf. Vol. 6,p. 15)2’3 and syntheses of 2,7-diamino-2,7-dimethyloct-4-ene1,8-dioic acid254and its y - m o n ~ l a c t o n e ~and ~’ of ethyl 4-thiage~anate.~’~ The 1-pro-R-hydrogen is lost on oxidizing geraniol with a cell-free extract from Cannabis sativa (Vol. 7, p. 9, ref. 96), asymmetric microbial reduction of (*)citronellal to (-)-citronello1 is reported,257and callus cultures of Nicotiana tabacum selectively hydroxylate linalool, dihydrolinalool, and the derived acetates at the trans-methyl group [e.g. to give (59)].258 0H
/‘CH,OH
2,4,4,6-Tetrabromocyclohexa-2,5-dienone in methylene chloride promotes the biomimetic cyclization of linalool and dehydrolinalool to (60;R=vinyl or ethynyl) as the major product with minor amounts of (61; X = Br, R =vinyl or ethynyl) in contrast to brominative cyclization with N-bromosuccinimide when (61 ; X = Br,
25’ 252
253 254
255
256 257 258
S . 4 . Hashimoto, S . 4 . Yamada, and K. Koga, J. Amer. Chem. SOC.,1976,98,7450. E.Klein and W. Rojahn, Dragoco Ber., 1977,24,55. J. H.Chan and H. M. Pitt, U.S. P. 4 006 196 (Chem. A h . , 1977,86,171 655). A . A . Akhnazaryan, M. A . Manukyan, and M. T. Dangyan, J. Org. Chem. (U.S.S.R.),1976,12,1854. M. A. Manukyan, A. A. Akhnazaryan, S. M. Asikyan, and M. T. Dangyan, Khim. gererotsikl. Soedinenii, 1977,453. K.-C. Liu and L.-C. Lee, Arch. Pharm., 1976,309,1019. Y . Yamaguchi, M. Aso, A . Komatsu, and T. Moroe, Nippon Nogei Kagaku Kaishi, 1976,50,443. T.Suga, T. Hirata, Y. Hirano, and T. Ito, Chem. Letters, 1976,1245.
Monoterpenoids
27
R=vinyl or ethynyl) predominates (cf. Vol. 1, p. 36; Vol. 2, p. 35).259 Base treatment of a 2-alkoxypyridinium tosylate of nerol gives expected (e.g. limonene 82%) cyclic hydrocarbons whereas the corresponding geraniol salt yields similar amounts of cyclic and acyclic hydrocarbons.260 SnC14-catalysed cyclization of the N-benzylimine derived from R-(+)-citronella1 yields the expected menthylamines after catalytic hydrogenation.261 The well known Diels-Alder cycloaddition of myrcene (43; X=H) and isoprene has been re-investigated thoroughly (cf Vol. 1, p. 10; Vol. 7, p. 13).262 Further papers which report Diels-Alder cycloaddition reactions involving geranic acid and ~ y c l o p e n t a d i e n e (37) , ~ ~ ~and methyl vinyl ketone,264citral enamines and methyl vinyl ketone or a ~ r y l o n i t r i l e and , ~ ~ ~(43; X = H ) and carbonyl compounds266provide expected results. Photocyclization of citronellyl iodide may be a free-radical process (cf Vol. 7, p. 13).267Manganese(II1) acetate oxidation of linalyl acetate under thermodynamic control results in expected free-radical 1,2-addition followed by 2,6-cyclization (Vol. 7, p. 14).268Allylic oxidation [i.e. to (62)] is now reported to predominate on treating (63; X = H ) with manganese(II1) acetate and only one mole of acetone or dimethyl malonate in contrast to previous results with excess addend (Vol. 7, p. 14); oxidation in acetic acid in the presence of bromide ion exhibits a different selectivity in forming (63; X = OAc), along with some allylic isomer, presumably via intervention of bromine free radical, allylic hydrogen abstraction, oxidation, and nucleophilic addition. Similar reaction with (64; X = H) yields (65; R = Me).268 Thiyl radical addition to geranyl acetate yields expected cyclic and acyclic adducts in proportions ranging
between 5 : 1 and 1: 17 depending upon photolysis conditions; Raney nickel desulphurization yields dihydrocyclogeranyl acetate and tetrahydrogeranyl acetate.269 T . Kato, I. Ichinose, T . Hosogai, and Y. Kitahara, Chem. Letters, 1976,1187; refs. 8 and 9 of this paper should be to p. 456 (not 465) and p. 1845 (not 1945) respectively. S. Kobayashi, M. Tsutsui, and T. Mukaiyama, Chem. Letters, 1976, 1137. 261 G . Demailly and G . SolladiC, Tetrahedron Letters, 1977, 1885. 262 W. Eisfelder and P. Weyerstahl, Annulen, 1977, 988. 263 H. Duttmann and P. Weyerstahl, Annalen, 1976, 1753. 264 S. Wgtanabe, K. Suga, H. Tsuruta, and T. Sato, J. Appl. Chem. Biotechnol., 1977, 27, 423. 265 S. H. Mashraqui and G. K. Trivedi, Indian J. Chem., 1977, 15B,305. 266 J. B. Hall, US.P. 3 981 924 (Chern. A h . , 1977,86,55 071); US.P. 3 965 186 (Chem. Ah., 1977,86, 29 435). 267 J. L. Charlton and G. J. Williams, Tetrahedron Letters, 1977, 1473. '" F. J. McQuillin and M. Wood, J. Chem. Res. (M), 1977, 752; the minor allylic component corresponding to (63) is incorrectly named in the experimental section. 269 M. E. Kuehllz and R. E. Damon, J. Org. Chem., 1977; 42, 1825. 259
260
28
Terpenoids and Steroids
The solvolysis of linalyl p-nitrobenzoate to (+)-a-terpineol has been shown, by deuterium and 13Clabelling experiments, to be consistent with the anti process [e.g. (66) -+ (67) + (68)], rather than by the syn process proposed by Winstein (Vol. 3, OR
(66)
(67)
(68)
p. 15).270 A new type of cyclization of geraniol, using thallium(II1) perchlorate, yields predominantly five-membered carbocycles (69), together with (70), a result
Ho&o
H
@
OH
(69)
(70)
which may have synthetic and biogenetic implications in the iridoid field.271 Superacid cyclization of citronellol (cf. Vol. 5, p. 20) yields inter alia (71) and (72), which results from the loss of a C-7 methyl Similar cyclization of citral yields (73) and (74), in contrast to the Wagner-Meerwein shifts and ring contrac-
(72)
(73)
(74)
tions observed with geraniol (Vol. 5, p. 20), presumably via protonation of the oxygen of the +-unsaturated aldehyde to an initial stable delocalized cation, rearrangement to further cations, some of which are spectroscopically detectabte, and rapid quenching.272A study of the mechanism of cyclization of citral at pH 2.5 has shown that major products are dehydrocineol (Vol. 5, p. 23) and the two diols (75) which may dehydrate to two other major products, uiz. the dienes (76); p-cymen-8-01 results from the air oxidation of (76).273Acid-catalysed cyclization of tricarbonylmyrceneiron followed by protonation with HBF,-CO yields (77; X = Z Me) after borohydride reduction.274Further chloroacetic acid hydration papers (cf. Vol. 6, p. 29) include hydration of 2,6-dimethylocta-2,6-dieneand of 2,6-dimethylocta- 1,6-diene2” and hydrative cyclization of the dihydromyrcene (63; X = H), O ’
271 272
273 274 275
S. Godtfredsen, J. P. Obrecht, and D. Arigoni, Chiiniu (Switz.), 1977, 31, 62. Y. Yamada, H. Sanjoh, and K. Iguchi, J.C.S. Chem. Comm., 1976,997. D. V. Banthorpe and P. A. Boullier, J.C.S. Perkin I, 1977, 114. B. C. Clark, jun., C. C. Powell, and T.Radford, Tetrahedron, 1977, 33, 2187. A. J. Pearson, Austral. J. Chem., 1976,29, 1841. K. Tanaka and Y. Matsubara, Nippon Kugaku Kuishi, 1977,514.
Monoterpenoids
29
predominantly to (78) (2,6,6-trimethylcycloheptanolis a minor cationic resin-catalysed condensation of limonene (via a -terpinene-see Vol. 6, p. 29) with the cresols has been reported.277 The reaction of citral, dihydrocitral, or 3-methylbut-2-enal with strong base to yield aldol-type dimers (79) has been thoroughly re-investigated; (79) may iso-
merize to a 1,4-diene, aromatize, or be partially reduced by serving as a hydrogen acceptor during a r o m a t i z a t i ~ n .Stereoselective ~~~ C- 1 methylation of geraniol and nerol is accomplished without change in olefin geometry, by treating the lithium alkoxymethylcuprates with NN-methylphenylaminotriphenylphosphonium iodide279 or the corresponding acetates with lithium dimethylcuprate;280 stereoselective C-3 methylation with lithium methylcyanocuprate probably results from alkyl-group transfer involving copper.”’ Similar C-1 stereoselectivity is observed with geranyl acetate-dimethyl malonate-[ (Ph3P)4Pd,Ph3P,THF],although with neryl acetate, alkylation at C-3 is preferred using dimethyl malonate compared with high regioselectivity at C-1 using methyl phenylsulphonylacetate.281 Whereas fluorochlorocarbene addition to geranyl methyl ether is not regioselecregioselectivity of addition is observed with dichlorocarbene and linalool [to yield (12; X=CCI2)] and is suggested for geraniol [to yield (11; X = CC12)]which is considerably less reactive;282similar regioselectivity is observed for citral diethyl acetal although dicyclopropanation predominate^."^ Dichlorocarbene addition to myrcene using tributylamine catalyst is regiospecific at the non-conjugated double bond (cf Vol. 6, p. 16).284 Uncatalysed cleavage of epoxides has been reported [e.g. tetrahydro(39) + dihydro-(64; X = OH)],285and oxidation of tetrahydrogeranyl acetate with ozone on silica gel yields dihydro-(65; R = H) predominantly with some 8-acetoxy6-methyloctan-2-one (cf. Vol. 7, p. 7).286 276 277
278 279
282
283 284
285
286
K. Tanaka and Y. Matsubara, Nippon Kagaku Kaishi, 1977,922; (63; X = H) is named incorrectly. E. Pottier and L. Savidan, Bull. SOC.chim. France, 1977, 557. A. F. Thomas and R. Guntz-Dubini, Helv. Chim. Acta, 1976, 59, 2261. Y. Tanigawa, H. Kanamaru, A. Sonoda, and S.-I. Murahashi, J. Amer. Chem. Soc., 1977, 99, 2361. J. Levisalles, M. Rudler-Chauvin, and H. Rudler, J. Organometallic Chem., 1977,136, 103. B. M. Trost and T. R. Verhoeven, J. Org. Chem., 1976,41,3215; formula (7) in this paper should have an ethenyl group at C-3 and not at C-4. K. Kleveland, L. Skattebol, and L. K. Sydnes, Acta Chem. Scand., 1977, B31,463. G. V. Kryshtal, A. Kh. Khusid, V. F. Kucherov, and L. A. Yanovskaya, Izoest. Akad. Nauk S.S.S.R., Ser. khim., 1977,709. Y. Kimura, K. Isagawa, and Y. Otsuji, Chem. ktters, 1977, 951. S. N. Merchant, S. C. Sethi, and H. R. Sonawane, Indian J. Chem., 1976,14B, 460. A. L. J. Beckwith, C. L. Bodkin, and T. Duong, Chem. Letters, 1977, 425.
30
Terpenoids and Steroids
Other papers of interest in this section report the sequential homogeneous hydrogenation of geraniol to citronellol and tetrahydr~geraniol,~~’ the reduction of citral to citronella1,288 electrolytic reduction of chiral 6-chlor0-2,6-dimethylreduction of 2-geranic acid using a chiral rhodium catalyst preferably to (3S)-(-)-3,7-dimethyloct-6-enoicacid,”* largely unsuccessful attempts at isoprenoid homologation using ~ - m e t h y l c y c l ~ b u t e n e - ~ ~ ~ ~ Prins - ~ n Mformale~,~~~ dehyde reaction on allo-ocimene (cf. Vol. 6 , p. 16),2y2phenylation-reduction of ~ i t r a l , *and ~ j reaction of dehydrolinalool with NN-dimethylformamide acetals to yield djenamines and enamine orthoformate (cf.Vol. 6, p. 6).2y4
Halogenated Monoterpenoids.-A reviewzy5and a brief discussion2y6have been published. Crews has reviewed his work with Plocamium and Microcladia ~pecies,~”including some results published s u b s e q ~ e n t l y . ~P.~ sandvicense ~-~~~ is r e p ~ r t e d ~ ~ to ’ . ~yield ~ ’ the two diastereomeric pentachloro-octatrienes previously reported by Faulkner (Vol. 6, p. 20) from P. cartilagineurn, whereas P. oregonurn yields oregonene A (80; X = C1) and the tentatively assigned (80; X = H) together with the isomer (81) already isolated from Aplysia californica (Vol. 7 , p. 18) and
CI
CI
(80)
(81)
the corresponding dehydrochlorinated molecules as previously reported in P. cartilagineurn (VoI. 6 , p. 20) by Faulkner; I3C n.m.r. data are included.zy8 The chirality at C-7 reported for (80; X = H) last year by analogy with the corresponding tribromo-compound reported earlier [Vol. 7, p. 18, formula (61)] has not been verified. From P. violaceurn, the preplocamenes are assigned structures (82; X = Br, Y = S-Br), (82; X=C1, Y =R-Cl), and (82; X=Cl, Y = S-Cl) by analogy with
”’ Y.Takagi, S . Teratani, S. Takahashi, and K. Tanaka, J. Mol. Catalysis, 1977, 2 , 321. 288
289 290
291
292 293 294
295
296
297
298
D. V. Sokol’skii, A. M. Pak, M. A. Ginzburg, and A. M. Khisametdinov, J. Appl. Chem. (U.SB.R.), 1976, 49, 2095; the identical results are also reported D. V. Sokol’skii, A. M. Pak, and M. A. Ginzburg, Maslo-Zhir. Prom., 1976, No. 7, p. 20. T. Nonaka, T. Ota, and K. Odo, Bull. Chem. SOC.Japan, 1977, 50,419; formula (11) is misprinted. D. H. Valentine, jun., Ger. Offen. 2 548 884 (Chem. Abs., 1976, 85, 94 550); see also refs. 221 and 248-250. S. R. Wilson and D. E. Schalk, J. Org. Chem., 1976, 41, 3928. K. Takabe, N. Ike, T. Katagiri, and J. Tanaka, Nippon Kagaku Kaishi, 1977, 1253. F. J. McEnroe, C.-K. Sha, and S. S . Hall, J. Org. Chem., 1976,41,3465. K. A. Parker, R. W. Kosley, jun., S. L. Buchwald, and J. J. Petraitis, J. Amer. Chem. SOC.,1976, 98, 7104. D. J. Faulkner, Tetrahedron, 1977,33, 1421; formula (88) in this paper is incorrect [see Vol. 7, p. 20, formula (77)]. R. E. Moore, Accounts Chem. Res., 1977,10,40. P. Crews in ‘Marine Natural Products Chemistry’, ed. D. J. Faulkner and W. H. Fenical, NATO Conference Series: IV, Marine Sciences, Vol. 1, Plenum Press, New York, 1977 (Proceedings of a conference on Marine Natural Products, Jersey, Channel Islands, October 1976), p. 21 1. Formulae (8) and (13) in this paper are identical, which may suggest an error. P. Crews, J. Org. Chem., 1977,42, 2634.
Monoterpenoids
31
Faulkner's violacene 2 (Vol. 7, p. 19),2')9and P. cosratum has yielded costatol (83),301the related costatone (S4),301.302and costatolide (85),302all confirmed by X-ray diffraction; spontaneous dehydration of the hemiacetal (84)to the expected
~~'~ trienones is ~ b s e r v e d . ~ " Various plocamenes from M i c r ~ c l a d i a ~ ~ 'and Plocamium 297*299 species have been discussed by Crews; plocamene A (violacene) and plocamene B (Vol. 6, p. 33) seem to be firmly established but the structure of plocamene C, claimed3" as an epimer of Faulkner's violacene 2, is still not adequately d i s c ~ s s e d ; ~comparison ~ ~ ~ ~ ~ ' of later data3" on M. coulteri analysis might suggest that Crews now regards plocamene C (Vol. 7, p. 19) as (86),297but structural proof has not been published. Plocamene D (87) is reported in various
CI
/ Cl
cldcl
papers297.299.300 with no reported comparison with. the compound of identical structure prepared by Faulkner on treating violacene with chromous ~ u l p h a t e ; ~no '~ details of its characterization have been published. Other potentially interesting halogenated dimethylethylcyclohexanes have been indicated297but reports of their characterization are needed; this also applies to the five new compounds (88), (89), (90), (91), and the biochemically significant (92) discussed by F a ~ l k n e r . ~ ~ '
(88) 299
300 301
302 303
(89)
(90)
P. Crews and E. Kho-Wiseman, J. Org. Chem., 1 9 7 7 , 4 2 , 2 8 1 2 ;formula (20)of this paper should have a chlorovinyl group instead of a 2-chloroethyl group. Plocamene B and plocamene D are reported here without comment, with absolute stereochemistry the same as violacene 2 (cf. refs. 297, 300). P. Crews, P. Ng, E. Kho-Wiseman, and C. Pace, Phyrochemisrry, 1976,15, 1707. R. Kazlauskas, P. T. Murphy, R.J. Quinn, and R. J. Wells, Tetrahedron Lerrers, 1976,4451. D. B. Stierle, R. M. Wing, and J. J. Sims, Tetrahedron Letters, 1976, 4455. J. S . Mynderse and D. J. Faulkner, J. Amer. Chem. Soc., 1 9 7 4 , 9 6 , 6 7 7 1 .
Terpenoids and Steroids
32
(91)
(92)
Artemisyl, Santolinyl, Lavandulyl, and Chrysanthemyl Derivatives.-The presence of (41) in lavender oil has been reported earlier.'18 Poulter has published the full details of his work (Vol. 5 , p. 14) on synthetic151and s t e r e ~ c h e m i c a l 'aspects ~~ of chrysanthemyl ester and alkoxypyridinium salt solvolyses (Vol. 3, pp. 20-22) and discussed its biosynthetic implications. Over 98% of the solvolysis products are now reported to be artemisyl derivatives which are formed from the primary cyclopropylcarbinyl ion (93) which results from predominant (86%) ionization of the antiperiplanar conformation of (21)-N-methyl-4-pyridinium iodide; the tail-totail product (96; 0.01%) may then result from the suprafacial migration of the cyclopropane ring bond as shown stereochemically in Scheme 3. This is consistent with earlier work (Vol. 7, p. 20, ref. 214) reporting the efficient rearrangement of the cyclobutyl cation (94) to (96) and its allylic isomer, uia the tertiary cyclopropylcarbinyl cation (95).ls3
The full paper on Julia's artemisia ketone (20; X = 0) synthesis (Vol. 5, p. 14) has. been a minor product in this synthesis is (97) which is also produced in good yield uia an alkylation-sulphoxide elimination sequence subsequent to [2,3] sigmatropic rearrangement reported by Julia earlier;305hydrolysis of (97) yields artemisia ketone (20; X = 0).304,305 The Cr"-catalysed attachment of the more substituted y-carbon of an ally1 group to a carbonyl carbon, even with a@-unsaturated aldehydes, has been used in an efficient synthesis of artemisyl alcohol (20; X=H,OH) from prenyl bromide and 3 - m e t h y I b ~ t - 2 - e n a l .Similar ~~~ reaction with the acetal(98) yields (99), which is readily hydrolysed and methylated to yomogi alcohol another synthesis of (100) involves a [2,3] sigmatropic rearrangemen? analogous to that reported by Julia.305 Thus the allylic ether (101) rearranges to the allylic alcohol (102) on treating with n-butyl-lithium; hydrolysis to the a@-unsaturated aldehyde and alkylation steps readily yield yomogi alcohol '04 305
3w
D. Michelot, G . Linstrumelle,and S. Julia, Synfh. Comm., 1977,7, 95. C. Huynh and S. Julia, Synrh. Comm., 1977, 7, 103; for the earlier work, see references therein Y. Okude, S. Hirano, T. Hiyama, and H. Nozaki, J. Amer. Chem. Soc., 1 9 7 7 , 9 9 , 3179.
Monoterpenoids
33
An elegant two-step synthesis of lavandulol (22) consists of the 1,4-addition of lithium dimethylcuprate to the allenic ester (103) followed by prenylation and reduction of the intermediate which is formed.307 Much effort this year has been expended on chrysanthemic acid syntheses. Aratani et al. have extended earlier work on asymmetric synthesis (Vol. 6, p. 21) by decomposing various alkyl diazoacetates in 2,5-dimethylhexa-2,4-dienein the presence of chiral copper complexes to yield up to 92% of trans-chrysanthemic acid in 88% dextrorotatory enantiomeric excess.3o8Mitra has used ozonolysis of (+)-a pinene to obtain, stereospecifically, the bromo-ketone (104) which undergoes Favorskii rearrangement to yield the anticipated ester (105) from which (+)-transchrysanthemic acid is readily obtained;309a second paper reports another route from (+)-car-3-ene initially to methyl (-)-cis-chrysanthemate or to (-)-dihydrochrysanthemolactone (106), both of which are convertible into (+)-trans-chrysan-
themic acid by known means, e.g. by the Matsui synthesis or the Sukh Dev modification (see Vol. 5 , p. 15, ref. 101).310An elegant one-step stereospecific synthesis of methyl (*)-trans-chrysanthemate in over 60% yield consists of mixing T H F solutions of methyl trans-4-oxobutenoate and isopropylidenetriphenylphosphorane (2.4 equivalents); the reaction probably proceeds via initial betaine formation at the aldehydic carbonyl group. A useful modification provides the synthetically useful trans-(107; R = CHO).311A second paper reports the first one-pot stereospecific synthesis of (*)-cis-chrysanthemic esters by reaction of a-butenolide (108) 307 308
309
310 311
M. Bertrand, G. Gil, and J. Viala, Tefruhedron Letters, 1977, 1785. T. Aratani, Y. Yoneyoshi, and T. Nagase, Tefruhedron Letters, 1977, 2599; T. Aratani, Y. Yoneyoshi, F. Fujita, and T. Nagase, Get. Offen. 2 634 663 (Chem. A h . , 1977.87, 68 506). For related work see also T. Nagase, T. Aratani, and M. Hazarna, Japan P. 137 955/1975 (Chem. A h . , 1976,85, 94 542). R. B. Mitra and A. S. Khanra, Synth. Comm., 1977,7, 245. A. S. Khanra and R. B. Mitra, Indian J. Chem., 1976,14B, 716. M. J. Devos, L. Hevesi, P. Bayet, and A. Krief, Tetrahedron Letters, 1976, 3911; A. Krief and L. Hevesi, Belg. P. 827 651 (Chem. Abs., 1976.85, 177 686); Ger. Offen. 2 615 159 (Chem. A h . , 1977, 86,72 921.
Terpenoids and Steroids
34
with the sulphur ylide (109) to yield (110) which is readily converted into cis-(107; R = CH,OH); another route to cis-(107; R=CH,OH) or the lactone (110) involves stereospecific addition of (109) to (1 1l).312 From methyl E-4,4-dimethoxybut-2-
+-/
PhzS-C
Me
THPOCH2 \
C02Me
c=c/
\Me
H
'
\H
enoate and (109), trans-[107; R=CH(OMe)*] is readily formed in 82% yield; elaboration of (107; R = CHO) to the individual pure racemic chrysanthemic esters is then ~traightforward.~~' Another synthesis313 of (*)-trans-chrysanthemic acid involves the known3I4alkylation of eucarvone (1 12) to (1 13) whose separation from 2,6,6,7-tetramethylcyclohepta-2,4-dienone is dependent upon the ease of oxidation of the latter by sodium chlorate and a catalytic amount of 0 ~ 0 ,ozonolysis ; of (1 13) and appropriate modification in a single synthetic stage yields (114) which is 0
(1 12)
(113)
..
(114)
epimerized and readily elaborated into methyl (*)-rrans-~hrysanthemate.~'~ Two further papers describe the synthesis of [ 1-3H]-(1R,3R)-(+)-trans-chrysanthemic acid315and a synthetic route to (*)-chrysanthemate analogues.316 Pyrocin (1 15) has been synthesized by Michael addition of 2-methylprop- 1-enylmagnesium bromide to the known butenolide (116) using (-)-sparteine-CuC1; base-catalysed debenzoylation yields (115) with a 2% optical yield; the conversion of (115) into ethyl (*)-trans-chrysanthemate was also investigated.317 The degradation of artemisia alcohol (20; X = H,OH) by retro-ene cleavage and by the novel [1,3] sigmatropic rearrangement (20; X = H,OH] --+(1 17) has been de~cribed.'~' Wittig rearrangement of allylic ethers of chrysanthemyl alcohol by competing [1,2], [ 1,4], homo-[2,5], and homo-[4,5] sigmatropic rearrangements is 312 313
314
'I5 'I6 317
M. Sevrin, L. Hevesi, and A. Krief, Tetrahedron Letters, 1976, 3915. S. C. Welch and T. A. Valdes, J. Org. Chem., 1977, 42, 2108. Ref. 5 in this paper should be to J.C.S. Perkin ZZ;see ref. 314. A. J. Bellamy and W. Krilly, J.C.S. Perkin ZI, 1972, 395. G.Pattenden and R. Storer, J. Labelled Compounds, 1976.12, 551. K.Kondo, K. Matsui, and Y. Takahatake, Tetrahedron Letters, 1976, 4359. A. Takeda, T. Sakai, S. Shinohara, and S.Tsuboi, Bull. Chem. SOC.Japan, 1977,50, 1133.
Monoterpenoids
35
c,; 0
0 T
QCOPh 0 (1 16)
(115)
(1 17)
reported3" and it has been shown that thermal acid-catalysed rearrangement products from trans-chrysanthemic acid result from cleavage of all three cyclopropane ring 5 Monocyclic Monoterpenoids
Cyc1obutane.-Grandisol syntheses have been r e v i e ~ e d , ~ ~and * * ~Trost's ~' full paper on grandisol and fragranol synthesis (Vol. 6, pp. 21, 22)3 has been published. Cyclopentanes, 1ridoids.-Two doidS.322.323
papers report the analysis and separation of iri-
The characterization of trans,trans-dolichodial (118) from Iridomyrmex humilis has been reported (cf. Vol. 6, p. 25)," and chrysomelidial (119) and plagiolactone (120; the assigned absolute stereochemistry is tentative) are present in the defensive secretion of Plagiodera v e r s i c ~ l o r a . ~ ~ ~
ACHO (118)
(119)
(120)
New CISiridoid glucosides, occurring as minor components, are bartsioside, or ~ or 106-deoxyaucubin (121; X = H, R = p-Glu), from Bartsia t r i x a g ~ , 'linaride, deoxyaucubin (122), from Linaria r n u r ~ l i s , and ~ * ~a third picroside, 6'-(4-hydroxy-
(121)
(122)
L. Crombie, G. Darnbrough, and G. Pattenden, J.C.S. Chem. Comm., 1976, 684. 319 D. A. Otieno, G. Pattenden, and C. R. Popplestone, J.C.S. Perkin I, 1977, 196. 320 J. A. Katzenellenbogen, Science, 1976,194, 139. 321 C. A. Hendrick, Tetrahedron, 1977, 33, 1845. 322 B. Meier and 0. Sticher, J. Chromatog., 1977,138,453. 323 0 .Sticher, Pharm. Acta Helv., 1977, 52, 20. 324 J. Meinwald, T. H. Jones, T. Eisner, and K. Hicks, Proc. Nut. Acad. Sci. U.S.A., 1977, 74, 2189; independent and unpublished work on these compounds by M. S. Blum, H. M. Fales, J. E. Wheeler, and G. W. K. Cavil1 is awaited. 325 A. Bianco, M. Guiso, C. Iavarone, P. Passacantilli, and C. Trogolo, Gazzetta, 1977,107,83. 318
Terpenoids and Steroids
36
3-methoxycinnamoyl)catalpol (cf. Vol. 3, p. 27; Vol. 6, p. 23), from Picrorhiza k~rrooa.~~~ The full paper on the synthesis of onikulactone and mitsugashiwalactone (Vol. 7, p. 24) has been p ~ b l i s h e d . ~ ”Whitesell reports two further useful sequences (cf. Vol. 7, p. 26) from accessible bicyclo[3,3,0]octanes which may lead to iridoids; (123; X=H2, Y = H) may be converted into (124) via (123; X = H2, Y = C02Me), the product of ester enolate Claisen rearrangement of the derived allylic alcohol and oxidative d e c a r b o ~ y l a t i o n ,whereas ~~~ (123; X = 0, Y = H) readily leads to (125), a known derivative of antirride (126) via an alkylation-dehydration-epoxidation-rearrangement sequence.329 Aucubigenin (121; X = OH, R = H), which is stable at -20°C and readily obtained by enzymic hydrolysis of aucubin (121; X = OH, R = P-Glu), is converted by mild acid into (127)330with no dialdehyde detected;331sodium borohydride reduction of aucubigenin yields the non-naturally occurring isoeucommiol (128; X=H,OH) probably uia the aldehyde (128; X =
01.~~’
eoMe
q$
phco**oMe
X H
OMe
(123)
(126)
OMe
(124)
(125)
(127)
(128)
New CI6 iridoid glucosides include mussaenoside (129; X = H , R = M e ) and shanzhiside methyl ester (129; X = OH, R = Me) from Mussaenda paruifEoru and M. ~ h i k o k i a n aipolamiidoside ,~~~ (28; X = H, R = Ac), the acetate of ipolamiide (28; X = R = H), whose stereochemistry is now assigned (cf.’Vol. 6 , p. 24), from Lamium a r n p l e s s i c a ~ l eand , ~ ~another ~ component from Phlomis fruticosa (cf. vol. K. Weinges and K.Kiinstler, Annalen, 1977, 1053. H. Ohta, T. Kobori, and T. Fujisawa, J. Org. Chem., 1977,42, 1231; some details are also published in T. Fujisawa, T. Kobori, and H. Ota (sic),Jap. P. 39 668/1976 (Chem. Abs., 1976.85, 108 823). 328 J. K. Whitesell and A. M. Helbling, J.C.S. Chem. Comm., 1977, 594; an intermediate is obviously lacking a double bond. 329 J. K. Whitesell, R. S . Matthews, and P. K. S. Wang, Synth. Comm., 1977, 7 , 355; compound (8) lacks an exocyclic methylene group. 330 A. Bianco, M. Guiso, C. Iavarone, P. Passacantilli, and C. Trogolo, Tetrahedron, 1977, 33, 847. 331 A. Bianco, M. Guiso, C. Iavarone, P. Passacantilli, and C. Trogolo, Tetrahedron, 1977, 33, 851; see Vol. 6, p. 24 for eucommiol. 332 Y. Takeda, H. Nishimura, and H. Inouye, Phytochemistry, 1977, 16, 1401. An earlier paper, H. Inouye, Y.Takeda, S. Saito, H. Nishimura, and R. Sakuragi, Yukuguku Zusshi, 1974, 94, 577, on gardenoside, shanzhiside (129; X = OH, R = H), and methyl deacetylasperulosidate from Gardenia jusminoides grundiflora was inadvertently omitted from earlier Reports; however, see Vol. 1, p. 20. 333 A. Bianco, M. Guiso, C. Iavarone, R. Marini-Bettolo, and C. Trogolo, Guzzenu, 1976, 106, 947; see, however, Vol. 7, p. 27, ref. 267 for an earlier report of the correct stereochemistry for ipolamiide. 326
327
37
Monoterpenoids
6, p. 24), the closely related lamiidoside (28; X = 4-hydroxycinnamoyloxy, R = H), a derivative of lamiide (28; X = O H , R=H).334 Previous reports (Vol. 5 , p. 17; Vol. 7, p. 24) did not recognize the identity of lamiide (28; X = OH, R = H) and durantoside. The 10-acetyl derivative of geniposide (Vol. 1, p. 20) is another component from Gardenia jasminoides grandiflora 335 and the structures of some iridoids present in Fouquieria species, including adoxoside (130), which is unknown to this Reporter, are only tentative at present.336 The structure of a compound previously named feretoside (Vol. 6, p. 24; Vol. 7, p. 24) by the authors has been revised to (131), which is methyl scandoside; it is disturbing that the revised structure (131) is assigned to a compound with different physical data, except for R f C0,Me
1
HO",
O-B-Glu
I
0-P-Glu
HO'
(129)
0,Me
Po O-fi-Glu
OH
(130)
(131)
value, from those recorded previously (Vol. 6, p. 24)and from a new source of Feretia apodanthera ; it is difficult to see why a relationship to gardenoside (Vol. 1,p. 20) was suggested (Vol. 6, p. 24).337 13C N.m.r. data are also recorded for some related known iridoids and monoterpenoid alkaloids.337 Papers reporting known valepotriates using the incorrect stereochemistry at C-7 and/or C-8 have been published (see Vol. 7, p. 25).338Four new valepotriates are kanokoside A (132; R =p-Glu), kanokoside B (133), kanokoside C (132; R = pgentiobiose), and kanokoside D (134; R = p - g e n t i ~ b i o s e ) . ~ ~ ~
; *o
HO
Hoq
H;@oo-P-G1u
',
H
H,COH 0 , C B u '
(132)
HO
CH,OR
02CBU'
(133)
HO'
0,CBu'
(1 34)
A significant synthetic achievement this year is Fleming's conversion (Scheme 4) of trimethylsilylcyclopentadiene (135) into the racemic aglucone acetate (136) which has already been converted into loganin (Vol. 1, pp. 20, 21; Vol. 4, p. 26). Cycloaddition of (135) to dichloroketen yields the adduct (137),340"whose conversion into the acetate (138) is straightforward; the key steps are the clean 334
335
A . Bianco, C. Bonini, M. Guiso, C. Iavarone, and C. Trogolo, Gazzena, 1977,107,67. Y. Takeda, H. Nishimura, 0. Kadota, and H. Inouye, Chem. andPharm. Bull. (Japan), 1976,24,2644.
m6 R. Dahlgren, S. R. Jensen, and B. J. Nielsen, Boran. Noriser, 1976, 129, 207. 337 F. Bailleul, P. Delaveau, A . Rabaron, M. Plat, and M. Koch, Phytochemistry, 1977, 16, 723. 338 N. Marekov, N. Handjieva, S. Popov, and I. Yankulov, Izuesr. Khim. (Bulgaria), 1975, 8, 672; M. Di Gusto and E. Mandrile, Reo. Farmaceur., 1976,118,77;H. Becker, R. Schrall, and W. Hartmann, Arch. 339 340
Pham., 1977,310,481. T. Endo and H . Taguchi, Chem. and Pharm. Bull. (Japan), 1977,25,2140. B.-W. Au-Yeung and I. Flemming, J.C.S. Chem. Comm., ( a ) 1977,79 [formula (1)obviously lacks two methyl groups]; ( b ) 1977, 81.
Terpenoids and Steroids
38
FI
Sih
SiMe, [iv, v
(139)
(140)
(136)
Reagents: i, CI,CHCOCI-Et3N; ii, Zn-AcOH-HzO; iii, MeCHNz-EtzO-MeOH; iv, excess Zn-AcOHHz0; v, NaOMe-MeOH; vi, NaBH4-MeOH; vii, MeSOzC1-py; viii, Et4N+AcO--MezCO; ix, CISO.LNCO-CCI~;x, NaN02-AcZO-AcOH; xi, NaOAc-HzO; xii, CHzN2; xiii, 03; xiv, MezS
Scheme 4
reaction of (138) with chlorosulphonyl isocyanate to give (139), which is best hydrolysed by sodium nitrite-acetic acid and aqueous sodium acetate to give (140), after esterification. Conversion into the loganin derivative (136) is then straightand, despite the fourteen steps, the overall yield compares very favourably with that reported earlier by Buchi. The previous report of a cyclopentene ester from Turkish tobacco (Vol. 6, p. 27) did not acknowledge the almost identical synthesis of the corresponding aldehyde R -( 141) by van T a m e l e r ~ ; ~ ~ ~ S-(141) is now reported.342 The name fulvoiridoid is used to describe pseudo-azulenic compounds with the highly conjugated cyclopenta[c]pyran structure, e.g. (142), the red-orange product from heating the aglycone of ipolamiide (28; X = R = H ) at pH 5.2; perchloric acid-acetic acid treatment of (28; X = R = H ) gives the two blue pyrilium salts (143), suggesting that the characteristic blue colour reactions of iridoids may be due to conversion of fulvoiridoids into the corresponding pyrilium 341
342
343
E. E. van Tamelen, G. M. Milne, M. I. Suffness, M. C. Rudler-Chauvin, R. J. Anderson, and R. S . Achini, J. Amer. Chem. Soc., 1970, 92,7202. J. F. Ruppert, M. A. Avery, and J. D. White, J.C.S. Chem. Comm., 1976, 978. A. Bianco, M. Guiso, C. Iavarone, R. Marini-Bettolo, and C. Trogolo, Guzzettu, 1976,106, 733.
Monoterpenoids
39
A secoiridoid, secogalioside (144), has been isolated from Galium album (the paper includes 13C n.m.r. data for a number of secoiridoids and derived and xylomollin (145) has been obtained from Xylocarpus molluscen sis l 3 to add to a number of biogenetically anticipatable secologanin-related compounds, e.g. morroniside and kingoside (Vol. 1, p. 19), and sarracenin (Vol. 7, p. 27). The full paper of Tietze’s biogenetic-type synthesis of secologanin aglucone methyl ether and sweroside aglucone methyl ether has been published (Vol. 5, p. and a second paper independently reports in full the rapid enzymic cleavage of secologanin t o the bicyclic hemiacetal previously described by R. T. Brown (Vol. 7, p. 27); longer reaction times result in the formation of (146).346 CHO C 0 , M e
(144)
(145)
(146)
Mass spectral data of some known monoterpenoid alkaloids have been analy~ed.~~~
p-Menthanes.-A number of species have yielded new thymol derivatives348and Syneilesis aconitifolia has also yielded D-a-terpineol-/3-D-glucopyranoside-3,4diangelicate.’’’ The diol (147) has been isolated349from Mentha gentilis in addition t o (148; R = Ac), which has been reported three times350without comparison with the known keto-alcohol (148; R = H);3s1the trio1 (149) has been isolated from Zanthoxylum b u d r ~ n g a . ~ ~ ~ 344
34s 346
347 348
349 350
3s1
3s2
K. Bock, S. R. Jensen, and B. J. Nielsen, Acta. Chem. Scand., 1976, B30, 743. G. Kinast and L.-F. Tietze, Chem. Ber., 1976, 109, 3626. G. Kinast and L.-F. Tietze, Chem. Ber., 1976, 109, 3640. W. Berg, D. Gross, H. R. Schiitte, and M. Herrmann, Pharmazie, 1977, 32,41. S. K. Zutshi and M. M. Bokadia, Indian J. Chem., 1976,14B, 711; F. Bohlmann, J. Jakupovic, and M. Lonitz, Chem. Ber., 1977,110,301;F. Bohlmann and C. Zdero, Phytochemistry, 1977.16, 1243; W. L. Lasswell, jun. and C. D. Hufford, ibid.,p. 1439. K. Umemoto and T. Nagasawa, Nippon Nogei Kagaku Kaishi, 1977,51, 245. T. Nagasawa, K. Umemoto, T. Tsuneya, and M. Shiga, Agric. and Biol. Chem. (Japan),1975,39,2083 (inadvertently omitted from last year’s Report); K. Umemoto and T. Nagasawa, Nagoya Gakuin University Review, 1976, 12, 117; T. Nagasawa, K. Umemoto, and N. Hirao, Nippon Nogei Kagaku Kaishi, 1977, 51, 81. J. Wiemann and Y. Dubois, Bull. Soc. chim. France, 1962, 1813. R. K. Thappa, K. L. Dhar, and C. K. Atal, Phytochemistry, 1976.15, 1568.
Terpenoids and Steroids
40
A (147)
A (148)
(149)
The most stable rotamer of menthone has been identified by combining selective excitation and gated decoupling of the Fourier-transform 13C n.m.r. ~pectrum.”~ The effect of glucosylation on the shielding of a - and P-carbon atoms in (+)- and (-)-menthol has been examined; the dependence of such shielding on alcohol chirality may be valuable in determining absolute configuration^.^^^ The chiral shift reagent tris[(hydroxymethylene)menthanato]europium has been reported.”’ N.m.r., i.r., and m.s. data have been reported for fourteen p-menth-8-enediols resulting from ,various selenium dioxide oxidations (e.g. see Vol. 6 , p. 30).3561.r. and Raman spectra of limonene, p-menth-1-ene, trans-isolimonene, p-menth-3ene, and trans-p-menth-2-ene have been a n a l y ~ e d . ~C.d. ’~ on 2-hydroxymethylenementhone (for which further synthetic data are and the corresponding chloromethylene derivatives have established the existence of a cisltruns enolic equilibrium, which is also reported for the corresponding carvone and camphor derivative^.^'^" Calorimetric data for carvoxime have been and kinetic data reported for the addition of trifluoroacetic acid to R-(+)-limonene in weakly polar solvents (cf.Vol. 6 , p. 29).360 In contrast to base-catalysed eliminations (e.g. Vol. 7, p. 33), cis-p-menth-2-ene is the exclusive product from reaction of truns-6-isopropylcyclohex-2-enolmesitoate or trans -4-isopropylcyclohex-2-en01 mesitoate with lithium dimethylcuprate; the corresponding cis-mesitoates yield the same mixture of trans-p-mentb-2-ene Two papers report related syntheses of the known and tr~ns-o-rnenth-2-ene.~~~ ’ R’ = R2 = 02CPri),363 thymol derivatives (150; R’=02CPri, R2= O A C ) , ~ ~(150; (15 1; R’ = R2= 02CPri),363and (15 1; R’ = OMe, R2 = H)363without novelty; the thermal rearrangement of (150; R’=OAc, R2=H), which has been obtained in improved yield in three steps from 4,7-dimethylcoumarin, to (152) may have applications in further thymol syntheses.364 Another application of polymer-bound Rose Bengalg8involves allylic photo-oxygenation of R -(+)-pulegone as a first step 353 354 355
356
357 358
359
360
362 363 364
R. Freeman, G. A. Morris, and M. J. T. Robinson, J.C.S. Chem. Comm., 1976, 754. R. Kasai, M. Suzuo, J.-I. Asakawa, and 0. Tanaka, Teirahedron Leiiers, 1977, 175. V. M. Potapov, V. G . Bakhmutskaya, 1. G. Il’ina, G. I. Vinnik, and E. G. Rukhadze, J. Gen. Chem. (U.S.S.R.), 1975, 45,2071. T. Tahara and Y . Sakuda, Kochi Joshi Daigaku Kiyo, Shizen Kagaku Hen, 1976, 24, 1 (Chem. Abs., 1977,86, 72 891). F. E. Fernandes Gomes, 0. D. Ul’yanova, and Y . A. Pentin, Russ. J. Phys. Chem., 1976,50, 1310. V. M. Potapov, G. V. Grishina, and I. K. Talebarovskaya, J. Org. Chem. (U.S.S.R.),( a ) 1976, 12, 2193; ( 6 ) 1976,12, 1399. H. A. J. Oonk, K. H. Tjoa, F. E. Brants, and J. Kroon, Thermochim.Acra, 1977,19,161; E. L. Meijer, J. G. Blok, J. Kroon, and H. A. J. Oonk, ibid., 1977, 20, 325. R. M. G. Roberts, J.C.S. Perkin ZZ, 1976, 1374. A. Kreft, Tetrahedron Leiiers, 1977, 1035. F. Bohlmann and J. Kocur, Chem. Ber., 1976, 109,2969. K. J. Divakar, B. D. Kulkarni, and A. S . Rao, Indian J. Chem., 1977,15B, 322. K. J. Divakar and A. S . Rao, Synih. Comm., 1976,6, 423.
Monoterpenoids
41
in the 1,3-carbonyl transposition sequence to produce S-(-)-pulegone; the reaction sequence is very similar to the unacknowledged scheme previously reported for (15) (Vol. 5 , p. 25).365 Anodic oxidation of 4-methylcyclohexanone enol acetate in the presence of absolute methanol-tetraethylammonium toluene-p-sulphonate yields the n-methoxy-ketone which, after Grignard reaction and hydrolysis, produces menthol viu a 1,2-carbonyl t r a n ~ p o s i t i o n .Complete ~~~ transfer of chirality, via a double suprafacial transition state, has been observed in the [3,3] sigmatropic rearrangement of the trichloroacetimidate [ 153; R = C(NH)CCl,] to the trichloroacetamide (154; R = C0CCl3), which is reminiscent of the [3,3] sigmatropic rearrangement reported earlier by Thomas and Ohloff (Vol. 1, p. 33); an elimination by-product is the corresponding mentha-1,5,8-triene (Vol. 1, p. 24).367Dehydrohalogenation of the endo- and exo-6-bromo-1,3,3-trimethyl-2-oxabicyclo[2,2,2]octane (80 :20) with potassium t-butoxide-DMSO yields dehydrocineol (Vol. 5 , p. 23) with minor amounts of (+)-pin01 (155) and (-)-isopinol(l56) to add to the small number of examples of cineol -+ pinol rearrangements (e.g. see Vol. 6, p. 31); using 1,5-diazabicyclo[5,4,0]undec-5-ene, the major product is (155; 85%) together with (156; 9%). Attempted dehydration of the corresponding alcohols yields (157).368Photo-oxygenation of p-mentha-3,8-diene, from isopulegol thio-
benzoate photolysis or isopulegol S-methylxanthate pyrolysis, followed by lithium di-isopropylamide cleavage of the derived endo-peroxide gave p - m e n t h ~ f u r a na, ~ ~ ~ further synthesis of which involves thermal decomposition of dimethyl diazomalonate in l-methoxy-5-methylcyclohexeneover trimethoxyphosphinecopper(1) iodide to yield (158) followed by reduction of the sodio-enolate and
'" H. E. 366
367
368
369
Ensley and R. V. C. Carr, Tetrahedron Letters, 1977, 513; Current Abstracts of Chemistry, Abstract 255 431 incorrectly identifies the product as S-(-)-pulegone. T. Shono, I. Nishiguchi, and M. Nitta, Chem. Letters, 1976, 1319. Y. Yamamoto, H. Shimoda, J.-I. Oda, and Y . Inouye, Bull, Chem. SOC.Japan, 1976,49,3247; for an earlier application of this method, see Vol. 7, p. 5. F. Bondzvalli, P. Schenone, S. Lanteri, and A. Ranise, J.C.S. Perkin I, 1977, 430; see also ref. 391. B. Harirchian and P. D. Magnus, Synrh. Comm., 1977, 7 , 119. For other syntheses of p-mentha-3,8diene, see R. G. Buttery and L. C. Ling, J. Agric. Food Chem., 1977,25, 291, and ref. 379.
Terpenoids and Steroids
42
a~idification;~~’ benzophenone-sensitized photolysis of methyl a-diazopropionate in l-methoxy-5-methylcyclohexeneto yield (159) also results in p-menthofuran after reduction, Fetizon oxidation, and acid treatment.370 Other papers of synthetic interest are the full paper on uroterpenol synthesis (Vol. 6, p. 27),371straightforward syntheses of 2-methyl-5-isopropenylanisole372and of a- and P-phellandrene,373and the preparation of 7,7,7-trifluoro-p-menthan-3-01~.~~~ Further work on p-menthane hydroxylation using Pseudomonas mendocina-SF (Vol. 6, p. 12) has resulted in isolating the metabolites (160; R = C H 2 0 H ) and (160;
(158)
(159)
(160)
R = C02H),375and more urinary metabolites formed from (+)-limonene (Vol. 7, p. 9) are reported in a species-comparative study (earlier papers in this series were inadvertently omitted from Vol. 6).” Microbial conversion of (-)-menthone, using a Pseudomonas putida strain, yields (+)-isomenthone, (10; R = H), (61; X = H, R = CH2C02H), and (58; stereochemistry unspecified) and the corresponding hydroxy-a~id.~~~ The Diels-Alder reaction of a -phellandrene with acrylic acid derivatives has been examined, apparently superficially377in contrast to the re-investigation of the reaction with benzalbisurethane, catalysed by B F , , E ~ , O - C U B ~The . ~ ~1,4-adducts ~ (161; endo: exo/37 : 63) may result effecJively fr6m the concerted [4, +2,] addition involving the immonium ion (PhCH=NHC02Et); however, with the corresponding unsubstituted immonium ion, formal 1,3-addition to a -phellandrene occurs essentially via the isomerized a -terpinene and isoterpinolene to yield [(162): (163)/84: 16].378 K0Bu‘-DMF is the preferred reagent in tosylate elimination reactions with no accompanying substitution reactions [(-)-menthy1 tosylate, (-)-bornyl tosylate, (+)-carvomenthyl tosylate]; the tosylate of (+)-dihydrocarveol (164) gives a good yield (85%) of (-)-p-mentha-3,8-diene and (-)-p-mentha-2,4(8)-diene as sole products, presumably via base-catalysed rearrangement of i~olirnonene.~’~ 370
37’ 372
373 374
375 376
377
378
379
E. Wenkert, M. E. Alonso, B. L. Buckwalter, and K. J. Chou, J. Amer. Chem. Soc., 1977, 99, 4778. A. Kergomard and H. Veschambre, Tetrahedron, 1977, 33, 2215. T. K. John and G. S. K. Rao, Indian J. Chem., 1976,14B, 805. B. Singaram and J. Verghese, Indian J. Chem., 1976, 14B, 1003. A. N. Blakitnyi, E. V. Konovalov, R. K. Orlova, A. P. Sevast’yan, Y. A. Failkov, and L. M. Yagupol’skii, U.S.S.R. P. 520 343 (Chem. Abs., 1976,85, 160 356). Y. Tsukamoto, S. Nonomura, and H. Sakai, Agric. and Biol. Chem. (Japan), 1977, 41, 435. 0. Nakajima, R. Iriye, and T. Hayashi, Nippon Nogei Kaguku Kaishi, 1976, 50,403. E. Patyk, H. Sadowska, and J. Wilczynska, Zeszyty Nuuk. Politech. kodz., Chem. Spozyw., 1976,28,79 (Chem. Abs., 1977,86,121544). G. R. Krow, K. M. Damodaran, D. M. Fan, R. Rodebaugh, A. Gaspari, and U. K. Nadir, J. Org. Chem., 1971,42,2486. Z. Rykowski and H. Orszanska, Roczniki Chem., 1976, 50, 1901; this paper implies but does not specify that (-)-p-mentha-3,8-diene is the minor product (40:60). Chem. Abs., 1977, 86, 121 536 states the opposite!
