A Specialist Periodical Report
Terpenoids and Steroids Volume 6 A Review of the Literature Published between September...
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A Specialist Periodical Report
Terpenoids and Steroids Volume 6 A Review of the Literature Published between September 1974 and August 1975
Senior Reporter K. H. Overton, Department of Chemistry, University of Glasgow Reporters D. V. Banthorpe, University College, London G. Britton, University of Liverpool B. V. Charlwood, King's College, London J. D. Connolly, University of Glasgow N. Darby, University of British Columbia, Vancouver, Canada J. R. Hanson, University of Sussex 0. N. Kirk, Westfield College, London T. Money, University of British Columbia, Vancouver, Canada P. J. Sykes, University of Edinburgh J. S. Whitehurst, University of Exeter R. B. Yeats, Bishop's University, Quebec, Canada @ Copyright 1976
The Chemical Society Burlington House, London, W I V OBN
ISBN: 0 85186 306 X ISSN: 0300-5992 Library of Congress Catalog Card No. 74-615720
Set in Times on Linotron and printed offset by J. W. Arrowsmith Ltd., Bristol, England Made in Great Britain
Introduction
Even a casual perusal of this volume will show that the health and vigour of terpenoid and steroid chemistry have in no way declined since the first Report in this series appeared in 1971. Nature continues to present us with the most unpredictable and challenging structures constructed from mevalonate. The toxic diterpenoids from Euphorbia species and the squalene-based Duphniphyllum alkaloids provide good recent examples. As X-ray analysis provides an almost routine procedure for unravelling even such complex structures, interest moves increasingly in the directions of biosynthesis and laboratory synthesis with a fruitful interplay in the area of biogenetically patterned synthesis. Characteristically, new instrumentation has been exploited and extended to the full, the outstanding example being 13Cn.m.r. spectroscopy and particularly its use as a non-destructive method for establishing labelling patterns in biosynthesis. Resourcefulness and ingenuity abound in meeting aesthetic and commercial challenges in the field of synthesis. As I hand over the task of Senior Reporter to my successor, Dr. J. R. Hanson, it is a pleasure to record my gratitude to all the colleagues who have written these Reports for their enthusiastic and unstinting collaboration. K. H. OVERTON
Contents Part I Terpenoids
Chapter 1 Monoterpenoids By R. B. Yeats
3
1 Physical Measurements: Spectra efc.; Chirality
3
2 General Synthetic Reactions
6
3 Biogenesis, Occurrence, and Biological Activity
10
4 Acyclic Monoterpenoids Terpenoid Synthesis from Isoprene 2,6-Dimethyloctanes Halogenated Monoterpenoids Artemisyl, Santolinyl, Lavandulyl, and Chrysanthernyl Derivatives
14 14 15 19 20
5 Monocyclic Monoterpenoids Cyclobutane Cyclopentanes, Iridoids pMen thanes o-Menthanes rn-Menthanes Tetramethylcyclohexanes Dimethylethylcyclohexanes Cycloheptanes
21 21 23 27 31 32 32 33 33
6 Bicyclic Monoterpenoids Bicyclo[3,1,O]hexanes Bicycle[2,2,11heptanes Bicyclo[3,l,l]heptanes Bicyclo[4,170]heptanes
35 35 35 41 45
7 Furanoid and Pyranoid Monoterpenoids
47
8 Cannabinoida and other Phenolic Monoterpenoids
48
V
Terpenoids and Steroids
vi
Chapter 2 Sesquiterpenoids By N. Darbyand T. Money
52
1 Farnesanes
52
2 Bisabolanes
56
3 Sesquicarane
59
4 Sesquipinane (Bergamotane), Sesquifenchane, Sesquicamphane, Santalane
60
5 Acorane, Carotane, Cedrane
61
6 Cuparane, Laurane, Trichothecane, Cyclotrichothecane
62
7 Chamigrane efc.
64
8 Amorphane, Cadinane, Copacamphane, Sativane, efc.
65
9 Himachalane, Longipinane, Longicamphane, Longifolane,
69
efc.
10 Humulane, Caryophyllane, Hirsutane, Protoilludane, Illudane, Marasmane
71
11 Germacrane, Eudesmane, Vetispirane
75
12 Guaiane, Aromadendrane, Pseudoguaiane
88
13 Mono- and Bi-cyclofarnesanes
91
14 Miscellaneous
94
Chapter 3 Diterpenoids ByJ. R. Hanson
96
1 Introduction
96
2 Bicyclic Diterpenoids Labdanes Clerodanes
97 97 99
3 Tricyclic Diterpenoids Naturally Occurring Substances The Chemistry of the Tricyclic Diterpenoids
100 100 102
4 Tetracyclic Diterpenoids The Kaurene-Phyllocladene Series Beyeranes Gibberellins Diterpenoid Alkaloids
105 105 107 109 111
Contents
vii
5 Macrocyclic Diterpenoids and their Cyclization Products
112
6 Miscellaneous Diterpenoids 7 Diterpenoid Synthesis
115
Chapter 4 Triterpenoids By J. D. Connolly
116
118
1 Squalene Group
118
2 Fusidane-Lanostane Group
120
3 Darnmarane-Euphane Group Tetranortriterpenoids Quassinoids
123 126 128
4 Shionane Group
129
5 LupaneGroup
130
6 Oleanane Group
132
7 UrsaneGroup
139
8 HopaneGroup
140
9 Serratane Group
141
Chapter 5 Carotenoids and Polyterpenoids By G.Britton
144
1 Introduction
144
2 Carotenoids New Natural Carotenoids New Degraded Carotenoids Stereochemistry Carotenoids Degraded Carotenoids Synthesis and Reactions Carotenoids Retinal Derivatives Other Degraded Carotenoids
144 144 147 148 148 149 149 149 153 155
...
Terpenoidsand Steroids
Vlll
Physical Methods and Physical Chemistry Separation and Assay Methods Mass Spectrometry 'H N.M.R. Spectroscopy 13CN.M.R. Spectroscopy X-Ray Crystallography Electronic Absorption Spectroscopy Retinal as Visual Pigment Model: Spectroscopy and Physical Chemistry Miscellaneous Physical Chemistry 3 Polyterpenoids and Quinones Polyterpenoids Quinones
Chapter 6 Biosynthesis of Terpenoids and Steroids By D. V. Banthorpe and B. V. Charlwood
162 162 163 163 163 164 164 165 165 165 165 166
169
1 Introduction
169
2 Acyclic Precursors
170
3 Hemiterpenoids
177
4 Monoterpenoids
177
5 Sesquiterpenoids
180
6 Diterpenoids
187
7 Sesterterpenoids
190
8 Steroidal Triterpenoids
190
9 Further Metabolism of Steroids
200
10 Non-steroidal Triterpenoids
208
11 Carotenoids
209
12 Polyterpenoids
21 1
13 Meroterpenoids
211
14 Methods
215
15 Chemotaxonomy
217
ix
Contents
Part 11 Steroids Chapter 1 Steroid Properties and Reactions By D. N. Kirk
22 1
1 Structure, Stereochemistry, and Conformational Analysis Spectroscopic Methods N.M.R. Spectroscopy Chiroptical Phenomena Miscellaneous
22 1 222 222 223 225
2 Alcohols and their Derivatives, Halides, and Epoxides Substitution and Elimination Ring-opening of Epoxides Esters, Ethers, and Related Derivatives of Alcohols Oxidation Reduction
226 226 230 232 233 234
3 Unsaturated Compounds Electrophilic Addition Epoxidation Miscellaneous Additions Reduction Oxidation Miscellaneous Reactions
234 234 236 237 239 240 24 1
4 Carbonyl Compounds Reduction of Ketones Other Reactions at the Carbonyl Carbon Atom Reactions involving Enolic Derivatives or Enamines Oxidation and Reduction Oximes, Tosylhydrazones, and Related Derivatives Carboxylic Acids
242 242 244 249 253 254 257
5 Compounds of Nitrogen and Sulphur
258
6 Molecular Rearrangements Contraction and Expansion of Rings ‘Backbone’ Rearrangements Aromatization of Rings Miscellaneous Rearrangements
260 260 262 265 266
7 Functionalization of Non-activated Positions
268
8 Photochemical Reactions
269 269 273
Unsaturated Compounds Miscellaneous Reactions
Terpenoids and Steroids
X
9 Miscellaneous
Chapter 2 Steroid Synthesis By P. J. Sykes and J. S. Whitehurst
274 276
1 TotalSynthesk
276
2 Halogeno-steroids
284
3 Oestranes
286
4 Androstanes
289
5 Pregnanes
306
6 Seco-steroids
310
7 Cholestane and Analogues
313
8 Steroid Insect and Plant Hormones
330
9 Steroidal Alkaloids
33 1
10 Sapogenins
335
11 Cardenolides
336
12 Bufadienolides
341
Errata
344
Author I ndex
345
Part I TERPENOIDS
1 Monoterpenoids BY R. €3. YEATS
An increase in the published work, coupled with restricted space available for this Report, makes it difficult to be comprehensive and critical. Regretfully some papers remain unreviewed, to be buried deeper in the chemical literature, while others that have eluded the referees escape deserved criticism. The practices of reporting the same results in more than one paper, of reporting work similar to that already published, and of eking out results into an unnecessary number of publications continue, and are to be deplored. In the interests of economy, a number of such papers are omitted from this Report. The change in authorship of this chapter and delay in the receipt of some publications in Canada make it inevitable that some significant papers have not been included; they will be covered in next year’s Report. Within these limitations, every effort has been made to cover this year’s monoterpenoid literature comprehensively. A useful volume on the chemistry of terpenoids and steroids has appeared.’ Nineteen topics in monoterpenoid chemistry are reviewed with a literature coverage to early 1973; the topics are particularly suitable for use in advanced lecture courses and cover biosynthesis, structural elucidation, and synthesis. Monoterpenoid alkaloid chemistry has been reviewed.2
1 Physical Measurements: Spectra etc.; Chirality A useful atlas of chiral molecules has appeared; the major monoterpenoids of known absolute configuration are illustrated, with a literature coverage to the end of 1971. 3 The reader should beware of printing errors: e.g. (+)-p-irone lacks a methyl group at C-2, (-)-(R)-a-cyclogeraniol lacks a double bond between C-2 and C-3, and (+)-&carotene has only 39 carbon atoms (p. 131); carvotanacetone is incorrectly indexed and the nomenclature and presentation of thujane monoterpenoids is different from that used in these Reports. Long-range coupling constants (4J3_exo-5-exo) have been measured in a series of 4-substituted bornanones (1;Y = 0)and correlated with a,;examination of corresponding nitrimines (1; Y = N-NO,) indicates that the polarity of the C=Y bond K. Nakanishi, T. Goto, S. Ito, S. Natori, and S. Nozoe, ‘Natural Products Chemistry’, Academic Press, New York, 1974, Vol. 1, Chapter 3, p. 39. V. A. Snieckus, in ‘Alkaloids’, ed. K. Wiesner, MTP International Review of Science, Organic Chemistry, Series 2, Vol. 9, Butterworths, London, 1975. W. Klyne and J. Buckingham, ‘Atlas of Stereochemistry-Absolute Configurations of Organic Molecules’, Chapman and Hall, London, 1974, pp. 77-93.
3
Terpenoids and Steroids
4
conformations of a@affects the magnitude of the coupling ~ o n s t a n t .The ~ unsaturated ketones can be determined5from the 'H n.m.r. spectra of corresponding free-radical oxazine nitroxides (2) and (3). 'H N.m.r. solvent shifts have been used to
Lb
-0'
X
fl R
(1)
(2)
(3)
identify a tertiary methyl group on a carbon bearing a hydroxy-group,' and hexafluorobenzene solvent shifts have been reported for twelve monoterpenoid aldehydes and ketones and shown to conform to the carbonyl reference plane rule.7 Shifts induced by [Eu(dpm),] have been used to confirm the structures of 5 3 dimethyl-6-methylenenorbornan-2-exo-01,~ the camphanone (4),9 and the conformation of methyl (*)-cis-pinonate. l o An iterative computer programme for simultaneous simulation of lanthanide-induced chemical shifts and spin-relaxation data has been developed and used on borneol." SchneiderI2 has computed the most probable lanthanide positions for [Eu(dpm),]-induced 'H shifts and [Yb(fod),]induced 13Cshifts for alicyclic compounds including a series of bicyclo[2,2, llheptane alcohols and ketones; the C-5/C-6 13Cn.m.r. assignments for camphenilone ( 5 ; X = 0)are shown to be Sm,23.24 p.p.m. and ~ 3 ~ ~ 2 4p.p.m. . 5 7 respectively,l2 and not
the reverse, as previously reported.I3 A preliminary paper on the TiCI,-induced shifts in the I3C n.m.r. frequencies of carvone, piperitone, camphor, and fenchone has appeared (Vol. 5 , p. 3).14 The trimethylsilyl group has been used to produce 13C n.m.r. shifts for signal assignment in bicyclo[2,2,l]heptanols, e.g. the borneols and a-fenchyl Arsenic trichloride is a useful solvent for 13Cn.m.r. spectra; 4
5 6
7 X 9
It1
I t 12 I3
14
15
D. G. Morris and A. M. Murray, Org. Magn. Resonance, 1974,6, 510 (Chem. Abs., 1975,82, 171 210 incorrectly refers to 4J3.,,o-5-endo). A . Rassat and P. Rey, Tetrahedron, 1974, 30, 3315. C. R. Narayanan and A. K. Kulkarni, Indian J. Chem., 1974, 12, 677. K. Tori, I. Horibe, H. Shigemoto, and K. Umemoto, Tetrahedron Letters, 1975, 2199. J. Paasivirta, H. Hakli, and K. Forsen, Finn, Chem. Letters, 1974, 165. E. B. Krymskaya, V. I. Moskvichev, T. F. Gavrilova, N. D. Antonova, I . S. Aul'chenko, and L. A. Kheifits, Zhur. priklad. Spektroskopii, 1975, 22, 865. E. Liepins, R. Kampare, and F. Avotins, Latv. P.S.R. Zinatnu Akad. Vestis, Kim. Ser., 1075,89 (Chem. Abs., 1975,83.43 502). P. Stilbs, Chem. Scripta, 1975, 7 . 59. H.-J. Schneider and E. F. Weigand, Tetrahedron, 1975, 31, 2125. J . B. Grutzner, M . Jautelat, J . B. Dence, R. A. Smith, and J. D. Roberts, J. Amer. Chem. SOC.,1970,92, 7107. A . K . Rose and P. R . Srinivasan, Tetrahedron Letters, 1975, 1571. H.-J. Schneider and R. Hornung, Annalen, 1974, 1864.
5
Monoterpenoids
however, alcohols and amines exhibit I3Cshifts for carbon atoms adjacent to these functional groups; C-2 and C-4 in (-)-menthol occur at 2 p.p.m. upfield from normal and C-3 4 p.p.m. downfield from TMS. Lanthanide shift reagents are compatible with the solvent but [Eu(fod),] and [Pr(fod),] show f3Cshifts in the opposite direction to those usually observed.16 The "C n.m.r. spectra of geraniol, nerol, cis- and trans-chrysanthemum carboxylic acids, and some derivatives have been recorded. l 7 Stothers has assigned the "C n.m.r. frequencies of a series of exo-methylenenorbornanes and has shown that the a-methyl carbon atoms are more shielded in the corresponding ketones than in the exo-methylene derivatives; no difference was observed in the 7,7-dimethyl shifts in camphor and in the corresponding exomethylene series. l8 A second paper" discusses I3C n.m.r. assignments in bicyclic compounds, including some with the pinane skeleton. 13C Spin-lattice relaxation has b'een reviewed and includes hitherto unpublished data on linalool, 1,2dihydrolinalool, and 1,2-dehydrolinal0ol.~~ Different methods of computer-matching the mass spectra of 122 monoterpenoids give the best results when six to eight of the most intense peaks are matched.21The mass spectral fragmentation patterns of various bicyclic ketones of the thujane and carane series, and of their deuteriated [e.g. (6; X = D)] analogues, did not produce any generalizations on the fragmentation patterns or on the deuterium content.22
A (6)
Raman circular intensity differentials (c.i.d.), which are observed in methyl asymmetric deformations and methyl torsions, may be valuable in probing chirality in monoterpenoids; (-)-limonene and (+)-carvone each show a broad, weak depolarized Raman band at 250 cm-' with a large c.i.d. The origin of these bands is not yet certain.*' in a modified Horeau analysis 1-(2-Phenylbutanoyl)imidazole (7) has been to determine the chirality of amines, alcohols [e.g. (-)-menthol], and carboxylic
(7) l6
ly 2"
Z1 22 23 24
A. K. Bose, M. Sugiura, and P. R. Srinivasan, Tetrahedron Letters, 1975, 1251. L. Crombie, R. W. King, and D. A. Whiting, J.C.S. Perkin I, 1975, 913. S. H. Grover and J. B. Stothers, Canad. J. Chem., 1975,53, 589. S. H. Grover, D. H. Marr, J. B. Stothers, and C. T. Tan, Canad. J. Chem., 1975, 53, 135 1. E. Breitmaier, K.-H. Spohn, and S. Berger, Angew. Chem. Intentat. Edn., 1975, 14, 144. R. J. Mathews and J. D. Morrison, Austral. J. Chem., 1974, 27, 2167. J. W. Wheeler and 0. 0. Shonowo, Org. Mass Spectrometry, 1974,9, 1173. D. Barron, Nature, 1975, 255, 458. H. Brockmann and N. Risch, Angew. Chem. Internat. Edn., 1974,13,664.
6
Terpenoids and Steroids
acids, and another exception to the octant rule has been reported, for (3R,5R)dimethylcyclohexanone and 3,3,5( R)-trimethylcyclohexanone, both of which have been synthesized from (+)-pulegone.*' (-)-Menthy1 esters continue to find applications in asymmetric induction; asymmetric reduction of substituted (-)-menthy1 cinnamates by photochemical hydrostannation2' and by lithium aluminium hydride or organomagnesium halides27 have been reported, and also double asymmetric reduction of (-)-menthy1 benzoylformate by diphenylsilane and [(+)DIOP]Rh(solvent)Cl (in 60% optical yield28 compared with only 6% optical yield with 1-benzyl- 1,4-dihydronicotinamidein the presence of magnesium perchlorate in the simple asymmetric reduction29). Further work on the resolution of monoterpenoids using micro-organisms has been reported (cf. Vol. 5 , p. 4).30y3' Thus (*)-bornyl chloroacetate is hydrolysed to (-)-(R)-borneol (78% optical purity), leaving the antipodal trichloroacetate,30and racemic trans-chrysanthemyl acetate yields (-)-trans-chrysanthemyl alcohol in low optical purity and unreacted (+)-trans-chrysanthemyl acetate (g.1.c. analysis of this mixture is erroneous!)31 using Trichoderrna sp. Racemic a-cyclogeranyl acetate gives ( -)-(S)-a -cyclogeraniol and ( + )-(R)-a-cyclogeranyl acetate in low optical purity with Bacillus subtilis var. Niger." The applications of liquid chromatography to terpenoids have been reviewed.32 Rapid separation of alcohols ( e .g. geraniol-nerolidol, geraniol-citronellol) by metal complex formation has been re-examined.33
2 General Synthetic Reactions Catalytic transfer hydrogenation and the use of monoterpenoids as hydrogen donor compounds have been reviewed.34 Pericyclic reactions continue to attract attention. Following the that silyl ethers of allylic acetates undergo [3,3] Claisen-type rearrangements to y6unsaturated acids, the high stereoselectivity of the rearrangement has been demonstrated using geraniol (8) (Scheme 1);36 the 76-unsaturated acid (9) has been converted into the Queen Butterfly pheromone (10). Allylic alcohols are converted into &unsaturated NN-dimethylamides on heating with NN-dimethylformamide ' acetals by a proposed [2,3] sigmatropic rearrangement of a ~ a r b e n e ; ~whereas linalool yields the amides (1 1) in synthetically useful yields, the method works poorly with y,y-disubstituted allylic alcohols such as geraniol (8). The ene-addition of N. L. Allinger and C. K. Riew. J . Org. Chem., 1975. 40. 1316. A. Rahm and M. Pereyre, J. Organometallic Chem., 1975, 88. 7Y. 27 D. Cabaret and Z . Welvart, J. Organometallic Chem.. 1974. 80, 185. zx I. Ojima and Y. Nagai, Chem. Letters, 1975. 191. 29 Y. Ohnishi, M. Kagami, and A. Ohno, J . Amer. Chem. Soc., 1Y75,97. 4766. -x)T. Oritani and K. Yamashita, Agric. and Biol. Chem. (Japan), 1974, 38, 196 1. 3 1 T. Oritani and K. Yamashita, Agric. and B i d . Chem. (Japan), 1975, 39, 89. x 0. Mot1 in 'Liquid Column Chromatography-A Survey of Modern Techniques and Applications', ed. Z. Deyl. K. Macek. and J. Janak, Elsevier, Amsterdam, 1Y75, p. 623. 3 3 K. B. Sharpless, A. 0. Chong, and J. A. Scott, J. Org. Chem., 1975,40, 1252. 3 4 G. Brieger and T. J . Nestrick. Chem. Rev., 1974. 74, 5h7. 3 5 K.E. Ireland and R. H. Mueller. J. Amer. Chem. Soc.. 1972. 94, 5897. J. A. Katzenellenbogen and K. J. Christy. J. Org. Chem., 1974, 39. 3315. 3 7 G. Biichi. M. Cushman. and H. Wiiest. J. Amer. Chem. Soc., 1974,96. 5563. 25
2(7
7
Monote rpenoid s
Reagents: i , mesitoyl chloride; ii, 0,; iii, isopropenylMgBr; iv, Ac,O-py; v, Bu"Li-isopropylcyclohexylamine-THF, - 78 " C ; vi, HMPA-t-butyldimethylsilyl chloride-THF; vii, hydrolysis; viii, LiAIH,.
Scheme 1
benzyne to (+)-carvomenthene, (+)-limonene, a-pinene, P-pinene, and car-3-ene (the formula is incorrect in the paper) has been investigated.'8
1,3-Dienes can be synthesized from allylic alcohols under mild conditions by the action of diethylaluminium 2,2,6,6-tetramethylpiperidideon an epoxy-silyl ether (Scheme 2);3ygeraniol (8) yields trans-p-ocimene (13) and nerol yields myrcene (12). Trisubstituted alkenes can be synthesized stereoselectively by treating the nickel complex (14) with an alkyl halide; prenyl bromide yields geranyl benzyl ether.40 Deuteriated alkenes [e.g. (15)] may now be synthesized in high yield41 from ketone t o s y l h y d r a ~ o n e by s ~ ~using tetramethylethylenediamine as solvent. Selective oxidation of alcohols to aldehydes and ketones in high yields continues to receive attention. Geraniol(8), as the triethyltin alkoxide, is oxidized with bromine and triethyltin methoxide; no double-bond isomerization is r e p ~ r t e d , in ~ ' contrast t o w w 4"
4i
42 41
G . Mehta and B. P. Singh. Tetrahedron, 1974, 30, 2409. S. Tanaka. A. Yasuda, H. Yamamoto, and H. Nozaki, J . Amer. Chem. Soc., 1975,97,3252. K. Sato. S. Inoue, and S. Morii. Chem. Letters, 1975. 747. J. E. Stemke and F. T. Bond, Tetrahedron Letters, 1975, 181.5. See R. H. Shapiro and E. C. Hornaman, J. Org. Chem., 1974,39, 2302 and references cited therein K. Saigo, A. Morikawa, and T. Mukaiyama, Chem. Letters, 1975, 145.
Terpenoids and Steroids
8
(13)
(12)
Reagents: i. vanadium acetylacetonate-t-butyl hydroperoxide; ii, Me,SiCI-Me,Si.NH.SiMe,py ; iii, diethylaluminium 2,2,6,6-tetramethylpiperjdide: iv, KF-aq. MeOH; v, PBr,, CuBr; vi, Z n .
Scheme 2
I
PhCH20H2C
CH,0CH2Ph
some isomerization using the Jones reagent.44Pyridinium chlorochromate oxidizes citronellol to the aldehyde in buffered solution, but yields pulegone when not Dimethyl sulphoxide is an excellent sdlvent for acidic sodium dichromate ~ x i d a t i o n .Oxidation ~~ of diols with silver carbonate on Celite can be to synthesize (*)-mevalonolactone labelled with deuterium, * ’C, or 14C,and isoprene can be converted into 3-methylbut-3-en- 1-01 by oxidation of the corresponding [(q’-C,H,)Zr(R)Cl] complex with oxygen.48 Chromic acid and periodic acid have been used for the oxidative deoximation of camphor.49 Anodic oxidation of limonene” is very similar to that of pinene (Vol. 4, p. 57). The rate constants for reaction of monoterpenoid hydrocarbons with ozone and with NO, have been measured and shown to be more sensitive to hydrocarbon structure for the ozone reaction. It is concluded that the least reactive hydrocarbons are destroyed in the atmosphere by NO, or by some species associated with its photolysis, whereas K. E. Harding, L. M . May, and K. F. Dick, J . Org. Chem., 1975, 40, 1664. E. J . Corey and J . W. Suggs. Tetrahedron Letters, 1975, 2647. Y. S. Rao and R. Filler, J . Org. (Them., 1974, 39, 3304. M. Fetizon, M. Golfier, and J.-M. Louis. Tetrahedron, 1975, 31, 171. T. F. Blackburn. J . A. Labinger, and J . Schwartz, Tetrahedron Letters, 1975, 3041. H. C. Araujo, G . A. L. Ferreira, and J. R. Mahajan, J.C.S. Perkin I, 1974, 2257. ‘T. Shono. A. Ikeda, J . Hayashi, and S. Hakozaki. J. Amer. Chem. SOC.,1975, 97. 4261.
IJ j5
47
4y
Monoterpenoids
9
reactive hydrocarbons would be expected to react with ozone. The endocyclic conjugated diene systems are especially reactive with ozone (as e ~ p e c t e d ! ) . ~ ~ Regeneratable polymeric organotin dihydride beads have been used to reduce halides selectively (e. g. 3-bromocamphor to camphor).52 P -Unsubstituted cyclohexenones undergo exclusive and almost quantitative 1,4-reduction by potassium tri-s-butylborohydride to the corresponding saturated ketone [e.g. (16)J;53reductive alkylation of carvone proceeds similarly to (17; R = M e , X=H).s3 In contrast,
(17)
(16)
sodium cyanoborohydride in acidic methanol or hexame thylphosphoramide gives mixtures of allylic and saturated Reductive deoxygenation of unsaturated p-tosylhydrazones with sodium cyanoborohydride in acidic DMFsulpholane yields E geometrical isomers stereoselectively, probably via a [ 1,5] sigmatropic rearrangement of an intermediate diazene; pulegone yields menth-3ene.55 The reaction of Gilman reagents with a,@-epoxy-oximes yields P-hydroxyketones [e.g. (17; X = OH)].s6 Vinyl copper compounds are converted stereospecifically into P,P-disubstituted cy -ethylenic acids by carbonation; nerol ( 18) was synthesized (Scheme 3)." Further papers on P-ketosulphoxide synthesis [e.g. of
(18) Reagents: i, Mg-Et,O; ii, CuBr; iii, M e C E C H ; iv, C0,-HMPA-P(OEt),;
v, LiAlH,.
Scheme 3 (19)]5s,59and on the application of a-sulphinylcarbonyl and related compounds to alkylative elimination have a p p e a ~ e d . ~ 'Other , ~ ~ synthetically useful reactions are 5'
E. P. Grimsrud, H. H. Westberg, and R. A. Rasmussen, Internat. J. Chem. Kinetics, 1975,7, 1st suppl., 183.
52
53 54
55 56
57 5R Sy
h1
N. M. Weinshenker, G. A. Crosby, and J. Y. Wong, J. Org. Chem., 1975,40, 1966. B. Ganern, J. Org. Chem., 1975,40, 146. R. 0. Hutchins and D. Kandasamy, J. Org. Chem., 1975,40, 2530. R. 0. Hutchins, M. Kacher, and L. Rua, J. Org. Chem., 1975, 40, 923. E. J. Corey, L. S. Melvin, and M. F. Haslanger, Tetrahedron Letters, 1975, 3117. J. F. Normant, G. Cahiez, C. Chuit, and J. Villieras, J. Organometallic Chem., 1974, 77, 281. R. M. Coates and H. D. Pigott, Synthesis, 1975,319. H. J. Monteiro and J. P. de Souza, Tetrahedron Letters, 1975, 921. B. M. Trost, W. P. Conway, P. E. Strege, and T. J . Dietsche, J. Amer. Chem. SOC., 1974,96, 7165. B. M. Trost and A. J. Bridges, J. Org. Chem., 1Y75, 40. 2014.
10
Terpenoids and Steroids
04S -C, H,-p- M e (19)
stereospecific dehalogenation using [HFe(CO)4]-,62formation of mesylates using ‘easy mesyl’ (MeS0,NMeEt,+FS0,-),h3 graphite bisulphate e ~ t e r i f i c a t i o nconver,~~ sion of alcohols into amides by chlorodiphenylmethylium hexachl~roantimonate,~~ dihydrofuran formation [e.g. (20)] from the photochemical irradiation of apunsaturated ketones in the presence of methanol and TiC14,6hand the conversion of nitrimines [e.g. (21)] into amides [e.g. (22)] using KCN.67
3 Biogenesis, Occurrence, and Biological Activity A monograph on the chemotaxonomy of flowering plants extensively lists plant products and their occurrence by broad chemical type;68 however, lists are not complete, as of 1969, and detailed references are not usually given. A classic lexicon of fragrant materials has been completely revised,69a review of essential oil analysis covering the period September 1972 to August 1974 has been published,70 and volatile leaf oil analysis in chemosystematic studies has been r e ~ i e w e d . ~ ’ Synthesis of labelled mevalonolactones continues to receive a t t e n t i ~ n , ~ ”and ~* new syntheses of ( *)-,( R ) - ,and (S)-mevalonolactones have been The isolation74of the energy-rich carboxylic ester (23) of prenyl mercaptan prompts the h2 63
h4 65
hh
h7 hX
h‘)
H . Alper, Tetrahedron Letters, 1975, 2257. J. F. King and J. R. du Manoir, J . Amer. Chem. Soc.. 1975, 97.2566. J . Bertin, H. B. Kagan, J . L. Luche, and R. Setton, J. Amer. Chem. Soc., 1974,96, 8113. D. H. R. Barton, P. D. Magnus, J. A. Garbarino, and R. N. Young, J.C.S. Perkin I, 1974, 2101. T . Sato, G . Izumi, and T. Imamura, Tetrahedron Letters, 1975, 2191. P. J . Kocienski and M. Kirkup, J . Org. Chem., 1975, 40. 1681. R. D. Gibbs. ‘Chemotaxonomy of Flowering Plants’, 4 vols., McGill-Queen’s University Press, Montreal, 1973. W. A. Poucher, ‘The Raw Materials of Perfumery’, ed. G . M. Howard, 7th Edn., Halsted, New York, 1975.
70 71 72
73
74
E. Guenther. G . Gilbertson, and R. T. Koenig, Analyt. Chem., l975,47, 139R. E. von Rudloff, Biochem. Syst. Ecol., 1975, 2, 131. J . W. Cornforth, F. P. Ross, and C. Wakselman, J.C.S. Perkin I , 1975, 429; J. W. Cornforth and R. T. Gray. Tetrahedron, 1975, 31, 1509. R. A. Ellison and P. K. Bhatnagar, Synthesis, 1974,719; F.-C. Huang, L. F. H. Lee, R. S. D. Mittal, P. R. Ravikumar, J . A. Chan, J . Sih, E. Caspi, and C. R. Eck, J . Amer. Chem. Soc., 1975,97,4144. V. C. Moran, P H. R. Persicaner, and D. E. A. Rivett, J. S. African Chem. lnst., 1975, 28, 47.
11
Monoterpenoids
(23)
search for further naturally occurring sulphur compounds and their significance in terpenoid biogenesis. A thiol is essential to both the enzymatic and non-enzymatic isomerization of geraniol (8); no aldehydes and no linalool were Banthorpe has shown that the biosynthesis of (+)-thuj-3-one* (24; 2S)76from [‘“CIacetate again exhibits asymmetric labelling (cf. Vol. 3, p. 7 ) , the ‘“Clabel being predominantly in the IPP-derived portion. Similar results are obtained with geraniol (8) and (+)-pulegone and suggest the existence of metabolic pools of a ~ e t y l - C o A . ~ ~
c;’ (24)
The suggestion of an alternative non-mevalonoid route in monoterpenoid biosynhas received some support in the efficient incorporation of L-[ U-’4C]valine into the DMAPP moiety of linalo01;~~ a pathway via deamination to dimethylacrylic acid is proposed. L-Leucine and L-valine are also incorporated, at least in part, into the DMAPP moiety of geraniol (8) and citronell01.~~ (1R,3R)-Chrysanthemic acid (25) is biosynthesized8* in Chrysanthemum cineruriaefoEium from (1R,3R)chrysanthemyl alcohol (26) but not from precursors with the lavandulyl (27) or artemisyl(28) skeletons (Scheme 4); (1R73R)-chrysanthemyl alcohol (26) has been
W. E. Shine and W. D. Loomis, Phytochemistry, 1974, 13, 2095. D. V. Banthorpe, 0. Ekundayo, J. Mann, and K. W. Turnbull, Phytochemistry, 1975,14. 707. 77 T. Suga, T. Hirata, T. Shishibori, and K. Tange, Chern. Letters, 1974, 189. 78 T. Suga, T. Hirata, and K. Tange, Chem. Letters, 1975, 131. 7y T. Suga, T. Hirata, and K. Tange, Chem. Letters, 1975, 243. Ho G. Pattenden, C. R. Popplestone, and R. Storer, J.C.S. Chew. Comm., 1975, 290.
75
7h
* The nomenclature used in previous Reports is used here (see Vol. 2, p. 37); Banthorpe names this compound (+)-isothujone.
12
Terpenoids and Steroids
isolated from the leaves of Artemisia ludouiciana.81In connection with the suggestiong2that cyclobutane derivatives may be involved in the biogenesis of artemisyl and santolinyl skeletons, the cyclobutanol (29) has been synthesizedg3from (-)-apinene. For further work on monoterpenoid biosynthesis, see Chapter 6, p. 177.
A Pseudomonas strain hydroxylates p-menthane to cis-p-menthan- 1 - 0 1 , ~and ~ microbiological reduction of carvotanacetone with Pseudomonas ovalis gives similar results'' to those obtained with carvone (Vol. 5 , p. 24, incorrectly reports inversion at C-4). (-)-Carvotanacetone (30) gives (+)-carvomenthone (3 l), (-)carvomenthol (32; X = H), and the corresponding (+)-neocarvomenthol, whereas (+)-carvotanacetone is reduced to (-)-isocarvomenthone (33; X = 0), (-)carvomenthone, and the isocarvomenthols (33; X = H, OH)? A further paperg6 describes the C- 1 epimerization of isodihydrocarvone (16; 1R) to dihydrocarvone (16; 1S) by Pseudomonas fragi.
The analysis of essential oils which contain monoterpenoids has contributed many papers to the literature this year; a disturbing number of analyses are trivial and furnish little that is new. The validity of the natural occurrence of minor components can be questioned in the light of isolation technique; linalyl acetate yields eleven ~~ of interest are: the major compomonoterpenoids on steam d i ~ t i l l a t i o n .Analyses nent (58%) of the steam-volatile leaf oil of Zieria aspalathoides is (-)-car-3-en-2one;" (+)-2,6-dimethyloct-7-en-4-one is the major component (97%) in Phebalium glandulosum subsp. glandulosum ;89 major components in Achillea millefolium essential oil (isolated by steam distillation!) are sabinene and artemisia ketone,90 which is incorrectly named by the authors as isoartemisia ketone (possibly from
xz x' x4 x5 Xh
x7
xx xy
K. Alexander and W. W. Epstein, J . Org. Chem., 1975, 40, 2576. For example see C. D. Poulter, J. Agric. Food Chem., 1974, 22, 167. 0,J . Muscio and C . D. Poulter, J . Org. Chem.. 1074, 39. 3288. Y. Tsukamoto. S. Nonomura. and H. Sakai, Agric. and Biof. Chem. (Japan), 1975,39,617 Y . Noma, S. Nonomura, and H. Sakai, Agric. and Biof. Chem. (Japan), 1Y74, 38, 1637. Y. Noma, S. Nonomura, and H. Sakai, Agric. and Biol. Chem. (Japan), 1975, 39,437. J . A. Picket, J . Coates. and F. R. Sharpe, Chem. and Ind., 1975, 571. E. V. Lassak and I . A. Southwell, Austral. J . Chem., 1974, 27, 2061. E. V. Lassak and I. A. Southwell, Austral. J . Chem., 1974, 27, 2703. A. J. Falk. L. Bauer. C. L. Bell, and S. J. Srnolenski. Lluydia, 1974, 37, 598.
Monoterpenoids
13
Devon and Scott's Handbook"'); essential oil from Salvia dorisiana"2 contains perillyl acetate and the rare methyl perillate (34; R = C0,Me); tricyclene is present in Agathis australis as a major component,y3 and cis-carveyl acetate is a major component in Japanese spearmint (Mentha spicata crispa).y4 Some rare oxygenated , ~ ~from Piper nigrum." menthanes have been isolated from Mentha g e n t i l i ~and
R
3 The defence secretion of the milliped Polyzonium rosalbum contains the spiromonoterpenoid polyzonimine (35);c)7 the isolation of the spirocyclic nitro-compound (36)98 might suggest a non-geranyl pyrophosphate biogenetic route from a pyrrolizidine alkaloid. The production of verbenone in the bark beetle Dendroctonus sp. may be associated with chemical communication."
Natural and synthetic pyrethroid insecticides have been reviewed,'"'' and the synthesis of pyrethrins related to bioresmethrin has appeared (cf. Vol. 5 , p. 16);''' the fluorinated pyrethroid fluorethrin has been synthesized and is superior to bromethrin and resmethrin as an insecticide;'02 the metabolism of cis- and transresmethrin in rats has been r e p ~ r t e d . " ~Further papers report the and 'I
Y2
y3 y4
95
T. K. Devon and A. I. Scott, 'Handbook of Naturally Occurring Compounds, Vol. 11, Terpenes', Academic Press, New York, 1972. A. F. Halim and R. P, Collins, J. Agric. Food Chem., 1975, 23, 506. L. H. Briggs, M. Kingsford, and G. W. White, New Zeuland J. Sci., 1974, 17. Y. T. Nagasawa, K. Umemoto, T . Tsuneya, and M. Shiga, Koryo, 1974, 108,45. ( a )T. Nagasawa, K. Umemoto, T. Tsuneya, and M. Shiga, Nippon Nogei Kagaku Kuishi, 1974,48,467; (b) T. Nagasawa, K. Umemoto. T . Tsuneya, and M. Shiga, Agric. and Biol. Chem. (Japan), 1975, 39, 5 5 3 ; (c) T. Nagasawa, K. Umemoto, T. Tsuneya, and M. Shiga, Nippon Nogei Kugaku Kaishi, 1975,49, 217.
Y7
J. Debrauwere and M. Verzele, Bull. SOC.chim. belges, 1975, 84. 167. J. Smolanoff. A. F. Kluge, J. Meinwald, A. McPhail, R. W. Miller, K. Hicks, and T. Eisner, Science, 1Y75,
98
J. Meinwald, J. Smolanoff, A. T. McPhail, R. W. Miller, T. Eisner, and K. Hicks, Tetrahedron Letters,
188, 734. 1975, 2367. yy
101
Io2
lo3
P. R . Hughes, J. Insect Physiol., 1975, 21. 687. M. Elliott, Chem. and Znd., 1074, 978. M. Elliott, N. F. Janes, and D . A. Pulman, J.C.S. Perkin I, 1974, 2470. D. G. Brown, 0. F. Bodenstein, and S. J. Norton, J. Agric. Food Chem., 1975, 23, 1 15. K. Ueda, L. C. Gaughan, and J. E. Casida, J. Agric. Food Chem., 1975,23, 106. V . Jarolim and F. Sorm. Coll. Czech. Chem. Comm., 1975.40, 1059; ibid., p. 1070.