Monoterpenoids
43
/
Ph
Base-aprotic solvent elimination has also been reported for 1-hydroxyneodihydrocarveyl tosylate and for 1-hydroxyneocarvomenthyl tosylate (epoxide and allylic alcohol Manganese(II1) acetate oxidation of (+)-p-menth-1-ene yields the two lactones (165; X=O, Y = CH2)and (165; X = CH2, Y = 0)as major products together with anticipated acetates;381similar oxidation of (+)-pulegone yields the C-2 acetates in low yield3" and oxidation of isomenthone in the presence of isopropenyl acetate results in acetonylation at C-2 and C-4.383 Further examples of the rearrangement of epoxides with K0Bu'-aprotic solvents (pyridine is favoured) have been reported (cf. Vol. 6, p. 44), e.g. (166) to (167), although with the corresponding 1,2-epoxy-
(165)
(166)
(167)
trans-p-menth-8-ene the expected aromatization is observed.384It is not clear why tosylate elimination from 1-hydroxyneocarvomenthyl t o ~ y l a t e ~ yields ~ ' (166; 98%) with little observed (167; 2%) under essentially identical conditions.384 Further papers from Arata's group on the rearrangement of limonene-1,2-epoxides over solid catalysts have been published (cf. Vol. 7, p. 31).385 Herz has carried out a thorough investigation of the ferrous ion-promoted decomposition of a-phellandrene epidioxides (168) and the corresponding epoxides [e.g. (169)].386 Products, formed by Fe"-Fe"' redox system-induced rearrangement, include inter alia (170)(173) and some derived epoxides, with no intramolecular 1,5-hydrogen abstraction The epoxide (169) decomposed rapidly on silica gel to the mixture [epoxy-(17l)+epoxy-(172); 1,4-trans-dialkyl]; all reported examples of such easy and unexplained rearrangements require hydrogen a to an epidioxide which must 380
381
382 383 384
"' 386
Z. Rykowski, K. Burak, and Z. Chabudzinski, Roczniki Chem., 1976,50,2107. K. Witkiewicz and Z. Chabudzinski, Roczniki Chem., 1976,50,1545;formulae (11) and (13) both lack a double bond. G . J. Williams and N. R. Hunter, Canad. J. Chem., 1976, 54, 3830. M. Chatzopoulos and J.-P. Montheard, Compt. rend., 1977,284, C,133. Z. Rykowski and K. Burak, Roczniki Chem., 1976, 50, 1709. K. Tanabe and K. Arata, Jap. P. 16 641/1976 (Chem. Abs., 1976,85,94 545); K. Arata, H . Takahashi, and K. Tanabe, Rocrniki Chem., 1976, 50, 2101; T. Yamada, K. Arata, M. Itoh, H. Hattori, and K. Tanabe, Bull. Chem. SOC.Japan, 1976,49,2946. J. A . Turner and W. Herz, J. Org. Chem., ( a ) 1977,42, 1895; ( b ) 1977,42,2006.
Terpenoids and Steroids
44
be cis to an adjacent e p o x y - g r o ~ p The . ~ ~ferrous ~~ ion-promoted rearrangement of ascaridole (174), via isoascaridole (175), to ascaridole glycol (176) has also been clarified. 386n
A (173)
A further paper on the reduction (lithium-ethylenediamine) of p-cymene has been The stereoselectivity of reduction of menthone and isomenthone to the corresponding menthols using dissolving metals and catalytic hydrogenation has been examined under a variety of conditions; for example Li-NH3 at -78 "C results in stereospecific reduction to menthol and isomenthol, respectively, in contrast to catalytic hydrogenation where high selectivity for menthol formation was not observed although good selectivity was observed for the other menthol isomers (e.g. neomenthol; 82%) with interesting selectivity shifts according to reaction temperature.388 A synthetic and mechanistic study of 13cineole hydrogenolysis reports cis - and trans -p-menthanes exclusively.389 pMentha-l$-diene can be synthesized efficiently by reductive cleavage of (153; R = H or Ac) or the C-2 epimeric carve01.~~'Another cineole + pinol rearrangement (see ref. 368) is observed in the lithium aluminium hydride reduction of the cineol chlorohydrin (177) which has been investigated mechanistically; excess hydride yields (178; X = H , endo-OH; 50%), (179; 32%), and (180; X=H; 11Y0) whereas one equivalent of hydride yields (177), (180; X = Cl), and (178; X = 0) and an epoxy precursor of (179).391 Thermal isomerization of (177) gave a mixture [(177): (180; X = C1)/20: 801 and data for the corresponding endo-dihalides have been reported.391bAlkene formation in the Ti" reductive coupling of menthone with itself392and the dehydrogenation of s o b r e r 0 1 ~have ~ ~ been described. 387 388 389 390 391
392
393
V. V. Bazyl'chik and P. I. Fedorov, Zhur. org. Khim., 1977,13, 1012; cf. Vol. 7, p. 32. J. Solodar, J. Org. Chem., 1976, 41, 3461. H. M. Hiigel, W. R. Jackson, C. D. Kachel, and I. D. Rae, Austral. J. Chem., 1977,30, 1287. I. Elphimoff-Felkin and P. Sarda, Org. Synth., 1977.56, 101. ( a ) J. Wolinsky, J. H. Thorstenson, and M. K. Vogel, J. Org. Chem., 1977, 42, 253; ( b ) M. K. Vogel, Diss. Abs. Internat. ( B ) , 1977, 37, 3969. D. Lenoir, Synthesis, 1977,553; for a related coupling between pulegone and acetone, see J. E. McMurry and L. R. Krepski, J. Org. Chem., 1976,41, 3929. S. S. Poddubnaya, Z. A. Surnina, V. G . Cherkaev, N. D. Antonova, and A . A . Skorubskii, Zhur. Vsesoyuz. Khim. obshch. im. D. I. Mendeleeva, 1976,21,455.
45
Monoterpenoids
OH
CI
Acylation of limonene at the disubstituted double bond is favoured by a factor of 2.3 over reaction at the trisubstituted double bond using acetyl hexachloroant i m ~ n a t e Mixed . ~ ~ ~ alkylcuprate alkylation of tricarbonylcyclohexadienyliron salts has been used to synthesize the a -phellandrene tricarbonyliron complex.395 Dichlorocarbene addition to limonene in the presence of 1,4-diazabicyclo[2,2,2]octane is almost 100% stereoselective at the trisubstituted double bond (no yield given) (cf. Vol. 6, p. 31);284in contrast to dibromocarbene addition to carvone (Vol. 7, p. 34), dichlorocarbene addition to the carveols is not regiospecific.**’ In an enamine alkylation study, piperitone (8; X = H) gave, in addition to the expected dienamines, two rearranged dienamines via ring opening and reclosure; hydrolysis yielded the o-menthenones (181).396Dauben’s full paper (Vol. 7, p. 34)on
pulegone and isopulegone tosylhydrazone decomposition397has been published. Other papers related to p-menthanes concern nitrosyl chloride addition to (*)-aterpineyl acetate,398 the stereochemistry and conformations of amino-oximes derived from limonene and p-menth-1-ene nitro so chloride^,"^ phenylationreduction of (+)-pulegone, piperitone (8; X = H), and ( - ) - ~ a r v o n e , ’ ~reactions ~ of a-terpinene in the presence of salicylic acid,400stereochemical assignment of cisand truns-1,S-terpin (!)401 and reaction of the cis-isomer with azide conversion of tetrahydrocarvone into an enol phosphate and reduction to p-menth-lene,403the non-photochemical reaction of (+)-pulegone with 4-phenyl- 1,2,4-tri394 395
396
397 398
399 400
401 402
403
H. M. R. Hoffmann and T. Tsushima, J. Amer. Chem. Soc., 1977,99,6008. A . J. Pearson, Austral. J. Chem., 1977,30, 345. Y. Bessiire and F. Derguini-BoumCchal, J. Chem. Res. ( M ) , 1977, 2301. W. G. Dauben, G. T. Rivers, and W. T. Zimmerman, J. Amer. Chem. Soc., 1977, 99, 3414. B. Singaram and J. Verghese, Indian J. Chem., 1977,153, 217. R. M. Carman, P. C. Mathew, G. N. Saraswathi, B. Singaram, and J. Verghese, Austral. J. Chem., 1977,30, 1323; see also ref. 413. I. I. Bardyshev, L. A . Popova, and E. F. Buinova, Vestsi Akad. Navuk belarusk, S.S.R., Ser. khim. Navuk, 1976, 112 (Chem. Abs., 1976,85, 177 634). B. Singaram, P. M. Abraham, G. N. Saraswathi, and J. Verghese, Indian J. Chem., 1976,14B, 934. A. Pancrazi, I. KaborC, and Q. Khuong-Huu, Bull. SOC.chim. France, 1977, 162. R. P. Gregson and R. N. Mirrington, Austral. J. Chem., 1976, 29, 2037.
46
Terpenoids and Steroids
a~oline-3,5-dione,~'~ isocarvoxime ~ y n t h e s i s , ~and ' ~ the constitution of the 1,scineol-ferric thiocyanate406and cymene-vanillin-sulphuric acid complexes.407 o-Menthanes.-Two earlier papers report syntheses of molecules with the omenthane carbon ~ k e l e t o n . ~ "Other . ~ ~ ~ papers of interest concern g.1.c. separation of 0- and p-menthenes and men thane^,^"* lithium-ethylenediamine reduction of o-cymene to o-menthadiene~,~'~ and neo-o-menthan-2-01 synthesis from ocreso~.~" rn-Menthanes.-The m-thymol derivative (182) has been isolated from Macowania h ~ r n a t u . ~ 1.r. ' ~ and Raman spectra of sylvestrene have been a n a l y ~ e d .A~ ~ ~ synthesis of the sesquiterpenoid frullanolide includes the formation of the mmenthane (183) via a modified ester enolate Claisen The stereochemistry and conformations of amino-oximes (184) derived from sylvestrene nitrosochloride by treatment with amines have been d i s c ~ s s e d ; last ~ ' ~ year's Report (Vol. 7, p. 30) omitted reference to AgN0,-DMSO dehydrohalogenation of sylvestrene n i t r o s ~ c h l o r i d e . ~ ~ ~
l_i_
OH (182)
HoNQ
C0,Me
(183)
(184)
Tetramethylcyc1ohexanes.-The structure of picrocrocinic acid from Gardenia jasminoides grundifloru has been established as (185) by relating it to picrocrocin (Vol. 4,p. 37).335
(185)
The formation of dihydrocyclogeranyl acetate via thiyl radical addition to geranyl and aldol-type condensations of citral, of dihydrocitral, anh of 3 - m e t h y l b ~ t - 2 - e n a l ~have ~ ~ been discussed already. a -Cyclocitral behaves 404 405
406 407 408 409
410
411 412 413
414
J. D. Shiloff and N. R. Hunter, Tetrahedron Letters, 1976, 3773. B. Singaram and J. Verghese, Current Sci., 1977, 46, 259. C. H. Brieskorn and W. Schlicht, Arch. Phurm., 1977,310,305; see also ref. 1756. H. Auterhoff and C. Baur, Arch. Pharm., 1977,310,518. V. V. Bazyl'chik, B. G . Udarov, and N. P. Polyakova, J. Anafyt. Chem. (U.S.S.R.),1976,31, 507. V. V. Bazyl'chik, I. I. Bardyshev, P. I. Fedorov, E. D. Skakovskii, and N. M. Ryabushkina, Vesrsi Akad. Navuk belarusk. S.S.R.,Ser. khim. Navuk, 1976,75 (Chem. Abs., 1976,85,94 497). V. V. Bazyl'chik, E. A. Ionova, and I. I. Bardyshev, Vestsi Akad. Nuvuk belarusk. S.S.R., Ser. khim. Nuvuk, 1976, 112 (Chem. Abs., 1977,86,140262). F. Bohlmann and C. Zdero, Phyrochemistry, 1977,16, 1583. W. C. Still and M. J. Schneider, J. Amer. Chem. Soc., 1977,99,948. D. J. Brecknell, R. M. Carman, B. Singaram, and J. Verghese, Austral. J. Chem., 1977, 30, 195; for related work see refs. 398, 399, and Vol. 5, p. 24. B. Singaram and J. Verghese, Indian J. Chem., 1976, 14B, 479; Chem. Abs., 1976, 85, 177633 incorrectly refers to NaN03-Me2SO dehydrochlorination.
47
Monoterpenoids
similarly to citral on treatment with fluorosulphonic a~id;’~’however, (74), from which a-cyclocitral and a-cyclogeranyl acetate are readily available, is now formed in fair yield (53%). In contrast, P-cyclocitral is less reactive, because of delocalized cation formation, being recovered largely unchanged (73%) along with methyl P-cyclogeranate (2370).272 The brominative cyclization of geranyl cyanide using 2,4,4,6-tetrabromocyclohexa-2,5-dienone-Lewis acid (15% yield) was omitted from earlier report^.^" Cyclization of (E+Z)-geranic acid using graphite bisulphate favours the formation of (186) over the conjugated cyclogeranic acid by 9 to l.416Deoxygenation of (187), which is readily available from 3-methylcyclohex-2-enone, with TiC1,LiAlH, reagent leads to y-cyclocitral (188) in good yield.417 Vilsmeier formylation of dihydroisophorone yields (189; X=Br or CI), which may be reduced selectively to (189; X = H ) using an improved catalyst (cf. ref. 420).,*’
CHO
(186)
(187)
(188)
(189)
Dimethylethylcyc1ohexanes.-Halogenated members of this class,29s~297~299~300~303 the formation of (77; X = Z - M e ) from m y r ~ e n e , ’and ~ ~ hydrative cyclization of dihydromyrcene to (78)276have already been reported. Extending their earlier work on Vilsmeier formylation (cf. Vol. 7, p. 36), Traas et al. have formylated the @unsaturated ketone isophorone almost exclusively at the more favoured exocyclic position to yield (190),419which may be selectively
090)
reduced without isomerization to the boll weevil pheromones (77; X=CHO, E :2 / 2 : 1) in high overall yield; an alternative route from isophorone involves reduction with sodium dihydrobismethoxyethoxyaluminateand dehydration prior to formylation and selective reduction.420 Alkylation of 3,3-dimethylcyclohexanone with O-ethyl S-ethoxycarbonylmethyl dithiocarbonate yields the boll weevil pheromone intermediate (77; X=E-C02Et) stereo~electively,~~~ although no 415
416
417 41R 419
420 421
T. Kato, I. Ichinose, S. Kurnazawa, and Y. Kitahara, Bioorg. Chem., 1975, 4, 188. J. P. Alazard, R. Setton, and H. B. Kagan, unpublished data reported in ref. 87; the name8’“ and are misprinted in these papers. T. Mukaiyama, K. Saigo, and 0.Takazawa, Chem. Letters, 1976, 1033. P. C. Traas, H. J. Takken, and H. Boelens, Tetrahedron Letters, 1977,2027. P. C. Traas, H. Boelens, and H. J. Takken, Rev. Trav. chim., 1976, 95, 308; W. Hoffmann and E. Mueller, Ger. Offen. 2 152 193 (Chem. Abs., 1973, 79, 18 212) have described an almost identical synthesis in slightly lower yield. P. C. Traas, H. Boelens, and H. J. Takken, Synth. Comm., 1976,6,489. K. Tanaka, R. Tanikaga, and A . Kaji, Chem. Letters, 1976, 917.
48
Terpenoids and Steroids
stereoselectivity is observed in the pyridinium chlorochromate (cf. Vol. 7, p. 30) oxidative rearrangement of 3,3-dimethyl-l-vinylcyclohexanol to (77; X=CHO).92 An alternative non-stereoselective route from 3,3-dimethyl-l-vinylcyclohexanol involves the previously reported242[3,3] sigmatropic rearrangement of a derived thionocarbamate as the key step. A routine synthesis of 1,4-dimethylcyclohex-3enyl methyl ketone does not refer to Thomas's improved synthesis (Vol. 5, p. 29).422 Cyc1oheptanes.-The C-1 -C-2 bond in y-thujaplicin is essentially single,423Co"P-thujaplicin-amine complexes have been and thermodynamic data on the U"'-P-thujaplicin complex have been calculated.425 The biomimetic cyclization of the silyl enol ether (191) to karahanaenone (192), using methylaluminium bis(trifluor0acetate) is almost q ~ a n t i t a t i v e ; ~(192) ' ~ is also synthesized by thermolysis followed by desilylation of the silyl enol ether (193) which is readily available from l-bromo-2-methyl-2-vinylcyclopropane and i ~ o b u t y r a l d e h y d e . ~ ~ ~ Dehalogenation of 3-bromo-1 -iodo-3-methylbutan-2-one with Zn-Cu couple on alumina in the presence of isoprene yields (192) and minor amounts of the isomers (194) and (195); however, dehalogenation with Fe2(C0)9 favours ( 195).428 Acetolysis of karahanaenol tosylate yields anticipated p-menthane derivatives and no f i ~ i f o ~ e n e . ~ ~ ~
6 Bicyclic Monoterpenoids
Bicyclo[3,1,0]hexanes.-Hach has concluded his efforts to provide preparativescale syntheses of pure (+)-thuj-3-one (30), and (-)-isothuj-3-one, and the four derived thujanols, uiz. (+)-thujan-3-01, (-)-isothujan-3-01, (+)-neothujan-3-01 (31), and (-)-neoisothujan-3-01 (for earlier related work see Vol. 2, pp. 30, 37, 38; Vol. 4, p. 42; Vol. 7, p. 36)."' A conformational study on these four thujanols indicates that they have a slightly developed boat-like conformation, whereas the five-membered ring in (+)-thuj-3-one (30) and (-)-isothuj-3-one is flat, according 422
423
424
425 426
427 428 429 430
0. P. Vig, S. D. Sharma, S . S. Bari, and M. Lal, Indian J. Chem., 1976, 14B,932. J.-E. Berg, B. Karlsson, A.-M. Pilotti, and A.-C. Wiehager, Actu Cryst., 1976, B32, 3121; for b-thujaplicin see Vol. 3, p. 55. B. Maiti and R. M. Sathe, J. Inorg. Nuclear Chem., 1977,39, 1244; cf. the Ni" complex (Vol. 7, p. 36). T.-M. Hseu, C. Chang, and K.-L. Hsu, J. Chinese Chem. Soc. (Taiwan), 1977,24,11. S . Hashimoto, A. Itoh, Y. Kitagawa, H. Yamamoto, and H. Nozaki, J. Amer. Chem. Soc., 1977, 99, 4192; see Vol. 7, p. 17 for a related organoaluminium-promoted cyclization. P. A. Wender and M. P. Filosa, J. Org. Chem., 1976, 41, 3490. R. Chidgey and H. M. R. Hoffmann, Tetrahedron Letters, 1977, 2633. C. Capellini, A. Corbella, P. Gariboldi, and G. Jommi, Guzzettu, 1977,107, 171. V. Hach, J. Org. Chem., 1977, 42, 1616. The nomenclature used by Whittaker (Vol. 5, p. 30) has already been noted; in addition, the formula given for (-)-thujan-3-01 is actually that of (+)-thujan-301. Further confusion in this field results from Banthorpe using149 the name (+)-isothujanol for the (+)-neoisothujanol structure; Banthorpe uses the same nomenclature as Whittaker.
Monoterpenoids
49
to evidence, from lanthanide-induced shifts in the ‘H n.m.r. spectrum, from rates of chromium trioxide oxidation, and from rates of a~etylation;~” this confirms earlier work (Vol. 5 , p. 30) on (-)-thujan-3-01 and (+)-neothujan-3-01 (31). The full paper by Whittaker concerning the carbonium ion derived from neothujan-3-01 (31) (cf. Vol. 5 , p. 30; Vol. 6, p. 35; Vol. 7, p. 36) has been p ~ b l i s h e d ; ~the ~’ products derived from solvolysis of thujan-3-01 (called isothujol) and neothujan-301 (31) (called neoisothujol) esters are compared with those from earlier work on the hydration of sabinene and a-thujene (Vol. 4, pp. 42, 43) as well as Norin’s tosylate a c e t o l y ~ e sand ~ ~interpreted ~ in terms of the ions (196) and (197); Whittaker interprets the formation of cyclopentenes from thujan-3-01 and neothujan-301 (31) in strong acid as proceeding uia ion (197), which predictably rearranges to the more stable (198), despite Sorensen’s view (Vol. 7, p. 36) that the first formed ion must be (199).431The products of reduction of umbellulone (200) (cf. Vol. 1, p. 39; Vol. 3, p. 57) and dihydroumbellulone (201; R’,R2=0),* using different reducing agents, have been interpreted based upon their respective conformations; complete assignment of ‘H and 13Cn.m.r. spectra indicated that dihydroumbellulone (201; R1,R2= 0)has a flattened boat conformation and that each of the ~’ derived alcohols (201; R’,R2 = H,OH) also exists in a boat c ~ n f o r m a t i o n . ~Both thermal and photochemical elimination of cyclohexyl isocyanide by a,a-carboncarbon bond cleavage fails with N-cyclohexylthujan-3-imine.434
Bicyclo[2,2,1]heptanes.-Vulgarole (202; R = Ac) has been isolated from Artemisia v u l g a r i ~and ~ ~ Ferula ~ dshizakensis has yielded a new borneol ester, isotschimgin (cfiVol. 3, p. 58).436 X-Ray diffraction studies of (~t)-carbocamphenilone,~~~ of (-)-camphene-8carboxylic and of a number of Money’s brominated camphor derivatives (Vol. 6 , p. 39; Vol. 7, p. 40) have been published; they include 8-bromo1,7-dibromo-4camphor,439 1,7-dibromo-3,3,4-trimethylnorbornan-2-one,440 431
432 433
434 435
436
437 438 439 440
C. M. Holden and D. Whittaker, J.C.S.Perkin ZI, 1976, 1345. T. Norin, Tetrahedron Letters, 1964, 37. C. M. Holden, J. C. Rees, S. P. Scott, and D. Whittaker, J.C.S. Perkin 11, 1976, 1342; on page 1344 line 14 ‘the 0-01’ should read ‘the p-01’. J. H. Boyer and K. G. Srinivasan, J.C.S. Perkin I, 1976, 1583. G. M. Nano, C. Bicchi, C. Frattini, and M. Gallino, PZuntu Med., 1976, 30, 211; see also ref. 459. V. N. Borisov, A. I. Ban’kovskii, V. I. Sheichenko, V. S. Kabanov, and M. G. Pimenov, Chern. Natural Compounds, 1976,12,598. J. P. Seymour, B. Lee, and A. W. Burgstahler, Acta Cryst., 1977, B33, 2667. P. C. Moews, J. R. Knox, and W. R. Vaughan, Tetrahedron Letters, 1977, 359. C. A. Bear and J. Trotter, Actu Cryst., 1975, B31, 903. C. A. Bear and J. Trotter, Actu Cryst.,1975, B31, 904.
* Named isodihydroumbellulone by the authors; see the footnote, Vol. 2, p. 37
50
Terpenoids and Steroids
dibromomethyl-3,3-dimethylnorbornan-2-one,441 and endo-3,9,9-tribromocamphor.442 ‘HN.m.r. signals of the C-8 and C-9 methyl groups of a series of bornane derivatives have been assigned.443 Further papers on 13C n.m.r. include chemical shifts of 1-substituted camphenilones, their derived N-nitro-imines, fenchone oxime, and fenchone N - n i t ~ o - i m i n eand ~ ~ ~of 4-substituted camphors, N-nitrocamphorimines, and d i a z o ~ a m p h o r s . ~ Raman ~~ c.i.d. spectral data have been extended to additional bicyclo[2,2, llheptane monoterpenoids (cf.Vol. 6, p. 36).446 C.d. data for (1R)-[2-’s0]- and (1R)-[1-2H]-a-fenchocamphoronequinone(cf. Vol. 4, p. 50) and rotational strengths for (1R)-camphorquinone and (19-1bromo-a-fenchocamphoronequinone have been ~ a l c u l a t e d . ~ ~ Further ’ fluorescence data for camphorquinone in the solid and gas phases have been reported (cf. Vol. 6, p. 35)448and a photoluminescence study includes data on camphor and fenchone fluorescence and p h o s p h o r e ~ c e n c e .The ~ ~ ~kinetics of mutarotation of (+)-3-bromocamphor and (+)-3-bromo-3-deuteriocamphor and of bromination of (+)-3-nitrocamphor and (+)-3-deuterio-3-nitrocamphor have been in~estigated,~” and the standard enthalpy of formation of camphor has been measured.451 The synthesis of camphor (80% optical purity) by heating optically pure dihydrocarvone at 400 “C for 20 h is reminiscent of Money’s racemic camphor synthesis (Vol. 1, p. 39) in that both correspond to a biogenetic-type synthesis via enol formation.452Further synthetic work on deuteriated camphors (see references therein and Vol. 3, p. 67; Vol. 4, p. 48; Vol. 7, p. 38 for earlier work) includes syntheses of optically pure [tb2H1]-,[8-2H2]-, and [8-2H3]-(-)-camphor (204) by modification of known reactions (Scheme 5)453 and the use of an improved Zn-Cu
(202)
(203)
(204)
Reagents: i, H’; ii, LiAID4; iii, PhCOCI; iv, Cr03; v, OH-; vi, PBr3; vii, Bu3SnD Scheme 5 441
442
443 444
44s 446 447
448 449 4s0
451 4s2 453
S. E. V. Phillips and J. Trotter, Acfa Cryst., 1976, B32, 1423. S.E. V. Phillips and J. Trotter, Acfa Crysr., 1977, B33, 200; last year’s Report erroneously reports the is the major X-ray crystal structure of this compound. Although endo-3,9,9-tribromocamphor component of the by-product in preparing 3,9-dibromocamphor, the X-ray structure reported last year (Vol. 7, p. 37, ref. 372) was of the minor by-product, the corresponding exo-isomer. L. Lacombe and L. Mamlok, J. Chem. Rex (M), 1977, 1401. F. C. Brown and D. G. Morris, J.C.S.Perkin Il, 1977, 125. D. G. Morris and A. M. Murray, J.C.S.Perkin 11,1976, 1579. L. D. Barron, J.C.S. Perkin Il, 1977. 1074. R. F. R. Dezentje and H. P. J. M. Dekkers, Chem. Phys., 1976.18, 189. P. Avouris, W. D. Hopewell, and M. A. El-Sayed, J. Chem. Phys., 1977,66, 1376. W. H. Waddell, N. J. Turro, and G. Farrington, Mol. Photochern., 1976, 7, 475. R. P. Bell and S. Grainger, J.C.S. Perkin II, 1976, 1606. W. V. Steele, J. Chem. Thermodynamics, 1977,9, 311. G. L. Lange and J. M. Conia, Nouveau J. Chim., 1977, 1,189. W. L. Meyer, C. E. Capshew, J. H.Johnson, A. R. Klusener, A. P. Lobo, and R. N. McCarty, J. Org. Chem., 1977,42,527.
Mono terpenoids
51
couple to prepare exo-[3-’Hl]-(+)-camphor (cf. Vol. 2, p. 39; Vol. 5 , p. 33) from 3 - b r o m o ~ a m p h o r . ~ ’Other ~ syntheses of interest include the syntheses of camphorquinone by Pummerer-type reaction during the oxidation of 3-phenylselenocamphor with thallium(II1) nitrate,455[8-14C]camphene,456the first example of a tetracyclic monoterpenoid (205),457 and an improved synthesis of ~amphenilone.~’~ Money et al. have accomplished the chemical functionalization of (-)-bornyl acetate, to yield (206) as the major product with smaller amounts of the 3-keto- and 6-keto-isomers of (206) and exo-(207; R = Ac), as well as microbiological hydroxylation using Helminthosporium sativum, to yield endo- and exo-(207; R=H) : 6exo-hydroxyborneol: (208; R=H)/5 : 1 : 2.459
(205)
(206)
(207)
(208)
The long-known rearrangement of a -bromocamphoric anhydride (209; X=Me) to (210; X = Me) has been shown to proceed via at least two competitive pathways to account for the observation, using (209; X = CD,), that the C-9 methyl group is the precursor of X [no (210; X = CD,) is obtained] but that the C-8 methyl group is the precursor of both the C-1 methyl group (71%) and the C-3 methyl group (29%) in (210; X = CH,). This paper also confirms the unequivocal methyl resonance
+-.{ x o
H F
...-.--
(209)
(2 10)
assignments in the ‘H n.m.r. of camphor and that the rearrangement (202) + (203) proceeds with no rearrangements resulting in r a ~ e m i z a t i o n . ~ In ’ ~ contrast, the acid-catalysed rearrangement of camphene into isobornyl acetate (Vol. 5 , p. 31) in the presence of CuC12 does not involve Nametkin rearrangement, thus allowing exclusive deuterium labelling of the C- 10 methyl group; P-pinene behaved similarly.460 Camphene reacts with chloroacetic acid-KBr to form the expected lactones without rearrangement.461 The rearrangement of fenchenes formed during the titanic acid-catalysed isomerization of a -pinene gives the expected results 454
45s
4s6 4s7 4SR 459 460 46‘
L. M. Stephenson, R. V. Gemmer, and S. P. Current, J. Org. Chem., 1977, 42, 212; Registry Numbers have been assigned incorrectly to these compounds, Y, Nago, M. Ochiai, K. Kaneko, A . Maeda, K. Watanabe, and E. Fujita, Tetrahedron Letters, 1977, 1345. J. E. Oliver, J. Labelled Compounds, 1977.13, 349. D . Heissler, F. Jung, J. P. Vevert, and J. J. Riehl, Tetrahedron Letters, 1976,4879. J. San Filippo, jun. and J. W. Nicoletti, J. Org. Chem., 1977, 42, 1940. M. S. Allen, N. Darby, P. Salisbury, and T. Money, J.C.S. Chem. Comm., 1977, 358. A. Heumann and B. Waegell, Nouoeau J. Chim., 1977,1,275. T. Kishimoto, H. Ishihara, and Y. Matsubara, Bull. Chem. SOC.Japan, 1977.50, 1897.
52
Terpenoids and Steroids
(see Vol. 3, pp. 59, 60; Vol. 4, p. 44).462 A thermodynamic and kinetic study, via acetoxylation-deacetoxylation,complements an earlier camphene study (Vol. 5, p. 31) and confirms the relative stability of a- and P-fenchenes as well as cyclof e n ~ h e n e .Synthetic ~~~ details have been published for the trifluoromethanesulphonates (211; X=H, Y = OSO2CF3; 35%) and (211; X = OS02CF3,Y = H; 65%) reported last year (Vol. 7, p. 37);464a second preliminary paper reports the same reaction-camphor treated with (CF3S02)20-CH2C12-Na2C03-but with different The authors describe (211; X = OS02CF3, Y = H) as the only bicyclic triflate together with carvenone (5) and carvacryl triflate; however, the authors’ limited spectral data46’ correspond most closely to those reported far (2 11; X = H, Y = OS02CF3).464 Similar reaction of fenchone (212; X = 0) yielded (213) and (214), and isofenchone (215; X = Me, Y = 0)yielded (215; X = OS02CF3,Y = CH2) and (216), as expected from carbonium ion rearrangement^.^^^ The addition of chlorine in carbon tetrachloride to camphene alcohol (2 17) yielded (218) quant i t a t i ~ e l y .Ring ~ ~ ~expansion of camphene to (219; X = 0,Y = H2)and (219; X = H2, Y = 0)occurs with PdC12-CuC12-02-H20.467
p by
& && Y (21 1)
(212)
(213)
(2 14)
(215)
OHC
\
OTf
Y (216)
(217)
(218)
(219)
Full details of Barton’s selenofenchone (212; X = Se) and fenchylidenefenchane and (212; X = 2-fenchylidene) synthesis (Vol. 6, p. 40) have been Wynberg has discussed the antipodal interaction effect in the reductive dimertzation of (+)- and (*)-camphor to bornylidenebornanes (Vol. 7, p. 41),469sensitized photo-oxidation of which has also been r e p ~ r t e d . ~ ”The CuC12-promoted dimerization of camphor-lithium enolate yields the expected mixture of dia462
463 464
465 466
467 468 469 470
G. A. Rudakov, T. N. Pisareva, and N. F. Ovsyukova, J. Org. Chem. (U.S.S.R.),1977, 13, 298; the formula given for cyclofenchene is actually that of tricyclene. Y. Castanet, F. Petit, and M. Evrard, Bull. Soc. chim. France, 1976, 1583. H. Bentz, L. R. Subramanian, M. Hanack, A. G. Martinez, M. G. Marin, and R. Perez-Ossorio, Tetrahedron Letters, 1977, 9. W. Kraus and G. Zartner, TetrahedronLetters, 1977, 13. J. S. Yadav, H. P. S. Chawla, and S. Dev, TetrahedronLetters, 1977, 201. P. Boontanonda and R. Grigg, J.C.S. Chem. Comm., 1977, 583. T. G. Back, D. H. R. Barton, M. R. Britten-Kelly, and F. S. Guziec, jun., J.C.S. Perkin I, 1976, 2079. H. Wynberg and B. Feringa, Tetrahedron, 1976, 32, 2831. H. Takeshita, T. Hatsui, and 0. Jinnai, Chem. Letters, 1976, 1059; for a related paper see F. McCapra and I. Beheshti, J.C.S. Chem. Comm., 1977,517.
Monoterpenoids
53
stereo isomer^,^^^ which also results from treating 3-bromocamphor with CO~(CO)~NaOH-PhCHZ~Et3C1--C~H6.472 A revised structure for the dicamphene selenide produced by selenium dioxide oxidation of camphene has been Camphor is one of the ketones investigated in a comparative stereochemical reduction study using both simple and complex main-group metal h y d r i d e ~ . ~ ~ ~ Base-promoted tosylate elimination from (-)-bornyl tosylate is reported to yield bornene as the only hydrocarbon using potassium t-butoxide in DMF,379 in DMS0,379and in benzene-(1 8 - ~ r o w n - 6 ) although ,~~~ a second report of reaction in DMSO detects some ~ a m p h e n e . ~ ~ ’ Beckmann rearrangement of 6-endo -chlorocamphor oxime (Vol. 7, p. 43) yields (220) and the cis- and trans-ring-fused (221),476and camphor oxime rearranges with hydrazoic acid in polyphosphoric acid to yield (222).477
Other papers of interest in this section report transamination of camphor-3carbothioamides with secondary cyclic a m i n e ~reaction , ~ ~ ~ of camphorquinone with dimethyl P - k e t o g l ~ t a r a t ethe , ~ ~use ~ of fenchone (212; X=O) in alkene formation from Grignard reagents,480 bromination of 2-endo-6-endo-dibromobornaneto yield 2,3,6-endo-tribromob0rn-2-ene,~~~ and camphor-en01 trimethylsilyl ether formation by quenching the reaction mixture of butyl-lithium and camphor tosylhydrazone with trimethylsilyl ~ h l o r i d e . ~ ”
Bicyclo[3,l,l]heptanes.-Spin-lattice relaxation time measurements have facilitated the 13C n.m.r. spectral assignments of paeoniflorin and albiflorin (Vol. 3, p. 71).483 trans-Pinocarveol (223) has been synthesized from P-pinene in t-butyl alcohol with hydrogen peroxide in the presence of a catalytic amount of selenium 471 472 473
474
475 476
477
478
479
480
481 482 483
Y. Ito, T. Konoike, T. Harada, and T. Saegusa, J. Amer. Chem. SOC., 1977, 99, 1487. H. Alper, K. D. Logbo, and H. des Abbayes, Tetrahedron Letters, 1977,2861. G . Mehta and U. R. Nayak, Indian J. Chem., 1977,15B, 419; for the earlier work see W. Zacharewicz, Roczniki Chem., 1936.16, 290. E. C. Ashby and J. R. Boone, J. Org. Chem., 1976,41,2890. R. A. Bartsch, J. R. Allaway, and J. G. Lee, Tetrahedron Letters, 1977, 779. C. H. Brieskorn and E. Hemmer, Arch. Pharm., 1977,310.65. T. Duong, R. H. Prager, J. M. Tippett, A. D. Ward, and D. I. B. Kerr, Austral. J. Chem., 1976, 29, 2667. A.-M. Lamazoutre and J. Sotiropoulos, Bull. SOC.chim. France, 1976, 1851. S. Yang-Lan, M. Mueller-Johnson, J. Oehldrich, D. Wichman, and J. M. Cook, J. Org. Chem., 1976, 41, 4053. M. T. Reetz and C. Weis, Synthesis, 1977, 135. R. M. Carman and G. J. Walker, Austral. J. Chem., 1977, 30, 1393. R. T. Taylor, C. R. Degenhardt, W. P. Melega, and L. A. Paquette, Tetrahedron Letters, 1977, 159. K. Yamasaki, M. Kaneda, and 0.Tanaka, Tetrahedron Letters, 1976,3965; the structure of albiflorin is incorrect in Chem. Abs., 1977, 86, 121 691.
Terpenoids and Steroids
54
The conversion of (+)-a -pinene into methyl (+)-truns-chrysanthemate was reported earlier."' Mori et al. have now synthesized the cis-verbenols [(32) and its enantiomer] in optically pure state using essentially the same route as used for trans-verbenol (Vol. 7, p. 41); in connection with optical purity and stereochemical comparisons based upon optical rotations, it is of interest to note that optically pure (32) has [a]::= -9.8" in chloroform and [a]: = +11.4" in methanol and +6.2" in acetone, emphasizing the value of using chiral designation^.^^' a-Pinene is metabolized in the rabbit to verbenol (32; unspecified stereochemistry) and traces of myrtenol (224; R=CH,OH); (-)-0-pinene similarly yields trans-pinocarveol (223; enantiomer), trans-myrtanol, a-terpineol, and p-menthl-ene-7,8-di01.~'~ The ene reactions between 0-pinene and ethyl propiolate (AlCl, catalyst),487 but-3-yn-2-one (ZnX,! catalyst^),^'' chloral (various Lewis acid catalysts),489and methyl cyanodithi~formate~~' have been described; using chloral, asymmetric induction is observed at the newly generated chiral centre depending upon the catalyst, varying between R : S/83 : 17 for the non-catalysed reaction and R :S/O : 100 for the TiC1,-catalysed reaction (cf. Vol. 5 , p. 39).-489[2,3] Sigmatropic rearrangement of the methyl cyanodithioformate-0-pinene adduct provides a useful functionalization at C-3.49' Reports of a-pinene rearrangement49' and the conversion of a-pinene into P - ~ i n e n e ~contribute '~ further papers to the literature. Manganese(II1) acetate oxidation of a-pinene yields two lactones analogous to those reported earlier381with (+)-p-menth- l-ene; however, the major product consists of derived acetates [of a-terpineol, cis-pin-3-en-2-01, and myrtenol (224;
(223)
(224)
R = CH,OH)] which suggests both carbonium-ion and free-radical mechanisms;493 oxidation of cis-verbanone (225; R=H) in the presence of isopropenyl acetate 484
485
486 487 488
489 490 491
492
4y3
J. M. Coxon, E. Dansted, and M. P. Hartshorn, O r g . Synth., 1976, 56, 25; an earlier synthesis, J. K. Crandall and L. C. Crawley, Org. Synth., 1973, 53, 17, was omitted from these Reports, cf. ref.'99. K. Mori, N. Mizumachi, and M. Matsui, Agric. and Biol. Chem. (Japan), 1976, 40, 1611; see also ref. 237 for optical rotations and related synthetic work. T. Ishida, Y. Asakawa, M. Okano, and T. Aratani, Tetrahedron Letters, 1977, 2437. B. B. Snider, J. Org. Chem., 1976,41, 3061. B. B. Snider, L. A. Brown, R. S. E. Conn, and T. A. Killinger, Tetrahedron Letters, 1977, 2831. G . B. Gill and B . Wallace, J.C.S. Chem. Comm., ( a ) 1977,380; ( b ) 1977, 382. B. B. Snider, N. J. Hrib, and L. Fuzesi, J. Amer. Chem. Soc., 1976, 98, 71 15. L. P. Petelina, M. I. Goryaev, G . N. Tupoleva, R. Suleeva, and V. A . Yagai, Izvest. Akad. Nauk karakh. S.S.R., Ser. khim., ( a ) 1976, 26(5), 81( Chem. Abs., 1977, 86, 72 900); ( b ) 1976, 26(6), 40 (Chem. Abs., 1977, 86, 121 538); ( c ) V.V. Bazyl'chik, N. P. Polyakova, V. S. Shavyrin, and N. I. Skrebkova, Izvest. Vyssh. Uchebn. Zaued., Khim. khim. Tekhnoi., 1976, 19, 234 (Chem. Abs., 1976, 85, 177 619); ( d ) Sh. B. Battalova, N. D. Pak, and T. R. Mukitanova, Vestnik Akad. Nauk kazakh. S.S.R., 1977, 33 (Chem. Abs., 1977,87, 23 516). G. L. Kaiser, ( a ) U.S. P. 4 000 207 (Chem. Abs., 1977, 86, 121 565); ( 6 ) U.S. P. 4 000 208 (Chem Abs., 1977,86, 121 564); ( c ) P. M. Koppel and W. I. Taylor, US.P. 3 987 121 (Chem. A h . , 1977,86, 55 599). K. Witkiewicz and Z. Chabudzinski, Roczniki Chem., 1977, 51, 475.
Monoterpenoids
55
gives (225; R = CH2COMe).383 Cobalt acetate-catalysed air oxidation of apinene in the presence of benzaldehyde yields less verbenone (45 ; unspecified stereochemistry) and verbenol but more a-pinene epoxide (-40%) than the cobalt abietate-catalysed oxidation (Vol. 3, p. 73).494The reaction of diphenyl diselenide with (+)-2a,3a -epoxypinane failed to give significant amounts of (226), as might have been anticipated although the corresponding cis-(226) should result cleanly from the 2@,3@-epoxypinane(Vol. 3, p. 72).49s Catalytic hydrogenation of apinene in the presence of Pd-exchange resin favours the formation of cis-pinane more so than with Pd-C catalyst; the stereoselectivity change in myrtenal (224; R = CHO) reduction is i n ~ i g n i f i c a n t .Hydroboration-oxidation ~~~ of myrtenyl acetate (224; R=CH,OAc), myrtenic acid (224; R=CO,H), and a series of myrtenic acid esters has been investigated; the formation of pinane-3,lO-diol is preferred for (224; R = C H 2 0 A c or R = CO,H) whereas the esters (224; R = C 0 ,alkyl) yield myrtanol [dihydro-(224; R = CH20H)] predominantly with no pinane3,lO-diol formation.497 Acetylation of @ -pinene with acetyl hexachloroantimonate proceeds in low yield.394 cis-8-Pinene (227) is formed (63% yield) in the K0Bu'-DMF elimination from the tosylate ester of isopinocampheol (l), along with a-pinene (15%) formed by syn -elimination;498 under the same conditions detosylation of 2a-hydroxy-3atosyloxypinane yields pinocamphone (228; S-Me) and isopinocamphone (228;
(225)
(226)
(227)
(228)
R-Me) with none of the well known ring-contracted ketone which is observed in protic solvents (Vol. 2, p. 54; Vol. 4, p. 63; Vol. 5 , p. 41).499Similar reaction of the isomeric 2a-hydroxy-3@-tosyloxypinane yields trans-pinocarveol (223 ; 74%) presumably via 2a,3a-epoxypinane (Vol. 6, p. 44).380 Further details of the photoaddition of N-nitrosopiperidine to a-pinene have been p~blished.~''The claim of a-fenchen-6-one oxime formation (Vol. 7, p. 43) has been retracted; the product is optically active carvone oxime.sol The stereochemistry and conformations of amino-oximes derived from a-pinene nitrosochloride have been examined.399 Wolinsky's re-examination of the reaction of a-pinene with hypochlorous acid has shown that the major product is (229; 90?!0);~~~this paper should be read in 494
495 496 497 498
499
500
A . M. Romanikhin, N. I. Popova, and E. K. Prudnichenko, Izvest. Vyssh. Uchebn. Zaved., Khim. khim. Tekhnol., 1977,20, 177 (Chem. Abs., 1 9 7 7 , 8 7 , 23 520). A. Uzarewicz and E. Zientek, Roczniki Chem., 1 9 7 7 , 5 1 , 181. C. Allandrieu, G. Descotes, J. P. Praly, and J. Sabadie, Bull. SOC.chim. France, 1977, 519. L. Borowiecki and E. Reca, Roczniki Chem., 1976, 50, 1689. Z. Rykowski, H. Orszanska, and Z. Chabudzinski, Bull. Acad. polon. Sci., Sir. Sci. chim., 1976, 24, 681. Z. Rykowski, K. Burak, and Z. Chabudzinski, Bull. Acad. polon. Sci., Sir. Sci. chim., 1976, 24, 771; Vol. 5, p. 41, ref. 303 should be to p. 2305 and not p. 2505. Y. L. Chow, S. K. Pillay, and H. H. Quon, J.C.S. Perkin ZZ, 1977, 1255; for earlier work see Vol. 7, p. 43. S. W. Markowicz, Roczniki Chem., 1 9 7 6 , 5 0 , 1641. J. Wolinsky and M. K. Vogel, J. Org. Chem., 1977, 42, 249.
56
Terpenoids and Steroids
conjunction with those reported earlier on cineol+ pinol rearrangement^.^" The nature of the products derived from (229) by treatment with base varies with reaction conditions. One product is (230) which undergoes a quasi-benzylic acid rearrangement and elimination to yield (23 1);502(230) is also readily converted into (+)-(232)502 from which (179)391" is readily obtained. The (-)-enantiomer of (232), which is available from (229) along with traces of (230) when the base treatment is refluxing aqueous potassium h y d r o ~ i d e , ~is' the ~ precursor of (177).391 COMe 0
OH
(229)
(230)
(231)
(232)
Further papers in this section include the hydrosilylation of a-pinene503 and of p-pinene,'" thiocyanation and selenocyanation of ~x-pinene,~'~ cationic poly'~ of (*)-cis -pinonic acid merization of a- and p -pinene e p ~ x i d e s , ~bromination with dioxan dibr~mide,~"and straightforward myrtenol (224; R=CH20H)50Eand tetrahydroperillyl alcoho1509syntheses from p -pinene epoxide.
Bicycl0[4,1,O]heptanes.--'~C N.m.r. and 'H n.m.r. data suggest that 3a,4a - and 3P,4p-thioepoxycarane exist mainly in the inverted boat onf formation.^'' No allylic oxidation is observed in the metabolism of (+)-car-3-ene in the rabbit, which yields small amounts of (233) and (234), together with trace amounts of m-cymen-8-01.~~~ Microbial reduction of car-3-ene-2,5-dione (235; X=Y = 0) using Rhodotorula mucilaginosa yields (235; X = S-H,OH, Y =O), dihydro-(235; X = O , Y=S-H,OH), and small amounts of (235; X=O, Y=S-H,OH) and dihydro-(235; X = Y = O).511
V. P. Yur'ev, I. M. Salimgareeva, and V. V. Kaverin, Zhur. obshchei Khim., 1977,47,592. V. P. Yur'ev, I. M. Salimgareeva, V. V. Kaverin, and G. A. Tolstikov, Zhur. obshchei Khim., 1977,47, 355. 505 A. Arase and Y. Masuda, Chem. Letters, 1976, 1115. E. R. Ruckel, R. T. Wojcik, and H.G. Arlt, jun., J. Macromol. Sci.-Chem., 1976, A10, 1371. '"'F. Avotins and E. Liepins, Law. P.S.R. Zinatnu Akad. Vestis, Kim. Ser., 1976,220 (Chem. Abs., 1976, 85, 177 621). A. Kergomard and J. Guyot, Fr. P. 2 267 296 (Chem. Abs., 1976,85,78 230). ' 0 9 A. F. Thomas and G. Ohloff, Swiss P. 581 592 (Chem. Abs., 1977,86,72 923). 'lo Y. Y. Samitov, 0. N. Nuretdinova, S. G . Vul'fson, A. P. Timosheva, and B. A. Arbuzov, Bull. Acad. Sci., U.S.S.R.,Div. Chem. Sci., 1976, 25, 2509. A. Siewinski, W. Peczynska-Czoch, A. Zabza, and A. Szewczuk, Tetrahedron, 1977.33, 1139. 504
Monoterpenoids
57
Isomerization of car-3-ene, predominantly to car-2- ene, over magnesium and calcium oxides has been examined mechanistically (cf, Vol. 6, p. 45)512and dehydrogenation of car-3-ene over chromia and chromia-alumina catalysts has been Sensitized photo-oxygenation of car-2-enesL4(named car-4-ene by the authors) has been re-examined more thoroughly and the absence of dioxetan formation reported. Manganese(Ir1) acetate oxidation has been extended to car-3ene; there is no excuse for not numbering formulae in this paper which is further complicated when it is stated that the lactone ring in the product is ‘cis’ to the cyclopropane ring. It would appear that the product is (236).5’5 Rearrangement of 3,4-epoxycarane (unspecified stereochemistry) over solid acids and bases may yield predominantly carbonyl compounds [e.g. (237)] or allylic alcohols [(238) or the exocyclic isomer] in contrast to 2,3-epoxycarane in which ring opening always occurs, with up to 100% stereoselectivity in favour of (lR,4R)-mentha-2,8-dien-l01 (cf. Vol. 6, p. 46).516 Isomerization of 3a,4a-epoxycarane with K0Bu’-pyridine yields (238) exclusively, presumably via the exocyclic isomer.384 3p,40 -Epoxy-
carane reacts rapidly with diphenyl diselenide to yield (3R)-(239) exclusively, but reaction with 3a,4a-epoxycarane was expectedly poorer and yielded (3S)-(239) (the authors number the carane skeleton incorre~tly).~’~ Hydroboration-oxidation of (3R)-(239) yields predominantly (240) along with (3R)-(241; R = Me) whereas (3S)-(239) yields (242) which is the major product using di-isoamylborane but the minor product using diborane [when the elimination-derived (3R)-(241; R = Me) predominate^.^" The same reaction has been reported again for the two 3,4e p o x y c a r a n e ~ ; ~3a,4cu-epoxycarane ’~ yields (3R)-(241; R = CH,OH) and (3s)(241; R = CH20H) along with some (3R)-(241; R = Me) whereas 3&4P-epoxycarane yields (243) predominantly, using diborane-oxidation, and exclusively, The expected lithium aluminium hydride using di-isoamylborane-oxidati~n.~~~ reduction of (244) has been reported.”’ Other papers in this section report catalytic hydrogenolysis of cis- and transcaranes to m- and p-rnenthane~,~~’ the stereochemistry of amines derived from ”* K. Shimazu, H. Hattori, and K. Tanabe, J. Catalysis, 1977,48, 302. V. Krishnasamy and L. M. Yeddanapalli, Canad. J. Chem., 1976,54,3458; ibid., 1977,55,3046. H. Takeshita and I. Kuono, Reports Res. Insr. Ind. Sci., Kyushu Univ., 1977, 65, 13. ’15 -K. Witkiewicz and Z. Chabudzinski, Rocrniki Chem., 1977,51,825; cf refs. 381,493. 516 K. Arata, J. 0. Bledsoe, and K. Tanabe, Tetrahedron Letters, 1976, 3861. 517 I. Uzarewicz, E. Zientek, and A. Uzarewicz, Rocrniki Chem., 1976, 50, 1515. 518 A. Uzarewicz, E. Zientek, and I. Uzarewicz, Rocrniki Chem., 1977, 51,723; this paper provides full details of and extends earlier (uncited) work (Vol. 3, p. 81, ref. 365). *19 B. A. Arbuzov, A . N. Karaseva, Z. G . Isaeva, and I. P. Povodyreva, Doklady Akad. NaukS.S.S.R.,1977, 233,366 (Chem. Abs., 1977,87, 102 438). 520 I. I. Bardyshev, G . V. Deshchits, and B. G . Udarov, Vestsi Akad. Navuk belarusk. S.S.R., Ser. khim. Navuk, 1976,67 (Chem.Abs., 1977,86, 16 793). 513 ’14
Terpenoids and Steroids
58
(242)
(243)
(244)
reduction (Vol. 6, p. 46) of the lactams formed by Beckmann rearrangement (Vol. 4, p. 65)of caranone ~ x i m e sand , ~ the ~ ~cyclic sulphites derived from carane-3a,4a-diol and carane-3P,4a-di01.~~~ 7 Furanoid and Pyranoid Monoterpenoids Pyranoid monoterpenoid alkaloids have been reviewed,141 and halogenated members of this class, (84) and (85), have already been discussed in the halogenated monoterpenoids The monoterpenoid ether (245) is reported from Artemisia trident at^;^^^ from reported mass spectral data it may well be identical with the previously reported (and uncited) arthole (Vol. 7, p. 20), the characterization of which is still not published. Loliolide (246) is claimed to be an in uiuo carotenoid degradation product in Cunscoru decussatu ; additional spectral data have been
(245)
(246)
Treatment of the selenide (19) with unbuffered 30% hydrogen peroxide-THF yields the cis- and truns-linalyl oxides (247) via [2,3] sigmatropic rearrangement.12* Kossanyi et al. have improved upon the efficiency of Vig's synthesis of the four lilac alcohols (248).236 The synthesis of the furanoid (249), formed during sulphuric The known halfacid-catalysed dimerization of isoprene, is ~traightforward.~~' 521 522
523
524 525
C. Wawrzenczyk and A. Zabza, Bull. Acad. polon. Sci., Sir. Sci. chim., 1976, 24, 939, 951. B. A. Arbuzov, I. S. Andreeva, and Z. G. Isaeva, Bull. Acad. Sci. U.S.S.R., 1976, 25, 1584; Chem. Abs., 1977, 85, 143 311 has the structures of these cyclic sulphites hopelessly in error, presumably because conformations and structural formulae have been confused from poor representations in the paper. H. Buttkus and R. J. Bose, J. Amer. Oil Chemists' Soc., 1977, 54, 212; for the essential oil analysis see H. A. Buttkus, R. J. Bose, and D. A. Shearer, J. Agric. Food Chem., 1977.25, 288. S . Ghosal, A. K. Singh, and R. K. Chaudhuri, J. Pharm. Sci., 1976,65, 1549. 0 .P. Vig and M. S. Bhatia, Reichstofe, Aromen, Korperpflegemirtel, 1976, 26, 78.
Monoterpenoids
59
HO (247)
ester acid (250) has been converted into perillene (25 1) under mild conditions (Scheme 6)4 and another useful synthesis of 3-substituted furans based upon the
Reagents: i, MezC=CHCH2CHO; ii, NaAIEtZHz; iii, p-TsOH; iv, A ~ z O ~ - C ~v,HB~u ;' AIH, ~ -40 "C
Scheme 6
alkylation of (252) could be used to synthesize perillene (251);526 Kondo has extended his sensitized photo-oxygenation of dienes (cf. Vol. 7, p. 46) to syntheses of the related perillaketone (253) and a-clausenane (254)"' New syntheses of
rosefuran (255) involve prenylation of 3-methyl-2-furylmagnesium or of 3-bromo-2-furyl-lithium followed by m e t h y l a t i ~ n and , ~ ~ a~ synthesis of elsholtzia ketone (256) has the [2,3] sigmatropic rearrangement of the lithio cyanhydrin ether (257) as the key step.530Further experimental details of Boll and Reffstrup's
An improved nectriapyrone synthesis (Vol. 7, p. 46) have been synthesis of dihydroactinidiolide is reported from 2,2,6-trimethylcyclohexanqne via aeginetolide (Vol. 6, p. 47), and the corresponding cis-tetrahydroactinidiolide (258) has been synthesized stereospecifically from the same starting material by 526
s27
529
s3'
H. Kotake, K. Inomata, S.-I. Aoyama, and H. Kinoshita, Chem. Lerrers, 1977, 73. K. Kondo and M. Matsumoto, Tetrahedron Letters, 1976, 4363; see ref. 533 for an alternative 3,6-dihydro-1,2-dioxin + furan conversion. A. Takeda, K. Shinhama, and S. Tsuboi, Bull. Chem. Soc. Japan, 1977, 50, 1903. N. D. Ly and M. SchlGsser, Helu. Chim.Acta, 1977,60, 2085. B. Cazes and S. Julia, Synrh. Comm., 1977, 7, 113. T. Reffstrup and P. M. Boll, Acta Chem. Scand., 1976, B30,613.
60
Terpenoids and Steroids
formic acid dehydration of the Reformatsky product (259).532An asymmetric synthesis of (258) has already been r e p ~ r t e d . ’ The ~ formation of 3-substituted furans in excellent yield in one step by treating 3,6-dihydro-l,2-dioxins with ferrous ion has obvious biosynthetic and synthetic implications, limited only by the accessibility of the appropriate d i e n e ~ . ~ ~ ~
8 Cannabinoids and other Phenolic Monoterpenoids The structures of six new geranyl-hydroquinone-derived compounds, from Cordia alliodora, provide additional support for proposed biogenesis in Cordia species (see Vol. 4,p. 69).534The isolation of ethuliacoumarin (260) and cycloethuliacoumarin (261) from Ethulia conyzoides suggests an ocimenone (54)biogenetic origin.535
(260)
(261)
Xanthochymol (262) from Garcinia xanthochymus, whose structure has now been determined by X-ray diffraction,536 is another compound of biogenetic interest. Cymopol (Vol. 7,p. 48)and its monomethyl ether have been ~ynthesized.’~’Other
Ho\
\
‘
532
B. Goyau and F. Rouessac, Compt. rend., 1976,283, C, 597.
533
J. A.Turner and W. Herz, J. Org. Chem., 1977,42,1900;for such diene syntheses see ref. 238.
534
535
537
G. D. Manners and L. Jurd, J.C.S. Perkin I, 1977,405. J. H.Tatum and R. E. Berry, Phytochernistry, 1977,16,1091. J. F. Blount and T. H. Williams, Tetrahedron Letters, 1976,2921. P. W. Raynolds, M. J. Manning, and J. S.Swenton, J.C.S. Chem. Comm., 1977,499.
Monoterpenoids
61
synthetic work of little novelty includes syntheses of m a h a r ~ i m b i n e , ~curry~~" anine,538band ~ u r r y a n g i n e(see ~ ~ Vol. ~ ~ 5 , p. 45) and the extension by Dike and Merchant of previous work to include other components of Flerningia wallichin, vir. the trimethyl ether of flemiwallichin B (cf. Vol. 7, p. 48)539and the dimethyl ether of flemichin A.540 An annotated bibliography (3045 references; 1964-1974) of marihuana has been p ~ b l i s h e d ~and ~ ' the pharmacology of m a r i h ~ a n a , ~the ~* and biochemical aspectss436of Cannabis, and the chemistry of ~ a n n a b i n o i d s ~have ~~" been reviewed. The analysis of THC and metabolites in physiological fluids has been A1-3,4-cis-THC has now been found in Cannabis safiva (Phenotype III);9 other papers reporting the characterization of compounds from Cannabis safiva concern conclusive identification and synthesis of ~ a n n a b i n o d i o lwhich , ~ ~ ~ is known to result from the photochemical irradiation of cannabinol (Vol. 7, p. 51), and the identification of A6-tetrahydrocannabinolic acid5j6 and (+)-cannabitriol (263);547 (263) and the corresponding C-2 ethyl ether may be e p ~ x i d e - d e r i v e d . ~ ~ '
Further 13C n.m.r. data on A'-THC, A6-THC, A1-3,4-cis-THC, and related substances have been reported (cf Vol. 3, p. 90).548Harvey has examined the use s38
( a ) N. S . Narasimhan, M. V. Paradkar, and A. M. Gokhale, Indian J. Chem., 1976,14B. 329; ( b )N. S.
539
Narasimhan and S.L. Kelkar, ibid., p. 430. S. Y. Dike, M. S. Kamath, and J. R. Merchant, Indian J. Chem., 1976,14B, 461.
540 541
s42
543
544
545
546 547
548
S. Y. Dike and J. R. Merchant, Chem. and Ind., 1976, 996. C. W. Waller, J. J. Johnson, J. Buelke, and C. E. Turner, 'Marihuana: An Annotated Bibliography', MacMillan Information, New York, 1976. W. D. M. Paton, 'Annual Review of Pharmacology', Vol. 15, ed. H. W. Elliott et al., Annual Reviews Inc., Palo Alto, 1975, p. 191. 'Cannabis and Health', ed. J. D. P. Graham, Academic Press, New York, 1976; ( a ) W. M. L. Crombie, p. 21; ( b ) L. J. King, J. D. Teale, and V. Marks, p. 77; ( c ) L. Crombie and W. M. L. Crombie, p. 43. 173rd A.C.S. Meeting, New Orleans, March 1977, Abstracts ANAL, Nos. 68-73, 89-94, and 110115. Some of this work has been published: ( a ) M. E. Wall, T. M. Harvey, J. T. Bursey, D. R. Brine, and D. Rosenthal, Research Monograph Series-National Institute of Drug Abuse (U.S.), 1976.7, 107; ( b ) D. E. Green, ibid., p. 70; ( c ) E. R. Garrett and C. A. Hunt, ibid., p. 33; J. Pharm. Sci., 1977,66, 20; (d) J. A. Vinson, D. D. Patel, and A. H. Patel, Analyt. Chem., 1977, 49, 163. R. J. J. C. Lousberg, C. A. L. Bercht, R. van Ooyen, and H. J. W. Spronck, Phytochemistry, 1977.16, 595; Chem. Abs., 1977,87, 102 442 has the structure of cannabinodid incorrect. For related work see Vol. 6, p. 48, ref. 356. L. Hanus and'Z. Krejci, Acta Univ. Palacki Olomuc., Fac. Med., 1975,74, 161 (Chem. Abs., 1976,85, 177 622). M. A. Elsohly, F. S. El-Feraly, and C. E. Turner, Lloydia, 1977, 40, 275. An earlier report of (-)-(263) was omitted from last year's Report; see W. R. Chan, K. E. Magnus, and H. A. Watson, Experientia, 1976, 32, 283. R. A. Archer, D. W. Johnson, E. W. Hagaman, L. N. Moreno, and E. Wenkert, J. Org. Chem., 1977, 42,490.
62
Terpenoids and Steroids
of new silyl ethers for g.c.-m.s. of ~ a n n a b i n o i d and s ~ ~of ~ cyclic alkylboronates for g.c.-m.s. of cannabinolic acids,ss0 and mass spectral data for C-6 and C-7 oxygenated A’-THC and A6-THC derivatives have been reported.5s1 The fragmentation of cannabinoid metastable ions has been Further syntheses of [4”,5”-2H2]-and [4”,5”-3H2]-A’-THC and -A6-THC have been described (cf. Vol. 7, p. 50),553and Crombie et al. have extended miniaturized synthesis and chromatographic analysis (cf. Vol. 6, p. 49) to cannabinoid large-scale syntheses of which using acid-catalysed terpenylation of methyl olivetolate have also been ester cleavage, using lithium npropylmercaptide, is accomplished without d e c a r b ~ x y l a t i o n .The ~ ~ ~full paper on the synthesis of A’- and A6-3,4-cis-THC has been published556 together with syntheses of A’- and A6-3,4-cis-cannabidio1557 and their anticipated acid-catalysed cyclization which is dependent upon acid c ~ n c e n t r a t i o n . ~Other ~ ’ papers of synthetic interest concern cannabinoid glucuronides,5sRside-chain thio-analogues of A6-THC from (+)-(lR,4R)-mentha-2,8-dien- 1-01and phloroglucinol thio-ether~,~” 2’-thiocannabinoids via 0-aryl thiocarbamate-S-aryl thiocarbamate rearrangement,560 which has also been used in 2’-thi0-8~*~-THC synthesis,s61and side-chain nitrogen analogues of A6-THC.562 Last year’s Report numbered some hydroxylated cannabinoid metabolites inconsistently. The numbering system used in these Reports (see Vol. 2, p. 61) requires that the pentyl side-chain be numbered C-1” -+ C-5”; references to microbiological hydroxylation last year (Vol. 7, pp. 5 0 , 5 1)designated as occurring at C-l’, C-2’, C-3’, C-4’, and C-5‘ referred to side-chain-hydroxylated metabolites which should have been numbered C- I”, C-2”, C-3”, C-4”, and C-5” respectively. The metabolic functionalization of cannabinoids is of continuing interest (cf. Vol. 4, p. 71; Vol. 7, p. 50). A3-THC may be hydroxylated at C-4 using Mycobacterium rhodochrous (together with aromatization) or at C-4” of the side-chain with Bacillus cereus or may be oxygenated at C-5 with Streptomyces species.563 A6-THC has been hydroxylated in both the ring system and the side-chain with Pellicularia filamentosa and Streptomyces l a ~ e n d u l a e and , ~ ~ further ~ evidence in favour of in uivo epoxy metabolites and derivatives in the mouse has been presented (cf, Vol. 4, 549
550 551
552
553
554
s55 s56
557
s58 559
56”
562
s63
564
D. J. Harvey, Biomed. Mass Specfrometry, 1977,4,265; Org. Mass Spectrometry, 1977, 12,473;see also E.E. Knaus, R. T. Coutts, and C. W. Kazakoff, J. Chromatog. Sci., 1976,14,525. D. J. Harvey, Biomed. Mass Spectrometry, 1977,4,88. S. Inayama, A. Sawa, and E. Hosoya, Chem. and Pharm. Bull. (Japan), 1976,24,2209. P. C. Burgers, G. Dijkstra, W. Heerma, J. K. Terlouw, A. Boon, H. F. Kramer, F. J. E. M. Kuppers, R. J. J. C. Lousberg, and C. A . Salemink, Adv. Mass Spectrometry Biochem. Med., 1976.1,391. H. Hoellinger, N.-H. Nam, J.-F. Decauchereux, and L. Pichat, J. Labelled Compounds, 1977,13,401. L. Crombie and W. M. L. Crombie, Phytochemistry, 1977,16,1413. L.Crombie, W. M. L. Crombie, R. Forbes, and A. Whittaker, J. Chem. Res. ( M ) , 1977,1301. D.B. Uliss, R. K. Razdan, H. C. Dalzell, and G. R. Handrick, Tetrahedron, 1977,33,2055; see Vol. 7, p. 50 for the preliminary report. G. R. Handrick, R. K. Razdan, D. B. Uliss, H C. Dalzell, and E. Boger, J. Org. Chem., 1977,42,2563. M.A. Lyle, S. Pallante, K. Head, and C. Fenseiau, Biomed. Mass Spectrometry, 1977,4,190. U.Kraatz, H. Wolfers, A. Kraatz, and F Korte, Chem. Ber., 1977,110,1776;the authors use the name (+)-frans-p-2,8-menthadien-l-ol for this menthadienol. H.-J. Kurth, U. Kraatz, and F.Korte, Annalen, 1976, 1313. K. Matsumoto, P. Stark, and R. G. Meister, J. Medicin. Chem., 1977,20, 17. F. Lotz, U . Kraatz, and F. Korte, Annalen, 1977,1132. B. J. Abbott, D. S. Fukuda, and R. A. Archer, Experientia, 1977,33, 718;formula I on p. 718 is incorrect. H.-J. Vidic, G.-A. Hoyer, K. Kieslich, and D. Rosenberg, Chem. Ber., 1976,109,3606.
Monoterpenoids
63
p. 71).M5 A'-THC is also converted into di- and tri-hydroxy metabolites in the mouse (cf. Vol. 7, p. 51 for similar cannabidiol metabolites).566 Further papers concerning anticipated cannabinoid functionalization' include in vitro rat liver dihydroxylation of c a n n a b i n 0 1 ~as~ ~well as predominant in oivo monohydroxyla t i ~ nthe , ~formation ~ ~ of hexahydrocannabinol-7-oicacids and some hydroxylated derivatives from A'-THC and A6-THC in mice,569 and the identification of a species-dependent series of homologous side-chain acids from A'-THC in the guinea pig, mouse, and rabbit.570 Intramolecular cyclization of cannabielsoin in benzene-toluene-p -sulphonic acid to the 1,s-cineol (264) is quantitative.571 The previously reported rearrangement
HO (264)
of la,2a-epoxyhexahydrocannabinolacetate using boron trifluoride etherate (Vol. 4, p. 72, ref. 338) has been re-investigated and the fluoro-acetate which accompanies ketone formation has now been shown to be (265) rather than the isomeric acetate.572 Further analysis of cannabidiol pyrolysis (see Vol. 6, p. 50) has identified (266),573and h.p.1.c. analysis is preferred over g.1.c. analysis for examin-
(265)
(266)
ing the decomposition patterns of acidic and neutral cannabinoids in cannabis resin.574
"' D . J. Harvey and W. D . M. Paton, J. Pharm. Pharmacol., 1977,29,498. D . J. Harvey, B. R. Martin, and W. D . M. Paton, J. Pharm. Pharmacol., 1977, 29,482. K. Fonseka and M. Widman, J. Pharm. Pharmacol., 1977,29, 12. ''' W.-A. Yisak, M. Widman, J.-E. Lindgren, and S. Agurell, J. Pharm. Pharmacol., 1977,29,487. s69 D. J. Harvey, B. R. Martin, and W. D . M. Paton, J. Pharm. Pharmacol., 1977,29,495. "O B. R. Martin, D . J. Harvey, and W. D . M. Paton, J. Pharm. Pharmacol., 1976,28,773. D . B. Uliss, G. R. Handrick, H. C. Dalzell, and R. K. Razdan, Experientia, 1977,33, 577. s72 T. Petrzilka, K. K. Prasad, and G. Schrnid, Helu. Chim. Acta, 1976, 59, 1963. 573 H. J. W. Spronck and R. J. J. C. Lousberg, Experientia, 1977,33,705. 574 R. N. Smith and C. G. Vaughan, J. Pharm. Pharmacol., 1977,29,286. s66
s67
2 Sesqu iterpenoids BY T. MONEY
1 Famesane Further investigations on the terpenoid constituents of various species of Euparorium have revealed the presence of two new acyclic sesquiterpenoids, (1) and ( 2)'
OH
OH (1)
R = C(Me)=CHMe
( 21
The same research group has also accomplished the synthesis of 5,7-dehydro-4oxonerolidol(3) by the route outlined in Scheme 1.' A new furanosesquiterpenoid
R = ...
Q
Reagents: i, C r ( 0 H k ; ii, Cr03-py; iii, CH,=CHMgBr; iv, MnO,;
Scheme 1
' F. Bohlmann and M. Grenz, Chem. Ber., 1977,110, 1321.
*
F. Bohlmann and R. Kramer, Chem. Ber., 1976,109,3362.
64
t, Ag,O;
vi, Me'C=CHLi
65
Sesquiterpenoids
( 5 ) has been added to the list of compounds isolated from soft coral3 (cf. Vol. 5, p. 70). 6-Hydroxymyoporone (6)4 and 6-hydroxy-2-dehydromy~porone~ have been
identified as two of several stress metabolites @hytoalexins*) produced by sweet potato which has been infected by fungi. Ipomeamorone (8) and its C-9 epimer have previously been reported as phytoalexins from diseased sweet potato and an alternative synthesis of these compounds has been accomplished by a synthetic route (Scheme 2 ) in which the furan ring system is constructed by photo-oxygenation of a 1,3-diene intermediate (716 (cf.Vol. 7, p. 53).
OH
OH
ivI
fi
v.
n
0
d %
I \
Reagents: i, lo2; is, Me,CO-; iii, HzSO,; iv, NIS-NaHCO,; v, BuLivii, AgN03-NCS-MeCN
Scheme 2
’
:I
(
;vi, BuLi-Me2CHCHzC1;
J. C. Coll, S . J. Mitchell, and G . J . Stokie, TetrahedronLerrers, 1977, 1539. L. T. Burka, L. Kuhnert, and B. J. Wilson, TetrahedronLerrers, 1974, 4017. H. lnoue, N. Kato, and 1. Uritani, PhyrochemisQ, 1977,16, 1063. K. Kondo and M. Matsumoto, TetrahedronLerrers, 1976, 4363.
* Phytoalexins are metabolites produced by damaged plants or plants infected with fungi, bacteria, or viruses.
66
Terpenoids and Steroids
A new synthesis of nerolidol(10) from geranyl bromide has been achieved by the use of the hydroxy-sulphoxide (9),'" a new prenylating agent (Scheme 3).7b
Reagents: i, PhSH-0,; ii, BuLi; iii, geranyl bromide; iv, Li-EtNH,
Scheme 3
2 Mono- and Bi-cyclofarnesane A recent investigation of marine red algae has shown that the major lipid-soluble metabolite of Laurencia obtusa, collected in the English Channel, is 3P-bromo-8epicaparrapi oxide (11)' (cf. isolation of a- and P-snyderol (12) from L. obtusa collected in Spain; Vol. 7, p. 54).
Br
m (1 1)
Br
(12)
The structure of aplysistatin (13), a potential anticancer agent isolated from Australian sea hare (Aplysia angasi) has been determined by X-ray crystallographic analysis.' Examination of the bark extracts of East African Warburgia plants has revealed the presence of warbuganal (14) and the known bicyclofarnesanes polygodial (15) and ugandensidial (16)." These compounds exhibit strong antifeedant activity in African army worms (Spodoptera species).
H
3r
/
O
' P. J. R. Nederlof, M. J. Moolenar, E. R. de Waard, and H. 0. Huisman,
lo
(a) Tetrahedron Letters, 1976, 3175; (b) Tetrahedron 1977,33,579. D. J. Faulkner, Phyrochemisrry, 1976, 15,1993. G. R. Pettit, C. L. Herald, M. S. Allen, R. B. Van Dreele, L. D. Vanell, J. P. Y. Kao, and W. Blake, J. Amer. Chem. Soc., 1977,99,263. I. Kubo, Y.-W. Lee, M. Pettei, F. Pilkiewicz, and K. Nakanishi, J.C.S. Chem. Comm., 1976, 1013.
67
Sesquiterpenoids
The structure of polyalthenol (17), a metabolite of the African plant Pofyafthia ofiueri, has been determined by analysis of its n.m.r. spectra." It has been suggested that the rearranged bicyclofarnesane structure of this compound is produced by 1,2-methyl shift of a drimane-type intermediate. A detailed account of the chemical and spectroscopic evidence for the structures of cochlioquinone-A (18a) and -B (18b) has been published.'* These compounds are metabolites of Cochliobofusmiyabeanus, a parasitic mould which grows on rice, and their unusual cyclofarnesane structure is probably derived in nature by introduction of a farnesyl unit into an aromatic precursor followed by cyclization of an intermediate bis-epoxide.
0
(18) a; R' = OH, R2 = H, R3= OAc b; R' = H, R2R3= 0
3 Bisabolane Full details of the chemical and spectroscopic evidence used to establish the structure of deodarone (19) have been published13 (cf.Vol. 4,p. 88; Vol. 6, p. 58). Further research on terpenoid insect hormones present in various species of fir has resulted in the isolation of juvabione (20), juvabiol (21), and epijuvabiol (22) from 0
'I
l3
M. Leboeuf, M. Hamonnikre, A. Cave, H. E. Gottlieb, N. Kunesch, and E. Wenkert, Tetrahedron Letters, 1976, 3559. L. Canonica, C. G . Casinovi, A. Fiecchi, C. Galeffi, G . B. Marini-Bettolo, A. Scala, and A. M. W. Torracca, Gazrenu, 1976, 106, 147; cf. L. Canonica, B. M. Ranzi, B. Rindone, A. Scala, and G . Scolastico, J.C.S. Chem. Comm., 1973, 213. S. Shankaranarayan,S. Krishnappa, S. C. Bisarya, and S. Dev, Tetrahedron, 1977,33, 1201.
68
Terpenoids and Steroids
Alpine fir (Abies l~siocarpa).'~Since the corresponding compounds present in Balsam fir have the R configuration at C-1' and both R and S configuration at C-3' it has been suggested that different biosynthetic pathways to juvabione-type compounds are operating in different species of fir.14 Chemical and spectroscopic evidence has been used to establish the structures of the new bisabolane-type compounds (23)-(25) isolated from Stevia species and Elephantopus rn011is.'~~ The structure of phyllanthocin (26a), the aglycone of the antileukaemic compound phyllanthoside (26b), has been established by X-ray crystallographic analysis.I6
COCH=CHPh
(25) R = Me,C=CH
(26) a; R = Me b; R = C16H2501o
The conditions used" to convert geranic acid (27) into filifolone (28) (cf. Vol. 1, p. 45; Vol. 2, p. 55) and piperitenone (29) have been applied to cis,trans- and trans,
trans-farnesic acids (30), and the expected formation of compounds (3 l t ( 3 3 ) has been confirled." When a mixture of cis,cis- and trans,cis-farnesic acid (34) was treated in a similar fashion the reaction product was a mixture of (32), (33), and the C-2 epimer of (31)." l4
Is '6
l7
J. F. Manville and C. D. Kriz, Canad. J. Chem., 1 9 7 7 , 5 5 2 5 4 7 . ( a ) F. Bohlmann, C. Zdero, and S. Schonewei, Chem. Ber., 1976,109, 3366; ( b ) F. Bohlmann and C. Zdero, ibid., 1976, 109, 3956. S. M. Kupchan, E. J . LaVoie, A. R. Branfman, B. Y. Fei, W. M. Bright, and R. F. Bryan, J. Amer. Chem. SOC.,1977,99,3199. q.J. J. Beereboom, J. Org. Chem., 1965, 30, 4230. A. Corbella, P. Gariboldi, M. Gil-Quintero, G. Jommi, and J. St. Pyrek, Experientia, 1977,33, 703.
69
Sesquiterpenoids
(32) R' = H, R2 = Me2C=CHCH2 (33) R' = Me2C=CHCH2, R2= H
(31)
AQONaOAcb
(31) (C-2 epimer)+(32)+(33)
Simple synthetic routes to bisabolol-3-one (35) (cu-bisabololone) (cf. Vol. 6, p. 5 8 ) and ar-turmerone (36) have been achieved by condensing the kinetic enolate
t vii, viii
GOH (37)
Reagents: i, LiNPri2-THF-MezC=CHCOMe; ii, TsOH-C6H6, A; iii, Me2CuLi; iv, LiNPr12-THF; v, H,O+; vi, LiAIH4; vii, HI04; viii, 90% HOAc
Scheme 4
70
Terpenoids and Steroids
derived from mesityl oxide with 4-acetyl- 1-methylcyclohexene and p-tolualdehyde respe~tively.'~"The same research group has also published an alternative synthesis of (Y -atlantone (37) (Scheme 4).19' Diastereomeric epoxides (39) and (40) derived from (-)-limonene (38) have been used to synthesize the diastereorneric a -bisabolones (41) and (42)2" (Scheme 5).
i-iv
(40)
(42)
Reagents: i, KCN-EtOH; ii, CH2=C(Me)CHzMgCI; iii, H,O+; iv, KOH-MeOH
Scheme 5
Previous studies2'" on the cyclization of geranyl diphenyl phosphate have been extended to the corresponding derivatives (43) of &,trans- and trans,transfarneso1.2'b The main reaction product was a mixture of isomeric bisabolenes (44), bisabolol ( 4 9 , and a mixture of isomeric farnesenes (46)."* It has been suggested
(43)
l9
2o 21
(46) (a) 0.S. Park, Y. Grillasca, G . A. Garcia, and L. A. Maldonado, Synrh. Comm., 1977,7,345;( b )F. L. Malanco and L. A. Maldonado, ibid., 1976.6, 515. A. Kergomard and H. Veschambre, Tetrahedron Letters, 1976, 4069. ( a ) R. C. Haley, J. A. Miller, and H. C. S. Wood, J. Chem. SOC.(C), 1969, 264; ( b )J. P. Larkin, D. C. Nonhebel, and H. C. S. Wood, J.C.S. Perkin I, 1976, 2524.
Sesquiterpenoids
71
that (48)220and jungianol (50),22bmetabolites of the plants Coreposus paruiuolia and Jungia maluaefolia, are biosynthesized by cyclization of bisabolane intermediates (47) and (49).”
+m“ \
/
(47)
+ql
RO
OH (49)
Norbisabolide (52), a C,, norsesquiterpenoid isolated from the root bark of Atlantia rn~nophylla,’~has been synthesizedz4 from (+ )-limonene monoepoxide (51)25by the reaction sequence shown in Scheme 6. Norbisabolide (52) co-occurs
..
Ill-v
M.
Q
OH
(51) Reagents; i, 0 3 ; ii, NaOAc-HOAc-NaI-Zn; vi, Cr03-MezCO-H30+
iii,
‘i, (52)
CH2CH2MgBr; iv, AczO; v, NaOH-MeOH;
Scheme 6
with (+)-a-bisabolene (53) and bisabolene oxide (54) and is probably biosynthesized by oxidative cleavage of (54) or a related compound.z4
4 Sesquipinane, Sesquicamphane, Sesquifenchane The recent isolation of P-trans-bergamotene ( 5 5 ) from the mycelium of A. fumigatusZ6and P. oualisZ7has provided indirect support for the proposed intermediacy F. Bohlmann and C. Zdero, ( a ) Chem. Ber., 1977, 110,468; ( b ) Phytochemistry, 1977,16, 239. J. D. Shringapure and B. K. Sabata, Indian J. Chem., 1976, 13, 24. 24 G. Feldstein and P. J. Kocienski, Synrh. Comm., 1977, 7 , 27. 25 q. W. Knoll and C. Tamm, Helu. Chim. Acta. 1975.58, 1162. 26 S. Nozoe, H. Kobayashi, and N. Morisaki, Teiruhedron Letters, 1976, 4625. ” D. E. Cane and G. G. S. King, Tetrahedron Letters, 1976, 4737. 22
23
Terpenoids and Steroids
72
of this compound in the biosynthesis of furnagillin (56) and ovalicin (57)(cfi Vol. 6, p. 181; Vol. 7 , pp. 62, 196).
OCOR
(56) R = (CH=CH)dCO2H
Further studies on the biosynthesis of ovalicin (57)have demonstrated the use of deuterium magnetic resonance in biosynthetic studies.” Compounds (59)--(62), structurally related to (-)-a-santalene (58), have been isolated from the essential oil of Lavandula oficinalis and L. hybrids." An alternative synthesis of a-santalol OH
’* 29
D. E. Cane and S. L. Buchwald, J. Amer. Chem. Soc., 1977, 99, 6132. R. Kaiser and D. Lamparsky, Tetrahedron Letters, 1977, 665.
73
Sesquiterpenoids
(66) has been accomplished3’ by adaptation of the previously published route to cw-~antalene.~~
(63)
(64) R=CH2Ph i, HMPA
5 Cuparane, Trichothecane, Laurane Proton and carbon- 13 n.m.r. spectral data have been used to establish the structure of satratoxin H (67), a metabolite of Stachybotrys Satratoxin H (67) and the other macrocyclic dilactone derivatives of trichotheca-9,12-diene-4,15-diol(68) produced by S. atra are responsible for the disease (Stachybotryotoxicosis) which affects livestock and humans after ingestion of food contaminated with this fungus. The structure of baccharin (69), a potent antileukaernic compound isolated from a Brazilian shrub (Baccharis megapotarnica), has been established by X-ray crystallographic analy~is.’~ Verrucarin K (70), another trichothecane derivative produced by a strain of Myrothecium uerrucaria, is of biosynthetic interest since it is the first member of the series which does not possess a 12,13-epoxide
0
OH OH (67) 30
31 32
” 34
K. Sato, S. Inoue, Y. Takagi, and S. Morii, Bull. Chem. SOC.Japan, 1976.49, 3351. E. J. Corey and M. F. Sernrnelhack, J. Amer. Chem. Soc., 1967,89, 2755. R. M. Eppley, E. P. Mazzola, R. J. Highet, and W. J. Bailey, J. Org. Chem., 1977, 42, 240. S. M. Kupchan, B. B. Jarvis, R. G. Dailey, W. Bright, R. F. Bryan, and Y. Shizuri, J . Amer. Chem. Soc., 1976,98,7092. W. Breitenstein and C. Tamm, Helu. Chim. Acta, 1977,60, 1522.
74
Terpenoids and Steroids
(69)
(70)
Trichodiene (72), the bicyclic hydrocarbon intermediate in trichothecane biosynthesis (cf. Vol. 7, p. 192; Vol. 6, p. 64; Vol. 4, p. 90) has been s ~ n t h e s i z e d ~ ~ (in tacemic form) from the known lactone (71) by the two stereoselective routes outlined in Scheme 7.
mo&m0 Po H
H
4
(711
H
'
,
/*
X I I I , XIV. VII
"./"'O ' THP
b-.,
(72) Reagents: i, LiNPr',-DME; ii, MeI; iii, Br(CH2),0THP-HMPA; iv p-TsOH-MeOH; v, Ca-NH3-THFHMPA; vi, Cr03-H30+-Me2CO; vii, CH2N2; viii, NaN(SiMe3h-DME; ix, HCI, 0 "C; x, DBU-xylene, A; xi, silica gel-15%AgN03; xii, CH2=PPh3-DMSO; xiii, MeOH-H+; xiv, HCI gas-CHZCI2; xv, collidine, A; xvi, LiAIH4; xvii, 10% NaOH; xviii, Li-NH3-EtOH
Scheme 7 35
( a ) S. C. Welch, A. S. C. P. Rao, and C. G. Gibbs, Synrh. Comm., 1976,6,485; ( b )S. C. Welch, A. S. C. P. Rao, and R. Y . Wong, ibid., p. 443.
75
Sesquiterpenoids
Re-examination of the chemistry and spectroscopic properties of bazzanene [formerly (73): cf. Vol. 1p. 76; Vol. 3, p. 841 has resulted in a revised structure (74) for this compound.36 (+)-Bazzanene (74) is therefore a diastereomer of (+)-
(73)
(74)
trichodiene (72) and it is interesting to note that a simple double-bond shift formally interconverts these compounds. The co-occurrence of bazzanene (74) with a- and P-pompene (75) (syn. (Y- and P-barbatene, syn. isogymno- and gymnomitrene; cf. Vol. 6, p. 63; Vol. 5, p. 53) in the liverwort Bazzania pompeana may indicate that the latter compounds are formed in nature by cyclization of bazzanene or a closely related compound. In this connection it is interesting to note that acid-catalysed cyclization of (+ jbazzanene (74) produces (f)-cyclobazzanene (76), a compound whose structure has been established by X-ray analysis.”
(75)
(76)
The ability of marine organisms to synthesize halogenated sesquiterpenoids (cf. ref. 105 and pp. 66, 79, 101) is further illustrated by the isolation of the lauranetype compounds (77)-(79)38 from red seaweed (Laurencia g l a n d ~ l i f e r a ) .The ~~ absolute configuration of aplysinol (80), a metabolite of various species of Lauren-
(77) R = H (78) R = B r
cia (red algae), has been established by X-ray analysis39and a new stereoselective synthesis of (*)-debromoaplysin (81) and (*)-aplysin (82) has been achieved by the route outlined in Scheme 8.4” 36
A. Matsuo and S. Hayashi, J.C.S. Chem. Comm., 1977,566.
37
A. Matsuo, H. Nozaki, T. Maeda, M. Nakayama, Y. Kushni, and S. Hayashi, J.C.S. Chem. Comm.,
38
M. Suzuki and E. Kurosawa, Tetrahedron Letters, 1976,4817. J. A. McMillan and I. C. Paul, Tetrahedron Letters., 1976, 4219; the compound numbers in this paper are erroneous. R. C. Ronald, Tetrahedron Letters., 1976, 4413.
1977,568. 39
40
Terpenoids and Steroids
76
(82)
(81)
Reagents: i, KOH-MeOH; ii, PBr3; iii, MeMgBr; iv, PPh3-(PPh3),RhCI; v, H,-PtO,-EtOH; Na2C03-Br2-C6H 14
vi,
Scheme 8
6 Acorane, Cedrane, Carotane An elegant, general synthetic route to spirocarbocyclic systems (cf. Vol. 5, p. 55) involving regiospecific ring cleavage of appropriate tricyclic ketones [cf.(83)+ (84)]
(83)
(84)
has been used in a recent alternative synthesis (Scheme 9) of (-)-acorenone B (85)4' (cf. Vol. 6, p. 62; Vol. 7, pp. 63, 64 for previous syntheses). Acorenone B (85) has recently been converted into its allylic isomer, acorenone (87), by rearrangement of the corresponding epoxy-ketone (86)42 (Scheme 10). An alternative synthesis of (*)-acorone (88) and (*)-isoacorone (89) (cf.Vol. 6, p. 61) has been achieved by a route (Scheme 11) in which the spiro[4,5]decane system is constructed by intramolecular aldol condensation of a 1,4-diketone inter~nediate.~, Further studies on the remote biological hydroxylation of sesquiterpenoids by mammalian systems (cf. Vol. 6, p. 62) have shown that dogs can hydroxylate 41
42 43
( a ) J. F. Ruppert, M. A. Avery, and J. D. White, J.C.S. Chem. Comm., 1976,978; ( b ) cf. J. F. Ruppert and J. D. White, ibid., p. 976. W. Rascher and H. Wolf, Tetrahedron, 1 9 7 7 , 3 3 , 5 7 5 . D. A. McCrae and L. Dolby, J. Org. Chem., 1977,42, 1607.
77
Sesquiterpenoids
(+)-cedrol (90) at the C-3, C-4,C-12, and C-15 positions.44 In a related investigation by the same research group it was shown that dry zonation*^ of cedryl acetate (9 1 ) results in stereoselective and regiospecific hydroxylation at C-2.46 The retention of configuration at C-2 in the product (92) is consistent with previous CCOR
R = OH, C1, or CHN2
I
iv
(R = CHN2)
(85) Reagents: i, CH,=C(CH,Br)CO,Et-Zn;
ii, H2-Pt02; iii, H2-Pd/CaC0,; iv, Cu; v, HCI; vi, H,-Rh/C
Scheme 9
Reagents: i, DIBAH; ii, m-C1C6H4C03H; iii, Cr03-Me2CO-H30+; iv, NH2NH2-MeOH-HOAc
Scheme 10 44 45
46
E. Trifilieff, Luu Bang, and G. Ourisson, Tetrahedron Lerrers, 1975, 4307. 0 . 2 . Cohen, E. Keinan, Y. Mazur, and T. H. Varkony, J. O g . Chem., 1975, 40,2141 and references cited; T. M. Hellman and G. A. Hamilton, J. Amer. Chem. SOC.,1974,96, 1530. E. Trifilieff, Luu Bang, and G. Ourisson, Tetrahedron Letters, 1977, 2991.
78
Terpenoids and Steroids
-
w Pxi-xiii
0
A
A
(88)
(89)
Reagents: i, Bu'NH~; ii, BuLi; iii, BrCH2CECSiMe3; iv, HCI-H2O; v, HgSO.,-H,S04-H20-THF; vi, NaOEt-EtOH; vii, NaOMe-HCOzEt; viii, AczO; ix, MezCuLi; x, H30+; xi, BH3,DMS; xii, H202-OH-; xiii, CrO3-Me2CO-H3O*
Scheme 11
HoflAc H (90) R = H (91) R = A c
conclusions concerning the stereochemistry of the dry ozonation procedure.45 The cyclic ether (94)47derived by oxidation cyclization of neoisocedranol (93).,*has been used in a recent synthesis (Scheme 12) of a-biotol (95)* (4-P-hydroxy-acedrene), a co-metabolite of a-cedrol in the essential oil of Biota o r i e n t ~ l i s . ~ ~ A new carotane sesquiterpenoid, linkiol, has been isolated from the plant Ferula linkii and assigned structure (96) on the basis of its chemical and spectroscopic pr~perties.~' 47
48 49
P. Brun and B. Waegell, Tetrahedron, 1976, 32, 1137. CJ P. Teisseire, M. Plattier, W. Wojnarowski, and G. Ourisson, Bull. SOC.chim. France, 1966, 2749. P. Brun, Tetrahedron Letters, 1977. 2269. A. G. Gonzalez, B. M. Fraga, M. G. Hernandez, J. G. Luis, R. Estevez, J. L. Biez, and M. Rivero, Phytochemistry, 1977,16,265.
* a-Biotol (95) has also been produced by selective dehydration by mammalian hydroxylation of a-cedrol (90); cf. ref. 44.
of the 4-hydroxy-derivative produced
79
Sesquiterpenoids
(93)
(94) OAc
(95) (+4-epimer) Reagents:
I,
P b ( 0 A c k ; ii, CSHsNHCI-Ac20; iii, p-N02C6H4C0,H; iv, BF,, Et20-C6H,; v, LiAlH,
Scheme 12
OCOC(Me)=CHMe
7 Chamigrane, Widdrane, Thujopsane A recent X-ray crystallographic study has resulted in a revised structure (98) for nidifocene, a minor metabolite of the Hawaiian marine alga Laurencia n i d i f i ~ a . In ~’ the previous structure (Vol. 7, p. 69) the positions of chlorine and bromine were reversed. An extension of previous work on the non-enzymic biogenetic cyclization of geranyl and farnesyl diphenylphosphatess2 has shown that (Z)-monocyclofarnesyl diethylphosphate (99) can be converted into (*)-a-chamigrene (100) in
(99)
’*S. M. Waraszkiewicz and K. L. Erickson, Tetrahedron Lefrers, 1977, 231 1.
(1 00)
’’ q.ref. 21; cf. T. Money, ‘Progress in Organic Chemistry’, Vol. 8, 1973, p. 29 and references cited; cf. Vol. 7, pp. 54, 69.
80
Terpenoids and Steroids
high yield (72%) by treatment with tetraisobutylaluminoxan (TIBA0).53 (*)-aChamigrene has also been synthesized by thermal cyclization of the isomeric tetraenes (102) derived from cis- and trans-p-ionol (101)54 (cf. synthesis of
bromochamigrene, Vol. 7, p. 69). Treatment of American cedarwood oil with acetic anhydride-polyphosphoric acid produces a tricyclic ketone (106) which has commercial value in the perfume industry. It has been suggested (cf. Vol. 3, pp. 116, 117) that this compound (106) is derived from (-)-thujopsene (103) (a principal component of cedarwood oil) by a reaction sequence which involves the intermediacy of p-chamigrene (104) and the tricyclic alkene (105). This proposal is supported by the fact that the sequence (103)+(105)+(106) can be accom-
plished in the laboratory. Recent independent studies in this area have culminated in the development of synthetic routes to the tricyclic alkene (105) (Scheme 13)and ketone (106) (Scheme 14).56
8 Cadinane, Amorphane, Copacamphane, etc. Chromolaenin (108) and 1-acetoxydihydroisochromolaenin(109) are new sesquiterpenoids which co-occur with eupatene (110) in several Chromolaena specie^.^' Experimental details have been provided5' for the stereospecific total synthesis of (+)-E-cadinene (1 12) and (-)-7,-cadinene (113) from the known enol ether (111) 53
54 55 56 57
Y.Kitagawa, S. Hashimoto, S. Iemura, H. Yamamoto, and H. Nozaki, J. Amer. Chem. SOC.1976, 98, 5030. F. Frater, Helv. Chim. Acta, 1977,60, 515. E.L. McDonald and J. S. Roberts, Tetrahedron Letters, 1976,4521. R. F. Tavares and E. Katten, Tetrahedron Letters, 1977, 1713. F. Bohlmann and C. Zdero, Chem. Ber., 1977,110,487. L. A. Burk and M. D. Soffer, Tetrahedron, 1976.32, 2083.
81
Sesquiterpenoids
Reagents: i, LCNH3-ROH; ii, Bu'O--DMSO; iii, maleic anhydride; iv, CF3C02H; v, Pb(OAc),+; vi, H2-Pd/C
Scheme 13
(106) Reagents: i, Li-NH3; ii, EtOH-THF; iii, KOBU'; iv, CH,=CHLi; v, A; vi, H,-Pd/C; vii, HCrCLi; viii, H20-HCOzH
Scheme 14
Terpenoids and Steroids
82
(Scheme 15) (cf. Vol. 1, p. 63). A further illustration of the use of known photochemical reactions in natural product synthesis is provided by the recent synthesis59
\i,
Reagents: CH,=PPh,-DMSO;
iv
ii, HCI-EtOH; iii, MeLi; iv, S0CI2-py
Scheme 15
of (*)-3-oxo-a-cadinol (116) and (*)-a-cadinol (117) from the dienone (114)* (Scheme 16). A complete account of the previously reported synthesis of (*)amorphene (120) has been published6' (cf.Vol. 5 , p. 60). An interesting feature of the synthetic route is the stereospecific construction of the amorphane skeletone by * [3,3] sigmatropic rearrangement (oxy-Cope) of the bicyclic alcohol (118). The structure of simularene (123), a new structurally interesting sesquiterpenoid isolated from soft coral (Sirnularia mayi), has been established by X-ray analysis.61 It has been suggested6' that the cyclosesquifenchene skeleton of simdarene (123) is derived by rearrangement of the intermediate (122) proposed in the biosynthesis of a-and P-copaene (124). An alternative synthesis of (*)-sativene (128) and (*)-copacamphene (129) (cf. Vol. 1, p. 66; Vol. 2, p. 77, Vol. 3, p. 108; Vol. 4, p. 106; Vol. 5 , pp. 60,63; Vol. 7,
'' D. Caine and A. S. Frobese, Tetrahedron Letters, 1977, 3107 6o "
R. P. Gregson and R. N. Mirrington, Austral. J. Chern., 1976, 29, 2037, C. M. Beechan, C. Djerassi, J. S. Finer, and J. Clardy, TehuhedronLetters, 1977, 2395.
* A synthesis of (*)-oplopanone from dienone (1 15) (Scheme 16) has previously been reported; see Vol. 3, p. 60; Vol. 5 , p. 114.
Sesquiterpenoids
83
(114) R = H (115) R = O M e
IX,
x
OCH
\
(117)
(1 16)
Reagents: i, hv-HOAc; ii, LiAIH4; iii, Cr03-Me2CO-H30+; iv, Li-NH3; v, LiNPr' PhzS2; vi, EtLi; vii, Pb(0Ac)z-HOAc; viii, KOH-MeOH; ix, NHzNH2-py-EtOH; x, KOBJItoluene
Scheme 16
-
I.B~'K-(E~O)~P~CI II.
OH
Farnesyl pyrophosphate - - - -+
L~-NH~-BU'OH
H
H
$p-JJ&J H
,:at& (121)
(122)
/
p. 7 3 ) has recently been achieved by a route (Scheme 17) in which the tricyclic framework of these compounds is produced by free-radical cyciization of a bromoalkene intermediate (127).'j2 A complete account of the previously reported synthesis of (+)-cis-sativenediol (135) (Vol. 6, p. 67) and (+)-trans-sativenediol 62
P. Bakuzis, 0. 0. S. Campos, and M. L. F. Bakuzis, J. Org. Chem., 1976, 41, 3261.
84
Terpenoids and Steroids
% -& & 0
0
0
(128)
( 1 29)
Reagents: i, LiNPrI2-DME; ii, MeI; iii, BuMgBr-HMPA; iv, CH2=CHCH2Br; v, PhSH-AIBN; vi, NCS; vii, CuO-CuCIz; viii, Me2C=PPh3-DMS0, -65 O C ; * ix, Bu3SnH; x, MeLi; xi, SOC12-py, 0 ° C
Scheme 17
(136) has been published63 (cf. Vol. 7, p. 73). The synthetic route (outlined in Scheme 18) involves an intermediate bicyclic enol (130) which was used by the same group in a previous synthesis of (+)-sativene and (+)-cyclosativene (cf. Vol. 5, p.bO; Vol. 7, p. 73). It has been ~ u g g e s t e dthat ~ ~ the oxidative cyclization of enol (130) to enone (133) (Scheme 18) involves internal Prins reaction of the corresponding aldehyde (131 j followed by oxidation of the derived alcohol (133). Since (- j-cis-sativenediol (137) has been chemically correlated with co-metabolites, prehelminthosporal (138), prehelminthosporol (139), isosativenediol (140), and victoxinine (141j, the synthetic route outlined in Scheme 18 also constitutes a formal total synthesis of the enantioners of these biologically interesting sesquiterpenoids. An alternative synthesis (Scheme 19) of (*)-sativenediol, (136)+ (137), and its congeners (138)-(141) has been accomplished by simple modification of a previous route to (*)-sativene (128).64 The modified route to the norsativane 64
E. Piers and H.-P. Isenring, Cunud. J. Chem., 1977, 55, 1039. J. E. McMurry and M. G. Silvestri, J. Org. Chem., 1976, 41, 3953.
* At 60 "C this reaction leads to the bromo-ketone (126)!
Sesquiterpenoids
HO
F AF O H
L
Y
Y
Y
OH (136)
(135)
(134)
Reagents: i, Cr03-py-CF3C02H; ii, LiNPr12; iii, Moo5-HMPA-py; iv, LiAIHl
Scheme 18
85
86
Terpenoids and Steroids
framework, cf (145), involves intramolecular alkylation of the enone tosylate (143) and it is interesting that the undesired product (144) of this reaction underwent subsequent vinylcyclopropane-cyclopentane rearrangement to provide the required tricyclic enone (145).
&
+-++@ A
0
:
H
OTs
(142)
(136)+(137)
(143)
@
/
\
(144)
&-4
Xo
2
0
H (146)
(145)
Reagents: i, MeSOCH2--DMSO; ii, 450 "C; iii, MeLi; iv, SOC12-py; v, HCI, 20°C. 3 days
Scheme 19
Aduncin, a picrotoxane sesquiterpenoid isolated from Dendrobium aduncum, has been assigned structure (147) on the basis of its spectroscopic properties and their similarity to those of a- and p-dihydropicrotoxinin (148).65 A full paper dealing with the previously reported synthesis of 4-epidendrobine (149)* has been published66(cf. Vol. 7, p. 74).
9 Himachalane, Longipinane, Longicamphane, etc. The stereochemistry of p-himachalene epoxide (15 l), onq of two diastereomeric epoxides [(151), (152)] previously isolated from Cedrus atlantica (Vol. 7, p. 60), '* 66
L. Gawell and K. Leander, Phyrochemistry, 1976,15, 1991. R. F. Borch, A. J. Evans, and J. J. Wade, J. Amer. Chem. SOC.,1977, 99, 1612.
* In ref. 66 and previous reports (Vol. 7, p. 74) this compound is described as 8-epidendrobine. In this report we have adopted the generally accepted numbering system for the picrotoxane framework. It should also be noted that 4-epidendrobine does not occur in nature.
Sesquiterpenoids
87
has been deter’mined by its conversion into himachalol (lSS).67 Isohimachalone (154)68and oxidohimachalene (153)6y have been isolated from the essential oil of Cedrus deodora and assigned structures (154) and (153) on the basis of their chemical relationship with p -himachalene (1 SO).
( I SO)
(151)
(153)
(154)
\
(152)
(155)
Chemical and spectroscopic evidence has been provided for the structure of the longipinane sesquiterpenoid vulgarone B (1S6), a co-metabolite of vulgarone A (157)” in the essential oil of Chrysanthemum ~lulgure.’~Vulgarone B (156) can be
(157)
(156)
photochemically isomerized to the vulgarone A (157) [cf. known conversion of verbenone (158) into chrysanthenone (159)] and it is possible that a similar rearrangement could occur in nature.
(159)
(158)
It has been suggested that the biosynthesis of (+)-secolongifolenediol (163) involves ring cleavage of an epoxy-alcohol (161) related to (- )-longifolene (160).” This proposal is supported by the co-occurrence of (160) and (163) in Helmin”
A. P. S. Narula and S. Dev, Tefruhedron, 1977, 33, 813.
‘* R. Shankaranarayan, S. Krishnappa, and S. Dev, Tetrahedron, 1977, 33, 885. 69 70
”
R. Shankaranarayan, S. C. Bisarya, and S. Dev, Tenuhedron, 1977,33, 1207. Y . Uchio, A. Matsuo, S. Eguchi, M. Nakayama, and S. Hayashi, Tetrahedron Letters, 1977, 1191. F. Dorn and D . Arigoni Experientiu, 1974,30, 851.
* This compound was previously named vulgarone; cf.
Vol. 7, p. 75.
88
Terpenoids and Steroids
thosporium sativum and H. victoriae” and laboratory analogy for the ring-cleavage process has been provided in a recent report”” describing the acid-catalysed rearrangement of the epoxy-alcohol (164) to the aldehyde (165). A related reac-
(166)
(167)
tion involving ring cleavage of homoallylic alcohols [e.g. (166) -+ (167)72”]has been used in a recent synthesis of (-)-secolongifolenediol (175) from (+)-longicyclene (168)726(Scheme 20).
(175)
(172)
(174)
(173)
Reagents: i, NBS; ii, Li2C03-dioxan-H20; iii, HC1044ioxan-H20; iv, C12-LizC0,; v, NaBH4
Scheme 20
’’ ( a )J. S. Yadav, H. P. S. Chawla, and S. Dev, Tetrahedron Letters, 1977, 201; ( b ) ibid., p. 1749.
Sesquiterpenoids
89
10-Ketolongibornane (176) has been produced by treatment of (+)-longicyclene (168) with lead t e t r a - a ~ e t a t e .The ~ ~ claim that this compound is ‘the truealongicamphor’ seems unjustified since (-)-longicamphor (177) and its enantiomer, as described in the literature, are derived by oxidation of the natural products (-)longiborneol (178) and its enantiomer. In addition longicamphor (177) belongs to a group of ‘sesquicamphors’ [campherenone (179), copacamphor (180), ylangocamphor (181), and longicamphor (177)) whose common structural feature is the attachment of an isoprenoid C, unit at the C-8 and, in some cases, the C-3 position of the basic camphor framework [cf. (182)].