Terpenoids and Steroids
14
insecticidal activity of monoterpenoid ether (both non-aromaticl" and aromaticlo6) and carbarnatel" juvenoids (cf.Vol. 5, p. 7). 4 Acyclic Monoterpenoids
Terpenoid Synthesis from Isoprene.-Interest continues in new syntheses of isoprene and its derivatives; the dioxan (37) is obtained'" in good yield by the Prins reaction of methylallyl chloride with formaldehyde (cf. Vol. 5, p. 8); free-radical addition of isopropyl alcohol to vinyl acetate yields compound (38) which gives isoprene by acid-catalysed reaction over alumina. (2)-2-Methylbut-2-en- 1-01 and dimethylallyl alcohol are readily available from trans-crotyl alcohol.' l o
(37)
Isoprene reacts with dimethylallyl chloride in the presence of CuCI-AI,O, to yield geranyl chloride, neryl chloride, lavandulyl chloride, and myrcene (12);' I ' reaction of (39; X = C1) with antimony trichloride gives ( E ) -and (2)-2,6-dimethylocta-2,5,7trien-4-one. ( E ) - and (2)-3,7-Dimethylocta-3,6-dienl-ols, geraniol (S), nerol (1 8), and the dienol (40) are prepared from isopentenyl acetate and prenyl chloride
in the presence of zincchloride,"2 and citral is obtained from isopentenyl acetate and (39; X = H) by acid-catalysed d e h y d r a t i ~ n . "A ~ further paper on the telomerization (cf. Vol. 5 , p. 8) of 2-methylbuta- 1,3-diene with 1-chloro-3-methylbut-2-ene and 3chloro-3-methylbut- 1-ene discusses the variation in kinetics and product formation with metal halide catalyst.' l 4 Further reports of tail-to-tail dimerization of isoprene
loh
108
109
i
G. Brieger and R. F. Ellis, J. Agric. Food Chem., 1975,23,335; M. Z. Krimer, 0.E. Krivoshchekova, A. A. Shamshurin, N. M. Gamper, A. P. Sazanov, and V. N. Burov, Zhur. Vsesoyuz.Khim. obshch. im. D. I. Mendeleem, 1974, 19, 708 (Chem. Abs., 1975, 82, 112 168). Y. Manabe, M. Matsui, and K. Mori, Jap. P. 117 438/1974 (Chern. Abs., 1975,83, 10 502). F. M. Pallos and J. J. Menn, U S . P. 3 888 888 (Chem. Abs., lY75,83, 114 683 gives an incorrect formula 11); F. M. Pallos and J. J. Menn, U S . P. 3 886 148 (Chem. Abs., 1975, 83, I14 681 gives an incorrect formula 11 also). H. Omichi, T. Miyakoshi, and S. Saito, Nippon Kagaku Kaishi, 1975, 714. K. Fukunishi, 1. Naito, and F. Mashio, Nippon Kagaku Kaishi, 1974, 2014. M. Schlosser and E. Hammer, Helv. Chim. Acta, 1974, 57, 2547. B. V. Burger. D. J. J. de Villiers. R. N. Laurie, C. F. Garbers, D. B. Smit, and H . E. Visagie, Anais Acad. brasif. Cienc., 1972, 44 (Suppl.), 383 (Chem. Abs.. 1975, 83, 97 612); cf. Vol. 2, p. 13. S. Chiang and A. Yasui, Jap. P. 20 163/1974 (Chem. Abs., 1975, 82, 43 620). N. Goetz and R. Fischer, Ger. Offen. 2 240 372 (Chem. Abs., 1975, 83, 10 516). K. V. Leets and E. A. Muks, J . Org. Chem. (U.S.S.R.).1974, 10. 1869.
Monoterpenoids
15
over palladium complexes have appeared (Vol. 5 , p. 8); (E)-2,7-dimethylocta1,3,7-triene is obtained selectively (go0/,) using palladium(tripheny1phosphine)acetylacetonate and rn-methoxybenzaldehyde' l 5 or by using sodium methoxide-[PdCl,(Bu;P),1 at 80 "C;' l 6 in the latter case, modifying the conditions yields the head-to-tail dimer (E)-2,6-dimethylocta- 1,3,7-triene selectively (cf. Vol. 4, p. 11; ref. 69 should read p. 600). Using [Pd(rr-C,H,)Cl],-NaOMeneomenthyldiphenylphosphine, the dimer 8-methoxy-3,7-dime thylocta- 1,6-diene was obtained''' in optically active form and converted into citronellol. Dimerization of isoprene using RhCl,,3H20-MeC0,Na-PPh, is reported to yield 2,3,6trimethylhepta- 1,5-diene and the 2,3,5trimethylhepta- 1,5-dienes, based upon spectroscopic evidence, in addition to tail-to-tail diene.l17 The dimer, obtained in good yield using sodium in triethylamine-di-isopropylamine,is 85 '/o myrcene (1 2). ''' n-Butyl-lithium-catalysed telomerization of isoprene with diethylamine has been used to synthesize very pure linalool and the related 2,6-dimethyloct-7-en-2,6diol in 67% and 5 1'/o yields respectively' l9 by the previously reported route from the geranyldiethylamine oxide (Vol. 5 , p. 12). Further telomerization papers from this Japanese group include sodium-initiated reactions of isoprene with sterically hindered primary amines to give aldimines with irregular head-to-head as well as headto-tail linking,'20 alkylation of lithiated N-(3-methylbutylidene)-t-butylamine to yield dihydrolavandulal and 5-t-butylaminomenth- 1-ene 12' (also reported simultaneously with minor experimental variations by the same group'22),and alkylation of lithiated a@-unsaturatedaldimines to yield isolavandulal aldimine (4 1).'*, Further syntheses with isoprene units are discussed in the next section.
2,6-Dimethyloctanes.-Ambrosial, from Ambrosia confertifioru, is a dehydrocitral, probably (E,E)-3,7-dimethylo~ta-2,4,6-trienal,'~~ and (E)-3,7-dimethylocta- 1,5,7trien-3-01 is a component of grape and wine aroma.'25 Two synthetic procedures are reported for converting geraniol (8) into geranyl chloride. 1 2 6 M. Anteunis and A . D e Smet, Synthesis, 1974, 800. M. Hidai, H. Ishiwatari, H. Yagi, E. Tanaka, K. Onozawa, and Y. Uchida, J.C.S. Chem. Comm., 1975, 170 (formulae 11, V, VI, and VII are incorrect). 117 F. Imaizumi, N. Ando, S. Hirayanagi, and K. Mori, Nippon Kagaku Kaishi, 1974, 1677. 118 J. Tanaka,T. Katagiri, K. Takabe. and A . Agata, Ger. Offen. 2 451 575 (Chem. Abs., 1975,83,59 1 15). I l 9 K. Takabe, T. Katagiri, and J . Tanaka, Tetrahedron Letters, 1Y75, 3005. lZo K. Takabe, S. Sakuma, T. Katagiri, and J. Tanaka, Nippofi Kagaku Kaishi, 1975, 564. I 2 l K. Takabe, H. Fujiwara, T. Katagiri, and J. Tanaka, Synth. Comm., 1975, 5 , 227. Iz2 K. Takabe, H. Fujiwara, T. Katagiri, and J. Tanaka, Tetrahedron Letters, 1975, 1239 (Curr. Abs. Chem. Index Chemicus, abstract No. 230 382 has formula 8 incorrect). IZ3 K. Takabe, H. Fujiwara, T. Katagiri, and J. Tanaka, Tetrahedron Letters, 1975, 1237. Iz4 J. Kumamoto, R. W. Scora, and W. W. Payne, J. Agric. Food Chem., 1975,23, 123. Iz5 P. Schreier, F. Drawert, and A . Junker, 2. Lebensm.-Untersuch., 1974, 155, 98. 126 J. G . Calzada and J. Hooz, Org. Synth.. 1974,54,63; G . Stork, P. A . Grieco, and M. Gregson, ibid.,p. 68. 115
116
16
Terpenoids and Steroids
Allylic alcohols [e.g. citronellol, geraniol (8), and nerol (18)] exhibit strong shielding at the y-carbon and deshielding at the &carbon in the 13C n.m.r. upon a ~ y l a t i o n . ~Cationic ~' exchange resins separate acyclic [e.g. myrcene (12)] from cyclic (e.g. limonene) monoterpenoids. lZ8 Cyclization of allo-ocimene, using alkali metal amines, may give cycloheptadienes or acyclic dienes depending upon the conditions used; 1,2,4-trimethylcyclohepta1,3-diene may be obtained exclusively with sodium-piperidine, and 2,6dimethylocta-2,4-diene (predominantly trans) is the major product using sodiummorpholine.*2YThe Prins formaldehyde reaction on myrcene (12), on the chelotropic adduct (42), and on the Diels-Alder adduct (43), has been inve~tigated;'~' F,C
CF,
\/
A (42)
A (43)
reaction occurs at the most substituted double bond to give the corresponding dioxan with the adducts, but reaction with myrcene (12) gives poor yields in contrast to the reactions with the reduced myrcenes 3,7-dimethylocta- 1,6-diene and 2,6dirnethyloct-2-ene, which proceed in high yield; the reaction with 2,6-dimethylocta2,6-diene is complex (two bisdioxanic compounds isolated) and 6,7-epoxymyrcene gives oxiran opening only (as expected). The reduction of myrcene (12) has been re-examined ;l 3 (E)-2,6-dimeth ylocta- 2,6-diene can be obtained stereospecificall y using [Cr(CO),J as catalyst and 6,7-epoxymyrcene is similarly reduced; reduction of the adduct (42) over palladium-charcoal followed by pyrolysis yields 6,7dihydromyrcene. Cyclothallation of myrcene (12) using thallium trinitrate gives 7,8dimethoxymenth- 1-ene and the allylic ether (44) by addition to the isolated double bond followed by disproportionation. 13* The double-bond reactivity of myrcene (12) has been investigated further by carbene addition;'33 dichlorocarbene yields the diastereomeric mixture (45) whereas ethoxycarbonylcarbene preferentially attacks the least substituted double bond from the less hindered side; carbene itself gives a complex mixture including the tricyclopropane (46). Sensitized photo-oxygenation of myrcene (1 2) and related compounds shows the carbon-carbon double-bond reactivity to be in the order trisubstituted alkene > 2-alkyl-1,3-diene> 1,ldisubstituted a1ke11e.l~~ Thus myrcene (12) - named P-myrcene - gives the hydroperoxides (47; X = OOH) and (48), which are further photo-oxygenated to the E. Wenkert, M. J. GaSiC, E. W. Hagaman, and L. D. Kwart, Org. Magn. Resonance, 1975, 7 , 51. D . H. Rosback, U.S. P. 3 882 184 (Chem. Abs., 1975,83, 43 543). 1 2 y G. Dauphin, Bull. SOC.chim. France, 1975, 1208. A . D e Srnet and M. Anteunis, Bull. SOC. chim. belges, 1974,83, 467. M. Anteunis and A. D e Srnet, Bull. SOC.chim. belges, 1974, 83, 477. I T 2 M. Anteunis and A. D e Srnet, Synthesis, 1074, 868. I T 3 A. D e Srnet, M. Anteunis, and D. Tavernier, Bull. SOC.chim. belges, 1975, 84, 67. M. Matsurnoto and K. Kondo, J. Org. Chem., 1975.40, 2259.
12'
IZx
Monoterpenoids
17
corresponding 1,2-dioxin [e.g (49)]; reaction at the diene also occurs with amyrcene (47; X = H)and 6,7-epoxy-2,6-dimethylocta1,3,6-triene (named epoxyhymenthrene). Myrcene (12) is isomerized to a 3 : 7 ratio of cis- and trans-ocimenes with rhodium nitrate-propan-2-01-acetyl chloride.'35
h (47)
OOH (48)
k." (49)
Ethyl geranate (50) has been synthesized highly stereoselectively (Scheme 5).136 An alternative route to the ester (51) by y-alkylation of 2-butynoic acid has been
Reagents: i, HC-CCH,MgBr; ii, Bu"Li; iii, ClC0,Et; iv, PhSH-PhSNa-EtOH; v, MeMgI-Cur, - 78 " C ,THF-Et ,O.
Scheme 5
followed by treatment with lithium dimethylcuprate to give the corresponding 2-isomer highly stereoselectively; reduction gives nerol (18).'37 The synthesis of previously reported lavandulyl methyl ether from isoprene,138the e l a b o ~ a t i o no' f~ ~ K. J. Ploner, J. Wild, and T. Sigg-Gruetter, Ger. Offen. 2 422 244 (Chem. Ah., 1975,82, 155 343). S. Kobayashi and T. Mukaiyama, Chem. Letters, 1Y74, 705. 137 B. S. Pitzele, J. S. Baran, and D. H. Steinman, J. Org. Chern., 1975,40, 269. 138 T. Sato, H. Kise, M. Seno, and T.Asahara, Yukaguku, 1975,24, 265. m S. Watanabe, K. Suga, T. Fujita, and N. Takasaka, J. Appl. Chem. Biotechnol., 1974, 24, 63Y. 13s
136
18
Terpenoids and Steroids
(Vol. 4,p. 10) isoprene oligomers (e.g. 2,6-dimethylocta- 1,7-diene) into the corresponding alcohols [e.g. (52)] via epoxide rearrangement, and the ~ynthesis'~' of the alcohol (53)(Vol. 3, p. 15) are straightforward. The isopropenylation of alkenes via the reaction of iodine with lithium trialkylisopropenylborates has been used to
(52)
(53)
synthesize d i h y d r ~ l i n a l o o l . 'The ~ ~ previously reported (Vol. 4,p. 15) scheme for hotrienol synthesis has been used for the synthesis of the cis-isomer (54).14* Pheromones of the male bark beetle Ips confusus have been the trienol(55) has been synthesized from the previously reported (Vol. 4,p. 15) allylic and ipsenol is obtained by heating the cyclobutene (56) which is prepared
Ho5 Ho3 (54)
from isovaleraldehyde and the anion of methylenecyclobutane.144 The absolute configuration of (-)-ipsenol (57) has been established as S by synthesis from L-leucine (Scheme 6).145 The reaction of linalool with boron trifluoride etherate has been re-examined; no pinenes or camphene were Dehydrolinalool reacts with methyl isopropenyl ether under acidic conditions by Claisen rearrangement to give the allene (58).14' Further papers in this section include reaction of monoterpenoid alcohols with paraformaldehyde-acetic anhydride-sodium rearrangement of the alcohol (47; X = OH) to the oxabicycloheptane (59) and the ketone (60),'49 and the rearrangement of a typical monoterpenoid vicinal hydroxy-ester to an epoxide.150 14i 142 143
IJ4 145
14h
14H 14y
Is*
0. P. Vig, 0. P. Chugh, V. K. Handa. and A . K. Vig, J. Indian Chem. SOC.,1975, 52, 161. N. Miyaura, H. Tagami, M. Itoh, and A . Suzuki, Chem. Letters, 1974, 1411. 0. P. Vig, B. Ram, U.*Rani, and J. Kaur, J. Indian Chem. Soc., 1974,51, 616. K. Mori, Agric. and Biof. Chem. (Japan), 1974, 38, 2045. S. R . Wilson and L. R. Phillips, Tetrahedron Letters, 1975, 3047. K. Mori, Tetrahedron Letters, 1975, 2187. Y. Fujita, S. Fujita, and H. Okura, Osaka Kogyo Gijutsu Shikensho Kiho, 1974, 25,211. M. A. Miropol'skaya, A. R . Bekker, M. G. Romanyuk, T. M. Filippova, N. I. Zakharova, and C. I. Sarnokhvalov,J. Org. Chem. (U.S.S.R.),1974, 10,1873. T. Kishimoto and Y. Matsubara, Nippon Nagaku Kaishi, 1975, 701. B. Corbier and P. Teisseire, Recherches, lY74, 19, 253. H. R. Ansari and R. Clark, Tetrahedron Letters, 1975, 3085.
19
Monoterpenoids
Reagents: i, HNO,; ii, LiAlH,; iii, p-TsCl-py; iv, aq. KOH; v, diethyl malonate-NaOEt; vi, aq. KOH; vii, aq. H,SO,; viii, CH,O-Et,NH; ix, PhSeH; x, BulAlH-THF; xi, Ph,P( Me)Br-NaH-DMSO.
Scheme 6
(58)
(59)
(60)
HalogenatedMonoterpenoids.-A separate section is devoted this year to halogenated monoterpenoids: twenty-four acyclic and four cyclic compounds in this class have been reported. A review of halogenated monoterpenoids and sesquiterpenoids has been published.lS1 The structures which have been elucidated so far may be grouped into two general categories; the first group possesses the 5,6-dichloro-2,6-dimethylocta1,3,7-triene structure (61;R = Me, X = H) with additional halogen substituents in the dimethylallyl pyrophosphate-derived methyl carbon atoms, and the second group has the
(61) IS1
Y. R. Naves, Rivista Ltal. Essenze-Profumi, Piante Ofic., Aromi, Saponi, Cosmet., Aerosol., 1975, 57, 181.
20
Terpenoids and Steroids
myrcene carbon skeleton (12) with halogen substituents most commonly in the isopentenyl pyrophosphate-derived portion of the molecule and none in the geminal dimethyl group. Following the earlier report of a halogenated monoterpenoid in Plucamium cartilagineum (Vol. 4, p. 12), Faulkner has isolatedlS2 the additional compounds (62; X = H, Y = 2-Cl), (62; X = Br, Y = 2-Cl), (63; X = Y = H), (63; X = H , Y=E-CI), (63; X = H , Y=Z-Cl), (63; X = B r , Y=E-Cl), (63; X = B r , Y = 2-CI), and the four compounds (64; X = Br, Y = H) and (64; X = Y = Br); from the same species a corresponding aldehyde (61; R = C H O , X=Cl) has been reported,lS3and the dibromotrichloro-monoterpenoid (65) has been reported in Aplysia californica. lS4 Two groups report the isolation of bromochloromyrcene compounds from Desmia (Chondrococcus) hornemanni collected in the Amami Islands155and in Hawaii.'56 They are (66; X = H, Y = Cl), (66; X = H, Y = Br), (66; X = 2-Br, Y = H), (66; X = E-Br, Y = H), (66; X = E-Br, Y = Cl), (66; X = 2-Br, Y = Cl), (67; X = C1, Y = Br), (67; X = Y = Cl), (68; X = Br, Y = Cl), and (68; X = C1, Y = Br). Two halogen-substituted ethyldimethylcyclohexanes and two halogenated furanoid monoterpenoids are reported in later sections.
Artemisyl, Santolinyl, Lavandulyl, and Chrysanthemyl Derivatives.-Yomogi alcohol (69) has been synthesized stereospecifically using the reaction of 1,3bis(methy1thio)allylcopper reagent (70) with the allylic halide (7 1) (Scheme 7).157 The isolation of the santolinyl ester of (2R,3S) configuration lends support to (1R,3R)-chrysanthemyl pyrophosphate being the biogenetic precursor of the santolinyl skeleton. 15* 152 I53
I54 1.55
IS6 157
I sx
J. S. Mynderse and D. J. Faulkner, Tetrahedron, 1975,31, 1063. P. Crews and E. Kho, J. Org. Chem., 1974,39,3303. C. Ireland, unpublished data. N. Ichikawa, Y. Naya, and S. Enomoto, Chem. Letters, 1974, 1333. B. J. Burreson, F. X. Woolard, and R. E. Moore, Tetrahedron Letters, 1975, 2155. K. Oshima, H. Yamamoto, and H. Nozaki, Buff.Chem. SOC.Jupun, 1975,48, 1567 J. Shaw. T. Noble, and W. Epstein, J.C.S. Chem. Comm., 1975, 590.
Monoterpenoids
21
(69) Reagents: i, -78 " C ;ii, Mn0,-CN --AcOH-MeOH;
iii, MeLi.
Scheme 7
Details of the preparation of methyl (-)-cis-chrysanthemate from (+)-car-3-ene have appeared (Vol. 5, p. 15 is mi~leading)."~Both (-)-cis- and (+)-transchrysanthemic acids are again reported from (+)-car-3-ene via ozonolysis;160this work is very similar to that reported (Vol. 5, p. 15) by Sukh Dev and illustrates the lamentable delay from receipt to publication in some journals. The decomposition of ethyl diazoacetate in 2,5-dimethylhexa-2,4-dienein the presence of the chiral copper complex (72) leads to cis- and truns-chrysanthemic acids in 60-70% optical yield; the degree of asymmetric induction is dependent upon the steric bulk of R' and R2 in (72).16' cis-Chrysanthemic acid has also been prepared from 3,3dimethylcyclopropene, isoprene, and 2-methylpropenylmagnesium bromide followed by treatment with carbon dioxide.'62
5 Monocyclic Monoterpenoids
Cyclobutane.-Four syntheses of grandisol (73) have been r e p ~ r t e d , ' ~ ~one - ' ~ of ~ which also led to fragranol (74) (Vol. 4, p. 23).166 Ozonolysis of compound (75), lSy
Iho
Ih1 Ih2 lh3
lh4 Ih5
W. Cocker, H. St.J. Lauder, and P. V. R. Shannon, J.C.S. Perkin I, 1975, 332; this paper follows that previously reported (Vol. 5, p. 15) which only reported the synthesis of methyl (+)-cis-2,2-dimethyl-3(2-methylene-3-oxobutyl)cyclopropanecarboxylate.It is disturbing to see different names used for the same compound in the two papers. Y. Gopichand, A. S. Khanra, R. B. Mitra, and K. K. Chakravarti, Indian J. Chem., 1975,13,433. T. Aratani, Y. Yoneyoshi, and T. Nagase, Tetruhedron Letters, 1975, 1707. B. V. Maatschappij, Dutch P. 02 879/1974 (Chem. Abs., 1975,83, 27 684). R. L. Cargill and B. W. Wright, J. Org. Chem., 1975,40, 120. P. D. Hobbs and P. D. Magnus, J.C.S. Chem. Comm., 1974,856. J. H. Babler, Tetrahedron Letters, 1975, 2045. B. M. Trost and D. E. Keeley, J. Org. Chem., 1975,40, 2013.
22
Terpenoids and Steroids
synthesized conventionally from the corresponding ci~-bicyclo[3,2,0]heptanone, yields the keto-acid (76),'63 which has previously been converted into grandisol(73).
(73)
(74)
(75)
(76)
A second synthesis of chiral grandisol (73) from trans-pinan-2P-01 (77; X = H) derived from (-)-P-pinene, as shown in Scheme 8, involves the useful photochemical
$-t
4
l-lll,+b
(77)
(73) t o
4-5
V-Vll,I'-.
.&&
p
H c . . ~ ~ . - ~ o A c ~ ~ H ' T (79)
H (78)
Reagents: i , Nitrite ester, hv; ii, A ; iii, ether-acetone-2% aq. HCl; iv, Ph,P=CH,-DMSO; v, bis-( I-isopropylethy1)borane;vi, H,O,-NaOH; vii, Ac,O-py; viii, POC1,-py, 0 " C ; ix, CrO,--py-CH,Cl,; x, H,-20 % Pd-C; xi, NaHC0,-MeOH, hv; xii, [(PPh,),RhCl]CH,Cl,; xiii, LiAlH,.
Scheme 8
cleavage of (78) to (79).164 Racemic grandisol (73) has been obtained from the cyclobutane (80) which is obtained from (81) by stereoselective intramolecular alkylation favouring the 2-isomer. 165 An efficient synthesis from methylacrolein utilizes 1-1ithiocyclopropyl phenyl sulphide in secoalkylation to yield the spiro[3,3]heptan- 1-one (82) which is readily ring-cleaved to (83) and transformed into grandisol (73); rearrangement of the intermediate cyclopropylcarbinol(84) by the less sterically favoured pathway leads to 20% of fragranol (74).166
23
Monoterpenoids PhS
PhS,
OMe (83)
Cyclopentanes, Iridoids.-The nomenclature, structure, and methods of isolation of iridoid glucosides have been r e ~ i e w e d ; the ' ~ ~occurrence of iridoids in the angiosperms has also been reviewed.'68 The use of I3Cn.m.r. in the structural elucidation of C,, iridoid glucosides has been reported'69 and the structures of leonuride (Vol. 5 , p. 17; it is not an acetate) and from Picrorhizu kurrooa (omitpicroside 2 (85; R = 4-hydroxy-3-methoxybenzoyl) ted'" from earlier Reports) were confirmed; no stereochemical details are given. The related 6-O-veratryl catalposide (85; R = 3,4-dimethoxybenzoyl) is present in Tecornellu u n d ~ l u t a , ' and ~ ' mioporoside (86), from Mioporus insulure, is the C-6 epimer of ajugol (Vol. 5 , p. 17);17*it appears that leonuride, from Leonurus cardiaca, is not identical with mioporoside (86) according to reported 'H n.m.r. data.'72"73 Further new iridoid glucosides from Guleopsis tetruhit (Vol. 2, p. 16) include gluroside (87)*" and 6-deoxyharpagide (88; R = H),175and from Guieopsis pubesCelts the acetate (88; R=Ac),l'' which is identical with reptoside isolated from Ajugu reptuns.'76 Macfadienoside, from Macfudiene cinancoides, is 10-hydroxyantirrhinoside (89) and is readily converted into the known antirrhinomelampyroside (90; R = COPh), isolated from Melurnpyrurn siluuticurn,
167
0. Sticher and U. Junod-Busch, Phurm. Actu Helv., 1975, 50. 127. S. R. Jensen, B. J. Nielsen, and R. Dahlgren, Botun. Notiser, 1975, 128, 148. G. Schilling, W.-D. Henkels, K. Kunstler, and K. Weinges, Annulen, 1975, 230. K. Weinges, P. Kloss, and W.-D. Henkels, Annulen, 1972, 759, 173. K. C. Joshi, L. Prakash, and L. B. Singh, Phytochemutry, 1075,14, 1441. A. Bianco, M. Guiso, C. Iavarone, and C. Trogolo, Gazzettu, 1975,105, 175. K. Weinges, P. Kloss, and W.-D. Henkels, Annulen, 1973, 566. 0. Sticher, A . Weisflog, U. Busch, and E. Rogenmoser, Schweiz. Apoth.-Ztg., 1974, 112, 523; Deut. Apoth.-Ztg., 1974, 114, 902. 0. Sticher, E. Rogenmoser. and A. Weisflog, Tetrahedron Letters, 1975, 291. M. Guiso, A . Agostini, and R. Marini-Bettolo, Guzzetru, 1974, 104, 403. A. Bianco. M. Guiso, C. Iavarone, and C. Trogolo. Gazzetta, 1974, 104, 731.
Inn
170 171
172 173 174
175 177
24
Terpenoids and Steroids
is a derivative of aucubin (90; R='H);178 the latter probably gives rise to the cyclopentenoid tetrol eucommiol(9 1 ) which is isolated from Eucommia ulmoides. 179 Feretoside (92) occurs in Feretia apodanthera.lsoThe c16 iridoid glucoside isolated from Stachytarpheta indica is identical with the previously unreported ipolamiide (93)lB2and hebenstreitia glycoside B.Is3 Other new iridoid glucosides are syringoxide (94) from Syringa ~ u l g a r i stecomoside ,~~~ ( 9 9 , which has a C-4 formyl group, , ~ ~ ~ (96) from Phlomis fruticosa,lg6nyctanthoside from Tecoma c a p e n ~ i sphlomiol (97) from Nyctanthes a r b o r - t r i S t i ~gardoside ,~~~ (98) and scandoside methyl ester, the 6P-anomer of the previously isolated methyl deacetylasperulosidate, from Gardenia jasminoides (cf. Vol. 1 , p. 20),'" and barlerin (99; R = H ) and its acetate (99; C0,Me
H o : &
Go HO
HO
Me*@o
CH,OH
0-P-Glu
(91)
0-P-Glu
(92)
(93)
HO
1
(94)
(96)
(95)
CO,H H O # ~ ~ ~
H
O
G
C0,Me
o RAcO O@o
HOH z c
0-P-Glu
(97)
0-P-Glu
(98)
0-P-Glu
(99)
R = Ac) from Barleria prionitis.18' Interest continues in iridoid glycosides from Valerianaceae. Three examples are now known with glucose linked to the C-11 rather than the C-1 hydroxy-group; they are patrinoside (100) from Patrinia scabiosaefolia, 1 9 0 the previously unreported villoside (1 0 l),19' and valerosidate B. Z. Ahn and P. Pachaly, Tetrahedron, 1974,30,4049. A. Bianco, C. Iavarone, and C. Trogolo, Tetrahedron, 1974,30,4 117. lHO P. Delaveau, B. Koudogbo, F. Bailleul, Q. Bognounou, and E. Randrianjohany, Compt. rend., 1974, 279, C, 613. IxlB. Tantisewie and 0. Sticher, Phytochemistry, 1975, 14, 1462. I x 2 M. L. Scarpati and M. Guiso, Gazzetta, 1969,99, 1150. I X 3 P. Kooiman, Acta Botan. Neerl., 1970, 19, 329. Ix4 S. Popov, Doklady Bolg. Akad. Nauk, 1975, 28, 331. I X 5 A. Bianco, M. Guiso, C. Iavarone, and C. Trogolo, Gazzetta, 1975, 105, 195. IX6A. Bianco, M. Chiso, C. Iavarone, and C. Trogolo, Gazzena, 1975, 105, 185. I X 7 H. Rimpler and J. U. Junghanns, Tetrahedron Lerrers, 1975, 2423. I X XH. Inouye, Y. Takeda, and H. Nishimura, Phytochemistry, 1974, 13, 2219. I X y S. C. Taneja and H. P. Tiwari, Tetrahedron Letters, 1975, 1995. l y O H. Taguchi and T. Endo, Chem. and Pharm. Bull. (Japan), 1974,22, 1935. I y l H. Taguchi, Y. Yokokawa, and T. Endo, Yakuguku Zasshi, 1973,93, 607.
25
Monoterpenoids
(102).'92The structure for valerosidate is incorrect in the previous Report (Vol. 5, p. 17). A new valepotriate has been isolated from Valerianu oficinalis and shown spectroscopically to be 7-epideacetylisovaltrate ( 1O3);ly3it is also shown to be related to didrovaltrate (104) stereochemically, but in view of the recently reported this assignment must be questioned. absolute configuration of didrovaltrate (104) lY2 The occurrence of iridoids in the Argentine ant Iridornyrrnex hurnilis has been re-investigated. I y 4
(103)
(104)
The aglucone of the dimethyl ester of forsythide (105)'95has been synthesized according to Scheme 9;ly6 when the aldehyde produced by photolysis of the
Me0,C
OH
(105) (107) Reagents: i. SOC12-C6H,; 11, C H 2 N , ; iii, hv, MeCN-H,O; iv, B,H,-THF; v, 1.5N N a O H ; vi, NaOMe-MeOH; vii, TsCl-py-CH,Cl,; viii, Bu'OK-Bu'OH; ix, h v ; x, 0.1N aq. MeOH-NaOH; xi, CH,N,; xii, Jones oxidation; xiii, CH,N,; xiv, OsO,; xv, H,S; xvi, Pb(O Ac),-C,H 6-K ,CO 3 .
Scheme 9 192
193 1% 195
1%
H. Inouye, S. Ueda, S. Uesato, T. Shingu, and P. W. Thies, Tetrahedron, 1974, 30, 2317. S. Popov, N8. Handjieva, and N. Marekov, Phytochemistry, 1974, 13, 2815. G. W. K. Cavil1 and E. Houghton, J. Insect Physiol., 1974, 20, 204Y. H. Inouye and T. Nishioka, Chem. and Pharm. Bull. (Japan), 1973,21,497. K. Furuichi and T. Miwa, Tetrahedron Letters, 1974, 3689.
26
Terpenoids and Steroids
keto-ester (106) is immediately epimerized with base, the desired cis-diester stereochemistry (107) is obtained. The same group also reports the synthesis of the trans-epimer of sweroside aglucone O-methyl ether (108) (cf. Vol. 5, p. 19).19'
(108)
Compound (109) was synthesized (Scheme 10) but attempts to convert it into jasminin (1 10) failed;198the secoiridoid (11l),obtained directly from jasminin (1lo), was condensed with (112) as its sodium salt [cf. Vol. 3, pp. 29,30; formula (105) is misprinted]. CH,OAc
0 Ho2cJb 4
0
ii-xi
L
OH
AcOH,C G - ,- 0 T s
i
(1 12) ,CH,OAc
Reagents: i, NaOEt; ii, C H , N , ; iii, Jones oxidation; iv, acetalization; v, B 2 l A 6vi, ; I,O,-NaOH; vii, aq. HOAc; viii, acetylation; ix, NaBH,; x, separation; xi, TsC1-py; xii, NaOH; xiii, ( 1 12)-DMF.
Scheme 10 Iv7
lVH
K . Furuichi. K. Abe, and T. Miwa, Tetrahedron Letters, 1974, 3685. Y . Asaka. T. Kamikawa, and T. Kubota, Tetrahedron, 1974, 30, 3257
Monoterpenoids
27
Hastatoside ( I 13)”’ has been synthesized as its tetra-acetate from verbenalin tetra-acetate.200The cyclopentene (114) has been isolated from Turkish tobacco and synthesized from menth- 1-ene.201
0-P-Glu (113)
(1 14)
The structure of the monoterpenoid alkaloid alangiside (115; R = H) has been confirmed by synthesis of the 0-methyl ether (115; R = Me) from secologanin and 3hydroxy-4-methoxyphenethylamine;202 the isolation of loganic acid from the same plant (Alangium larnarckii) is consistent with biosynthetic theory.
(115)
p-Menthanes-The oxygenated p-menthanes (1 16)-( 119) are present in Mentha gentili~,~’ and Piper nigrum has yielded menth-6-en-3-01, mentha-3,g-dien- 1-01, mentha-l(7),5-dien-2-01, and mentha-1(7),2-dien-4-01;~~ (-)-menthyl-P-D, ~ ~the ~ C , , ketone (120), from glucoside has been isolated from Mentha u r ~ e n s i sand Cedrus atlantica and C. deodaru, which is synthetically related to (+)-limonene, is undoubtedly a sesquiterpenoid degradation The syntheses of isoterpinolene, terpinolene, isolimonene a-terpinene, y terpinene, and rnentha-3,g-diene in >97% purity have been described205in connection with their base-catalysed isomerization.206 Limonene has also been synthesized, along with the corresponding rn-menthadiene, by the action of iodine on a lithium trialkylis~propenylborate.’~~ The synthesis of the two uroterpenols (12 1) demonstrates that naturally occurring (+)-uroterpenol is a mixture of (121) with some of the enantiomer~;~’~ the syntheses depend upon the separation of the corresponding IY9 H. Rimpler and B. Schafer, Tetrahedron Letters, 1973, 1463. zoo Y. Umehata and T. Miwa, Tetrahedron Letters, 1975,3195. Zo1 T. Chuman and M. Noguchi, Agric. and Biol. Chem. (Japan). 1975, 39,567. zo2 A. Shoeb, K. Raj, R. S. Kapil, and S. P. Popli, J.C.S. Perkin Z, 1975, 1245; see Vol. 2, p. 17. 203 I. Sakata and T . Mitsui, Agric. and Biol. Chem. (Japan), 1975, 39, 1329. 204 D. R. Adams, S. P. Bhatnagar, R. C. Cookson, and R. M. Tuddenham, Tetrahedron Letters, 1974,3903. 205 A. Ferro, Rivista Ztal. Essenze-Profumi, Piante Offc., Aromi, Saponi, Cosmet.,Aerosol., 1974,56,61 1 . A. Ferro and Y. R. Naves, Helv. Chim. Acta, 1974,57,1141. 207 A. Kergomard and H. Veschambre, Tetruhedron Letters, 1975, 835.
28
Terpenoids and Steroids
epoxides by spinning band distillation. (No reference is made to the previously reported separation; cf. Vol. 5, p. 22.) Anodic oxidation (cf. Vol. 4, p. 57) of the enol-acetate (122) yields optically pure (-)-carvone, the yield varying with the electrolyte and the Acylation of alkenes has now been used to synthesize piperitenone from cis-geranic acid A new synthesis of diosphenol has also led to the isomeric isodiosphenol (123).'" Pulegone, via enamine alkylation with methyl vinyl ketone, yields the monoterpenoid alkaloid fabianine (124)."'
(121)
(1 23)
( 122)
( 124)
Marshall has applied the reductive decyanation-elimination of P, y-epoxy-nitriles to allylic alcohols2'* in a synthesis of cis- and trans-pulegol (Scheme 11) which is converted into ( f ) - p ~ l e g o n e . ~ ~ ~
Reagents: i, NaCH(CN)PO(OEt),; ii, Pr',NLi-MeI-HMPA;
iii, m-CIC,H,CO,H;
iv, N a - N H ,
.
Scheme 11
The conformational equilibria of the four 2-methoxymenthanes and the four 3-methoxyrnenthanes (cf. Vol. 2, p. 27) have been studied using 'H n.m.r. and with optical rotation and rotatory dispersion. 'H N.m.r. studies have T. Shono, I. Nishiguchi, T. Yokoyama, and M. Nitta, Chem. Letters, 1975,433. T. Kobayashi, S. Kumazawa, T. Kato, and Y. Kitahara, Chem. Letters, 1975, 301. 2 1 0 H. Shibata and S. Shimizu, Agric. and Bid. Chem. (Japan), 1974,38, 1741, 2 1 1 P. Teisseire, B. Shimizu, M. Plattier, B. Corbier, and P. Rouillier, Recherches, 1974, 19, 241. 212 J . A. Marshall and G. M. Cohen, J. Org. Chem., 1971, 36, 877. 2 L 3 J . A. Marshall, C. P. Hagan, and G. A. Flynn, J. Org. Chem., 1975, 40, 1162. 214 D. Voisin and B. Gastambide, Bull. Soc. chim. France, 1975, 375. 20x
zOy
29
Monoterpenoids
demonstrated the formation of the cyclopentyl cation (125) from the unsaturated hydrocarbons formed when menthol is treated with concentrated sulphuric acid; such cations react with vanillin to give coloured f u l v e n e ~ . ~ * ~
(1 25)
(126)
(127)
A re-investigation of the Diels-Alder addition of butadiene to (-)-carvone has led to a reassignment of the structures of the major adduct (126) and the minor adduct (127).2'6 The isolation of the diol (128) on treating the ketone (129) with methylmagnesium iodide is the result of a [2,3] sigmatropic rearrangement to (130);217this rearrangement may find application in artemisyl synthesis.
( 129)
( 130)
( 128)
Rearrangement of limonene with a cationic exchange resin, rather than with soluble acids,218substantially reduces polymer formation. Limonene is hydrated using chloroacetic acids to furnish (+)-a-terpineol selectively in high yield, depending upon the The oxidation of (-)-perillaldehyde (34; R = CHO) with Caro's acid in methanol The oxidayields the ester (34; R = C0,Me) and 4-isopropenylcyclohexanone.220 tion of limonene with t-butyl perbenzoate or t-butyl peracetate gives, after ester hydrolysis and chromic acid oxidation, (-)-carvone and piperitenone as the main products together with products resulting from allylic oxidation at the other positions;221these results are not as economically useful as those previously reported (Vol. 1, p. 26). Selenium dioxide-hydrogen peroxide oxidation of (+)-limonene to the alcohol (131) is considered to arise by ene-addition between selenous acid and (+)-limonene followed by dehydration to the allylselenic acid (1 32) which undergoes a [2,3] sigmatropic rearrangement followed by solvolysis to (13 1).222 This mechanism is inconsistent with previous reports that (13 1) is optically active (cf. Vol. 1,p. 25 ; Vol. 4, p. 29); this reported optical activity is probably due to impurities in (131). 215 216
H.Auterhoff and H. Bertram, Arch. Pharm., 1974,307,742. T.Harayama, H.Cho, and Y. Inubushi, Tetrahedron Letters, 1975, 2693.
A. F. Thomas and R. Dubini, Helu. Chim. Acta, 1974, 57, 2084. E. Pottier and L. Savidan, Bull. Soc. chim. France, 1975, 654. 2 1 y Y. Matsubara, K. Tanaka, M. Urata, T. Fukunaga, M. Kuwata, and K. Takahashi, Nippon Kagaku Kaishi, 1975, 855. 220 M.Ito, K. Abe, H. Abe, K. Yamada, and T. Masamune, Bull. Chem. Soc. Japan, 1974.47, 3173. 221 C. W. Wilson and P. E. Shaw, J. Agric. Food Chem., 1975,23,636. 222 H. P. Jensen and K. B. Sharpless, J. Org. Chem.. 1975, 40, 264. 217
2Ix
30
Terpenoids and Steroids
Selenium dioxide oxidation of isopulegol acetate (133; 3R) and neoisopulegol acetate (133; 3 s ) is allylic oxidation is consistent with the Sharpless mechanism but a different mechanism is proposed. I I
(131)
(132)
(133)
Epoxidation of y-terpinene with superoxybenzimidic acid is more stereoselective and efficient than with perbenzoic acid, giving the epoxides (134) (cf.Voi. 4, p. 30).224
A (134)
Manganese dioxide oxidation of cis-pulegol (1 17) and trans-pulegol is reported to give pulegone and epoxides.**’ The limonene epoxides (135) are cleaved by Ti(OCHMe,), to an equimolar mixture of the allylic alcohols ( 136),225and cleavage of the trans-epoxide (1 35) with amine-HF complexes yields the fluorohydrin (137) stereospecifically.226The same unexpected result is observed with the corresponding trans-carvomenthene epoxide.226
(135)
(136)
( 1 37)
Cyclic hydroboration of ( +)-limonene with thexylborane yields the pure borabicyclic compound ( 138), which is oxidized to the diol(32; X = OH) or protonolysed with acetic acid to yield pure (-)-carvomenthol (32; X = H ) after the usual ~ x i d a t i o n . ~ The ~ ’ treatment of dialkylcyanothexylborates with trifluoroacetic anhydride followed by oxidation as a route to ketones has been used with (+)-limonene to give the two bridged-ring ketones ( 139).228 The addition of dichlorocarbene to (+)-trans-isolimonene (mentha-2,8-diene) gives predominantly the diastereoisomers from reaction at the least substituted 227 224
225 22h 227 22r(
T. Tahara and Y . Sakuda. Yukagaku, 1975,24, 301. S. A. Kozhin and E. I. Sorochinskaya, Zhur. obshchei Khim., lY74,44, 2350. Y. Takagi, K. Kokami, and K. Hayashi, Jap. P. 58 031/1Y75 (Chem. Abs.. 1975,83,97 638). G. Farges and A . Kergomard, Bull. SOC.chim. France, 1975, 315. H. C. Brown and C. D. Pfaffenberger, Tetrahedron, 1975, 31, 925. A Pelter. K. Smith, M. G. Hutchings. and K. Rowe, J.C.S. Perkin I. 1975, 129.