(179)
(180)
‘
(181)
‘
Oxidative cyclization of longifolol (183)74 has been used to provide intermediates, (184)and (189, in a recent synthesis (Scheme 2 1) of loqgifol-7( 15)-en56-01 (186) and its co-metabolite longifolan-3a,7a-oxide ( 1 8 7 p (cf. Vol. 3, p. 131). A full paper on the biosynthesis of culmorin (188)76has appeared (cf. Vol. 7, pp. 76, 192).
10 Homulane, Caryophyllane A new elegant stereoselective synthesis of humulene (192) has been achieved by a route (Scheme 22) in which the 11-membered-ring framework [cf. (191)] is produced by cyclization of the 11-allylpalladium complex derived from intermediate (190).77 Buddledin-A (193), -B (194), and -C (195) are new piscicidal sesquiterpenoids which have recently been isolated from the root bark of Buddleju d a ~ i d i i . ~ ~ The caryophyllane framework of these compounds has been established by spectroscopic data and X-ray analysis of the mono-bromohydrin (196) derived from buddledin A (193).78 An extension of previous on the cyclization of the epoxy-ketone (197) derived from caryophyllene has shown that the base-cataiysed cyclization of the isomeric epoxy-ketones (198) and (199) provides compounds S. N. Suryawanshi and U. R. Nayak, Tetrahedron Letters, 1977, 2619. Cf.J. Lhomme and G. Ourisson, Tetrahedron, 1968, 24, 3177. P. K. Jadhav and U. R. Nayak, Tetrahedron Lerrers, 1976,4858. 76 J. R. Hanson and R. Nyfeler, J.C.S. Perkin I, 1976, 2471. ” Y. Kitagawa, A. Itoh, S. Hashimoto, H. Yamamoto, and H. Nozaki, J. Amer. Chem. SOC.,1977.99, 3864. 78 Y. Yoshida, J. Nobuhara, M. Uchida, and T. Okuda, Tetrahedron Lerters, 1976, 3717. 79 D. H. R. Barton and A. S. Lindsey, J. Chem. Soc., 1951,2988. ” 74
’’
Terpenoids and Steroids
90
@
+
6::""
OH
v, v i j
vii, v i j
(186)
(187)
Reagents: i, Pb(0Ach-12; ii, CrO3-HOAc; iii, LiAIH4; iv, NBS-Bu'OH-py; v, KHS04, A; vi, Na-PrOH; vii, Ac2O-py, A; viii, H+
Scheme 21
OH (188)
(201)-(203) as major products.80 The formation of these compounds can be explained by considering the steric accessibility of the epoxide group to the derived enolate ions. The first total synthesis of (*)-marasmic acid (212) (cf. synthesis of isomarasmic acid, Voi. 1. p. 81) has been accomplished by the reaction sequence shown in E. W. Warnhoff and V. Srinivasan, Cunud. J. Chem., 1977,55, 1629.
91
Sesquiterpenoids
OTs
(1921
Reagents: i, CH2COE(Me)CO2Me; ii, AczO-py, A; iii, NaH-THF; iv, (Ph3P)4Pd-Ph2PCH2CHzPPh2HMPA-THF; v, LiAIH4; vi, TsCI; vii, KOBu'-THF, 0°C; viii, Et2AINMePh; ix, NCS-Me2S; x, Et,N; xi, NHzNHTs
Scheme 22
(193) R = O A c (194) R = O H (195) R = H
0&
____* KOH-MeOH
0
)I
OH
0
KOH-B"'OH
H' 0
@
H20
+
92
Terpenoids and Steroids
H 0 ( 1 99)
Hfy H
HO" (203)
Scheme 23." A schematic representation of the postulated involvement of a protoilludane intermediate (2 13) in the biosynthesis of various sesquiterpenoid
e
a. (205)
(204)
CO,R
H
o
z
X
CO,R
VI
t
\
\
\
H
H (20to
(210)
&*
CO,R
H (207) R = But, X = CHzBr
(211)
(2 12)
Reagents: i, CHz=CHOEt-ZnCIz; ii, HOAc-NaOAc; iii, DIBAH; iv, (2-bromoethyl)maleicanhydride; v, Me2=CHz-H+; vi, KOBU'-HOBU'-C~H~; vii, DIBAH-toluene, -78 "C; viii, NaBH,; ix, COC12-quinoline; x, DMSO-NEt,; xi, CF3COZH
Scheme 23
''
W. J. Greenlee and R. B. Woodward, J. Amer. Chem. SOC.,1976,98, 6075.
93
Sesquiterpenoids
structures is outlined in Scheme 24 and the results of various biosynthetic investigations using 14C- or I3C-labelled acetate and mevalonate are consistent with this general scheme (cf. Vol. 4., p. 112; Vol. 5, pp. 69, 180; Vol. 7, pp. 82, 197).
Illudane
seco-Illudane
t
Illudalane (seco-protoilludane)
(21 3) Protoiliudane
Fornannosane (seco-protoilludane)
1
Marasrnane
1
Hirsutane
Vellerane
Lactarane (seco-vellerane)
Scheme 24
Further indirect support for this proposal has been provided by the recent demonstration that A6-protoilludene (214) and compounds (2 15)-(220), belonging to some of the structural classes shown in Scheme 24, co-occur in the fungus Fomitopsis insuluria.82 Blennin A (221) and blennin B (222) have been identified as new metabolites of the inedible mushroom Lactarius blennius and a revised structure has been propojed for the co-metabolite, blennin C (223).83 An attempt to synthesize velleral (224) has provided a compound (225) which would seem to be 82
83
S. Nozoe, H. Kobayashi, S. Urano, and J. Furukawa, Tetruhedron Lerrers, 1977, 1381 and references cited. G. Vidari, M. De Bernardi, P. Vita-Finzi, and G. Fronza, Phyfochemistry, 1976, 15, 1953.
94
Terpenoids and Steroids
P”
R
(224) R = C H O (225) R = C0,Me
(223)
one or two steps removed from the natural Unfortunately attempts to complete the final stages of the velleral synthesis are not described in this paper.84
11 Germacrane The diverse biological activity (allergenic, antitumour, fungitoxic, phytotoxic, cytotoxic, etc.) of germacranolides (226a and b) and other sesquiterpenoids containing aP-unsaturated y-butyrolactone units has been reviewed.85 During the period of
Q wo (226a)
84
”
0
(226b)
T. Fex, J. Froborg, G. Magnusson, and S. Thoren, J . Org. Chern., 1976, 41, 3518. E. Rodriguez, G . H. N. Towers, and J. C. Mitchell, Phytochemistry, 1976,15, 1573; cf. Vol. 4, pp. 116, 133; Vol. 5, pp. 75, 87; Vol. 6, pp. 76, 78; Vol. 7, pp. 83, 88, 96, 103, 104.
Sesquiterpenoids
95
coverage structures or revised structures have been proposed for the Eollowing germacranolides: pectorolide (227), vernopectolide-A (228), and vernopectolide-B (229) ( Vernonia pectoralis);86 nobilin (230), 3-epinobilin, l,lO-epoxynobilin, 3dehydronobilin, eucannabinolide (23 l), and hydroxyisonobilin (232) (Anthemis n~bilis),'~*~'15-deoxygoyazensolide (233) ( Vanillosmopsis e r y t h r o p a p p ~ ) ; ~ ~ (Me)=CH,
R ' o q R 2
/ R
'OCOC(Me)=CHMe 0
HO
0
0 0
(227) R = CHzOH (228) R = CHzOAc (229) R = C H O
(230) R' (231) R'
= R2= H = Ac, RZ= OCOC(CH20H)=CHCH20H
0
0
co I
C (Me)=C H
desacetyleupaserrin (234) (Helianthus p u m i l i ~ )herbolides ;~~ A (235), B (236), and C (237) (Arternisia herba ~ l b a ) ; eupaformosanin ~' (238),92" eupatolide (240)92b and eupaformonin (239)92' (Eupatorium formosanum); euperfolitin (241) and , ~ -acetoxyzacatechinolide ~ (243) and euperfolin (242) (Eupatorium p e r f ~ l i a t u m )la 1-oxozacatechinolide (244) (Calea z a ~ a t e c h i c h i ) , ~ lactone ~" (245) (Chrysan~' themum poteriifolium),946lactone (246) (Inula b r i t t ~ n i c a ) ; ~peroxycostunolide (247) and peroxyparthenolide (248) (Magnolia grandijlora),95 verlotorin (syn. peroxycostunolide), and artemorin (249).95 B. Mompon and R. Toubiana, Tetrahedron, 1976,32, 2545. M. Holub and Z. Samek, Coil. Czech. Chem. Comm., 1977,42, 1053. Z. Samek, M. Holub, H. Grabarczyk, B. Drozdz, and V. Herout, Coil. Czech. Chem. Comm., 1977,42, 1065. 89 W. Vichnewski, J. N. C. Lopes, D. D. S. Filho, and W. Herz, Phytochemistry, 1976,15, 1775. 90 W. Herz and R. DeCroote, Phytochemistry, 1977,16, 1307. 9 ' R. Segal, S. Sokoloff, B. Haran, D. V. Zaitschek, and D. Lichtenberg, Phytochemistry, 1977,16, 1237. 92 (a) K.-H. Lee, T. Kimura, M. Haruna, A. T. McPhail, K. D. Onan, and H.-C. Huang, Phytochemistry, 1977, 16, 1068; (b) A. T. McPhail and K. D. Onan, J.C.S. Perkin XI, 1975, 1798; (c) ibid., 1976, 578. 93 W. Herz, P. S. Kalyanaraman, G. Rankikrishnan, and J. F. Blount, J. Org. Chem., 1977,42, 2264. y4 (a) F. Bohlmann and C. Zdero, Phytochemistry, 1977, 16, 1065; ( b ) F. bohlmann and D. Ehlers, ibid., p. 137; ( c )F. Bohlmann and C. Zdero, ibid., p. 1243. '' F. S. El-Feraly, Y.-M. Chan, E. H. Fairchild, and R. W. Doskotch, TetrahedronLetters, 1977,23, 1973. 86
Terpenoids and Steroids
96
HO..R
(CH,OH)=CHMe
0
0 (234)
(235) (236) 1,2-epoxide (237) 5,6-epoxide
R1oQoR* 0
0 (238) R' = Ac, R2 = COC(CH,OH)= CHCHPOH (239) R' = Ac, R2 = H
R
-
q
,
:
C
(Me)=C H M e
HO
0 (241) R = O H (242) R = H
(245)
0 (243) R = H,OAc (244) R = O
(247) R = O O H (248) R = OOH, 4,s-epoxide (249) R = O H
Spectroscopic evidence has been provided for the structure of the germacrane derivatives (250)-(253), isolated from several Ligularia species96(cf. p. 53). Two research groups have published synthetic routes to germacradiene systems based on the well known Cope rearrangement which interconverts germacradienes [cf: (254)] and elemenes (1,2-divinylcyclohexane derivatives) [cf.(255)]. In one report the total synthesis of (+)-costunolide (258) has been achieved by Cope rearrangement of (+)-dehydrosaussurea lactone (257) derived from santonin (256) 96
F. Bohlmann, D. Ehlers, C. Zdero, and M. Grenz, Chem. Ber., 1977, 110,2640.
97
Sesquiterpenoids
~
4
RO
0
(253) R = COC(Me)=Me
(250) R' = R2 = H, R3= R4= COC(Me)=CHMe (251) R' = H, R2 = R3 = R4= COC(Me)=CHMe (252) R2 = H, R' = R2 = R4= CO(Me)=CHMe
(255)
(254)
(Scheme 25)'7 (cf. Vol. 7, p. 99 and references cited). In a related study the synthesis of isoacoragermacrone (26 1) is accomplished by oxy-Cope rearrangement of compound (260) derived from isopiperitenone (259).98 Subsequent isomerization of (261) produced (*)-acoragermacrone (262) and (*)-preisocalamenediol (263)98 (Scheme 26) (cf. Vol. 4, p. 119; Vol. 5 , p. 71; Vol. 7, p. 85). Further studies on the acid-catalysed cyclization of germacradienes (cf. Vol. 7,
n,. - oq,. q,.
0
0
0
'
O
0
0-
'
0
1
(256)
(257)
(258)
Reagents: i, TsNHNH2; ii, LiNPr',-THF; iii, 03-CH2C12-MeOH; iv, NaBH4; v, ArSeCN-PBu3-THFpy; vi, H202-THF; vii, LiNPr',-PhS&ePh-HMPA-THF; viii, A, 200 "C, g.1.c.
Scheme 25 97 98
P. A. Grieco and M. Nishizawa, J. Org. Chem., 1977, 42, 1717 W. C. Still, J. Amer. Chem. Soc., 1977,99,4186.
98
Terpeno ids and Steroids
Reagents: i, Me2CHC(Li)=CH2; ii, KH-THF-18-crown-6; Me,SnLi; v, Me,SiCI; vi, MnOz
iii, LiNPr',-THF-HMPA-HOAc;
iv,
Scheme 26
p. 85) have shown that isoacoragermacrone (261) and acoragermacrone (262) can be cyclized to cadinane- (264) and (266), eudesmane- (267)-(269), and guaiane-
H 1 .OR 80% HOAc -
A
ether
(264) a ; R = H
HOAc -PhSH
(265)
+ HO,C**
H
Sesquiterpenoids
99
type (265) corn pound^.^^" Experimental details of previous studies on the cyclization of epoxygermacrone (270)* (Vol. 7, p. 85) as well as related results on the cyclization of the isomeric epoxide (271) and epoxy-acetate (275) have also been described in a recent paper.99b
(275)
(276)
A new approach to the cyclodeca-l,5-diene systems [cf. (281) and (282)] characteristic of germacranolides involves a photochemical-cycloaddition and thermalcycloreversion sequence shown in Scheme 27."' 12 Eudesmane
An extension of previous investigations on the sesquiterpenoid constituents of Ambrosia species has resulted in the isolation and structural elucidation of granilin (283) and ivasperin (284)."' A similar compound (285) has been identified as a co-metabolite of germacranolide (246) (cf. p. 96) in h u l a britt~nica.~~' Several independent investigations have shown that many of the sesquiterpenoid constituents of liverworts are enantiomeric to the same compounds isolated from vascular plants (Vol. 6, pp. 63, 89). A recent investigation has shown that essential oils of two liverworts of the genus Diplophyllum (albicans and taxifolium)contain ent-aselinene (286), ent-selina-4,ll-diene (287), and diplophyllin (288).'02 The latter 99 loo
'O'
lo*
M. Niva. M. Iguchi, and S. Yamamura, ( a )Bull. Chem. Soc. Jupan. 1976, 49,3148; ( b ) ibid., p. 3137. G. L. Lange, M.-A. Huggins, and E. Neidert, TefruhedronLetfers, 1976, 4409. W. Vichnewski, 1. K. Shuhama, R. C. Rosanske, and W. Herz, Phytochemisfry, 1976.15, 1531. Y. Ohta, N. H. Andersen, and C.-B. Liu, Tetrahedron, 1977, 33, 617.
* This compound was incorrectly named isoacoragermacrone epoxide in Vol. 7, p. 85.
Terpenoids and Steroids
100
mo""... Ram
Reagents: i, h v ; ii, NaBH,; iii, A
Scheme 27
HO
HO
(285) R = COCH=CMe2
(284)
(283)
(286)
0
(288)
(287)
compound shows significantly greater antitumour activity than its enantiomer and this represents the first demonstration of chiral selectivity in the cytotoxicity ofsesquiterpenoid a-methylene-y-butyrolactones. Albicanol (289), another constituent of D. a6bicans, has been chemically correlated with (-)-drimenol (290), a (OH
(289)
(OH (290)
constituent of the liverworr Bazzania trilobata, and it has been noted that, in general, the stereochemistry of drimanes found in liverworts is the same as that found in vascular p1ants.l''
101
Sesquiterpenoids
mm
Cinnamate esters of rupestrinol (292) and p-chaenocephalol (293) have been identified as co-metabolites of rupestrol cinnamate (291) in the shrub Verbesina rupestris'03(cf.Vol. 2, p. 146). HO
H8
HO PhCH=CHCO'
I1
0
I
OH
COCH=CHPh
0 (291) R = O H (292) R = H
(293)
An investigation of the constituents of Mexican species of the genus Eupatorium has resulted in the isolation of sesquiterpenoids belonging to the eudesmane (294a and b), eudesmanolide (295a and b), cadinane (296), and guanolide (297)
'"4
(294) a; R = 0 b; R = H,OH
(29% and b)
20H)=CHCH20H
0 0 (296)
(297)
There has been much interest recently in terpenoid metabolites of marine organisms1os and two recent reports in this area describe the independent identification of the bromoeudesmane (298) as a constituent of red seaweed ?r
(298) '03 '04
Io5
V. G. S. Box, V. Bardouille, and W. R. Chan, Phytochemistry, 1977,16,987. F. Bohlmann, J. Jakupovic, and M. Lonitz, Chem. Ber., 1977,110, 301. (a) q.Vol. 1 , p. 74; Vol. 2, p. 84; Vol. 4, pp. 96, 142; Vol. 5, pp. 48,55, 70, 77, 78, 84; Vol. 6, pp. 64, 65, 87-89, 91-93; Vol. 7, pp. 18-20, 5 4 - 6 0 , 65-71, 123; ( b ) 'Marine Natural Products Chemistry', ed. D. J. Faulkner and W. H. Fenical, Plenum, New York, 1977.
102
Terpenoids and Steroids
(Laurencia) collected in Australia'"6 and Calif~rnia.'"~ This compound represents the first naturally occurring brominated sesquiterpenoid belonging to the eudesmane (selinane) group. 4,ll-Epoxy-cis-eudesmane (300), the defence pheromone of the West African termite, has been synthesized from 10-epi-y-eudesmol (299) by means of an i,Hg(OAc)z-THF-H20,
+
11.2 NaBH4-HO-
OH
,'
H 0
H'
0
internal oxymercuration reaction.lo8 Simple functional group transformations also form the basis of a reported synthetic route from the known dienone (302) to intermedeol (307) via the naturally occurring diene (304)109a*b (Scheme 28).
(302)
iiil
(305) Reagents: i, NH2NH2-KOH-(CH20H)2; ii, m-CIC6H4C03H; iii, LiAIH4
Scheme 28
Chemical and spectroscopic evidence has been provided for the structure of 30-epijunenol (308), a new member of the rare cis-eudesmane group of sesquiterpenoids."' Rosifoliol, a component of the leaf oil of Australian native raspberry (Rubus rosifolius) has been assigned structure (309) on the basis of its spectroscopic lo6 lo'
lo' lo9
'lo
A . F. Rose and J. J. Sims, Tetrahedron Letters, 1977, 2935. 6. M. Howard and W. Fenical, J. Org. Chem., 1977, 42, 2518. R. Baker, D . A . Evans, and P. G. McDowell, J.C.S. Chem. Comm., 1977, 11 1. ( a )L. H. Zalkow, M. Smith, G. L. Chetty, A . W. Shaligram, and P. Ingwalson, J. Org. Chem., 1976,41, 3710; ( b ) cf. J. W. Huffman, C. A . Miller, and A . R. Pinder, ibid., p. 3705. A . F. Thomas, M. Ozainne, R. Decorzant, F. Naf, and G. Lukacs, Tetrahdron, 1976, 32, 2261.
-
Sesquiterpenoids
103
(310)
(309)
(308)
properties and chemical correlation with (- )-8-selinene ( 3 1(I)."' Other components of the leaf oil are bicyclogermacradienes (31 l), 10-epi-y-eudesmol (299), and the trisnor-sesquiterpenoid pregeijerene ( 3 12).'" The key feature of a
( 3 12)
(31 1 )
new synthetic route to (*)-occidentalol (314) (cf. Vol. 3 , p. 150; Vol. 4, p. 119) is the cyclization of a suitably substituted cyclohexadiene aldehyde (3 13) derived from m-toluic acid"' (Scheme 29). It seems reasonable to assume that
CO, Me C0,Me x, ii. x i 1
t
t-
CHO OAc
(3 14)
(313)
Reagents: i , Li-NH3-Br(CH2)40CH2Ph; i i , L I A I H ~ iii, ; TsCI-py; iv, LiBHEt,-HMPA; v. Na-NHxBuOH; vi, NCS-MezS-toluene; vii, AgzO; viii, MeOH-HC; ix, CIC02Et-
X,
NaH;
XI,
M n 0 2 ; xi], Ac20-HCI0,; xiii, Ag20-NaOH;
XIV,
I?!;
CH2N,; xv, MeLi
Scheme 29
modification of this approach would be of value in the synthesis of eudesmanolides and germacranolides. An interesting new approach to a-substituted acrylic esters 'I1 'I2
1. A . Southwell, Tetruhedron Letters, 1977, 873. J . A . Marshall and P. G. M. Wuts, J . Org. Chem., 1977. 42, 1794
104
Terpenoids and Steroids
[cf. (316)+ (317)] has been successfully incorporated into the first total synthesis of the allergenic sesquiterpenoid frullanolide (318)11-’(Scheme 30) (cf. Vol. 4, p.
(3 17)
q& O
o
&Q (3 18) *
o
Reagents: i, H,02-OH-; ii, NH2NH2,H20-MeOH; i i i , LiNPri2; iv, CH,=CHCOCI; v, pyrrolidinc; vi, Et,SiCI; vii, toluene, A; viii, Me2S04-K2C0,-MeOH; ix, KOH-MeOH; x, K13-NaHC03H 2 0 ; xi, DBu-THF. A
Scheme 30
124; Vol. 5 , p. 76). Related studies have shown that the butenolide derivative (319) can be used as an annulating agent in the construction of linear tricyclic y-lactones [cf. (322) and (323)] and it is expected that this methodology may be applied to the synthesis of naturally occurring eude~manolides.”~ Acetyl, benzoyl, cinnamoyl, and nicotinyl esters of polyols based on the dihydroagarofuran framework [cf. (324) etc.] have been established as constituents of ‘I3
’I4
W. C. Still and M. J . Schneider, J . Amer. Chem. SOC.,1977.99.948. A . G . Schultz and J . D. Godfrey. J . Org. Chem., 1976, 41, 3494.
Sesquiterpenoids
105
mO \
'
-..
ii.i.:2O,-MeS03H K2CO3-MeOH
COzMe
(323)
0 CO,Me
OH
(322)
various genera of Celastraceae (Celastrus, Euonymus, Muytenus, and Cuthu) (cf. Vol. 4, p. 125; Vol. 6, pp. 77,78; Vol. 7, p. 90). Further investigations in this area have resulted in the isolation of various esters of celorbicol (324) and isocelorbicol (325) from the seeds of Celustrus orbicufatus,115 maytoline (326), maytine (327), and maytolidine (328) from Muytenus serratu,"6 euonymine (329) and neoeuonyand cassinin (33 1) from Cussine mine (330) from Euonymus sieb~fdiunu,"~ mutubelicu (Celastraceae). ' l R
"C3;-ii
AcO
OAc OAc
/
R 2
(324) R' = H, R2 = OH (325) R' =OH, R2 = H
(326) R' =OH, R2 = Ac (327) R' = H, R2 = Ac (328) R' = OAc,R2= COPh
(329) R' = Ac, R2 = OH (330) R' = H, R2 =OH (33 1) R' = COPh, R2= H
Re-examination of spectroscopic and chemical evidence has led to a revised structure for mortonin (334).lI9 The proposed biosynthesis of mortonin (334) involves ring cleavage of a dihydroagarofuran derivative (333) and this proposal is indirectly supported by the co-occurrence of mortonin (334) and dihydroagarofuran derivatives [cf. (326)-(33 l)] in the same family of plants (Celastraceae). 'I5 'I6
'I7 'Is
'''
C. R. Smith, R. W. Miller, D . Weisleder, and W. K. Rohwedder, J. Org. Chem., 1976, 41, 3264. S. M. Kupchan and R. M. Smith, J. Org. Chem., 1977,42, 115. K. Yamada, K. Sugiura, Y. Shizuri, H. Wada, and Y. Hirata, Tetrahedron, 1977, 33, 1725. H. Wagner, R. Bruning, H. Lotter, and A. Jones, Tetrahedron Letters, 1977, 125. L. Rodriguez-Hahn, M. Jiminez, E. Diaz, C. Guerrero, A. Ortega, A. Romo de Vivar, Tetrahedron, 1977, 33, 657.
106
Terpenoids and Steroids
@
HO
H + H o @ H +COH H o p j
(332)
(333)
(334) R=COPh
13 Vetispirane, Elemane The recent upsurge of interest in phytoalexins has been maintained during the past year.”” Particular attention has been given to phytoalexins produced by potato tubers which have been infected with fungi (Phytophthora infestans, Fusarium avenaceum, Phoma exigua var. foveata) or bacteria (Erwiniu carotovora var. atrosepticu), and sesquiterpenoids previously identified from this source include lubimin (3354, 9-hydroxylubimin* (336), solavetivone (337), anhydro-P-rotunol (338), phytuberin (339), rishitin (341), and rishitinol (340) (cf. Vol. 4, p. 125; Vol. 5, p. 80; Vol. 6, p. 80; Vol. 7, p. 94). Full papers on the structural elucidation of lubimin (335),’” 9-hydroxylubimin” (336),”’ rishitin (341),lZZaand phytuberin (339),1’3,’’4 and a detailed account ”” of the synthesis of rishitin (341) from (-)-a-santonin (256) have been published. In addition 9-hydroxylubimin (336), whose relative configuration was previously established by X-ray analysis (Vol. 7, 94), has been assigned the absolute configuration shown, on the basis of n.m.r.
For previous references to phytoalexins see Vol. 4, p. 125; Vol. 5, p. 80; Vol. 6, p. 80; Vol. 7, pp. 52, 94. N. Katsui, A. Matsunaga, H. Kitahara, F. Yagihashi, A. Murai, T. Masamune, and N. Sato, Bull. Chem. SOC.Japan, 1977, 50, 1217. ( a ) T. Masamune, A. Murai, M. Takasugi, A. Matsunaga, N. Katsui, N. Sato, and K. Tomiyama, Bull. Chem. SOC.Japan, 1977,50, 1201; (b) A. Murai, K. Nishizakura, N. Katsui, and T. Masamune, ibid., p. 1206. D. T. Coxon, K. R. Price, B. Howard, and R. F. Curtis, J.C.S. Perkin I, 1977, 53. D. L. Hughes, J.C.S. Perkin I, 1976, 1338.
*Two numbering systems, (A) and (B), for tRe parent vetispirane structure are being used in the literature. In this and previous Reports we have adopted the IUPAC (A) rather than the biogenetic numbering (B).
107
Sesquiterpenoids
(338)
(339)
(34 1)
(340)
(342)
and c.d. spectral data.'25 A new phytoalexin isolated from potatoes infected with Phytophthora infestuns, has been identified as 6-epilubimin (342).lz6 The structure and absolute configuration of the aglycones, (343)-(346), of vetispirane
R3
(343) R' = R3= H, R2 = O H (344) R' = R2= H, R3 = OH (345) R' =OH, R2,R3= H
(346)
glucosides isolated from flue-cured Virginia tobacco have been deduced from X-ray analysis and chemical correlation with (- )-solavetivone" (337).lZ7O Further investigations on the biosynthesis of phytoalexins (cf. Vol. 7, p. 94) have established labelling patterns in lubimin (335), 9-hydroxylubimin (336), solavetivone (337), phytuberin (339), and rishitin (341) derived from [ 1,2-13C]acetate which are consistent with their proposed derivation from a eudesmane precursor.128 The spiroketone (347), previously used as an intermediate in the synthesis of several vetispirane sesquiterpenoids (cf. Vol. 5 , p. 79) has been converted into (f)-solavetivone (337) by the sequence of reactions shown in Scheme 31.129 '21 la'
'21
12' 129
N. Katsui, H. Kitahara, F. Yagihashi, A . Matsunaga, and T. Masamune, Chem. Leriers, 1976, 861. N. Katsui, F. Yagihashi, A. Matsunaga, K. Orito, A. Murai, and T. Masamune, Chem. Leiters, 1977, 723. (a) R. C. Anderson, D. M. Gunn, J. Murray-Rust, P. Murray-Rust, and J. S. Roberts, J.C.S. Chem. Comm., 1977,27; ( b )T. Fujimori, R. Kasuga, H. Kaneko, and M. Noguchi, Phytochemistry, 1977,16, 392. A. Stoessl and E. W. B. Ward, Tetrahedron Letters, 1976, 3271. K. Yamada, S. Goto, H. Nagase, and A. T. Christensen, Tefrahedron Leiiers, 1977, 554.
* This compound has also been isolated from tobacco
Terpenoids and Steroids
108
. -
H
(347)
...a%
4-=-
k0
I' 0%
b
O OH H OH
QH
OH
OH
Reaction: i, LiNPr',-PhSeSePh; ii, m-CIC,H4C03H; iii, NaHC03-toluene; iv, CHz=C(Me)MgBr-CuITHF; v, NH2NH2-KOH-(CHzOH)2; vi, Os04-THF-py; vii, (CO,Hh-MeOH-H,O; viii, (PhO)$Me I--BF3, Et20-MeCN; ix, Zn-NH4C1; x,
Scheme 31
Two additional synthetic routes to (*)-p-vetivone (350) have been d e ~ e l o p e d . ' ~In~ one " ~ ~of these a suitably substituted spirocyclic system [cf. (349)] is constructed by addition of Me,CuLi to the fulvene derivative (348).130 Subsequent functional group modification (cf. Scheme 32) provides (*)-p-vetivone (350). In the other total ~ynthesis'~' the well-known intramolecular alkylation of para-substituted phenols has been used to produce a spirocyclic intermediate (353) which can be converted into (*)-p-vetivone (350) (cf. Scheme 33). Sesquiterpenoids based on the axane skeleton (354) have been reported previously as metabolites of marine sponges or algae (cf. Vol. 5, p. 77; Vol. 6, p. 89). Further investigations in this area have revealed the presence of axisonitrile-4 (355), axisothiocyanate (356), and axamide-4 (357) in the sponge Axinella cannabina. 1 3 2 ~ 1 3 3 These compounds are A'O"'-derivatives of known metabolites (axisonitrile-1 erc.) of this sponge and are included in this section because their biosynthesis may involve rearrangement of a eudesmane precursor. P-Elemenone (359), a compound which co-occurs with germacrone (358) in Bulgarian zdravetz oil and which can be formed from germacrone (358) by thermal rearrangement, has recently been synthesized by a route (Scheme 34) in which the 13' 13'
133
G. Biichi, D. Berthet, R. Decorzant, S. Grieder, and A. Hauser, J. Org. Chem., 1976,41, 3208. K. Uneyama, K. Okamoto, and S. Torii, Chem. Letters, 1977,493. A. Iengo, L. Mayol, and C. Santacroce, Expn'entia, 1977,33, 1 1 . M. Adinolfi, L. De Napoli, B. D. Blasio, A. Iengo, C. Pedone, and C. Santacroce, Tetrahedron Letters, 1977.2815.
Sesquiterpenoids
3
%
---.
109
iv-vii
~
---. 0
(348)
(349)
O
q
-
viiil
9
L
-
q
CN OH
(3.50) Reagents: i, Me2CuLi; ii, MeCOCI-PhNMe2; iii, NH=NH; iv, NaOH-EtOH; v, MeC0,H; vi, BuLi; vii, TSOH-C,&; viii, MeC6H4NC; ix, MeMgBr; x, MeLi; xi, CrO,-py; xii, TSOH-C6H6, A
Scheme 32
+ 1-1V H O W ; ,
Hoy+/,JCo2Me
(35 1 )
(352)
oq I.
(350)+c-10 epimer
-
.
(353) Reagents: i, LiNPr',-Me,CO;
ii, SOCl2-py; iii, LiAIH4; iv, TsC1-py; v, KOBU'; vi, Me2CuLi; vii, RhCI3
Scheme 33
(354)
(355) R = N C (356) R=NCS (357) R = NHCHO
110
Terpenoids and Steroids
(359)
(358)
1, 2-divinylcyclohexane system [cf. (362)] is produced from the diselenide intermediate (361).13, (Other studies on the use of elemane derivatives as intermediates in the synthesis of germacranolides etc. are described on p. 97).
(362) Reagents: i, Li-NH3-Bu'OH-THF;
(359) ii, LiNPr'2-(EtO)2POCI; iii, Li-EtNH,;
vi, o-N02C6H4SeCN-Bu3P; vii, H,02-THF; x, MeI; x i , MezCuLi
iv, 03-MeOH; v, NaBH,;
viii, HCI-THF; ix, CS2-Li+
Scheme 34
Complete details of the previously reported total synthesis of the antiturnour elemanolides vernolepin (363) and vernomenin (364) (Vol. 7, p. 97) have been Other research groups have reported the synthesis of compounds (365)-(367) which could be of considerable value as intermediates in alternative synthetic routes to vernolepin and v e ~ n o m e n i n . ' ~ ' - * ~The ~ antitumour activity of 134 135
G. Majetich, P. A . Grieco, and M. Nishizawa, J. Org. Chem., 1977, 42, 2327. P. A. Grieco, M. Nishizawa, T. Oguri, S. D. Burke, and N. Marinovic, J. Amer. Chem. Sac., 1977.99, 5773.
"'S. Danishefsky, P. F. Schuder, T. Kitahara, and S. J. Etheridge, J. Amer. Chem. Soc., 1977,99,6066. 137 13" 139
P. M. Wege, R. D. Clark, and C. H. Heathcock, J. Org. Chem., 1Y76,41, 3144. M. Isobe, H. Iio, T. Kawai, and T. Goto, Tetrahedron Letters, 1977, 703. S. Torii, T. Okarnoto, and S. Kadono. Chem. Lefters, 1977, 495.
Sesquiterpenoids
111
" F '
0
I'
OH (364)
(363)
&---o 0
H
(365)
C0,Me
: H C0,Me
(366)
(367)
vernoiepin (364) has also stimulated research on the synthesis of compounds of similar type and recent investigations have shown that ( f )-deoxyvernolepin (369), synthesized by the route outlined in Scheme 35, is more potent than vernolepin as an antitumour agent.I4" The structural elucidation of micordilin (370), a complex elemanolide produced by a medicinal plant (Mikania cordifofia),has been determined by X-ray crystallographic a n a 1 y ~ i s . l ~Germazone ~ (371), a component of the essential oil of Geranium mucrorrhizum (zdravetz oil), is the first example of a new structural type of sesquiterpenoid and it has been suggested that the biosynthesis of this compound involves cyclization of the co-metabolite, germacrone (358).14' In previous i n v e s t i g a t i o n ~ 'it~ ~was noted that an unidentified product from the reaction of patchoulol (patchouli alcohol) (372) with Pb(OAc), (cf. Vol. 7, p. 112) was transformed to an unsaturated alcohol after g . 1 A~ recent ~ ~ analysis ~ of the spectroscopic data for these compounds has led to the proposal that the initial reaction product is the bicyclic enone (374) which undergoes internal Prins reaction o n the g.1.c. column to furnish the unsaturated alcohol (375)144(cf. cedrane framework p. 78). Cybullol (377), previously reported as a metabolite of Bird's Nest fungi (cf. Vol. 7, p. 95), and geosmin (379), a degradation product of cybullol and the fungal metabolite responsible for the 'earthy' aroma of freshly ploughed soil, have been synthesized by the routes outlined in Schemes 36 and 37.145
14 Eremophlane, Bakkane (Fukinane), Ishwarane Acid-catalysed rearrangement of 11,12-dihydroparadisiol (382) to 11,12-dihydrovalencene (383) has provided further support for the 1,2-methyl shift postu14" I4l 142 143
'44 145
P. A. Grieco, J. A. Noguez, and Y. Masaki, J. Org. Chem., 1977, 42, 495. W. Herz, P. S. Subramaniam, R. Murari, N. Dennis, and J. F. Blount, J. Org. Chem., 1977, 42, 1720. E. Tsankova and I. Ognyanov, Tetrahedron Letters, 1976, 3 8 3 3 . B. A. Gubler, Promotionsarbeit, E. T. H., Zurich, 1965; cf. G. Mehta and B. P. Singh, Tetrahedron Letters, 1975, 4495. A. F. Thomas and M. Ozainne, J.C.S. Chetn. Comm., 1977, 120. W. A. Ayer, L. M. Browne. and S. Fung, Canad. J. Chem., 1976, 54,3276.
112
Terpenoids and Steroids
MHe 0 , CO
J H
J.
h
xi-xiii.
viii
OAc C0,Me
OAc C 0 , M e
XV
-
xviii,xix,
0 OAc C0,Me
oq H
OAc C0,Me
O
'0
OH
0
HO (369) Reagents: i, NaH-MeI-THF; ii, BH3-THF-HO- iii, Cr03,2py-CHzC12; iv, NaH-(MeO)zC04ioxan; v, NaH-BrCH2COZMe;vi, Ba(0Hh-A; vii, Na-Pr'OH; viii, CH2Nz; ix, Ac20-py; x, HCI-THF; xi, CHz=C(OAc)Me-TsOH; xii, 03-MeOH-CH2Cl2; xiii, NaBH4-HO-; xiv, MsC1-py, 0 "C; XV, BBr3-CHzC12,-78 "C; xvi, O-NO&H~S~CN-BH~--DMF; xvii, HzOz-THF; xviii, KzC03-MeOH; xix, TSOH-C6H6; xx, LiNPr'Z-CHzO-HMPA; xxi, MsCI-py, b
Scheme 35
0
(370)
Sesquiterpenoids
(374)
(375)
lated in the biosynthesis of eremophilane sesquiterpenoids from eudesmane prec u r s o r ~(cf. ~ Vol. ~ ~ 4,p. 131; Vol. 6, p. 184; Vol. 7, p. 100). Although it has also been shown that addition of [3-14C]paradisiol (381) to grapefruit results in the formation of radioactive valencene (382) the significance of this observation will
“O.-rn OHj
(377) Reagents: i, LiAIH4; ii, A; iii, hv-O2CH2CI2, -78 “C, Rose Bengal; iv, Al-Hg-ether; v, H2-Pt0,, 40 psi
Scheme 36
(378)
(379)
Reagents: i, H202-NaOH-MeOH; ii, Li-NH,; iii, (CH2SH)2-BF3-HOAc; iv, Raney Ni(W-2kEtOH
Scheme 37 146
C. A. Miller and A. R. Pinder, J.C.S. Chem. Comm., 1977, 230
114
Terpenoids and Steroids
ultimately depend on whether or not the radioactivity is specifically located at C-3 in ~ a 1 e n c e n e . lThe ~ ~ alternative structure (385) proposed for nardostachone has been invalidated by the recent demonstration that synthetic (385), derived from ( f )-7-epinootkatone (384), has spectroscopic properties which differ from those of
(384)
(385)
the natural A further investigation of the South American plant Tessaria absynthioides has revealed the presence of eremophilane derivatives (386) and (387) as co-metabolites of the known compounds tessaric acid (388) and carrissone (389).14' A new sesquiterpenoid, eremofortin C (390), has been isolated from cultures of Penicillium roquefortii and its structure determined by chemical correlation and spectral comparison with known metabolites [eremofortin A (391), PR toxin (392)] of this organism'49 (cf. Vol. 6, p. 84; Vol. 7, p. 97).
(386) R' (387) R' (388) R'
(390)
14'
(389)
= H2, R2 = C 0 2 H = 0,R2 = C 0 2 H
OH
AcO
'41
= H2, R2 = CH,OAc
CHO
AcO
AcO
(391)
W. D. Saunders and A. R. Pinder, Tetrahedron Letters, 1977, 1687. F. Bohlmann, C. Zdero. and M. Silva, Phyfochemistry, 1977, 16, 1302. S. Moreau, M . Cacan. and A. Lablache-Combier, J. Org. Chem., 1977, 42. 2632
(392)
Sesquiterpenoids
115
Alternative synthetic routes to (*)-eremophilone (395) have been achieved by two research group^^^^.'^^ (cf.Vol. 5, p. 82; Vol. 6, p. 84 for previous syntheses). In one of the routes15" (Scheme 38) the required stereochemistry at C-7 is achieved at
)
xv. xvi, xif
HO
(395) Reagents: i, (CH2=CH)zCuLi-Bu3P; ii, LiAIH4-EtzO; iii, m-CIC6H4CO3H; iv, CrO3-3,S-dimethylpyrazole-CHzClz; v, KOBu'-HOBu'; vi, MnOz; viii, Ph3P=CHC02Me-CH2C12; viii, (CH,OH),-H+; ix, [CH2=C(Me)]2CuLi; x, HCI-H20-THF; xi, Li-NH,; xii, Cr03-pyCH2C12; xiii, NaOH-MeOH; xiv, 250 "C; xv, H202-NaOH-MeOH; xvi, NH2NH2,HzO-I If
Scheme 38
an intermediate stage by 1,4-addition of an isopropenyl group to a syn-cyclopropyl acrylic ester (394). In the other total synthesis1'' (Scheme 39) the required stereochemistry is produced by l,4-addition of Grignard reagent (397) to the enone (396). The isolation of eremophilane derivatives (398)-(402) from several Ligularia species96.152*153 and (403a-c) from Gynoxys and Pseudogynoxys 150
15'
I"
F J F Y
E Ziegler, G R Re~d,W L Studt, and P A Wender, I Org Chem, 1977, 42, 1991 Ficini and A M Touzin, Tetrahedron Lefters, 1977. 1081 Bohlmann dnd A Suwita, Chem Ber, 1977, 110, 1759 Moriyama and T Takahashi, Bull Chem Soc Japan, 1976.49, 3196
Terpenoids and Steroids
116
.
..
MgBr
(397)
9"
YR
0 ii
iii -vJ
0
fi
vi,vii,iv
Reagents: i, CuI-THF; ii, HCI-H20; iii, Ac20; iv, CHZ=CHOEt-H+; v, OH--H20; vi, Cr03-pyCH2C12; vii, NaOMe-MeOH; viii, NaBH4-MeOH, 0 "C; ix, Li-EtNHz; x, Cr03-MezCOH2S04; xi, alumina, 280 "C; xii, H202-OH-; xiii, CrClz
Scheme 39
(398) R' = H, R2 = COC(Me)=CHCH,OH (399aand b) R' = COC(Me)=CH2, R2= Ac or H (400aand b) R' = COC(Me)=CHMe, R2 = Ac or H
(402) R = COC(Me)=CHMe
(401) a; R = OH b;R=H
= RZ= COC(Me)=CHMe b; R' = COCH=CMe2, R2 = COC(Me)=CHMe c; R' = H, R2 = COC(Me)=CHMe
(403) a; R'
117
Sesquiterpenoids
species154has been reported. An extension of previous studies (cf Vol. 6, p. 85) on the hepatotoxic constituents of the plant Tetrudymu glubrutu resulted in the isolation of tetradymodiol (404) and the determination of its Structure by X-ray An alternative synthesis of (*)-cacalol (405) and confirmation for the ".~ Vol. 7, structure of the co-metabolite cacalone (406) have been p ~ b l i s h e d ' ~ ~(cf. pp. 100-102). Compounds (407) and (408a-c) related to cacalol (405) have been isolated rccently from various Senecio ~pecies"~ where they co-occur with a variety of eremophilane derivatives. The co-occurrence of cacalane and eremophilane compounds provides indirect support for the proposed biosynthetic relationship (1,2 methyl shift) between these sesquiterpenoid groups.
(407)
(408)a; R' =Me, R2= CHO b; R' = R2= CHO c; R' = CHO, R2 = CH20Ac
Experimental details for the previously reported synthesis of ( f)-bakkenolide-A (41 1) (syn. fukinanolide) have been provided in a recent paper which also describes the potential of [2,3]sigmatropic rearrangement in natural product In the particular case of bakkenolide-A the correct configuration at C-7 is achieved by [2,3]sigmatropic rearrangement of the intermediate (409) (cf. Vol. 5, p. 8 5 ) . A NNHTs
I54 15s
156
15' 15'
F. Bohlmann, M. Grenz, and A . Suwita, Phyrochemistry, 1977, 16, 774. P. W. Jennings, J. C. Hurley, S. K. Reeder, A . Holian, P. Lee. C. N. Caughlan, and R. D. Larsen, J. Org. Chem., 1976, 41, 4078. ( a )F.Yuste and F. Walls, Austral. J. Chem., 1976,29,2333;( b )F. Yuste, E. Diaz, and F. Walls, J. Org. Chem., 1976,41,4103. F. Bohlmann, C. Zdero, and M. Grenz, Chem. Ber., 1977, 110,474. F. Bohlmann, K.-H. Knoll, C. Zdero, P. K. Mahanta, M. Grenz, A. Suwita, D. Ehlers, N. LeVan, W.-R. Abraham, and A . A. Natu, Phytochernisfry, 1977,16, 965. D. A . Evans, C. L. Sims, and G. C. Andrew?, J. Amer. Chem. SOC..1977,99,5453.
Terpenoids and Steroids
118
recent report describes the distribution of bakkenolide-A (4 11) in Petasites species and also makes the interesting observation that the cytoxicity of bakkenolide-A compares favourably with that of several sesquiterpenoids containing a-methylene-y-lactone rings160(cf.pp. 94, 112). An extension of previous studies on the synthesis of ishwarane (413) (cf. Vol. 4, p. 132) and the diterpenoid trachylobane (414) has provided an improved procedure for the conversion of the previously reported intermediate (412) into ishwarane (413).161
=**OH
i, M\CI-py, O T , 11,
.
L1AlH4-Et20 ,
I
I
15 Guaiane, Pseudoguaiane A general investigation of acid-catalysed rearrangement of unsaturated sesquiterpenoids has shown that a-bulnesene (415), a-guaiene (416), guaiol (417), or cy -gurjunene (4 18) provides ent- 10-epizonarene (4 19), bicyclohumulene (420) is converted into 6-selinene (421), and (-)-y-muurolene (422) rearranges to (-)zonarene (423).16' The structural elucidation of several new guaiane derivatives found in plants has been reported during the past year. These include (424)-(426)
,
n2s04,
A (419)
-
Q O H
(420) I6O
'" I62
(421)
G. R. Jamieson, E. H. Reid, B. P. Turner, and A. T. Jamieson, Phytochemistry, 1976, 15, 1713. R. B. Kelly and S. J. Alward, Canad. J. Chem., 1977, 55, 1786. G. Mehta and B. P. Singh, J. Org. Chem.. 1977. 42, 632.
Sesquiterpenoids
119
QOH
(424)
(425)
(426)
from the Chilean plant Pleocarphus revolutus,lh3 arctolide (427) from Arctotis g r a n d i ~ , 'eufoliatin ~~ (428) from Eupatorium perf~liaturn,~~ (429h(432) from Poduchaenium eminens,lhsu(433) and (434) from various Arctotis and (435) from Liabum species.16" The structure and relative configuration of the first furanoguaiane derivative, gnididione (436), has been recorded16' and X-ray analysis has resulted in a revised structure (437) for chrysartemin B, a metabolite of Chrysanthemum morifolium.168
(428)R = COC(Me)=CHMe
(431) (432) 11,13-dihydro
(433) (434) 11,13-dihydro
(429)R = H (430)R = O A c
(435)R = COC(Me)=CHMe
M. Silva, A. Wiesenfeld, P. G. Sammes, and T. W. Tyler, Phylochemisrry, 1977, 16. 379. 2. Samek, M. Holub, B. Druzdz, and H. Grabarczyk, Coil. Czech. Chem. Comm., 1977.42, 2217 ( a ) F. Rohlmann and N. Le Van, Phyruchemistry, 1977. 16, 1304; ( b ) ibid., p. 487. F. Bohlmann, M. Grenz, and C. Zdero, Phyrochemisrry, 1977, 16, 285. "' S. M. Kupchan, Y. Shizuri, R. L. Baxter. and H. R. Haynes, J. Org. Chem., 1977,42,348. 16* T. Osawa. D. Taylor, A. Sumki, and S. TamUrd, Tefrahedron Letters, 1977. 1169. lb3
L64 165
Terpenoids and Steroids
120
(436)
(437)
0
Interest in the antitumour properties of pseudoguanianolides has led to the discovery of several new biologically active members of this structural group. A comprehensive survey of the cytoxic constituents of Sendai Helenium autumnale plants has resulted in the isolation of 2-methoxydihydrohelenalin (438),169npicrohelenin (439),169bhalshalin (440),169cakihalin (44 and a novel sulphonyl
(438) R1 =Me, R2 = 0 (439) R’ = Ac, R2= H,OH
pseudoguaianolide, sulferalin (442).169cFurther examination of the biologically active extract of Helenium microcephalum has revealed the presence of new antitumour constituents, microhelenin-A (443),l7O” -B (444),170b and -C (445),”Ob as well as the previously known norguaianolide mexicanin-E (446). Other papers in this area report the isolation of carpesiolin (447) from Carpesium abrotanoide~,’~’
(444) R = COC(Me)CH,Me (445) R = COC(Me)=CHMe
(446) 169
170
171
(447)
F. Yoshizaki, Hererocycles, 1976, 5, 373; (b) Y. Kondo, T. Tomimori, N. Hiraga, and T. Takemoto, ibid., 1977, 6, 19; (c) Y. Kondo, F. Yoshizaki, F. Hamada, J. Imai, and G. Kusano, Tetrahedron Letters, 1977, 2 155. ( u ) K. H. Lee, Y. Imakura, and D. Sims, J. Pharm. Sci., 1976,65, 1410; (b) K. H. Lee, Y. Imakura, D. Sims, A. T. McPhail, and K. D. Onan, Phytochemistry, 1977, 16, 393. ( a ) Y. Kondo, F. Hamada, and
M. Maruyama and S. Omura, Phytochemistry, 1977, 16. 7 8 2 .
Sesquiterpenoids
121
2,3-epoxyambrosin (448) from the aerial parts of Ambrosia ~ u m a n e n s i s , 'and ~~ isoguaiene (449) and 11-hydroxyisoguaiene (450) from the roots of Purthenium hysterophorus.17'
0
(449) R = H (450) R = O H
(448)
16 Miscellaneous Norbotryal acetate (451) has been identified as a co-metabolite of botrydial (452) in cultures of the plant pathogen Botrytis cine re^'^^ (cf. Vol. 6, p. 95; Vol. 7, pp. 105, 195). Further examination of the metabolites of Porella species has revealed the presence of the pinguisane derivative (453).'74 It has been that
(452)
(453)
(453) may be a biosynthetic precursor of other pinguisane-type compounds, (454)-(457), produced by this plant. The novel structure of isocomene (458), a
(454) R = M e (455) R = C02Me
(456) R = M e (457) R = C 0 2 M e
(458)
new metabolite of the toxic plant rayless goldenrod (Isocoma Wrightii), has been established by X-ray analysis. 175 The structure (460) previously proposed for albene (cf. Vol. 5, p. 59) has been assigned to a compound whose spectroscopic properties differ from those of authentic albene.'76 Since compound (460) is derived from a thio-ether (459) 17* 173
'71
F. Bohlmann, C. Zdero, and M . Lonitz, Phyfochemisfry, 1977, 16, 575. 0. Cuevas and J . R. Hanson, Phytochemistry. 1977, 16, 1061. Y. Asakawa, M. Toyota, and T. Ahatani, Tetrahedron Letters, 1976, 3619. L.H. Zalkow, R. N. Harris, D. Van Derveer, and J. A. Bertrand, J . C S . Chem. Comm., 1977,456. W. Kreiser, L. Janitschke, and W. S. Sheldrick, J.C.S. Chem. Comm., 1977, 269.
122
Terpenoids and Steroids
whose structure has been confirmed by X-ray analysis, a revised structure has been proposed for albene. Unfortunately this structure and the new evidence in its favour are not provided in this paper.176
3 Diterpenoids BY J. R. HANSON
1 Introduction This chapter follows the pattern of the previous Reports, with sections based on the major skeletal types of diterpenoid. The literature which has been covered is that available to August 1977. The value of the I3C n.m.r. correlations recorded in previous years has been demonstrated by the ease with which a number of new structures have been elucidated. The resolving power of high-field (220 and 270 MHz) proton n.m.r. has also been put to good use in some recent structural studies. Marine organisms have continued to afford novel diterpenoids. Progress in this area has been reviewed.’ Some of the new skeleta which have been described are reminiscent of sesquiterpenoids. An interesting review’ describes the detection of diterpenoids in resins used in works of art and in archaeological specimens. A series of phytanylglyceryl ethers has been obtained3 from the lipids of thermoacidophilic bacteria, and geranylgeranylglycerol was detected4 in the brown alga Dilophus fasciola. 2 Bicyclic Diterpenoids
Labdanes.-The configuration at C-13 of the bicyclic diterpenoids has been a problem that has extended over many years. A method of differentiating between manool and 13-epimanool using n.m.r. chiral shift reagents has been d e ~ c r i b e d . ~ Tetrahydroabienol has been shown6 to be a mixture of C-13 epimers. Oxygenation at C-12 is found in some tobacco diterpenoids. The per-acid oxidation of (122)abienol has been used7 in the synthesis of (12R,13R)- and (12S,13S~-8,12epoxylabda- 14-en- 13-01 together with some 8,13-ethers. The cationic cyclization of labda-8(17),12- and labda-8(17),13(16)-dien-14-01~ has been examined* in
’
‘International Symposium o n Marine Natural Products’, Aberdeen, September, 1975, Pure Appl. Chem., 1976,48, 1-44; D. J . Faulkner, Tetrahedron, 1977,33, 1421. J. S. Mills and R. White, Studies in Consemation, 1977, 22, 12. M. de Rosa, S. de Rosa, A . Gambacorta, and J. D. B u ’ h c k , Phyfochemistry, 1976,15, 1995. V. Amico, G . Oriente, M . Piattelli, C. Tringali, E. Fattorusso, S. Magno, and L. Mayol, Experientia, 1977, 33, 989. A . H. Connor and J. W..Rowe, Phyfochemistry, 1976,159, 1949. R. M. Carman and G . W. Zerner, Austral. J. Chem., 1976,29,2091. I. Wahlberg, K. Karlsson, T. Nishida, K. P. Cheng, C. R. Enzell, J. E. Berg, and A . M. Pilotti, Acra Chem. Scand., 1977, B31,453. P. Sundararaman and W. Herz, J. Org. Chem., 1977,42,806.
123
124
Terpenoids and Steroids
attempts to synthesize the tricyclic strobane skeleton. However, the A"-isomer (1) gave the tricyclic diterpenoid (2) whereas the products from the A'3"6'-isomer (3) were the compounds (4) and (5). It is interesting that these represent two different modes of cyclization.
Jungermanool (6) is a new labdadienediol which has been isolated' from Jungermania terticalyx. 4-Epi-isocommunic acid [labda-8( 17),13(16),14-trien-18oic acid] has been isolated'' from Callitris rhomboidea (Cupressaceae). A number of Stevia (Compositae) species have been examined" for terpenoids, and cativic acid has been isolated from S. jaliscensis. 6P-Acetoxylabda-8( 17)-en- 15-oic acid has been isolated from Cistus, hirsutus and its structure established" by interrelationship with 6-oxocativic acid. Extraction of the resin of Aruucaria bidwillii has affordedI3 a number of neutral diterpenoids including ent-labda-8,13E-dien15-01 and its 15-acetate, ent-8~,15-dihydroxylabda-13-ene, and both 8a and 8P epimers of methyl ent-8-hydroxylabda- 13-en- 15-oate. Communic acid and 3acetoxylabda-8( 17),13-dien-15-oic acid have been isolated14 from Metasequoia glyptostroboides. The angelate ester (7) of dendroidinic acid has been obtained"
' A. Matsuo, T. Nakamoto, M. Nakayama, and S. Hayashi, Expen'entia, 1976,32,966. lo
l3 l4
J. S. Prasad and H. G. Krishnamurty, Phytochernisfry, 1977,16,801. F. Bohlmann, C. Zdero, and S. Schoneweiss, Chern. Ber., 1976, 109, 3366. J. de Pascual Teresa, J. G. Urones, and A. Montes Sanchez, Anales de Quim, 1976,72,713. R. Caputo, L. Mangoni, P. Monaco, L. Pdosi, and L. Previtera, Phytochemistry, 1976.15, 1401. S. Braun and H. Breitenbach, Tetrahedron, 1977,33, 145.
Diferpenoids
125
from Agerafina dendroides. The unusual seco-9,lO-structure (8) was also proposed for hebeclinolide, a furanoid diterpenoid obtained from another Eupatorium (Compositae) species, Hebeclinium macrophyllum. The 7-galacto-pyranoside of a new diterpenoid triol, acanthospermol (9), has been isolated16 from Acanfhospermum hispidum (Compositae).
d o ,;isI..OH / i O
0.
HO'
'OH
Sideritis (Labiatae) have been a rich source of novel bi- and tetra-cyclic diterpenoids." Andalusol (lo), which has been isolated18 from S. arborescens, was assigned the enf-labdane configuration. Its structure was deduced by a combination of spectroscopic'measurements and an X-ray analysis of the degradation product (11).
Some new diterpenoid oxides have been obtained'' from Eupatorium jhanii. They are jhanol (12) and its 18-acetate together with jhanidiol (13) and its 18monoacetate and diacetate. Their structures were established by correlation with manoyl oxide and by an examination of their 13C n.m.r. spectra. llp-Hydroxymanoyl oxide (14) has been isolated from Juniperus oxycedrus.20 A group of new 11 -oxomanoyl oxide derivatives (1 5 a - e ) has been obtainedz1 from Coleus forskohlii (Labiatae). Their oxygenation pattern is reminiscent of that of the tricyclic diterpenoids which have beecobtained from other Coleus species. Is l6
Is
l9
*"
F. Bohlmann and M. Grenz, Chem. Ber., 1977, 110, 1321. A. G . R. Nair, S. S. Subramanian, F. Bohlmann, S. Schoneweiss, and T. J. Mabry, Phylochemistry, 1976,15, 1776. 'Terpenoids and Steroids', ed. K. H. Overton (Specialist Periodical Reports), The Chemical Society, London, 1976, Vol. 6, p. 106 and previous volumes. M. Mpez, C. von Carstenn-Lichterfelde, B. Rodriguez, J. Fayos, and M. Martinez-Ripolli, J. Org. Chem., 1977,42,2517. A. G. Gonzalez, J. M. Arteaga, J. L. Breton, and B . M. Fraga, Phytochemistry, 1977, 16, 107. J. de Pascual Teresa, A. San Feliciano, and M. J. Miguel del Corral, Farm. Nueua, 1976, 41, 343 (Chem. Abs., 1977,86,29 949). S. V. Bhat, B. S. Bajwa, H. Dornauer, N. J. de Souza, and H. W. Fehlhaber, Tetrahedron Letters, 1977, 1669.
Terpenoids and Steroids
126
H
(12) R - H (13) R = O H .,,\
(15) a; R' = H, RZ= 0-OH, R3= P-OAc, R4 = H
3$
R?
b; R ' = H , R 2 = R 3 = P - O H , R 4 = H c; R' = a-OH, Rz= P-OH, R3= 0-OAc, R4= OH d; R' = a-OH, Rz= R3 = 0-OH, R4 = OH e ; R' = a-OH, Rz = 0-OAc, R3 = P-OH, R4 = O H
Vitexilactone, obtained from Vitex cannabifolia (Verbenaceae), has been shownz2 to have the structure (16). It has been correlated with rotundifuran. An interesting iron(ir)-catalysed decomposition of unsaturated cyclic peroxides derived from butadienes leadsz3to 3-alkylfurans. This procedure has been used to convert the peroxide (17) from cis-biformene into the furan (18). Some diterpenoid furans arez4 amongst the constituents of Austroeupatorium inulaefolium (Compositae). These include the diketone austrofoiin (19), the corresponding 12-alcohol, and the 15-alcohol (20). A triol, austroinulin (21), was also identified.
a: do
fl H
H
H OAC
(16)
p / O
*' 23
*'
H. Taguchi, Chern. and Pharrn. Bull. (Japan), 1976,24, 1668. J. A. Turner and W. Herz, J. Org, Chem., 1977,42, 1900. F. Bohlmann, C. Zdero, and M. Grenz, Chern. Ber., 1977, 110, 1034.
/I
Y
Diterpenoids
127
The 15,16: 3,18-di-isopropylidene, 15,16-diacetyl, and 16-mono-O-acetyl-3,18isopropylidene derivatives of lagochilin have been isolated2' from Lagochilus pubescens. A number of new diterpenoids have been obtained from Baffota (Labiatae) species. These include ballonigrin (22; R = Hz) and ballonigrinone (22; R = 0) from B. rupestris.26 7a-Acetoxymarrubiin (23) and ballotenol (24) were isolated2' from B. nigra. Their structures were established by examination of their 'H and 13C n.m.r. spectra.
A group of new tetranorditerpenoids (25)-(27) has been isolatedz8 from the metabolites of Acrostafagmus species. They are clearly related to the antifungal antibiotic LL-Z1271a (see p. 147) which has previously been isolated from this fungus. 0
c,.Ilr. CO,H
Clerodanes.-In a study of South African Mucowania species, a cis-clerodane acid (28) and labdanolic acid were obtainedz9from M. glandulosa. Deoxymarrubialactone (29) has been isolated3' from Chaiturus marrubiastrum. Linarienone (30) is another cis-fused clerodane which has been obtained3' from the roots of Linaria japonica (Scrophulariaceae) and correlated with linaridial. The bacchotricuneatins A (31) and B (32) are two new diterpenoid lactones which were isolated3' from Baccharis trkuneata (Astereae) and whose structures were determined by a combination of spectra and X-ray analysis. 25
Z . I. Mavlyankulova, U. N. Zamutdinov, and Kh. A . Aslanov, Khim. prirod. Soedinenii, 1977,46.
'' G . Savona, F. Piozzi, J. R. Hanson, and M. Siverns, J.C.S. Perkin I, 1977, 322. 27 28
29 30
31
32
G . Savona, F. Piozzi, J. R. Hanson, and M. Siverns, J.C.S. Perkin I, 1977, 497. M. Sat0 and H. Kakisawa, J.C.S. Perkin I, 1976, 2407. F. Bohlmann and C. Zdero, Phytochernistry, 1977,16, 1583. D. P. Popa and L. A. Salei, Khirn. prirod. Soedinenii, 1976,399 (Chem. Abs., 1976,88, 124 188). I. Kitagawa, M. Yoshihara, and T. Kamigauchi, Tetrahedron Letters, 1977, 1221; I. Kitagawa, M. Yoshrhara, T. Tani, and I. Yosioka, Chem. and Phurm. Bull. (Japan), 1976,24,294. H. Wagner, R. Seitz, V. M. Chari, H. Lotter, and W. Herz, Tetrahedron Letters, 1977,3039.
Terpenoids and Steroids
128
AcO
I 0
II
/
/
\
CH,OC C=C Me
Me
H
I
(30)
The ajugarins are a group of trans-clerodanes [I ( 3 3 ) ; I1 ( 3 3 ; 6a-OH);I11 ( 3 3 ; 4a-OH,4/3-CH20H)] which were as insect antifeedants from the leaves of Ajuga remota (Labiatae). Their structures were established by a combination of 'H and I3C n.m.r. studies. Corylifuran, which is a clerodane isolated from Croton corylifolius (Euphorbiaceae), has been assigned34the structure (34) on the basis of an X-ray analysis and a circular dichroism study. Examination of Mallotus repandus (Euphorbiaceae) has afforded35 mallotucin A which is identical with teucrin and the dimethyl ester, mallotucin B ( 3 5 ) . Some further aspects of the chemistry of teucrin A have been described.36 Acid-catalysed cyclization of the pentaol (36), obtained by the reduction of teucrin A with lithium aluminium hydride, affords the cther (37). Teucrin PI, isolated from Teucrium polium (Labiatae), has an interesting structure ( 3 8 ) which is related to this.
: C0,Me
Me0,C
Me0,C
C0,Me
OAc
OAc (33)
(34)
(35)
I. Kubo, Y . W. Lee, V. Balogh-Nair, K. Nakanishi, and A. Chapya, J.CS. Chem. Comm., 1976,949. 34 B. A. Burke, W. R. Chan, E. C. Prince, P. S. Manchand, N. Eickman, and J. Clardy, Tetruhedron, 1976, 32,1881. 35 T. Kawashima, T. Nakatsu, Y. Fukazawa, and S. Ito, Heterocycles, 1976,5, 227. '' A. M. Reinbol'd and D. P. Popa, Khim. prirod. Soedinenii, 1976,752; D. P. Popa, Phan Thug Anh, and L. A. Salei, ibid., 1977, 49. 33
Diterpenoids
129
P O H
'OH
OH
3 Tricyclic Diterpenoids
Naturally Occurring Substances.-Pimara-8(9),15-diene (39) has been detected37 as a metabolite of the fungus Trichothecium roseum. However, it is not an intermediate in the biosynthesis of rosenonolactone. The dihydroxyabietene (40) and its 7a-hydro~y-A~"~'-isomer have been obtained3' from Nepeta granatensis (Labiatae). lsoaplysin-20 (4 l ) is a bromine-containing diterpenoid which has been isofrom the sea-hare, Aplysia kurudai. The location and stereochemistry of the bromine atom suggest that it may play a role in the cyclization stages of the biosynthesis.
& & ,& H I
H
(39)
, H CH20H (40)
H
OH
'CH20H
Br' (41)
A further paper has appeared4' describing salvin and salvin monomethyl ether (42) as antimicrobial substances from Salvia officinalis.Arucatriol(43) and galdosol (44) are related phenolic diterpenoids from Salvia canariensis (Labiatae).41
37 3R
39 40
41
B. Dockerill and J. R. Hanson, J.C.S. Perkin I, 1977, 324. A. G. GonzBlez, J. L. Breton, C. R. Fagundo, and J. M. Trujillo, Anales de Quim., 1976,72,65. S . Yamamura and Y. Terada, Tetrahedron Letters, 1977,2171. V. D. Dobrynin, M. N. Kolosov, B. K. Chernov, and N. A. Derbentseva, Khim. prirod. Soedinenii, 1976,686. A. G. Gonzilez, B. M. Fraga, J. G. Luis, and A. G. Ravelo, Anales de Quim., 1975,71,701.
130
Terpenoids and Steroids
Horminone and the 14-methoxytaxodione (45) have been obtained4' from another Labiate, Hyptis fruticosa. Some more highly oxygenated abietanes have been isolated from Coleus species. Coleon L is a labile diosphenol(46) from Coleus sornaliensis. It rapidly tautomerizes to afford the 6,7-diketone, coleon K. This has led to a revision of the structures of coleons H, I, and 1'. Coleon H is the 15-alcohol corresponding to coleon L whilst coleon I bears the same relationship to coleon K. Coleon I' is the 3-formate. Coleon S (47) and the corresponding diketone, coleon T, have been obtained from Plectrunthus caninus (Labiatae).44 A further paper has appeared45on the diterpenoid quinones of Salvia ballotaeflora, conacytone, icetexone (48), and its ortho-quinone tautomer, romulogarzone. The full paperj6 on the X-ray analysis of icetexone has been published, as has that on the tumour-inhibitory diterpenoids barbatusin and cyclob~tatusin.~~ The unusual C- 1-C- 1 1 four-membered ring of cyclobutatusin can be generated photochemically. Thus irradiation of barbatusin (49) gives48dehydrocyclobutatusin (50).
(46) R' = R2= OAc, R3 = OH (47) R' =OH, R2= R3 = H
The structure ( 51) of a tumour-inhibitory diepoxide, jolkinolide B, isolated from Euphorbia jolkinii, has been established49by X-ray analysis. Three further polar cytotoxic dilactones (52)-(54) have been isolated5' from Podocarpus nagi. Their 42
44
45
46 47
48
49
''
F. Marletti, F. Delle Monache, G. B. Marino-Bettolo, M. do Carmo, M. de Araujo, M. de Salete Barros Cavalcanti, I. L. D'Albuquerque, and 0. GonGalves de Lima, Guzzerra, 1976,106, 119. P. Ruedi and C. H.Eugster, Helv. Chim. Acta, 1977.60, 1233. S . Arihara, P. Ruedi, and C. H. Eugster, Helv. Chim. Acta, 1977,60, 1443. X. A. Dorninguez, F. H. Gonzalez, R. Aragon, M. Gutierrez, J. S. Marroquin, and W. Watson, Plunfa Med., 1976,30,231 (Chem. Abs., 1977,86,21658). Z. Taira, W. H. Watson, and X. A. Dorninguez, J.C.S. Perkin 11, 1976, 1728. R. Zelnik, D. Lavie, E. C. Levy, A. H. J. Wang, and I. C. Paul, Tetrahedron, 1977,33, 1457. R. Zelnik, I. A. McMillan, I. C. Paul, D. Lavia, V.G. Toscano, and R. R. DaSilva, J. Org. Chem., 1977, 42,923. D. Uemura, C. Katayama, and Y. Hirata, Tetrahedron Letters, 1977,283. Y. Hayashi, Y. Yuki, T. Matsurnoto, and T. Sakan, Tetrahedron Letters, 1977,2953.
Diterpenoids
131
structures were established by a careful analysis of their ‘H n.m.r. spectra. An X-ray analysis has been published5’ of a related dilactone, inumakilactone D (55).
OH
co-0
co-0 0
OH
co-0
co-0 (55)
(54)
The momilactones are a group of growth inhibitors which have been isolated from rice husks. X-Ray analysis of momilactone C (56)” and of annonalide (57) ~~ the unusual 9-PH stereochemistry. (from Annona c o r i ~ c e a ) established Annonalide has been converted into momilactone B (58). Momilactone A has the
(56)
(57)
(58)
stereochemistry (59). A number of chemical transformations of the momilactones have been de~cribed,’~ including the retro-aldol cleavage of ring A of momilactone B to afford compounds such as (60). Ineketone (61) is another growth and germination inhibitor of rice. It has been assigned” the unusual rearranged structure with a A*(14)-do~ble bond. The metabolites of Acrernoniurn luzulue (Oosporu uirescens), virescenosides D and H,
** 53 54
55
M.Kodarna, C. Kabuto, M. Sunagawa, and S. Ito, TetrahedronLetters, 1977, 2909. M. Tsunakawa, A . Ohba, N. Sasaki, C. Kabuto, T. Kato, Y. Kitahara, and N. Takahashi, Chem. Letters, 1976, 1157. F. Orsini, F. Pellizoni, A. T. McPhail, K. D. Onan, and E. Wenkert, TetrahedronLetters, 1977, 1085. T. Kato, H. Aizawa, M. Tsunakawa, N. Sasaki, Y. Kitahara, and N. Takahashi, J.C.S. Perkin I, 1977, 250. T. Kato, M. Tsunakawa, N. Sasaki, H. Aizawa, K. Fujita, Y. Kitahara, and N. Takahashi, Phytochemistry, 1977,16,45.
132
fl
HO'. ,..
co-0
Terpenoids and Steroids
o
.
].93
I3C N.m.r. spectroscopy has played a major role in structural determination in the diterpenoid series. Some further compounds in the beyerene (stachene) series have been examined94and the substituent effects have been rati~nalized.’~ 89 90 91
92
93
94
95
M. Node, H. Hori, and E. Fujita, Chem. and Pharm. Bull. (Japan),1976,24,2149. M . Node, H. Hori, and E. Fujita, J.C.S. Perkin I, 1976, 2144. E. Fujita, M. Node, and H. Hori, J.C.S. Perkin f, 1977, 611. N. Fukuzawa, N. Funamizu, Y . Kitahara, and T. Kato, Chem. Letters, 1976, 1253. E. Fujita and M. Ochiai, J.C.S. Perkin I, 1977, 1182: T. Taga, T. Higashi, H. Iizuka, K. Osaki, M. Ochiai, and E. Fujita, ACIUCrysr., 1977, B33, 298. A. A. Chalmers, C. P. Gorst-Allman, and L. P. L. Piacenza, Tetrahedron Letters, 1977, 1665. C. von Carstenn-Lichterfelde, C. Pascaul, R. M. Habanal, B. Rodriguez, and S. Valverde, Tefiahedron, 1977,33, 1989.
137
Diterpenoids
Gibberellins.-A collection of reviews, mainly of a biological character, concerning the gibberellins has appeared.96 The A15(16)-isomerof gibberellin A, has been detected,' in Picea sitchensis. Gibberellin A,, (86) is formed,' from gibberellin A, in Gibberella fujikuroi. Gibberellins A,, (87), A,, (88), and A4, (89) and a new kaurenolide, 7p,12a-hydroxykaurenolide (90), have been isolated99 from Cucurbita pep0 and their structures proven. Gibberellins A1,, AZ5,and A45 have been identified'"" by g.c.-m.s. in Pyrus communis (pear) seed. 16,17-Dihydroxygibberellin A, is formed'"' from gibberellin A, in chloroplast sonicates of Pisum sativum.
HO CO,H
co-0 (88) R=P-OH,(Y-H (89) R = (Y-OH,P-H
(90)
A number of [2+ 21 adducts across the A''2'-double bond of gibberellic acid have been briefly described. The full paper on their X-ray structure has now appeared. Gibberethione, which has been regarded as a possible gibberellin deactivation product, has been preparedlo3from gibberellic acid by the addition of thiopyruvic acid to the AI-3-ketone. Papers have appeared describing the prepand of gibberellin A,.1o5A aration of trititiated gibberellins AZ0,A5, and number of gibberellin glucosides have been isolated and now the partial synthesis of 3 - 0 - and 13-0-glucosyl derivatives of gibberellic acid has been described. lo6 96
97 98
99
loo lo' lo*
Io3 Io4 Io5
'06
'Gibberellins and Plant Growth', ed. H. N. Krishnamoorthy, Wiley-Eastern, Delhi, 1975. R. Lorenzi, P.F. Saunders, J. K. Heald, and R. Horgan, Plant Sci. Letters, 1977,8, 179. A. G. McInnes, D. G. Smith, R. C. Durley, R. P. Pharis, G. P. Arsenault, J. MacMillan, P. Gaskin, and L. C. Vining, Canad. J. Biochem., 1977,55, 728. H. Fukui, K. Koshimizu, S. Usuda, and Y. Yamazaki, Agric. and Biol. Chern. ( J a p a n ) , 1977,41, 175; H. Fukui, R. Nemori, K. Koshimizu, and Y. Yamazaki, Agric. andBioZ. Chem. ( J a p a n ) , 1977,41, 181. G. C. Martin, F. G. Dennis, P. Gaskin, and J. MacMillan, Phytochemistry, 1977,16, 605. I. D. Railton, 2. Ppanzenphysiol., 1977, 81, 323. L. Kutschabsky, G. Reck, B. Voigt, and G. Adam, Tetrahedron, 1976, 32,2021. T. Yokota, H. Yamane, and N. Takahashi, Agric. and Biol. Chem. ( J a p a n ) , 1976, 40, 2507. N. Murofushi, R. C. Durley, and R. P. Pharis, Agric. and Biol. Chem. ( J a p a n ) , 1977,41, 1075. T. Yokota, D. R. Reeve, and A. Crozier, Agric. and Biol. Chem. ( J a p a n ) , 1976,40,2091. G. Schneider, G. Sembdner, and K. Schreiber, Tetrahedron,1977,33, 1391.
138
Terpenoids and Steroids
The preparation of a number of gibberellic acid amino-acid conjugates has also been described.lo7 Another chemical conversion of gibberellin A,, into gibberellin A, through the oxidative decarboxylation of the C-20 carboxy-group with lead tetra-acetate has been reported.'" Photolysis of the methyl ester of the isogibberellin (91) (gibberellin C) p r o c e e d ~ " ~through a Norrish Type I cleavage to afford a secoaldehyde which then undergoes an intramolecular [2 + 21 cycloaddition to give the oxetan (92).
HO CO,Me
C0,Me
In continuation of previous work, the reactions of gibberellin A, and A, with neutral manganese dioxide have been examined.'" The products include those of decarboxylation and of lactonization on to C-15. The full paper describing the interesting bridgehead C- 13 fluorination of gibberellins with fluoramine has appeared."' A number of papers on the biological activity of gibberellins and their derivatives have appeared."' The stimulation of plant mRNA synthesis by gibberellic acid has been noted.'I3 A review of some aspects of gibberellin biosynthesis has been p~b1ished.l'~ The origin of both the oxygen atoms of the lactone ring of the C,, gibberellins lies in the C-19 carboxy-group of the Cz0 precursor^.^'^ There was no loss in " 0 content when gibberellin A,, alcohol (93), labelled in the 19-carboxy-group, was fed to Gibberellafujikurui, and the C,, gibberellins, such as gibberellic acid, were isolated. The metabolism of a number of gibberellins by higher plants has been studied. The content of endogenous gibberellins in higher plants changes during seed development, maturation, and germination.l16 Gibberellins A,, A,, A5, and A,, were fed to immature bean seeds for 3 and 10 day periods. Gibberellin A, (94) was converted by hydroxylation at C-13 into gibberellin A, (95) and thence by hy-. droxylation at C-2 into gibberellin A, (96) whilst gibberellin A,, (97) was con'07
'08
'09
'lo 'I'
'''
'I6
M. Lischewski and A . Guenter, 2. Chem., 1976,16,357; G. Adam, M. Mischewski, F. J. Sych, and A. Ulrich, Tefruhedron, 1977, 33, 95. N. Murofushi, I. Yamaguchi, H. Ishigooka, and N. Takahashi, Agric. and Biol. Chem. ( J u p n ) , 1976, 40,247 1 . G. Adam and T. V. Sung, Tetrahedron Leffers,1976,3989. E. P. Serebryakov and V. F. Kucherov, Tetrahedron, 1976,32, 2599. R. E. Banks and B. E. Cross, J.C.S. Perkin I, 1977, 512. G. V. Hoad, R. P. Pharis, I. D . Railton, and R. C. Durley, PZuntu, 1976,130, 113; S. Okuda, S. Sanai, Y. Kimura, S. Tamura, and A. Tahara, Agric. and Biol. G e m . (Japan), 1976, 40, 1327; T. W. A . Jones, PhyfochemDtry, 1976,15, 1825. L. D . Wasilewska and K. Kleczkowska, European J. Biochem., 1976,66,405. J. R. Bearder and V. M. Sponsel, Biochem. SOC.Trans., 1977,5,569. J. R. Bearder, J. MacMillan, and B. 0. Phinney, J.C.S. Chem. Comm., 1976, 834. H. Yamane, N. Murofushi, H. Osada, and N. Takahashi, Phytachemistry, 1977,16,831; I. Yamaguchi and N. Takahashi, Plunf Cell Physiol., 1976,17,611.
Diterpenoids
139
verted into gibberellins A, (95), A, (96), and A,, (98). Gibberellin was only converted into the glucosyl ester as the seed matured. Gibberellin A, (94) was also converted"' into gibberellins A, (95) and A34(99) by the germinating pollen of Pinus attenuata.
(93)
(94) R'
= R3= H, R2 = OH K' = H, R2 = R3 = OH (96) R' = R2= R3= OH (97) R' = R2 = H, R3= OH (98) R' = OH, R2 = H, R3=OH (99) R' = R2 = OH, R3 = H
(95)
Grayanotoxim-Pieris japonica (Ericaceae) contains a number of diterpenoid toxins. An X-ray analysis of pieristoxin G (100) has been published'18 and the structures (101)-(103) have been assigned''' to asebotoxins VI, VIII, and IX respectively.
HO OH
Diterpenoid Alkaloids.-The structure and synthesis of the diterpenoid alkaloids have been reviewed.I2' The subject is also covered in detaiI in the Specialist Periodical Report o n the Alkaloids. A number of new alkaloids with the entkaurene skeleton have been isolated from Anopterus glandulosus and A. macleayanus. The structure of the major alkaloid anopterine (104) was assigned121 A. Kamienska, R. C. Durley, and R. P. Pharis, Plant Physiol., 1976, 58, 68. H. Fukuyama, T. Tsukihara, Y. Katsube, M. Katai, and H. Meguri, Chem. and Pharm. Bull. (Japan), 1976,24277'5.
I2O
12'
H. Hikino, M. Ogura, S. Fushiya, C. Konno, and T. Takemoto, Chem. and Pharm. Bull. (Japan), 1977, 25, 523. S. W. Pelletier and S. W. Page, in 'Alkaloids', ed. K. Wiesner, MTP International Review of Science, Organic Chemistry Series Two, Vol. 9 , Butterworths, London, p. 53. N. K. Hart, S. R. Johns, J. A. Lamberton, H . Suarcs, and R. I. Willing, Austral. J. Chem., 1976, 29, 1295.
Terpenoids and Steroids
140
on the basis of chemical and spectral studies and an X-ray analysis of the methiodide of anopteryl alcohol tetra-acetate. Minor alkaloids include"' anopterimine (1 OS), its N-oxide, and some alkaloids with additional hydroxy-groups at C-1 or C-3. 0
II
0-c-c=c
OR
/
H
Me
\
( 104) R = C-C=C
II
0
/Me 'H
The isomerization of atisine to isoatisine and the conformational analysis of rings E and F of atisine, veatchine, and related alkaloids have been by 13C n.m.r. spectroscopy. 12-0-Acetylnapelline is a new alkaloid which has been isolatedIz5from Aconitum karakolicum. The alkaloids of Delphinium staphisagria have been reviewed.'26 Delphidine has been shown to possess the structure ( 106)127whilst delphirine (107) possesses the unusual C- 1 hydroxy-group."* Staphigine and staphirine are bisditerpenoid alkaloids which have been ~ b t a i n e d "from ~ D . staphisagria. Examination of D. tricorne a f f ~ r d e d ' ~a" new alkaloid tricornine (108) which was shown to be 18-acetyl-
R2
(106) R' = a-OH, R' = OMe, R3 = H, R4 = OAc, R5=OH (107) R' = p-OH, R2 = OMe, R3 = H, R4= OH, R5 = OH (108) R' = H, R2= OAc, R3 = R4= OH, R5= OMe (109) R' = p-OMe, R2 = o-02CC6H4NHAc,R3 = R4 = R5= OH
lZ3 124
12'
'26
'21
'"
N. K. Hart, S. R. Johns, J. A. Lamberton, H. Suares, and R. A. Willing, Austral. J. Chem., 1976,29, 1319. S. W. Pelletier and N. V. Mody, Tetrahedron Letters, 1977, 1477. S. W. Pelletier and N. V. Mody, J. Amer. Chem. SOC.,1977,99, 284. M. N. Sultankhodzhaev, L. V. Beshitaishvili, M. S. Yunusov, and S . Yu. Yunusov,. Khim prirod. Soedinenii, 1976, 681. S. W. Pelletier and N. V. Mody, Heterocycles, 1976,5, 771. S. W. Pellktier, J. K. Thakkar, N. V. Mody, Z . Djarmati, and J. Bhattacharyya, Phytochemistry, 1977, 16, 404. S. W. Pelletier and J. Bhattacharyya, Tetrahedron Leners, 1976, 4679. S. W. Pelletier, N. V. Mody, Z. Djarmati, and S. D. La@, J. Org. Chem., 1976, 41, 3042. S. W. Pelletier and J . Bhattacharyya, Phytochemistry, 1977,16, 1464.
Diterpenoids
141
lycoctonine. A 'T n.m.r. study of delsemine, previously isolated from D. semibar' it was a mixture of bases arising from batum and D. tricorne, ~ h o w e d ' ~that methyl-lycaconitine during work-up. An alkaloid isolated'32from D. dictyocarpum is N-acetyldelectine (109). Veratroylpseudoaconine, pseudoaconitine, and indaconitine have been from Aconiturn falconeri. Bishaconitine, previously isolated from this source, is probably a mixture. Two novel alkaloids, falaconitine (110) and mithaconitine (1 1 l), are the first naturally occurring members of this series with an 8(15)-double Umbrosine, from A. unbrosurn, has been assigned135the structure (1 12).
& ---.-.
,OMe
Me
-------
L- -N HO-'
H a OMe OMe (110) R = veratroyl (111) R = benzoyl
OMe (112)
5 Macrocyclic Diterpenoids and their Cyclization Products Incensole (113) and isoincensole oxide (114) have been ~ y n t h e s i z e dfrom ' ~ ~ mukulo1 by methods which allow the determination of their stereochemistry. The X-ray analysis of a thunbergadienediol (115), obtained from Greek tobacco, has been described.13'
A large number of cembrane diterpenoids have been obtained from marine organisms, particularly soft corals. 2-Hydroxynephthenol (116) was isolated138 from Litophyton uiridis. A dehydro-derivative (117) of epoxynephthenol was S. W. Pelletier and J. Bhattacharyya, Tefmhedron Letters, 1977, 2735. B. T. Salimov, M. S. Yunusov, and S. Yu. Yunusov, Khim. prirod. Soedinenii, 1977, 128. 133 S. W. Pelletier, N. V. Mody, and H. S. Puri, Phytochernistry, 1977,16, 623. 134 S. W. Pelletier, N. V. Mody, and H. S. Puri, J.C.S. Chern. Comm., 1977, 12. 135 V. A. Tel'nov, N. M. Colubev, and M. S. Yunusov, Khim. prirod. Soedinenii, 1976, 675. 136 T. Kato, C. C. Yen, T. Uyehara, and Y. Kitahara, Chem. Letters, 1977, 565. 13' A. J. Aasen, A. Pilotti, C. Enzell, J. E. Berg, and A. M. Pilotti, Actu Chem. Scund., 1976, B30,999. 13' B. Tursch, J. C. Braekman, and D. Daloze, Bull. Soc. chim. belges, 1975,84, 767. 13' 13'
Terpenoids and Steroids
142
isolated'39 from a Surcophyton species and its structure established by X-ray crystallography. Lobolide (118) was obtained14' from a Lobophytum species. The full paper o n the X-ray analysis of lobophytolide (119) has appeared.14' The structure and absolute configuration of sinulariolide (120) have been dete~mined.'~' 6-Hydroxysinulariolide (1 12) and 11-dehydrosinulariolide (122) are minor diterpenoids of the soft coral S i n u l a r i ~ ~ e x i b i l i sAsperdiol(l23) .'~~ is a marine anticancer agent which has been isolated'44 from the gorgonians Euniceu asperulu and E. toumeforti. Its structure was established through an X-ray analysis.
@
R2 (120) R' =@-OH,R2 = H (121) R' = R2 =,f-OH (122) R ' = O , R = H
mm
The oxidation of various cembrane diterpenoids by chromium trioxide has been noted.145 The full paper on the X-ray analysis of ovatodiolide and ovatodiolic acid has appeared.'46 Detailed n.m.r. studies have led147to the structures (124)-(127) K'0 0
OH
-'.O
(124) R' =cinnamate;'R2 = CH20H (125) R' = cinnamate, R2 = Me '31
14' '41 143 144
145 146
'41
R2 (126) R' (127) R'
= H,
RZ= 0 R2= H,OH
= Ac,
J. C. Coll, G. B. Hawes, N. Liyanage, W. Oberhansli, and R. J. Wells, Austral. J. Chem., 1977, 30, 1305. Y. Kashman and A. Groweiss, Tetrahedron Letters, 1977, 1159. R. Karlsson, Acta Cryst., 1977, B33, 2032. R. Karlsson, Actu Cryst., 1977, B33, 2027. M. Herin and B. Tursch, Bull. SOC.chim. belges, 1976,85, 707. A. J. Weinheimer, J. A. Matson, D. van der Helm, and M. Poling, Tetruhedron Letters, 1977, 1295. V. A. Raldugin, V. K. Fedorov, and V. A. Pentegova, Khim. prirod. Soedinenii, 1976, 313. R. Toubiana, M. J. Toubiana, A. T. McPhail, R. W. Miller, and K. Tori, J.C.S. Perkin II, 1976, 1881. D. Uemura, K. Nobuhara, Y. Nakayama, Y. Shizuri, and Y. Hirata, Tetrahedron Letters, 1976 4591
Diterpenoids
143
respectively for a group of new lathyrane diterpenoids, jolkinols A, B, C, and D, which were isolated from Euphorbia jolkini. The toxic and irritant diterpenoid constituents of the Euphorbiaceae have continued to attract attention.'48 A combined t.1.c.-m.s. technique for the identification of these inflammatory toxins has been described.'49 Ingenol has been detected'" in the latex of Euphorbia seguieriana. The 12-0-isobutyl-13-acetoxy20-angelate (128) of phorbol has been i ~ o l a t e d ' ~from ' the latex of E. frankiana and E. coerulescens and some aromatic esters of 12-deoxyphorbol (129) and proresiniferatoxin (130)were found'52 in E. poisonii. The same latex afforded'" the candletoxins A and B which are esters of 12-deoxy-16-hydroxyphorbol.The former is the 13-phenylacetatc-16-a-methylbutyrate-20-acetate(131) and the a latter is the C-20 desacetyl derivative. The latex of E. tirucalli ~ontains"~.'~' series (132)-(140) of highly unsaturated esters of phorbol and 4-deoxyphorbol together with some 3-0-acylingenol derivatives esterified with the same unsaturated fatty acids.
8' "OCAr 0 CH ,OC Ar
I1
CH,0R4
0
20
( 1 30)
(128) (129) (13 1) (132) (133) (134) (135) (1 36) (137) (138) (139) (140)
R' = 02CCH2Pri,R2 = OAc, R3 = H, R4 = OAng, R5= O H R' = H, R2 = OzCAr, R3= R4= H, R5 = OH R' = H, Rz= 02CAr, R3= 02CBu",R4 = Ac, R5 = OH R' = O,C(CH=CH),CH,CH,Me, R2 = OAc, R3 = R4 = R5 = H R' = OAc, R2 = O2C(CH=CH),CHZCHzMe,R3= R4= R5= H R' = OAc, R2 = 02C(CH=CH)5CH2CH2Me,R3 = R4 = R5= H R' = OAc, R2 = 02C(CH=CH)4(CHz)4Me,R3= R4= R5= H R' = 02C(CH=CH)ZCH2CH2Me, R2 = OAc, R3 = R4 = H, R' = OH R' = 02C(CH=CH)3CH2CH2Me, R2= OAc, R3= R4 = H, R5 = OH R' = OZC(CH=CH),CH2CH2Me,R2 = OAc, R3= R4 = H, R5 = OH R' = OzC(CH=CH),(CH2),Me, R2 = OAc, R3 = R4 = H, R5= OH R' = OAc, R2 = 02C(CH=CH)5CH2CH2Me,R3 = R4 = H, K' = OH
Odoracin (141) is an insecticidal constituent of Daphne odora which contains an unusual deca-2,j-dienoate ortho-ester function. ' 5 6 Gnidilatidin (142) and gnidi14R 149
Y. Hirata, Pur Appl. Chem., 1975, 14, 175. F. J. Evans, R. J. Schmidt, and A. D. Kinghorn, Biomed. Mass Specfromefry, 1975,2,126 (Chem. A h . ,
1976,85, 143 324). R. R. Upadhyay, M. H. Zarintan, and M. Ansarin, PIunru Med., 1976,30, 196 (Chem. A h . , 1976,85, 139 787). Is' F. J. Evans, Phyfochemistry, 1977,16, 395. Is* R. J. Schmidt and F. J. Evans, Phytochemistry, 1976,15, 1778. 1 5 3 R. J. Schmidt and F. J. Evans, Experienfiu, 1977, 33, 1197. G. Furstenberger and E. Hecker, Tetrahedron Leffers, 1977,925, "'G. Furstenberger and E. Hecker, Exprienfia, 1977, 33, 986. S. Kogiso, K. Wada, and K. Munakata, Agric. and Bid. Chem. ( J u p n ) , 1976,40, 21 19. ''O
Terpenoids and Steroids
144
glaucin (143) are antileukaemic diterpenoid esters which have been obtained'" from Gnidia lutifolia and G. glaucus (Thymelaceae). Gnidimacrin (144) and its C-20 palmitate are related macrocyclic esters which were isolated from G. subcorduta. Their structures were established'" by X-ray analysis. A novel diterpenoid hydrocarbon, flexibilene (1 45), possessing a 15-membered ring has been from the soft coral Sinuluriu flexibilis.
Me
(141) R' = (CH=CH),(CH,),Me, R2 = 02CPh, R3 = H (142) R' = (CH2),Me, R2 = 02CPh, R3= 02C(CH ) Me (143) R' = (CH=CH),(CH,),Me, R2= O,CPh, R3b402C(CH2)14Me
6 Miscellaneous Diterpenoids Investigations into marine organisms have led to the isolation of a number of new skeletal types of diterpenoid. Some of these are prenylated relatives of sesquiterpenoid skeleta. Thus dilophol (146), obtainedI6' from the brown alga Dilophus ligulatus, has a ten-membered ring which is reminiscent of a germacrene. The unusual structures of dictyoxepin (147) and dictyolene (148) from Dicfyotu ucutibola were detennined161by X-ray analysis. lS7
lSR
lS9
'"
S. M. Kupchan, Y. Shizuri, W. C. Sumner, H. R. Haynes, A. P. Leighton, and B. R. Sickles, J. Org. Chem., 1976,41,3850. S. M. Kupchan, Y. Shizuri, T. Murae, J. G. Sweeny, H. R. Haynes, M. S. Shen, J. C. Barrick, R. F. Bryan, D. van der Helm, and K. K. Wu, J. Amer. Chem. Suc., 1976,98,5719. M. Herin, M. Colin, and B. Tursch, Bull. SUC.chim. beiges, 1976,85,801. V. Amico, G. Oriente, M. Piattelli, C. Tringali, E. Fattorusso, S. Magno, and L. Mayol, J.C.S. Chem. Cumm., 1976, 1024. H. H. Sun, S. M. Waraszkiewicz, K. L. Erickson, J. Finer, and J. Clardy, J. Amer. Chem. SUC.,1977,99, 3516.
Diterpenoids
145
(148)
A group of guaiane diterpenoids including dictyol B acetate (149) and dictyotadiol (150) has been obtained162from the brown seaweed Dictyotu dichotomu. Dictyol C (151) from Aplysiu depiluns, dictyol D (152) from Dictyotu dichotomu, and dictyol E (153) from Dilophus 1igulul;Usare further examples of this structural type.'63 The em-epoxide of pachydictyol A (154) was from Dictyotu flabellutu.
(149) (151) (152) (153)
R' = H, R2 = OAc, R3 = H R'=R2=R3=H R'=OH, R Z = R 3 = H R'=R'=H, R ~ = O H H 0-
I
I
( 154)
Sacculatal (155) and its C-9 epimer, isosacculatal, are165two diterpenoid dialdehydes which contribute to the pungent odour of the liverwort, Trichocoleopsis succulutu. Their structures bear a resemblance to the sesquiterpenoid drimanes. A diterpenoid analogue of the cadinene group is found'66 in the structure of dihydroxyserrulatic acid (156),from Eremophilu serrulutu (Myoporaceae). Ptilosarcone (157) is a toxin which was i~olated'~'from the sea pen, Ptilosurcus gurneyi. Its structure was assigned by comparison of its n.m.r. spectrum with that of 163
'"
D. J. Faulkner, B. N. Ravi, J. Finer, and J. Clardy, Phytochemisiry, 1977,16, 991. B. Danise, L. Minale, R. Riccio, V. Arnico, G. Oriente, M. Piattelli, C. Tringali, E. Fattorusso, S. Magno, and L. Mayol, Experientia, 1977,33,413. K. J. Robertson and W. Fenical, PhytochemisQ, 1977, 16, 1071. Y.Asakawa, T. Takemoto, M. Toyota, and T. Aretani, Tetrahedron Letters, 1977, 1407. K. D . Croft, E. L. Ghisalberti, P. R. Jefferies, C. L. Raston, A. H. White, and S. R. Hall, Tenahedron, 1977,33,1475. S. J. Wratten, W. Fenical, D . J. Faulkner, and J. C. Wekell, Tetrahedron Letters, 1977, 1559.
Terpenoids and Steroids
146
briarein A (158), a constituent of Briareum asbestinum, whose structure had been determined by X-ray analysis.16* Stylatulide (159) is another sea pen toxin whose structure was also determined’”’ by X-ray analysis. Xenicin (160) is a diterpenoid possessing an unusual nine-membered ring. It was i ~ o l a t e d ”from ~ the soft coral Xenia elongatu and its structure was proven by an X-ray analysis.
OAc
0
AcO--
,OAc
.
-CI
0
(1 59)
Bromosphaerol (161) is a dibromo-diterpenoid from the red alga Sphaerococcus coronopifolius. Its structure was determined”’ through a combination of n.m.r. spectroscopy and X-ray analysis of a degradation product. A group of novel diterpenoids has been isolated from the sticky secretions of the frontal glands of nasute termite soldiers. The structure of trinervi-2P,3a,9a-triol J. E. Burks, D. van der Helm, C. Y. Chang, and L. S. Ciereszko, Acfu Cryst., 1977, B33,704. S. J. Wratten, D. J. Faulkner, K. Hirotsu, and J. Clardy, J. Amer. Chem. Soc., 1977,99, 2824. D. J. Vanderah, P. A. Steudler, L. S. Ciereszko, F. J. Schmitz, J. D. Ekstrand, and D. van der Helm, J. Amer. Chem. Soc., 1977,99, 5780. E. Fattorusso, S. Magno, C. Santacroce, D. Sica, B. di Blasio, C. Pedone, G. Impellizzeri, S. Mangiafico, G. Oriente, M. Piattelli, and S. Sciuto, Guzzeftu, 1976, 106, 779.
lbY ”O
147
Diterpertoids
9-0-acetate (162), 'which possesses a bridgehead double bond, was e~tablished'~' by X-ray analysis. The structures of the congeners were then related to this by a series of spectral correlation^.^'^ Cinnzeylanine (163) and its desacetoxy alcohol, cinnzeylanol, are insecticidal polyhydroxylated pentacyclic diterpenoids, which were isolated from Cinnamonum zeylunicum. Their structure, which is similar to that of ryanodine, was established by X-ray
Br
HO
OH (161)
( 162)
(163)
7 Diterpenoid Total Synthesis Synthetic endeavours have continued in the diterpenoid series. The cyclization of geranylgeranic acid chloride to derivatives of cembrene, and their conversion into cembrene itself, have been d e ~ c r i b e d . " ~Some further extensions of the route to macrocyclic diterpenoids based on the intramolecular cyclization of epoxysulphides and the subsequent modification of the macrocylic product have been described. 176 A stereoselective total synthesis of the antifungal mould metabolite (*)-LLZ1271a (165) from the readily available Wieland-Miescher diketone, tliu the keto-lactone (164), has been d e ~ c r i b e d . 'A~ ~synthesis of grindelic acid (167) from the unsaturated 7-toluene-psulphonate (166) utilized'78 an intramolecular solvolysis of the toluene-psulphonate to construct the 9-1 3 ether bridge. A n alternative synthesis of the tricyclic intermediate (168), together with the elaboration of C-4 with the configuration of both podocarpic and dehydroabietic acids, has been r e ~ 0 r t e d . IIn~ ~a stereoselective total Synthesis''' of (*)-callitrisic acid and (*)-podocarpic acid, the C-4 stereochemistry was established by reductive methylation of the enol-ether (169). In an A + B --+ C approach to diterpenoid total synthesis, the Michael addition of t-butyl P-keto-esters to the unsaturated aldehyde (170) formed"' a key step. 172
173
174
179
'"
G. D. Prestwich, S . P. Tanis, J. P. Springer, and J. Clardy, J. Amer. Chem. SOC., 1976,98,6061. G. D. Prestwich, S. P. Tanis, F. G. Pilkiewicz, I. Miura, and K. Nakanishi, J. Amer. Chem. SOC.,1976, 98.6062. A.'Isogai, A. Suzuki, S. Tamura, S. Murakoshi, Y. Ohashi, and Y. Susuda, Agric. und Biol. Chem. (Jupan), 1976,40,2305. T. Kato, T. Kobayashi, T. Kumagai, and Y. Kitahara, Synrh. Comm., 1976,6, 365. M. Kodama, K. Shimada, and S. Ito, Tetrahedron Lerrers, 1977, 2763. S. C. Welch, C. P. Hagan, D. H. White, W. P. Fleming, and J. W. Trotter, J. Amer. Chem. Soc., 1977, 99,549. M. Adinolfi, G. Laonigro, M. Parrilli, and L. Mangoni, Gazzefru,1976, 106, 625. J. W. Huffman and P. G. Harris, J. Org. Chem., 1977,42, 2357. S. C. Welch, C. P. Hagan, J. H. Kim, and P. S. Chu, J. Org. Chem., 1977,42,2879. W. L. Meyer, R. A. Manning, P. G. Schroeder, and D. C. Shew, J. Org. Chem., 1977,42,2754.
Terpenoids and Steroids
148
The subsequent cyclization of the adduct (171) afforded tricylic compounds such as (172). The stereochemistry of these products has been the subject of detailed study. This approach has been used'" in a total synthesis of methyl (*)-dehydroabietate. The synthesis of bicyclic compounds such as (173) with angular C-10 functionality has also been r e p ~ r t e d . " ~ A convenient synthesis of (*)-taxodione, (*)-ferruginol, and (*)-sugiol the addition of a substituted benzyl chloride moiety to the aldehyde group of cyclocitral and subsequent oxidation. Cyclization of the product (174) afforded the tricyclic system (175) which was then elaborated further. This 0
M 2& e:
(168)
0
(po
@
H
0
Et0,C (173)
0
(174)
"'W. L. Meyer and C. W. Sigel, J. Org. Chem., 1977,42,
0 (175)
2769. W. L. Meyer, T. E. Goudwin, R. J. Hoff, and C. W. Sigel, J. Org. Chem., 1977.42, 2761. T.Matsumoto, S. Usui, and T. Morimoto, Bull. Chem. SOC.(Jupun),1977,50, 1575.
Diterpenoids
149
approach has been utilized'85 in a synthesis of (*)-maytenoquinone and (*)-dispermol. The of ferruginol and methyl 12-hydroxydehydroabietate at C-11 with benzoyl peroxide to afford the 1l-phenols has provided a route for the synthesis of taxoquinone, royleanone, and horminone from ferruginol. Some studies directed at the total synthesis of the triepoxide triptolide have been reported.'** The synthesis of the furan (176)lS9and its conversion into the triester ( I 77) as an intermediate in the synthesis of fujenoic acid have been described."" The metalammonia reduction of some polyfunctional tetrahydrofluorenes with the object of preparing intermediates for gibberellin synthesis has been noted.'"
(176)
(177)
The full paper has appeared on a synthesis of steviol.1'2 The route was based on the stereocontrolled photoaddition of allene to the cyclopentene- l-aldehyde (178), reduction of the aldehyde, and then solvolysis of the methanesulphonate (179). Papers on the synthesis of the aromatic ether (180)193 and o n the constructiqn of the C/D ring system of the alkaloid ~ h a s m a n i n ehave ' ~ ~ been published.
T. Matsumoto and T. Ohmura, Chem. Lefters, 1977,335. T. Matsumoto and S. Harada, Chem. Letfers, 1976, 13 11. T. Matsumoto, Y. Ohsuga, S. Harada, and K. Fukui, Bull. Chem. Soc. (Japan), 1977,50,266. "'F. T. Sher and G. A. Berchtold, J. Org. Chem., 1977,42,2569. T. Kato, T. Suzuki, N . Ototani, H. Maeda, K. Yamada, and Y. Kitahara, J.C.S. Perkin I, 1977,206. I9O T. Kato, T. Suzuki, N. Ototani, and Y. Kitahara, Chem. Letters, 1976, 887. 19' Y. Yamada and H. Nagaoka, Synthesis, 1977, 577. IYzF. E. Ziegler and J . A. Kloek, Tetrahedron, 1977,33, 373. 193 T. Kametani, Y. Kato, T. Honda, and K. Fukumoto, J. Amer. Chem. Soc. 1976,98,8185. 194 K. Wiesner, 1. H. Sanchez, K. S. Atwal, and S. F. Lee, Cnnad. J. Chem., 1977,55, 1091.