Monoterpenoids
31
(139)
(138)
double bond22Ywhereas the addition of dichlorocarbene by the phase-transfer technique to (*)-limonene in the presence of a quaternary ammonium catalyst gives (140) or the bis-adduct depending upon the catalyst
( 140)
A further paper on the reductive dimerization of (+)-pulegone describing additional dimers has been published (cf. Vol. 4, p. 36).231 The conjugate addition of trimethylaluminium to pulegone in the presence of nickel a ~ e t y l a c e t o n a t eand ~ ~ the ~ conjugate addition of vinylmagnesium bromide in the presence of copper iodide and isopropyl sulphide have been Other papers related to p-menthanes concern vinylaziridine formation from pulegone oxime and from carvone-NN-dimethylhydrazone m e t h i ~ d a t e , *non~~ ozonolytic cleavage of 1O-trichloromethyl-limonene,235 and the stereochemistry of l-chloro- l - n i t r o ~ o - p - m e n t h a n e and s ~ ~ of ~ dihydropinol rearrangements (cf. Vol. 2, p. 34y3’
o-Menthanes.-The o-menthane lactone (141) has been isolated from the urine of the koala bear (Phascolarctos cinereus) along with the p-menthene lactones ( 142);238 the lactones may result from Q - or P-pinene ring-opening.
(142) 22y
230 231
232
233 234
235 236 237
238
I. I. Bardyshev, V. 1. Lysenkov, D. A . Fesenko, and B. G. Udarov, Zhur. org. Khim., 1975, 11, 503. T. Hiyama, H. Sawada, M. Tsukanaka, and H. Nozaki, Tetrahedron Letters, 1975,3013. J. M. Font-Cistero, E. Forne, and J. Pascual, Anales de Quim., 1974, 70, 1004. L. Bagnell, E. A . Jeffery, A . Meisters, andT. Mole, Austral. J . Chem., 1975, 28, 801. G. Alexandre and F. Rouessac, Bull. Soc. chim. belges, 1974,83,393. R. Chaabouni and A . Laurent, Synthesis, 1975,464. J. Alexander and G. S. K. Rao, Chem. and Ind., 1975,707. T. Bosch, G. Kresze, and J. Winkler, Annalen, 1975, 1009. A. Siemieniuk, K. Piatkowski, and H. Kuczynski, Bull. Acad. polon. Sci., Sir. Sci. chim., 1974,22. 1009. I . A. Southwell, Tetrahedron Letters, 1975, 1885.
32
Terpenoids and Steroids
rn-Menthanes.-Carvestrene is a mixture of various m -menthadienes and m~ y m e n e these ;~~~ m-menthadienes may be transformed into one another by trichloroacetate or by t-butoxide treatment.240 Further catalytic reduction of mmenthadienes has been reported (Vol. 3, p. 51),241and spectral data have now been provided for the second component (143) of Wallach's sylveterpineol (cf.Vol. 3, p. 51);242 the synthesis of the corresponding diene (144) has been achieved via the isopropenylation reported earlier.'41
c, ( 143)
( 144)
Tetramethy1cyclohexanes.-Esters of ferulol ( 145) are present in Scaevola Eobelia 243 and Cenolophium f i ~ c h e r(cf. i ~ Vol. ~ ~ 5 , p. 28), and spectroscopic data are recorded for the ester (146) of the isomeric hydroxy-aldehyde isolated from the latter and from Bupleurum gilbraltari~um.'~~
( 145)
( 146)
The biogenetic-type asymmetric cyclization of citral gives (+)-a-cyclocitral of R, and not S, configuration as previously reported (Vol. 4, p. 38).245 13 C N.m.r. chemical shifts and spin-relaxation times have been reported for p - c y c l o ~ i t r a lMass . ~ ~ ~spectral data have been recorded for a -pyronene (147), which fragments similarly to allo-ocimene through common ions.247 Brief acid-catalysed treatment of a -pyronene (147) gives predominantly the diene (148),248 whereas prolonged treatment gives p- and y-pyronene. The ratio of the a and p -cyclocitryl derivatives ( 149) formed by acid-catalysed cyclization of geranyl phenyl sulphide or geranyl phenyl sulphone varies widely with the catalyst and the solvent a - and p-ionones have been synthesized from these derivatives (1 49).245, G. N. Saraswathi, N. V. Muraleedharan, and J. Verghese, Indian J. Chem., 1974, 12, 561. B. Singararn and J . Verghese, Current Sci., 1974.43.669. 2 J 1 1. 1. Bardyshev, R. I. Zen'ko, E. N. Manukov, G . I. Voitekhovskaya, and K. A. Mikhalkovich, Vestsi Akad. Navuk Belarusk. S.S.R., Ser. khim. Navuk, 1974, No. 6, 59 (Chem. Abs., 1975,82, 171 213). 242 P. M. Abraham and J. Verghese, J. Indian Chem. SOC., 1975, 52, 175. 243 F. Bohlmann, J. Jacob, and M. Grenz, Chem. Ber., 1975, 108, 433. 244 F. Bohlmann, C. Zdero, and M. Grenz, Chem. Ber., 1975, 108, 2822. 245 M. Shibasaki, S. Terashima, and S. Yarnada, Chem. and Pharm. Bull. (Japan), 1975, 23. 279. *4h R. S. Becker, S. Berger, D . K. Dalling, D. M . Grant, and R. J. Pugmire, J. Amer. Chem. SOC.,1974,96, 7008. 247 L. E. Brady, D. H. Williams, S. C. Traynor, and K . J . Crowley. Org. Mass Spectrometry, 1975,10, 1 16. 24x W. Cocker, K. J . Crowley, and S. G . Traynor, J.C.S. Chen. Comm., 1974,982. *4v S. Torii. K. Uneyama, and M. Isihara, Chem. Letters, 1975, 479.
23v
240
Monoterpenoids
33
Dimethylethylcyc1ohexanes.-Two new halogenated monoterpenoids are violacene (150) from Plocarniurn v i o l a c e ~ r na, ~1,4-dimethyl~~ 1-ethylcyclohexane which can be rationalized biosynthetically from the cyclization of an acyclic precursor via a bromonium ion, and plocamene B (15 l), again from Plocarniurn violaceurn, which may be the first member of a series of non-isoprenoid monoterpenoids from this species . 2 5 1
( 150)
(151)
Attempts to synthesize the boll weevil pheromones (152; Z-X = CH,OH), (152; Z-X = CHO), and (152; E-X = CHO) by the biogenetic-type cyclization of ygeraniol (153; X = CH,OH) failed, but the corresponding ester (153; X = C0,Et) was easily cyclized and rearranged to yield the alcohols (152; X = CH20H), which readily gave the aldehydic pheromones (152; X = CHO).252
(152)
i-' (153)
Cycloheptanes.-3,6,6-Trimethylcyclohepta-2,4-dienone has been isolated from Piper nigrurn.y6 The iron carbonyl-promoted [3+ 41 cycloaddition of bromo-ketones to. 1,3-dienes provides a convenient way, via 2-oxyallyls, of synthesizing tropones and hence thujaplicins. The synthesis of nezukone (154; X = H)253has been reported from a,a,a',a'-tetrabromoacetone and 3-isopropylfuran. Similarly, from 2isopropylfuran, P-thujaplicin (154; X = OH) has been synthesized from the corresponding tropone by known methods, and a -thujaplicin synthesis requires isopropyl substitution in the ketone Karahanaenone (155) is a minor product from pyrolysis of the benzoate (156).'41 250
251 252
253 254
J. S. Mynderse and D. J. Faulkner, J. Amer. Chem. SOC.,1974, 96, 6771. P. Crews and E. Kho, J. Org. Chem., 1975, 40, 2568. R . H. Bedoukian and J. Wolinsky, J. Org. Chem., 1975,40, 2154. Y . Hayakawa, M. Sakai, and R . Noyori, Chem. Letters, 1975, 509. R . Noyori, S. Makino, T. Okita, and Y. Hayakawa, J. Org. Chem., 1975, 40, 806.
Terpenoids and Steroids
34
( 1 56)
(1 55)
( 154)
Measurement of activation energy and entropy has not distinguished between antara-antara Cope rearrangement and other concerted processes in the photochemical rearrangement of y-thujaplicin 0-methyl ether to the bicycloheptadienones (1 57) and (158).*" The hexatriene-cyclohexadiene disrotatory elec-
A
I
(1 57)
(158)
trocyclization of the enolate ion (159) of eucarvone to the bicyclic enolate anion (160) has been examined by 'H n.m.r., which indicates that (160) is slightly more stable than (159) but is more reactive, by a factor of two, than (159) to methylation.2shThe anion (159) reacts with oxygen to yield the 1,4-semidione (161)whereas the 1,4-semidione (162) is the only paramagnetic species detected by e.s.r. when the bicyclic acetoxy-ketone (163) is treated with base in DMS0;257these two 1,4semidiones are interconverted by oxidation-reduction and valence isomerization.
0'
245
2Th
257
R . Miyarnoto and T. Mukai, Nippon Kagaku Kaishi, 1974, 169 I. A. J. Bellamy, W. Crilly, J. Farthing, and G. M. Kellie, J.C.S. Perkin I. 1974, 241 7. G. A. Russell, R. t.Blankespoor, J . Mattox, P. R. Whittle, D. Symalla, and J. R. Dodd, J. Amer. Chem. Soc.. lY73. 96.7240.
35
Monoterpenoids
Photochemical irradiation of y,&epoxyeucarvone above 327 nm yields the diketone (164) and the bicyclic ketone (165) from the expected biradical; Lewis-acid rearrangement of y,6-epoxyeucarvone gives the diketone (164) and the lactone (166).258 0
( 164)
0
(165)
( 166)
6 Bicyclic Monoterpenoids
Bicycle[3,1,0]hexanes.-The reactions of isot huj-3 -one (24 ; 2R)* with N bromosuccinimide have been examined together with the oxidation of a -thujene by selenium dioxide and by chromium t r i o ~ i d e autoxidation ;~~~ of Q -thujene in the presence of copper abietate yields umbellulone ( 6 ; X = H).259Detection of the carbonium ion derived from neothujanol (Vol. 5, p. 30) is said to be consistent with observations with cis -bicyclo[3,1,O]hexan-3-01. 260 alcohol ( 167) has been isolated from Chrysanthemum japonense.26' The conversion of (&)-camphor into the substituted camphene (1 68) by BF,,Et,Ocatalysed addition of ethyl diazoacetate should prove useful in sesquiterpenoid synthesis; the isomeric camphene (169) is also obtained, but is converted quantitatively into (168) on treatment with zinc-acetic acid.262The luminescence spectra of
Bicyclo[2,2,l]heptanes.-NoJiguki
7H (0Et)CO Et
A
yH(OEt)CO,Et
H
(167)
(168)
(169)
solid camphorquinone have been clarified and defect phosphorescent emission is shown to be due to camphorquinone itself;263a revised model has been developed to interpret the absorption and emission spectroscopy of a-dicarbonyl The conformations of the endo-camphor-carbothioamides(170; R' = H, R2= Ph) have been examined spectroscopically and c.d. measurements interpreted using an octant rule for the N-C=S c h r o m o p h ~ r e ; in ~ "contrast ~ to (170; R' = H, R2= Ph), 25x z5y
260
Z6I 262 2h3
264 Z65
A. P. Alder and H. R. Wolf, Helv. Chim. Acta, 1975, 58, 1048. A. N. C. Catalan and J. A. Retamar, Anais Acad. brasil. Cienc., 1972, 44 (Suppl.), 360 (Chem. Abs., 1975, 83, 114 647); A. Cesar, N. Catalan, and J. A. Retamar, Essenze Deriu. Agrum., 1974, 44, 35 (Chem. Abs., 1975,82,73 195). P. A. Buttrick, C. M. Y. Holden, and D. Whittaker, J.C.S. Chem. Comm., 1975, 534. A. Matsuo, Y. Uchio, M. Nakayama, Y. Matsubara, and S. Hayashi, Tetrahedron Letters, 1974,4219. H. J. Lui, J. Org. Chem., 1975, 40, 2252. D. B. Larson, J. F. Arnett, A. Wahlborg, and S. P. McGlynn, J. Amer. Chem. SOC.,1974,96, 6507. J. F. Arnett, G. Newkome, W. L. Mattice, and S. P. McGlynn, J. Amer. Chem. SOC.,1974, 96, 4385. A. M. Lamazouttre and J. Sotiropoulos, Bull. SOC.chim. France, 1974, 2989, 2995 [Chem. Abs., 1975, 83. 10 422 incorrectly names (170; R1= Me, R2 = Ph)].
* Chemical Abstracts does not use the prefix 'iso' used in these Reports.
Terpenoids and Steroids
36
(170)
(170; R'= Me or Ph, R2= Ph) have the two dipoles, C=O and C=S, unfavourably aligned by steric constraints. Measurements on (+)-3-bromocamphor and on (-)-3bromocamphor-rr-sulphonic acid illustrate the use of Raman c.i.d. in determining absolute Further papers on 13Cn.m.r. not reported in Section 2 include chemical shifts of 1-substituted ~ a m p h e n e sand ~ ~ 4-substituted ~ tricyc1enes.268New evidence OR carbonium ion rearrangements related to camphene has been published; low-temperature 'H n.m.r. and 13C n.m.r. observations of the camphenehydro-cation (17 1)269 in S0,ClF-FS0,H and on a series of corresponding polymethyl tertiary 2-norbornyl have established that in the cation (17 1)
(171)
the 3-em-methyl group migrates almost exclusively (cf.Vol. 5, p. 33) in the simple Nametkin rearrangement and is accompanied by a second degenerate rearrangement which is the slower Wagner-Meerwein shift followed by a 6,2-hydride shift and a reverse Wagner-Meerwein shift (cf.Vol. 3, p. 59 for related work). The previously reported (Vol. 4, p. 44; cf. Vol. 5 , p. 3 1) lower stereospecificity reported by Stothers for the racemization of camphene with acid may be interpreted as involving less internal stabilization of (171) via C-2-C-6 bonding in the presence of the more nucleophilic solvent used. Rate constants have been recorded for migratory aptitudes for exo- and endo-3,2-methyl and 3,2-hydride shifts.270 The irreversible rearrangement of ( 171) to [( 172) and (173)] at -30 "C is also reported and relates to
( 172)
(173)
the well-known behaviour of many terpenoids, e.g. Q -terpineol, in fluorosulphonic acid, and to E-fenchene protonation (Vol. 3, p. 59).269Similarly, the cations derived 2hh 2h7 2hX 26y
270
L. D. Barron and A. D.Buckingham, J.C.S. Chem. Comm., 1974, 1028. D. G. Morris and A. M. Murray, J.C.S. Perkin II, 1975, 539. D. G. Morris and A. M. Murray, J.C.S. Perkin II, 1975, 734. R. Haseltine, E. Huang, K. Ranganayakulu, and T. S. Sorensen, Canad. J. Chem., 1975,53, 1056. R. P. Haseltine and T. S. Sorensen, Canad. J. Chem., 1975, 53, 1067.
Monoterpenoids
37
from 2-endo-phenylborneol and 2-phenylborn-2-ene are ( 174) below -40 "C, and, at -10 "C, the ring-opened ( 175).271Rearrangement of (176), synthesized from camphorquinone, to (177) in cold concentrated sulphuric acid probably proceeds via the ring-opened carbonium ion (1 78).272Acetolysis of the endo- and eno-ethynyl ethers (179) to yield (ISO), which is further transformed to the acetate (18l),exhibits a ratio k,,, : kendoof 5 :
Base-catalysed rearrangement of the anhydride (182) to the acid (183) involves C-8 methyl migration,274 and HBr elimination from em-2-bromoapobornanecarboxylic acid (184; R = H) proceeds by y-elimination whereas the corresponding methyl ester gives p-elimination in addition; other esters (184; R = Et, Pr, or Bu) give only p - e l i m i n a t i ~ nBrown . ~ ~ ~ has used flC1 and DCl addition
& 0
to bicyclic olefins, e.g. bornylene, camphene, and a-fenchene, to support the view that hydrochlorination cannot proceed via symmetrical non-classical carbonium ions but by trapping classical norbornyl cations prior to full e q ~ i l i b r a t i o n ;the ~~~ paper reviews the classical versus non-classical carbonium ion controversy. A more detailed examination of the reduction of bicyclo[2,2, llheptane sultones [e.g. (185)]with lithium aluminium hydride reveals the formation of the corresponding sulphinates, hydroxy-mercaptans, and sulphur-free alcohols progressively, with *7L 272
273 2'4
275
*7h
J. M. Coxon, A. J. Jones, C. P. Beeman, M. U. Hasan, and I. D. Rae, Tetrahedron Letters, 1975, 577. P. Wilder, jun. and W.-C. Hsieh, J. Org. Chem., 1975, 40, 717. A. Kergomard, J. C. Tardivat, and J. P. Vuillerme, Bull. SOC.chim. France, 1975, 297. J. H. Johnson, Diss. Abs. Internat. ( B ) , 1974, 35, 2657. L. Borowiecki and W. Wodzki, Roczniki Chem., 1975,49, 899. H. C. Brown and K.-T. Liu, J. Amer. Chem. Soc., 1975,97, 600.
Terpenoids and Steroids
38
(185)
neighbouring group alkoxide participation in desulph~rization.~’~ Ion-pair composition studies of complex metal hydrides in THF have been used to explain the stereoselectivity of reduction of camphor.278 Manganese(II1) acetate oxidation (cf. Vol. 3, p. 34) of camphene gives (186) as a 95 : 5 mixture by carboxymethyl radical insertion; no rearranged products were obtained, in contrast to p -pinene which gave Wagner-Meerwein products only, and no free-radical The E - and Z-isomers of (187) probably result from a non-concerted biradical intermediate formed by benzyne addition to camphene.28* Benzyl-lithium adds to the aminocamphor (1 88) exclusively from the exo-side whereas only the competing enolization reaction occurs with more sterically hindered ~ r g a n o m e t a l l i c s . ~ ~ ~
(1 86)
(187)
( 1 88)
Dye-sensitized photo-oxygenation of the norbornenes (189; X = Me) and (190; X = H), which have been synthesized cleanly from the acid (1 9 l), occurs in a one-step cyclic process via a dipolar transition state with n o evidence for a perepoxide intermediate; (189; X =Me) gives the alcohol (190; X = OH) from the corresponding allylically rearranged hydroperoxide along with some exo-alcohol and the ketone
X (189)
(190)
(191)
(192) which is a secondary photoproduct; (190; X = H ) gives the alcohol (189; X = CH20H), again by preferred endo-attack.282 Photochemical irradiation of (&)-camphor and 2,2-dirnethyl-3-phenyl-2H-azirine gives a 1 : 1 stereoisomer mixture (193) via the known cyclopentene aldehyde ( 194).283 277 27x 27y
2H0 2x1 2x2
2x3
J . Wolinsky and R. L. Marhenke, J. Org. Chem., 1975, 40, 1766. E. C. Ashby, F. R. Dobbs, and H. P. Nopkins, J. Amer. G e m . Soc., 1075, 97, 3158. M. E. N. Narnbudiry and G . S. K. Rao, Zndian J. Chern., 1975, 13. 6 3 3 . G. Mehta and B. P. Singh, Tetrahedron Letters, 1974, 4297. A. H. Beckett, N. T. Lan, and G . R . McDonough, Tetrahedron, 1975,31, 1557. C. W. Jefford and A. F. Boschung, Helv. Chim. Acta, 1974, 57, 2242. P. Claus. P. Gilgen, H.-J. Hansen, H. Heimgartner, B. Jackson, and H . Schmid, Helv. Chim. Acta, 1974, 57.2173.
Monoterpenoids
39
The full paper o n Money's conversion of camphor into 8-bromocamphor (195;
X = H) has appeared (Vol. 4, p. 100;Vol. 5 , p. 33); the rearranged dibromide {196) is a 2-Bornene reacts with N-bromosuccinimide to give the rearranged dibromide (197);285brornination with bromine in DMF and with Br,,Et,O is also Treatment of 9-bromocamphor (198; X = H) with Na-K alloy, folldwed by oxidation, yields the dihydrocarvone (16; 1S ) in high yield together with some of the cis-isomer (16; 1R).286The bromination of endo-3-bromocamphor with Br2ClS0,H gives (198; X = Br), whereas under the same conditions camphor undergoes .rr-bromination with partial racemization to give (198; X = Br) and the enantiomer in which the C-8 and (2-10 methyl groups are i n t e r ~ h a n g e d The . ~ ~ ~reaction between iodine azide and terpenoid alkenes has been extended to 2-bornene and camphene
(195)
( 196)
(197)
(198)
(cf. Vol. 4, p. 58) in MeCN at -35°C and conforms to the generally accepted mechanism for electrophilic addition. In contrast to the reaction of chlorine aeide with camphene (Vol. 3, p. 63), the major products are (199; X = N,, Y = CH21)and (5; X=CHI), with only a small quantity of (2'00) in a ratio of 15 : 1 0 : l.287
(199)
(20)
Ranganathan also reports iodine azide addition to camphene in MeCN at -10 "C to give two compounds;288 the minor component is ( 5 ; X=CHI) and the major component is probably (199; X = N,, Y = CH21)and not the proposed unstable (199; X = I, Y = CH2N,). 2-Bornene yields (201) and the endo-azide (202) as major products, together with a small amount of the isomeric e ~ o - a z i d e . ~ ' ~ 2x4 285
2H6 ZR7
Z8ti
C. R. Eck, R. W. Mills, and T. Money, J.C.S. Perkin I, 1975, 251. L. Borowiecki and M. Welniak, Roczniki Chem., 1975, 49, 559. D. P. G . Hamon, G. F. Taylor, and R. N. Young, Synthesis, 1975, 428. B. Bochwic, G. Kuswik, and B. Olejniczak, Tetrahedron, 1975,31, 1607. S. Ranganathan, D. Ranganathan, and A. K. Mehrotra, Tetrahedron Letters, 1973, 2265,
Terpenoids and Steroids
40
(201)
(202)
(203)
Stothers has published a more complete account of the homoenolization of fenchone (203; X = 0)with t-butyl [2H]alcohol and potassium t-butoxide at 185 "C (Vol. 4, p. 48) and shown that proton exchange occurs at the five @-positions;kinetics for the five exchange processes are reported.28y The condensation of 1,2-diamin0-4-nitrobenzenewith bornane-2,3-dione has been i n ~ e s t i g a t e d . ~Catalytic ~' hydrogenation of fenchone oxime (203; X = NOH) gives the imine (203; X = NH) exclusively, whereas camphor oxime gives only the em-amine (204); reduction with di-isobutylaluminium hydride yields predominantly heterocyclic secondary amines; thus (203; X = NOH) gives (205) as the major product together with (206) and (204) and its endo-isomer.2'1
(204)
(205)
(206)
In a continuing investigation of the reaction of Grignard reagents with thioketones (cf. Vol. 4, p. 52; Vol. 5 , p. 35), which is also reviewed,2y2thiocamphor and thiofenchone did not react with vinylic Grignard reagents.293 Thiocamphor, unlike camphor, condenses with m a l o n ~ n i t r i l e .Heating ~ ~ ~ the fenchone derivatives (203; X = NN=PPh,) with selenium in the presence of tri-n-butylamine gives the blue selenoketone (203; X = Se) which with (203; X = NN=PPh,), gives the sterically hindered alkene (207).2y5
(207)
Further papers of interest in the bicyclo[2,2, llheptane series include the hydrolysis of (-)-menthy1 and (+)-bornyl m a n d e l a t e ~ , ~dehalogenation ~' of 2,2dimethylnorbornane-3-spiro-l'-(2',2'-dibromocyclopropane),297 the sodium 2x') 2y0
2y1
2y2 2y3
2y4 295
29h zy7
A. L. Johnson, J. B. Stothers, and C. T. Tan, Canad. J . Chem., 1975, 53, 212. W. E. Hahn and Z . Cebulska, Roczniki Chem., 1975,49, 973. Y. Girault, M. Decouzon. and M. Azzaro, Bull. SOC.chim. France, 1975, 3 8 5 . D . Paquer, Bull. SOC.chim. France, 1975, 1439. M . Dagonneau. J. Organometallic Chem., 1974, 80, 1. Y. A. Sharanin and L. G. Sharanina, Khim. geterotsikl. Soedinenii, 1974, 1432. T. G. Back, D . H. R. Barton, M. R. Britten-Kelly, and F. S. Guziec, J.C.S. Chem. Comm., 1975, 539. S. Imaizumi, Y. Senda, J. lshiyama, and S. Aso, Nippon Kagaku Kaishi, 1975, 866. G. Mehta and S. K. Kapoor, J. Organometallic Chem., 1974, 80, 213.
Monoterpenoids
41
borohydride reduction of ketonorbornanecarboxylic acids [e.g. (19 1)],298the synthesis of camphor-en01 trimethylsilyl ether,299and the stereochemistry of 2chloro-2-nitrosobicyclo[2,2, l l h e p t a n e ~Two . ~ ~ further ~ papers on the condensation of phenols with ~ a m p h e n e ~and ~ ~with . ~ ~fenchene301 ' as a function of acidic catalysis have appeared (cf. Vol. 2, p. 47; Vol. 4, p. 44; Vol. 5 , p. 36).
Bicyclo[3,1,l]heptanes.-An 0-P-D-glycoside of (-)-cis-chrysanthenol (208) has been isolated from Dicoria c a n e s ~ e n and s ~ ~nopinone ~ from the essential oil of Piper r~igrurn.~~ The adsorptive separation of pinenes on Zeolites is The C-6 and C-7 13 C n.m.r. chemical shifts in bicyclo[3,1, llheptanes support other known conformational evidence and confirm that cis-pinane and cis-myrtanol(209; X = OH) have a bridged-boat conformation, that trans-myrtanol has a bridged-chair conformation, and that trans-2-pinanol and myrtenol (210; X = OH) have Y-shaped conformations; verbenone (21 l ; R',R2 = 0),and trans-verbenol(21 l ;R' = H, R2= OH) give anomalous results which may be due to a conjugation effect; the bridged-chair
conformation of nopinone (cf. Vol. 2, p. 49) is c ~ n f i r m e d . ~The ' ~ influence of conformation and methyl substituent groups on the double-bond reactivity of bicyclo[3,1, llheptenes has been calculated and correlated with rates of hydroborat i ~ n . ~Horeau's '~ method for determining absolute configuration applies to vicinal diols, e.g. to the four known isomeric pinane-2,3-diol~.~O~ The synthesis and structural data (X-ray and 'H n.m.r.) for (+)- and (-)-bis-(vpineny1)nickel have now been published; the corresponding halides are useful for resolving chiral pho~phines.~" and mercuric acetate in Synthetic routes to trans-verbanone are boiling methanol converts P-pinene into a 65 : 35 mixture of the myrtenol ether (212; R = Me) and the trans-pinocarveol ether (213; R = Me).309 E.-H. El-Semman and H. Geiger, Annalen, 1975, 75. G . C. Joshi and L. M. Pande, Synthesis. 1975,450. W. Minemathu and Y. Mathubara. Nippon Kagaku Kaishi, 1974, 2361. 301 I. S. Aul'chenko, T. F. Gavrilova, V. 1. Moskvichev, L. A. Kheifits, N. D. Antomova, and E B. Krymskaya, Zhur. org. Khim., 1975, 11, 738. 302 M. Miyakado, N. Ohno, H. Hirai, H. Yoshioka, and T. J. Mabry, Fhytochemistry, 1974, 13, 2881. 303 A. J. De Rossef and R. W. Nenzil, U.S. P. 3 851 006 (Chem. Abs., 1975,82,73 245); J. W. Priegnitz, I .s. P. 3 845 151 (Chem. Abs., 1975,82, 86451). 304 C. M. Holden and D. Whittaker. Org. Magn. Resonance, 1975, 7, 125. 305 H.-P. Gervais and X. Desalbres, J. Chim. phys., 1975, 72, 477 (Chem. Abs., 1975, 83, 96 245 is inaccurate). 30fr D. P. G. Hamon, R. A. Massy-Westropp, and T. Pipithakul, Austral. J. Chem., 1974,27,2199 (Chem. Abs., 1975, 82, 31 397 is unsatisfactory). 307 B. Henc, H. Pauling, G. Wilke, C. Kriiger, G . Schroth, and E. G . Hoffmann, Annalen, 1974, 1820 (cf. Vol. 3, p. 71). 3OX A. G. Fallis, Canad.J . Chem., 1975, 53, 1657. 3 0 ~A. Kergomard, J. C. Tardivat, and J. P. Vuillerme, Bull. SOC.chim. France, 1974, 2572. 2~
299
3(m
Terpenoids and Steroids
42 CH,OR
OAc
(212)
(213)
(214)
(215)
Acetolysls of the allylic ether (212; R = Me) gives cis-myrtanal(214), p-cymene, and the fenchane (2154, whereas (2 13; R = Me) gives (212; R = Ac), the fenchane (216), and p-cymene as major products.”’ Formation of the cis-(214) requires protonation of the double bond and allylic rearrangement; the stereospecific formation of (21 5) may be attributed to the trans nature of (213; R = Me).
OAc
(216)
Rate constants and activation energies for liquid- and gas-phase isomerization of been determined.310The activity of metal sulphate monohydrates in isomerizing a-pinene is correlated with the strength of co-ordination of the water of crystallization to the metal Pyrolysis of chrysanthanol acetate (217; R = Ac) gives citronella1 and the ( E ) -and (Z)-3,7-dimethylocta-1,6-dien-l-ol acetates in 20, 28, and 3% yields respectively; formation of the enol acetates is consistent with a biradical or a concerted pathway.312Further work directed towards C-l-C-7 bond pyrolysis of pinane derivatives shows C- 1-C-7 : C- 1-C-6 bond cleavage ratios of 4 : 5 1 for (2 17; R = Ac), 13 : 22 for (2 1 7; R = H),6 : 7 for (2 18; R = H),and 43 : 35 for (218; R = M e ) ; the expected acyclic and cyclic alcohol, aldehyde, and ketone pyrolysis products are obtained.313The ene reaction between P-pinene and methyl cy -pinene have
H
R
(2 17)
(2 18)
pyruvate gives an equimolar mixture of ( R ) - and (S)-(219).314 Three papers reporting pyrolysis over a Cu-Zn catalyst concern a - ~ i n e n e ,(-)-cis-pinane ~’~ (209; X = H),31hand myrtanol (209; X = OH),which gives (220) as the major product K. Rhstama and 0. Harva, Finn. Chem. Lefters, 1974, 132. R. Ohnishi, A. Matsui, and K . Tanabe, Bull. Chem. SOC.Japan, 1974, 47, 2595. j I 2 P. A. E. Cant, J. M. Coxon, and M. P. Hartshorn, Austral. J. Chem., 1975, 28, 391 (formula Y is misprinted). 3 1 2 P. A. E. Cant. J. M. Coxon, and M. P. Hartshorn, Austral. J. Chem., 1975, 28, 621. 3 1 4 H. K. Spencer and R. K. Hill, J. Org. Chem., 1975,40,2 17; H. K. Spencer, Diss. Abs. Internat. ( B ) ,1975, BIO
35,4843. 315
>Ih
Y. Matsubara, Y. Fujihara, and C. Hata, Jap. P. 32 104/1975 (Chem. Abs., 1975,83,97 640). Y . Fujihara, C. Hata, and Y. Matsubara, Yuki Gosei Kagaku Kyokai Shi, 1974, 32, 933.
Monoterpenoids
43
(65%) and (221) as the minor product ( 1 l'%) under optimum conditions;"' (-)perillaldehyde (34; R = CHO) is obtained similarly in 'high yield' (63%!) from (-)-myrtenol (210; X = OH) with 'negligible amounts of by-products' (at least four, 3 2 Y 0 ) . ~ l ~
(2 19)
(220)
(221)
The Beckmann rearrangement of pinocamphone oxime [(2S)-(222; X = NOH)] and isopinocamphone oxime [(2R)-(222; X = NOH)], using toIuene-p-sulphonyl chloride in aqueous acetone containing sodium hydroxide, is now r e p ~ r t e dl 8; ~both oximes adopt flattened-boat conformations, like the parent ketone [(2R)-(222; X = O)], according to 'H n.m.r. data, and rearrange to the lactams (223), which also adopt a flattened-boat conformation, with little evidence of nitrile formation.318 (Some 'H n.m.r. data for isopinocamphone oxime are misprinted.)
(222)
(223)
The effect of solvent and metal cation on the hydroboration of a - and P-pinenes in the presence of acetic acid is described"' and B,H,-LiBH, hydroboration has now unfortunately the discusbeen extended (cf. Vol. 3, p. 81) to 2,lO-epo~ypinane;~~' sion is poor and products are inadequately described.'20 Hydroalumination of a and P-pinene has been'reported with di-isobutylaluminium (cf. Vol. 5 , p. 38); with the less-hindered sabinene, hydroalumination is less stereo~pecific.~~' Heating (209; X = Al/J with carbon dioxide gives the acid (209; X = C0,H) (Chemical Abstracts omits the use of carbon dio~ide).~,' The free-radical chlorination of P-pinene gives myrtenyl chloride (2 10; X = Cl) as the major monochloride, with only a trace of other monochlorides (cf. a-pinene, Vol. 4, p. 58), and 4,lO-dichloropinene is the major dichloride with a small amount of 6,7-dichloromentha- 1,8-diene.322Free-radical insertion into P-pinene does not occur during manganese(m) acetate oxidation under acidic conditions, as reported However, in the presence of earlier (camphor is the only identified cupric salts, manganese(II1) acetate oxidative addition of cyclopentanone to Ppinene yields the ring-opened (224) together with some hydrogen-transfer product 317
31x
319
320 321
322
Y. Fujihara, C. Hata, and Y. Matsubara, Yukagaku, 1975, 24, 314. A. Zabza, C. Wawrzenczyk, and H. Kuczynski, Bull. Acad. polon. Sci., Sir. Sci. chim., 1974, 22, 855 (Chem. Abs., 1975,82, 73 196 has formulae IV and VI incorrect); cf Vol. 4, pp. 37, 51, 66. I. Uzarewicz and A. Uzarewicz, Roczniki Chem., 1975,49, 1113. E. Segiet-Kujawa and A. Uzarewicz, Roczniki Chem., 1974, 48, 2303. V. P. Yur'ev, A. V. Kuchin, T. 0.Yakovleva, and G. A. Tolstikov, Zhur. obshchei Khim., 1974,44,2084 (Chem. Abs., 1975,82, 16 936). 1. Uzarewicz and A. Uzarewicz, Roczniki Chem., 1975, 49, 409 (Chem. Abs., 1975, 83, 10 433 is incorrect).
44
Terpenoids and Steroids
(225; R = 2-ketocyclopentyl), which is the sole product of oxidation using di-t-butyl Similarly di-t-butyl peroxide-catalysed free-radical addition of tetraas hydrothiophen to P-pinene yields (225; R = tetrahydr0thiophen-2-y1),~~~ expected from the previously reported diethyl phosphite addition (Vol. 5, p. 40):
(225)
(224)
Zinc bromide isomerization of the epoxy-acetates (226; R = H or Me) gives predominantly the trans-keto-acetates (227; X = H or Me, Y = OAc) with retention of configuration,whereas thermal isomerization of (226; R = Me) gives the cis-(227; X = OAc, Y = Me) by a concerted mechanism; the less hindered (226; R = H) gives the less stable trans-(227; X = H, Y = OAc) owing to the above acid-catalysed-type mechanism competing effectively with the concerted mechanism.325 2a,3aEpoxypinane gives (228) in high yield with potassium t-butoxide in pyridine,”‘ and
OAc (226)
(227)
(228)
two further reports of the acid-catalysed cleavage of 2a,3cr-epoxypinane have been published; results with ethereal hydrogen chloride differ from those reported by Cocker, who used hydrogen bromide (Vol. 2, p. 41), with regard to bicyclo[2,2, llheptane products but may reflect differences in isolation proced u r e ~ ; ~ *homoallylic ’ rearrangements with amine-hydrofluoride complexes f avour the formation of p-menthane alcohols (62’/0).~*~ 2 p,3 P-Epoxypinane formation (in 87% yield) is reported again (cf. Vol. 3, p. 72), but unfortunately the Chemical Abstract is too brief to evaluate this The full paper on the photo-isomerization of cis-verbanone has been published (Vol. 4, p. 61); truns-verbanone gives the same products but in opposite proport i o n ~ . ~Direct, ” ~ and sensitized, photochemical rearrangement of 4-methylverbene (229) gives 3-methylenelimonene, from the corresponding triplet biradical, in J. Y. Lallemand. Tetrahedron Letters, 1975, 1217. R. Lalande, M.-J. Bourgeois, and B. Maillard, J. Heterocyclic Chem., 1975, 12,509. .32s Y. Bessiere. M. M. El Ga’ied, and G. Boussac, Canad. J. Chem., 1975, 53, 738. 3 2 6 2. Rykowski, K . Burak. and Z . Chabudzinski, Roczniki Chem., 1974, 48, 1619. R 2 7 U. Lipnicka and Z . Chabudzinski, Roczniki Chem.. 1975,49, 307. 32x G. A. Tolstikov, U. M. Dzhemilev, and V. P. Yur’ev in ‘Teor. Prakt. Zhidkofazn. Okisleniya (Mater. Vses. Konf. Okisleniyu, Org. Soedin. Zhidk. Faze)’, 2nd, 1973, ed. N. M. Emanuel, Nauka, Moscow, 1974, p. 280 (Chem. Abs., 1975, 83. 79 468). 32R 324
Monoterpenoids
45
(229)
contrast to the well known verbenone-chrysanthenone photochemical rearrangement (Vol. 5, p. 40).32y This disproportionation pathway may also account for the small quantity of isopiperitenone resulting from verbenone photorearrangement.””O Treatment of the alkenylpotassium (210; X = K) with dimethoxyfluoroborane and peroxide gives (+)-myrtenol (210; X = OH) contaminated with 2% of transpinocarveol(213; R = H).331Alkylation of the .rr-ally1 complex (230) occurs directly on carbon from the more hindered side of the molecule to yield (23 l).332Heating a or P-pinene with pentacarbonyliron yields the chiral ring skeletal enantiomers (232) and (233) by .rr-ally1 cyclobutane ring-expansion.”’
(23 1)
(232)
Further papers of interest in the bicyclo[3,1, llheptane series report acidcatalysed addition to p h e n ~ l s , ”dehalogenation ~ of 7,7-dimethylnorpinane-2-spirol’-(2’,2’-dibromocyclopropane),2’7 and a synthesis of 2-pinan01.”~
Bicyclo[4,1,0]heptanes.-The presence of (-)-car-3-en-2-one in Zieria aspalathoides has already been mentioned.s8 The enthalpies of combustion, formation, and isomerization of car-2-ene and car3-ene have been reported;’”$ the activation energy for the titanium-catalysed first-order isomerization of car-3-ene into car-4-ene and various menthadienes is 20 kcal mol-’ at 150-160 0C.336 Isomerization of car-3-ene over metal oxide catalysts varies substantially depending upon the metal catalyst other Russian work reports diene formation from the vapour-phase isomerization of car3-ene but this Reporter is unable to assess the significance of the work from Chemical Abstracts in the absence of the original paper.338 32V 330 33 I 332 333 334 33s
336
337 338
P. S. Mariano and D. Watson, J. Org. Chem., 1974, 39, 2774. W. F. Erman, J. Amer. Chem. SOC.,1967,89, 3828. G . Rauchschwalbe and M. Schlosser, Helv. Chim. Acfu, 1975, 58, 1094. B. M. Trost and L. Weber, J. Amer. Chem. Soc., 1975, 97, 1611 ; see also ref. 60. A. Stockis and E. Weissberger, J. Amer. Chem. SOC., 1975,97,4288. Stepan Chemical Co., Fr. P. 2 216 252 (Chem. A h . , 1975,83, 10 507). M. P. Kozina, V. A . Aleshina, G. L. Gal’chenko, E. F. Buinova, and I. I. Bardyshev, Vestsi Akad. Navuk Belarusk. S.S.R., Ser. khim. Navuk, 1975, No. 1, 14 (Chem. Abs., 1975,83, 27 363). V. A. Vyrodov, L. P. Meteshkina, andT. G. Goryunova, Gidroliz. Lesokhim. Promyshlennost.,1974, No. 7, 30 (Chem. Abs., 1975,82, 57 955). K. Tanabe, K. Shimazu, and H. Hattori, Chem. Letters, 1975, 507. V. V. Bazyl’chik, V. S. Shavyrin, V. N. Gusakov, and N. P. Polyakova, Zhur. priklad. Khim., 1975,48, 5 8 2 (Chem. Abs., 1Y75,83, 97 578).
46
Terpenoids and Steroids
Acetolysis of the tosylate (234) results in skeletal rearrangement to (235),3’” and 2a,3a-epoxycarane rearranges to (1S,4S)-mentha-2,8-dien- 1-01 in the presence of metatitanic cis- and trans-car-3-ene thioepoxides are readily available from
kH (234)
(235)
the corresponding oxygen analogues by treatment with (EtO),P(S)SH.’41 Autoxidation of cis- and trans-caranes gives mixtures of h y d r o p e r o ~ y c a r a n e sAn . ~ ~element ~ of novelty is introduced into carzne chemistry with the synthesis of trans-3,4iminocarane (236) via the iodocarbamate (237), which is derived easily from (+)car-3-ene; the stereochemistry of ring-opening has been examined.”’ The lithium aluminium hydride reduction of the lactam from the Beckmann rearrangement of
caranone oxime is reported.344 The effect of solvent and metal cation on the hydroboration of car-3-ene in the presence of acetic acid has been described.”” cisand trans-Caranes are now shown to be ring-opened with mercuric acetate followed by sodium borohydride treatment to yield S-lO% of the rn-menthanols (238) as well as the corresponding p-menthanols as previously reported (Vol. 3, p. 82).345
B . A . Arbuzov, Z . G. Isacva, and R. R. D’yakonova, Izuest. Akad. Nauk S.S.S.R., Ser. khim., 1975,972 (Chem. Abs.. 1975, 83. 07 588 is too brief and structure IV appears to be in error). SCM Corporation. Dutch P. 1 1 335/ 1973 (Chem. Abs., 1975,83,79 413); J. 0. Bledsoe, J. M, Derfer, and W. E. Johnson. Ger. Offen. 2 343618 (Chern. Abs., 1975, 83, 10515). 0.N. Nuretdinova, G. A . Bakaleinik. and B. A . Arbuzov, Izvest. Akad. Nauk S.S.S.R.,Ser. khim., 1975, 962 (Chem. Abs.. 1975.83, 97 586). I. I. Bardyshev, G. V. Deshchits, E. F. Buinova, and B. G. Udarov, Doklady Akad. Nauk Bolgursk. S.S.R., 1974, 18, 013 (Chem. Abs.. 1975, 82, 16937). A. Kubik. K . Piatkowski, and H. Kuczynski, Roczniki Chem., 1974, 48, 1225. C. Wawrzenczyk. A. Zabza, and H. Kuczynski, Bull. Acad. polon. Sci., Sir. Sci. chim., 1975, 23, 377. I. I. Bardyshev, E. F. Buinova, G. V. Deshchits, and V. V. Khmelnitskaya, Zhur. org. Khim., 1975,11, 1424.
lZi‘)
l4I
342
341 744
34s
47
Monoterpenoids 7 Furanoid and Pyranoid Monoterpenoids
The halogenated monoterpenoids (239) and (240) have been isolated from Chondrococciis hornernanni as meniioned in the section on halogenated monoter~ e n 0 i d s . The l ~ ~ antibiotic nectiapyrone (241) is unusual in being isolated from a
(239)
(240)
(241)
fungus, Gyrosfroma rni~souriense.~~" The monoterpenoid alkaloid enicoflavine ~ mixture which on standing (242), from Enicosternrna h y s s o p i f o l i ~ r nis, ~a~cis-trans yields gentianine (243), gentiocrucine (244), and crotonaldehyde; a third monoter~~~ penoid alkaloid (245) has now been isolated from Gentiana m a ~ r o p h y l l a .Nerol CHO
OHC
oxide (246) is present in Bulgarian rose The monoterpenoid lactone ' a degradation product of a aeginetolide (247), from Aeginetia i n d i ~ a , ~is~probably higher terpenoid, and the known structurally related dihydroactinidiolide has been detected in the supracaudal scent gland secretion of the red The four furanoid
monoterpenoids (248) and (249) have been isolated from Greek tobacco, Nicotiana tubacum, and their structures confirmed by synthesis (Scheme 12)352and by lanthanide shifts of the pure alcohols (250). 346
347 34x
349
350 35 1 352
M. S. R. Nair and S. T. Carey, Tetrahedron Letters, 1975, 1655. R . K. Chaudhuri, A. K. Singh, and S. Ghosal, Chem. and Ind., 1975, 127. Z. Xue and X. T. Liang, K'o Hsuch TungPuo, 1974,19,378 (Chem. Abs., 1975,82,13 964; the abstract is generally unsatisfactory; it does not name the plant species or the compound isolated, and in this Reporter's opinion the second author's name is incorrect). C. Ehret and P. Teisseire, Recherches, 1974,19,287. S. S. Dighe and A. B. Kulkarni, Indian J. Chem., 1974, 12, 413. E. S. Albone, Nature, 1975, 256, 575. S.-0. Almqvist, A. J. Aasen, J. R. Hlubucek, B. Kimland, and C. R. Enzell, Actu Chem. Scund., 1974, B28.528.
48
Terpenoids and Steroids
li
0
Reagents: i, m-chloroperbenzoic acid; ii, POC1,-py ; iii, Pt0,-H,.
Scheme 12
A new synthesis of the pyran (251), confusingly named linaloyl oxide, has been reported. 2,6-Dimethyl- 1,2-epoxyhept-5-ene gave (252) with 2-lithio- 1,3-dithian almost quantitatively, and boron trifluoride-catalysed cyclization to (253) readily led to (251).'53
8 Cannabinoids and other Phenolic Monoterpenoids
Reviews of the natural occurrence of ~ a n n a b i n o i d s ' ~and ~ of their therapeutic potential have been Four new cannabinoids are reported from Cannabis extracts, cannabifuran (254; R = CHMe,), dehydrocannabifuran [254; R = C(Me)=CH,], cannabichromanone (255 ) , and 2- k e t ~ - A ~ - T H c . ~ ~ ~
.;:"-- rtl.y-fi HO (254) \
353 354
35s
C5Hll
(255)
C5HI 1
S. Tori;, K. Uneyama, and M. Isihara, J. Org. Cbem., 1974, 39, 3645. L. Hanus and Z. Krejci, Acta Univ. Palackianae Olomuc., Fac. Med., 1974, 71, 239. R. A. Archer in 'Annual Reports in Medicinal Chemistry', ed. R. V. Heinzelman, Academic Press, New York, 1974, Vol. 9. J. Friedrich-Fiechtl and G. Spiteller, Tefrabedron, 1975, 31. 479.
49
Monoterpenoids
The phenolic hydroxy-group in THC's is important to their pharmacological and analgesic properties may be due to metabolism to 7-hydroxyderivatives (using normal monoterpenoid n ~ m b e r i n g ) . ~ ~ ' 1-Nor- 1p hydroxyhexahydrocannabinol is a potent analgesic.359 Cannabinol is a rapidly The activity of A6-THC- and formed metabolite of A'-THC and A6-THC in cannabidiol-containing polymers is r e p ~ r t e d . ~ ~ ' The X-ray crystal structure of Ah'-tetrahydrocannabinolicacid B is and one of the previously reported (Vol. 4, p. 75) dihydrobenzofurans from the citric acid-catalysed condensation of orcinol with menth-4-en-3-01 is shown to be (256) by X-ray analysis.363G.c.-m.s. assay of Ah'-THC-OMeallows the detection of 1 ng ml-* plasma of A'-THC.364 The mass spectral fragmentation of A'-THC, A6-THC, and some isomeric cannabinoids to the prominent m/e 231 ion has been examined.365 Miniaturized syntheses of 32 natural, or potentially natural, cannabinoids are reported in connection with their chromatographic analysis.366 H
(256)
The synthesis of 1-nor-A6-THC (Vol. 5 , p. 45) is accompanied by formation of 1~ o ~ - A ' - T H C ,and ~ ~ '8-nor-cannabinoids have been s y n t h e s i ~ e d . ~Razdan ~' et al. now report a one-step synthesis (cf. Vol. 5 , p. 44) of A'-THC from cis-chrysanthenol (208) and olivetol, which may parallel a biogenetic pinane route to A'-THC; no A6-THC is formed.36s The stereochemistry of cannabielsoin (257) (cf.Vol. 5 , p. 44) is now confirmed by synthesis from the epoxide (258); the 8 P-hydroxymethyl-A'THC is similarly synthesized from the corresponding epoxide (259) by cleavage of
(257) (258) (259) D. B. Uliss, H. C. Dalzell, G. R. Handrick, J. F. Howes, and R. K. Razdan, J. Medicin. Chem., 1975,18, 213. 3sH R. S. Wilson and E. L. May, J. Medicin. Chem., 1975, 18, 700. 35y R. S. Wilson and E. L. May, 168th A.C.S. Meeting, September 1974, Abstracts MEDI, No. 1 I . 3h0 N. K. McCallum, B. Yagen, S. Levy, and R. Mechoulam, Experientia, 1975, 31, 520. B.-Z. Weiner and A. Zilkha, European J. Med. Chem.-Chimica Therapeutica, 1975, 10, 79. 362 E. Rosenqvist and T. Ottersen, Acta Chem. Scand., 1975, B29,379. 3*3 E. F. Serantoni, L. Merlini, R. Mongiorgi, and L. R. di Sanseverino, Gazzetta, 1974, 104, 1153. 364 J. J. Rosenfeld, B. Bowins, J. Roberts, J. Perkins, and A. S. Macpherson, Analyt. Chem., 1974,46,2232. 365 J. K. Terlouw, W. Heerma, P. C. Burgers, G. Dijkstra, A. Boon, H. F. Kramer, and C. A. Salemink, Tetrahedron, 1974,30, 4243. 3~ L. Crombie and W. M. L. Crombie, Phytochemistry, 1975, 14, 213. 367 P. E. Bender and B. Loev, 168th A.C.S. Meeting, September 1974, Abstracts ORGN, No. 86. I h XR. K. Razdan, G. R. Handrick, and H. C. Dalzell, Experientia, 1975, 31, 16.
-7s7
Terpenoids and Steroids
50
the oxiran at the more hindered New syntheses of the A'-THC metabolites 7hydroxy-A'-THC, 6a-hydroxy-A1-THC, and 6 P-hydroxy-A'-THC are reported, and the corresponding dihydroxy-compounds have been synthesized for the first time.370Base-induced epoxide-allylic alcohol rearrangement of the epoxide (260) to [(261) and (262)] is controlled by the steric bulk of the base; 1ithium-N-
(260)
(26 1)
(262)
isopropylaniline favours (262), whereas lithium-Me,SiNHBu' favours (26 1). Thermodynamically controlled SN'isomerization of (261) with hydrogen bromideacetic acid, acetolysis, and reduction gives 7-hydroxy-A'-THC (cf. Vol. 4, p. 72); a similar reaction sequence starting with A6-THC gives the C-6-hydroxy-analogues of (261) which, via osmium tetroxide oxidation, leads to 6P,7-dihydro~y-A'-THC.'~' The synthesis of aza-THC (263) and its activity have been (cf. Vol. 4, p. 74; VOl. 5 , p. 43). 1
(263)
The stability and kinetics of degradation of A'-THC at pH 1have been examined; a mixture of A6-THC, (264), (265), and an unidentified precursor of cannibinol was
(264)
(265)
Further work on the pyrolysis of cannabidiol (266) (cf. Vol. 5 , p. 44) yielded A'-THC and cannabinol, and two products tentatively identified as (267) and (268) .373 w 770
371
372
D. B. Uliss, R. K. Razdan, and H. C. Dalzell, J. Amer. Chem. Soc., 1974,96, 7372. C. G. Pitt, M. S. Fowler, S. Sathe. S . C. Srivastava, and D . L. Williams, J. Amer. Chem. SOC.,1975,97, 3708. N. Castognoli. jun., M. S. Cushman, and L. K. Low, 168th A.C.S. Meeting, September 1974, Abstracts MEDI, No. 8. E. R. Garrett and J . Tsau, J. Pharm. Sci., 1974,63, 1563 (formula IV is misprinted). F. J . E. M. Kuppers, C. A. L. Bercht, C. A. Salemink, R. J. J. C. Lousberg, J. K. Terlouw, and W. Heerma, J. Chromatog., 1Y75. 108, 375; Tetrahedron, 1975,31, 1513.
51
Monoterperioids
(266)
(267)
(268)
Two further papers report lithium-ammonia reductive cleavage of some A3-THCand selenium dioxide oxidation of A'-THC and A6-THC.375In related the latter, it is shown that A'-THC yields oxidation products predominantly from attack at C-6, whereas A6-THCis oxidized preferentially at the exocyclic allylic C-7 methyl group, to yield, for example, (269). CHO
374
375
R. K. Razdan, H. G. Pars, W. R. Thompson, and F. E. Granchelli, Tetrahedron Letters, 1974,4315. S. Inayama, A. Sawa, and E. Hosoya, Chem. and Pharm. Bull. (Japan), 1974,22, 1519.
2 Sesquiterpenoids BY N. DARBY AND T. MONEY
1 Farnesanes
-
Two new nerolidol derivatives (1) and (2) have been isolated from Anthemis austriaca Lacq. and a similar compound (3) has been identified as a metabolite of
A/
(3)
Tanacetum aucherianum.' A structurally related sesquiterpenoid, 8-hydroxybrickellol (5), has been synthesized* from an acetylenic precursor (4)by the route outlined in Scheme 1. OH
HOCH,C=CHC-CH Me
I a HOCH,C=CH-C-C-C-CH=CH, I I Me
(4)
Me
liii
(5) Reagents: i, EtMgBr; ii, MeCOCH =CH,; iii, LiAlH,; iv, MnO,; v, Me,C=CHCH,MgBr.
Scheme 1
trans-a-Farnesene (9) and p-farnesene (10) have been synthesized3by a route in which diethflaluminum 2,2,6,6-tetramethylpiperidide (DATMP)is used to achieve regio- and stereo-selective conversion of oxiran intermediates, (7a) and (7b), into diols (8a) and (8b) (Scheme 2). A recent report describes an elegant stereoselective * F. Bohlmann, C. Zdero, and H. Schwarz, Chem. Ber., 1974, 107, 1074. F. Bohlmann and H.-J. Bax, Chem. Ber., 1974,107, 1773. 'S. Tanaka, A. Yasuda, H . Yamamoto, and H. Nozaki, J . Amer. Chem. Soc., 1Y75,97, 3 2 5 2 .
.2
52
53
Sesquiterpen oids
Reagents: i, [VO(acac),]-Bu'OH; ii, Me,SiCI-(Me,Si),NH; MeOH-H,O; v, PBr,; vi, Zn.
iii, DATMP-C,H,,
0 "C; iv, KF-
Scheme 2
synthesis of a-sinensal (18), one of the sesquiterpenoid constituents of Chinese orange oil (Citrus sinensis L.).4 One of the key steps in the synthetic sequence (Scheme 3) involves Cope rearrangement of the aldehyde intermediate (15) and although this provides a mixture of a-sinensal(l8) and the corresponding 2-isomer (16) quantitative conversion of the latter into the more stable E-isomer can be achieved by treatment with SOz. It is suggested that this novel isomerization proceeds via the intermediate (17). The isolation and structural elucidation of 12-acetoxy- 1 0 , l l-dehydrongaione (19)5(Stilpnophyturn linifuliurn),freelingnite (20)6 (Eremophila freelingi), and the lactones (21)-(25)7 (Athanasia spp.) have been described. Full details of the G. Buchi and H. Wuest, J. Amer. Chem. Soc., 1974,96, 7573. F. Bohlmann and C. Zdero, Chem. Ber., 1974,107, 1071. 6 D. W. Knight and G. Pattenden, Tetrahedron Letters, 1975, 1115. F. Bohlmann and M. Grenz, Chem. Ber., 1975,108,357. 5
Terpenoids and Steroids
54
OCH
(16)
,
(18)
(17)
Reagents: i, NaNH,; ii, CH, =CHMgBr; iii, PBr,; iv, Me,NCH,CN-KOBu'; v, CuSO,,SH,OEtOH; vi, xylene, A ; vii, SO,.
Scheme 3
55
Sesquiterperzoids
0
(23) OAc
(25)
previously reported* synthesis of freelingyne (26), a congener of freelingnite (20), are provided in a recent publication.' The absolute configuration of (+)-davanone (27), a major component of the essential oil of Arternisia pullens, has been determined by the collaborative efforts of two research groups." Related investigations have resulted in the isolation, structural elucidation, and synthesis of various minor
(27)
(28)
components of the oil. These include davana ether (28),l' the isomeric C,, davanafurans ( 3 O a - ~ l )and , ~ ~a C, nor-sesquiterpenoid (32). l 3 Synthetic routes to the davanafurans (30a-d)12 and (32)13 from linalyl oxide (29) (-)-linalyl acetate (31) are shown in Schemes 4 and 5.
(30a-d) Reagents: i, O,, -70°C; ii, Zn-HOAc; iii,
oLi
; iv, LiAlH,-AlCl,.
Scheme 4 T. Money, in 'Terpenoids and Steroids', ed. K. H. Overton (Specialist Periodical Reports), The Chemical Society, London, 1975, Vol. 5, p. 46. D. W. Knight and G. Pattenden, J.C.S. Perkin I, 1975,641. 10 A. F. Thomas, W. Thommen, B. Willhalm, E. W. Hagaman, and E. Wenkert, Helu. Chim. A m , 1974, 57, 2055. 1 1 A. F. Thomas and R. Dubini, Helu. Chim. Actu, 1974,57, 2076; cf. A. F. Thomas and G. Pitton, ibid., 1971,54,1890. 12 A. F. Thomas and R. Dubini, Helu. Chim. Actu, 1974, 57, 2066. 13 A. F. Thomas and M. Ozainne, Helu. Chim. Actu, 1974, 57, 2062. 8
Terpenoids and Steroids
56
'CHO
1
iii
(32) Reagents: i, S e O , ; ii, Na,CO,-H,O-MeOH,
pH 12; iii, MeMgI; iv, CrO,.
Scheme 5
Further studies on the biological interconversion of trans7trans-farnesol(33) and cis,trans-farnesol(34) have shown that in a fungal system (H. s a t i u ~ mthe ) ~ 1-pro-R ~ hydrogens are exchanged, whereas in a plant system" (cell-free extracts of Androg-
2 Bisabolanes
Two new sesquiterpenoids isolated from the roots of Ptilostemon chamaepeuce have been assigned structures (38) and (39) on the basis of their spectroscopic properties and chemical behaviour. l8 The isomeric y-bisabolenes (40a and b), postulated l4
l5 Ih
I*
K. Imai and S. Marumo, Tetrahedron Letters, 1974, 4401. K. H. Overton and F. M. Roberts, J.C.S. Chem. Comm., 1974, 385; Phytochemistry, 1974,13,2741. R. C. Jennings, K . J. Judy, and D . A. Schooley, J.C.S. Chem. Comm., 1975,21. M . G. Peter and K. H. Dahm, Helv. Chim. Acta, 1975, 58, 1037. F. Bohlrnann. N. Rao, and H. Schwarz, Chem. Ber., 1974, 107,650.
57
Sesquiterpenoids
(38) R (39) R
=
=
(40a and b)
CH20H CHO
intermediates in sesquiterpenoid biosynthesis, have been synthesized by an elegant route (Scheme 6) in which the tetrasubstituted double-bond system was constructed
(404
(40b)
Reagents: i, CH, =CMeMgBr; ii, EtOCH=CH,-Hg(OAc),;
iii, Ph,P=CMe,.
Scheme 6
by Claisen rearrangement of an intermediate vinyl ether (4 1 ) . 1 9 Both ( E ) - y bisabolene (40a) and the corresponding Z-isomer (40b) were eventually produced but the difficult task of assigning E or 2 configurations to the separated stereoisomers remains to be accomplished. A simple and highly stereoselective route (Scheme 7) to ap-unsaturated aldehydes having the E configuration has been used in a new
+
PhS02CH
'
Me
' 0
PhSO, CH
CHO (42) Reagents: i, Bu"Li; ii, HOAc-H,O; iii, 10% aq. Triton B.
Scheme 7 lY
D. J. Faulkner, and L. E. Wolinsky, J. Org. Chem., 1975,40, 389
\
0
58
Terpenoids a n d Steroids
*
synthesis of ( )-nuciferal (42).*' The structurally related sesquiterpenoids a bisabolol-3-one (43) and deodarone (44) have been synthesized21 (Scheme 8) and a related compound (45) has been isolated from Artemisia molinieu Gueze1.22
bshAp
0
\
C0,Me
OH
1
iv
0
(43)
(44) Reagents: MeCH=CHCO,H-C,,H,Li; H 0-Me CO.
ii, MeOH-H';
iii, MeMgI; iv, 0 - 0 , - H + ; v, HCI0,-
Scheme 8
(45)
As part of a general investigation of terpenoid synthesis from isoprene units it has been shown that condensation of limonene (46) with senecioyl chloride in the presence of stannic chloride, followed by dehydrochlorination, provides a new simple synthetic route to a mixture of cis- (47) and trans-atlantones (48).23nUsing acetyl chloride instead of senecioyl chloride in the synthetic sequence provides a C,, trisnor-sesquiterpenoid (49) which co-occurs with trans-atlantone in the essential oil of Cedrus a t l a n t i ~ a . ~ ~ '
(47)
20
22
23
R
= CH=CMe,
(48)R = CH=CMe, (49)R = Me
K . Kondo and D. Tunemoto, Tetrahedron Letters, 1975, 1007. Y. Gopichand and K. K. Chakravarti, Tetrahedron Letters, 1974, 3851. F. Bohlmann and C. Zdero, Chem. Ber., 1975, 108, 2153. ( a ) D. R. Adams, S. P. Bhatnagar, R. C. Cookson, and R. M. Tuddenham, Tetrahedron Letters, 1974, 3197; ( b ) ibid.,p. 3903.
Sesquiterpenoids
59
The possible involvement of isomeric bisabolols in sesquiterpenoid biosynthesis has been in~estigated.’~
3 Sesquicarane Elvirol(5 l),a metabolite of Elviru bifloru, represents a structural type which could be derived in nature by ring cleavage of sesquicarane precursor [cf. (50)]. Recent synthetic routes2s,26to this sesquiterpenoid are oulined in Schemes 9 and 10.
9
c v-vii -- CHO
(51) Reagents: i, A ; ii, B,H,; iii, H,O,; iv, Ph,PBr,; v, Ph,P=CHOMe; vi, H , O + ; vii, Ph,P=CMe,.
Scheme 9
liii
Q2@ (51) Reagents: i, PhLi-Et,O; ii, MeCOCH,CH,CH =CMe,; iii, Na-NH,-Et,O-EtOH; DMF.
Scheme 10
24
25
2h
W. Knoll and C. Tamm, Helv. Chim. Actu, 1975, 58, 1162. F. Bohlmann and D. Kornig, Chem. Ber., 1974, 107,1777. N. R. Dennison, R. N. Mirrington, and A. D. Stuart, Austral. J. Chem., 1975, 28, 1339.
iv, NaSEt-
Terpenoids and Steroids
60
4 Sesquipinane (Bergamotane), Sesquifenchane, Sesquicamphane, Santalane An alternative synthesis of (f)-sesquifenchene (53) has been described2’ in which stereoselective methylation of an appropriate bicyclo[2,2, llheptane derivative (52) is the key step (Scheme 11). Isoepicampherenol (54), a sesquiterpenoid whose MeO,C,,H
“
7-0 O
d
O
I
(52)
SO,C,H,Me
Reagents: i, HBr; ii,
O\ / M e
lo”n
, TsOH-C,H,;
S02C,H,Me
iii, LiNPrl-THF-MeI;
d
iv-vii
I
iv, Bu,SnH-Me,-
C(CN)N =NC(CN)Me,; v, LiAIH,; vi, TsC1-py; vii, NaI-Me,CO; viii, MeC,H,S0,Na; ix, BuLi; x, Me,C=CHCH,Br; xi, Li-EtNH,; xii, HOAc-H,O; xiii, Ph,P=CH,-DMSO.
Scheme 11
natural occurrence was recently predicted,28has been isolated from leaves and twigs of Verbesina rupestris.’’ Synthetic routes to the racemic and optically active forms of this compound have been previously The structure and relative configuration of clausantalene ( 5 3 , a sesquiterpenoid isolated from the roots of Clausena indica Oliv., have been determined by the direct X-ray method.31
27
28 29 30
P. A. Grieco and Y. Masaki, J. Org. Chem., 1075,40, 150, G. L. Hodgson, D. F. MacSweeney, and T. Money, J.C.S. Perkin I, 1973, 21 13. V. G. S. Box and W. R. Chan, Phytochemistry, 1975,14, 583. C. K.Eck, G. L. Hodgson, D. F. MacSweeney, R. W. Mills, and T. Money, J.C.S.Perkin I, 1974,1938. B. S. Joshi, D. H. Gawad, and D. J. Williams, Experientia, 1975, 31, 138.
61
Sesquiterpenoids 5 Acorane, Carotane, Cedrane
The identification of acoradiene (58) as a minor by-product in the conversion of carotol (56) into daucene (57) has that the absolute configuration of this compound is enantiomeric to that previously assigned. Stereoselective routes from
(57)
(56)
(58)
R-pulegone (59) to y-acoradiene (63), 8-acoradiene (65), and the enantiomers (67) and (68) of acorone and isoacorone have been described (Scheme 12).33 An idteresting feature of the synthetic sequence is the use of stannic chloride to improve
Pi
Br (59) t
0
A (67)
A (68)
Reagents: i, Br,-Et,O; ii, NaOEt-Et,O; iii, 0,, -96°C; iv, (CH20H),-H+; v, LiAlH,; vi, H,O-H+; vii, DCC; viii, CH,=CMe-CH =CH,-SnCl,; ix, LiPr'; x, SOC1,-py; xi, B,H,; xii, H,O,-NaOH; xiii, CrO,.
Scheme 12 32 33
L, H. Zalkow and M. G. Clower, Tetrahedron Letters, 1975,75. J. N. Marx and L. R. Norman, J. Org. Chem., 1975,40, 1602.
62
Terpenoids and Steroids
the regiospecificity of the Diels-Alder spiroannelation reaction [(60)+ (61)]. (*)Acorenone-B (71) has been synthesized3" by the route shown in Scheme 13. In this case spiroannellation was accomplished by treating the monocyclic dienol (70) with formic acid.
+
o
(6%
*
p
A
(70)
p
OCHO
1
iii--vi
(71) Reagents: i, CH,=CH(CH,),MgBr; ii, 5 5 % H C 0 , H ; iii, H+-H,O; iv, CrO,; v, H,-Pt; vi, K0Bu'-MeI; vii, Br,-CH,Cl,, 0 "C, LiBr-Li,CO,-DMF.
Scheme 13
The introduction of hydroxy and carbonyl groups at unactivated positions of terpenoids is usually accomplished by rnicro-organi~ms.~~ However, recent studies have shown that rabbits can hydroxylate cedrol (72) at a remote unactivated methylene group to provide a mixture of products (73a and b) and (74a and b).36 Patchoulol (298) has also been functionalized iir a similar fashion (cf.p. 90).
H (72)
(73a and b)
(74a and b)
6 Cuparane, Laurane, Trichothecane, Cyclotrichothecane (*)-Cuparene (76) has been synthesized by a simple route (Scheme 14) in which the five-membered ring is constructed by photocyclization of an appropriate thioketone (75y7 34
35
3h
37
H. Wolf and M. Kolleck, Tetrahedron Letters, 1975, 45 1. Cf. G. S. Fonken and R. A. Johnson, 'Chemical Oxidations with Microorganisms', Marcel Decker, New York, 1972. L. Bang and G. Ourisson, Tetrahedron Letters, 1975, 1881. P. de Mayo and R. Suan, J.C.S. Perkin I, 1974, 2559.
63
Sesquiterpenoids
1
iv-vi
.O
(76) Reagents: i, NaNH,-Pr"1; ii, H,S-HC1, -63 "C; iii, h v ; iv, Hg(OAc),-HOAc; v, BH,-THF; vi, Cr0,-H+ : vii, NaNH,-MeI; viii, (CH,OH),-NH,NH,-Na.
Scheme 14
The isolation of R-(-)-cuparene (77), and R-(-)-S-cuparenol (78) from the liverwort, Bazzania pompeana, is consistent with the general tendency of this type of plant to produce sesquiterpenoids enantiomeric with those found in higher plants38
(77) R (78) R
= =
H OH
(cf. p. 89). Co-occurring with these compounds are the tricyclic hydrocarbons a -pompene (79) and p -pompene (80), whose revised structure^^^ are now identical with those previously assigned to a- and P-barbatene4' (syn. isogymnomitrene and gymn~rnifrene~~). Gymnomitrol (8 l), the original member of this structural class (cyclotrichothecane), is a major metabolite of the liverwort, Gymnomitrion obtusum (Lindb.) Pears., and a recent report41provides a full account of the spectroscopic and chemical evidence used in the determination of its structure and absolute configuration. In addition, minor components (79), (go), and (82)-(86) of the liverwort extract have been shown to be components of the same structural type.4'
(80) R
R (82) R (81) 3x
3y 40
41
= = =
H OH OAC
A. Matsuo, M. Nakayama, T. Medda, Y. Noda, and S. Hayashi, Phytochemistry, 1975,14, 1037. A. Matsuo, H. Nozaki, M. Nakayama, Y. Kushi, and S. Hayashi, Tetrahedron Letters, 1975, 241. N. H. Anderson, C. R. Costin, C. M. Kramer, Y. Ohta, and S. Huneck, Phytochemistry, 1973,12,2709; cf. ref. 8, p. 53. J. D. Connolly, A. E. Harding, and I. M. S. Harding, J.C.S. Perkin I, 1974, 2487 and references cited therein.
moA Terpenoids and Steroids
64
O2J-J
-0
(83) R (84) R (85) R
= =
H, H,P-OAc H,c~-OAC
A cell-free extract obtained from T. roseurn has been shown to convert trans,transfarnesyl pyrophosphate into trichodiene (87), the bicyclic hydrocarbon precursor of the trichothecane sesquiterpenoid~.~~ Related studies in this area have also been Chemical and spectroscopic evidence has been reported which is consistent with the structure assigned to vetisporin (88), a new antibiotic isolated from Verticimonosporium d i f i ~ c t u r n . ~ ~
7 Chamigrane etc. Interest continues in the isolation and structural elucidation of halogenated sesquiterpenoids produced by marine organisms (e.g.algae). Many of these compounds are chamigrane derivatives and new members of this group include prepacifenol epoxide (89)46 from Aplysia cafifornica, elatol (90)47 from Laurencia efata, nidifidienol (91)48from Laurencia nidifica, and the compounds (92) and (93)49from
Bro g+/+
OH
(J& OH
42 43 44
45 46 47
4x
4v
(89) (90) R. Evans and J . R. Hanson, J.C.S. Chem. Comm., 1975, 231. B. Muller, R. Achini, and C. Tamm, Helv. Chim. Acta, 1975, 58, 471. B. Muller and C. Tamrn, Helu. Chim. Acta, 1975, 58, 483. H. Minato, T. Katayama, and K . Tori, TetrahedronLetters, 1975, 2579. D. J. Faulkner, M. 0. Stallard, and C. Ireland, Tetrahedron Letters, 1974, 3571. J. J . Sims, G. H. Y . Lin, and R. M. Wing, Tetrahedron Letters, 1974, 3487. S. M. Waraszkiewicz and K. L. Erickson, Tetrahedron Letters, 1975, 281. B. M. Howard and W. Fenical, TetrahedronLetters, 1975, 1687.
(91)
CI
65
Sesquiterpenoids
(92)
(93)
various Laurencia species. Related studies in this area have revealed the presence of perforenone A (95), perforenone B (96), and perforatone (97) in ether extracts of sun-dried Laurencia p e ~ f o r a t a These . ~ ~ compounds represent a new structural type which may be derived in nature by rearrangement of an enzyme-bound chamigrane precursor (94).
%
enzyG\
-enzyme@
e/
----+
(94)
1
(95) R (96) R 0,
=
=
H C1
A"
I
I
(97)
8 Amorphane, Cadinane, Copacamphane, Sativane, etc. Sesquiterpenoids containing isocyanide or isothiocyanate groups are uncommon (cf. pp. 87 and 89) and obviously present an interesting biosynthetic problem. The co-occurrence of amorphane derivatives (98)-( 100) containing isocyanide, isothiocyanate, and formamide groups in a marine sponge (Hulichondria SP.)~'(cf.p. 9 3 ) provides indirect support for the proposed5* biosynthetic relationship between isocyanide and formamide groups. Further research on the metabolites produced by
AH
(98) R (99) R (100) R
51 52
= = =
NC NCS NHCHO
A (101) R = OH (102) R = OMe (103) R = H
A. G. Gonztilez, J. M. Aguiar, J. D. Martin, and M. Norte, Tetrahedron Letters, 1975, 2499. B. J. Burreson, C. Christophersen, and P. J. Scheuer, 1.Amer. Chem. Soc.,1975,97,201. Cf.H. Achenbach and H. Grisebach, Z. Naturforsch., 1965,20b, 137.
Terpenoids and Steroids
66
cotton plants (Gossypium spp.) infected with Verticillium albo-atrum has revealed the presence of hemigossypol (101), 6-methoxyhemigossypol (102), and 6deoxyhemigossypol (103).53 Related studies have also shown that (101) and (102) are metabolites of the healthy plants where they co-occur with the dimeric sesquiterpenoids gossypol (104), 6-methoxygossypol (lOS), and 6,6'-dimethoxygossypol ( 106).54 Re-appraisal of the spectroscopic properties of lacinilene C, a metabolite of frost-killed cotton bracts, has resulted in a revised structure (107) for this compound. 55 CHO OH
OH
CHO
R' = R 2 = OH R' = OMe, R2 = OH R' = R2 = OMe In a new stereospecific synthesis of (*)-cyclosativene (1 10) construction of the tetracyclic framework is accomplished by alkyne capture of the homoallylic cation derived from the norbornene derivative (109)? An outline of the synthetic route is shown in Scheme 15. (104) (105) (106)
88 ,o,a,,,,
-
\
x, xi
0
3 /
tviii --&oTs
tix-
I
OCH,CF,
\\
(109)
xiii-xvi+
OAc
(1 10) Reagents: i, CH, =CHCH,OH-K,CO,, 0 "C; ii, LiAIH,; iii, Ph,PBr,; iv, LiCFCH-NH,v, MeLi; vi, Na-NH,; vii, TsCl; viii, CF,CO,H-py; ix, CH,CH,NH,-DMSO; H+-H,O; X, NaOMe-HC0,Et; xi, H+-Ac,O; xii, LiCuMe,; xiii, LiAlH,; xiv, MsC1-py; xv, K0Bu'-Bu'OH; xvi, H,-Pd.
Scheme 15 A. A. Bell, R. D. Stipanovic, C. R. Howell, and P. Fryxell, Phytochemistry, 1975, 14, 225. 54 R. D. Stipanovic, A. A. Bell, M. E. Mace. and C. R. Howell, Phytochemistry. 197.5. 14. 1077. ss R. D. Stipanovic. P. J. Wakelyn. and A. A. Bell, Phytochemistry. 197.5. 14. 1041. 5h S. W. Baldwin and J. C. Tomesch. Tetrahedron Letters, 1075, 1055. 53
67
Sesquiterpenoids
The structure and stereochemistry of cis-sativenedioI(l11) and trans-sativenediol (112) have been establisheds7 by n.m.r. spectroscopy and, in the case of the cis-isomer, by conversion into the diethyl acetal (1 13) of helminthosporal (1 15). Both diols co-occur with prehelminthosporol (1 14), helminthosporal (1 15), and helminthosporol(ll6) in Helminthosporium sativum and Cochliobolus seturiae and a definitive statement on the possible biosynthetic relationship between these compounds is expected in the near future. Two related sesquiterpenoids, (1 17)and (1IS), having the isosativane skeleton have also been identified as metabolites of H. s a t i ~ u m The . ~ ~ structures assigned to these compounds are based on chemical correlation with cis-sativenediol (1 11) (cf. Scheme 16) and it is reasonable to
(111) R' (112) R'
=
=
OH,R2 = H H , R Z= OH
(113) R' (114) R'
= =
R2 = OEt OH,R2 = H
(115) R = CHO (116) R = C H 2 0 H
(118) R = H (119) R = AC
( 1 17)
1
1
iii
120)
(121)
Reagents: i, HOAc; ii, H,O-NaOH; iii, POC1,-py.
Scheme 16
presume that a similar rearrangement process occurs during their biosynthesis. cis-Sativenediol(111) is a plant growth promoter5' with gibberellin-like activity and it is interesting to note that (~)-14-norhelminthosporic acid (122) and the related s7
5x
M. Nukina, H. Hattori, and S. Marumo, J. Amer. Chem. SOC., 1075,97. 2542. F. Dorn and D. Arigoni. Experienria. 1Y75, 31. 7 5 3 .
68
Terpenoids and Steroids
(122) R (123) R
= =
(124) R
C02H CHO
(125) R
= =
CO,H CHO
nor-sesquiterpenoids (123)-( 125), having a structural similarity to gibberellic acid (126), have also been shown to possess similar biological p r o p e r t i e ~The . ~ ~ synthesis of compounds (122)-(125) has been a c ~ o m p l i s h e dby ~ ~the route outlined in Scheme 17.
er I +
& v
Br [4: I] (122) Reagents:
1,
Li-NH,-MeI;
-70 "C; vi,,
ii, KOH-(CH,OH),;
+ (124)
-
(125)
+ (123) (17 : 31
iii, BF,,Et,O; iv, H,-Pd; v, Ph,P=CH2,
C
NCH,CN-DMSO; vii, KOBu'; viii, (CO,H),-H,O;
ix, CrO,;
x, C H , N , ; xi, NaOMe; xii, NaOH-H,O.
Scheme 17
A new method of hydroxylating the C-2 position in dendrobine (127) has recently been achieved.6" Bromination of the keto-lactam (129) derived from dendrobine (127) followed by hydrolysis provides the 2-hydroxy-derivative (130) which can be 59
6o
L. N. Mander, J. V. Turner, and B. G. Coombe, Austral. J. Chem., 1974,27, 1985. M. Suzuki, K. Yamada, and Y. Hirata, Chem. Letters, 1Y7.5, 611.
69
Sesquiterpenoids
reductively transformed in low yield to 2-hydroxydendrobine (128) and nobiline (132) (Scheme 18).60
/N yR. $
----+3B R'
H
A
,Ao
(129) R (130) R
(127) R = H
(128) R
C0,Me
,
0 '
= OH
= =
H OH
'q 0
/
H 0'
A 0 Reagents: i, Zn(BH,),-DME, 0 "C ; ii, NaH-DME, 0 ° C ; iii, Et,O+BF,-; 0 ° C ; v, HCl-MeOH.
iv, NaBH,-DME,
Scheme 18
9 Himachalane, Longipinane, Longicamphane, Longifolane, etc.
A synthetic route from (+)-longifolene (133) to (+)-himachalene dihydrochloride (140) and (*)-ar-himachalane (141) has been reported.61The sequence of reactions (Scheme 19) includes an interesting intramolecular 1,5-hydride shift [cf. (135)] and a base-catalysed fragmentation reaction involving the tricyclic ketone (138). Full experimental details of previously reported62syntheses of ( )-longiborneol (142), (*)-longicamphor (143), and (*)-longicyclene (144) have been published.63 The involvement of triple bonds in polyolefin cyclizations has provided elegant synthetic routes to steroids and t r i t e r p e n ~ i d s Extension .~~ of these studies to the sesquiterpenoid area has recently resulted in a novel synthesis of (k)-longifolene (148).65A
*
61
62 63 64
6s
G. Mehta and S. K. Kapoor, J. Org. Chem., 1974,39, 2618. S. C. Welch and R. L. Walters, Synth. Comm., 1973, 3, 15; ibid., p. 419. S. C. Welch and R. L. Walters, J. Org. Chem., 1974, 39, 2665. C'. W. S. Johnson, M. B. Gravestock, R. J. Parry, R. F. Meyers, T. A. Bryson, and D. H. Miles, J. Amer. Chem. SOC.,l971,93,433O;W. S . Johnson, M. B. Gravestock, and B. E. McCarry, ibid., p. 4332; D. R. Morton and W. S. Johnston, ibid., 1973.95, 4419 and references cited therein. R. A. Volkmann, G. C. Andrews, and W. S. Johnson, J. Amer. Chem. SOC., 1975,4777.
Terpenoids and Steroids
70
1" \
(139)
( 140)
( 1 38)
(136) R (137) R
= =
CF,CO
H
(141)
Reagents: i, C F , C O , H ; C r 0 , - M e , C O - H + ; iii, MeSOCH, ; iv, N H , N H 2 - K O H - ( C H 2 0 H ) , ; v, HC1-HOAc; vi, chloranil; vii, Pd-C.
Scheme 19
(142)
(143)
(144)
key feature of the synthetic sequence (Scheme 20) is the acid-catalysed cyclization of the enynol(l46) to a tricyclic enol(l47) which can subsequently be converted into ( f )-longifolene by conventional procedures. The previous assignment of stereochemistry to isolongifolene epoxide (149)66has been confirmed by epoxidation studies with analogous substrate~.~' It has also been concluded that the factors controlling the stereochemistry of epoxidation are the bicyclohepty! moiety and the C-2p methyl group. hh
67
J. A. McMillan, I. C. Paul, V. R. Nayak, and S. Dev, Tefruhedron Letters, 1974, 419. C. W. Greengrass and R. Ramage, Tetrahedron, 1975,31,689.
Sesquiterpen oids
71
dp
I
vii. viii
Q-.Q%@ xii, xiii
(148) Reagents: i, [MeC -CfCH,),],CuLi; ii, MeCOCl; iii, MeLi-Et,O, 0 "C; iv, Br,-CH,Cl,; v, 2,4,6-Me,C,H2C02- + N H 4 ; vi, LiAlH,; vii, CF,CO,H; viii, K,CO,; ix, ZnBr,; x, NaBH,CN; xi, TsOH; xii, Ru0,-HIO,; xiii, LiNPri-MeI; xiv, MeLi; xv, SOCI,-py.
Scheme 20
I
(149)
Recent investigations68designed to elucidate the biosynthetic route to culmorin (150) are described in Chapter 6.