4 Triterpenoids BY J. D. CONNOLLY
1 Squalene Group The biogenetic-type rearrangement of terpenoids has been reviewed.' The latest results from van Tamelen's laboratory concerning terpenoid terminal epoxide polycyclizations indicate that ring A is formed with a high degree of neighbouring n-bond participation during epoxide opening and suggest that the overall process is not fully concerted but involves a series of conformationally rigid cyclic carbonium ion intermediates.' Further detailed study of the substrate specificity of yeast squalene synthetase has been reported' (see Vol. 7, p. 130). The enzyme is very sensitive to changes in substrate. For example, 10,ll-dihydrofarnesyl pyrophosphate was converted into 2,3,22,23-tetrahydrosqualene with only 60% of the efficiency of farnesyl pyrophosphate whereas 6,7-dihydro- and 6,7,10,11 -tetrahydro-farnesyl pyrophosphates were not metabolized. The first of the two binding sites has a greater preference for farnesyl pyrophosphate and this accounts for the formation of the unsymmetrical squalene product when mixtures of farnesyl pyrophosphate and a modified substrate are used. The importance of the methyl groups, especially that at C-3, for binding is emphasized by the low efficiency of conversion of 3-desmethylfarnesyl, E,E-3-methylundeca-2,6-dien1-yl (l), and E,E-7desmethylfarnesyl pyrophosphates. The prenylated cyclobutanones (2) and (3) Y
O
P
do
P
R' (2) R' = geranyl, R' = H (3) R' = geranyl, R' = tetrahydrogeranyl
~ compounds have weak activity as inhibitors of yeast squalene ~ y n t h e t a s e .The were prepared by polar cycloaddition of the ketene-immonium cations (4) and (5) to the tetraene (6). The synthesis failed when the intermediate (7), with a geranyl substituent, was used. The full details of the resolution of 2,3-dihydrosqualene-2,3-
*
R. M. Coates, Fortschr. Chem. org. Nuhustoffe, i 9 7 6 , 33, 73. E. E. van Tamelen and D. R. James, .I. Amer. Chem. SOC., 1 9 7 7 , 9 9 , 9 5 0 .
' W. N. Washburn and R. Kow, Tetrahedron Letters, 1977, 1555.
P. R. Ortiz de Montellano and R. Castillo, Tefruhedron Letters, 1976, 41 15.
150
151
Triterpenoids
(6) R = geranyl
(4) R = H (5) R = tetrahydrogeranyl (7) R = geranyl
diol and the synthesis of (3R)- and (3S)-2,3-epoxy-2,3-dihydrosqualene have appeared.' The biosynthetic implications for the cyclization of squalene of the fact that natural sterols have the same configuration at C-20 have been discussed6 and are illustrated in Scheme 1.
Scheme 1
Squalene 2,3-oxide is converted into a-amyrin by microsomes of bramble cell suspension culture^.^ This system is particularly useful for studying a-amyrin since it constitutes more than 70% of the pentacyclic triterpenoid fraction. Squalene is one of the major products when [2-'4C]mevalonate is fed to a cell-free system of retarded young iris leaf (Iris hollaidica).8 Investigation of the biosynthesis of sitosterol in the pea from (3RS,2R)- and (3RS,2S)-[2-'4C,2-3H]mevalonate suggests that the pattern of transformation of the tetracyclic moieties is the same in the pea and in rat liver tissues regardless of whether cycloartenol or lanosterol is the p r e c u r ~ o r An . ~ independent I3C n.m.r. study of the spin-lattice relaxation times of squalene supports the conclusion reported last year (see Vol. 7, p. 131) that the conformation of the molecule does not alter greatly on increasing the aqueous content of the medium." These results render unlikely t h e suggested 'coiling' explanation for the selective terminal oxidation of squalene with N-bromosuccinimide. The biosynthesis of triterpenoids in the latex of Hoya australis, H. carnosa, Euphorbia pulcherrima, and related species has received detailed attention."*" R. B. Boar and K. Damps, J.C.S. Perkin I, 1977,709. W. R. Nes, J. E. Varkey, and K. Krevitz, J. Amer. Chem. SOC.,1977,99, 260. ' J. W. Elder, P. Benveniste, and P. Fonteneau, Phyfochemistry,1977,16,490. ' N. Ceccarelli, A. Alpi, R. Lorenzi, and M. Benetti, PIanf Sci. Letters, 1977,8, 257. J. K. Sliwowski and E. Caspi, J. Amer. Chem. Soc., 1977, 99, 4479. '" J. M. Brown and D . R. M. Martens, Tetrahedron,1977, 33,931. I ' H. W. Groeneveld and J. Koning, Actu Botun. Neerl., 1976, 25, 227. *'H. W. Groeneveld, Acta Botan. Neerl., 1976, 25, 459.
Terpenoids and Steroids
152
The timing of triterpenoid biosynthesis in developing Sorghum bicolor grains and in Pinus pinea has been i n ~ e s t i g a t e d . ’ ~ ” ~ The detailed structure of caldariellaquinone (12), a unique benzo[b]thiophen~ experi4,7-quinone from Caldariella acidophila, has been e 1 ~ c i d a t e d . lFeeding ments with I3C-labelled acetate helped to define the nature and biosynthetic origin of the C,’ isoprenoid chain.
The chemistry of the Daphniphyllum alkaloids has been reviewed. “J’ Terpenoid alkaloids are also reviewed in the Specialist Periodical Report ‘The Alkaloids’. Two new alkaloids, deoxyyuzurimine (13) and isodaphnilactone B (14), have been isolated from the leaves of Daphniphyllum gracile.’”
2 Fusidane-Lanostane Group The enedione (15), a tetracyclic intermediate o n a synthetic route to fusidic has been synthesized from the a-methylene-ketone (16) (Scheme 2). The first step, involving a Diels-Alder reaction with a substituted acrylate (17), provides a new versatile annelation procedure. Further modification of (15) by a route worked out on model systems (see Vol. 4, p. 318) afforded the tetracyclic enone (24) with the desired trans-syn-trans geometry (Scheme 3 ) . This compound (24) has also been prepared by degradation of fusidic acid.*’ Attempts to introduce the C- 11 oxygen function necessary for the synthesis of fusidic acid have not been very 13
14 19
16
17
in IY
20
M. A. Palmer and B. N. Bowden, Phyfochemisfry, 1977,16,459. M. L. McKean and W. R. Nes, Lipids, 1977, 12, 382. M. De Rosa, S. De Rosa, A. Gambacorta, L. Minale, R. H. Thomson, and R. D. Worthington, J.C.S. Perkin I, 1977,653. S . Yamamura and Y. Hirata, ‘The Alkaloids’, Vol. XV, ed. R. H. K. Manske, Academic Press, New York, 1975, p. 41. S. Yamamura and Y. Hirata, in ‘Alkaloids’, ed. K. Wiesner, M.T.P. International Review of Science, Organic Chemistry Series Two, Volume 9, Butterworths, London, 1976, p. 161. S. Yamamura and Y. Terada, Chem. Letters, 1976, 1381. R. E. Ireland, P. Beslin, R. Giger, U. Hengartner, H. A. Kirst, and H. Maag, J. Org. Chem., 1977,42, 1267. R. E. Ireland, R. Giger, and S. Kumata, J. Org. Chem., 1977,42, 1276.
Triterpenoids
153
(15) Reagents: i, A, 180"C; ii, LiAIH4-Et20; BuLi-THF-TMEDA-CIPO(NMe2)z;iii, Li-Ph2-THF, MeI; iv, O-,-MeOH, Me2S; v, 0. 18M-KOH-H20-MeOH; vi, Li-NH3-THF-H20, MeI, H 3 0 +
Scheme 2
i, vi-viii,
H
@oTB:-x,,
0
:
t
S
0
H
O H
iiiJ
T
B
S
H
(23)
(24)
Reagents: i, Li(OBut)3AIH-THF; ii, (CH2oH)2-Hf-C6H6; iii, ButMe2SiCI-imidazole-DMF; iv, MCPBA-CH,CI,; v, BF3-CH&; vi, LDA-THF, CIPO(NMe2)2-THF-HMPA; vii, Lix, DDQ-C&; xi, (Ph3P)3RhCIBu'OH-THF-EtNH2; viii, H30+; ix, NaH-HC02Et-C,&; C6H6; xii, LDA-THF, Me1
Scheme 3
154
Terpenoids and Steroids
successful. A method has been devised” for the introduction of the characteristic 17(20)-Z-iso-octenoic acid side-chain of fusidic acid and related compounds to a tetracyclic intermediate (25) with a 17-ketone (Scheme 4). Separation of the (20R)- and (20S)-isomers of (26) followed by acetylation and dehydration gave methyl diacetoxyfusidate (27) and methyl diacetoxylumifusidate (28) respectively.
I:...
0
(26) 111, IV
(28)
1
@OR)
(27)
Reagents: i, BuLi-Pr\NHd-methyIhept-5-enoic acid; ii, CH2N2; iii, Ac20-py; iv, POC13-py
Scheme 4
In an approach to the stereocontrolled creation of the acyclic side-chain of tetracyclic triterpenoids and other natural products, Trost and his colleagues have converted the acyclic starting compound (29) into the cyclopropanoid intermediate (31) via the diazo-ketone (30).22 The key step in the scheme is the cleavage of the cyclopropane with lithium dimethylcuprate to give (32). The stereochemistry at C-7 is determined by the configuration of the double bond in (29). The c.d. and U.V. spectra of a series of triterpenoid olefins have been mea~ured.’~ The Scott-Wrixon rules can be used to correlate the sign of the c.d. curves with molecular structure. A 21
22 23
M. Tanabe, D. M. Yasuda, and R. H. Peters, TetrahedronLetters, 1977, 1481. B. M. Trost, D. F. Taber, and J . B. Alper, Tetrahedron Letters, 1976, 3857. A. F. Drake, P. Salvadori, A. Marsili, and I. Morelli, Tefmhedron, 1977, 33, 199.
Triterpenoids
155
(29) R = H,H
(30) R = N ,
paper o n the semiempirical derivation of "C n.m.r. shifts includes some triterpenoid~.'~ Photolysis of the imidazolide (33) of 3/3-acetoxy-25,26,27-trisnorlanost-8-en24-oic acid to give (34) has the advantages of simpler experimentation and higher
(34)
yields over other photochemical methods for degradation of the lanosteror sidechain.25 The full paper on the functionalization of the 4a-methyl group of lanosterol by thermolysis of the azidoformate has appeared." Another group has reported similar results by thermolysis or photolysis of the corresponding azidocarbonate." Nitrite photolysis has been used as a conformational probe in a series of 6a- and 6P-nitrites of 4,4-dimethylandro~tanes.~~ Kadsuric acid ( 3 3 , a new A-secolanostane, has been isolated from the stems of Kadsura japonica.2y Several lanostanes with methylated side-chains have been reported. These include 24,25-dimethyl-lanosta-9( 1 1),23-dien-3P-d (36) and the corresponding acetate (37) and ketone ( 3 8 ) from Quercus myrsinaefolia,3" 24,24dimethyl-lanosta-9(11),25-dien-3P-y1 acetate (39) from the leaves of Q. gilz~a,~' and O-methylclausenol (40) from the aerial parts of Clausena pentaphylla.32 The structure (41) has been proposed for citrullonol from the neutral portion of the oil of Cifrullus c o l o ~ y n t h i s The . ~ ~ configuration of the methyl group at C-4 of citrostadienol (42) from Calendula officinalis has been revised to a.34 24-Methylenelanost-8-en-3/3-01 has been detected for the first time in higher plants, in the H. Beierbeck, J . K. Saunders, and J. W. ApSimon, Canad. J. Chem., 1977,55,2813. S . Iwasaki, Helv. Chim. Acta, 1976, 59, 2753. P. F. Alewood, M. Benn, J. Wong, and A . J. Jones, Canad. J. Chem., 1977,55,2510. '' J . J . Wright and J. B. Morton, J.C.S. Chem. Comm., 1976, 668. 2R J . M. Midgley, J. E. Parkin, and W. B. Whalley, J.C.S. Perkin i, 1977, 834. 29 Y. Yamada, C.-S. Hsu, K. Iguchi, S. Suzuki, H.-Y. Hsu, and Y.-P. Chen, Chem. Letters, 1976, 1307. 3" W.-H. Hui and M.-M. Li, J.CS. Perkin I, 1977, 897. 3 1 Y. Tachi, Y. Kamano, J . Sawada, I . Tanaka, and H. Itokawa, Yakugaku Zasshi, 1976,96, 1213. 32 M. D. Manandhar, A . Shoeb, R. S. Kapil, and S. P. Popli, Experientia, 1977,33, 153. 33 L. Yankov and S. Khusein, Doklady bolgarsk. Akad. Nauk, 1975,28, 1641. 34 J . St. Pyrek and A. Schmidt-Szalowska, Roczniki Chem., 1977,51, 951. 24
2s
26
156
H
2
Terpenoids and Steroids
HO,C:
(35)
(36) R = H,P-OH (37) R = H,P-OAc (38) R = O
pi
(39) R = H H,POAc, ,B-OMeo R' = H
\
HO
HO
I
(4 1)
(42)
seeds of Brassica n a p ~ s The . ~ ~methyl ethers of cycloartenol and parkeol are new natural products from Chionochloa species.36a Polycarpol, from the bark of Polyalthia oliveri, is 15a-hydroxyagnosterol.366 Crystal structure analysis of the major isomer (43) formed on autoxidation of 3a-hydroxy-4,4,14a-trimethyl-l9-nor1Oa-pregna-5,16-diene-ll,20-dione (44) followed by reduction of the intermediate hydroperoxide has confirmed the 17a configuration which had been assigned to the hydroxy-group.37 The conformation of the 17-acetyl group in both isomers has been studied in different solvents. A second compound, formed in addition to (45)in the rearrangement of
vo HO"
&EH
(43) 35 36
37
@ CH,OH
\
(44)
(45)
T. Itoh, T. Tamura, and T. Matsumoto, Phyfochemistry, 1976.15, 1781. (a)G . B. Russel, H. E. Connor, and A. W. Purdie, Phyfochemistry, 1976,15, 1933; ( b )M. Hamonnikre, A. Fournet, M. Leboeuf, A. Bouquet, and A. Cave, Compt. rend., 1976,282, C, 1045. P. R. Ensiin, J. Coetzer, and G . J. Kruger, J.C.S.Perkin II, 1977, 402.
Triterpenoids
157
(46) with boron trichloride, has been shown by X-ray analysis to have the structure (47).38Presumably it arises by the trapping of an intermediate cationic species by chloride ion. The full details of the preparation of the stable dithiet derivative (48) have appeared39 (see Vol. 7, p. 134). Irradiation of the lanostadiene (49) yielded the photoproduct (50) whose structure has been confirmed by X-ray analysis.
& -0
(49)
CI
AcO
(50)
Hydrolysis of thelothurins A and B, the defensive saponins of the Indo-Pacific sea cucumber Thelonota ananas, with aqueous acetic acid yields the genuine aglycones (51) and (52) whose structures were proved chemically by interrelation
(51)
(52)
with seychellogenin acetate.40 Hydrolysis of the saponin mixture with stronger acid led to the formation of the artifacts (53)-(58) with a 9( 11)-double bond.41 Feeding experiments with labelled acetate have resulted in only low incorporation into the sap on in^.^^^^ However, an impressive incorporation (18%) of [3-3H]lanosterol into holotoxinogenin (59) by the sea cucumber Stichopus californicus has been reported.43 Oxidation of (59) resulted in loss of tritium. An X-ray structural 3x
39 40
41 42 43
T. Prange, C. Pascard, G. Sozzi, and M. Fetizon, TetrahedronLetters, 1977,245. R. B. Boar, D. W. Hawkins, J. F. McGhie, and D. H. R. Barton, J.C.S. Perkin I, 1977, 515. A. Kelecorn, D . Daloze, and B. Tursch, Tefruhedron, 1976,32, 2313. A. Kelecom, D. Daloze, and B. Tursch, Tetruhedron, 1976,32, 2353. G. B. Elyakov, V. A. Stonik, E. V. Livina, and V. S. Levin, Comp. Biochem. PhysioL, 1975,52B, 321. Y. M. Sheikh and C. Djerassi, J.C.S. Chem. Comm., 1976, 1057.
Terpenoids and Steroids
158
(53) R' (54) R'
= H.
RZ= Ac
= R2 = Ac
(57) R * = R ' = H (58) R' = H, R2 = AC
(55) R' (56) R'
=R ~ H = = H, R2 = Ac
(59) R ' = H
analysis of 17-deoxy-22,25-epoxyholothurinogeninacetate (60) has been publi~hed.~~
Acetylshengmanol (6 I), an unstable sapogenin from Cimifuga japor~ica:~is a likely precursor of cimigenol (62)and cimigol (63). It occurs as a xyloside. The parent xyloside was converted into cimigenol on acid hydrolysis and to cimigol xyloside on treatment with alkali. The details of the crystal structure of passifloric acid methyl ester (64), from PassifIora edulis, have appeared.46 Mollic acid 3p-Dglucoside (65)is a structurally related saponin from the leaves of Combretum
P" -
... ...
44
45 46
S. G. Il'in, B. L. Tarnopol'skii, Z . 1. Safina, A. N. Sobolev, A. K . Dzizenko, and G. B. Elyakov, Doklady Akad. Nauk S.S.S.R., 1976,230, 860. N. Sakurai, T. Inoue, and M. Nagai, Chem. and Pharm. Bull. (Japan), 1976,24, 3220. G. D. Andreetti, G. Bocelli, and P. Sgarabotto, J.CS. Perkin II, 1977, 605.
Triterpenoids
159
H .......
0
OH
* (64) R 1= H, R2 = M e
As (64)
!F AcO
(65) R'
= P-D-GIu, R2 = H
%I
CO,H
(66)
rn~ffe.~ On ' treatment with acid it undergoes the same cyclopropane transposition [to (66)] as (64) (see Vol. 7, p. 134). Partial syntheses of mangiferolic acid (67),48 buxandonine (68)49 and cycloprotobuxines A (69) and F (70)4' from cycloartenol, and ambolic acid (71)48from cyclolaudenol have been reported. Papers on the Buxus alkaloids include contri-
(68) R' = 0,R2= NMe, (69) R' = H,a-NMe,, R2 = NMe, (70) R' = H,a-NHZ, R2 = NMe, 47
4x 4y
(7 1) R' = H,p-OH
K. H.Pegel and C. B. Rogers, Tetrahedron Letters, 1976,4299. C . Singh and S. Dev, Tetrahedron, 1977, 33, 817. C.Singh and S.Dev, Tetrahedron, 1977, 33, 1053.
Terpenoids and Steroids
160
butions to the stereochemistry of cyclobuxaminesOand L-cycloprotobuxine C5’ and a tentative structure for cyclobuxargentine G.” The full details of the conversion of cycloeucalenol into [ 19-2H]obtusifoliol by the microsomes of Zea mays in D,O have appeareds3 (see Vol. 7, p. 135). The formation of a A’(11) intermediate in the enzymatic cleavage of the cyclopropane ring is excluded by the incorporation of only one deuterium atom. Both cyclox ~ ~ artenol and lanosterol are converted into normal sterols by Saprolegnia f e r ~ and Chlorella e l l i p ~ o i d e a . ~ ~ The transformation of the lanostane keto-epoxide (72) into the cucurbitacin derivative (73) has been achieved with boron trifluoride in acetic anhydride.56 The presence of the acetic anhydride appears to favour the backbone rearrangement. The structure of (73) was confirmed by correlation with the oxidation product (74) of deoxybryogenin acetate. Two new cucurbitacin glycosides, arvenins I (75) and I1 (76) from Anagallis arvensis, have been reported.57
(73) R = H,POAc (74) R = O
(75) (76) 23,24-dihydro
3 Dammarane-Euphane Group Several interesting dammaranes have been isolated from the male flowers of Alnus serrulatoides.s840 Alnuserol (77)” and alnuselide (78)s9 have the uncommon
’(’ Z. Voticky and V. Paulik, Coll. Czech. Chem. Comm., 1977, 42, 541. B. U. Khodzhaev, R. Shakirov, and S. Yu. Yunusov, Khim. prirod. Soedinenii, 1976, 554. K. I. Kuchkova, Z. Voticky, and V. Paulik, Chem. Zuesti, 1976,30, 174. A. Rahier, L. Cattel, and P. Benveniste, Phytochemistry, 1977, 16, 1187. J. D. Bu’Lock and A. U. Osagie, Phytochemistry, 1976,15, 1249. 5 5 L. B. Tsai and G. W. Patterson, Phytochemistry, 1976, 15, 1131. 56 Z. Paryzek, Tetrahedron Letters, 1976,4761. 57 Y. Yamada, H. Hagiwara, and K. Iguchi, Tetrahedron Letters, 1977, 2099. ” T. Hirata, K. Murai, T. Suga, and A. Christensen, Chem. Letters, 1977, 95. ’9 T. Hirata, R. Ideo, and T. Suga, Chem. Letters, 1977, 711. T. Hirata, R. Ideo, and T. Suga, Chem. Letters, 1977,283.
’*
53
‘’
161
Triterpenoids
feature of oxygenation at C-11. The structure of the former was confirmed by X-ray analysis. Alnuserol (77) was converted into alnuselide (78) by abnormal Beckmann rearrangement of the corresponding oxime followed by hydrolysis. Alnuseric acid (79) was synthesized from alcincanone (go), with which it
(78)
(79)
(80)
co-occurs, by a similar route.60 Dammar-24-ene-3a, 17a,20-triol (81) and betulafolienetetraol oxide (82) have been obtained from the leaves of Betufu
4
HO-’
OH
HO” (8 1)
(82)
costatu.61The latter was formed together with its 24-epimer on treatment of betulafolienetetraol (83) with perbenzoic acid. Other new compounds include betulafolienepentaol(84) from the leaves of B . plutyphylla6’ and bacogenin A3 (85), a new sapogenin from Bacopa r n ~ n n i e r a . ~ ~ The full details of the determination of the configuration of the trisubstituted epoxide of aglaiol (86) have appeared.64 During the course of this work three new compounds, the ketone (87), the keto-diol(88), and the trio1 (89), have been found 61
N. I. Uvarova, G. V. Malinovskaya, and G. B. Elyakov, Tetrahedron Lerters, 1976, 4617
63
R. S. Chandel, D. K. Kulshreshtha, and R. P. Rastogi, Fhyrochemistry, 1977,16, 141.
64
R. B. Boar and K. Damps, J.CS. Perkin I, 1977, 510.
’’ B. H. Han and B. J. Song, Fhyiochernistry, 1977,16, 1075.
Terpenoids and Steroids
162
in Agluiu odoruta. It is interesting that the configuration at C-24 in (88) and (89) (24R) is the opposite to that in (86) and (87).
(86) R=H,F-OH (87) R = O
(88) R = O (89) R = H,P-OH
The I3C n.m.r. resonances of a series of 20-hydroxy-dammarane derivatives related to the ginseng sapogenins have been assigned." The chemical shifts of C-17, C-21, and C-22 are characteristic of the C-20 configuration especially in the presence of a 12P-hydroxy-group. New saponins from Punax ginseng have been ~ e p o r t e d . ~ "The ' ~ ~structures of chikusetsusaponins L,, L9,, and L,, have been elucidated.6* Chikusetsusaponin L,, (90) is the first 12-0-glucoside in this series. Photosensitized oxidation of (90) followed by reduction afforded chikusetsusaponin L a (91)Tirucalla-7,24-dienol (92) from tea seed oil6' and the aldehyde (93), corare responding to methyl isomasticadienoate, from the berries of Schinus rn~lle,~' new natural products. Sapelins A and B, from Burseru klugii, have cytotoxic activity7' (see Vol. 1 , p. 172). J. Asakawa, R. Kasai, K. Yamasaki, and 0. Tanaka, Tetrahedron, 1977,33, 1935. S. Yahara, 0. Tanaka, and T. Komori, Chem. and Pharm Bull. (Japan), 1976,24, 2204. S. Yahara, K. Matsuura, R. Kasai, and 0.Tanaka, Chem. and Pharm. Bull. (Japan), 1976,24, 3212. '' S. Yahara, R.Kasai, and 0. Tanaka, Chem. andfharm. Bull. (Japan),1977,25, 2041. T. Itoh, T. Tamura, and T. Matsumoto, Lipids, 1976, 11, 434. 7u T . Pozzo-Balbi, L. Nobile, G. Scapini, and M. Cini, Gazzerra, 1976,106, 7x5. 71 S. D. Jolad, R. M. Wiedhopf, and J. R. Cole, J. Pharm. Sci., 1977, 66, 889.
65
66
67
163
Triterpenuids
(92)
(93)
Tetranortriterpen0ids.-The I3C n.m.r. assignments for a large group of limonoids have been r e p ~ r t e d . ~The ' chemistry of azadirachtin has been reviewed73(see Vol. 6, p. 162). Anthothecol (94) and hirtin (95) have been interrelated uiu the trione (96).74 Dysobinin (97) is a new tetranortriterpenoid from Dysuxylum binect~riferum.~' An intermediate in a projected limonoid synthesis has been shown to have structure (98) by X-ray analysis.76 An unusual feature of harrisonin (99), a compound with insect antifeeding, cytotoxic, and antibacterial properties from Hurrisonii u b y s ~ i n i c u is ,~~ the stable hemiacetal function. The novel structure (100) has been reported for cyclo~~ epiatalantin, an interesting new limonoid from Atuluntiu m u n ~ p h y l l u . Base cleavage of (1 00) followed by methylation gave epiatalantin (101). Chemical and spectroscopic evidence has been for the revised structures (102) and (103) of atalantin and atalantolide. 2-(4-Ethylphenoxy)triethylamine and 2-(3,4-dimethoxyphenoxy)triethylamine markedly reduce the biosynthesis of limonoids in citrus leaves, presumably by inhibition of cyclase activity." Radio-tracer studies have revealed that limonoids are synthesized in the leaves of citrus and transported to the fruit.'l The fruit tissue does not appear to be capable of the de nuuo synthesis of limonoids from acetate or mevalonate. 72
73 74
75
l6 77
78 79
Hn
D . A. H . Taylor, J. Chem. Res. ( S ) , 1977, 2. K. Nakanishi, Recent Adv. Phytochem., 1975,9,283. B. A. Burke, W. R. Chan, J. R. Rawle, and D. R. Taylor, Experientiu, 1977,33,578. S . Singh, H. S. Garg, and N . M. Khanna, Phytochemzslry, 1976,15, 2001. K. Neupart-Laves and M. Dobler, Cryst. Structure Comm., 1977,6, 183. I. Kubo, S. P. Tanis, Y.-W. Lee, I. Miura, K. Nakanishi, and A. Chapya, Heterocycles, 1976, 5 , 4 8 5 . D . L. Dreyer, R. D . Bennett, and S. C. Basa, Tefruhedron, 1976,32, 2367. B. Sabata, J. D . Connolly, C. Labbe, and D . S. Rycroft, J.C.S. Perkin I, 1977, 1875. S. Hasegawa, H. Yokoyama, and J. E. Hoagland, Phyrochemisfry, 1977,16, 1083. S. Hasegawa and J. E. Hoagland, Phytochemzsfry, 1977, 16, 469.
*
Terpenoids and Steroids
164
0
OH
Me0,C
(94)
OH (95)
fl
0
'OAc
Me0 CN
AcO (97)
0 'OH
Triterpenoids
165
The structures of two complex highly oxygenated tetranortriterpenoids related to prieurianin (see Vol. 6, p. 126) have been elucidated." Dregeanin (104) from Trichilia dregeana and rohitukin (105) from the seeds of Aphnamixis polystacha both exist as a mixture of conformers in solution at room temperature. Xyloccensins A (106), B (107), D (log), and F (109) are new bicyclononanolides from the seed of Xylocarpus m o l u ~ c e n s i s .The ~ ~ 1,8-hemiacetal function is a new feature in this series. Selenium dioxide oxidation of carapin afforded a product which has been assigned structure (110) with a 3,g-hemiacetal bridge. This compound (110) occurs naturally in Cedrela glaziovii.
I
v I
Y Ok oco 0
CH2 Q
oco
0
0
AcOH,C
1
HO
(106) R' = COPr' or COBu', R2= H (107) dihydro-( 106) (108) R' = COPr'or COBu', R2= OH (109) dihydro-( 108)
Pentanortriterpen0ids.-A clearer picture of the structural and stereochemical relationships among the cneorins and tricoccins, pentanortriterpenoids from Cneorum tricoccon and Neochamaelea pulverulenta, is beginning to emerge. The stereoisomeric forms of the olefin (111) and the alcohol (112) are summarized in Tables 1 and 2. Tricoccin R, (113) has a methoxy-group attached to C-30 but undergoes easy loss of methanol to give cneorin B1.84The structure of tricoccin S, (1 14) has been confirmed by X-ray analy~is.~'The corresponding methyl acetal, 82
83 84
85
J. D . Connolly, D . A. Okorie, D . L. D e Wit, and D . A. H. Taylor, J.CS. Chern. Comm., 1976,909. J. D . Connolly, M. A. MacLellan, D . A. Okorie, and D . A. H. Taylor, J.C.S. Perkin I, 1976, 1993. A. Mondon, D. Trautmann, B. Epe, and U. Oelbermann, Tetrnhedron Lerrers, 1976:3291. A. Mondon, D. Trautmann, B. Epe, and U. Oelbermann, TerruhedronL.efrers,1976,3295.
Terpenoids and Steroids
166
tricoccin S,, (115), also occurs naturally. Tricoccins S, (116) and S, (117) are stereoisomers of (114).
(114) R = H (115) R = M e
(116)
Table 1 Stereoisomers of the olefin (1 1 1) Configuration at C-7 C-9 C-37 R S S S S S R S R R S S S (Ri*, R R (S) R
Cneorin C Cneorin C, Cneorin B Cneorin B, Tricoccin R, Tricoccin R,
* Uncertain assignment,
Table 2 Stereoisomers of the alcohol (1 12)
Cneorin D Cneorin H Cneorin N Cneorin 0 Tricoccin &
C-7 S R S R S
Configuration at C-8 C-9 S S S S S S S S R S
C-17 S S R R R
Triterpenoids
167
Quassinoids.-The antileukaemic activity of some quassinoids ha5 revived interest in this group. Three new biologically active compounds have been isolated.86-8* Quassimarin (1 18) occurs in Quassia amara with the inactive simalikalactone D (119).86Bruceoside A, from Brucea javanica, is the glucoside (120).87The third
(118) R=OAc (119) R = H
compound, samaderine E (121) from Samadera indica, is accompanied by a novel quassinoid, samaderine A (122), whose structure has been established by X-ray analysis.'* Bruceine Q (123) is a new bitter principle from Brucea sumafrana.8y
?"
'
OH (123)
In approaches to a synthesis of quassinoids, the ketone (124), derived from cholic acid, has been converted into the lactone (125), with the C-7 stereochemistry of quas~inoids.~~~~' 86 R7
90
9'
S. M. Kupchan and D. R. Streelman, J. Org. Chem., 1976,41,3481. K.-H. Lee, Y. Imakura, and H.-C. Huang, J.C.S. Chem. Comm., 1977,69. M. C. Wani, H . L. Taylor, M. E. Wall, A. T. McPhail, and K. D . Onan, J.C.S. Chem. Comm., 1977, 295. H.-C. Chiang, Proc. Nat. Sci. Council Purr 1 (Taiwan), 1975, 8, 139. J. R. Dias and R. Ramachandra, Tetrahedron Letfers, 1976,3685. J. R. Dias and R. Ramachandra, J. Org. Chem., 1977, 42, 1613.
Terpenoids and Steroids
168
4 Shionane-Baccharane Group Methyl trisnorshionanoate (126) has been synthesizedY2 from friedelan-19a-01 (127) uia the ring-contracted intermediate ( 1 28) and the trisnor-ketone (129). Irradiation of (129) in methanol afforded the desired ester (126). An investigation of the effect of solvent on the backbone rearrangement of 3p,4@-epoxyshionane (130) by boron trifluoride etherate has shownY3that nucleophilic solvents tend to interrupt the rearrangement at an early stage (see Vol. 6, p. 130).
The baccharane derivative (13 1) is formed by Lewis acid-catalysed rearrangement of both the a- and @-epoxides (132) and (133) of the A18-isomer of betulin d i a ~ e t a t e The . ~ ~ rearranged product has been synthesized by an independent (131) route. The stereochemistry of the @-epoxide(133) has been confirmed by X-ray analysis.
’)’Y. Yokoyama, T. Hirao, T. Tsuyuki, Y. Moriyama, T. Murae, and T. Takahashi,
Tetrahedron Lerrers,
1977,273. 93 y4
M. Tori, K. Tachibana, Y. Moriyama, T. Tsuyuki, and T. Takahashi, Chern. Letters, 1976, 1359. (a) E. Suokas and T. Hase, Actu Chern. Scund., 1977, B31, 23 1; ( b ) ibid., p. 182.
169
Triterpenoids
&
H,OAc
AcO (13 1)
(132) ( 133) P-epoxide
5 Lupane Group
The structure of benulin (134), a lupene hemiacetal from Bursera arida, has been confirmed by X-ray analy~is.’~An investigation of several Senecio species has resulted in the isolation of a series of lupane derivatives which include the acids (135), (137), and (139), the corresponding aldehydes (136), (138), and (140), the ketone (141), and betulonic acid.” Three more triterpenoids (142)-( 144) have
-f
-4
HO” (135) Alycz1),R = C 0 2 H (136) A ’ Y ( 2 1 ) , R = C H 0 (137) AI2, R = C 0 2 H (138) A12, R = CHO (139) A’‘’ I ) , R = C 0 2 H (140) Arc’’), R = C H O (141) A”(z’), R = M e
(142) R ’ = 0 , R 2 = M e , R 3 = O H (143) R’ = H,D-OAc, R2 = CHO. R3 = H (144) R’ = H$-OH, R2 = CH,OH, R3 = H ”
F. Ionescu, S. D. Jolad, J. R. Cole, S. K. Arora, and R. B. Bates, .I. Org. Chem., 1977,42, 1627. K. H. Knoll, C. Zdero, P. K. Mahanta, M. Grenz, A. Suwita, D. Ehlers, N. Le Van, W.-R. Abraham, and A. A. Natu, Phyrochemistry, 1977,16,965.
’‘ F. Bohlmann,
Terpenoids and Steroids
170
been obtained from the stems of Lithocarpus polystachya" (see Vol. 6, p. 122). Other new natural products include 3~-acetoxy-30-norlupan-20-one(145) from Claoxylon polot,'s 3P-hydroxylup-20(29)-en-30-ol(146) and lupane-3@,30-diol (147) from Quercus ~ h a m p i o n i ilup-20(29)-ene-2a,2@-diol ,~~ (148) from the bark of Pterocarpus santalinus," and betulic acid 3-O-P-~-glucoside(149) from the leaves of Eryngium bromeliifolium. '('O
04.
HOH,C-J
Q
HOH,CG(
n2
9
\
\
\
(145) R ' = H,P-OAc
(148) R' (149) R'
(146) R' = H,P-OH
(147) R' = H,P-OH
= H, R ' = OH, R3 = M e = B-D-G~u,R2 = H, R3= C 0 2 H
The confusion surrounding the structure of thurberine (calenduladiol) has been resolved'0'.'02 (see Vol. 7, p. 142). It is identical with beyeriadiol, 3p,l6p-dihydroxylup-20(29)-ene (150), from Beyeria laschenaulrii."' Authentic lupane-3,12dione (15 l), prepared from 3P,28-diacetoxylup- 12-ene, is not identical with the corresponding thurberine derivative."' A necessary consequence of this work is the revision of the structure of resinone, from Fluoresia resinosa, to 3-0x0-16phydroxylup-20(29)-ene ( 1 52)?
0
(150) R = H,P-OH (152) R = O 97 98 9y
100 101
(151)
W.-H. Hui and M.-M. Li, Phytochemistry, 1977, 16, 1 1 1 . W.-H. Hui, M.-M. Li, and Y.-C.Lee, Phytochemistry, 1977,16,607. N. Kumar and T. R. Seshadri, Phytochemistry, 1976,15, 1417. K. Hiller, K. Q. Nguyen, P. Franke, and R. Hintsche, Pharmnzie, 1976, 31,891. J . St. Pyrek and E. Baranowska, Roczniki Chem., 1977,51, 1141.
Triterpenoids
171
Acid-catalysed isomerization of the olefins (153)-(155), obtained on decarboxylation of lupan-28-oic acid, resulted in the formation of the lup-17-ene derivative (156) with inversion at C-19 and not 28-norlup-l3(18)-ene (157) as previously ~uggested.'"~ Further studies have been reported on a series of lupan12-one104 and 29-hydroxy-30-norlupan-20-one (1 S8)'" derivatives. The nitrone (159) and the N-hydroxy-lactam (160) were produced on irradiation of 3pacetoxy-28-nitrosyloxylupane(161).Io6
(153) R = H
(154) R = H
(155) R = H
o=/CHzoH
(156) R = H
1
(157) R = H
-/
CH,OAc
(158) R = O A c
(159) R = O A c
(160) R = O A c
(161) R = O A c 102
I03
I 04
I05 1W
J. Protiva, F. Turecek, and A. Vystrkil, Coll. Czech. Chem. Comm., 1977,42, 140. G . V. Baddeley, C. J. R. Fookes, and S. K. Nigam, Austral. J. Chem., 1976,29, 2707. V. Pouzar and A. Vystrtil, Coll. Czech. Chem. Comm., 1976,41,3452. V . Pouzar and A. VystrEil, Coll. Czech. Chem. Comm., 1977,42,2224. J. Protiva, M. BudkSinsky, and A. Vystrtil, CON. Czech. Chem. Comm., 1977.42, 1220.
Terpenoids and Steroids
172
Dehydrogenation of lupenone pnitrophenylhydrazone with iodine and t-butoxide followed by treatment with aqueous TiCl, gave the AI-3-ketone glochidone in 50% yield.Io7 The trihydroxylupane (162) is formed on hydroboration of betulin. lo*
(162) R = O H
6 Oleanane Group Arjunglucosides I (163) and I1 (164) from Terminalia arjuna are the glucose esters of arjungenin and arjunolic acid r e s p e c t i ~ e l y . 'The ~ ~ full details of the structure elucidation of arjungenin are included in this paper. Three lyxosides (165)-(167) have been obtained, together with 16cu,21P,22a,28-tetrahydroxyolean-12-en-3-
HO..
"R HO CH,OH
(163) R = O H (164) R = H
(165) R = O H (166) R = O A c (167) R = H
one (168), from the bark extract of Planchonia careya following mild acid hydrolysis.l'o Another ketotetrol, harpullone (169), occurs in the bark of Harpullia pendula."' Barrigenic acid (170) is a sapogenin from the fruits of Barringtonia acutangula"' while acutangulic acid (171) is found in the 1 e a ~ e s . l Olean-13(18)'~ ene-2P,3P-diol (172) and olean-12-ene-3@,28,29-triol(173) have been isolated from Salvia h~rrninurn"~ and the stems of Hedyotis a~utangula''~ respectively. Other new oleanane natural products include the three lactones (174)-(176) from Rhodomyrtus tornentosa,"6 olean- 12-ene-3,16-dione from Quercus lo' I"'
'09 'lo
'I1 'I2
'I4
A. Chatterjee and A. Banerjee, Indian J. Chem., 1977, B15,87. L. G. Matyukhina and I. A. Sdtykova, ZhuL obshchei Khim., 1976,46, 2759. T. Honda, T. Murae, T. Tsuyuki, T. Takahashi, and M. Sawai, Bull. Chem. SOC.Japan, 1976,49,3213. P. W. Khong and K. G. Lewis, Ausfrul. J. Chem., 1977,30, 1311. R. F. Cherry, P. W. Khong, and K. G. Lewis, Ausfral. J. Chem., 1977,30, 1397. A. K. Barua, P. Chakrabarti, A. S. D. Gupta, S. K. Pal, A. Basak, S. K. Banerjee, and K. Basu, Phytochemistry, 1976,15, 1780. K. G . A. S. S. Narayan, L. R. Row,and C. S. Sastry, Cunenr Sci., 1976,45,518. A. Ulubelen, C. H. Brieskorn, and N. Oezdemir, Phytochemistry, 1977,16, 790. W.-H. Hui and M.-M. Li, Phytochemistry, 1977, 16, 1309. W.-H. Hui and M.-M. Li, Phyfochernisfry, 1976,15, 1741.
Triterpenoids
173
fl
'0H E H
R' HO (168) R ' = H , R 2 = O H (169) R' = OH, R2 = H
(170) R=CO,H
(171) R = M e
X20H R HO (172) R = O H
(173) R = H
(175) R=H,Lu-OH (176) R = O
174
Terpenoids and Steroids
p-peltoboykinolic acid acetate from Astilbe rivularis”7 (see barnbusaef~lia,~~ Vol. 1, p. 190), and assorted triterpenoid esters from Mimusups litturalis1‘8and Saussurea lappa.”’ Daturanolone, from Datura fastuosa, has been shown to be identical with daturaolone (177) from D. innoxia.”’
(177)
Full papers _ _ on the crystal structures of echinocystic acid diacetate bromolactone121 and papyrogenin A’22 have appeared. The structure of 3p,16/3dimethoxyoIean-12-en-28,21/3-olide (178) has been confirmed by X-ray analy-
(178)
s ~ s . ”Another ~ crystal structure of campanulin (dendropanoxide) (196) (p. 178) has been published’24 (see Vol. 3, p. 214). A short stereoselective synthesis of the pentacyclic key intermediate (179) in Ireland’s syntheses of friedelin and alnusenone (see Vol. 7, p. 149) is outlined in Scheme 5.Iz5 Forced Wolff-Kishner reduction of the ketone ( I 85) from arjunic acid and. subsequent methylation and acetylation afforded the 13aH derivative (186).”‘ Conversion of acacic acid lactone (187) into dihydrosapogenin B (1 88) establishes the l8PH configuration of (187).’*’ Phosphorus oxychloride converts (187) into ‘I7
120 lZ1
124
IZ5
127
B. S. Sastry and E. V. Rao, Indian J. Chem., 1977,15B, 494. R. Banerji, G. Misra, and S. K. Nigam, Fitoterapia, 1977,48, 68. P. P. Pai and G. H. Kulkarni, Current Sci., 1977, 46, 261. M. Ahmad, M. A. Hai, A. Khaleque, and M. A. W. Miah, Indian J. Chem., 1976,14B, 1007. C. H. Carlisle, P. F. Lindley, and A. Perales, Acta Cryst., 1976, B32, 3053. S. Amagaya, M. Takai, Y. Ogihara, and Y. Iitaka, Acta Cryst., 1977, B33, 261. R. Roques, L. Comeau, R. Fourme, R. Kahn, and D. Andre, Acta Cryst., 1977, B33, 1682. F. Mo, Acta Cryst., 1977, B33, 641. T. Kametani, Y. Hirai, F. Satoh, and K. Fukumoto, J.C.S. Chern. Comm., 1977, 16. T. Honda, T. Murae, T. Tsuyuki, and T. Takahashi, Chem. Letters, 1977, 271. A. S. R. Anjaneyulu, M. Bapuji, M. G. Rao, L. R. Row, P. C. S. A. Sastry, and C. Subrahmanyam, Indian J. Chem., 1977, 15B, 1.
Triterpenoids
175
SO '\
Me0
CN
(179) Reagents: i, isoprene, A; ii, NaNH,-liq. NH,; iii, A; iv, BuiAiH-C6H6; v, NH'NHz-KOH
Scheme 5
the triene (189).'28 Attention has been given to the preparation of the isomeric 2,3-di01s,'*'-'~' 2,3-ket01s,'~'-'~~ and ring A lac tarn^'^^ of several pentacyclic triterpenoids.
A. S. R. Anjaneyulu, M. Bapuji, and L. R. Row, Indian J. Chem., 1977, 15B, 7. D. R. Misra, H. N. Khastgir, M. Sung, and L. J. Durham, Indian J. Chem., 1976, 14B, 41 1 . K. Chattopadhyay, D. R. Misra, and H. N. Khastgir, Indian J. Chem., 1977,15B, 21. G. R. Mallavarapu, T. S. Rarnaiah, and V. V. Bai, Current Sci., 1977,46, 252. '31 K. Chattopadhyay, D. R. Misra, and H. N. Khastgir, Indian J. Chem., 1976,14B, 839. 133 D. R. Misra, H. N . Khastgir, M. Sung, and L. J. Durham, Indian J. Chem., 1976, 14B, 407. 134 T. S. Ramaiah, S. K. Ramraj, K. L. Rao, and V. V. Bai, J. Indian Chem. SOC., 1916, 53, 664. '21
129
176
Terpenoids and Steroids
Several papers dealing with the reactions of glycyrrhetic acid derivative^'^^-'^^ have been published. The distribution and structural elucidation of saponins have been re~iewed.'~' Glucuronides with a free carboxy-group and carbohydrate residues at C-2' and C-4' are readily cleaved with acetic anhydride in refluxing pyridine to give the genuine a g l y ~ o n e '(see ~ ~ Vol. 7, p. 145). Details of the mass spectra of a series of permethylated oleanane saponins have been discussed. 140 The increasing use of 13C n.m.r. spectroscopy in the structural investigation of saponins is reflected in the number of papers which have appeared in this area. The 13C resonances of ~ a i k o g e n i n sand ~ ~ ' ~aikosaponins~~' from Burpleum falcatum and of other acylated sap on in^'^^ have been assigned and the data applied in the structure elucidation of minor sap on in^^^^ from the same source. Glycosidation shifts and their stereochemical dependence have been discussed for a wide range of glycosides and a g l y ~ o n e s . ' ~ ~ ~ ' ~ ~ Publications have appeared on the following saponins: sakurasosaponin from the root of Primula ~ i e b o l d i , 'saponin ~~ A from the stem bark of Anthocephalus 136 13'
S. Rozen, I. Shahak, and E. D. Bergmann, Israel J. G e m . , 1975, 13, 234. R. K. Gayanov, H.-0. Kim, M. P. Irismetov, and M. I. Goryaev, Zhur. org. Khim., 1977.13, 895. R. K. Gayanov, H.-0. Kim, M. I. Goryaev, and M. P. Irismetov, Zhur. obshchei Khim.,1976,46,2375. K. Hiller and G. Voigt, Phnrmazie, 1977, 32, 365. I. Kitagawa, Y. Ikenishi, M. Yoshikawa, and K. S. Im, Chem. and Pham. Bull. (Japan), 1977, 25, 1408.
141 142
143
144
'41 146
'41
R. Higuchi, T. Komori, and T. Kawasaki, G e m . andPharm. Bull. (Japan), 1976,24,2610. K. Tori, Y. Yoshimura, S. Seo, K. Sakurawi, Y. Tomita, and 5.Ishii, Tetrahedron Lefters, 19764fii3. K. Tori, S. Seo, Y. Yoshimura, M. Nakamura, Y. Tomita, and H. Ishii, Tetrahedron Letfers, 1976,4167. K. Yamasaki, R. Kasai, Y. Masaki, M. Okihara, H. Oshio, S. Takagi, M. Yamaki, K. Masuda, G. Nonaka, M. Tsuboi, and I. Nishioka, Tefiahedron Letters, 1977, 1231. H. Ishii, S. Seo, K. Tori, T. Tozyo, and Y. Yoshimura, Tefrahedron Letters, 1977, 1227. K. Tori, S. Seo, Y. Yoshimura, H.Arita, and Y. Tomita, Tetrahedron Letters, 1977, 179. R. Kasai, M. Suzuo, J. Asakawa, and 0. Tanaka, Tetrahedron Letters, 1977, 175. I. Kitagawa, Y. Ikenishi, M. Yoshikawa, and I. Yosioka, Chem. and Pharm. Bull. (Japan), 1976, 24, 2470.
Triterpenoids
177
~adarnba,'~' songorosides C , G , I, M, and 0 from Scabiosa s o o n g o r i ~ a , ' ~ ~ ~ ~ ~ ~ caulosides C-G from Caulophyllum r o b u s t ~ m , 'and ~ ~ ,lebbekanin ~~~ E from Albizzia lebbek.153 Two new taraxeranes (190) and (191) have been isolated from Quercus barnb~saefolia.~~ Isomultiflorenone (192) and isomultiflorenol acetate (193) are new natural products from Cucurbita lundelliana and Vernonia fasciculata155 respectively. Studies on the allylic oxidation and bromination of taraxeryl acetate (194)156and on the Lewis acid-catalysed rearrangement of (1 94) and friedelan01'~~ have been reported.
(190)R' = 0,R' = H (191)R' = H,P-OH, R2= OH; 1,2-dihydro (194)R' = H,P-OAc,R2= H; 1,2-dihydro
(192)R = O (193)R = H,/3-OAc
Full papers have appeared on the friedelanes from Hydnocarpus octandra"' and Trichadenia ~eylanica,~'~ the mechanism of the photochemical reaction of friedelin with acetone,'6o and the rearrangement of 3p74P-epoxyfriedelane (195) to
149
''I
'53
'" '51
160
N. Banerji and N. L. Dutta, Indian J. Chem., 1976,14B, 614. A. Akimaliev, P. K. Alimbaeva, L. G. Mzhel'skaya, and N. K. Abubakirov, Khim. prirod. Soedinenii, 1976,472. A. Akimaliev, P. K. Alimbaeva, L. G. Mzhel'skaya, and N. K. Abubakirov, Khim. prirod. Soedinenii, 1976,476. N. S. Chetyrina, L. I. Strigina, Y. N. El'kin, and V. V. Isakov, Tezisy Doklady Vses. Simp. Bioorg. Khim., 1975. 13. L. I. Strigina, N. S. Chetyrina, and V. V. Isakov, Khim. prirod. Soedinenii, 1976,619. 1. P. Varshney, R. Pal, and P. Vyas, J. Indian Chem. Suc., 1976,53, 859. K. Seifert, H. Budzikiewin, and K. Schreiber, Pharmazie, 1976, 31, 816. N. K. Narain, Canad. J. Pharm Sci., 1977,12, 18. K. Chattopadhyay, D. R. Misra, and H. N. Khastgir, IndianJ. Chem., 1976, 14B,403. A. Chatterjee, S. Mukhopadhyay, and K. Chattopadhyay, Tetrahedron, 1976,32, 3051. S. P. Gunasekera and M. U. S. Sultanbawa, J.C.S. Perkin I, 1977, 418. S. P. Gunasekera and M. U. S. Sultanbawa, J.CS. Perkin I, 1977,483. H. Shirasaki, T. Tsuyuki, T. Takahashi, and R. Stevenson, Bull. Chem. SOC.Japan, 1977,50,921.
Terpenoids and Steroids
178
dendropanoxide (campanulin) ( 1 96).16' Trichadenal (197) and acetyltrichadenal (198) are new friedelanes from T. ~ e y l a n i c a . 'Reaction ~~ of 3@,4P-epoxyfriedelane (195) with boron trifluoride ctherate in benzene, instead of ether, afforded germanicol (199)16' in addition to the known rearrangement products (see Vol. 6, p. 137).
(197) R = H (198) R = A c
7 Ursane Group
Jacoumaric acid (200) and jacarandic acid (201) have been isolated from Jacaranda c a ~ c a n a . ' ~Three ~ ' ' ~ new ~ 13aH-ursane lactones (202)-(204) have been reported ~ ~ new compounds include barbinervic acid (205) from Mallotus r e p a n d ~ s . 'Other from the leaves of Ckthra barbinervis'66and the bauerene derivative myrtifolic acid (206) from the bark of Mesua myrtifolia. 16' The methyl resonances in the proton spectra of a series of ursenes have been assigned.'68
HO..