10 HumuIane, Caryophyllane, Hirsutane, ProtoiUudane, IUudane, Marasmane An investigation of the acid-catalysed cyclization of humulene (15 1) has provided results6' identical with those outlined in last year's Report.' The isolation7' of 70
J. R. Hanson and R. Nyfeler, J.C.S. Chem. Comm., 1975, 171. W. G. Dauben, J. P. Hubbell, and N. D. Vietmeyer, J, Org. Chem., 1975,40, 379. K. Yoshihara and Y. Hirose, Bull. Chem. SOC.Japan, 1975,48,2078.
Terpenoids and Steroids
72
(151)
a-neoclovene (155a), p-neoclovene (155b), a-panasinsene (1 56a), and ppanasinsene (156b) from the root oil of the Ginseng plant is of considerable interest since their biosynthesis presumably involves a reaction sequence similar to that postulated in the acid-catalysed conversion of caryophyllene ( 152) into neoclovene (1 55).7'.72
i-eH+ / (1 55a and b)
1-H'
(1 5621 and b)
The stereospecific conversion of the synthetic tricyclic ketone (1 57)73into ( 5 ) hirsutic acid (1 59) has been ac~ornplished'~ by the short reaction sequence shown in Scheme 2 1.
H (157) Reagents: i, Formalin-K,CO,; EtOH, 0 "C.
H
(158) ii, LiI-DME; iii, H,O,-MeOH-NaOH,
(1 59) -36 " C ; iv, NaBH,-
Scheme 21 W. Parker, R. A. Raphael, and J. S. Roberts, J. Chern. Soc. ( C ) ,1969, 2634. T. F. W. McKillop, J . Martin, W. Parker, J. S. Roberts, and J. R. Stevenson, J. Chem. Soc. (C),1971, 3375.
F. Sakan, H. Hashimoto, A. Ichihara, H. Shirahama, and T. Matsumoto, Tetrahedron Letters, 1971, 3703.
H. Hashimoto, K. Tsuzuki, F. Sakan, H. Shirahama, and T . Matsumoto, Tetrahedron Letters, 1974,3745.
73
Sesquiterpe noids
Further investigation of the metabolites of Clitocybe illudens has revealed the presence of neoilludol (1 60), the allylic isomer of illudol (16 1).75A new synthetic
OH
OH ( 160)
(161)
approach to hypacrone ( 1 65) has been described in which the seco-illudane skeleton is constructed by condensation of the trimethylsilyl ether (162) with 1,ldiacetylcy~lopropane.~~ It should be noted, however, that the isolation of pure hypacrone (165) from the equilibrium mixture obtained in the final photoisomerization reaction (Scheme 22) has yet to be accomplished.
+
.x
L1
CO,H
4
uco2H & --%
iii
/
(163)
Reagents: i, (COCI),; ii, AICI,; iii, LiNPri-Me,SiCl; iv,
COMe
, TiC1,; v, 190 “C.
COMe
Scheme 22
Pyrovellerolactone (169) has been synthesized7’” by a synthetic route in which the hydroazulene intermediate (168)776is constructed (Scheme 23) by a procedure similar to that used in a previous synthesis of bulnes01.~~ A novel feature of the 75
76 77 78
M. S. R. Nair and M. Anchel, Tetrahedron Letters, 1975, 1267. Y. Hayashi, M. Nishizawa, and T. Sakan, Chem. Letters, 1975, 387. ( a )J. Froborg,G .Magnusson, and S. Thortn, J. Org. Chem., 1975,40,1595; ( b )ibid., 1974,39,848. cf.J. A. Marshalland J. J. Partridge, Tetrahedron, 1969, 25, 2159.
Terpenoids and Steroids
74
1
ii, iii
OH
0
Reagents: i, MeLi; ii, LiAlH,; iii. MsCl; iv, Bu'C0,H-Bu'C0,Na;
v, anodic oxidation; vi, HCI.
Scheme 23
synthetic route is the use of anodic oxidation to accomplish conversion of a furan ring into the corresponding unsaturated y-lactone. A new compound (1 7 l), structurally related to pyrovellerolactone (169), has been isolated from Lactarius scrobiculatus and'assigned the epoxy-lactone structure on the basis of its spectroscopiccharacteristics. 79
7y
G . Vidari, L. Garlaschelli, M. De Bernardi, G. Fronza, and P. Vita Finzi, Tetrahedron Letters, 1975, 1773.
Sesquiterpenoids
75
11 Germacrane," Eudesmane, Vetispirane
The structures of peucephyllin (172)80(PeucephyZZurn Schotrii Gray) and the related cytotoxic germacranolide eupaformonin (173)81 (cf. p. 93) (Eupatoriurn forrnosurn
0 (172) R' = OAC, R2 = H, R 3 = COPr' (173) R' = H, R 2 = OAC,R3 = H
Hay.) have been elucidated by X-ray crystallographic analysis. Chemical and spectroscopic evidence has been used to deduce the structure of marginatin (174), a germacranolide which occurs in several Vernonia species.82The absolute configuration of ageratriol(l76) has been determined by chemical means and the assignment is consistent with its postulated biosynthesis from agerol ( 175).83 HO
OH
I
1
OH I1
I
The root bark of the tulip poplar (Liriodendron turipiferu L.) has previously been shown to contain cytotoxic germacranolides such as costunolide (177), tulipinolide (178), and epitulipinolide (179).84aFurther studiesx4' have revealed the presence of lipiferolide (180) and epitulipinolide diepoxide (181) in this plant and it has been
HI
x2
x3 x4
M. J. Begley, G . Pattenden, and T.. J. Mabry, Tetrahedron Letters, 1975, 1105. A. T. McPhail, K. D. Onan, K.-H. Lee, T . Ibuka, and H.-C. Huang, Tefrahedron Letters, 1974,3203. W. G. Padolina, N. Nakatani, H. Yoshioka, T. J. Mabry, and S. A. Monti, Phytochemistry, 1974, 13, 2225. R. Grandi, A. Marchesini, U. M. Pagnoni, and R. Trave, Tetrahedron, 1974,30, 3821. (a) R. W. Doskotch, C. D. Hufford, and F. S. El-Feraly, J.C.S. Chem. Comm., 1972, 1 f37 and references cited therein; (6) R. W. Doskotch, S. L. Keely, C. D. Hufford, and F. S. El-Feraly, Phytochemistry,1975, 14.769.
* The structures shown for phantomolin and chrysandiol in Vol. 58 were printed incorrectly and should be amended to (i) and (ii) respectively.
(ii)
76
Terpenoids and Steroids
shown that these compounds also possess cytotoxic activity. It is interesting to note that other lactonic metabolites of L. tulipzera such as epitulipdienolide (182) and y-liriodienolide (183) are biologically inactive.
(177) R (178) R (179) R
H a-OAc = fi-OAc
(180)
=
=
qcq/ HO 1
0
0
0
(182)
(183)
The truns,truns- (184) and cis,truns-furanogermacrene (185a) derivatives and their corresponding Cope-rearrangement products, (186a) and ( 1 8 7 p have been
(186a) R (186b) R
(185a) R (185b) R
= =
= =
0
H,
0 H,
found to co-occur in the rhizomes of Curcuma zedoaria Roscoe.*“ Pyrenolide (lSS), a minor constituent of Liutris pycnostuchya, is the first seco-germacranolide to be detected in nature.” It is reasonable to assume that compounds of this type are biosynthesized by ring cleavage of an appropriate germacranolide precursor [cf. (188)] and it is perhaps significant that pyrenolide (189) and the various germacranolides isolated from Liatris species have the same absolute configurations at C-6, C-7, and (2-8. xs.
Cope rearrangement of the corresponding desoxy-compound (1XSb) provides a trans-product (186b);
Xh
cf. K. Takeda and I . Horibe, J.C.S. Perkin I, 1975, 870 and ref. 8, p. 7 3 . H. Hikino. C. Konno, K. Agatsuma. T. Takemoto, 1. Horibe, K. Tori, M. Ueyama, and K. Takeda, J.C.S.
x7
Perkin I, 1975, 478. W. Herz and R. P. Sharma, J. Org. Chem.. 1974,39, 392.
77
Sesquiterpenoids
The identification of dihydro-a-agarofuran (191) as a microbial oxidation product of valencene (190) has resulted in a revised configuration for dihydro-P-agarofuran
(193), a component of sandalwood oil.**Since dihydro-P-agarofuran (193) is the rearrangement product of the termite metabolite 4,l l-epoxy-cis-eudesmane ( 192)8 BF,-Et,O ____)
,'
H
H-
' 0 (192)
0 (193)
the relative configuration of the latter compound can also be asigned. N.m.r. and mass spectroscopic data have been used to determine the structure and configuration of four new sesquiterpenoids [malkangunin (194), celapanin (199, celapanigin (196), and celapagin (197)] isolated from Celastrus paniculufus Willd.8' Similar
Q '
HOOT OCOPh
R3
Ac
(195) R' (196) R' (197) R'
R3 = Ac, R 2 = furoyl, R4 = nicotinyl R3 = Ac, R2 = PhCO, R4 = nicotinyl = Ac, R3 = H, R 2 = PhCO, R4 = nicotinyl = =
agarofuran-type sesquiterpenoids isolated from Euonyrnus europeaus L.90 and Euonymus alatus" have been identified as simple esters of the basic alcohol structures ( 198)90and (199).90,91 KH
Ky
yo y1
S . K. Paknikar and C. G. Naik, Tetrahedron Letters, 1975, 1295. H. Wagner, E. Heckel, and J. Sonnenbichler, Tetrahedron, 1975,31, 1949. H. Budzikiewicz and A. Romer, Tetrahedron, 1975, 31. 1761. K. Sugiura, Y. Shizuri, K. Yamada, and Y. Hirata, Tetrahedron Letters, 1975, 2307
Terpenoids and Steroids
78
OH HO \ OH
OH HO j OH HO..(Jq
HO..@
HO
OH
H
H
A new method of constructing isopropylidene functionality has been illustrated recently in the synthesis of 4( 14),7(11)-selinadiene (202), a eudesmane derivative present in hops.92 Interest continues in the isolation, structural elucidation, and
synthesis of cytotoxic eudesmanolides (203), guaianolides (204), and pseudoguaianolides (205) (cf. p. 90). Thus the development of a simple synthetic \
:::::, 0
(203a)
(2044
(20%)
\
L
(203b)
(204b)
(205b)
route (Scheme 24) to (*)-yomogin (207) has been prompted by the potential use of this compound as a synthetic precursor of biologically active g~aianolides.’~ The starting material (206) in the synthesis of yomogin has also been used in a stereoselective total synthesis of ( *)-telekin (209) (Scheme 25).”4 92
y3 94
G. H. Posner, G. L. Loomis, and H. S. Sawaya? Tetrahedron Letters, 1975, 1373. D. Caine and G. Hasenhuettl, Tetrahedron Letters, 1975, 743. R.B. Miller and E. S. Behare, J. Amer. Chem. SOC., 1974, 96, 8102.
79
Sesquiterpenoids
Reagents: i, Pyrrolidine-C,H,; ii, BrCH,CO,Et; iii, KBu',BH-THF; iv, (CH,OH),-H LiNPri-CH,O; vi, MsC1-py, A ; vii, Me,CO-H+ ; viii, DDQ-dioxan.
+
: v,
Scheme 24
Bu'CO,
H Me0,C [xi, xii
Lo +xiii-xv HO'- *
H
H
O
H*
*
C 0m ,Me
(209) Reagents: i, Li-NH,; ii, (EtO),POCl; iii, Li-EtNH,; iv, m-ClC,H,CO,H; v, LiNPr;-Et,O; vi, Bu'COC1-py; vii, Me,CO-H+ ; viii, pyrrolidine-C,H,; ix, BrCH,CO,Et; x, NaH-Me,CO; xi, KOH-MeOH; xii, CH,N,; xiii, CH,OH-Me,NH; xiv, MeI; xv, DMF, 180°C.
Scheme 25
80
Terpenoids and Steroids
Extensive investigations by several research groups have demonstrated that certain plants (e.g. potato, sweet pepper, tomato) which have been inoculated with fungi produce antifungal sesquiterpenoids known as phytoalexins. Virus infection produces a similar response and a recent report describes the isolation and structural elucidation of glutinosone (2 lo), a compound produced by Nicotiana glutinosa (tobacco) plants which have been infected with tobacco mosaic Related studies by the same group have shown that glutinosone (210) and capsidiol(211) are also produced by Nicotiana tabacum and Nicotiana clevelandii plants which have been infected with tobacco necrosis virus.95b Phytuberin (213), a phytoalexin produced by potato tubers inoculated with blight fungus (Phytophthora infestans), was originally assigned structure (2 12) on the basis of its chemical and spectroscopic However, a recent X-ray analysis of its dihydro-derivative has led to the revised seco-eudesmane structure (2 13).96b
HOO
q
HO"
(212)
(213)
New chemical and spectroscopic e ~ i d e n c e ~has " ~resulted ~~ in a revised structure for lubimin (214), a vetispirane phytoalexin produced by white potato tubers injected with Phytophthora infestans. Related i n v e ~ t i g a t i o nhave ~ ~ ~also ~ revealed the presence of 4-hydroxylubimin (21 5) and 2,3-dihydroxygermacrene (2 16) in diseased potato tubers and a biogenetic scheme linking most of the known sesquiterpenoid phytoalexins has been
Ho9 R
.
(214) R
=
R
=
(215) 95 Yh
YJ 98
H" O
O
F
y'
H OH
( a ) R. S . Burden, J. A. Bailey, and G. G. Vincent, Phytochemistry, 1975, 14, 221; ( b ) ibid., p. 597. ( a ) D. T. Coxon, R. F. Curtis, K. R. Price, and B. Howard, Tetrahedron Letters, 1974,2363; ( b ) D. L. Hughes and D. T. Coxon, J.C.S. Chem. Comrn., 1974,822. N. Katsui, A. Matsunaga, and T. Musamune, Tetrahedron Letters, 1974, 4483. ( a )A. Stoessl, J. B. Stothers, and E. W. B. Ward, J.C.S. Chem. Comm., 1974,709 and references cited therein; ( b ) ibid., 1975,431.
81
Sesquiterpenoids
An excellent review of the isolation, structural elucidation, total synthesis, and postulated biosynthesis of sesquiterpenoids based on the spiro[4,5]decane (vetispirane) skeleton has been published.99 Further studies on the development of alternative routes to the vetispirane sesquiterpenoids have been described. In one report"' the spirocyclic acetal (217), previously used as an intermediate in the has been converted into (-)-agarospirol synthesis of (-)-a-acorenol (218),101*102 (219) and (-)-p-vetivone (220) by the reaction sequence outlined in Scheme 26.
J
J
J
(217)
iv-vii
OH
-a V
viii, ix
itOH
C0,Me
oqoq
2
C0,Me
(219)
1
xi, xii
xiii, xiv,
/tOAc (220) Reagents: i, 0,; ii, Me,S; iii, 5 % KOH; iv, H,-Pd; v, Br,-NaOH; vi, CH,N,; vii, HCI; viii, Ph,P=CH,; ix, TsOH; x, MeLi; xi, NaOAc-Ac,O; xii, Na,CrO,-HOAc-Ac,O; xiii, BF,-Et20; xiv, AgN0,-Al,O,.
Scheme 26 Yy
100 101
lo2
J. A. Marshall, Fortschr. Chem. org. Naturstoffe, 1974,31, 283. M. Deighton, C. R. Hughes, and R. Ramage, J.C.S. Chem. Comrn., 1975,662. I. G. Guest, C. R. Hughes, R. Ramage, and A. Sattar, J.C.S. Chem. Cornm., 1973, 526. Cf. R. W. Mills and T. Money, in 'Terpenoids and Steroids', ed. K. H. Overton (Specialist Periodical Reports), The Chemical Society, London, 1974, Vol. 4, pp. 93-94.
82
Terpenoidsand Steroids
Other investigators have used a new synthetic route103in which the spiro[4,5]decane system is formed by condensation of a P-dicarbonyl compound [e.g. (221)] with a cyclopropyl phosphonium salt (222).lo4 The bicyclic keto-ester (223) produced in this way was subsequently converted into ( f )-anhydro-P-rotunol (224), (*)-pvetivone (220), (*)-P-vetispirene (225), (*)-linesol (226), and (*)-a-vetispirene (227) (Scheme 27).Io3 An alternative approach to the vetispirane system involves
\
C0,Et
(223)
oq e1. ii-
- -H C0,Et
OH l i v , vii
\
iv, v
J 0
(_+)-B-Vetivone(220)
iv. iii
OH
ki OH
(226)
(225)
(227)
Reagents: i, MeLi; ii, HCl; iii, 10-camphorsulphonic acid; iv, LiAIH,; v, NCS-Me,S; vi, H,-Pd; vii, Ac,O-py; viii, Li-EtNH,; ix, Ac,O-NaOAc; X, BF,-Et20.
Scheme 27 103
W. G. Dauben and D. J. Hart, J. Amer. Chem. SOC.,1975,97, 1622. Cf. P. L. Fuchs, J. Amer. Chem. SOC., 1974,96, 1607.
Sesquiterpenoids
83
intramolecular acylation of an appropriate acid chloride (229) and this reaction has been incorporated into a new stereoselective synthesis of (*)-P-vetivone (220) (Scheme 28).lo5
lv t vi, vii
'pReagents: i, CH,=CHCN-Triton B-Bu'OH; ii, Ph,P=CH,-DMSO; iii, NaOH-H,O; iv, (COCI),; v, SnC1,-CS,, - 2 5 " C ; vi, HC0,Et-NaOEt; vii, DDQ; viii, Me,CuLi; ix, MeOH-H,O, 195 "C.
Scheme 28
Three research groups have developed synthetic routes which provide the basic ring system of the plant-growth-inhibitory seco-eudesmanolides (elemanes) vernolepin (230), vernodalin (23 l),lo6 and vernomenin (232). In one approach1"
A/B
0
(230) R = H (231) R = COC=CH,
I CH,OH
base cleavage of the keto-dithian (233) followed by acid hydrolysis provided the lactone (234). The required angular vinyl group [cf. (230)-(232)] was subsequently introduced by the reactions outlined in Scheme 29. In another approachlo8 conjugate addition of a vinyl group to the enone (237) followed by ozonolysis, reduction, and hydrolysis provided (236) in ca. 65% overall yield. Alternative routes to (236) involve second-order Beckmann fragmentation of the oxime (239) or ozonolysis of the enol acetate (240).lo8" G. Bozzato, J.-P. Bachmann, and M. Pesaro, J.C.S. Chem. Comm., 1974, 1005. R. Toubiana. B. Mompon, C. M. Ho, and M.-J. Toubiana, Phytochernistry, 1975, 14, 775. lo' J . A. Marshall and D. E. Seitz, Synth. Comm., 1974, 4, 395. R. D. Clark and C. H. Heathcock, Tetrahedron Letters, 1974, 1713. lnKa P. A. Grieco, K. Hiroi, J. J . Reap, and J. A. Noguez, J. Org. Chem., 1Y75,40, 1450. los
Terpenoidsand Steroids
84
(233)
Reagents: i, KOH-Bu'OH; ii, H,O-H'; iii, MeOS0,F-C,H,; iv, NaOH-H,O; v, H,O-H+; vi, p-TsOH-C,H,; vii, Ra-Ni-Me,CO; viii, 0,; ix, NaBH,; x, HCl; xi, (CH,=CH),CuLi; xii, Me,SiCI; xiii, MeSO,CI-py; xiv, 0,; xv, NaBH,-NaOH.
Scheme 29
A second stereoselective total synthesis of ( f )-eremophilone (243) has been accomplished using 7-epinootkatone (242) as intermediate.lo9The latter compound was synthesized from (-)-P-pinene (241) by modification of the published procedure''* and subsequently converted into eremophilone (243) by the series of functional-group transformations shown in Scheme 30. A mycotoxin isolated from Peniciffiurnroqueforti has been assigned the highly oxygenated eremophilane structure (244) on the basis of chemical and spectroscopic evidence. l 1 The structure and IOU
110
'I1
J. E. McMurry, J. H. Musser, M. S. Ahmad, and L. C. Blaszczak, J. Org. Chem., 1975, 40, 1829. A. Van der Gen, L. M. Van der Linde, J. G. Witteween, and H. Boelens, Rec. Truu. chim., 1971,90, 1034. R. Wei. H. K. Schnoes, P. A. Hart, and F. M. Strong, Tetrahedron, 1975,31, 109.
Sesquiterpenoids
85
1
iii
(243) Reagents: i, NaH-HMPA; ii, Ac,O; iii, NaBH,; iv, A c , O - N ~ N M e , E t N H , ; v, 160 "C; k=f vi, m-CIC,H,CO,H-CH,CI,, 0 "C; vii, HC10,-C,H,; viii, NaOMe-MeOH.
Scheme 30
absolute configuration of tetradymol (245), one of the toxic constituents of Tetradyrniu glabrutu, have been determined by X-ray crystallographic analysis of its 12-chloromercury derivative.' l 2 Chemical and spectroscopic evidence has shown
that over seventy new furanoeremophilanesisolated from Othonna,' '3a Euryops,' 13' and S e n e c i ~ " ~species " are simple esters of the basic structures (246)-(260). The
(246) X
=
H or R'CO,
(247)
(248) X
=
H, or 0
Ii2
P. W. Jennings, S. K. Reeder, J. C. Hurley, C. N. Caughlan, and G. D. Smith, J. Org. Chem., 1974,39,
113
3392. F. Bohlmann, C. Zdero, and M. Grenz, ( a ) Chern. Ber., 1974,107, 3928; ( b ) ibid., p. 2730; ( c ) ibid., p. 2912.
*
86
Terpenoids and Steroids X
0
R lRCO,
R" (249)
(250) X (251) X
R
OCOR = =
H, or 0, R' H, or 0, R'
=
=
H OH
(252) R = H or OCOR R' = H or OH
rn OCOR
(253) (254) (255) (256)
X X X
0, R = OCOR' H,, R = H = H,, R = OH X = H,, R = OCOCMe=CH,
(257) R'
= =
(258)
=
H or OCOR
0
(259)
(260) R
=
H or COR'
seco-eremophilanes (26 1)-(263) co-occur with some of these compounds and independent studies have shown that compounds (255) and (256) are also present in
\
OH
0
0
(261)
(262)
(263)
the genus Ligularia.1'4 The absolute configuration of (+)-farfugin A (264), a compound presumably derived in nature by ring cleavage of an appropriate eremophilane precursor, has been determined by chemical correlation with a known compound (265)."'
]Is
T . Sato, Y. Moriyama, H. Nagano, Y. Tanahashi, and T. Takahashi, Bull. Chem. SOC.Japan, 1975,48, 112. M. Tada. Y. Moriyama, Y. Tanahashi, and T. Takahashi, Bull. Chem. SOC.Japan, 1975, 48, 549.
Sesquiterpenoids
87
A new total synthesis of (*)-valeram (271) has been achieved using a reaction sequence (Scheme 3 1) in which the cis-5,lO-dimethyldecalinsystem is constructed OBu'
OTHP
0
li-iii
(270) X = 0 (271) X = H, Reagents: i, H+-H,O; ii, MsC1-py; iii, LiBr-Me,CO; iv, Me,CuLi-C,H,,
0 "C;v, HMPA, 0 "C.
Scheme 31
by stereoselective conjugate addition of a methyl group to the enone (268) followed by intramolecular cycloalk'frlation of the intermediate enolate ion (269)."" Full details of the previously reported' synthesis of (*)-p-gorgonene (272) have been published. ' l7
Structural elucidation of the terpenoid constituents of marine plants and animals has revealed the presence of several compounds whose novel structures often have chlorine, bromine, or isocyanide substituents (cf. pp. 65 and 89). 9-Isocyanopupukeanone (273) is a recent example of a marine sesquiterpenoid isolated from a
G. H. Posner, J. J. Sterling, C. E. Whitten, C. M. Lentz, and D. J. Brunelle, J. Amer. Chem. SOC.,1975, 97, 107. *I7
R. K. Boeckman and S. M. Silver, J. Org. Chem., 1975, 40, 1755.
88
Terpenoids and Steroids
sponge (Hymeniacidon sp.) and from the comparatively rare mollusk (Phyllidia uaricosa) which feeds on sponges of this type.ll8 The complex structure of this metabolite was partially elucidated by chemical and spectroscopic evidence and eventually established by X-ray crystallographic analysis.' '' It is included in this section of the Report since an eremophilane intermediate may be involved in its biosyn thesis.
12 Guaiane, Aromadendrane, Pseudoguaiane A continuation of recent studies on acid-catalysed terpenoid rearrangements has led to the observation that 10-epizonarene (275) is formed when a solution of guaiol (274) is treated with concentrated sulphuric acid. ' l 9 Unfortunately an explanation
for the apparent stereoselectivity of this rearrangement has not been provided. Recent reports have described the isolation and structural elucidation of the following guaianolides: graminiliatrin (276),I2O deoxygraminiliatrin (277),'*' graminichlorin (278),'" spicatin (279),'*l epoxyspicatin (280)'*' (Liatris spp.), C1
ye
H @ o
OCOC=CHCH,OAc
H ,
H ;
0
(276) (3,4-epoxy) (277) 'I9
Iz0 '*I
I
(j_ _
3 \
'Ix
OCOC Me I =CHCH,OAc
* oH
0 (278)
B. J. Burreson, P. J. Scheuer, J. Finer, and J. Clardy, J. Amer. Chem. Soc., 1975,97, 4763. G. Mehta and B. P. Singh, Tetrahedron Letters, 1975, 1585. W. Herz, J. Poplawski, and R. P. Sharma, J. Org. Chem., 1975, 40, 199. B. Karlsson, A.-M. Pilotti, A.-C. Wiehager, I. Wahlberg, and W. Herz, Tetrahedron Letters, 1975,2245.
89
Sesquiterpenoids
(279) (280) (3,4-epoxy)
mikanokryptin (281)'22 (Mikania spp.), carolenalone (282)'23 (Helenium autumnale), and compounds (283)-(285)'24 (Osmitopsis asteriscoides). Sesquiterpenoids containing the comparatively rare isocyanide and isothiocyanate groups seem to be characteristic metabolites of marine sponges (cf. pp. 65 and 87). Further investigations in this area have resulted in the isolation of aromadendrane derivatives, axisonitrile-2 (286),'25a axisothiocyanate-2 (287),' 256 and axamide-2 (288).125bAxamide-1 (291),129ba rearranged eudesmane derivative, co-occurs in
(286) X = NC (287) X = NCS (288) X = NHCHO
(289) X (290) X (291) X
NC NCS = NHCHO = =
the same species of sponge (Axinella cannabina) with the previously reported compounds axisonitrile- 1 (289) and axisothiocyanate- 1 (290). A further illustration of the tendency of liverworts to produce sesquiterpenoids which are enantiomers of those found in higher plants (cf. p. 63) is provided in a recent report126which describes the isolation of (+)-cyclocolorenone (292) and (-)-maalioxide (293) from 123 124 125
W. Herz, A. Srinivasan, and P. S. Kalyanaraman, Phytochemistry, 1975,14233. A. T. McPhail, K. D. Onan, H. Furukawa, and K.-H. Lee, Tetrahedron Letters, 1975, 1229. F. Bohlmann and C. Zdero, Chem. Ber., 1974,107, 1409. E. Fattorusso, S. Magno, L. Mayol, C. Santacroce, and D. Sica, ( a )Tetrahedron, 1974,30,3911;( b )ibid., 1975,31, 269. A. Matsuo, N. Nakayama, S. Sata, T. Nakamoto, S . Uto, and S . Hayashi, Experienfiu, 1974,30, 321.
90
Terpenoids and Steroids
Plagiochila acanthophylla subsp. japonica. Taylorione (294), a congener of myliol (295) in the liverwort Mylia taylorii, has been assigned the seco-aromadendrane structure (294) on the basis of chemical and spectroscopic evidence.lz7
(292)
(294)
(293)
(295)
Synthetic entry into the pseudoguaianolide skeleton has finally been achieved. 12' The known hydroazulenol (296) was used as starting material and converted into ( f)-4-deoxydamsin (297) by the series of simple functional-group transformations outlined in Scheme 32.
3, I-iii
iv-vi
__* /--
CO,H
0 (296)
L i i , viii
xi-xiii f--
9 0
0
0
Reagents: i, m-ClC,H,CO,H; ii, LiAIH,; iii, Cr0,-Me,CO; iv, Ac,O-NaOAc; v, LiICABrCH,CO,Me; vi, KOH- MeOH; vii, H,-PtO,; viii, Ac,O-NaOAc; ix, H,-PtO,; x, NaH-HC0,Et; xi, NaBH,; xii, TsCl; xiii, py.
Scheme 32
A further study on the oxidation of terpenoid compounds by mammalian systems (cf. p. 62) has shown that patchoulol(298) is oxidized by rabbits to give a mixture of diol(299) and hydroxy-acid (300).'29 Subsequent oxidative decarboxylation of (300) provided norpatchoulenol(301), the major odour carrier of patchouli oil. It has been suggested that a similar oxidative transformation of patchoulol occurs during the biosynthesis of norpatchoulenol in the plant.12yCedrol(72) has also been oxidized by rabbits (cf. p. 62) and it is interesting to note that the hydroxylated products are A. Matsuo, S. Sato, M. Nakayama, and S. Hayashi, Tetrahedron Letters, 1974, 3681. L28
J. A. Marshall and W. R. Snyder, J. Org. Chem., 1975, 40, 1656.
129
L. Bang and G . Ourisson, Tetrahedron Letters, 1975, 22 1 1 .
91
Sesquiterpenoids
normal metabolites of certain plants. Thus it would seem that mammalian and plant oxidases can functionalize certain sesquiterpenoids with the same regiospecificity. An elegant new stereoselective synthesis of patchouli alcohol (298) has been acc~rnplished"~ by a four-step sequence in which the tricyclic framework is constructed by intramolecular Diels-Alder reaction [Scheme 33 ; (303b) + (304)l.
(302)
Reagents: i, Y
L
(303a)
i
(303b)
1ii
; decalin-KOBu', 280 " C ;iii, H,-Pd.
Scheme 33
13 Mono- and Bi-cyclofarnesanes Phaseic acid (305)and dihydrophaseic acid (306a) are formed when (+)-abscisic acid (304) is fed to certain plants (e.g. tomato, bean, etc.). The stereochemistry of these compounds has recently been established13' by spectroscopic analysis (n.m.r. and i.r.) of the epimeric 4'-dihydrophaseic acids (306a and b) derived by reduction (NaBH,) of phaseic acid (305). The structures of several new sesquiterpenoids isolated from a marine sponge (Disidea pallescens) have been assigned on the basis of spectral characteristics and 130 131
F. Naf and G. Ohloff, Helu. Chim. Actu, 1974,57. 1868. B. V. Milborrow, Phytochemistry, 1975,14, 1045.
92
Terpenoids and Steroids 0
r p o y c o 2 H (304)
(305)R
=
(306a) R (306b) R
= =
0 H,a-OH H&OH
chemical interrelationship^.'^^^-^ Pallescensins 1-3 [(307)-(309)]132" have are monocyclofarnesane skeletons while pallescensins A-G [(310)-(3 16)]'32'",c probably derived in nature by cyclization of an appropriate monocyclofarnesane precursor. 13"
(307)
(309)
c'--?:" \
(315)
(314)
(316)
A new sesquiterpenoid (317) isolated from the roots of a Turkish plant (Tunucetum species) has been assigned a structure whose biosynthesis may involve 0
132
G. Cimino, S. De Stefano, A. Guerriero, and L. Minale, (a) Tetrahedron Letters, 1975, 1417; ( b )ibid., p. 1421; ( c ) ibid.. p. 1425.
Sesquiterpenoids
93
rearrangement (172-methyl shift) of a monocyclofarnesane precursor. 133 Related studies of Anthemis 134 and Artemisia 135 species have revealed the presence of monocyclofarnesane (318)134and bicyclofarnesane derivatives (3 19)135 and (320).'34 Co-occurring with the latter compound in species of Anthemis are aciphyllic acid (321) and the cis-isomer (322) of eupaformonin (173) (p. 75). Me0 0 /O
OMe
(319) R (320) R
= =
H,a-OH 0
AcO.'
0
Paniceins Al, B1, B2, B3, and C have been isolated from a marine sponge (Huiichondria panicea) (cf. p. 65) and assigned structures (323)-(327).136 These
(325) OH
(326) 133
135
13*
F. Bohlmann, C. Zdero, and H. Schwartz, Chern. Ber., 1975, 108, 1369. F. Bohlmann and C. Zdero, Chern. Ber., 1975,108, 1902. F. Bohlmann, D. Schumann, and C. Zdero, Chern. Ber., 1975,107,644. G . Cimano, S . De Stefano, and L. Minale, Tetrahedron, 1973, 29, 1565.
OH
(327)
Terpenoids and Steroids
94
compounds are probably formed in nature by condensation of a rearranged monocyclofarnesane unit with hydroquinone. The attachment of a rearranged bicyclofarnesane unit to hydroquinone or benzoquinone is clearly illustrated in the structures of other marine sponge metabolites, avarol (328) and avarone (329).13’ Zonarol (330) and isozonarcrl (331), fungitoxic constituents of brown seaweed, are examples of compounds in which the normal bicyclofarnesane framework is linked to hydroquinone. 138 OH
0
& OH I
(329)
H
(331)
14 Miscellaneous
Recent synthetic studies (Scheme 34) have shown that the seco-amorphane structure (332) previously assigned to humbertiol is incorrect. 139
(332) Reagents: i, MeLi; ii, EtOCH =CH,-Hg(OAc),; CH,=CHLi.
iii, 130 “ C ; iv, MeMgI; v, Cr0,-Me,CO; vi,
Scheme 34 177
138
IW
L. Minale, R. Riccio, and G. Sodano, Tetrahedron Letters, 1974, 3401. W. Fenical, J . J . Sims, D. Squatrito, R. M. Wing, and P. Radlick, J. Org. Chem., 1973, 38, 2383. A. Hoppmann and P. Weyerstahl, Chem. Ber.. 1974, 107. 1102.
Sesquiterpenoids
95
The structure and absolute configuration of pinguisone (333) have been determined by a combination of spectroscopic data (ms. and 13Cn.m.r.) and X-ray analysis of its p-bromobenzylidene derivative. '41 Appropriate chemical transformations and n.m.r. evidence have been used to assign structures to the fungal antibiotic sesquiterpenoids botrydial (334) and its dihydro-derivative (335).14' The structure of the latter compound has also been confirmed by single-crystal X-ray diffraction using direct
a 0 (333)
140
141 142
3
mo
OAc
(334)
OAc (335)
A. Corbella, P. Gariboldi, G. Jommi, F. Orsini, A. DeMarco, and A. Irnmirzi, J.C.S. Perkin I, 1974, 1875. H.-W. Fehlhaber, R. Geipel, H.-J.Mercker, R. Tschesche, and K. Welmar, Chem. Ber., 1974,107,1720. H. J. Lindner and B. von Gross, Chem. Ber., 1974, 107, 3332.
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 covered is that available to August, 1975. A useful review of diterpenoid chemistry has appeared.’ Some aspects of the distribution of diterpenoids in plants have been discussed.2 An interesting feature of the new diterpenoids described over the past few years is the increase in the number with skeleta based on the macrocyclic ring formed by the cyclization of geranylgeranyl pyrophosphate at the distal double bond. This mode of cyclization has formed the basis of a biogenetically patterned synthesis’ of (*)-nephthenol(2) and (*)-cembrene A from the distal epoxide of geranylgeranyl phenyl thioether (1).
The 13C n.m.r. resonances of a number of groups of diterpenoids have been assigned. These include tricyclic di t e r p e n ~ i d sthe , ~ kaurenolides,s and the gibberelK. Nakanishi, T. Goto, S. Ito, S. Natori, and S. Nozoe, ‘Natural Product Chemistry’, Academic Press, New York, 1974, Vol. 1 . G . Ourisson, in ‘Chemistry in Botanical Classification’, ed. G. Bendz and J. Santesson, Academic Press, New York, 1974, p. 129. M. Kodama, Y. Matsuki, and S. Ito, Tetrahedron Letters, 1975, 3065. J. Polonsky, G. Lukacs, N. Cagnoli-Bellavita, and P. Ceccherelli, Tetrahedron Letters, 1975, 481. J. R. Hanson, G . Savona, and M. Siverns, J.C.S. Perkin Z, 1974, 2001.
96
Diterpenoids
97
l i n ~ . These ~ . ~ results have found application in structural and in biosyntheSiS.4,7,9. 10 The unusual isocyanide of geranyl-linalool and the corresponding formamide and isothiocyanate have been isolated' from a marine sponge (Halochondria species). Ligantriol (3), isolated from Liatris elegans (Compositae), is a highly oxygenated derivative of geranylnerol;12 mass spectroscopy and I3Cn.m.r. spectroscopy played a valuable role in its formulation.
2 Bicyclic Diterpenoids Labdanes.-Sclareol has been obtained in large quantities from Salvia sclarea (Labiateae). Manool has now been ~ b t a i n e d from ' ~ this plant. In the past few years a number of bicyclic diterpenoids have been found in Sideritis species. Barbatol(4) is a new diterpenoid which has been isolated from S. arborescens (C~mpositae).'~ Its structure followed from an interrelationship with ent- 13-epimanoyl oxide (olearyl oxide). The labdane group of diterpenoids have provided the source of relays for several synthetic studies. A degradation has been r e p ~ r t e d 'of ~ this group of diterpenoids via ambreinolide (9,an oxidation product both of the triterpenoid ambrein and of manool, to compounds possessing the sesquiterpenoid drimane skeleton [e.g. (6)]. The extension of the side-chain of sclareol and the cyclization of
(4)
(5)
(6)
the products has been studiedI6 as a route to higher terpenoids. The oxidation of exocyclic olefins by thallium(I1x) nitrate has been examined17 using labda-8( 17)-en13-01 (7) as a substrate. The products were mainly C-7 allylic nitrate esters and their hydrolysis products. Labda-7,14-dien-13 (S),17-diol(8) has been proposed" as the structure for sagittariol which was isolated from Sagittaria sagittifolia (Alismaceae). Imbricataloic acid has been obtained" together with agathic acid 19-monomethyl ester from Pinus massoniana needles. The labdane acid, anticopalic acid, has been 6
1"
I1
13 14
I8 1')
I. Yamaguchi, N . Takahashi, and K. Fujita, J.C.S. Perkin Z, 1975, 992. R. Evans, J. R. Hanson, and M. Siverns, J.C.S. Perkin I, 1975, 1514. I . Yamaguchi, M. Miyamoto, H. Yamane, N. Murufushi, N. Takahashi, and K. Fujita, J.C.S. Perkin Z, 1975,996. M. R . Adams and J. D . Bu'Lock, J.C.S. Chem. Comm., 1975,389. K. D . Barrow, R, B. Jones, P. W. Pemberton, and I. Phillips, J.C.S. Perkin I, 1975, 1405. B. J. Burreson and P. J. Scheuer, J.C.S. Chem. Comm., 1974, 1035; Tetrahedron, 1975,31, 2015. W. Herz and R.P. Sharma, J. Org. Chem., 1975,40, 192. D . P. Popa and L. A. Salei, Khim. prirod. Soedinenii, 1974, 405. C. von Carstenn-Lichterfelde, B. Rodriguez, and S. Valverde, Experienh'a, 1975, 31, 757. S. W. Pelletier, S. Lajsic, Y. Ohtsuka, and Z. Djarmati, J. Org. Chem., 1975, 40, 1607. J. M. Mellor, H. T. L. Liau, and Kun-She Low, J.C.S. Perkin I, 1975, 1009. P. K . Grant, H. T. L. Liau, and Kun-She Low, Austral. J. Chem., 1975, 28, 903. S. C. Sharma, J. S. Tandon, and M. H. Dhar, Phytochemistry, 1975,14, 1055. D . F. Zinkel and W. B. Critchfield, Phytochemistry, 1974, 13, 2876.
Terpenoidsand Steroids
98
(8)
(7)
prepared2' by photolytic cleavage of the tertiary allylic alcohol (9) to form the unsaturated ketone (10). Carbon atoms C-14 and C-15 were introduced by a Wadsworth-Emmons reaction. The 13,14-doubIe bond of methyl sciadopate has hitherto been assigned the cis-stereochemistry because of the ease with which a furan ring is formed from oxidation products of the 15,16-diols. However, n.m.r. studies*l have shown that methyl sciadopate has a trans-butenediol side chain (1 1). CH,OH
(9)
(10)
(1 1)
Hedychenone (12) is a furanoid diterpenoid from the rhizomes of Hedychium spicatum (Zingiberaceae).22A number of furanoid diterpenoids have been isolated from Leonotis species including nepetaefolinol (13) and two related diterpenoids, leonotinin (1 4) and the dilactone ( 15)23from L. nepetaefolia.
6 0
,'
co-0 2o 2' 22 *7
co-0 H
D o Khac Manh Duc, M. Fetizon, and M. Kone, Tetrahedron,1975,31, 1903. J. S. Mills and I. A. Stenhouse. Tetrahedron, 1974, 30, 4021. S. C. Sharma, J. S. Tardon, H. Uprety, Y. N. Shukla, and M. H. Dhar, Phytochernistry, 1975,14,1059. K . K. Purushothaman, S. Vasanth, and J. D. Connolly, J.C.S. Perkin I , 1974, 2661.
Diterpenoids
99
C1erodanes.-The X-ray structure determination of the cis-clerodane (16) has been This confirms the stereochemistry of a number of Solidago diterpenoids which have been correlated with this lactone. Linaridial (17), an unstable cisclerodane dizldehyde, has been isolated25from Linaria japonica (Scrophulariaceae). A number of clerodane diterpenoids have been isolated26 from Stachys annua (Labiatae), including annuanone (18) and the corresponding saturated ketone and
diol. The absolute stereochemistries of teucrin A (19) and a number of related diterpenoids have been determined.27Structures have been assigned27to teucrin B (20), teucrin E (21), teucrin F (22), and teucrin G [2,3-epoxide of (22)] from Teucrium chamaedrys, and teucvidin (23), a minor diterpenoid isolated28from T. viscidum var. miquelianum.
1:-1
’OH
p
P
0
p HO
24
25
26
27
zn
OH
G. Ferguson, W. C. Marsh, R. McCrindle, and E. Nakarnura, J.C.S. Chem. Comm., 1975, 299. I. Kitagawa, M. Yoshihara, T. Tani, and I. Yosioka, Tetrahedron Letters, 1975, 23. D. P. Popa and T. M. Orgiyan, Khim. prirod. Soedinenii, 1974,324. D. P. Popa, and A. M. Reinbol’d, Khim. prirod. Soedinenii, 1974, 321, 589. I. Uchida, T. Fujita, and E. Fujita, Tetrahedron, 1975, 31, 841.
O
100
Terpenoidsand Steroids
The diterpenoid (24) an unusual intramolecular Diels-Alder reaction to afford (25) in which the furan ring acts as a dienophile adding across the 1( 10),2(3)-double-bond isomer of the parent diterpenoid. The absolute stereochemistry of the trans-clerodane caryoptin (26) has been determined3’ by conversion into a C-6 ketone and comparison of the 0.r.d. and c.d. curves with those of similar derivatives obtained from clerodin.
1 CH,OH C0,Me OAc
(26)
3 Tricyclic Diterpenoids
Naturally Occurring Substances. - The abietadienol (27) and its corresponding aldehyde have been isolated3’ from the oleoresin of Pinus koraiensis. Suaveolic acid (28) and the related alcohol suaveolol, have been from the leaves and stems of Hyptis suaveolens (Labiatae). Their structures were determined by X-ray analysis. Pimara-8( 14),15-diene, abieta-8,11,13-triene, and 13-epimanoyl oxide have been detected33 in the oleoresin of Pinus taiwanensis. lla,12PDiacetoxysandaracopimara- 15-en-8 p-01 (29) has been obtained34along with the
11- and 12-monoacetates from Osteospermum subulatum. Pimaric, isopimaric, abietic, and dehydroabietic acids have been isolated35 from the resin of Daemonorops draco (dragon’s blood resin). The bark of the New Zealand ‘miro’ tree, Podocarpus ferrugineus, which was the original source of ferruginol, has been E. L. Ghisalberti, P. R. Jefferies, and 1’. G . Payne, Tetruhedron, 1974, 30, 3099. S. Hosozawa, N. Kato, and K. Munakata, Tetrahedron Letters, 1974, 3753. 3 i V. A. Raldugin and V. A. Pentegova, Khim. prirod. Soedinenii, 1974, 674. ’* P. S. Manchand, J . D. White, J. Fayos, and J. Clardy, J. Org. Chem., 1974, 39, 2306. 3 3 J. J. Liu, K. C. Lin, and Y. S. Cheng, Phytochemistry, 1975, 15, 1375. 34 F. Bohlmann and Z. Christa, Chem. Ber., 1975, 108, 362. v F. Piozzi, S. Passannanti, M. P. Paternostro, and G. Nasini. Phytochemistry, 1974, 13, 2231
2y
Diterpenoids
101
thoroughly re-examined3' and shown to contain a wide range of diterpenoids including isopimarol, isopimaric acid, sandaracopimaric acid, ferruginol, sugiol, sugiyl methyl ether, xanthoperol, royleanone, 6-dehydroroyleanone7 cryptojaponol, Sp-hydroxy-6-oxa-6-norsugiyl methyl ether, 2-ketoferruginol, and 2pacetoxysugiyl methyl ether. A continuing of the Podocarpus sp. P. lambertius revealed the presence of 3P-hydroxytotarol(30) and the C- 19 carboxylic acids (31; R = H), (31 ; R = Me, macrophyllic acid), and lambertic acid (32). Isophyllocladen17-01was isolated from the leaves. Inuroylanol(33) and 7-ketoroyleanone (34) have been isolated3' from h u l a royleana (Compositae). They form missing links in the oxidative sequence between ferruginol ( 3 9 , sugiol, and the more highly oxidized
l i d :' l . ci:$l: K
HO
'%
H
HO,C
OMe
(34)
(33)
(35)
Coleus diterpenoids. Coleus species have been a rich source of highly oxidized spiroabietanes, a number of which have been described recently. Coleons M (36; R=Ac), N (37), P (38), Q [12a-hydroxy-epimer of (38)], and coleon R, which possesses 3 a - , 12a-, and 6 /3-acetoxy-groups and a 7a-hydroxy-group, have been isolated3' from Plectranthus caninus whereas coleon 0 (36; R = H) was isolated from Coleus somaliensis. OR
OAc
L&
OAc
U
* o
'OAc
OAc
OH (36)
(37)
H
U
I1
'0H
OH (38)
3H
E. Wenkert, J. de P. Campello, J. D. McChesney, and D. J. Watts, Phytochemistry, 1974, 13, 2545. J. de P. Campello, S. F. Fonseca, C. J. Chang, and E. Wenkert, Phytochemistry, 1975, 14, 243. S. V. Bhat, P. S. Kalyanaraman, H. Kohl, N. J. de Souza, and H. W. Fehlhaber, Tetrahedron, 1975,31,
3y
S. Arihara, P. Ruedi, and C. H. Eugster, Helv. Chim. Actu, 1975, 58, 343.
36 3'
1001.
102
Terpenoids and Steroids
The 2-methylaminoethyl esters of the Erythrophleum alkaloids readily rearrange to the amides and this has in the past caused some confusion. The conditions for the isolation of the esters from Erythrophleum chlorostachys have now been carefully defined.40 3P-Acetoxynorerythrosuamine (39) is a new highly cytotoxic alkaloid4' from this source. Podolide (40) is an anti-leukaemic norditerpenoid dilactone4*'from Podocarpus this is the first compound in this group of lactones to show g r ~ c i l i o rAlthough .~~ tumour-inhibitory activity, it does bear a formal similarity to taxodione. Details of the crystal structure of nagilactone A diacetate (4 1) have been given,43and nagilacfrom the bark of P. purdieanus. tone C has been The structure of lagascol(42), from Sideritis ~ e r r a t awas , ~ ~defined by a correlation with the 1la-alcohol, lagascatriol, previously obtained from this source.
r-Y
CHCO,CH,CH,NHMe
AcO
Me0,C
The Chemistry of the Tricyclic Diterpenoids.-Podocarpic acid has made a useful starting material for a number of transformations. The oxidative decarboxylation of the C-4 carboxy-group has provided a route to the functionalization of ring A. However, the decarboxylation affords a mixture of olefins. Methods for isomerization of the 12-methoxy- 19-norpodocarpatetraene mixture obtained by the oxidative decarboxylation of 0-methylpodocarpic acid with lead tetra-acetate have been examined.46 The iodine-catalysed isomerization gave mainly the exocyclic isomer. During the demethylation of 12-methoxypodocarpatriene with hydrogen iodide and hydrogen bromide in acetic acid inversion of configuration can occur at C-5 and
41
JL 43 JJ
44
4h
M . J. Falkiner, A. J. Faux, J . W. Loder, and R. H. Nearn, Austral. J. Chem., 1975, 28, 645. J . W. Loder and R. H. Nearn, Tetrahedron Letters, 1975, 2497. S . M. Kupchan, R. L. Baxter, M. F. Ziegler, P. M. Smith, and R. F. Bryan, Experientia, 1975,31, 137. K. Hirotsu, T. Higuchi, A. Shimada, Y. Hayashi, andT. Sakan, Bull. Chem. SOC.Japan, 1975,48,1157. E. Wenkert and C. J. Chang, Phytochemistry, 1974. 13. 1991. T. G . de Quesada, B. Rodriguez, and S. Valverde, Phytochemistry, 1975, 14. 517. R. C. Cambie, B. A. Grigor, R. C. Hayward, and A. J. Nielson, Austral. J. Chem., 1974,27,2017; R. C. Cambie, B. R. Davis. R. C . Hayward, and P.D. Woodgate, Ausrraf. J. Chem., 1975,28,631.
Diterpe noids
103
C-10, presumably via a path involving the intervention of a C-10 carbonium ion, elimination, and reprotonation. An unusual fragmentation of ring A has been in the treatment of 6a -hydroxy-7-oxoabieta-8,11,13-triene(43) with toluene-p-sulphonyl chloride. The formation of the /3 -naphthol (46) may proceed via the enol (44), followed by a methyl migration to (45) and then fragmentation.
OH
fl \
1
OH
In a number of tricyclic diterpenoids the C-10 methyl group has migrated to C-9. Several studies of this rearrangement have been reported; its induction by the boron trifluoride-catalysed cleavage of 8,9-epoxides has been in~estigated.~’ When the substrate was the C-19 alcohol (47), the ether (48) was formed together with the spiro-ketone (49). Reversed ‘backbone’ rearrangements have been observed4”in the
$-&H+
HOCH,
&
HOCH,
formic acid-catalysed rearrangement of dolabradiene (50). The products, which include the hydrocarbons (51)-(54), reflect the intervention of carbonium ions at C-4, C-5, C-10, C-9, and C-8. Of particular interest is the formation of the C-8 47
4x
49
T. Matsumoto, S. Imai, H. Masuda, and K. Fukui, Chem. Letters, 1974, 1001. R . C. Chmbie and W. A. Denny, Austral. J. Chem., 1975,28, 1153. M. Kitadani, C. Kabuto, K. Sakai, A. Yoshikoshi, and Y. Kitahara, Chem. Letters, 1974, 963.
Terpenoids and Steroids
104
(51) [C-8 epimers]
(52)
aPunsaturated Z=O > saturated C=0.26 Tritium n.m.r. spectroscopy has been used to demonstrate the stereospecific la,2/3-(trans) dehydrogenation of testosterone by micro-organisrn~,~' which contrasts with the reaction using DDQ, where 1a,2a-(cis) dehydrogenation accompanies the trans reaction.
Chiroptical Phenomena. Halogenated keto-steroids are among examples of compounds which illustrate an alternation of the relative ordering of halogen atoms (particularly F and I) in their effect on the n + T * transition energy of ketones, as the number of carbon atoms separating the halogen from the carbonyl group increases from one to five. The effect is observable in either U.V. or c.d. measurements, and is attributed partly to alternation of charges along a carbon chain induced by an electronegative (or electropositive) substituent. This factor may be modified by .rr-donation from lone pairs in the substituenk2* The abnormally weak negative 2o *I
22
23 24
25 26 27
2x
H. Hikino, T. Okuyama, C. Konno, and T. Takemoto, Chem. and Pharm. Buil. (Japan), 1975,23,125. S . Lang, D. N. Lincoln, and V . Wray, J.C.S. Perkin 11, 1975, 344. P. H. Solomo'n, K. Nakanishi, W. E. Fallon, and Y .Shimizu, Chem. and Pharm. Bull. (Japan), 1074,22, 1671. J. W. ApSimon, H. Beierbeck, and J . K. Saunders, Canad. J. Chem., 1975,53,338. G . Englert, W. Arnold, H. Els, A. Fiirst, A. Meier, and W. Meister, Helv. Chim. Acta, 1964,57.1549. W. Arnold, W. Meister, and G . Englert, Helv. Chim. Acta, 1974, 57, 1559. H. Hosoda, K. Yamashita, and T. Nambara, Chem. and Ind., 1975,650. A. Fratiello and C. S. Stover, J. Org. Chem., 1975, 40, 1244. J. M. A. Al-Rawi, J. A. Elvidge, R. Thomas, and B. J. Wright, J.C.S. Chem. Comm., 1974, 1031. E. E. Ernstbrunner and J. Hudec, J. Amer. Chem. SOC.,1974,96, 7106.
224
Terpenoids and Steroids
Cotton effect observed for 5a-cholest-6-en-3-one, once thought to indicate a boat conformation of ring A, is now re-interpreted as a consequence of inductive withdrawal of electrons from the carbonyl group by the olefinic bond. This 0 withdrawal effect outweighs any v-donation from the olefinic bond because the ring structure is somewhat flattened by the unsaturation, so that the 4,5-bond is not suitably aligned for efficient through-bond coupling of the two v-systems (3). Some other 78 - and 6~-unsaturated ketones show enhanced Cotton effects because their bond and orbital directions are more favourable to through-bond coupling of the carbonyl and the olefinic v-bond
C.d. data for steroidal acetates and acetamides have been analysed empirically to obtain numerical values of contributions t o the total Cotton effect attributable to Although no attempt was made to individual C-C bonds of the steroid ~keleton.~’ discuss the nature of the perturbation of the chromophore by structural features, the results of this analysis permit predictions of A E for acetates in decalin-like structures and provide data for testing theoretical treatments of these chromophores. The sign of the 7~ -+ n* Cotton effect (205-235 nm) for conjugated butenolides [e.g. (4)] is controlled by the nature of substitution at the y-carbon atom, the butenolide ring itself being essentially planar. The configuration at C-5 in the butenolide (4) is associated with a negative Cotton effect at 235 nm. The sign seems to depend upon the relative polarizabilities of groups X and Y in the component structure (5).3’ OAc
(4)
Calculated c.d. curves for bis-(p-dimethylaminobenzoates)of sterbidal diols show excellent agreement with experimental results. The Cotton effects of the two esters are coupled even at large separations (e.g. at 12.8 A in the diester of D-homo-Saandrostane-3P,lSP-diol), resulting in splitting of the c.d. curve into a pair of oppositely signed maxima near 323 and 295 nm, respectively. The signs and magnitudes of the maxima are related to the relative orientations and the separation of the two dipoles and provide evidence of the absolute configuration of the molecule (‘exciton chirality’ method).32 Quantum-mechanical calculations based upon onedimensional electron gas theory give rotational strengths for butadiene systems 2c) 30 31
72
G. P. Powell, R. N. Totty, and J. Hudec, J.C.S. Ferkin I, 1975, 1015. L. Bartlett, D. N. Kirk, and P. M. Scopes, J.C.S. Perkin I, 1974, 2219. I. Uchida and K. Kuriyama, Tetrahedron Letters, 1974, 3761. S. L. Chen, N. Harada, and K. Nakanishi, J. Amer. Chem. SOC., 1974,96, 7354.
Steroid Properties and Reactions
225
which reproduce the 0.r.d. curve of lumisterol fairly closely between 320 and 220 nrn. '' Steroidal 2,4-dienes, and related compounds such as levopimaric acid, exist as equilibrium mixtures of two conformations on the evidence of force-field calculations; the proportions depend upon the pattern of substitution. Cotton effects are dependent both upon conformer populations and upon substituent Positive Cotton effects (c.d.) are reported for both 3 a - and 3P-trimethylstannyl5a-cholestanes, at 203 nm and 210 nm, r e ~ p e c t i v e l y . The ~ ~ compounds were studied in connection with an evaluation of the effects of 'p'-trimethylstannyl substituents in cyclohexanone analogues, which provide evidence of through-bond coupling to augment that already recognized for electronegative s u b ~ t i t u e n t sThe .~~ circular dichroism associated with the enone systems of cholest-4-en-3-one and 3 p acetoxycholest-5-en-7-onehas been recorded for samples oriented by an electrical field in a nematic phase composed of cholesteryl chloride and cholesteryl l a ~ r a t e . ~ ~ New rules are proposed for the correlation of D-line molecular rotations with structures of steroid derivative^.^^ This work extends an earlier analysis39and in the present case relates mainly to data for substituents at C-3, C-5, and C-6. Miscellaneous. New support the previously proposed mechanisms for mass-spectral fragmentation of the steroid ring D. Mass spectra are reported for a series of steroidal ~ a p o g e n i n sand , ~ ~ for acetates and acetonides of ecdysterone and v i t i c ~ s t e r o n e .The ~ ~ advantages and disadvantages of various ionization techniques for obtaining mass spectra have been assessed for a range of compounds, including two 16,22,26-oxygenated c h o l e s t e r ~ l s Differences .~~ between appearance and ionization potentials provide a distinction between 5 a - and 5P-steroids, reflecting the differences in strain energy.44 Chemical ionization mass spectrometry of cholesteryl alkanoates gives distinct ion peaks for different fatty-acid components, allowing the analysis of mixtures from natural sources such as egg yolk.45 0.r.d. and 'H n.m.r. measurements usefully augment g.1.c.-m.s. for the identification of isomeric cholestane hydrocarbons. Seven such compounds, isomeric at C-5, C-8, C-14, C-17, and C-20, have been studied as part of a programme concerned with the identification of hydrocarbons from geological sources.46 Methods for the resolution of overlapping curves in i.r. spectra have been reviewed, with 17-0~0-5a-androstan-3~-yl thiophen-2-carboxylate among the examples.47 E.s.r. spectra are reported for the novel steroidal biradical (6)." 31
34 35 36 97
38
39
40 41
42
43
44 45 46 47 48
H. J. Nolte and V. Buss, Tetrahedron, 1975, 31, 719. G. A. Lane and N. L. Allinger, J. Amer. Chem. SOC., 1974,96, 5825. J. Hudec, J.C.S. Perkin Z, 1975, 1020. Ref. 6, 1972, Vol. 2, p. 235. H.-G. Kuball and T. Karstens, Angew. Chem. Internat. Edn., 1975,14, 176. S. Yamana, Bull. Kyoto Univ. of Education ( B ) , 1975, No. 46, p. 9. Ref. 6, 1973, Vol. 3, p. 294. D.C.Mammato and G. A. Eadon, J . Org. Chem., 1975,40,1784. A. M. Dawidar and M. B. E. Fayez, J. Pharm. Sci., 1974,63,140. I. L. Zatsny, M. B. Gorovits, Y. V. Rashkes, and N,. K. Abubakirov, Khim.prirod. Soedinenii, 1975,155. H. M. Fales, G. W. A. Milne, H. U. Winkler, H. D. Beckey, J . N. Damicc, and R. Barron, Analyt. Chem., 1975,47,207. V. I. Zaretskii and L. Kelner, Tetrahedron, 1975, 31, 85. T. Murata, S.Takahashi, and T. Takeda, Analyt. Chem., 1975,47, 577. L. J. Mulheirn and G. Ryback, J.C.S. Chem. Comm., 1974, 886. D.J. Chadwick, J. Chambers, and R. L. Snowden, J.C.S. Perkin ZZ, 1974, 1181. K. Metzner and L. Libertini, Tetrahedron Letters, 1975, 81.
Terpenoids and Steroids
226
2 Alcohols and their Derivatives, Halides, and Epoxides Substitution and Elimination.-Dimethylformamide bis-(2,2-dimethylpropyl) acetal [Me,NCH(OCH,CMe,),] in refluxing acetic acid-toluene converts 5a cholestan-3a- or 3p-01 into the acetate of the alcohol of inverted configuration. Use of 4-nitrophenol as the acidic component gives the 4-nitrophenyl steroidal ether, again with inversion of c ~ n f i g u r a t i o n .The ~ ~ reaction must involve formation and replacement of a mixed acetal containing the steroid as one of its alkyl components. Use of the 2,2-dimethylpropyl (‘neopentyl’) acetal is dictated by the need to avoid nucleophilic substitution in an alkyl group of the reagent, to allow time for exchange with the steroid. The scope of nucleophilic substitution of steroidal alcohols by reaction in THF with a mixture of diethyl azodicarboxylate, triphenylphosphine, and a carboxylic acid has been extended by use of a phenol instead of a carboxylic acid. 5a -Cholestan-3P-ol gave 3a -phenoxy-5a -cholestane, or the 3a -pbromophenoxy-analogue, by use of the appropriate phenol. Uracil afforded 2,4-bis(cho1estan-3a-y10xy)pyrimidine7with use of hexamethylphosphoramide (HMPA) as solvent instead of THF. Use of oestrone as the phenolic component allows alkylation by a similar p r o c e d ~ r e . ~ ’The reaction between cholesterol, triphenylphosphine, diethyl azodicarboxylate, and benzoic acid gave a mixture of at least six products. The expected cholest-5-en-3a-yl benzoate was accompanied by products derived from the 3,5-cyclocholesteryl cation and by the abnormal product 3a,5-cyclo-5a-cholestan-6a-yl benzoate (7), probably derived from an interbenzoate (8).51 mediate 3a,5-cyclo-5a-cholestan-4~-yloxytriphenylphosphonium New mechanistic conclusions are reported regarding the conversion of alcohols into chlorides with carbon tetrachloride and triphenylph~sphine,~~ which has found application in steroid hemi is try.^^
’
(7) R = u-OBZ f
-
(8) R = P-OPPh, OBZ H. Vorbruggen, Annalen, 1974, 821. M. S. Manhas, W. H. Hoffman, B. Lal, and A. K. Bose, J.C.S. Perkin Z, 1975, 461 5 1 R. Aneja, A. P. Davies, and J. A, Knaggs, Tetrahedron Letters, 1975, 1033. s 2 I. Tomoskozi, L. Gruber, and L. Radics, Tetrahedron Letters, 1975, 2473. s53 R. Aneja, A. P. Davies, and J. A. Knaggs, Tetrahedron Letters, 1974, 67.
49
Steroid Properties and Reactions
227
The stereochemistry of fluorination of alcohols by phenyltetrafluorophosphorane or diphenyltrifluorophosphorane depends upon structure. Saturated 3P- or 3 a alcohols react with inversion, to give the 3-fluoro-derivatives of opposite configuration (S,2 mechanism), along with the A2-olefin. Cholesterol reacts, as usual, to give the 3P-fluoro-compound with retention of configuration, but also gives dicholesteryl ether as a major product. The bromohydrin (9) reacts via an intermediate bromonium ion (10) to give the 6P-fluoro-compound (1 l).54 Phenyltetrafluorophosphorane also reacts smoothly with trimethylsilyl ethers of 3P-hydroxyA5-steroids to give 3P-flUoro-derivati~es.~~ The normal Ritter reaction fails with
AcO
R OH (11) R = F (9) R
=
cholesterol, but the recently prepared chlorodiphenylmethylium and dichloro(pheny1)methylium salts, (12) and (13) respectively, promote reaction between cholesterol and acetonitrile to give the 3P-nitrilium ion (14).56 Quenching with water then affords 3P-acetamidocholest-5-ene (15). Other nucleophiles may be adde< -as alternatives to water to produce a variety of products [e.g. Bun4NN3+tetrazole (16); Et2NH+ amidine (17); EtOH +amidate (18)].
(16)
R
=
(17)
R
=
N
x
\N’N Y Me
+ *. (14) R = MeC=N (15) R = Me-C-NH
II
0
>N Et,N Me
>N
(18) R =
EtO
16a-Substituents of various types (N3, SCN, SeCN, SEt, NH2, NHAc) have been introduced by treating 16P-bromoestra-1,3,5(lO)-triene-3,17P-diol with appropriate nu~leophiles.~’ Reaction of either 17a -hydroxy- 16a-hydroxymethylandrostane (19) or its 17P,16p-isomer with hydrogen bromideacetic acid gave the corresponding 17-acetoxy- 16-bromomethyl derivative, via nucleophilic opening of a cyclic acetoxonium ion (20) by bromide 54
55
56 5’ 58
Y. Kobayashi, I. Kumadaki, A. Ohsawa, M. Honda, and Y. Hanzawa, Chem. and Pharm. Bull. (Japan), 1975,23, 195. N, E. Boutin, D. U. Robert, and A. R. Cambon, Bull. SOC.chim. France, 1974, 2861. D. H. R. Barton, P. D. Magnus, J. A. Garbarino, and R. N. Young, J.C.S. Perkin I, 1974, 2101. K. Ponsold, J. Schlegel, B. Schonecker, and K. Schubert, Pharmazie, 1975,30,32. G. Schneider and I. Weisz-Vincze, Tetrahearon Letters, 1975, 2115.
Terpenoids and Steroids
228
Me
(19)
(20)
A one-step allylic rearrangement -of a 17P-hydroxy-17a-vinyl steroid (21) in acidified acetic acid-acetic anhydride gave the 21-acetoxypregn- 17(20)-ene (22) in 60-65% yield,59improving upon an earlier two-step sequence uia the 2 l-chloroderivative. 17P-Hydroxy-17a-vinyl steroids (21) are converted into (E)-pregn17(20)-enes (24) by reaction first with thiourea and hydrochloric acid to give the rearranged thiuronium salt (23), followed by reduction with sodium-ammonia.60
ilYH=cH2
/CH20Ac
The (20S)-20-vinylpregnan-20-ol (25), which was the major product from reaction of vinylmagnesium bromide with the pregnan-20-one, is dehydrated or rearranged with substitution in acetic acid to give the three products (26)-(28).61
(25)
(26)
(27)
(28)
The substitution reactions of a-bromo-ketones to give a’-acetoxy-ketones are generally considered to proceed vih an enol, with allylic (S,2’) substitution in the cis stereochemical sense.62 A new investigation of the reaction between 4P-bromo-3oxo-5P-steroids (29) and acetate ion shows that the initial product is the 2a-acetoxyketone (30), which rearranges rapidly under the reaction conditions to give the stable 5y
h2
D. 0.Olsen and J. H. Babler, J. Org. Chem., 1975, 40, 255. H. Schick, Pharmazie, 1975, 30, 30. Y. Letourneux, M. M. L. Lo, N. Chaudhuri, and M. Gut, J. Org. Chem., 1975,40, 516. M. S. Newman, ‘Steric Effectsin Organic Chemistry’, Wiley, New York, 1959, p. 97; D. N. Kirk and M. P. Hartshorn, ‘Steroid Reaction Mechanisms’, Elsevier, Amsterdam, 1968, p, 387.
229
Steroid Properties and Reactions
2P-acetoxy-isomer (3 l y 3 The conclusion that this allylic substitution occurs by a trans mechanism seems inescapable, for all reasonable alternative mechanisms seem to have been eliminated by a series of further e x p e r i m e n t ~ . ~ ~
(30) 2u-AcO (31) 2P-AcO
3~-Chloro-5a-cholestane-5,6P-diol(32) is one of a variety of diols which afford epoxides in high yield on treatment with the sulphurane (33);the 5ay,6a-epoxide(34) was formed.64 An inyestigation of the dehydration of steroidal alcohols by the reagent MeO,CNSO,NEt, establishes that a trans mechanism is preferred, contrary to earlier Attempted coupling of a bisnorcholan-22-yl tosylate (35)with 3,3-dimethyl-allylmagnesiumbromide resulted instead in the 22,22’-dimer (36), together with the parent bisnorcholane (37). A bisnorcholanylmagnesium bromide intermediate is considered to take part in Wurtz-type coupling, or to be hydrolysed to the alkane during work-up.66
I
OMe (35) R = OTs (36) R = tz (37) R = H
Rates of solvolysis of 17-substituted 5a-androstan-3-yl- tosylates show greater sensitivity to the electronic effects of C-17 substitution than can be attributed to simple dipole-dipole or charge-dipole interactions between the centres of substitution and reaction. Moreover the solvolysis rates observed in formic, acetic, and trifluoroacetic acids do not reflect the pronounced differences between solvent 63 64
hs 66
T. T. Takahashi and J. Y. Satoh, Bull. Cltem. SOC.Japan, 1975,48,69. J. C. Martin, J. A. Franz, and R. J. Arhart, J. Amer. Chem. SOC.,1974, 96, 4604. J. S. O’Grodnick, R, C. Ebersole, T. Wittstruck, and E. Caspi, J. Org. Chem., 1974,39, 2124. S. K. Dasgupta and M. Gut, J. Org. Chem., 1975,40, 1475.
230
Terpenoids and Steroids
dielectric constants in any clear way. The authors suggesth7 that the rate effects exceed those expected because solvent interactions with negative poles effectively delocalize the negative charge into the solvent and so reduce its interaction with other charged centres in the steroid molecule. The results and discussion, however, leave the reader with the feeling that much remains to be done in this field before substituent effects over long distances are properly understood. Ring-opening of Epoxides.-Recent workhxon the reactions of 4,S-epoxy-3-oxosteroids with hydrogen halides has now been reported in full.h’ Different modes of reaction are recognized. The 4p,SP-epoxy-ketone (38) reacts with HF by pcleavage of the epoxide (at C-51, giving first the 5a-fluoro-4P-alcohol(39);epimerization at C-4 then gives the more stable cis-fluorohydrin (40). @-Cleavageat C-4 occurs with HCl in aqueous acetone, giving the 4-chloro-4-en-3-one (41) by dehydration of the first-formed 4,s-chlorohydrin. When chloroform-ethanol was used as the solvent, the 4-chloro- (41) and 2a-chloro-4-en-3-ones (42) were formed afford products of either ptogether. Similar reactions of 172-epoxy-3-oxo-steroids or a-cleavage, or with HF the 4p-fluoro-1-en-3-one (43).6y
Suitably substituted steroidal epoxides can undergo apparent cis-cleavage, paralleling reactions which are well known in sugar chemistry. The 6P-hydroxy-3methoxy-4a75a-epoxides (44), for example, react via the 4a-hydroxy-SP,GPepoxide (45), which then suffers normal diaxial opening with acids to give the 4a,5a,6P -trio1 (46). The 3-methoxy-substituent apparently inhibits 4a75a-epoxide opening at C-4. The 6-0x0-analogue (47) reacts with acetic acid to give the 7 a acetoxy-derivative (49), by a cine-substitution accompanying epoxide opening (48) at C-5.70 h7 6x
h‘’
P. E. Peterson and D. M. Chevli, J. Org. Chem., 1974,39, 3684. Ref. 6, 1973, Vol. 3, p. 303. M. Neernan and J . S . O’Grodnick, Canad. J. Chem., 1974, 52, 2941. G. A . Morrison and J. B. Wilkinson, TetrahedronLetters, 1965, 2713.
Steroid Properties and Reactions
23 1
Me0
Me0 0
H
OH
‘Ac
(47)
(49)
Some 10P-substituted derivatives of 19-nortestosterone have been prepared by opening of a 5a,lOa-epoxide (Scheme l).71
X
=
C1, N,, NH,, CN, SCN, OAc, SH, SEt, SAC, NHR, etc.
Scheme 1
The isomeric 3-iodo-4@,5P-epoxides (50) are reduced either by sodium naphthalide or by butyl-lithium to give the allylic alcohol (51), apparently by a non-concerted mechanism involving a rate-determining one-electron transfer .72 71 72
K. Ponsold, W. Schade, and M. Wunderwald, J. prakt. Chem., 1975,327, 298,307, 319. S. K. Pradhan and M. Girigavallabhan, J.C.S. Chem. Comm., 1975, 591.
232
Terpenoids and Steroids
(50)
(51)
6a-Methyl-6@,19-epoxy-5a-steroid derivatives (52), obtained from the 6 p hydroxy-6a-methyl compounds by reaction with lead tetra-acetate, are cleaved by acidified acetic anhydride to give mixtures of the 19-acetoxy-6-methyl-A5- and -A6-compounds ( 5 3 ) and (54),as well as the 6-methylene isomer (55).73
AcO
J3iy A :
@ :
AcO
Me ( 5 3 ) As (54) A6 ( 5 5 ) 6-=CH,
Esters, Ethers, and Related Derivatives of Alcohols.-Rates of acetylation of 7 a hydroxy-5@-cholan-24-oicacid derivatives are sensitive to substitution at the 3aand particularly at the 12a-position. Polar substituents at C-3 enhance the rate slightly, whereas a 12a-hydroxy-group can cause a 6-1 8-fold acceleration, probably by complexing with the N-acetylpyridinium ion before delivering it to the nearby 7 a -hydroxy-group (56). Kinetic measurements were made very conveniently by measuring methyl group signals for reactant and product in the 'H n.m.r. spectra of reacting solutions (in pyridine-acetic a n h ~ d r i d e ) .Continued ~~ of ester hydrolysis under the influence of the imidazolyl-steroid derivative (57)has indicated
that rate enhancements attributed to hydrophobic steroid-alkyl chain interactions are much smaller than earlier had suggested. Esterification of steroidal 73 74 7s
76
G. Doria, P. Gaio, A. Andreoni, E. Dradi, and C. Gandolfi, Farmaco, Ed. x i . , 1974, 733. J. F. Baker and R. T. Blickenstaff, J. Org. Chem., 1975, 40, 1579. J. P. Guthrie and Y. Ueda, J.C.S. Chem. Comm., 1974,991. Ref. 6, 1975, Vol. 5, p. 262.
233
Steroid Properties and Reactions
hydrogen succinates with steroidal alcohols in the presence of NN’-carbonyldiimidazole gives disteroidal succinates with either the same or different steroidal A method for acetylating components, which can have useful biological activitie~.~’ hindered tertiary alcohols is described on p. 245. Ferric chloride catalyses the cleavage of ethers by acetic anhydride: cholesteryl methyl ether gives cholesteryl acetate in 87% yield.78Pentafluorophenyldimethylsilyl ethers of steroid alcohols are described as excellent derivatives for gas chromatography, being stable, volatile, and detectable at picogram levels with an electron-capture d e t e ~ t o r . ’ ~The dimethylphosphonates and dimethylthiophosphonates have been prepared from a series of common hydroxysteroids.80 Cholesterol reacts with palmitic aldehyde diethyl acetal to give the mixed cholesteryl ethyl acetal (58),which gives the alkenyl ethers (59) on reaction with aluminium powder or with thionyl chloride.*’
OEt (59) cis
(58)
+ trans
Oxidation.-Silver carbonate on celite (Fetizon’s reagent) reacts non-selectively with a pregnane-18,20-diol(60),giving the lactone (61) and the lactol (62).82Special conditions have been described for the selective oxidation of Sa-androstane-3&6@diol with Fetizon’s reagent to give the 3-0x0-derivative as major product. The 3&6a-diol readily gives the 3-0x0-derivative in good yield.83
(60)
(61)
(62)
Pyridinium chlorochromate, described as a safe, stable, and readily prepared alternative to the chromium trioxide-pyridine complex, is a convenient oxidant for primary and secondary and should find use in steroid chemistry. Dimethyl sulphide ‘ditriflate’, prepared from DMSO and trifluoromethanesulphonic anhydThe biological ride at -78 “C, has been used to oxidize 3-hydro~y-steroids.~~ 77
78 79
R2
83
H. Kuhl and H.-D. Taubert, Steroids, 1974, 24, 613. B. Ganem and V. R. Small, J. Org. Chem., 1974,39, 3728. E. D. Morgan and C. F. Poole, J. Chromatog., 1975,104, 351. K. Jacob, W. Vogt, I. Fischer, and M. Knedel, Tetrahedron Letters, 1975, 1927. E. M. Bagaturova, G. E. Bannikova, and G . A. Serebrennikova, Zhur. org. Khim., 1975,11, 965. M. Fetizon, M. Golfier, and J.-M. Louis, Tetrahedron, 1975, 31, 171. Sir E. R. H. Jones, G. D. Meakins, J. Pragnell, W. E. Muller, and A. L. Wilkins, J.C.S. Perkin Z, 1974, 2376.
s4 85
E. J. Corey and J. W. Suggs, Tetrahedron Letters, 1975. 2647. J. B. Hendrickson and S. M. Schwartzman, Tetrahedron Letters, 1975, 273.
234
Terpenoids and Steroids
conversion of 19-hydroxy-androgens into oestrogens involves a stereospecific removal of the pro-R hydrogen atom from C-19, as a proton; the pro-S hydrogen appears in the formic acid which is liberated when the 19-aldehyde breaks down by a C-10-C-19 bond fragmentation of retro-aldol type.86 Rates of oxidation of 3Phydroxy-A’-steroids by cholesterol oxidase show wide variations dependent upon side-chain Shortened side chains compared with that of cholesterol cause lower rates of oxidation, indicating that enzymic recognition involves the whole steroid molecule. (63) has been reduced by Reduction.-1 a,2a-Epoxycholesta-4,6-dien-3-one lithium-liquid ammonia under strictly controlled conditions to give a mixture which included 45% of the la,3/3-dihydroxy-5a-6-ene(64), and 20% of the A’-isomer.88 The A6-compound was used in the preparation of 1a,3P-dihydroxycholesta-5,7diene, required for the synthesis of la-hydroxy-vitamin D3.
(63)
(64)
Reductions of 4,4-dimethyl-5,6-epoxy-steroidswith lithium-ethylamine show abnormalities associated with steric effects of the C-4 s u b s t i t ~ e n t s .Unlike ~~ the corresponding reactions of 5,6-gpoxycholestanes, the reductions in the 4,4-dimethyl series are not regiospecific. 4 a -Methylcholesterol is obtained directly in good yield with LiAlH, in large excess by reduction of 6~-bromo-4-methylcholest-4-en-3-one (3a,4P-[’H2] when LiAlD, was used). Lower proportions of reducing agent gave mixtures containing the 4 a - and 4P-methyl i ~ o m e r s . ’The ~ reason for this difference is not yet clear. Sodium borohydride in refluxing propan-2-01 dechlorinates 5a,6PdichIoro-steroids to give the parent A5-compounds. The 3 a -hydroxy-derivative shows enhanced reactivity which is attributed to a neighbouring-group effect in relation to 5a-C1. Several possible mechanisms are Hydrogenolysis of either cholest-5-ene-3P,7cu-diol or the 5-ene-3/3,7P-diol with AIHCI2 (or A1DCl2) gives mainly the product of a attack at C-7, but cholest-4-en-3a-ol and -3p-01 react with differing stereoselectivities, showing that the presumed allylic cation intermediates have different characteristics. Two allylic cations with different conformations in ring A, separated by a significant energy barrier, are suggested as a possible explanation.y2
3 Unsaturated Compounds Electrophilic Addition.-trans-Diequatorial diols are not readily prepared from olefins in the steroid series. The ring-opening of epoxides generally gives transdiaxial products, whereas acyloxonium ions (65), formed during the Prkvost sf, XN xy
9o 91
‘I2
D. Arigoni, R. Battaglia, M. Akhtar, and T. Smith, J.C.S. Chem. Comm., 1975, 185. A. G. Smith and C. J. W. Brooks, J. Chromatog., 1974,101, 373. D. Freeman, A. Acher, and Y. Mazur, Tetrahedron Letters, 1975, 261. M. Adinolfi, G. Laonigro, and L. Mangoni, Garzetta, 1974, 104, 799. F. F. Knapp, jun. and G. J. Schroepfer, jun., J. Org. Chem., 1974,39, 3247. Y. Houminer, J.C.S. Perkin I, 1975, 277. I. M. Cunningham and K . H. Overton, J.C.S. Perkin I, 1974, 2458.
Steroid Properties and Reactions
235
reaction, normally afford cis-axial-equatorial or trans-diaxial diols according to reaction conditions. A modified Prkvost reaction has been devised to overcome this limitation. 'Treatment of 5a-cholest-2-ene with iodine and the silver salts of very bulky acids (e.g. mesitoic acid) gave esters of the trans-diequatorial 2a,3@diol(66) in yields of up to 58%. The reaction is controlled by steric inhibition of axial approach of the carboxylate ion to attack the intermediate 2P,3P-acyloxonium ion (65).93 Even better results (77% yield of 2a,3P-diol) came from use of the 2a,3a-acyloxonium ion, formed by the action of boron trifluoride on 5cucholestane-2a,3a -diyl ethyl orthobenzoate (67), which is readily available from the 2a,3a -diol. Another modification of the Prkvost reaction described briefly last year, Use of iodine and potassium iodate in acetic acid at 60°C is now reported in provides a cheaper alternative to iodine-silver acetate, converting 5a -cholest-2-ene into the iodohydrin acetate (68) in good yield. Similar reactions of other olefins are described.
(68)
(67)
Conflict between electronic (Markovnikov) and conformational control in the electrophilic additions of alkenes is well known in steroids and generally leads to the conformationally preferred diaxial addition product. Methoxybrominations of 2methyl-5a-cholest-2-ene (69) and its 3-methyl isomer (7 1) illustrate control by a combination of conformational and electronic factors; the products indicate that the first-formed bromonium ion equilibrates between the 2a,3a and the 2/3,3P configurations before suffering nucleophilic attack by methanol. The major product (72) from the 3-methyl compound results from methanolysis of the less stable 2@,3Pbromoriium ion, axial attack at the tertiary C-3 being the most favourable mode of reaction.95
(49) y3 94 95
(70)
(71)
R. Caputo, L. Mangoni, and L. Previtera, Steroids, 1975, 25, 619. L. Mangoni, M. Adinolfi, G. Barone, and M. Parrilli, Gazzettu, 1975, 105, 377. M. Parrilli, G. Barone, M. Adinolfi, and L. Mangoni, Gazzettu, 1973, 103, 1265.
(72)
236
Terpenoids and Steroids
Some reactions of 3~,5-diacetoxy-6-nitrimino-5tu-cholestane (73) confirm the revised structure recently assigned to this product, formed from cholesteryl acetate and nitrous acid.y6 The derived salt (74) was protonated at nitrogen to give the secondary nitramine (75) or methylated to give the tertiary nitramine (76). Some further features of this series of compounds are still being inve~tigated.'~
(73)
R
(74) (75)
R
(76) R
= =
H Me
Full details" of the reactions of Pb(OAc),-HF with pregnen010ne~~ include evidence for the formation of the organo-lead derivative (77) and a variety of rearranged products containing fluorine. Products depend upon the ratio of HF to Pb(OAc),, which appears to determine the composition of a mixture of reactant species of the types represented by (AcO),PbF, and possibly H,PbF,. Electrophilic character is ascribed to the fluorinated Pb'" reagents. Oxymercuration of a 5-ene (e.g. cholesterol) with mercury(1) trifluoroacetate gave in low yield the 4 a - o x o - ~ homo-B-nor-compound (79), probably by a semipinacolic rearrangement of the cis-addition product (78).'"