Rl&02H
Ho--
,
R2
(201) R' =OH, R2= Me (205) R' = H, R2 = CH20H
161
M. Tori, T. Torii, K. Tachibana, S. Yamada, T. Tsuyuki, and T. Takahashi, Bull. Chem. SOC.Japan, 1977, 50, 469. M. Tori, T. Tsuyuki, and T. Takahashi, Chem. Lerters, 1977,699. 163 M. Ogura, G. A . Cordell, and N . R. Farnsworth, Phytochemistry, 1977,16,286. 164 M. Ogura, G. A . Cordell, and N. R. Farnsworth, Lloydia, 1977,40, 157. 165 W.-H. Hui and M.-M. t i , Phyrochernistry, 1977,16, 113. M. Takani, K . Kubota, M. Nozawa, T. Ushiki, and K. Takahashi, Chem. and Pharm. Bull. (Japan), 1977, 25, 981. 16' S. P.Gunasekera and M. U. S. Sultanbawa, J.C.S. Perkin I, 1977, 6. 16* G. Romeo, P. Giannetto, and M. C. Aversa, Org. Magn. Resonance, 1977,9,29. '62
Triterpenoids
179
(202) R = H,P-OH (203) R = H,POBz (204) R=H,(u-OH
8 Hopane Group 21 aH-Hop-22(29)-ene-3&3O-diol (207) and the corresponding aldehyde (208) have been isolated from Rhodomyrtus tomentosa."5 Other new hopane natural products include 6&22-dihydroxyhopane (209) from the fern Cheilanthes marantae'" and 2 1aH-hopane-3P,22-diol and hop- 17(2l)-en-3-one from Quercus ~hampionii.~'
OH (207) R = CH20H (208) R = C H O
The main triterpanes in Russian petroleum are C,,-,, 1 7 a H - h o p a n e ~ . ~ ~ ~ * ~ ' ~ A crystal structure analysis of tetrahymanol (210) has a p p e a ~ e d . ' ~The ' methyl resonances in the proton spectra of tetrahymanol and tetrahymanone have been assigned.173
(210) I70
I72 173
A. G. Gonzalez, C. Betancor, R. Hernindez, and J. A. Salazar, Phytochemisny, 1976,15, 1996. S. D. Pustil'nikova, N. N. Abryutina, G. R. Kagramanova, and A. A. Petrov, Geokhimiya, 1976, 460. A. A. Petrov, S. D. Pustil'nikova, N. N. Abryutina, and G . R. Kagramanova, Neftekhimiya, 1976, 16, 41 1 D. A. L a n g , W. L. Duax, H. L. Carrell, M. Berman, and E. Caspi, J. Org. Chem., 1977,42,2134. T. A. Wittsruck and E. Caspi, J. Chem. Res. ( S ) , 1977, 180.
Terpenoids and Steroids
180 9 Stictane-Flavicane Group
The structure of retigeradiol, from the lichen Lobaria retigeru, has been revised to stictane-3&22a-diol (2 1 l)."' It was originally thought to be taraxerane-3/3,19Pdiol. The ketol previously isolated from Centrariu niuuli~''~is probably 22ahydroxystictan-3-one (212).'"
(211) R=H,P-OH (212) R = O
'71 '71 176
R. E. Corbett, C. K. Heng, and A. L. Wilkins, Austral. J. Chem., 1976,29, 2567. T. Bruun, Acra Chem. Scand., 1969, 23, 3038. A. L. Wilkins, Phyrochemistry,1977,16,608.
5 Carotenoids and Polyterpenoids BY
G. BRllTON
1 Introduction The main lectures from the 4th International Symposium on Carotenoids, held at Bern, Switzerland, in 1975 have been published in a book' that is intended to serve as a supplement to the 1971 Isler monograph.2 The first part, dealing with carotenoid chemistry, consists of chapters on the 13Cn.m.r. spectra of carotenoids,'" carotenoid-protein complexes,'b carotenoid glycosides," new structures,ld carotenoid stereochemistry," the synthesis of carotenoids and related polyenes," the enol-ether synthesis of polyenes,18 and the commercial synthesis of carotenoids."' Biologically important 'degraded carotenoids' are dealt with in papers on the apocarotenoid system of sex hormones and prohormones in Mucorales" and on xanthoxin and abscisic acid,'' and three contributions discuss the early steps,lk later reactions," and photoregulation of carotenoid biosynthesis.'" Another book, a 'Key to Car~tenoids',~ extends the list of natural carotenoids in the 1971 monograph.4 Reviews published include a summary5 of progress in the chemistry and biology of fat-soluble vitamins and carotenoids over the past 10 years, chapters on carotenoids6 and hormones' in filamentous fungi, and a survey of ionones, irones, and their derivatives in Nature.8
2 Carotenoids New Structures.-The 'Key to Carotenoid~'~ lists all carotenoids found in Nature up to the middle of 1975, and gives extensive references to occurrence and physical, chemical, and spectroscopic properties. An outline of work on the eluci-
'
Pure Appl. Chem., 1976,47, pp. 97-243, also published as 'Carotenoids-4 (Berne, 1975'). ed. B. C. L. Weedon, Pergamon Press, Oxford, 1977; (a) G. P. Moss, p. 97; (6) P. F. Zagalsky, p. 103; ( c ) H. Pfander,p. 121; ( d ) S. Liaaen-Jensen, p. 129; (e) J. Szabolcs, p. 147; V, B. C. L. Weedon, p. 161; ( g ) S. M. Makin, p. 173; (h) F. Kienzle, p. 183; (i) J. D. Bu'Lock, B. E. Jones, and N. Winskill, p. 191; 0') R. S. Burden and H. F. Taylor, p. 203; ( k ) B. H. Davies and R. F. Taylor, p. 21 1; (1) G. Britton, p. 223; ( m ) W. Rau, p. 237. 'Carotenoids',ed. 0. Isler, Birkhauser, Basel, 1971. 0. Straub, 'Key to Carotenoids-Lists of Natural Carotenoids', Birkhauser,Basel, 1976. 0. Straub, in ref. 2, p. 771. ' 0. Isler, Experienfia, 1977,33,555. T. W. Goodwin, Filamentous Fungi, 1976,2,423. ' J. D. Bu'Lock, Filamentous Fungi, 1976, 2, 345. Y . R. Naves, Rivista Ital. Essenze, Profumi, Piante Ofic., Aromi, Saponi, Cosmet., Aerosol., 1976, 58, 505.
181
Terpenoids and Steroids
182
dation of new carotenoid structures over the period 1970-1975 lished.Id
has been pub-
Acyclic Carotenoids. Two pigments from Rhodopseudomonas sphaeroides have been identifiedg as methoxyspheroidene [ l,l'-dimethoxy-3,4-didehydro1,2,1',2',7',8'-hexahydro-+,+-carotene (l)] and methoxyspheroidenone [ 1,l'dimethoxy-3,4-didehydro-1,2,1',2',7',8'-hexahydro-$,+-caroten-2-one (2)]. Ano-
(1) R = H , H (2) R = O
ther Rhodopseudornonas species, Rps. viridis, contains small amounts of crossconjugated carotenoid aldehydes including 13-cis-$,$-caroten-2O-al (3) and a novel 1,2-dihydro-derivative." The methods used could not distinguish between the alternative structures 3,4-dide hydro- 1,2-dihydro- +-caroten-20-al (4) and 3',4'-didehydro- 1 ',2'-dihydro- +-caroten-2O-al (5).
+,
3 +,
R' -
RZ
L
L ...
...
b
a
(3) R ' = R ~ = ~ (4) R' = b, R2= a (5) R ' = a , R 2 = b
Monocyclic Carotenoids. Eighteen carotenoid hydrocarbons have been isolated from the ladybird beet,le Coccinella septempunctata." Amongst the minor' components were detected small amounts of the new y-ring derivatives 3',4'didehydro-y,$-carotene (6), 7',Sf-dihydro-y,$-carotene (7), and 7',8',1 1',12'tetrahydro- y, $-carotene (8). Bicyclic Carotenoids. A major pigment of the bacterium Rhizobium lupini, 2,3,2',3'-di-trans-tetrahydroxy-P,P-caroten-4-one (9), is the first natural carotenoid to be described with oxygen substituents at positions 2, 3, and 4 of the ring.I2 Also present were 2,3,2'(or 3')-trihydroxy-@,@-caroten-4-one, (10) or (1 l),
lo
"
'*
G. Britton, H. C. Malhotra, R. K. Singh, S. Taylor, T. W. Goodwin, and A. Ben-Aziz, Phytochemtstry, 1976,15, 1971. G. Britton, H. C. Malhotra, R. K. Singh, T. W. Goodwin, and A. Ben-Aziz, Phytochemistry, 1976,15, 1749. G. Britton, W. J. S. Lockley, G. A. Harriman, and T. W. Goodwin, Nature, 1977, 266,49. H. Kleinig, W. Heumann, W. Meister, and G. Englert, Helv. Chim. Acfu, 1977,60, 254.
183
Carotenoids and Polyterpenoids
and carotenoids that appear to be identical to the recently characterizedI3 caloxanthin [P,P-carotene-2,3,3’-triol (1 2)] and nostoxanthin [P$-carotene-2,3,2’,3’tetrol (1 3)].
(9) X ’ = X 2 = y 1 = Y 2 = O H , R = O (10) X’ = x2= Y’ =OH, y2= H, R = o ( I 1) X’ = Y ’ = y2= OH, x2= H, R = o (12) X I = Y ’ = Y’ = OH, x2= H, R = H,H (13) X ’ = X Z = Y ’ = Y 2 = O H , R = H , H
A minor carotenoid of the alga Coccolithus huxleyi has been identifiedz4 as 3’-desacetyl- 19’-n-hexanoyloxyfucoxanthin [5,6-epoxy- 19’-n-hexanoyloxy-3,3’,5’trihydroxy-6‘,7’-didehydro-5,6,7,8,5’,6‘-hexahydro-~,~-~aroten-8-one (14)]. Two
CO
I
(CH,),Me (1.1)
C-5 epimers of 6,7-didehydro-5,6,5’,6‘-tetrahydro-P,P-carotene-3,5,3’,5‘,6’pent01 (15), isolated as minor constituents of a sample of neoxanthin [5’,6‘-epoxy6,7-didehydro-5,6,5’,6’-tetrahydro-P,P-carotene-3,5,3’-triol (16)] from Trollius europaeus, may be artefacts.I5 In Sarcina lutea, sarcinaxanthin [2,2’-bis-(4i3 i4
*5
R. Buchecker, S. Liaaen-Jensen, G. Borch, and H. W. Siegelman, Phyrochemzsrry, 1976, 15,1015. S. Hertzberg, T. Mortensen, G. Borch, H. W. Siegelman, and S. Liaaen-Jensen, Phytochernistry, 1977, 16, 587. R. Buchecker and S. Liaaen-Jensen, Phytochemishy, 1977, 16, 729.
184
Terpenoids and Steroids
HO
,,go”
(16) R = O
hydroxy-3-methylbut-2-enyl)-y,y-carotene (17)] occurs at least partly esterified with a C9H,,C0,H acid.16
(17) R =
Animal tissues have yielded several carotenoids of previously unknown structure. Chiriquixanthins A and B from a yellow frog, Ate6opus chiriquiensis,, have been found” to be epimeric ~,~-carotene-3,3’-diols (18) and (19) differing
(18) X = H , Y = O H (19) X = O H , Y = H
only in their stereochemistry at C-3. Major carotenoids of the stick insect Curuusius morosus are esters of P,P-caroten-2-01 (20) and P,P-carotene-2,2’-diol (21).18Also present” are six 2-oxo-derivatives, 3,4,3’,4’-tetradehydro-fi,fi-carotene-2,2’-dione (22), 3,4-didehydro-p,p-carotene-2,2’-dione (23), 2’-hydroxy-3,4didehydro-P,P-caroten-2-one (24), 2‘-hydroxy-P,P-caroten-2-one (25), P,Pcaroten-2-one (26), and P,P-carotene-2,2’-dione (27). Parasiloxanthin [7,8-dihydro-P,P-carotene-3,3‘-diol (28)] and 7,8-dihydroparasiloxanthin [7,8,7‘,8’-tetrahydro-p,P-carotene-3,3’-diol (29)] have been isolated from a Japanese fish, Parasilurus asotus.“ The presence of the 7,8-dihydro structure was deduced from the ‘H n.m.r. spectrum.
’‘ ” ”
’’
S. Hertzberg and S. Liaaen-Jensen, Actu Chem. Scund., 1977, B31, 215. A. Bingham, H. S. Mosher, and A. G. Andrewes, J.C.S. G e m . Comm., 1977,96. H. Kayser, Z. Narurforsch., 1976, 31c, 646. H. Kayser, Z. Nuhrrforsch., 1977,32c, 327. T. Matsuno, S. Nagata, and K. Kitamura, Tetrahedron Letters, 1977,4601.
Carotenoids and Polyterpenoids
185
b
a
(20) R’ = a (X = H,OH), R’ = a (X = H,H) (21) R’ = R’ = a = H,OH) (22) R 1 = R 2 = b
(x
( 2 3 ) R’ = b, R 2 = a ( X = 0)
(24) R’= b, R2 = a (X = H,OH) (25) R’ = a (X = 0),R’ = a (X = H,OH) (26) R’ = a ( X = 0),R’= a (X = H,H) (27) R’= R2 = a (X = 0)
Two aryl carotenoids from marine sponges, clathriaxanthin” and tedaniaxanthin,” have been assigned the structures 3-hydroxy-P,~-caroten-4-one (30) and 2,3-didehydro-P,x-caroten-3-01(3 1). Clathriaxanthin, normally present as an ester, is readily autoxidized to form the corresponding diosphenol clathricine [3-hydroxy-2,3-didehydro-P,X-caroten-4-one (32)]. The trivial nomenclature is very confusing since this structure was previously assigned to another sponge carotenoid, tedanin.23
Apocarotenoids. The natural occurrence of neurosporaxanthin methyl ester [methyl 4‘-apo-P-caroten-4‘-oate (33)] in the fungus Verticillium agaricinum has been reported.24 Carotenoid Glycosides. The chemistry and distribution of carotenoid glycosides have been reviewed.’“ A dihexoside (presumed diglucoside) of sarcinaxanthin has been detected in Sarcina lutea.‘6 The gliding bacterium Herpetosiphon giganteus contains a series of esterified glycosides, the 1’-X-0-acylglucosyloxy-, 1’-X- 0acyldiglucosyloxy-, and 1’-diglucosyloxy-derivativesof 3’,4‘-didehydro-l’,2’-dihydro-P,+-caroten-4-one (34), which were identified from their m.s. and ‘H n.m.r. spectra.” Carotenoproteins. These complexes are arousing increasing interest as the form in which many carotenoids probably exist in vivo. The carotenoprotein field has been reviewed.” Two reports have described new blue carotenoproteins, a canthaxanthin (35)-lipovitellin of crustacean origin26and, from a marine chondrophore, an astaxanthin (36) complex which dissociates into different pigment forms at different ionic strength^.^' Further details have been obtained concerning the quaternary structure of the lnbster exoskeleton astaxanthin complex, crustacyanin.28 Algal sources have also yielded carotenoid-protein complexes. A water-soluble
*’ Y. Tanaka and T. Katayama, Bull. Jup. SOC.Sci. Fisheries, 1976,42, 801. 22
23 24
” 26 27
Y. Tanaka, Y. Fujita, and T. Katayarna, Bull. Jup. Soc. Sci. Fisheries, 1977,43, 761. N. Okukado, B U N Chem. Soc. Jupun, 1975,48, 1061. L. R. G. Valadon and R. S. Mummery, Phytochemishy, 1977,16,613. H. Kleinig and H. Reichenbach, Arch. Microbiol., 1977,112, 307. P. Z. Zagalsky and B. M. Gilchrist, Comp. Biochem. Physiol., 1976,55B, 195. P. F. Zagalsky and P. J . Herring, Phil. Trans. Roy. Soc. London, Ser. B., 1977, 279, 289. R. Quarmby, D. A. Norden, P. F. Zagalsky, H. J . Ceccaldi, and R. Daumas, Comp. Biochem. Physiol., 1977,56B, 5 5 .
Terpenoids and Steroids
186
chromoprotein from the green alga Scenedesmus obliquus has violaxanthin [5,6,S',6'-diepoxy-5,6,S',6'-tetrahydro-/3,/3-carotene-3,3'-diol (37)] together with
H
0 a
b
d
e
C
0 f
h
(28) R' = a , R2 = b (X = OH) (29) R ' = R ~ = ~ (30) R' = c (Y =OH), R2 = d (31) R ' = e , R 2 = d (32) R'==f, R 2 = d
(33) R' = b (X = H), R2 = CH=CH-CH=C(Me)CO,Me (34) R * = c (Y = H), R2 = g (35) R' = R2 = C (Y = H) (36) R ' = R ~ = c ( Y = o H ) (37) R' = R 2 = h
some neoxanthin (16) as its carotenoid components,29 and the photosynthetic light-harvesting complex from several marine dinoflagellates has been identified as a peridinin [5',6'-epoxy-3,5,3'-trihydroxy-6,7-didehydro-S,6,5',6'-tetrahydro10,11,2O-trinor-/3,~-caroten-19',1 l'-olide-3-acetate (38)]-chlorophyll-a prot ein . ' 3073
I
Lnu
'' R. Powls and G. Britton, Biochirn. Biophys. Acta, 19'76, 453, 270.
'"B. B. Prtzelin and F. T. Haxo, Plantu (Berlin),1976, 128, 133. 3'
P.-S.Song, P. Koka, B. B. PrCzelin, and F. T. Haxo, Biochemisiry, 1976, 15, 4422
187
Carotenoids and Polyterpenoids
Degraded Carotenoids. Several compounds have been described and characterized which are related structurally to carotenoids and may be biodegradation products of carotenoids. The structure of the vitamin A dimer kitol has been determined as (39).32Three metabolic products of retinoic acid (40) have been isolated from rat urine and characterized as (44), ( 4 3 , and (46).33Rat faeces yielded three further products (41), (42),and (43).34 YH,OH
X (40) X = H,H, R = Me (41) X = O , R = M e
(42) X = H,H, K = C H 2 0 H (43) X = H,H, R = CHIOH, 9,10-&
CO,H
0
"
O0
H
2
W
(44) R = M e (45) R=CH,OH
Examination3' of the flavour constituents of the passion fruit Pussiflora edulis has yielded the novel ionone derivatives (47) and (48). Edulans I and 11, (49) and (50),36and dihydroedulans 1 and 11, (51) and (S2)," from the same source have been characterized fully. Two bicyclodamascenones, (53) and (54),have been identified as components of the flavour of Virginia t o b a c ~ o , ~and ' several ionone, damascone, and cyclocitral derivatives are present amongst the many volatile compounds produced during flue-curing of this t o b a c ~ o . ~ ' T. Yano, Kyushu Daigaku Nogakuba Gakugei Zasshi, 1976,31,41 (Chem. Abs., 1977,86, 90 087). R. Hanni, F. Bigler, W. Meister, and G. Englert, Helv. Chim. Acfa, 1976, 59, 2221. R. Hanni and F. Bigler, Helu. Chim. Acfa, 1977,60, 881. 35 F. Naf, R. Dkorzant, B. Willhalm, A . Velluz, and M. Winter, Tefrahedron Lefrers, 1977, 1413. 36 F. B. Whitfield and G. Stanley, Austral. J. Chem., 1977, 30, 1073. 37 G. D. Prestwich, F. B. Whitfield, and G. Stanley, Tetrahedron, 1976, 32, 2945. '' E. Demole and P. Enggist, Helu. Chim. Acra, 1976, 59, 1938. 39 1. Wahlberg, K. Karlsson, D. J. Austin, N. Junker, J . Roeraade. C. R. Enzell, and W. H. Johnson, Phytochemisfry, 1977, 16, 1217.
32
33
34
Terpenoids and Steroids
188
(47) X = H,OH (48) x - 0
(49) R’ = Me, R2 = H (SO) R’ = H, R2=Me
(51) R ’ = M e , R 2 = H (52) R’ = H, R2 = Me
Stere0chemistry.-Various aspects of carotenoid stereochemistry are dealt with extensively in two reviews.’d‘ The (6’s) configuration has been assigned to natural P,y-carotene (55) from Culoscyphu fulgens by c.d. correlation with P,y-carotene samples enriched in the (6’R) and (6’s) enantiomers synthesized from partly resolved y-ionone (64).40 The same configuration was established for C-6 and C-6‘ of the Cs0carotenoid sarcinaxanthin.16 The substituents at C-2 and C-6 are in a cis relationship and the double bond of the C, substituent is E (56). Bacterial zeaxanthin [&/3-carotene-3,3’-diol (57)] rhamnoside has the (3R,3’R) configuration and an a-L-rhamnopyranosyl glycosidic link.41C.d correlation has shown that the end groups in ‘asterinic acid’ [7&didehydroastaxanthin (58) + 7,8,7’,8’-tetradehydroastaxanthin (59)] have the same (3s) chirality as lobster astaxanthin [3,3’dihydroxy-/3,/3-carotene-4,4’-dione (60)].42 The ~,~-carotene-3,3’-diols chiriquixanthins A and B represent the first examples of two carotenoid epimers being present in the same source. Their chirality was established as (3R,6R,3’$6’R) (18) and (3S,6R,3’S,6’R) (19) respectively, the 3,6-cis or trans stereochemistry following from ‘H n.m.r. considerations and the (6R,6’R) chirality being assigned from the c.d. curves. Chiriquixanthin A is the first example of a carotenoid in which the two end-groups are constitutionally identical but stereochemically different.” The trans arrangement of 2- and 3-hydroxy-groups in 2,3,2’,3‘-tetrahydroxy@,P-caroten-4-one (9) and related compounds was deduced from the ‘H n.m.i. spectra of the tetra-acetates,12 although it is not yet established whether the absolute configurations at C-2 and C-3 are the same as in caloxanthin (12) and nostoxanthin (13). The absolute configurations of heteroxanthin [(3S,5S,6S,3’R)-7’,8’-didehydro5,6-dihydro-P,P-carotene-3,5,6,3‘-tetrol (61)] and diadinoxanthin [(3S,5R,6S, 3’R)-5,6-epoxy-7’,8’-didehydro-5,6-dihydro-~,~-carotene-3,3’-diol (62)] from Euglena grucilis have been established” by chemical reactions, hydrogenbonding studies (Lr.), ‘Hn.m.r., and c.d. 19’-Hexanoyloxyfucoxanthin (65) has been shown14 to have the same stereochemistry (3S,.5R,6S,3’S,SfR,6’S)as fuco40 41
42
M. Hallenstvet, R. Buchecker, G. Borch, and S. Liaaen-Jensen, Phytochemtsm, 1977,16, 583 S. Hertzberg, G. Borch, and S. Liaaen-Jensen, Arch. MicrobioL, 1976,110,95. R. Berger, G. Borch, and S. Liaaen-Jensen, Acta Chem. Scad., 1977, B31, 243.
Carotenoids and Pofyterpenoids
189
xanthin [5,6-epoxy-3,3',5'-trihydroxy-6',7'-didehydro-5,6,7,8,5',6'-hexahydroP,P-caroten-S-one 3'-acetate (66)]. ,
a+e.: e.. c"
0
___
HO
HO
HO
OH
0 d
f
e
HO
HO h
g
(55) (56) (57) (58) (59)
R'=a(X=H),R2=b R' = R~ = c R'=R2=a(X=OH) R' = d, R2 = e R' = R2 = d
(60) (61) (62) (63)
R'=R2=e R'=f,R2=g R'=h,R2=g R' = R2 = a (X = H)
(65) R = CH20CO(CH2),Me (66) R = M e
Synthesis and Reactions.-Curotenoids. Several review^'^^^"''^ survey recent progress in the synthesis and chemistry of carotenoids and related polyenes. Two other
190
Terpenoids and Steroids
reviews on recent developments in sulphone chemistry4' and the Wittig reaction in industrial practice4, include work on syntheses in the carotenoid and vitamin A series. The preparation of p-carotene [@$-carotene (63)] in 50% yield by reductive coupling of retinaldehyde (67) with TiC1,-LiAIH, has been described. Similarly p-ionone (68) gives the symmetrical olefin (69).45 The enolic p-diketone caro-
(69)
tenoids mytiloxanthin C3,3',8'-trihydroxy-7,8-didehydr~-p,~-caroten-6'-one (70)] (71)] have been and trikentriorhodin [3,8-dihydroxy-~,~-caroten-6-one ~ y n t h e s i z e d .The ~ ~ intermediate protected methyl ketone (77), prepared from (+)-camphor, underwent Claisen-type condensation with the ester (72) obtained from the dial (73) by successive Wittig reactions. The product (74) on acid treatment gave (7 1). 9-cis-Mytiloxanthin was prepared by Claisen condensation of the protected ester (75) with (77), followed by acid cleavage of the protecting acetal group and Wittig reaction on the resulting apoaldehyde (76). All attempts to prepare all-trans-(70) failed. In a synthesis o f optically active (2S)-P,P-caroten-201 (78) the key chiral intermediate (2S)-2-hydroxy-P-ionone (79) was prepared by fermentative reduction of 2-oxo-p-ionone (80) by baker's yeast.47 An improved route to (80) is described. The intermediate 8,8'-diapo-20-acetoxycarotene-8,8'-dial(81)48 has been used4' to synthesize the cross-conjugated carotenoid aldehydes X,X-caroten-20-al (82), (2R,2'R)-2,2'-bis-(3-methylbutyl)-3,4,3',4'-~~trahydr~-~,~-caroten-20-a1 (83), and (2R,6R,2'K,6'R)-2,2'-dimethyldecapreno-~,~-caroten-25-al (84). Wittig condensation of (81) with the appropriate phosphonium salts in the presence of butylene- 1,2-oxide to avoid excess base prevented formation of undesired condensation products due to oxidation of the acetoxy-group of (81) to the corresponding aldehyde. The synthesis of one such product ( 8 5 ) is reported.49 The model compounds (2R,6S,2'R,6'S)-2,2'-dimethyly, y-carotene (87) and (2R,2'R,6'S)-2,2'-dimethyLP,y-~arotene (88) have been prepared5' by standard methods from natural (+)-(2S,6R)-cis-y-irone (86). Similarly, optically active 43 44
45 46
47 48 49
P. D. Magnus, Tetrahedron, 1977,33, 2019. H. Pommer, Angew. Chem. Znfernar. Edn., 1977, 16. 423. A. Ishida and T. Mukaiyama, Chem. Letters, 1976, 1127. A. K. C h o p , G. P. Moss, and B. C. L. Weedon, J.C.S. Chem. Comm., IY77,467. M. Ito, R. Masahara, and K. Tsukida, TefruhedronLetfers, 1977, 2767. J. E. Johansen and S . Liaaen-Jensen, Acru Chem. Scand., 1975, B29, 315. J. E. Johansen and S. Liaaen-Jensen, Tetrahedron, 1977,33, 381. A. G. Andrewes, G . Borch, and S . Liaaen-Jensen, Acfu Chem. Scund., 1977, B31,212.
Carotenoids and Polyterpenoids
191
OX a
.*,
\
d
(70) R' = a ( X = H), R'= b (71) R1 = a (X = H), R2 = c (72) R ' = c , R ' = d (73) R' = R' = CHO
"H
O
W
(79)
o
e
(74) R' = B (X = Me$&), RZ= c
(75) R ' = d . R ' = e (76) R' = a (x= H), R'
= CHO
192
Terpenoids and Steroids CHO
a
b
C
(82) R = a
(83) R = b
(84) R = c
(86)
samples of y-ionone (64), partly resolved as the menthydrazones, were used for the synthesis of P,y-carotene (55) samples enriched in the (6’R) and (6’s)enantiomer~.~’ The Cs0 carotenoid decaprenoxanthin [2,2’-bis-(4-hydroxy-3-methylbut-ienyl)-&,e-carotene (89)] has been prepared from the functionalized a-irone derivative ( 9 9 , the synthesis of which is outlined in Scheme l.51 In the mixture of (89) isomers formed, those with 2,6-trans end-groups predominated. O n treatment with MnO, in acetone, carotenoid diosphenols are converted into 2-nor-analogues which possess a cyclopentenedione end-group.s2 Thus astacene [3,3’-dihydroxy-2,3,2’,3’-tetradehydro-~,/3-carotene-4,4’-dione (90)] yields the blue pigment violerythrin [2,2’-dinor-/3$-carotene-3,4,3’,4’-tetraone (91)]. Cathodic cleavage of acetate from retinyl acetate (96) and crustaxanthin tetraacetate (92) gives novel and convenient routes to, respectively, axerophtene (97) 51
A. K. Chopra, B. P. S. Khambay, H. Madden, G . P. Moss, and B. C. L. Weedon, J . C S . Chem. Comm.,
52
1977,357. R. Coman, A. P. Leftwick, and B. C. L. Weedon, J . C S . Perkin I. 1976, 2140.
193
Carotenoids and Polyterpenoids
and 3,4,3',4'-tetradehydro-@,p-~arotene(93), hydrocarbons that otherwise are difficult to prepare.53 Treatment of diadinoxanthin (62) bistrimethylsilyl ether with lithium aluminium hydride affords the bistrimethylsilyl ether of diatoxanthin (94), although similar
a
b
C
e
d
f
h
g
(87) R 1 = R 2 = a (88) R' = b, R2 = a (89) R' = R~= c (90) R' = R 2 = d
1
(91) (92) (93) (94)
R'=R2=e R' = R2 = f R'=R2=g R' = h, R2 = i
conversion of free (62) does not occur. With aqueous acid, (62) yields heteroxanthin (61).15 In acid solution, p,p-carotene-2,2'-diol (2 1) is specifically dehydrogenated and rearranged to ketones with retro structures, behaviour analogous to that of P,P-caroten-2-01 (2O).', The final product from the diol is 4,5-dihydro-4,5'reti-o-P,P-carotene-2,2'-dione ( 101).I8 Hydrogenation of the 3,4-double bond is observed as a side-reaction during NaBH, reduction of 3,4,3',4'-tetradehydro-P,Pcarotene-2,2'-dione (22).' Retinol Derivatives. Aryl sulphones have been used in two new syntheses in the vitamin A series. Reaction of P-cyclocitryl phenyl sulphone (102) with the bromocompound (103) gives the intermediate sulphone (104), which on base-catalysed elimination affords methyl retinoate (98)." Alternatively retinol (99) has been prepared in high yield by condensation of the CIS bromide (105) with the Cs hydroxy-sulphone (106),followed by elimination of sulphinic The syntheses
'' J. C. Gourcy, M. Hodler, B. Terem, and J. H. P. Utley, J.C.S. Chem. Comm., 1976, 779. 54 55 56
H. Kayser, Tetrahedron Letters, 1975, 3743. K. Uneyama and S . Toni, Chem. Letters, 1977, 39. G. L. Olson, H.-C. Cheung, K. D. Morgan, C. Neukom, and G. Saucy, J. Org. Chem., 1976,41,3287.
Terpenoids and Steroids
194
( 8 ~ ) )viii,iii
MeOzC
wpp '
(95) Reagents: i, (CH20H)2; ii, N,CH,CO,Et; iii, LiAIH4; iv, BF3-AcOH-H3PO4; v, THP; vi, Wittig reaction; vii, PPh3-HCI-MeOH; v k , C14dial
Scheme 1
(96) R=CH,OAc (97) R - M e (98) R = C 0 2 M e
(99) R=CI-120H ( 1 00) R = COOP(OH)20
0
0
(101)
BrH2C&m2m
~ H z (102) s O z p h
(103)
Carotenoids and Polyterpenoids
195 S0,Ph
S0,Ph
Pco of ring and four side-chain dihydroretinoic acids and their esters and of several vitamin A analogues with a substituted aromatic ring have been de~cribed.’~ Standard methods, especially Horner reactions, were used. The Wittig reaction was used in the synthesis of the vitamin A furanone derivates (107) and (108).5R High specific activity [ 1l-3H]-all-rruns-a-retinyl acetate (109) has been ~ r e p a r e d . ~The ’ chemical synthesis of all-trans-retinoyl phosphate (100) in 1015% yield from retinoic acid has been reported.“
Conditions have been for catalytic hydrogenation of the acetylene group of the vitamin A synthesis intermediate (110). Several chemical reactions of geometrical isomers of the product (11 1) and its acetate and of (110) have been described .63,64
’’ B. A. Pawson, H.-C. Cheung, R.-J. L. Han, P. W. Trown, M. Buck, R. Hansen, W. Bollag, U. Ineichen, 5R 59
6o
62
63 64
H. Pleil, R. Riiegg, N. M. Dunlop, D. L. Newton, and M. B. Sporn, J. Medicin. Chem., 1977,20, 918. J. F. Blount, R.-.I. L. Han, B. A. Pawson, R. G. Pitcher, and T. H. Williams, J. Org. Chem., 1976,41, 4108. R. L. Hale, W. Burger, C. W. Perry, and A. A. Liebman, J. Labelled Compounds Radiopharmaceuticals, 1977,13, 1 2 3 . J. P. Frot-Coutaz and L. M. DeLuca, Biochem. J., 1976, 159,799. M. A. Veksler, G. P. Chernysh, E. A. Oger, E. G. Koreshkova, and G. I. Samokhvalov, Khim.-Farm. Zhur., 1976, 10, 92. E. A. Ozer, T. M. Beloslyudova, G. P. Chernysh, and G. I. Samokhvalov, Khim.-Farm. Zhur., 1976, 10, I l l . G. P. Chernysh, V. M. Kozhukhovskaya, L. V. Yanchuk, N. M. Savel’eva, and G. I. Samokhvalov, Zhur. org. Khim., 1976, 12, 2624. G. P. Chernysh, V. M. Kozhukhovskaya, T. M. Filippova, A. R. Becker, N. M. Savel’eva, L. V. Yanchuk, T. A. Gritsenko, Zh. K. Torosyan, and G. I. Samokhvalov, Zhur. org. Khim., 1977,13,53.
Terpenoids and Steroids
196
( 1 10)
(111)
Some conversion into the anhydrovitamin (1 12) occurs during silica gel t.1.c. of retinyl palmitate in non-polar Some new colour reactions of vitamin A are reported to be better than the Carr-Price reaction.66 The kinetics and mechanism of acid-catalysed isomerization of retinyl acetate into the trans-retroderivative (113) have been s t ~ d i e d . ~Oppenauer ' oxidation of kitol (39) results in specific cyclopentanol-cyclopentanone oxidation.6H
(112)
(113)
Other Degraded Carotenoids. A new synthesis6' of the fungal sex hormone (*)(7E,9E)-trisporic acid B methyl ester (114) utilized as the key step a Michael-aldol sequence on the p-keto-ester (1 15) to yield the highly functionalized cyclohexenone ( 1 16). The latter underwent Wittig reaction with the phosphonium salt (117) to give (1 14). After basic alumina-catalysed hydrogen exchange in tritiated
C02Me
@"'OMe)* 0 (116)
water, 1-hydroxy-4-keto-a-ionone(118) was used in a Wittig reaction to give tritiated (RS)-abscisic acid (1 19) of high specific a~tivity.~'Reformatsky or Wittig reactions have been used in the synthesis of 36 different 3-methyl-5-aryl penta-2,4dienoic acids and esters, analogues of abscisic acid.7' The 2,3,4,6-tetra-O-acetylR. Dobrucki, Acra Polon. Pharm., 1976, 33, 131. E. F. Lang and H. S. Lang, Deut. Lebensm.-Rundsch., 1977,73, 5. G . P. Chernysh, V. M. Kozhukhovskaya, N . M. Savel'eva, T. M. Filippova, A. R. Becker, and G . I. Samokhvalov, Khim.-Farm. Zhur., 1976,10, 101. " T. Yano, Kyushu Daigaku Nogakubu Gakugei Zasshi, 1976,31,49 (Chem. Abs., 1977,87,52 840). " J. A. Secrist, C. J. Hickey, and R. E. Norris, J. Org. Chem., 1977, 42, 525. 'O D. Walton, R. Wellner, and R. Horgan, Phytochernisfry, 1977,16, 1059. " S. Bittner, M. Gorodetsky, I. Har-Paz, Y . Mizrahi, and A. E. Richmond, Phytochemistry, 1977, 16, 1143.
66
67
Carotenoids and Polyterpenoids
197
p-D-glucopyranosyl esters of abscisic acid and p-ionylideneacetic acid (120) have been prepared by treatment of the acid with a-acetobromoglucose in the presence of trieth~lamine.~'Two paper^^^.^^ describe a new synthesis of y-ionone (64) in which the key intermediate (121) is prepared from y-cyclocitral (122) and acetone in the presence of Bu2BS03CH2CF3.
(118) x = o (119) X = CHC02Me
(121)
(122)
Syntheses have been reported for several other natural products related structurally to carotenoids, viz. dihydroactinidiolide (123) and tetrahydroactinidiolide (124),75,76trans- and cis-a-damascone (125),77dihydroedulans I and 11, (51) and (52),37 bicyclodamascenones A and B, (53) and (54),3' the diastereoisomeric caparrapi oxides (126),78 (*)-a-chamigrene (1 27),79 and the novel passion-fruit ionone derivatives (47) and (48).35
Photochemical isomerization of trans-p-ionol (128) in benzene gave the 7-cisisomer in high yield.'" The photochemical behaviour of y,6- and &&-unsaturated carbonyl compounds of the dihydroionone series has been studied in detail, and H. Lehmann and H. R. Schette, J. prakt. Chem., 1977, 319, 117. T. Mukaiyama, K. Saigo, and 0.Takazawa, Chem. Letters, 1976, 1033. K. Hermann, Nachr. Chem., Tech. Lab., 1977,25, 120. 7 5 S. Torii, K. Uneyama, and M. Kuyama, Tefruhedron Letters, 1976, 1513. '' B. Goyau and F. Rouessac, Compt. rend., 1976,283, C, 597. 7 7 H. J. Liu, H. K. Hung, and G. L. Mhehe, Tetrahedron Letters, 1976,4129. 78 P. Lombardi, R. C. Cookson, H. P. Weber, W. Renold, A. Hauser, K. H. Schulte-Elk, B. Willhalm, W. Thommen, and G. Ohloff, Helv. Chim Acta, 1976,59, 1158. 79 G. Frater, Helv. Chim. Acta, 1977,60, 515. *O V. Ramamurthy and R. S. H. Liu, Org. Phofochem. Synth., 1976,2,70. 72
73 74
198
Terpenoids and Steroids
many products of U.V.irradiation have been characterized.81 In a surveyx2of the selective reduction of @-unsaturated carbonyl compounds with alkali-metal carbonyl chromates [M+HCr,(CO),, -1 or carbonyl ferrates [M+HFe(CO), -1 it was found that a - and p-ionones, (129) and (68), give the corresponding 7,8-dihydroionones in 50-5S% yield.
( 1 28)
(129)
Physical Methods and Physical Chemistry.-Separation and Assay Methods. A procedure for h.p.1.c. of plant pigments has been used to separate the carotenoids of spinach and of a diatom.83 H.p.1.c. separations of citrus carotenoids,8-6 and of retinal (67) isomer^^^.^^ have also been reported. Carotenoid mixtures have also been separated efficiently and rapidly by centrifugal c h r ~ m a t o g r a p h y . ~ ~ 13 C N.M.R. Spectroscopy. This powerful technique is not yet being used routinely in carotenoid analysis, but the review by Mossla discusses methods and applications and tabulates chemical shift data obtained for a range of carotenoids. Elsewhere” the 13C n.m.r. spectra of (3S,3’S)-astaxanthin (60), its IS-cis-isomer, its diacetate, and its IS,lS’-didehydro analogue are presented and assigned, along with ‘H n.m.r., u.v., and c.d. data.
Circular Dichroism. Several papers’4-‘774G42,59.90 report the use of c.d. correlations in establishing the absolute configurations of carotenoids. One report” sounds a cautionary note since the signs of all maxima in the c.d. spectrum of 15-cis-(3S,3’S)-astaxanthin are opposite to those of the all-trans-isomer. Electronic Absorption Spectroscopy. Absorption spectra have been obtained for radical cations and anions generated from a number of carotenoids [phytoene (7,8,11,12,7’,8’,11’,12’-octahydro-~,I,!J-carotene) (135) and canthaxanthin (p,pcarotene-4,4’-dione) (130)] and related polyenes [7,7‘-dihydro-P-carotene (1 3 l), 0
’’
**
M. P. Zink, H. R. Wolf, E. P. Miiller, W. B. Schweitzer, and 0.Jeger, Helv. Chim. Acta, 1976,59, 32. G. P. Boldrini, A. Umani-Ronchi, and M. Panunzio, Synthesis, 1976, 596.
’’ K. Eskins, C. R. Scholfield, and H. J. Dutton, J. Chromatog., 1977, 135, 217.
I . Stewart and U. Leuenberger, Alimenta, 1976, 15, 33. U . Leuenberger, Chimia (Switz.), 1976, 30,496. I. Stewart, J. Assoc. Ofic. Analyt. Chemists, 1977,60, 132. *’ K. Tsukida, A. Kodama, and M. Ito, J. Chromatog., 1977, 134, 331. ’’ F. G. Pilkiewicz, M. J. Pettei, A. P. Yudd, and K. Nakanishi, Exp. Eye Res., 1977, 24, 421. ” H. Pfander, F. Haller, F. J. Leuenberger, and H. Thommen, Chromafographia, 1976, 9. 630. 9” G. Englert, F. Kienzle, and K. Noack, Helv. Chim. A c f a , 1977, 60, 1209. x4
” Rb
Carotenoids and Polyterpenoids
199
heptapreno-@-carotene (132),decapreno-@-carotene(133), and dodecapreno-Pcarotene (134)]. Broad absorption maxima were observed at much longer wavelengths than those of the parent molecule. Theoretical calculations are in broad agreement with the experimental findings.”’
(132) x = 2 , y = 1 (133) x = y = 3 (134) x = y = 4
Resonance Raman Spectroscopy. A review” of the interpretation of resonance Raman spectra of biological molecules includes a consideration of carotenoids and retinal derivatives. Another review93 of resonance Raman studies of visual pigments deals extensively with retinals. Excitation profiles of the coherent antiStokes resonance Raman spectrum of 0-carotene have been p r e ~ e n t e d . ~ ~ Resonance Raman spectroscopic methods have been used for the detection of very low concentrations of carotenoids in blood plasmag5and for the determination of carotenoid concentrations in marine phytoplankton, either in situ or in acetone extracts.’6 X-Ray Crystallography. The crystal and molecular structure of dl-2-cis-4-transabscisic acid (7-trans-9-cis, carotenoid numbering) has been determined by the X-ray method.”’ X-Ray crystallographic data are presented for the retinal derivative (107)? Miscellaneous Physical Chemistry. A review of the year’s literature (mid- 1975mid- 1976) on excited states of biomolecules including carotenoids and related polyenes has been published.”’ Various aspects of the physical chemistry of carotenoids have been reported, including electron donor-acceptor proper tie^,^^"^" 9’ y2
93 Y4 y5
” yx yy
loo
J . Lafferty, A. C. Roach, K. S. Sinclair,T. G . Truscott, and E. J. Land, J.C.S. Faradayl, 1977,73,416. A. Warshel, Ann. Rev. Biophys. Bioeng., 1977, 6 , 273. R. Callender and B. Honig, Ann. Rev. Biophys. Bioeng., 1977,6, 33. L. A. Carreira, T. C. Maguire, and T. B. Malloy, jun., J. Chem. Phys., 1977, 66, 2621. A. J . Rein, D. D. Saperstein, S. H. Pines, and P. C. Kadlick, Experientia, 1976,32, 1352. L. C. Hoskins and V. Alexander, Analyf.Chem., 1977,49, 695. H. Ueda and J. Tanaka, Bull. Chem. SOC.Japan, 1977,50, 1506. R. D. Fugate and P.-S. Song, Phorochem. and Photohiol., 1976,24, 629. V. Mairanovskii, A. A. Engovatov, N. T. Ioffe, and G . 1. Samokhvalov, Khim.-Farm. Zhur., 1976, 10, 105. N. T. Ioffe, A. A. Engovatov, and V. Mairanovskii, Zhur. ohshchei Khim., 1 9 7 6 , 4 6 1 6 3 8 .
200
Terpenoids and Steroids
eiectrochromism,’O1and electrical conduction studies.lo* Several papers103-”3 discuss spectroscopic and physicochemical properties of carotenoids in vivo, e.g. in chloroplast membranes, chromatophores, and photosynthetic reaction centres.
Spectroscopy and Physical Chemistry of Retinal and Visual Pigments. Several reviews and symposium proceedings discuss the spectroscopic, photochemical, or physicochemical properties of retinal and related compounds, and of natural and model visual pigments derived from them.92’93”8”14-’’* In addition, many papers have been published dealing with specific aspects of the spectroscopy (u.v., n.m.r., resonance Raman) of retinals and rhodopsins”y-128 or with aspects of the photochemistry and physical chemistry of retinal derivatives which may be relevant to the functioning of rhodopsin and other visual pigment^.'*^-'^^ The bacterial purple
lo’
’05
lo‘
lb7
Io9
I” I13
’”
‘I9 IZo
IZ1
’’’ Iz3
IZ5
IZ8
13” 131
13’
13’
R. Reich and K.-U. Sewe, Photochem. and Photobiof., 1977, 26, 11. T. J. Lewis and R. Pethig, in ‘Excited States of Biological Molecules, Proceedings of the International Conference, 1974’, ed. J. B. Birks, Wiley, Chichester, 1976, p. 342; D. K. Das Gupta and M. K. Barbarez, ibid., p. 353. M. C. Kung and D. DeVault, Photochem. and Phofobiof.,1976,24, 87. C. E. Swenberg, R. Dominijanni, and N. E. Geacintov, Phofochem.and PhofobioL, 1976.24.601, H. Conjeaud, M. Michel-Villaz, A. Vermeglio, and P. Mathis, F.E.B.S.Leners, 1976, 71,138. K. Matsuura and M. Nishimura, Biochim. Biophys. Acfa, 1977,459,483. G. S. Beddard, R. S. Davidson, and K. R. Trethewey, Nature, 1977, 267, 373. K.-U. Sewe and R. Reich, 2. Nahtrforsch., 1977, 32e, 161. G. P. Borisevich, A. A. Kononenko, and A. B. Rubin, Phofosynfhetica,1977, 11,81. A. Kageyama, Y. Yokohama, S. Shimura, and T. Ikawa, Plunt Cell Physiol., 1977, 18,477. K.-U. Sewe and R. Reich, F.E.B.S. Leners, 1977,80, 30. R. J. Cogdell, S. Celis, H. Celis, and A. R. Crofts, F.E.B.S. Lefters, 1977, 80, 190. S. S. Brody and M. Brody, Photochem. and Phofobiol., 1977, 26, 57. ‘Excited States of Biological Molecules, Proceedings of the International Conference, 1974’, ed. J. B. Birks, Wiley, Chichester, 1976: B. Rosenberg, p. 509; R. Azerad, R. Bensasson, M. B. Cooper, E. A. Dawe, and E. J. Land, p. 531; T. Rosenfeld, A. Alchalel, and M. Ottolenghi, p. 540; S. J. Formosinho, p. 555. W. L. Stone and E. A. Dratz, Photochem. and Photobiol., 1’177, 26, 79. S . E. Ostroy, Biochim. Biophys. Acta, 1977, 463, 91. T. Kakitani and H. Kakitani, Kagaku No Ryoiki, 1976, 30, 870 (Chem. Abs., 1977, 86, 1137). ‘Biophysics of Structure and Mechanism’, 1977, Vol. 3: W. Sperling, P. Carl, C. N. Rafferty, and N. A. Dencher, p. 79; T. G. Ebrey, p. 95; A. Lewis, p. 97; B. E. Kohler, p. 101; F. J. M. Daemen and S. L. Bonting, p. 117; R. Henderson and P. N. T. Unwin, p. 121; C. N. Rafferty, p. 123; J. Wyman, N. A. Dencher, and K. Hamacher, p. 127; K. Kirschfeld and N. Franceschini, p. 191. M. Sulkes, A. Lewis, A. T. Lemley, and R. Cookingham, Proc. Nuf. Acad. Sci. U.S.A., 1976,73,4266. R. S. Becker, G. Hug, P. K. Das, A. M. Schaffer, T. Takemura, N. Yamamoto, and W. Waddell, J. Phys. Chem., 1976, 80,2265: T. Takemura, P. K. Das, G. Hug, and R. S. Becker, J. Amer. Chem. SOC.,1976,98, 7099. B. Honig, A. D. Greenberg, U. Dinur, and T. G. Ebrey, Biochemisfzy, 1’176, 15,4593. R. Mathies, A. R. Oseroff, T. B. Freedman, and L. Stryer, in ‘Tunable Lasers, Applications, Proceeding of the Loen Conference‘, Springer Series Optical Science, 1976, p. 294. D. S. Kliger, S. J. Milder, and E. A. Dratz, Photochem. and Phofobiol., 1977, 25, 277. S. J. Milder and D. S. Kliger, Photochem. and Phofobiol., 1977, 25, 287. R. Mathies, T. B. Freedman, and L. Stryer, J. Mol. Biof., 1977, 109, 367. Y. Inoue, Y. Tokito, R. Chujo, and Y. Miyoshi, J. Amer. Chem. SOC.,1’177,99, 5592. S. Hotchandani, P. Paquin, and R. M. Leblanc, Photochern. and Photobiof., 1977, 26, 167. G. Hug and R. S. Becker, J. Chem. Phys., 1976,65,55. J. W. Laing, M. G. Sceats, S. A. Rice, and R. M. Gavin, Chem. Phys. Leners, 1976, 41,419. R. M. Hochstrasser, D. L. Narva, and A. C. Nelson, Chem. Phys. Letters, 1976,43, 15. D. Huppert, P. M. Rentzepis, and D. S. Kliger, Phofochem. and Photobiof., 1977, 25, 193. A. tfarriman and R. S. H. Liu, Photochem. and Phofobiol., 1977,26, 29. T. Rosenfeld, 0. Kalisky, and M. Ottolenghi, J. Phys. Chem., 1977, 81, 1496. H. Kakitani, T. Kakitani, and S. Yomosa, J. Phys. SOC.Japan, 1977,42, 996
Carotenoids and Polyterpenoids
201
membrane retinal-protein complex bacteriorhodopsin has also received considerable a t t e n t i ~ n . ' ~ ~ ' ' ~ ~ - ' ~ ' Biosynthesis and Metabolism.-Path ways and Reactions. Two reviews of carotenoid biosynthesis discuss, respectively, the early stepslk and the later reactions." The former paperlk deals with the mechanism of formation of phytoene and the series of desaturation reactions by which phytoene is converted into lycopene, and carotenoids. The second also describes in detail the biosynthesis of bacterial paper'' presents details of the mechanism and stereochemistry of cyclization and the other reactions that involve the carotenoid C-1 -C-2 double bond and the later modifications, especially the introduction of oxygen functions. Kinetic studies of the incorporation of the I4C-labelled precursors mevalonic acid, isopentenyl pyrophosphate, and phytoene into C40 carotenes by Halobacterium cutirubrum cell-free preparation^'^' produced results consistent with the pathways outlined in Schemes 2 and 3 . Only the trans-isomers seemed to be involved. A mutant strain,14' PG1, of the green alga Scenedesmus obliquus accumulates phytoene (135), phytofluene (136), and &-carotene (137) in place of the
(135)
normal cyclic carotenoids when grown in the dark. On illumination, these acyclic precursors are converted into p-carotene and xanthophylls. Kinetic studies'" support the operation of the pathway outlined in Schemes 2 and 3, but in this case the 15-cis-isomers of phytoene, phytofluene, and perhaps &-carotene seem to be i m p ~ r t a n t . ' ~Direct ' demonstration of the incorporation of the accumulated acyclic precursors into cyclic carotenoids was achieved by illuminating dark-grown cells after resuspension in deuterium oxide. Under these conditions, deuterium was incorporated specifically at C-2 of the ring of carotenoid molecules formed by cyclization in D,O of accumulated acyclic precursors (Scheme 4).15*A similar procedure has been used with a Flavobacterium species.'53 Cells grown in the presence of nicotine accumulated lycopene (139) which was converted into R. Henderson, Ann. Rev. Biophys. Bioeng., 1977, 6, 87. R. H. Lozier and W. Niederberger, Fed. Proc., 1977, 36, 1805. T. Schreckenbach and D . Oesterhelt, Fed. Proc., 1977,36, 1810. 13' W. V. Sherman and S. R. Caplan, Nature, 1977,265, 273. '41 J. J. Englander and S. W. Englander, Nature, 1977, 265, 657. 14' A . Campion, J. Tzrner, and M. A. El-Sayed, Nature, 1977,265,659. '41 M. A . Marcus and A . Lewis, Science, 1977,195, 1328. M. J. Pettei, A. P. Yudd, K. Nakanishi, R. Henselman, and W. Stoeckenius, Biochemistry, 1977, 16, 1955. 144 B. Aton, A . G . Doukas, R. H. Callender, B . Becher, and T. G. Ebrey, Biochemistry, 1977,16,2995. 145 M. M. Long, D . W. Urry, and W. Stoeckenius, Biochem. Biophys. Res. Comm., 1977,75,725. '41 T. Schreckenbach, B. Walckhoff, and D. Oesterhelt, European J. Biochem., 1977,76,499. '41 F. Tokunaga, R. Govindjee, T. G. Ebrey, and R. Crouch, Biophys. J., 1977, 19, 191. 14R S. C. Kushwaha, M. Kates, and J. W. Porter, Canad. J. Biochem., 1976, 54, 816. IJ9 R. Powls and G. Britton, Arch. Microbial., 1977, 113, 275. G . Britton, R. Powls, and R. M. Schulze, Arch. MicrobioL, 1977, 113, 281. Is' G . Britton and R. Powls, Phytochemistry, 1977, 16, 1253. 15* G. Britton, W. J. S. Lockley, R. Powls, T. W. Goodwin, and L. M. Heyes, Nature, 1977, 268, 81. Is3 G . Britton, W. J . S. Lockley. N. J . Patel, and 1 '.W. Goodwin, F.E.B.S. Letters, 1977, 79, 281. 13'
13'
13*
Terpenoids and Steroids
202
.c
(139)
Scheme 2
Carotenoids and Polyterpenoids
203
Scheme 4
zeaxanthin (57) on removal of the inhibitor; zeaxanthin produced by cyclization in D 2 0 contained deuterium substituents at C-2and C-2’. The incorporation of ‘“C-labelled neurosporene (138), lycopene, and y-carotene (141) into p-carotene by cell extracts of Phycomyces blakesleeanus mutants has been demonstrated.’’“ Addition of unlabelled lycopene or p-zeacarotene (140) caused approximately equal reduction of the incorpsration of [‘“C]neurosporene into p-carotene, indicating that the alternative routes of Scheme 3 are of equivalent importance. The absolute configuration of C-6‘ of natural @,?-carotene ( 5 5 ) is opposite to that of all C,, carotenoids with an &-ring e n d - g r ~ u p . ~ ’Opposite foldings of the aliphatic precursor are therefore required for cyclization to produce the y- and &-end-groups. Inhibitors have been used to investigate the biosynthesis of 1,2-dihydroneurosporene [ 1,2,7,8-tetrahydro-$,$-carotene (143)] and related 1,2-dihydrocarotenoids in Rhodopseudomonas viridis, and possible alternative sequences are presented.”’ The C-1,2hydrogenation reaction is inhibited by CPTA [2-(4chloropheny1thio)triethylammonium chloride], a compound known to inhibit cyclization and C- 1,2-hydration in other systems, thus indicating possible similarity of the reactions involved. The cyclization inhibitor nicotine prevents formation of the Cso carotenoid bacterioruberin [2,2‘-bis-(3-hydroxy-3-methylbutyl)-3,4,3’,4‘-tetradehydro1,2,1’,2’-tetrahydro-$,$-carotene-l,l’-diol (144)], which is normally the main pigment of Halobacterium cutirubrum, and lycopene then accumulates.156 The identification of other compounds that appear in smaller amounts, notably bisanhydrohacterioruberin ~2,2’-bis-(3-methylbut-2-enyl)-3,4,3’,4’-tetradehydro1,2,1’,2’-tetrahydro-$,$-carotene-l,l’-diol (145)], suggests that nicotine inhibits hydration of the double bond of the added C, side-chain more readily than addition of the Csside-chain and C-1 hydroxy-group. Pathways for the biosynthesis of the cyclopentane carotenoids capsanthin [3,3’dihydroxy-p,~-caroten-6’-one ( 146)] and capsorubin [3,3’-dihydroxy- K , K -carotene-6,6’-dione (147)]have been proposed from consideration of the carotenoids identified in extracts of lilies and red peppers.157
Enzyme Systems. Carotenoid biosynthesis by crude cell-free preparations from Halobacterium cutirubrum (p-car~tene),’“~ Phycomyces blakesleeanus mutants (pcarotene),’ 54,’ ’’ and a Neurospora crussu mutant (phytoene) has been dernon~trated.’‘~Detailed studies of carotenogenic enzymes from tomato fruit P. M. Bramley, Aung Than. and B. H. Davies, Phyfochemistry, 1977, 16,235. G. Britton, R. K. Singh, H. C. Malhotra, T. W. Goodwin, and A. Ben-Aziz, Phyfochemistry, 1977.16, 1561. S. C. Kushwaha and M. Kates, Canad. J. Biochern., 1976, 54, 824. Is’ L. R. G. Valadon and R. S . Mummery, Z. Pflantenphysiol., 1977,82,407. P. M. Bramley and B. H. Ihvies, Phyfochernisiry, 1976, 15, 1913. ”’ G. S . Bobowski, W. G. Barker, and R . E. Subden, Canad. J . Bot., 1977,55, 2137. Is’
Terpenoids and Steroids
204
a
b
OH
d
C
HO
OH e
f
HOh
(143) (144) (145) (146)
R1=a,R2=b R1=R2=c R'=R2=d R1=e,R2=f
(147) (148) (149) (150)
R'=R2=f R'=R2=g R1=g,R2=b R'=e,R2=h
plastids have been continued by Porter and co-workers, who have achieved partial purification of the phytoene-synthesizing enzyme system'60 and dissociation of a prelycopersene pyrophosphate [ = prephytoene pyrophosphate ( 1 5 l)] synthetase, mol. wt. 40 000, from the phytoene synthetase complex (mol. wt. 200 OOO).'61 CH,OPP
(151)
Regulation. Inhibition continues to be useful for the elucidation of some details of carotenoid biosynthesis; some examples have been reported above. 153-155~1564-[P"O
"'
B. Maudinas, M. L. Bucholtz, C. Papastephanou, S. S. Katiyar, A. V. Briedis, and J. W. Porter, Arch. Biochem. Biophys., 1977,180,354. M. A. Islam, S. .4.Lyrene, E. M. Milier, jun., and J . W. Porter, J. Biol. Chem., 1977,252, 1523.