(77)
(78)
(79)
The acid-catalysed hydration of 3a,5-cyclo-Sa-androst-6-ene occurs without stereoselectivity: deuteriated solvent resulted in androst-5-en-3p-01 with equal proportions of 7 a - and 7P-de~terium.~" Epoxidation.-A polystyrene-based resin substituted by peroxidized carboxygroups converted cholesteryl acetate in only moderate yield into the 5,6-epoxides, although some other olefins reacted more efficiently."' Epoxidation of 3a,5-cyclo5a-androst-6-en- 17-one (3-C1C6H,C0,H) gave the unstable 5a,6a -epoxide (80), which readily opened with participation of the cyclopropane ring to give 3P,7adihydroxyandrost-5-en- 17-one (8 l),as well as other products depending upon the 10P-Hydroperoxy- 17P-hydroxyoestr-4-en-3-one (82) undergoes an O6
M. Onda, Y. Konda, and R. Yabuki, Chem. and Pharm. Bull. (Japan), 1975,23,611. M. Ephritikhine and J. Levisalles, Bull. Soc. chim. France, 1975, 339. Ref. 6, 1975, Vol. 5 , p. 240. I . Torrini and A. Romeo, Tetrahedron Letters, 1975, 2605. J. C. Orr and J. M. Broughton, J. Org. Chem., 1975, 40, 1949. C. R. Harrison and P. Hodge, J.C.S. Chem. Comm., 197-4, 1009. R. C. Cambie, P. W. Thomas, and J. R. Hanson, J.C.S. Perkin I, 1975, 323.
')'
98
loo
Iol
Steroid Properties and Reactions
237
intermolecular epoxidation in presence of alkali to give - 4P,5-epoxy-l0/3,17pdihydroxy-5P-oestran-3-one(85).lo3 The compounds (83) and (84) have been isolated as intermediates, establishing an intermolecular mechanism whereby one molecule, as the hydroperoxy-anion, provides the oxygen atom for epoxidation of a second molecule.
& '
0
(83)
Miscellaneous Additions. -The conversion of testosterone into 4-methyltestosterone via a modified Simmons-Smith methylenation of the A3?'-dien3-yl trimethylsilyl ether lo4 has now been varied by employing the A294-dien-3-yl trimethylsilyl derivative (86), produced by trapping the kinetically controlled dienolate. The end product, via (87), was 2a-methyltestosterone (88).lo5 A 2 y 4 -
(86)
(87)
(88)
Palladium diacetate catalyses the reaction of diazomethane with a$-unsaturated ketones to give cyclopropyl ketones in high yields. Steroidal examples include formation of the products (89) and (90) from the corresponding enones.lo6
H (89)
Vinylmagnesium bromide in the presence of cupric acetate reacts with ap-unsaturated ketones to give the conjugate-addition with stereochemistry Io3 Io4 105
lo6 lo'
M. Maumy, Bull. SOC.chim. France, 1975, 2895. Ref. 6, 1974, Vol. 4, pp. 361-362. C. Girard and J. M. Conia, Tetrahedron Letters, 1974, 3327. U, Mende, B. Radiichel, W. Skuballa, and H. Vorbriiggen, Tetrahedron Letters, 1975, 629. H. Mori arid R. Oh-Uchi, Chem. and Pharm. Bull. (Japan), 1975, 23,559, 980.
Terpenoids and Steroids
238
following that found with saturated Grignard reagents (0.g. AI6-20-ketone --* 16avinyl; 19-nor-A4-3-ketone+ SP-vinyl; A'-3-ketone + la-vinyl). Some transformations of the vinyl substituents are described.lo7 New and efficient total syntheses of (+)-oestr-4-ene-3,17-dione,(+)-oestrone 3-methyl ether, and their 13P-ethyl analogues include Michael additions to bicyclic units (91) as a key step.lo8
(91)
Hydroboration of the ergost-22-ene side chain, with thermal isomerization of the borane intermediate before oxidation, gives the 26-hydro~y-derivative."~Various cholestenes readily form palladium r-ally1 complexes by reaction either with bis(benzonitri1e)palladium dichloride in boiling chloroform or with disodium tetThe former system gave fewer rachloropalladate (in HOAc-Ac,O-NaOAc). isomeric products, cholest-Sene affording only the dimeric a-4-6q-complex (92), in 71% yield. Other products isolated from suitable reactant olefins include p-46q-, a - and P-3-5q-, and a-5-7q-complexes7 all as dimers. The complexes are reduced by LiAlH, to give cholestenesll" or oxidized by 3-chloroperbenzoic acid in The .rr-ally1 complex (92), for the presence of pyridine to give allylic example, gave cholest-5-en-4a-01 (93).
OH (92)
(93)
Diazocyclopropane adds to a pregn- 16-en-20-one to give a pyrazole derivative, while a 4-en-3-one undergoes ring expansion to form A-homo-products. The formation of compounds (95) and (96) from pregna-4,16-diene-3.20-dione(94)
(94) R. A. Micheli, Z . G. Hajos, N. Cohen, D. R. Parrish, L. A. Portland, W. Sciamanna, M. A. Scott, and P. A. Wehrli, J. Org. Chem., 1975,40,675; N. Cohen, B. L. Banner, W. F. Eichel, D. R. Parrish, and G. Saucy, ibid., p . 68 1 . E. Mincione, F. Feliziani, and 0. Rossi, Ann. Chim. (Italy), 1973, 63, 297. D. N. Jones and S. D . K n o x , J.C.S. Chem. Comm., 1975, 165. D. N. Jones and S . D. Knox, J.C.S. Chern. Comm., 1975, 166.
l°K
109
lo I
239
Steroid Properties and Reactions
illustrates these reactions. Saturated 3-OXO-5~u -steroids afforded complex mixtures including cyclobutanone derivatives (97), whereas saturated pregnan-20-ones gave only cyclobu tanones (98). l 2 Phenyl azide adds regioselectively on to a pregn-16-en-20-one, to give the [17a,l6a-d]-triazoline (99), along with the aziridine (loo), but a 17methoxyandrost-16-ene adds phenyl azide mainly in the opposite sense to give the [16a,l7a-d]-triazoline (101). Electron density distribution in the AI6-olefinic bond is an important controlling factor in deciding the regioselectivity of these additions. l 3
(99)
(100)
(101)
Cholesta- 1,3-diene, -3,5-diene, and -4,6-diene react with PhI(OAc),-Me,SiN, to give the la-azido-2-en-4-one, GP-azido-4-en-3-one, and 4P-azido-5-en-7-one, respectively. Reduction.-Olefinic bonds may be reduced electrochemically without attack on other functional groups. The oestratetraene (102), for example, was reduced only at
(102)
the As-position to give the 8a - or 8P-oestradiol derivatives, depending upon temperature. Isolated As unsaturation affords the 5a -dihydro-derivative, and 4-en3-ones give mixtures of 5a - and 5p -dihydro-compounds, without reduction of ketonic groups.115 P.Bladon and D. R. Rae, J.C.S. Perkin I, 1974, 2240. B. Green and D.-W. Liu, Tetrahedron Letters, 1975, 2807. 1 1 4 F. Cech and E. Zbiral, Tetrahedron,1975,31, 605. '15 K. Junghans, Chem. Ber., 1974,107,3191. llZ
Il3
240
Terpnoids and Steroids
Solvent quality controls the hydrogenation of ergosterol (or its acetate) over Raney nickel.'16 When pure ethyl acetate is used, for example, reduction proceeds smoothly to 5a-ergost-7-en-30-01, but the presence of a little acetaldehyde, 4dimethylaminobenzaldehyde, dimethylaniline, or a similar contaminant, stops the reaction at the 7,22-diene stage. Oxidation.-Singlet oxygen, generated chemically from NaOCl-H,O,, attacks vitamin D3 in methanol to afford the dimethoxy-diene (103), which loses methanol over several hours to give a mixture of isomeric methoxy-trienes (1O4).ll7 OMe
Q
G
HO
'C8H17 C8H17
Sensitized photo-oxygenation of 5a-androsta-14,16-diene (105) gave the 14phydroxy-15-en-17-one (106).'18 The 14,16-diene was obtained by allylic bromination of the 16-ene and dehydrobromination with 1,5-diazabicyclo[5,4,0]undec-5ene. Other bases were less efficient. Cholest-4-en-3P-01 and its 5a-A6- and 5a-A7-isomersgave complex mixtures of oxidation products on treatment with 6oCoy-radiation in air. Reaction paths are discussed and compared with those occurring in photosensitized and free-radical oxidations.'1y 1-Methyl-1 1-0x0-oestrone (107) is converted by DDQ in 1%aqueous dioxan into the 9P-hydroxy-derivative (lOS), apparently by hydration of an intermediate quinone methide.I2'
(107) (108)
'IR
lZo
X X
= a-H = /3-OH
W. Tadros and A. L. Boulos, Helv. Chim. Acta, 1975,58, 668. J. Bland and B. Craney, Tetrahedron Letters, 1974, 4041. J.-C. Beloeil and M. Fetizon, Compt. rend., 1974, 279, C, 347, M. J. Kulig and L. L. Smith, J. Org. Chem., 1974, 39, 3398. G. M. Buchan, J. W. A. Findlay, and A. B. Turner, J.C.S. Chem. Comm., 1975, 126.
Steroid Properties and Reactions
24 1
Miscellaneous Reactisns.--Both the Liebermann-Burchard (H,SO,-Ac,O-HOAc) and Zak (H,SO,-HOAc-Fe”) colour reactions for cholesterol are oxidative processes, leading to production of SO, and Fe2’, respectively. Spectrometric studies indicate that a carbocation derived from cholesta-3,5-diene is an intermediate in both processes. The carbocation suffers successive dehydrogenations to yield a pentadienylic cation with the blue-green colour typical of the Liebermann-Burchard reaction (A,,, 620 nm); further reaction is thought to lead to a cholestahexaene sulphonic acid (A,, 410 nm). In the Zak reaction, a trienylic cation (A,,, 478 nm) and a tetraenylic cation (A,,, 563 nm; red) are thought to be formed121in stepwise pseudo-first-order oxidative steps.122 Serum cholesterol assays by the Zak method (FeCl,) suffer interference from some other physiologically important steroids, but the Parekh-Jung modification, using Fe(OAc),, is said to be somewhat more specific for cholesterol. 123 Products from the reaction of androsta-3,5-diene with dichloroacetic acid include 3,3’-bi(androsta-3,5-diene)and a trimer with 3,3’- and 6,3”linking of steroid units, each isolated in low yield.’,, The conversions of various steroidal 1,4-dien-3-ones (109) into 5-ene-la,3Pdiols (1 11)via deconjugation to the 1,5-dien-3-one, reduction to the 1,5-dien-3P-ol (110), and hydroboration have been described in a series of papers.’25 The corresponding 5,7-diene- 1a73P-diols(118), required for photo-isomerization as a key step in the preparation of la-hydroxylated derivatives of vitamin D, have been obtained either by allylic bromination-dehydrobromination of the 5-ene- 1a,3Pdiols or by the alternative route outlined in Scheme 2. The key step in this reaction sequence is the protection of the 5,7-diene system as the adduct (116)with 4-phenyl1,2,4-triazoline-3,5-dione, to allow selective epoxidation of the A1-olefinic bond. Although the hydroxypropiolic acid (119) is stable, the 17-acetate (120) readily hydrates and decarboxylates to give the 17P-acetoxy-17a-pregnan-20-one ( 121),’26 possibly with participation of the acetoxy-group via an orthoacetate. Bacterial A5-3keto-steroid isomerase is deactivated irreversibly by 5,lO-seco-steroidal compounds of type (122), which appear to bond covalently to the enzyme.12’ Acid-catalysed deuterium exchange in the phenolic ring converts oestrogens into 2,4-dideuteri&derivatives, with isotopic exchange also at C- 16 if a 17-0x0-group is present. 12* C-Trimethylsilyl groups have been introduced into oestrogens at C-2 and C-4 by treating the trimethylsilyl ethers of 2-bromo- and 4-bromo-oestradiols with chlorotrime thylsilane and sodium. ’29 Sodium bis(met hoxyethox y) aluminium
121
123
I26
I27 ‘28 ‘29
R.W. Burke, B. I. Diamondstone, R. A. Velapoldi, and 0.Menis, Clin. Chem., 1974, 20, 794. R. A. Velapoldi, B. 1. Diamondstone, and R. W. Burke, Cfin. Chem., 1974, 20, 802. A. C. Parekh, C. Sims, R. W. Fong, M. Caranto, and D. H. Jung, Steroids, 1975, 25, 525. C. H. Brieskorn and G . Greiner, Chem. Ber., 1974,107, 2702. C. Kaneko, S. Yamada, A. Sugimoto, M. Ishikawa, S. Sasaki, and T. Suda, Tetrahedron Letters, 1973, 2339; C. Kaneko, S. Yamada, A. Sugimoto, Y. Eguchi, M. 1shikawa;T. Suda, M. Suzuki, S. Kakuta, and S. Sasaki, Steroids, 1974,23,75;C. Kaneko, A. Sugimoto, Y. Eguchi, S. Yamada, M. Ishikawa, S. Sasaki, and T. Suda, Tetrahedron, 1974. 30, 2701; H. Sakarnoto, A. Sugimoto, and C. Kaneko, Chem. and Pharm. Buff.(Japan), 1974,22,2903;N. Ikekawa, M. Morisaki, N . Koizumi, Y. Kato, and T. Takeshita, ibid., 1975, 23, 495;C. Kaneko, A. Sugimoto, S. Yarnada, M. Ishikawa, S. Sasaki, and T. Suda, ibid., 1974,22, 2101; C. Kaneko, J. Synth. Org. Chem. Japan, 1975,33,75. L. J . Chinn, B. N. Desai, and J. F. Zawadzki, J. Org. Chem., 1975,40, 1328. F. H. Batzold and C. H. Robinson, J. Amer. Chem. SOC.,1975,97, 2576. R. C. Murphy, Steroids, 1974, 24, 343. V. N. Zontova, V. M. Rzheznikov, and K. K. Pivnitsky, Zhur. obshchei Khim., 1 9 7 5 , 4 5 6 9 9 ,
Terpenoids and Steroids
242
-
2 steps
0
HO
HQ
+
(1 17) (+ l,!l,2/I-isomer)
Scheme 2
(119) (120)
R R
=H =
AC
dihydride surprisingly dehydrogenates oestra-l,3,5( 10),7-tetraene (equilin) derivatives to give the 1,3,5(10),6,8-pentaene~.'~' 4 Carbonyl Compounds
Reduction of Ketones.-Reduction of a series of C-5-substituted 5cu-cholestan-3ones (123) with LiAlH(Bu'O), gave C-3 alcohols with axial : equatorial ratios which showed no obvious correlation with any of the usual steric or electronic parameters Ix)
.I. C. Hilscher, Clhem. Ber., 1975, 108, 727.
243
Steroid Properties and Reactions
associated with the substituents. A new interpretation of such data relates the product ratios to the length of the C-4-C-5 bond: estimates of bond lengths were derived from data for C-C bonds in a set of simple aliphatic compounds carrying the same s ~ b s t i t u e n t s . ~It~ 'is proposed that the effectiveness of hyperconjugation between the C-4-C-5 cr-bond and the carbonyl rr*-orbital varies with the bond length, and controls the relative rates of attack of the nucleophile on a - and P-faces of the carbonyl group by rendering the rr*-orbital dissymmetric.
HO
* H
R
(125)
R = C1, F, OH, OMe, Me, or CN Last year's p r o p o ~ i t i o n 'that ~ ~ the stereochemistry of reduction of unhindered cyclohexanones by hydride donors is controlled by unequal electron density on the two faces of the carbonyl bond has been supported by arguments based upon the stereochemical outcome of numerous related According to this theory nucleophilic attack (e.g.by BH,-) occurs mainly from the 'axial' direction because the vacant antibonding rr*-orbital is distorted by interaction with the symmetric a@ C-C antibonding u*-orbital(126), whereas electrophilic attack comes mainly from the 'equatorial' direction because the filled bonding rr-orbital is distorted by interaction with the symmetric aP C-C bonding 0-orbital (127). As well as predicting the stereochemistry of ketone reduction, this hypothesis apparently leads to the correct stereochemistry for a variety of other reactions having known examples in steroid chemistry.
( 126)
( 127)
5 a-Androstan-3-one is among cyclohexanone analogues which demonstrate
measurable effects of substitution at C-4 (cyclohexanone numbering) on the stereochemistry of reduction of the carbonyl group by complex h y d r i d e ~ . ' ~ ~ I3l 132
133 134
C. Agami, A. Kazakos, and J. Levisalles, Tetrahedron Letters, 1975, 2035. J. Klein, TetrahedronLetters, 1973,4307. J. Klein, Tetrahedron, 1974,30, 3349. J.-C. Richer, D. Perelman and N. Baskevitch,.Tetrahedron Letters, 1975, 2627.
Terpenoids and Steroids
244
Reduction of 5,6~-dibromo-5a-cholestan-3-one (128) by sodium borohydride in ethanol is subject to steric effects, giving cholest-5-en-3a-01 (130) as the main product. The 3a-hydroxy-5o76P-dibromide(129) is thought to be formed first and to suffer reductive elimination of the bromo-substituents with participation by the 3 a - h y d r o ~ y - g r o u p . 'This ~ ~ convenient route to the 5-en-3a-01 is competitive in yields with some older routes.
-c/
Br (128)
OH
Br (129)
OH (130)
Triethylaminoaluminium hydride is described as a useful reducing agent for steroidal ketones, converting unhindered ketones mainly into the thermodynamically favoured alchols. 136 The reported reduction of steroid ketones by thiourea S , S - d i o ~ i d e 'in ~ ~strongly alkaline alcoholic solutions is now shown to result mainly from a direct hydride transfer from alkoxide ions present in the The thiourea dioxide plays an almost insignificant part in the reaction. Attempts to resolve (*)-3 -methoxy- 14a -hydroxy-D- homo-oes tra- 1,3,5( 10)-trien- 17-one by reduction with LiAlH, in the presence of (-)-quinine or (-)-menthol were unrewarding, but microbiological methods were successful. 13' 3-0x0-steroids of the 5a79P,10a-or the 5@,9P,lOa-('retro')series are reduced in the normal stereochemical senses by sodium borohydride or by propan-2-01-trimethyl phosphitechloroiridic acid, giving the corresponding 3-equatorial and 3-axial alcohols, respecti~e1y.l~'
Other Reactions at the Carbonyl Carbon Atom.-1 1P -Hydroxy- 11a -methyl 5a steroids, prepared by Grignard or methyl-lithium reactions with the 11-ketone, are known to dehydrate under acidic conditions to give the 11-methylene- rather than the 1l-methyl-AY'"'-derivatives. 14' Parallel reactions are now reported in the 191l-methylene- 19-nor-compound (13 1)is also accessible from the n o r - ~ e r i e s The .~~~ corresponding 11-ketone by a Wittig reaction (on the 1l-oxo-3,17-bis-aceta1), which fails in the androstane series because of steric hindrance at C-11 from the 10P-methyl group. The 1l-(E)-ethylidene-19-nor-derivative(132) was prepared similarly. Trimethylsilylmethylmagnesium chloride converted the 11-oxo-oestrone derivative (133) into the 11a-trimethylsilylmethyl-l1~-alcohol(134), which reacted with acid to give the 11-methylene derivative (135), although in this series the more stable conjugated 9(11)-ene (136) resulted when the 1la-methyl-11Palcohol was dehydrated with 135 136 137 138
139 140 141 142
Y. Houminer, J. Org. Chem., 1975, 40, 1361. S. Cacchi, B. Giannoli, and D. Misiti, Synthesis, 1974, 728. Ref. 6, 1975, Vol. 5, p. 247. R. Caputo, L. Mangoni, P. Monaco, G. Palumbo, and L. Previtera, Tetrahedron Letters, 1975, 1041. L. Eignerova, and Z . Prochazka, Coll. Czech. Chem. Comm., 1974,39, 2828. W. Gibb, J. Jeffery, D. N. Kirk, and H. Mahdi, Biochem. J., 1975, 145, 483. J. Elks, J. Chem. Soc., 1960, 3333; D. N. Kirk and V. Petrow, ibid., 1961, 2091. A. J. van den Broek, C. van Bokhoven, P. M. J. Hobbelen, and J . Leemhuis, Rec. Trau. chim., 1975,94, 35.
245
Steroid Properties and Reactions
(134)
(135)
(136)
Increased steric hindrance in the 9a-methyl-11-0x0-oestrone derivative (137) does not prevent attack by methylmagnesium bromide to give the 9 a , l la-dimethylllp-alcohol (138), opening the way to novel patterns of substitution in ring c (Scheme 3).14' The acid-catalysed dehydration of the 11P-alcohol (138) with rearrangement is noteworthy, giving the novel 11,1l-dimethyl-8-ene (139). Acetylation of the hindered tertiary alcohol (138) was effected with refluxing acetic
(137
AcO
Reagents : i, MeMgBr; ii, TsOH-toluene; iii, CaH,-Ac,O; iv, pyrolysis; v, m-CIC,H,CO3H ; vi, LiAIH,; vii, H,-Pd; viii, B,H,,NaOH-H,O.
Scheme 3 143
R. V. Coornbs, J. Koletar, R. P. Danna, and H. Mah, J.C.S. Perkin I, 1975, 792.
246
Terpenoids and Steroids
anhydride-calcium hydride, a powerful and useful system which avoids acidic conditions. Trimethylaluminium in a hydrocarbon solvent exhaustively methylates ketones: 144 5a-cholestan-3-one gave 3,3-dimethyl-5a-cholestanein good yield (other related transformations, C O H + CMe145and C 0 2 H + CMeg,146have not yet been applied to steroids). 20-p-Tolylpregnane derivatives have been prepared from pregnenolone, by a Grignard reaction. ' 4 7 The products were examined as alternative substrates to cholesterol for enzymic degradation to pregnenolone. A new procedure for elaborating steroidal side chains is illustrated in Scheme 4.14' The several steps
L
J
CH,-S-Ph
JPh
11
0
COMe
Reagents: i, Li+C(Me)=CH,; ii, PhSCI; iii, Li'NEt,; iv, PhSSPh; v, HgC1,--MeCN-H,O.
Scheme 4
achieve the equivalent of an aldol condensation, leading overall to a two-carbon homologation, with or without chain branching. Other new metallated reagents offer further synthetic possibilities, starting from ketones. 17-0x0-steroids react with the a -1ithio-derivative of ethyl diazoacetate to give the adduct (140), which rearranged with acid to give the D-homo keto-esters (141) and (142). The isocyanide (143), metallated at the a-carbon atom, also reacts with 17-0x0-steroids to give the formylamino-methylene derivative ( 1 4 9 , via an addition-rearrangement sequence involving the oxazoline ( 144).149 144
lU5
14h 147 148 14y
A. Meisters and T. Mole. Austral. J. Chem., 1974, 27, 1655. D. W. Harney, A. Meisters, and T. Mole, Austral. J. Chem., 1974, 27, 1639. A. Meisters and T. Mole, Austral. J. Chem., 1974, 21, 1655. R. B. Hochberg, P. D. McDonald, M. Feldman, and S. Lieberman, J. Bid. Chem., 1974, 249, 1277 B. M. Trost and J. L. Stanton, J. Arner. Chem. SOC.,1975, 97,4018. U. Schollkopf, B. Bhnhidai, H. Frasnelli, R.Meyer, and H. Beckhaus, Annalen, 1974, 1767.
Steroid Properties and Reactions
247
CNCH,CO,Et (143)
(145)
(144)
Butadiynylsodium converts ~-oxo-,~ - o x o - ,17-oxo-, or 20-0x0-steroids into butadiynyl carbinols [e.g. (146)]. Hydration (Hg2'-H') was accompanied by cyclization to give a spiro-methylfurenone [ e . g (147)].I5O
&\
".Lo 0
bc-
C
/ H
H
The carbanion derived from isopropyl dichloroacetate adds on to 5a-cholestan-3one to give the 3~-hydroxy-3tr-carboxydichloromethylderivative (148) under kinetic control, or the a-chloroglycidic ester (149) under thermodynamic contr01.'~' The latter compound rearranges in refluxing dioxan to give the 3P-chloro-3a-oxalyl derivative (150).
& '
HO,CC12
H
P r 1 (O l1 2 C "0& k yH
' & lo=c C \
COZPri
H
C0,Pr' (148)
(149)
(150)
The Wittig reactions between 3P-hydroxypregn-5-en-2O-one and a series of alkylidenetriphenylphosphoranes(from :CH2 to :C6HI2,including iso-derivatives) 150 151
P. K. Gupta, J. G. L1. Janes, and E. Caspi, J. Org. Chem., 1975,40, 1420. 8 . Castro and J. Amos, Bull. SOC.chim. France, 1974, 2559.
Terpenoidsand Steroids
248
gave a range of A20'22'-olefins. The isopentylidenephosphorane gave cholesta5,20(22)-dien-3p-ol, the acetate of which gave cholesteryl acetate on hydrogenat i ~ n . 'This ~ ~ reaction sequence apparently gives only the natural (20R)-isomer. Prolongation of the Wittig reaction caused formation of 3p-phenoxy-derivatives; a separate experiment confirmed that the phosphonium salt was responsible for 0-phenylation. A Wittig reaction, using the previously unknown tri-n-butyl-( 1methoxycarbonylprop-2-ylidene)phosphorane,has been used for a single-step conversion of a 16a-acetoxyandrostan-17-one (151) into the norchol-l7(20)-enate (152).15' Related compounds, required for the synthesis of sapogenins with the unusual C-23 spiro-acetal structure, were obtained by condensing a 16aacetoxypregnan-20-one with the diethylcyanome thylp hosphona te carbanion, which afforded the A20(22)-unsaturatednitrile (153), and thence, in several steps, the corresponding aldehyde. 154
(151)
(152)
(153)
The recently described tosylmethyl isocyanide has been modified to afford an efficient conversion of 17-0x0-steroids into 17-cyano-derivatives (17paccompanied by 17a-isomers). The method has been used for the conversion of androstan- 17-ones into pregnan-20-ones, by treating the intermediate 17-cyanoderivatives with methyl-lithium. 156 Steroidal ketones are among others which react with T-allylnickel bromide complexes to give homoallylic alcohols [e.g. (154)l. By using the 2-ethoxycarbonylally1 derivative, 5a-cholestan-3-one was converted into a mixture of the isomeric a-methylene-y-butyrolactones ( 155).lS7 Diethyiene orthocarbonate (156) with an acidic catalyst readily converts ketones into their ethylene acetals at room temperature.lS8 Yields were high with either 3pacetoxypregn-5-en-20-oneor 1 1a -acetoxypregn-4-ene-3,20-dione.
2-Hydroxy- or 2-me thoxy -tetr ahydrof urans [e. g. the 18,20-epoxy-20-methoxysteroid (157)] react with HN,-BF, to give the nitrogen-insertion product (159), a Is2 153 154
156
157 15*
J. P. Schmit, M. Piraux, and J. F. Pilette, J. Org. Chem, 1975, 40, 1586. A. Scettri, E. Castagnino, and G. Piancatelli, Guzzettu, 1974, 104, 437. G. Piancatelli and A. Scettri, Guzzerta, 1974,104, 343.
Ref. 6, 1975, Vol. 5, p. 249. J. R. Bull and A. Tuinman, Tetrahedron, 1975,31,2151; J. R. Bull, J. Floor, and A. Tuinman, ibid., p. 2157. L. S. Hegedus, S. D. Wagner, E. Z. Waterman, and K. Siirala-Hansen, J. Org. Chem., 1975,40, 593. D. H. R. Barton, C. C. Dawes, and P. D. Magnus, J.C.S. Chem. Comm., 1975,432.
Steroid Properties and Reactions
[,g1 i ,s
249
dihydro-oxazine ; the key step is apparently a rearrangement of the azido-cation (158), with expulsion of n i t ~ 0 g e n . l ~ ~ , 6 M G M e
(157)
aN-~ZN
(158)
T
(159)
The 18 + 20-hemiaceta1(160) gave novel dimers (163) on reaction with toluenep-sulphonic acid in benzene, through attack of the vinyl ether (161) on the oxonium ion (162), followed by an intramolecular hydride transfer from C-16' to C-2O.l6' Me
Reactions involving Enolic Derivatives or Enamines.-The methylation of cholest4-en-3-one via the kinetically favoured lithium A2j4-dienolate(164) gives the 2p(165) and 2a-methyl (166) derivatives in a ratio approximating to 2 : 3. The product, earlier thought to be homogeneous, and then assigned the 26 configuration, has now been recognized as a mixture, by n.m.r. and h.p.1.c. studies. A second methylation at C-2, using CD31, confirmed the low stereoselectivity by giving labelled 2,2-dimethylcholest-4-en-3-one (167) with the 2a -CD, and 2P-CD, forms in 2 : 3 ratio.16' 2p-Methylated and 2,2-dimethylated oestr-4-en-3-ones have been obtained by adding KOBu' to a solution of the parent steroid in THF containing a suitable molar proportion of methyl iodide at -70 "C, conditions which allow kinetic control. Testosterone similarly gave the 2,2-dimethyl compound (17p -OH was protected as the THP ether).'62 C. Monneret, P. Choay, and Q. Khuong-Huu, Tetrahedron,1975, 31, 575. Y. Pepin, H.-P. Husson, and P. Potier, Tetrahedron Letters, 1975,493. 1 6 1 K. M. Patel and W. Reusch, J. Org. Chern., 1975,40, 1504. 162 L. Nedelec, J . C. Gasc, and R. Bucourt, Tetrahedron, 1974,30, 3263.
159
I6O
Terpenoids and Steroids
250
0
iiO
(165) R = a-H (166) R = b-H (167) R = CD,
( 1 64)
Methylation of the ~-norcholestan-3-ones(168) with KOBu' and methyl iodide gives mainly the SP-methyl derivative (169), with a little of the Sa-methyl isomer (170). Configurations were confirmed by conversion into the corresponding 5 methyl- A-norcholestanes (hydrocarbons) which were also obtained via benzilic acid rearrangements of the corresponding 5-methylcholestane-2,3-diones(171), with ring contraction t o afford the hydroxy-esters (172), followed by further degradation. l h 3 Methylation (K0Bu'-MeI) of an ~-homoandrost-4a-en-3-one gives the 4,4-dime thy1 derivative. 64
G@
Me
O R
(168) R = a- or /3-H (169) R = p-Me (170) R = a-Me
Me0,C
(171)
Me (172)
4-Hydroxymethyl-4-methyl steroid derivatives (177) have been prepared from 4en-3-ones (173) by reductive methoxycarbonylation (Li-NH,, C02, then methylation with CH,N,), followed by methylation of the P-keto-esters (175) and finally reduction with LiAlH, to give separable isomeric diols (177).'65
a
0
Me
: H
C0,Me
(174)
(173)
Me0,C-
a 1
0
ti0
HO
HOCH, Me
Intramolecular alkylation occurs when 19-hydroxytestosterone (178) (as 17acetate) is treated with any one of three reagent systems. Iodine and acetone, for example, give 4P- and 6P-alkylated products (179) and (180). The reactions lh3 164 164
M. Audouin and J. kevisalles, Bull. SOC.chim. France, 1975, 695. H. Velgovh and V. Cerng, Coll. Czech. Chem. Comm., 1974,39,2476. M. R. Czarny, K. K. Maheshwari, J. A. Nelson, and T. A . Spencer, J. Org. Chem., 1975,40, 2079.
Steroid Properties and Reactions
25 1
proceed through the A3.’-dienol, which is alkylated by an iodo-ether function generated at C-19 by the reagents. Comparable reactions occur with HgC1,CICH,SMe, or with trimethyl orthoformate and toluene-p-sulphonic acid, the latter system giving 2 P - and 4P-alkylated products.lh6 Me
0
(180)
(181)
Dimethylaminomethylene derivatives of some steroidal ketones have been prepared by an aldol-type condensation with DMF, catalysed by perchloric 17P-Hydroxy-Sa-androstan-3-one reacted normally at C-2, giving the derivative (181), while Sa-androstan-17-one gave the product of condensation at C-16. 30x0-SP-steroids have long been known to brominate mainly at C-4, and the products are stable to the usual reaction conditions. Iodine monobromide (two moles) converts methyl 3-0x0-SP-cholanate first into the 4P-bromo-ketone, but the liberated iodine and HBr together catalyse rearrangement to give the 2P-bromoketone, which is s!ightly the more stable.1682-Carboxyethyltriphenylphosphonium perbromide (Ph,PCH,CH,CO,H Br3-), a stable and readily prepared crystalline compound, converts ketones into a - bromo-ketones in 60-80% yields. Examples include 4,4-dimethylcholest-S-en-3-one, which gave the 2-bromo-deri~ative.’~~ The cyclic vinyl ether (182),”’ postulated last year as an intermediate in the 21-acetoxylation of the hemiacetal (183), can be prepared in good yield by heating the hemiacetal with aluminium isopropoxide in toluene under argon, followed by direct chromatography on basic a 1 ~ m i n a . IThe ~ ~ vinyl ether was converted into the 20,21-diol (184) either by reaction with osmium tetroxide or by acetoxylation with lead tetra-acetate, followed by hydrolysis. The ‘hypoiodite’ reaction, followed by oxidation, allows direct conversion of a 2 1-acetoxypregnan-20P-ol (185) into the 18-iodo-20-ketone (186), which is solvolysed in the presence of silver acetate to provide a new route to the 21 -acetate of 18-hydroxydeoxycorticosterone hemiacetal (1 87).17’ w.6 167
168 169
170 171
C. Luthy, H.-R. Schlatter, and W. Graf, Helv. Chim. Acra, 1975, 58, 1120. L. N. Volovelsky, M. Y . Yakovlena, N. V. Popova, and V. G. Khukhryansky, Zhur. obshchei Khim., 1975,45, 1153. Y. Yanuka and G. Halperin, J. Org. Chem., 1974,39, 3047. V. W. Armstrong, N. H. Chishti, and R. Ramage, Titruhedron Letters, 1975, 373. Ref. 6, 1975, Vol. 5, p. 252. M. Biolaz, J . Kalvoda, and J. Schmidlin, Helv. Chim. Acta, 1975, 58, 1425,
Terpenoids and Steroids
252
flCH2
\
Enolates may be converted directly into a-hydroxy-ketones by reaction with the molybdenum peroxide complex MoO,,py,HMPA. The 17-ketone (lSS), transformed into its enolate with lithium di-isopropylamide at -70°C, gives the 16ahydroxy- 17-ketone (189) in 75% yield.'72 Carbonyl transposition to the vicinal position can be effected in high yield by a new five-step process.'73 A 17-oxo-steroid (188) was transformed into the 16-ketone (193) via the phenylthioketone (190) and the 16-phenylthio-16-ene (192) by the route illustrated in Scheme 5.
(188) R = H (189) R = OH
Reagents : i, Lithium N-cyclohexyl-N-isopropylamide-THF, - 78 "C; PhSSPh-HMPA, 0 "C; ii, NaBH,MeOH; iii, MeSO,CI-py; iv, Bu'OK-DMSO; v, HgCI,-MeCN-H,O.
Scheme 5
The formation and decomposition of the enol sulphite (195) derived from the ketol A cyclopropanone (196), or an equivalent dipolar (194) is now reported in intermediate resulting from loss of SOz, has been trapped as the diene-addition product (197) with furan. E. Vedejs, J. Amer. Chem. SOC., 1974,96, 5944. B. M. Trost, K . Hiroi, and S. Kurozumi, J. Amer. Chem. SOC.,1975,97, 438. J . Levisalles, E. Rose, and I. Tkatchenko, Bull. SOC.chim. France, 1975, 345.
253
Steroid Properties and Reactions
HO Me'
Some novel annelation reactions of 3-pyrrolidino-3,5-dienes leading to furans and ind01esl~~ are illustrated in Scheme 6.
Ar
Reagents : i, Substituted phenacyl bromides (ArCOCH,Br); ii, Diazonium salts (ArN,+BF,-)-DMF iii, POCI,, followed by O H - .
;
Scheme 6
Oxidation and Reduction.-The Baeyer-Villiger oxidation of a 4-en-3-one normally inserts an oxygen atom between C-3 and C-4, but in the presence of a 6 p bromo-substituent (198) it leads to formation of the alternative 3-oxa-product (199). Some of the normal 4-oxa-product appears also to be formed, but reacts to give the ester-lactone (200) by further oxidative 175
176
M. S. Manhas, J. W. Brown, U. -K. Pandit, and P. Houdewind, Tetrahedron, 1975, 31, 1325 M. S. Ahmad, Shafiullah, and M. Mushfiq, Austral. J. Chem., 1974,27,2693.
Terpenoids and Steroids
254
t 199)
(198)
(200)
Phenyl ketones (201), readily prepared from compounds with cholanic acid or lanosterol side chains, are degraded in alkaline solution by molecular oxygen, giving bisnorcholanic acids (202). Decarboxylation with lead tetra-acetate in benzene, with a little pyridine, completed the degradation to a pregnane derivative, giving the mixed 20-acetates (203) with overall yields in the range 3O-4O0h for the two steps. 77 0
Chlorotrimethylsilane with zinc in THF reduces 3-oxo-5a-steroids directly to A2-olefinic derivatives, but most other oxo-groups are unreactive, allowing selective attack on the 3-oxo-group in d i ~ n e s . ' ~The * 5P-steroidal iminium perchlorate (204), ~ b t a i n e d ' ~by ' ' reduction of the A"-unsaturated analogue with the Hantzsch ester (a dihydropyridine), can be reduced further with the same reagent to give the 3P-pyrrolidinium salt (205) stereospecifically. lX"
Oximes, Tosylhydrazones, and Related Derivatives.-Ketoximes afford enimides in refluxing acetic anhydricle-pyridine." Theproduct (207) from 5a-cholestan-3-one oxime (206), for example, gave 3-acetylamino-5a-cholest-2-ene (208) in 93% yield after Chromatography on alumina. Use of succinic instead of acetic anhydride, with pyridine, gave the enimide (209) which was stable to chromatography. A radical mechanism is proposed. Reduction of ketoximes by Cr", VII, or Ti"' salts in acetic anhydride affords the same enamides, by acetylation of the intermediate imines. The
17') IH''
M. Fetizon, F. J. Kakis. and V. Ifinatiadou-Ragoussis, Tetrahedron, 1974, 30, 3981. P. Hodge and M. N. Khan, J.C.S. Perkin I, 1975, 809. U. K. Pandit, F. R. M . Cabrk, R. A. Gase, and M. J . de Nie-Sarink, J.C.S. Chem. Comm., 1974, 627. U. K. Pandit, K. A. Gase, F. R. M. CabrC, and M. J . de Nie-Sarink, J.C.S. Chem. Comm., 1975, 21 1. R. B. Boar, J. F. McGhie, M. Robinson, D. H. R. Barton, D. C. Horwell, and R. V. Stick, J.C.S.Perkin 1, 1975, 1237.
Steroid Properties and Reactions
255
enamide (208) exhibits rather low reactivity towards most electrophiles, but can be oxidized with ozone, peroxy-acid, or lead tetra-acetate to give the (Y -acetoxyketone, or may be hydrolysed by acid to regenerate the ketone. Enimides are even less reactive, except to hydrolysis."'
(207) R = AC (208) R = H
(209)
5a-Cholestan-6-one reacts with hydroxylamine only on heating, when the antioxime is formed. 5P-Cholestan-6-one, in contrast, readily forms the anti- and syn-oximes in 3 : 1 ratio. Configurations have been correlated with n.m.r. spectra, and are confirmed by Beckmann rearrangements, which proceed with retention of configurations at C-5 under either acid-catalysed or photolytic conditions. 182 Of several methods for the unsymmetrical cleavage of 3-0x0-5p-steroids to give 2,3seco-derivatives, the preferred route'83 begins with a cine-substitution of the 4pbromo-3-ketone to give the 2P-acetoxy-ketone; the oxime of the 2-hydroxy-ketone is then fragmented under Beckmann conditions to give the cyano-aldehyde (210). 5,6-Seco-cyano-ketones (212) and (213) result from Beckmann cleavage of 5a -hydroxy-6-oximino-steroids (21l).'"