Carotenoids and Polyterpenoids
205
(Diethylamino)ethoxy]benzophenone,a known cyclization inhibitor, blocks spirilloxanthin [l,l'-dimethoxy-3,4,3',4'-tetradehydro-l,2,1',2'-tetrahydro-~,~-carotene (148)] biosynthesis in Rhodospirillum rubrum and causes the accumulation of lycopene and anhydrorhodovibrin [l-methoxy-3,4-didehydro-1,2-dihydro-~,~carotene (149)].'62 The inhibitory effect of nicotine on the biosynthesis of cyclic carotenoid in a Flavobacterium 163 and in banana leavesLh4has been described. Pyridazinone herbicides prevent the formation of coloured carotenoids in algae165 and plant'66 systems, and similar effects have been observed with the fungus Verticillium agaricinum in the presence of various nitrogenous heterocyclic corn pound^.'^^ Very large increases in the carotene content of citrus fruit have been achieved by treatment with series of synthetic amines and esters.168"6y Regulatory effects of p - i ~ n o n e , ' ~trisporic " a ~ i d , ' ~ " retin01,'~~ ,'~~ and p e n i ~ i l l i n ' ~ ~ on carotene production by Blakeslea trispora have been described. Light is a major regulatory influence on carotenoid synthesis in many plant and microbial systems. A review of this photoregulation has been published.'" Other papers report the photoinduction of the biosynthesis of phytoene and other carotenoids in strains of Neurospora crassa.'74,'7s Further genetic studies have provided additional information about the regulat ion of car0tenoge nesis in Phycomyces blakesleeanus. 76 Carotenoid Metabolism and Metabolites. A scheme has been proposed for the metabolism of @-carotene by the stick insect Carausius morosus to give p,@caroten-2-01 (20) and p,p-carotene-2,2'-diol (2 1) via intermediate 2-0x0compounds such as (27)."," Feeding experiments have shown that in the goldfish lutein [P,~-carotene-3,3'-diol(1 50)] and zeaxanthin are converted into astaxanthin (60) whereas @-carotene and canthaxanthin (130) are not.177 Further suggest that marine red fish such as sea bream cannot oxidize the 3- and 4-positions of the p-ring. In the intestine of a freshwater fish, Sacchobranchus fossilis, p-carotene was converted into retinoic acid (40) whereas 3,4-didehydroretinol (152) and 3-hydroxyretinol (153) were obtained from l ~ t e i n . " ~The breakdown of E. P. Hayman and H. Yokoyama, J. Bacrerioi., 1976, 127, 1030. G. Britton, D. J. Brown, T. W. Goodwin, F. J. Leuenberger, and A. J. Schocher, Arch. Microbioi., 1977,113,33. l h 4 J. Gross and C. Costes, Physiol. vigitale, 1976,14, 427. lh5 D. Urbach, M. Suchanka, and W. Urbach, Z. Naturforsch., 1976,31c, 652. l h 6 H. K. Lichtenthaler and H. K. Kleudgen, 2. Nahtrforsch., 1977, 32c, 236. lh7 L. R. G . Valadon and R. S . Mummery, Microbios., 1976, 15, 203. S. M. Poling, W.-J. Hsu, and H. Yokoyama, Phytochemisrry, 1976,15, 1685. l h 9 S. M. Poling, W.-J. Hsu, F. J. Koehm, and H. Yokoyama, Phytochemistry, 1977,16, 551. '71 E. P. Feofilova, T. V. Fateeva, and V. A. Arbuzov, Mikrobiologiya. 1976, 45, 169. 17' S. Rao and V. V. Modi, Experientia, 1977.33, 31. 172 E. P. Feofilova and M. N. Bekhtereva, Mikrobiologiya, 1976, 45, 557. 173 H. G. Desai and V. V. Modi, Phytochemispy, 1977, 16, 1373. I74 J. C. Lansbergen, R. L. Renaud, and R. E. Subden, Canad. J. Bot., 1976, 54, 2445. '71 U. Mitzka and W. Rau, Arch. Microbioi., 1977, 111, 261. 176 F. J . Murillo and E. Cerdi-Olmedo, Mol. Gen. Genet., 1976, 148, 19. 177 Y. Tanaka, T. Katayama, K. L. Simpson, and C. 0. Chichcster, Bull. Jap. SOC.Sci. Fisheries, 1976,42, 885. '71 Y. Tanaka, T. Katayama, K. L. Simpson, and C. 0.Chichcster, Bull. Jap. Soc. Sci. Fisheries, 1976,42. 11 77. 179 A. B. Barua and U. C. Goswami, Biochem. J., 1977,166, 133. lh2
lh3
Terpenoids a n d Steroids
206
HO
( 153)
@-carotene to retinal and apocarotenals and the conversion of the latter into apocarotenoic acids in chicken and rat intestine have been described.'" The mechanism of formation of vitamin A from carotene is discussed in a review.181 When retinoic acid is fed to rats, several new metabolites (41)-(46) can be isolated from the and
3 Polyprenols The CSs polyprenol (154) obtained from leaves of Magnolia campbellii has been shown to be a mixture of cis- and trans-isomers.'8z The preparation of dolichyl phosphate (155) by a pea cell-free extract has been d e ~ c r ib e d . ' * Evidence ~ has been obtained that a lipid, containing N-acetylglucosamine, which was obtained from Phaseolus vulgaris hypocotyls, consists of a mixture of the dolichol (156) derivatives dolichyl pyrophosphate N-acetylglucosamine and dolichyl pyrophosphate di-N-acetyl~hitobiose.'~~
(154)
(155) X = OP03HZ (156) X = O H
4 Isoprenylated Quinones The best known isoprenylated quinones are the benzoquinone ubiquinone (157) and the naphthoquinone menaquinone (158), which normally occur in natural tissues as a mixture of homologues (isoprenylogues) with different chain lengths. ~ ~ menaquinone'86 isoprenylogues Analysis of the mixtures of u b i q u i n ~ n e 'or present in various species has been used in the chemotaxonomic characterization of bacteria. R. V. Sharma, S. N. Mathur, A. A. Drnitrovskii, R. C. Das, and J. Ganguly, Biochim. Biophys. Actu, 1977,486, 183. N. Babushkina, Suvrem. Med., 1977, 28,46 (Chem. Abs. 1977,87, 51 919). Is' W. Sasak, T. Mankowski, and T. Chojnacki, Chem. and Phys. Lipids, 1977, 18, 199. l X 3 G . R. Daleo and R. Pont Lezica, F.E.B.S. Letters, 1977, 74, 244. I X 4L. Lehle, F. Fartaczek, W. Tanner, and H. Kauss, Arch. Biochem. Biophys., 1976, 175,419. Ix5Y. Yarnada, E. Nakazawa, A. Nozaki, and K. Kondo, J. Gen. Appl. Microbiof., 1976,22, 285. lX6 M. D. Collins, T. Pirouz, M. Goodfellow, and D. E. Minnikin, J. Gen. Microbiol., 1977, 100,221. " I
207
Carotenoids and Polyterpenoids M e o * M H
0
M eO 0 ri
(158) R = M e
(157)
Chemistry.-The chemical structures of several bacterial menaquinones (MKs) with partly saturated isoprenoid side-chains have been studied. Spectroscopic (u.v., ix., m.s., and 'H n.m.r.) and chromatographic data have been recorded for the tetrahydro-MK8 and -MK9 mixture of some nocardioform and coryneform bacteria.lS7 The main component tetrahydro-MK9 has the second and third isoprene residues from the quinone ring saturated,'88 i.e. has structure (159), 20
(1 59)
[ = menaquinone-9 methyl-3-II,1II-tetrahydromul tipreny1"- 1,4-napthoquinone (IIJII-HJ]. Acfinomyces ofiuaceus contains a variety of hydrogenated menaquinones,''' the main components being MK-9 (II-H2), MK-9(I17111-H4), MK-9(I17111,1X-H6), MK-9(II,III,VIII,I~-H~),MK-tS(TI-H,), MK-8(I17111-H4), M K - 8 ( ~ ~ , ~ ~ ~ , vand ~ ~MK-8(II,III,VII,VIII-H,). ~-H6), The separation of plant isoprenoid lipids, including ubiquinone, phylloquinone [- MK-4(1I,III,IV-H6], and plastoquinone (160) by h.p.1.c. has been de~cribed.'~' Caldariellaquinone, from an extremely thermophilic and acidophilic bacterium Caldariella acidophila, is a unique sulphur-containing benzoquinone with structure (16I), 6-(3,7,11,15,19,23-hexamethyitetracosyl)-5-methylthiobenzo[~]thiophen4,7-quinone. The structure was deduced from spectroscopic data (including 'H and 13Cn.m.r.) and chemical degradation.'" 0
0
( 160) I8n
'91
19'
(161)
Y. Yamada, G. Inouye. Y. Tahara,.and K. Kondo, Biochirn. Biophys. Acra, 1977,486, 195. G . Inouye, Y. Yarnada, Y. Tahara, and K. Kondo, Agric. and Biol. Chem. (Japan), 1977,41,917. S. G. Batrakov, A, G. Panosyan, B. V. Rosynov, I. V. Kohova, and L. D. Bergel'son, Bioorg. Khim., 1976, 2, 1538. H. K. Lichtenthaler and U. Prenzel, J. Chromatogr., 1977, 135,493. M. DeRosa, S. DeRosa, A. Garnbacorta, L. Minale, K. H. Thomson, and R. D. Worthington, J.C.S. Perkin I, 1977, 653.
208
Terpenoids and Steroids
Bi0synthesis.-Ubiquinone. The identification"' of 3,4-dihydroxyhexaprenylbenzoate (162) in a Saccharomyces cerevisiae mutant strain that cannot synthesize ubiquinone suggests that ( 1 62) may be an intermediate in ubiquinone-6 biosynthesis in eukaryotes, in contrast to the pathway via 2-polyprenylphenol which operates in prokaryotes. In mammalian systems alternative routes have been discussed for ubiquinone biosynthesis in rats.lY3Some properties of mitochondria1 4-hydroxybenzoate-polyprenoltransferase have been described. Menaquinone. The incorporation of [2-14C]mevalonateand [2-'4C]-2-methyl- 1,4naphthoquinone into MK-4, normally considered a bacterial quinone, has been demonstrated in marine invertebrates such as crabs and tarf fish."^ Incorporation into 2,3-epoxy-MK-4 (163) was also observed. Cell-free extracts have been prepared from Escherichia coli which catalyse the conversion of o-succinylbenzoic acid (164) into 1,4-dihydroxy-2-naphthoicacid (165) and menaquinones.'y6 In the presence of farnesyl pyrophosphate the major menaquinone produced was MK-3. Genetic studies with mutants of E. coli K12 that require (164) offer support for the generally accepted pathway for MK biosynthesis via (164) and (165).'y7 The enzyme system that catalyses the attachment of the polyprenyl side-chain to 1,4-dihydroxy-2-naphthoicacid to form demethylmenaquinone-9 (166) has been isolated from E. coli."'
(163)
(162)
(164)
(165)
( 166)
Other Quinones. The isoprenoid nature of the C,, side-chain of caldariellaquinone (161) has been established by incorporation studies with [13C]acetate.191
'9j '9j
194
195
'91
198
R. R. Goewert, C. J . Sippel, and R. E. Olson, Biochem. Biophys. Res. Comm., 1977,77,599. A . M. D. Nambudiri, D. Brockman, S. S. Alam, and H. Rudney, Biochem. Biophys. Res. Comm., 1977, 76, 282. T. Nishino and H. Rudney, Biochemistry, 1977.16, 605. V. T. Burt, E. Bee, and J. F. Pennock, Biochem. J., 1977,162,297. R. W. Bryant, jun. and R. Bentley, Biochemistry, 1976,15,4792. J . R. Guest, J. Bacteriol., 1977, 130, 1038. B . Shineberg and I. G . Young, Biochemistry, 1976,15, 2754.
Part I1 STER 0I DS
1 Physica I Methods BY D. N. KIRK
This chapter reviews the year's published work on physical and analytical aspects of steroid chemistry. N o attempt has been made to survey the enormous number of routine applications of spectroscopic methods to structure determination. Attention has been concentrated mainly upon those developments of a fundamental nature which increase our understanding of the physical techniques and the phenomena which they explore. The major advances reported this year in the area of spectroscopy lie in the interpretation and applications o f "C n.m.r.; tritium n.m.r. has made its appearance as a method for the analysis of labelled steroids. The short sections on analytical mcthods give the Reviewer's selection of significant advances in radioimmunoassay and chromatographic methods of interest to chemists.
1 Structure and Conformation The 'deformed-chair' conformation of ring A in a 4,4-dimethyl-3-oxo-Sa -steroid has been confirmed by an X-ray study of a 17P-benzoyloxyandrostane derivative.' The results agree with those of an earlier study of the 17-i0doacetate,~and with the geometry indicated by force-field calculations. Dipole moments calculated by the application of 'molecular mechanics' to 5a-androstane-3,17-dioneand its distorted 4,4-dimethyl derivative are larger than those observed:' the reasons for these deviations are not yet clear. 11-0x0-9a- and 11-0x0-9P-derivatives (1) of oestradiol 3-benzyl ether equilibrate in favour of the 9p-isomer (90°h).3 The free-energy difference (1.47 kcal mol-') could not be reproduced by molecular mechanics calculations,
PhCH,O
'
pH '
N. L. Allinger, U. Burkert, and W. H. Decamp, Tetrahedron, 1977, 33, 1891. G. Ferguson, E. W. Macaulay, J. M. Midgley, .I. M. Robertson, and W. B. Whalley, J.C.S. Chem. Comm., 1970,954. C. D. b a n g . J. S. Baran. N. L. Allinger, and Y. Yuh, Tetrahedron, 1976, 32. 2067.
21 1
Terpenoids and Steroids
212
although the 9p-isomer was predicted to be the more stable by a small margin. The ketones were obtained from the 9( 11)-ene via epoxidation followed by treatment with alkali.3 Steroidal 8-en-1 1-ones (2) prefer the cis (14p) rather than the trans (14a) configuration at the C/D ring junction, irrespective of substitution at C-17.4 This experimental finding, which confirms conclusions based upon force-field calculations, contrasts with the configurational preferences of 15-0x0-steroids at C-14, which vary according to the nature of alkyl substituents at C-17. The variation in relative stabilities of cis- and trans-hexahydroindanones according to substitution patterns is further illustrated by an extensive collection of data for compounds of type (3) in the etiojervane series, which have been equilibrated at the
(3) 5 a - H or A5
(2)
ring-junction position designated by the authors at C-12 (C-13 according to the preferred IUPAC system, unless ‘abeo’ nomenclature is used). Analyses were based primarily o n ‘H n.m.r. data.5 The reported (in 1969)6 isolation of two stable ‘rotamers’ of 20-methyl-20-(2hydroxyethoxy)pregn-5-ene-3/3,17a-diol (4)is contradicted by X-ray analysis of the diacetate of the major ‘rotamer’, which shows it to be the D-homoandrostane derivative (5).’ Me
(4)
(5)
N.m.r. evidence has indicated that vitamin D3 exists in solution as a mixture of the alternative chair conformers in ring A . X-Ray ~ data now show that the same is true of the crystalline vitamin, which comprises an equimolar ratio of the conformers with 3-OH equatorial and axial, respectively.’ Strong hydrogen-bonding between hydroxy-groups results in an extended helix of molecules about an axis D . G. Patterson, C. Djerassi, Y. Yuh, and N. L. Allinger, J. Org. Chem., 1977,42, 2365. and T. Masamune, Bull. Chem. SOC.Japan, 1976, 49, 1602, 1612; T. Masamune, A. Murai, K. Nishizakura, T. Orito, S. Numata, and H. Sasamori, ibid., p. 1622. ‘Terpenoids and Steroids’, ed. K. H. Overton (Specialist Periodical Reports), The Chemical Society, London, 1971, Vol. 1, p. 265. ’ C. M. Weeks, G. J. Kruger, W. L. Duax, T. Makino, and Y. Osawa, Steroids, 1977,29, 261. ’ Ref. 6, 1977, Vol. 7, p. 230. Trinh-Toan, H. F. DeLuca, and L. F. Dahl, J. Org. Chem., 1976, 41, 3476.
’ A . Murai, T. Nishimura,
Physical Methods
213
defined by the associated hydroxy-groups, the two conformers occupying alternate positions. X-Ray crystallography confirms the structure of the anthrasteroid (6), derived from cholesta-5,7-dien-3@01 by rearrangement of the 4-phenyl- 1,2,4triazoline-3,5-dione adduct (7) with boron trifluoride."
RO' (6)
(7)
The 1,ll-etheno-derivative (8) of oestrone methyl ether has an unusually flat structure, as a consequence of the presence of the extra aromatic ring." X-Ray analysis has established the geometry of 3a,17a-dihydroxy-4,4,14a-trimethyl19-nor-l0a-pregn-5-ene-l1,20-dione (9)12 and the configuration of the S=O bond in 2a,3a-epithio-5a-androstan-l7fl-ol ( R ) S-oxide (lO).I3
2 N.M.R. Spectroscopy 'H Spectra.-Assignments of 'H signals to 4-methyl substituents in 4-methylated cholesterols and related compounds are aided by their large downfield shifts (0.2-0.3 p.p.m.) in pyridine compared with spectra in c h l o r ~ f o r m .Spectra '~ of the lo
I'
N. Bosworth, A. Emke, J. M. Midgley, C. J. Moore, W. B. Whailey, G. Ferguson, and W. C. Marsh, J.C.S. Perkin I, 1977,805. C. G. Pitt, D. H. Rector, D. H. White, M. C. Wani, A. T. McPhail, and K. D. Onan, J.C.S. Perkin I, 1977, 131.
*'P. R. Enslin, J. Coetzer, and G. J. Kruger, J.C.S. Perkin 11, 1977,402. l3 l4
H. Koyama and H. Nakai, J.C.S. Perkin il, 1977, 741. T. Iida, T. Tamura, N. Miura, and T. Matsumoto, Steroids, 1977, 29, 453.
Terpenoids and Steroids
214
4-methylated 3-0x0-derivatives show appreciable downfield shifts only for the equatorial 4a-methyl proton signals.“ The ‘H signals due to side-chain methyl groups have been assigned for a series of compounds of the ergostane and stigmastane series.‘s The C-25 methyl groups give coincident or overlapping signals at 100 MHz for cholestanes and ergostanes (24-Me), but are just resolved into two doublets for stigmastanes (24-Et). Examination of ‘H spectra over the temperature range -50 to +60°C has allowed the assignment of preferred side-chain conformations to a series of 22-substitued and 22,23-disubstituted sterols:16 The 20,22-bond in particular avoids those conformations which would compress the C-22 substituent against C-16. Solutions of pregnane-3,20-diols, -3,16a,20-triols, and -3,17a,20-triols in CDCl’ and [2H,]pyridine show ‘H spectral solvent shifts which depend upon configurations at C-2O.I7 The C-18 protons in particular show solvent shifts which are larger for 20p- than for 20a-ols, allowing assignments of configuration. The observed effects are rationalized in terms of the magnetic anisotropies of pyridine molecules associated with hydroxy-groups in their preferred conformations.” A simple quantitative analysis of a mixture of diastereosiomeric secondary carbinols ( e . g steroidal 3a- and 3,C?-alcohols) can be achieved by measuring the lanthanide-induced shifts and integrals of ‘H methoxy signals for the mixture of esters formed with ( R ) - (+ )-a-methoxy-a-trifluoromethylphenylacetic acid (Mosher’s reagent). In 14 pairs of alcohols studied, the (R)-isomer invariably showed the larger lanthanide-induced shift of the methoxy signal, caused apparently by preferential complexing when the methoxy-group lies on the same side of the ester framework (11) as the ‘smaller’ component (R,) rather than the larger (RJ of the carbinol structure.’*
RL (1 I ) ( R )configuration
3H Spectra.-Pulsed Fourier-transform 3H n.m.r. spectroscopy of labelled steroids, with noise-modulated proton decoupling, is an effective method for the location and quantitative determination of tritium. Testosterone, progesterone, oestrone, and related compounds were labelled by a variety of methods including catalytic tritiation of unsaturated bonds and exchange via enolization.” The 3H n.m.r. method of analysis is unique in revealing the quantitative distribution of tritium atoms. The first paper to appear on this topic” indicates that nuclear Overhauser enhancement (NOE) is not a problem in making ’H measurements, but a more recent paper’” states firmly that suppression of NOE is essential. Examples of studies with NOE suppression include a demonstration that a sample supposed to I’ l6
”)
2”
T. A. Wittstruck, J . K. Sliwowski, and E. Caspi, J.C.S. Perkin I , 1977, 1403. M. Nakane and N. Ikekawa, J.C.S. Perkin I, 1977, 1426. G. Cooky, D. N. Kirk, R. E. Morgan, and M. L. SB e Melo, J.C.S. Perkin I, 1977. 1390. S. Yamaguchi and F. Yasuhara, Tetrahedron Lerters, 1977, 89. J . M. A. A1 Rawi, J . P. Bloxsidge, J. A. Elvidge, and J . R. Jones, Steroids, 1976, 28, 359 L. J . Altman and N . Silberman, Steroids, 1977, 29, 557.
Physical Methods
215
be [ 1~,2P-3H(N)]testosteronecontained at least four distinct molecular species ([lp,2P-3H,], [1p-3H], [2p-3H], and [la,2a-3Hz]). 13 C Spectra.-A new extensive semi-empirical analysis of 13C chemical shift data for saturated hydrocarbons, alcohols, amines, ketones, and olefins has led to a set of parameters which allows the calculation of carbon resonances for a wide variety of carbocyclic structures, including steroids, as well as for N-heterocycles.” The compounds all have essentially rigid six-membered rings in the chair conformation. The basis of the calculation is the initial selection of the parameter appropriate to the pattern of a-substitution on the carbon atom in question (primary, secondary, tertiary, or quaternary; C-0, C-N, etc.). This is followed by the addition of increments to allow for the presence of more remote structural features, particularly for the number of H-H interactions of 1,3-diaxial type, any exocyclic C-C gauche interactions, and syn-axial interactions with &carbon atoms (or the corresponding geometrical dispositions involving heteroatoms). Calculated I3C chemical shifts rarely deviate by more than f 3 p.p.m. from observed values.” Non-bonded interactions with y-hydrogen atoms are now considered unsatisfactory as an explanation of the upfield shifts commonly associated with gauche y-substitution. It is argued” that the apparent y-effect could equally well result from the absence of that p-hydrogen atom which the y-substituent replaces [cf. (12)+(13)]. On the basis of 13Cdata for a large number of pairs of compounds, the
H
P
@
H Ry;1, (shielding)
(12)
[@D]
Ayrn,
H;c~
-“r;r’. H
(NoeffLt)
(13)
authors’’ demonstrate that an interaction of ‘1,3-(syn)diaxial’ type between a hydrogen atom on the carbon under observation and a hydrogen atom on the P-carbon produces a deshielding which amounts on average to some 5 p.p.m. Removal of the P-hydrogen atom, either by alkyl substitution (C,) or by the introduction of unsaturation of C,, results in the loss of the deshielding due to the @-hydrogen atom which has previously been interpreted as a y-substituent effect. The magnitudes of the observed shifts depend mainly on the number of 1,3(syn)diaxial-type H-H interactions which are removed by the structural change. Discussion” covers compounds with heteroatom substituents as well as those with essentially hydrocarbon structures. Chemical shifts for monohydroxy-steroids may be used additively to predict those for diols, except in cases where the two functional groups are in a 1,2relationship or in certain 1,3-relation~hips.~~ Steric ioteractions of hydroxy-groups in 1,2-gauche or 1,3-diaxial relationships are thought to explain some of the observed deviations from additivity, which closely resemble those asociated with 22
23
H. Beierbeck, J. K . Saunders, and J. W. ApSirnon, Cunad. J. Chern., 1977,55,2813. H. Beierbeck and J . K. Saunders, Cunud. J. Chem., 1976,54,2985. C. L. VanAntwerp, H. Eggert, G. D. Meakins, J . 0,Miners, and C. Djerassi, J. Org. Chern., 1977,42, 789.
216
Terpenoids and Steroids
analogous OH-C o r C-C interactions. Deviations found for 1,2-diaxial (antiperiplanar) and 1,3-axial-equatorial diols probably result from electronic perturbations which are not yet fully understood. Sa-Substitution (14), whether by methyl or by polar groups, causes a marked downfield shift (2-8 p.p.m.) of the 10P-methyl I3C resonance.24 This is another example of mutual interactions of anti-periplanar groups. Such groups are linked by a periplanar zig-zag of cr-bonds, suggesting that the n.m.r. effects may be related to phenomena observed in other fields (e.g. c.d.), where delocalized MOs have recently been invoked as a basis for interpreting through-bond effectsz5 Methyl substitution into ring A adjacent to an epoxide may cause an anomalous upfield shift of the C, signal [e.g. of C-1 in a fcu-methyl-2,3-epoxide (15) or (16)].
(16)
(15)
(14)
The effect is discussed in terms of distortions of the normal half-chair conformation of the epoxycyclohexane ring, although the precise cause of the anomaly is not yet clear.26 The data serve as a warning for chemists using 13Cspectra for structural analysis of compounds with non-rigid conformations. Cholesterol samples biosynthesized from [5-I3C]- and from [3',4-I3C2]mevalonate, respectively, showed I3C distributions in accordance with the accepted biosynthetic sequence (Scheme 1). 13C N.m.r. spectra of the I3C-enriched products not only revealed the positions of the labels, but also showed the expected I3C-l3C
0
Me OH H02$&FH,0H 2 0
4
[5-13~]meva~onate
o [3',4- '3~2]meva~onate
HO
+$-I3 23
pro-(R) 25
27CH3
pr0-W
13
C distribution in cholesterol from labelled mevalonate, and stereochemistry at C-25 Scheme 1
24
25
26
W. A. Ayer, L. M. Browne, S. Fung, and J. B. Stothers, Canad. J. Chem., 1976.54, 3272. See, for example ( a ) T. D. Bouman and D. A. Lightner, J. Amer. Chem. Soc., 1976,98,3145, ( b ) D. N. Kirk and W. Klyne, J.C.S. Perkin I, 1974, 1076; see also refs. 36 and 37. M. Sangart, B. Septe, G. Btrenger, G. Lukacs, K. Tori, and T. Komeno, TetrahedronLetters, 1977,699.
Physical Methods
217
spin couplings over one bond (11-12) and over three bonds (12-16)). The resonances due to the non-equivalent C-26 and C-27 were separately assigned, and it is proposed for purposes of nomenclature that C-26 should be designated the pro-(R)-methyl group, which originates from C-2 of mevalonate, and C-27 the pro-(S)-methyl group, from C-3' of mevalonate. The configuration at C-25 is decided by the stereochemistry of reduction of the A24-bondof lanosterol, which is indicated in Scheme 1 by circled H atoms.27 Erroneous earlier assignments of C-15 and C-16 resonances in some pregnan20-ones have been corrected.'" The new conclusions have allowed evaluation of substituent effects due to 17a-OH and 17a-Br groups. 13C N.m.r. spectroscopy has been applied in a study of the steroidal trisaccharides thevetin A and B, particularly the manner of linkage of the sugar units, leading to structures (17) and (18) re~pectively.'~
OH
HO
Me0 (17) R = C H O (18) R = M e
13
C Spectra are also reported for some glucoside and mannoside derivatives of alcohols of a sterol type,30 and for a series of steroidal Sofanum alkaloids with various E/F-ring ~ t r u c t u r e s . ~ ~ A report3* o n the preparation of 6~-[1311]iodomethyl-19-norcholest-5( 10)-en30-01 of high purity points out the possible dangers in relying too heavily upon 'H n.m.r. spectra in identifying new steroids and estimating their purity. The 13C spectrum is better able to reveal impurities, because of its resolution of peaks due to individual carbon atoms. 13CN.m.r. data can be used to assign configurations to tosylhydrazones, oximes, and other imine derivative^.^^ l3C-l9F Couplings have been observed for 17a-fluoro-oestr-4-ene and some 3-fluoro-~teroids.~~ 27
29
30
31 32 33
34
G. Popjik, J. Edmond, F. A . L. Anet, and N. R. Easton, jun., J. Amer. Chem. Soc., 1977,99, 931. D. J. Kim, L. D. Colebrook, and'T. J. Adley, Canad. J. Chem., 1976.54, 3766. K. Tori, T. T. "hang, M. Sangark, and G. Lukacs, Tetrahedron Lerrers, 1977, 717. R. Kasai, M. Suzuo, J. Asakawa, and 0.Tanaka, Tetrahedron Lerrers, 1977, 175; K. Tori, S. Seo, Y . Yoshimura, H. Arita, and Y. Tomita, ibid., p. 179. R. Radeglia, G. Adam, and H. Ripperger, Tetruhedron Lerrers, 1977,903. K. N. Scott, M. W. Couch, T. H. Mareci, and C. M. Williams, Steroids, 1976, 28, 295. J. Casanova and J.-P. Zahra, Tetrahedron Letters, 1977, 1773; C. A. Bunnell and P. L. Fuchs, J. Org. Chem., 1977,42,2614. H.-J. Schneider, W. Gschwendtner, D. Heiske, V. Hoppen, and F. Thomas, Terrahedron, 1977, 33, 1769.
218
Terpenoids and Steroids
3 Chiroptical Phenomena The dependence of ketone c.d. on coupling paths between the carbonyl group and perturbing substituents3’ has how been correlated with the calculated (CND0/2) degrees of twist of the no- and .rr*-orbitals, resulting from the chiral pattern of s u b s t i t ~ t i o n .A~ ~series of steroidal and other ketones, with F, CI, and other heteroatoms (X) separated from the carbonyl group by between one and five C-C bonds, provided the examples (Scheme 2). Coupling paths associated with strongly consignate effects of substituents ideally lie along periplanar zig-zags of C-C bonds, although the non-planar five-bond zig-zag in compounds of type (23) also appears to be permissible. Other bond-paths are generally ‘non-coupling’, and often produce weakly dissignate substituent effects.
Me
ii’ 0
,!
(22)
(23)
(24)
Examples of zig-zag coupling paths: Substituent X is separated from the carbonyl groups by 1, 2, 3, 4 , and 5 C-C bonds, respectively, in structures (19)-(23). Structure (24) illustrates a coupling path which extends into a ‘front octant’ region Scheme 2
An extension of the CND0/2 calculations to ‘front octant’ regions3’ suggests that the ‘front octant’ sign reversals which have been established empirically may be best interpreted on the basis of a quadrant rule, supplemented by a rule for the recognition of ‘coupling’ and ‘non-coupling’ bond paths between the ‘front octant’ substituent and the carbonyl group. A ‘coupling path’ extending into a ‘front octant’ region is illustrated in (24). The effect of the ‘coupled’ interaction again emerges as a twisting of the no-orbital, which is known to be highly delocalized through the hydrocarbon framework. An empirical analysis of c.d. data38 for compounds containing a chiral cyclopentanone ring (e.g. ring D in steroids) has led to the proposal that the observed 35 36
37 38
Ref, 6, 1971, Vol. 1, p. 273; 1972, Vol. 2, p. 235. M. R. Giddings, E. E. Ernstbrunner, and J. Hudec, J.C.S. Chem. Comm. 1976,954. M. R. Giddings, E. E. Ernstbrunner, and J. Hudec, J.C.S. Chem. Comm., 1976,956. D. N. Kirk, J.CS. Perkin I, 1976, 2171.
219
Physical Methods
Cotton effects (n47r*) arise primarily from dissignate (‘anti-octant’) effects of C,-H bonds (Figure l a ) rather than from the ‘octant’ dispositions of the carbon atoms (or bonds) of the ring itself, as has been implied by conventional octant projections lacking the ‘a’-hydrogen atoms (Figure lb).3YThe concept of dissignate C,-H effects, of magnitude proportional to sin’ o (Figure l c ) has been extended to some compounds with twisted cyclohexanone rings.38
(4
09
(4
Figure 1 (a) a t a n t projection of twisted cyclopentanone with a-hydrogen atoms. (b) Octant projection without a-hydrogen atoms. ( c ) Newman projection of O=C-C,-H to show torsion angle o
0.r.d. data for a highly purified sample of 17P-hydroxy-4,4-dimethyl-5aoestran-3-one4’ differ only slightly from a previous report. A new empirical analysis of c.d. data for 228 chiral olefinic c ~ m p o u n d s , mostly ~’ of steroid or terpenoid types, has substantially confirmed the earlier proposal of ‘reverse-octant’ (dissignate) effects of saturated non-polar substituents. The wide scope of this study, however, has revealed numerous regularities which include some instances of consignate behaviour. Olefinic compounds. were classified according to their ‘ethylene’ substitution type (i.e. as 1,l-di-, 1,2-di-, tri-, or tetra-substituted ‘ethylenes’). Each class gives c.d. maxima (generally two o r three) at characteristic wavelengths. The lowest-energy c.d. band for compounds of the 1,l-disubstituted type, with an exocyclic methylene group, generally exhibits carbonyl-like consignate effects of substituents, but the reverse is true for the other three classes of olefin. Apparent anomalies in previously reported data for olefins of the tetrasubstituted class are shown to arise from lack of differentiation between two distinct low-energy c.d. bands, which can appear in the ranges 215-225 nm and 195-210 nm, respectively. One or other of these bands is often very weak or unobservable. It is now clear that they arise from distinct electronic transitions [Probably 7r-b3s (Rydberg) and v-m*, respectively]; each shows its own pattern of sensitivity to substituent effects.41 Numerical ‘group increments’ which have been derived from experimental data may be used to ‘predict’ values of A& for new chiral olefins, although their reliability is markedly less than that achieved by an earlier similar analysis of c.d. data for ketone^.^' Although the acetyl side-chain in 3a,17a-dihydroxy-4,4-14a-trimethyl-l9-nor1Oa -pregn-5-ene-l1,20-dione(9) has the normal conformational preference in the crystal, the carbonyl oxygen atom almost eclipsing C-16, c.d. and other 39 4u
41 42
W. Klyne, Bull. SOC.chim. France, 1960, 1396; Tetrahedron, 1961, 13, 29. J. M. Midgiey, W. B. Whalley, P. A. Dodson, G . F. Katekar, and B. A. Lodge, J.C.5. Perkin I, 1977, 602. J. Hudec and D. N. Kirk, Tefrahedron, 1976,32,2475. See Ref. 256.
220
Terpenoids and Steroids
spectroscopic studies suggest that a second conformer is stabilized by intramolecular hydrogen-bonding in solutions in non-polar solvents. The C- 17 isomeric ketol (25), however, exists only as a single conformer, without intramolecular hydrogenbonding. Molecular models show that the 14a-methyl group imposes a conformational restraint on the l7a-acetyl side-chain. M e ?H
The c.d. spectra of cholest-5-ene and some of its simple derivatives have been examined in detail as part of a study of olefins of diverse Evidence provided by blue-shifts of the lowest-energy c.d. maximum (ca.210-200 nm) in solvents of high internal pressure, particularly at low temperatures, indicates that the ~ + 3 s(Rydberg) assignment favoured by some earlier workers is correct. The stronger c.d. band centred near 185 nm is considered to arise from the valence-shell .rr,+n-z transition. Many olefins, however, show a distinct couplet of oppositely signed c.d. bands assigned to mixing of ?r,+n-,* and mx--+n-; transitions. This paper is valuable in containing discussion and diagrams of the Rydberg 3s and the n-: -orbital, and transitions involving these orbitals, which have only recently become of interest to organic chemists. The possible roles of olefin torsion and of static and dynamic coupling mechanisms are also Another paper44 dealing with c.d. data for methylated cholest-5-enes and cholest-6-enes, and for ‘overcrowded’ t-butyl derivatives, bases discussion on the postulate of a n--bu* c.d. band, considered to lie between the Rydberg n-+3s and n-+n-* bands. It is suggested that olefin torsion becomes important in certain highly substituted derivatives, where the sign of the c.d. curve is reversed in the long-wavelength region. U.V. and c.d. data for 18 highly substituted steroid and triterpenoid olefins include some additional examples which for the most part follow the ‘dissignate’ sector rule with respect to the lowest-energy transition and a ‘consignate’ rule for the next transition of higher energy.45 Calculations of oscillator and rotatory strengths for skewed dienes have been refined by the inclusion of allylic substituents, rather than concentrating only on the skew angle of the butadiene component as in the past. The CNDO/S method has given results quite close to those observed experimentally, and reported last year, for steroidal 1,3-dienes (26); the apparent anomaly of a sign reversal depending upon the number of allylic methyl groups is excellently reproduced by the calculations, showing that the perturbation of the diene n--orbitals by mixing with a-type molecular orbitals is a major contributing factor. The CND0/2 method of calculation is far less satisfactory than CNDO/S in this instance.46 The 0.r.d. curve 43
44
45 46
A. F. Drake and S. F. Mason, Tetruhedron,1977,33,937. J . K. Gawronski, Tetruhedron,1977,33, 1235. A. F. Drake, P. Salvaldori, A. Marsili, and I. Morelli, Tetrahedron, 1977, 33, 199. J . S. Rosenfield and E. Charney, J. Amer. Chem. Soc., 1977, 99, 3209.
22 1
Physical Methods
R2
(26) R' and R2 = H or Me
of cholesta- 1,3,7-triene differs only slightly from that of the 1,3-diene, implying similar chirality of their cisoid conjugated diene component^.^^ Amino-steroids of various types form c.d.-active complexes with copper(I1) succinimidate, by amine exchange in a solution of [CuSu2 'Pr2] (Su = succinimidate, 'Pr = i~opropylamine).~" Cotton effects associated with d-d transitions appear in the regions of 700 and 600nm, although quantitative measurement of rotatory strengths is not possible under the conditions used. A tentative 'torsion angle rule' relates the signs of the c.d. bands to the predicted conformation of the complex about its N-Cu bond. C.d. data are reported for some steroidal alkaloids which have a nitrogen atom in 'side-chain' positions.49 An analysis of c.d. data for the 260 nm n - m transition of episulphides, including some steroidal derivatives, provides support for a rather complicated symmetry rule, which divides space around the chromophore into a total of 16 regions. A dynamic coupling mechanism is pr~posed.~'
4 Mass Spectrometry
The mass-spectral fragmentations of cholesterol and its analogues with varied side-chains display well-known ( M -85)' and ( M - 111)' ions; several fragmentation pathways proposed by earlier workers are now shown to be incorrect, since they fail to explain new data obtained with the aid of eleven deuteriumlabelled derivatives. The A5-olefinic bond triggers fragmentations through complex multi-stage processes, which involve hydrogen-transfer steps. The proposed mechanisms, which are compatible with the observed fate of deuterium labels, are illustrated in Scheme 3.'' Fragmentations of A'-enes include the. retro-Diels-Alder (RDA) cleavage of ring B (Scheme 4).52 New data show a marked dependence o n stereochemistry at the A ~ ring B junction: R D A cleavage is most strongly favoured in compounds of the 5/3 (cis) configuration, as would be required for a concerted process controlled by orbital symmetry. Although other instances of R D A cleavage (e.g. of a A2-5asteroid) appear to be non-concerted, it is proposed that a 'quasi-thermal' symmetry-controlled R D A reaction is energetically favourable for those compounds of the 5P-series where initial allylic cleavage of the strained 13,14-bond can readily afford a 13,14-seco radical cation of type (27). M. H. Barnes and W. B. Whalley, J.C.S. Perkin I, 1977,828. F. Kerek, G. Snatzke, K. Ponsold, and B. Schonecker, Tetruhedron, 1977, 33,2013. G. P. Moiseeva, R. Shakirov, M. R. Yagudaev, and S. Yu. Yunusov, Khim. prirod. Soedinenii, 1976, 623; G . P. Moiseeva, R. Shakirov, and S. Yu. Yunusov, ibid, p. 650. " G . Gottarelli, B. Samori, I. Moretti, and G . Torre, J.CS. Perkin ZZ, 1977, 1105. " S. G. Wyllie, B. A. Amos, and L. TokCs, J. Org. Chem., 1977,42, 725. 5 2 J. S. Dixon, 1. Midgley, and C. Djerassi, J . Amer. Chem. Soc., 1977,99, 3432. 47 4R
49
Terpenoids and Steroids
222
1
gt
t.
R
R
R
1
H.9 ( M - 85)'
R
( M - 1 1 I)+ R
Mass-spectral fragmentation of cholesterol and its analogues with As-unsaturation: pathways to account for ( M - 85)+ and ( M - 111) ions
Scheme 3
18-Norpregnanes give mass spectra which closely resemble those of the corresponding compounds possessing the methyl group (C-18). Extensive hydrogen migration is indicated by the mass spectra of 20-hydroxy-l S-nor-Sa-pregnan- 12ones, labelled with deuterium.53 Some peculiarities of the mass spectra of vitamin D3 and related molecules have been Metastable ion studies in a doublefocusing mass spectrometer have been used for the analyses of mixtures of steranes and related corn pound^.^^ 53
Y . Shimizu, Steroids, 1976, 28, 159.
55
E. J. Gallegos, Analyt. Chem., 1976,48, 1348.
'' W. H. Okamura, M. L. Hammond, H. J. C. Jacobs, and J. van Thuijl, Tetrahedron Letters, 1976,4807.
223
Physical Methods
e, R&
H
R
Mass-spectral fragmentation of Sp -steroidal 7-enes, including a ‘quasi-thermal’ retro-DielsAlder cleavage Scheme 4
5 Miscellaneous Physical Properties The vibrational structure and polarization properties of the phosphorescence spectra of testosterone and two other 4-en-3-ones indicate that excitation to the lowest ~~ to earlier triplet state ’( r,.rr*)causes little change in g e ~ m e t r y ,contrary conclusions. A sharply contrasting phosphorescence spectrum from 3P-acetoxycholest-5-en-7-one indicates that emission in this compound is from the 3(n,7r*) rather than the 3(7r,7r*) state. Studies of electron-spin exchange in rigid nitroxyl Biradicals of types such as (28) reveal variations with structure and with solvent polarity, but only a small temperature coefficient.”
56
57
C. R. Jones and D. R. Kearns, J. Amer. Chem. SOC.,1977,99, 344. E. K. Metzner, L. J. Libertini, and M. Calvin, J. Amer. Chem SOC.,1977,99,4500.
Terpenoids and Steroids
224
The phase transitions of cholesteryl nonanoate have been studied with a new apparatus for thermal analytical microscopy.'* The enantiomer ratio of some chiral sulphoxides can be changed from racemic to a modest preference for one enantiomeric form by dissolution in a cholesteryl ester in its liquid-crystalline ('cholesteric') ~ t a t e . ' ~5,6-Epoxycholestan-3-yl p-nitrobenzoates exhibit liquid-crystal properties, but 5,6-diols and dibromides are inactive.60 Differential pulse polarography has been used for the estimation of progesterone, testosterone, and related 4-en-3-ones in some parenteral formulations (in oil or aqueous suspensions).6'
6 Analytical Methods Radioimmunoassay of Steroids.62-6~-Hydroxycortisol 21-acetate (29) reacted selectively in cold pyridine with carboxymethoxylamine, giving the 3-(O-carboxymethy1)oxime: the 2 1-acetoxy-group seemingly slows competing reaction with the 20-ketone. The BSA conjugate was used to raise an antibody for the RIA of 6P -.hydroxyc~rtisol.~~ A novel anchorage of 3P-hydroxyandrost-5-en- 17-one (DHA) to BSA was achieved via C-19, by forming the 0-(carboxymethyl) oxime (30) of the 19CH,OAc
(29)
CH,CO,H
(30)
aldehyde.64 To this end it was necessary to protect the 17-0x0-group of 19hydroxy-DHA as its ethylene acetal before oxidizing at C- 19 (with Cr0,-pyridine) to the 19-aldehyde; the free 3P-hydroxy-group survived the brief reaction which was sufficient to oxidize the primary 19-hydroxy-group. Other steroidal 0-(carboxymethy1)oximes which have been prepared for linkage to BSA include those of 30,16cu -dihydroxypregn-5-ene-7,20-dione6'(at C-7), 3-
hydroxyoestra-1,3,5(10),7-tetraen-l7-0ne,~~ 3a-hydroxy-5~-androstan-17-one ('etiocholanolone'),67 and 17P-hydroxyandrost-4-ene-3,ll-dione(at C-3).68 0K. S. Kunihisa and S. Hagiwara, Bull. Chem. SOC.Jupun, 1976, 49, 2658. W. H. Pirkle and P. L. Rinaldi, J. Amer. Chem. Soc., 1977, 99, 3510. V. G. Atabekyan, and A. S. Sopova, Zhur. org. Khim., 1976,12,2263. 6 1 L. G. Chatten, R. N. Yadav, and D. K. Madan, Phurm. Aclu Hefu., 1976,51,381. 62 Ref. 6, Vol. 7, 1977, p. 309. 6 3 B. K. Park, P. H. Rowe, M. Osborne, and P. D. G. Dean, F.E.B.S. Letters, 1976,68,237. 64 T. A. Rance, B. K. Park, P. H. Rowe, and P. D. G. Dean, J. Steroid Biochem., 1976,7, 677. B. K. Park and P. D. G. Dean, J. Steroid Biochem., 1976,7,697. 66 B. K. Park, T. A. Rance, and P. D. G. Dean, F.E.B.S. Letters, 1976,71, 18. " K. Sat0 and N. Ohsawa, Steroids, 1977, 29, 295. " T. H. Simpson and R. S. Wright, Steroids, 1977, 29, 383. 58
59
6o M. V. Mukhina,
Physical Methods
225
(Carboxymethy1)-oximes are normally prepared in a single step from ketones, but the 11-0x0-group in 17/3-hydroxy-5a-androstane-3,ll-dione was too hindered to react with 0-carboxymethy!hydroxylamine. Instead the 11-oxime, obtained by selective cleavage of the 3,1l-dioxirne, was treated with alkaline sodium chloroacetate to prepare the hapten (31) for linking to BSA via C-11.69 HO,CCH,O
Compounds described as the 15.$-carboxymethyl derivatives (32) of oestrone and oestradiol have been described as haptens, without any evidence as to their configurations at C-15, or their homogeneity.” The method of synthesis (via Michael addition of malonic ester to the 15-en-17-one) normally gives 15psubstituted Some 15/3-carboxyethylmercaptoandrostane derivatives (33), obtained by addition of methyl 3-mercaptopropionate to androst-15-enOH
CH2C0,H