OH NC C*
H
(212)
NOH
(213)
Application of the Beckmann cleavage route to the preparation of 18norandrostan-17-onesls5 (219) has been improved by intermediate formation of the 13-carboxy-13,17-seco-nitriles (217), which cyclized with base to form the 1 3 a - and 136-isomers of the a-cyano-ketone (218) and thence the 18-nor-13a- and -13pandrostan-17-ones (219).lg6 A similar reaction sequence has been employed for H. Suginome and H. Takahashi, Bull. Chem. SOC.Japan, 1975,48, 576. J. K. Paisley, R. B. Warneboldt, and L. Weiler, Canad. J. Chem., 1974, 52,810. M. S. Ahmad, N. K. Pillai, and 2. H. Chaudry, Austral. J. Chem., 1974, 27,1537. Ref. 6, 1975, VoI. 5, p. 258. J. C. Chapman and J. T. Pinhey, Austral. J. Chem., 1974, 27,2421.
lH2
Ix3 Ix4 lX5
lx6
Terpenoids and Steroids
256
removal of the 10P-methyl group, a l-oximino-steroid being converted via a series of 1,lO-seco-derivatives into an oestran- l-one derivative.'86 NOH
(218) R = C N (219) R = H
Although tosylhydrazones are among the most readily prepared crystalline derivatives of ketones, they have not been employed as protecting groups because no procedure has been available for efficient regeneration of the ketone. Three simple methods have now been reported. Treatment with sodium hypochlorite (commercial bleach solution) gives good recovery of simple ketones from their tosylhydr a ~ o n e s ' ~and ' clearly deserves study for steroidal analogues. Addition of N bromosuccinimide to a solution of a tosylhydrazone in methanolic acetone causes rapid evolution of nitrogen. After treatment with sodium hydrogen sulphite, the mixture gives the parent ketone or aldehyde in high yield. Steroidal 3-ketones have been recovered from their derivatives by this procedure. 18' Titanium trichloride, already known to cleave oximes to their parent ketones, also gives excellent recovery of steroid ketones from their t o s y l h y d r a ~ o n e s , 'as ~ ~ well as from their 2,4dinitrophenylhydrazones. 190 The reaction is mild and selective in the presence of most other functional groups, and is said to give high yields. Conjugated cyclohexenones are transformed into isomeric enones by a five-step sequence,'" illustrated in Scheme 7 for the conversion of cholest-4-en-3-one into 5a -cholest-2en-4-one. Application of the same procedure to 5a-cholest- l-en-3-one gave the 3en-2-one. The tosylhydrazone elimination step (iv) represents a novel application of a known reaction. Similar decomposition of the unsaturated tosylhydrazone (220) afforded the rather inaccessible 2,4-diene (221) in good yield. 1,2Dimethoxyethane was the most satisfactory solvent. 19* A new selective and very mild method for the re'duction of ketone tosylhydrazones to hydrocarbons offers promise for steroid chemistry: reduction with 'catecholborane' and buffered hydrolysis gives the hydrocarbon in good yield.'93 2,4Dinitrobenzenesulphonylhydrazine is superior to toluene-p-sulphonylhydrazinefor 187
T.-L. Ho and C. M. Wong, J . Org. Chem., 1974, 39, 3453. G. Rosini, J. Org. Chem., 1974, 39, 3504. B. P. Chandrasekhar, S. V. Sunthankar, and S. G. .Telang, Chem. and Ind., 1975, 87. J . E. McMurry and M. Silvestri, J. Org. Chem., 1975, 40, 1502. M. K. Patel and W. Reusch, Synth. Comm., 1975. 5, 27. G. Phillipou and R. F. Seamark, Steroids, 1975, 25, 673. G. W. Kabalka and J . D. Baker, jun., J. Org. Clhem., 1975, 40, 1834.
Ix8
L8'1
192
IY3
257
Steroid Properties and Reactions
Reagents : i, H,O,-NaOH
; ii,
MeONa-MeOH ; iii, TsNHNH, ; iv, 2MeLi ; v, H + .
Scheme 7
(220)
(221)
the Eschenmoser cleavage of aUp -epoxy-ketones to acetylenic ketones under mild conditions.194 Carboxylic Acids.-The etienic acid (222) is smoothly converted into pregnenolone (223) by direct reaction with methyl-lithium, or into 20-0x0-21-norcholesterol (224) by use of i~ohexyl-lithium,'~~ suggesting a simple general method for the elaboration of various side chains.
HO
&P (222)
(223) R = Me (224) R =(CH,),CHMe,
A 26-hydroxy-furostan (225) is readily prepared by reductive cleavage of a spirostan. The corresponding carboxylic acid (226) was lactonized with rearrangement (in Ac,O-TsOH) to give the isomeric products (227) and (228). Hydroboration of the A16-lactone (227) gave a 16a,22R,26-triol(229), providing a novel entry into side-chain-hydroxylated ~ t e r 0 i d s . l ~ ~ 194 195 IVh
E. J. Corey and H. S. Sachdev, J. Org. Chem., 1975,40, 579. S. Danishefsky, K. Nagasawa, and N. Wang, J. Org. Chem., 1975, 40, 1989. A. G. Gonzhlez, C. G. Francisco, R. Freire, R. Hernandez, J. A. Salazar, and E. Suhez, Tetrahedron Letters, 1974, 4289.
258
Terpenoids and Steroids
(225) R = CH,OH (226) R = CO,H
5 Compounds of Nitrogen and Sulphur Reduction of saturated 1-oximino-5a-steroids with usual reagents gives the l a amino-derivatives. The previously unknown 1p -amino-compounds have now been obtained by reduction of the A*-unsaturated 1-oxime. Hydrogenation (Pt-H,) leads to the saturated la- and lp-amines directly, while zinc-acetic acid gave the unsaturated amines which could be hydrogenated in a separate step to give the saturated amines.Iy7 The four isomeric 16-azido- 17-alcohols, and thence the 16amino-17-alcohols, have been prepared by the routes indicated in Scheme 8 [3methoxyoestra-l,3,5(1O)-trieneseries]. The 1Gp717p-epoxidegave a mixture of two trans -azido-alcohols. 98 Continued study of the photolysis of steroidal azides has confirmed that the most usual reactions are ( a )hydrogen migration to give imides and ( b ) alkyl migration to give aza-compounds (see Scheme 9 for example^).'^^ Nitrene insertion to give a pyrrolidine has been observed in only one instance, the low-yield conversion of a 6P-azide into the 6p719-imino-derivative (230). Reactions of 20-azido- and 6 p azido-3cw,5cr-cyclosteroids are also described.19' Thermolysis or acid-catalysed decomposition of azides2O0sometimes afford mixtures of products similar to those resulting from photolysis (e.g. from 3-azido-steroids) but in other cases acidcatalysed reactions give only the product or products of alkyl migration. Conformational features of the reactants appear to be responsible for the observed differences; acid-catalysed reactions give products resulting from migration of that alkyl group which is anti to the departing nitrogen molecule, whereas photochemical or thermal reactions involve selective migration of the bond overlapping the p,-orbital at N, (Scheme 9). 197 19x
C. Marazano and P. Longevialle, Bull. SOC.chim. France, 1975, 1307. B. Schonecker and K. Ponsold, Tetrahedron, 1975,31, 1113. A. Pancrazi and Q. Khuong-Huu, Tetrahedron, 1975,31, 2041. A. Pancrazi and Q . Khuong-Huu, Tetrahedron, 1975, 31,2049.
lyY
200
Steroid Properties and Reactions
259 OH
Reagents : i, N,- ; ii, NaBH,.
Scheme 8
22 %
45 %
1
N 9J
T5
H + H,O
irH 6”’
Scheme 9
Reduction of a 20-N-benzyliminopregnane with diborane gives the 20s- and 20R -benzylamines in 55 : 45 ratio. The corresponding imine (23 1)derived from the chiral (S)-(-)-a-phenylethylamine was reduced asymmetrically to give only the 20S-amino-derivative, which afforded the pure 20s-amine (232) after debenzylation. 201 201
G. Demailly and G. SolladiC, Tetrahedron Letters, 1975, 2471.
Terpenoids and Steroids
260
(231)
(232)
A 16a-bromo-ketone (233) reacts with 1,2-diaminoethane to give the dihydropyrazine (234); the required oxidation step probably uses atmospheric oxygen.2o2 Some further steroidal tetrazoles and bis-tetrazoles have been prepared from ketones by the action of hydrazoic acid-boron trifluoride.203
(233)
(234)
Steroidal 1,4-dien-3-ones react with phosphorus pentasulphide in an inert solvent to give the purple-blue 1,4-diene-3-thiones (235) (A,,, 330 and 565-580 nrn).’O4 The thiones are remarkably stable, but can be oxidized to give syn- and anti-Soxides, which are separable but are interconverted on standing. Diphenyldiazomethane reacts with the dienethione at room temperature to give the 3(diphenylmethylene)-1,4-diene(236) (Y - (238) and 2,3-dithia-5 (Y -steroids (239) have 2-Selena- and 2-tellura-~-nor-5 been obtained by treating the seco-dibromide (237) with Na,Se, Na,Te, and Na,S,, respectively.205
(235 1
(237)
(238) X = Se or Te (239) X = S-S
6 Molecular Rearrangements Contraction and Expansion of Rings.-4-Azido-4,6-dien-3-ones (240) rearrange either thermally or photochemically to give products with the 56 -cyano-A-nor-A6 structure (241) in high yields.206 A rather similar contraction occurred in ring B 202
2u3
2ar
P. Catsoulacos and E. Souli, J. Heterocyclic Chem., 1975,12, 193. H. Singh and R. K. Malhotra, J.C.S. Perkin I, 1975, 1404. D. H. R. Barton, L. S. L. Choi, R. H. Hesse, M. M. Pechet, and C. Wilshire, J.C.S. G e m . Comm., 1975,
557. 205
206
G. Zanati, G. Gaare, and M. E. Wolff, J. Medicin. Chern., 1974, 17, 561. E. M. Smith, E. L. Shapiro, G. Teutsch, L. Weber, H. L. Herzog, A. T. McPhail, Pui-Suen Wong Tschang, and J. Meinwald, Tetrahedron Letters, 1974, 3519.
Steroid Properties and Reactions
26 1
during oxidation of the 7a-hydroxy-bp-azide (242) with Jones' reagent, giving the B-nor-cyano-ketone (243).*07 The 6P-azido-7-ketone is presumably formed first, and the rearrangement is thought to involve an uhstable 4,5-epoxide, resulting from further oxidation of the dienone system.
(241)
(240)
(242)
(243)
The 2-methy1-4P,SP-epoxy-3-ketone (244) reacts with methoxide ion to give the three products (245)-(247).208 A Favorskii-type rearrangement is clearly responsible for producing the A-nor-lactone (245), and is considered also to account for the other two products. The 2-methoxy-2-methy1-4-en-3-one(246), however, could possibly result from direct attack of methoxide ion on the A2-en01derivative of the epoxy-ketone (cine substitution), followed by elimination of a SP-hydroxy-group to give the a@ -unsaturated ketone. The occurrehce of Favorskii rearrangement in the 2-methylated compound (244) contrasts with a simple nucleophilic opening of the unsubstituted 4P,SP-epoxy-3-ketone: this is one of several recent examples in which an a -substituent favours Favorskii rather than alternative reactions.208
&
Me--0
0
(246)
(247)
The oxidation of a 12-hydrazone (248) with lead tetra-acetate provided a novel route to rearranged steroids with the c-nor-D-homo structure (249), although another isomer was formed simultaneously. Dehydration of a C- 12 cyanohydrin with thionyl chloride gave the 13a-cyano-c-nor-~-homo-compounds (250) and (25 1).209 An exploration of the electronic features of the D-homoannulation of 17ahydroxypregnan-20-ones by boron trifluoride, in an attempt to account for the 207 208
209
M. Kocijr, M. Gomulka, W. Kroszczyiiski, and J. St. Pyrek, Tetrahedron Letters, 1975, 165. R. W. Mouk, K. M. Patel, and W. Reusch, Tetrahedron, 1975,31, 13. H. Mitsuhashi, Y. Shimizu, T. Moriyama, M. Masuda, and N. Kawahara, Chem. and Pharm. Bull. (Japan), 1974,22, 1046.
Terpenoids and Steroids
262
(249)
(250) A 1 7 ( 1 7 a ) (251) A17a(18’
specificity of the reaction path, has given inconclusive results.210 Kinetic measurements showed that the reaction is retarded more by 1 6 a - than by lla-benzoyloxygroups, but that p-substituent effects in the ester groups are small. With other data, referring to the 16P-methy1, 16-methylene, and hl4-unsaturated derivatives, these observations led to the suggestion that steric factors influencing the intermediate formation of a cyclic boron complex of the 1”a-hydroxy- and 20-0x0-functions are no less important than electronic effects in controlling the rate of rearrangemenL210 The consistent migration of the secondary C-16 rather than the quaternary C-13 under these conditions still awaits interpretation. ‘Backbone’ Rearrangements.-The backbone rearrangement of Sa-cholestane4P,5-diol 4-acetate (in D,SO,-DOAc-Ac,O) proceeds without incorporation of deuteriurn,,l’ establishing the concerted nature of this rearrangement, although some related reactions are known to proceed through a stepwise deprotonationreprotonation mechanism.212 Conformational factors are invoked to account for the occurrence of backbone rearrangement in the 4P-acetoxy-compound, in contrast with the simple dehydration of 5a-cholestane-4a,5-diol 4-acetate, which gives the A5-compound. In the latter case, prolonged reaction allowed equilibration of the primary product, cholest-5-en-4a-yl acetate, with the less stable cholest-5-en-4P-yl acetate: the two isomers ultimately reached a 3 : 1 ratio, respectively. Surprisingly, the allylic substitution leading to inversion at C-4 does not appear to be accompanied by allylic rearrangement, which would have afforded 6-acetoxy-A4-compounds. Further stereochemical features of these reactions have been explored by deuterium-labelling and are interpreted in terms of conformations available to C-5 carbocations in various systems.211Substituted benzoate groups at C-6 influence the rate of the Westphalen rearrangement in accordance with Hammett substituent constants, giving a reaction constant ( p ) consistent with carbocation formation at C-5.*13 Complex rearrangements involving both the steroid backbone and the cholestane side chain were observed when either the ‘Westphalen’ diacetate (252) or 5acholestane-2a,5-diol(253) was treated with HF at -60 “C. The 25-fluoro-product (254) was isolated in low yield from the 2,5-diol, and an analogous product resulted from the Westphalen diacetate. Inversion of the configuration at C-20 to give the unnatural (20s)-isomer is thought to involve stereospecific hydride transfer from C-25 to a C-20 carbocation; subsequent nucleophilic attack at C-25 gives the 25fluoro-compound. A hydride transfer from C-20 to C-13 is postulated to account for llo 211
*l2
*I3
D. N. Kirk and A. Mudd, J.C.S.Perkin I, 1975, 1450. E. T. J . Bathurst, J . M. Coxon, and M. P. Hartshorn, Austral. J, Chern., 1974, 27, 1505. Ref. 6, 1974, Vol. 4, p. 374; 1975, VoI. 5, p. 266. D. N . Kirk, Tetrahedron, 1975, 31, 1299.
263
Steroid Properties and Reactions
the 13p configuration in the resented in diagram (255).
The two hydride transfer steps are rep-
OH
(6-a' (252)
HO..
H
(253)
@
\
Me
Me
(255) (254)
A Westphalen-type rearrangement occurred when a 19-hydroxy-steroid (256) was treated with the HgC1,-ClCH,SMe reagent system (p. 251 ). The product (258) incorporated the methylene group from the reagent as part of the tetrahydrofuran ring bridging the 5 p - and 6p-positions, as a result of electrophilic attack of the 19-methyleneoxonium ion (257) on the A5-olefinic bond, followed by migration of C-19. Similar reactions occur in related steroid derivatives.,15
(257)
0' (258)
An earlier report216described the isomerization of oestr-4-ene-3,17-dione (259) by the hyperacidic system HF-SbF5 to give the 14P-isomer (260), through a rearrangement involving the steroid backbone. When a hydrocarbon (methylcyda lopentane or cyclohexane) was present in the solution, hydride transfer from the hydrocarbon to intermediate steroidal carbocations gave saturated 8a - and 8p3,17-diketones, (261; 13%) and (262; 76'/0).~~' Deuterium-labelling established that C-8 is the main point of hydrogen acceptance, with some attack also at the 7P-position. The involvement of secondary as well as tertiary carbocations is 214 215
216 217
A . Ambles, C. Berrier, and R. Jacquesy, Bull. SOC.chim. France, 1975, 835. H.-R. Schlatter, C. Liithy, and W. Graf, Helu. Chim. Acra, 1975,58, 1339. Ref. 6, 1974, Vol. 4, p. 373. J.-C. Jacquesy, R. Jacquesy, and G. Joly, Tetrahedron Letters, 1974, 4433.
264
Terpenoids and Steroids
indicated. When hydrogen gas was used as the reducing agent, the anthrasteroid diketone (263) was the major product. A novel mechanism including a 1,3-hydride shift (6p -+ l o p ) is suggested as a key step in this skeletal r e a r ~ a n g e m e n t . ~ ~ '
M0&
o
/
0
(259) 1 4 ~ - H (260) 14p-H
H 8
H (261) 8a-H (262) 8p-H
s\"' H..
H
0 (263)
The reported218 isomerization at C-13 during the acetolysis of ~ - h o m o - h androstan-17ap-yl tosylate (264), which gave the 17aa-acetoxy-13a-derivative, involves a more complicated reaction sequence than this observation alone sugg e s t ~ . Use ~ ' ~of deuterioacetic acid led to incorporation of up to seventeen deuterium atoms, probably distributed according to the pattern indicated by asterisks in diagram (266). The key intermediate appears to be the c-homo-olefin (265), which undergoes extensive double-bond migration by the protonatisn-deprotonation mechanism before reverting to the D-homoandrostane framework, but with the 1 3 a configuration. A detailed mechanism is
(264)
(265)
(266)
Multiple protonation in the hyperacidic system HF-SbF, converts oestrone isomers (267) into 4,9-dien-3-ones (268) of various configurations.220 8a-Oestrone7for example, gives the same dienone (8a714a)as does oestrone itself, but 14P-oestrone gives the 8a714P- and 8P714P-dienones. N.m.r. study in deuteriated solvents demonstrated the intermediacy of allylic cations in ring B. Two rearrangement mechanisms are thought to be involved, one an intermolecular deprotonationprotonation and the other proceeding through intramolecular hydride transfers.220
*18
*I9 22n
Ref. 6, 1974, Vol. 4, pp. 371-372. I. Khattak, D. N. Kirk, C . M. Peach, and M. A. Wilson, J.C.S. Perkin I, 1975, 916. J.-P. Gesson, J.-C. Jacquesy, R. Jacquesy, and G. Joly, Bull. SOC.chim. France, 1975, 1179.
265
Steroid Properties and Reactions
Aromatization of Rings.-Phosphorylation of prednisolone (269) at C-2 1 with pyrophosphoryl chloride is accompanied by a novel fragmentation with rearrangement to give the highly toxic 9,10-seco-c-nor-aldehyde(270) as its 3,21diphosphate. Simpler analogues, including either the 1lp- or the 1la-hydroxy-1,4dien-3-one structure, suffered the same reaction.221 CH,OH
CH,OH
I
o=P F * / \
c1'
Cl
I
co
HO
0
-424
~
(269)
(270)
Full particulars have been published of the very ready aromatization of 2phydroxy- 19-0xoandrost-4-ene-3,17-dionein neutral aqueous media.222Slight alkalinity accelerates the reaction: possible mechanisms are discussed. 4P,5-Epoxy6 a -hydroxy-SP -androstan- 17p -yl acetate and 2a,3a -epoxy-bp -hydroxy-5a androstan- 17P-yl acetate are new additions223to the long list of 'A/B-trifunctional' steroids which aromatize to give 4-methyloestra-1,3,5( 10)-trienes in HBrA c O H . ~A~new ~ route to anthrasteroids comprises the conversion of a 5,7-diene and reaction of the into its adduct (27 1) with 4-phenyl-1,2,4-triazoline-3,5-dione adduct with boron trifluoride etherate.22s The structure (272) of the product was established by X-ray crystallography. 17
RO-'
In a further study of routes to steroids with an aromatic ring C , 18-norandrost-13enes (273) were found to give 7a-hydroxy-18-norandrosta-8,11,13-trienes (274) on reaction with selenium dioxide, while the 18-norandrosta-7,13-dienesreacted with mercury(I1) acetate to give the 7a-acetate (276), as well as its 7P-epimer. Mechanisms, including stepwise dehydrogenations, are discussed.226 221
222 223 224 225
226
T. Miki, K. Hiraga, H. Masuya, T. Asako, S. Fujii, K. Kawai, K. Kikuchi, S. Shintani, and M. Yamazaki, Chem. and Pharm. Bull. (Japan), 1974,22, 1439. H. Hosoda and J. Fishman, J. Amer. Chem. SOC.,1974,96, 7325. D. Baldwin and J. R. Hanson, J.C.S. Perkin I, 1975, 1107. Ref. 6, 1972, Vol. 2, p. 309; 1973, Vol. 3, p. 391; 1974; Vol. 4, p. 376; 1975, Vol. 5, p. 269. N. Bosworth, J. M. Midgley, C. J. Moore, W. B. Whalley, G. Ferguson, and W. C. Marsh, J.C.S. Chem. Comm., 1974,719. C. L. Hewett, S. G. Gibson, I. M. Gilbert, J . Redpath, D. S. Savage, T. Sleigh, and R. Taylor, J.C.S. Perkin I, 1975, 336.
266
Terpenoids and Steroids
(273) 7,g-saturated (275) A7
(274) R = H (276) R = A C
A new aromatization of ring c has been achieved by treating the 16a,17aepoxypregn-8-ene-7,11,20-trione system (277) with zinc chloride in acetic anhydride.227The product (278) was accompanied by the diene-trione (279). Use of other acidic reagents, or of the 7-deoxy-analogue of compound (277), failed to give an aromatic product. COMe
Me
(277)
Miscellaneous Rearrangements.-A new method for effecting migration of the 10P-methyl group to the 9p-position, corresponding to its location in cucurbitacins, comprises treatment of a 9a -amino- 11-oxo-derivative with nitrous acid.228 The reaction was carried out on the corticosteroid bismethylenedioxy (BMD) derivative (280) and gave a 9P-methyl-19-nor-5(1O)-ene.At the same time, however, the BMD system, previously regarded as a very stable protection for the dihydroxy-acetone side chain, was oxidized by the nitrous acid to a 20hydroxy- 17a,2O-methylenedioxypregnan-21-oic acid, giving the reaction product (281). A mechanism involving the selective hydrolytic opening of the more exposed of the dioxolan rings, followed by oxidation of the primary C-21 seems reasonable. The formation of cholest- 14-ene derivatives by hydrochlorination(282) is accompanied at low temperature by the dehydrochlorination of A8‘14)-01efin~ formation of 17a-cholestane derivatives, which become the main products at -60 to -78 0 ~ ~ 2 2 9 . 2 3It0 is suggested2” that an acid-catalysed contraction of ring c leads to a 22’
zzx 22y
*70
C. L. Hewett, J. Redpath, and D. S. Savage, J.C.S. Perkin Z, 1975, 1288. L. P. Makhubu, Z. G. Hajos, and G. R. Duncan, Canad. J. Chem., 1974,52, 1744. E. Caspi, W. L. Duax, J. F. Griffin, J. P. Moreau, andT. A. Wittstruck, J. Org. Chem., 1975,40,2005. M. Anastasia, M. Bolognesi, A. Fiecchi, G . Rossi, and A. Scala, J . Org. Chem., 1975, 40, 2006.
Steroid Properties and Reactions
#
267
40...H
\
AcO (281)
(280)
C-13 spiranic intermediate (283) which is then protonated at the 17P-position, reversing the rearrangement to give the 14-chloro-14/?,17a-cholestane (284). Dehydrochlorination proceeds readily to give the 17a-14-ene (285).
Ix,
'GH17
\
@
- -C,H, 7
\
(284)
(285)
Dehydration of a 9a,l la-dimethyl-1 lp-alcohol proceeds with rearrangement (p. in hyperacidic media 245). Full details of the isomerization of pregnan-20-0nes~~~ have now appeared:232the product is an equilibrated mixture of isomers at C-13 and C- 17. Boron trifluoride etherate in acetic anhydride effects smooth rearrangement of 6~-methoxy-3a,5a-cyclosteroids into their 3 ~ - a ~ e t o ~ y - A ~ - a n a l o g u19es.~~~ Iodocholesterol (286) rearranges in refluxing propan-2-01 or other solvents to give the 6~-iodomethy1-19-nor-5(10)ene(287). Conditions favourable to the formation of 19-iodocholesterol from the 19-tosyloxy-derivative also give the rearranged product (287).234
CH,I (286) 231
232 233 234
(287)
Ref. 6, 1975, Vol. 5, p. 273. J.-C. Jacquesy, R. Jacquesy, and J.-F. Patoiseau, Bull. SOC.chim. France, 1974, 19.59. C. R. Narayanan, S. R. Prakash, and €3. A. Nagasampagi, Chem. and Id.1974, , 966. M. Kojima, M. Maeda, H. Ogawa, K. Nitta, and T. Ito, J.C.S. Chern. Cornrn., 1975, 47.
Terpenoids and Steroids
268
The direction of ring-opening of 5,10-epoxy-9(11)-enes by bases depends upon Thus the a-epoxide (288) loses a proton from C-12 with the reaction potassium t-butoxide to give the 5a-hydroxy-9’11-diene (289)’ but lithium dialkylamides favour formation of the lOa-hydroxy-4,9(1l)-diene (290). These and related results suggest that the lithium dialkylamides are poorly dissociated, and favour a 1,2- rather than a 1,4-epoxide-opening
(288)
(289)
(290)
6p,19-0xido-2,17-dihydroxyandrosta-1,4-dien-3-one (29 1) undergoes a complex rearrangement under ‘benzilic acid’ conditions to give the very unusual furopyranone derivative (292); the structure (292) rests on X-ray analysis as well as spectroscopic data.236
Ho&0 oH
H O &:
(29 1)
(292)
7 Functionalizationof Non-activated Positions
Two novel variations on ‘remote oxidation’ involve radical relay mechanisms. Chlorine radicals generated by photolysis of iodobenzene dichloride are carried by the iodine atom of a suitable iodo-aryl ester of 5cu-cholestan-3a-01 to permit hydrogen abstractions from C-9 or C-14, depending upon the ester employed.237 The rn-iodobenzoate (293) afforded the 9a-chloro- and thence the cholest-9(11)ene derivative (294), whereas the p-iodophenylacetate similarly gave a 14-ene. Me H
@c*H17
RO’.
H (294)
(293) 235 23h 237
G. Teutsch and R. Bucourt, J.C.S. Chem. Comm., 1974, 763. R. J. Chorvat, R. H. Bible, jun., and L. Swenton, Tetrahedron, 1975, 31, 1353. R. Breslow, R. J. Corcoran, and B. B. Snider, J. Amer. Chem. SOC.,1974,96, 6791.
Steroid Properties and Reactions
269
Alternatively, the aromatic ring of an unsubstituted phenylacetate can itself act as a carrier, apparently forming a loose complex with a chlorine atom. Sa-Cholestan3a-yl phenylacetate with iodobenzene dichloride, irradiated in dichloromethane, gave the A'"''-olefin in 53% yield, with no detectable A14-isomer.237The radicalcarrier principle has been used to introduce A9(")-~nsaturationin a novel synthesis of cortisone from its 11-deoxy-analogue (Reichstein's S).238
8 Photochemical Reactions Unsaturated Compounds.-Toxisterols-A, -B, and -C, found in small amounts among the products of irradiation of ergosterol in ethanol, have the C-8 spiran structures (295), with differing configurations at C-4 and C-8.239 In acidic solution they afford the corresponding benzene derivatives (296). Also among the products of photolysis were de-AB-ergost-22-ene derivatives of types (297) and (298), resulting from ph~to-fragmentation.~~'
R (297) R' R' R'
= R2 = H = OEt, RZ =
(298) R
=
H or Me
H = H, R 2 = OEt
that the stereochemistry of photochemical addition of an olefin on It is to an .a@-unsaturatedketone is determined by the preferred conformation of the excited state of the enone. As a test case in the steroid series, allene adds to cholest4-en-3-one (299) to give the 4a,5a-adduct (301). The excited enone is considered to have excess negative charge at C-5 (300), which is therefore pyramidal and results in a preference for formation of the product with the S a - c ~ n f i g u r a t i o n . ~ ~ ~ 23a 23y
240
R. Breslow, B. B. Snider, and R. J. Corcoran, J. Amer. Chem. Soc., 1974,%, 6792. A. G. M. Barrett, D. H. R. Barton, M. H. Pendlebury, L. Phillips, R. A. Russell, D. A. Widdowson, C. H. Carlisle, and P. F. Lindley, J.C.S. Chem. Comm., 1975, 101. A. G. M. Barrett, D. H. R. Barton, R. A. Russell, and D. A. Widdowson, J.C.S. Chem. Comm., 1975, 102. K. Wiesner, Tetrahedron, 1975,31, 1655.
270
Terpenoids and Steroids
2,5-Dimethylhexa-2,4-dieneand a 4,6-dienone undergo photo-addition to give a mixture of isomeric 4,5-adducts of type (302), including 4a,5a-, 4a,5p-, and 4@,5/3-adducts. 4-Methylpenta- 1,3-diene adds in the same orientation. The mechanistic and stereochemical features are discussed; both dienes are of the type which function as substituted alkenes rather than as Diels-Alder diene~.*~'
(300)
(299)
1
CH,=C=CH,
@ ;
o& //:y
0
H*C (301)
(302)
A further study of photochemical reactions of Byunsaturated ketones has produced results including those illustrated in Scheme
& ocf?+o&'
0
OMe
gy
50 %
30 %
&
0
II
--3
0
TY
0 Reagents : i. his, MeOH; ii, hv, beniene
242 24-3
Scheme 10 G. R. Lenz, Tetrahedron, 1975,31, 1587. J. Pusset, M.-T. Le Goff, and R. Beugelmans, Tetrahedron, 1975,31,643.
H
27 1
Steroid Properties and Reactions
Novel cyclization products are obtained by U.V. irradiation of suitable methoxyenones and dimethoxy-enones. Examples include the conversion of a 19-methoxy4-en-3-one (303) into the tetrahydrofuran (304) and the cyclization of a 19,19dimethoxy- 1-en-3-one (305) to give another tetrahydrofuran (306).244
(305)
(306)
The enol ester (307) undergoes a photo-Fries rearrangement, giving a P-diketone, isolated in its enolic form (308).245
"& Q ac-, \
II
O
y
y
J
\
H
H ..'0...
(307)
H
(308)
Ethers (309) of 4-hydroxycholest-4-en-3-oneafford oxetanols (3 lo), accompanied by small amounts of the isomeric compounds (3 1l ) , on p h o t o l y ~ i s . ~ ~ ~ Irradiation of a 4,6-dien-3-one (312) in pyridine containing CFJ gives the 4-trifluoromethyl derivative (313); the corresponding reaction of a 3,5-dien-7-one gives both the 6-trifluoromethyl-dienone and the 3P-trifluoromethyl-5-en-7-0ne.~~~
"@
H,
'1R
P
2 R '
R2
"
(309) R' = R2 = H R' = H, R2 = Me R1 = R2 = Me R' = H, R2 = Ph 244
245 246
247
M. KarvaS, F. Marti, H. Wehrli, K . Schaffner, and 0.Jeger, Helu. Chim. Actu, 1974, 57, 1851. D. Veierov, T. Bercovici, E. Fischer, Y. Mazur, and A. Yogev, Helv. Chim. Acta, 1975,58, 1240. A. Enger, A. Feigenbaurn, J.-P. Pete, and J. L. Wolfhugel, Tetrahedron Letters, 1975, 959. G. H. Rasmusson, R. D. Brown, and G. E. Arth, J. Org. Chem., 1975,40,672.
272
Terpenoids and Steroids
@
0
O R‘
@
0
R (312) R = H (313) R = CF,
The photo-addition of ethoxycarbonylnitrene on to unsaturated steroids and the photo-rearrangements of steroidal 4-azasteroidal 5-en-3-ones have been reviewed.248 Some further details of the mechanisms of photo-equilibration and fragmentation of cholest-5-en-3/3-01 and -4-en-3/3-01 have been elucidated by the use of a variety of aromatic compounds as Reaction is favoured by use of phenolic compounds which can associate with the reactant. Fragmentation, which leads via the unsaturated aldehyde (314) to the oxetan (315), is particularly favoured by the presence of phenol, with dioxan as solvent, and is most efficient with the 4-en-3/3-01.
\ A (314)
(315)
Structures (316) with an oxetan ring, recently for two iodocompounds obtained during the ‘hypoiodite reaction’ of cholesterol, have now been revised.251 Spectroscopic and X-ray data show the compounds to be iodo-acetals (317), converted by de-iodination and reaction with BF,-acetic anhydride into the dihydropyran (318). Photolysis of the oxime of a 1,5-dien-3-one gave mainly rearranged ketonic products, isomers of type (319), which are also obtained by photo-rearrangement of the 1,5-dien-3-0ne.*~~
(318) 248
24‘1 250 251 252
(319)
R. P. Gandhi, S. Garg, and S. M. Mukherji, J. Indian Chem. SOC.,1974,51, 324. D. Guenard and R. Reugelmans, Cornpt. rend., 1975,280, C, 1033. Ref. 6, 1975, Vol. 5, p. 282. H. Suginome, A. Furusaki, K. Kato, and T. Matsumoto, Tetrahedron Letters, 1975,2757 J. RepollCs, F. Servera, and J.-J. Bonet, Helu. Chirn. Acta, 1974, 57, 2454.
Steroid Properties and Reactions
273
Sensitized photo-oxygenation of 3-morpholino-5a-cholest-2-ene (320) led to a mixture of the 2,3-dione (322) and the 3-morpholino-3-en-2-one (323). Model experiments at low temperature confirmed the formation of an unstable dioxetan (321) as the key intermediate, formed by addition of singlet oxygen on to the olefinic bond of the e ~ ~ a m i n e . ~ ~ ~
1
Sensitized photo-oxygenation of 3 p -acetoxy-5a -cholest-7-ene proceeds stepwise through the 7a-hydroperoxy-8( 14)-ene (324) to the 7a,8a-bis-hydroperoxy-14ene (325), accompanied by its 8 p -isomer; reduction of the bis-hydroperoxides gave the corresponding di01s.’~~
Miscellaneous Reactions.-Irradiation of acetoxy-steroids in HMPA-H,O at 254 nm gives the corresponding hydrocarbons in high yields.255Photolysis of either a 12a-azido- (326) or a 9a-azido-11-ketone (328) gave the corresponding aza-chomo-compound (N-acylimine) (327) or (329), respectively. Azido-ketones in rings A or D gave complex mixtures of The 4’,4’-dimethyloxazolidine-N-oxyl (‘doxyl’) derivative (330) of 4,4-dimethyl5a-cholestan-3-one was converted into a variety of different products under photolysis, depending upon the solvent and reaction Photolysis in benzene 253 254 2s5
2s6
2s7
H. H. Wasserman and S. Terao, Tetrahedron Letters, 1975, 1735. G . 0. Schenck, W. Eisfeld, and 0 . - A . Neumiiller, Annalen, 1975, 701. H. Deshayes, J.-P. Pete, C. Portella, and D. Scholler, J.C.S. Chem. Comm., 1975, 439. W. A. Court, 0. E. Edwards, C , Grieco, W. Rank, and T. Sano, Canad. J. Chem., 1975,53,463. J. A. Nelson, S. Chou, and T. A. Spencer, J. Amer. Chem. SOC.,1975,97, 648.
274
Terpenoids and Steroids
solution under nitrogen gave a mixture which included the cyclized derivatives (331) and (332), as a result of hydrogen abstraction from the 4P-methyl group by the excited nitroxide which has the required ( 3 R )c ~ n f i g u r a t i o n . ~ ~ '
9 Miscellaneous
Micro-techniques have been described for the efficient conversion of steroids into derivatives, using only nanogram quantities.259 The Wolff-Kishner removal of 0x0-groups, the conversion of ketones into alcohols or ethylene-acetals, the oxidation of alcohols to ketones, and the formation of trimethylsilyl ethers were used in the extensive programme concerned with the preparation of steroid samples for g.1.c. analyses and the derivation of quantitative data on the g.1.c. behaviour of steroids to permit calculation of retention times under standardized conditions. This systematic investigation has so far covered 3-, 11-,and 17-substituted androstanes and 3-, 11-, and 20-substituted pregnane derivatives.259 The interconversions260of steroids or terpenoids by hydrogen transfer on Raney nickel in boiling p-cymene have been reviewed.261 The cholesteric mesophase formed by cholesteryl p-nitrobenzoate at 200 "C has been used as the solvent to effect an asymmetric synthesis; trans-but-2-enyl p-tolyl ether gave the product of an ortho-Claisen rearrangement, 2-(but-l'-en-3'-yl)-4methylphenol. This material exhibited circular dichroism, although neither the optical yield nor the configuration of the product is yet known.262 Decarboxylation of ethylphenylmalonic acid in cholesteryl benzoate at 160 "C (cholesteric liquidcrystalline phase) also proceeded with asymmetric induction to give (R)-(-)-2phenylbutyric acid, with 18% optical yield."' Electric dipole moments are reported for some esters of 5a-cholest-8(14)-en-3@-01; there is some slight correlation with melting points.26J 7SH 259
2h0
2hZ 263 264
T. B. Marriott, G. B. Birrell, and 0. H. Griffith, J. Amer. Chem. SOC.,1975,97, 627. F. A. Vandenheuvel, J . Chromatog., 1975, 103, 113. S. K. Banerjee, D. Chakravarti, R. N. Chakravarti, and M. N. Mitra, Tetrahedron, 1968,24,6459 R. N. Chakravarti, J . Indian Chem. SOC., 1975, 52, 1. F. D. Saeva, P. E. Sharpe, and G. R. O h , J. Amer. Chem. SOC.,1975,97, 204. L. Verbit, T. R. Halbert, and R. B. Patterson, J. Org. Chem., 1975,40, 1649. J. M. Pochan, J. E. Kuder, J. Y. C. Chu, D. Wychick, and D. F. Hinman, Canad.J. Chem., 1975,53,5 8.
Steroid Properties and Reactions
275
A review of the properties and uses of cholesterol includes references to such diverse information as complex formation, inclusion in cosmetics, liquid crystals, solubilities, and ice Carcinogenicity associated with 5,6a-epoxy-5a cholestan-3/3-01 (‘cholesterol a -oxide’) may account for earlier indications that cholesterol samples can contain carcinogens: hydroperoxides, including the 7hydroperoxycholesterolswhich result from autoxidation, have been shown to epoxidize cholesterol in low yields.266
265 266
E. S. Lower, Drug and Cosmetic Ind., 1975, 54. L. L. Smith and M. J. Kulig, Cancer Biochem. Biophys., 1975, 1, 79.
3
L/
Steroid Synthesis BY P. J. SYKES AND J. S. WHITEHURST
1 Total Synthesis The use of ring C/D intermediates in steroid synthesis is being further pursued as the compounds can be obtained purely chemically in the natural configuration without the necessity of resolution. In continuation’ of previous work2 (Scheme 1) the
E! (1)a; R = Me
b;R=Et
OQ
C02H
(2)
(3)
OBu‘ l.H
OBu‘
!1
H
H2C (4)
@)
0
CO,Et (5)
H
& (7)
Me0
\
(8)
Reagents : i , Methylmagnesium carbonate-DMF; ii, H,-MeOH-10 % Pd-BaSO,; iii, 37 ”/, aq. HCHODMSO-piperidine; iv, NaOMe-MeOH-(5); v, m-MeOC6H,CH,MgC1-THF-CuI ; vi, MeOHconc. HC1.
Scheme 1
*
R. A. Micheli, Z . G. Hajos, N. Cohen, D. R. Parrish, L. A. Portland, W. Sciamanna, M. A. Scott, and P. A. Wehrli, J. Org. G e m . , 1975, 40,675. ‘Terpenoids and Steroids’, ed. K. H. Overton (Specialist Periodical Reports), The Chemical Society, London, Volume 5, p. 289.
276
Steroid Synthesis
277
dextrorotatory compounds (1) are carbonated directly with methylmagnesium carbonate in DMF to yield the acids (2). The reduced compounds (3) reacted smoothly with formaldehyde in DMSO containing piperidine or pyrrolidine to form the vinyl ketones (4a) and (4b). Addition of (5) to (4) gave (6; X = P-Bu'O, a - H ) and from this were obtained 19-nor-ster0ids.~Addition of rn-methoxybenzylmagnesium chloride to (4) furnished3 dextrorotatory (7) which on HCl-MeOH cyclization produced (8) and thence oestranes of natural stereochemistry. The annulating agent (5) was produced' by a new method (Scheme 2). Surprisingly, methyl vinyl ketone is not considered to be an intermediate in the step
(9)
(5)
(12) Reagents : i, Aq. HCHO; ii, HOCH,CH,OH-toluene-conc. toluene-Na,CO, ; v, CO(OEt),-Et,O-NaH.
H,SO,, 0 "C; iii, aq. NaHSO, ;iv, aq. NaHC0,-
Scheme 2
(9) -+ (10). A more direct preparation4 of (5) is that of the alkylation of the dianion of ethyl acetoacetate with the bromide (12).
j
0
(13) a; R = Me b ; R = Et
S0,Ph
&(14)
.C-CH
\ SOtPh
(15)
1
iii
(6b;X= 0)
0 (16) Reagents : i, Paraformaldehyde-PhSOzH-(HOCH2CHz)3N-AcOH ; ii, H,-10% Pd/C-EtOH-l% HCl; iii, (5)-NaH-pentane-benzene.
Scheme 3 N. Cohen, B. L. Banner, W. F. Eichel, D. R. Parrish, G. Saucy, J.-M. Cassal, W. Meier, and A. Fiirst, J. Org. Chem., 1975,40, 681. G. Stork and J. d'Angelo, J. Amer. Chem. SOC.,1974,96,7114.
278
Terpenoidsand Steroids
In a beautifully straightforward synthesis5 of mnorgestrel(l6) (Scheme 3 ) the key reaction is the transformation of dextrorotatory (13b) into (14) ( 8 5 % ) with paraformaldehyde and benzenesulphinic acid in triethanolamine-acetic acid. To avoid dialkylation at least a 3 : 1 volume ratio of triethanolamine to acetic acid is needed. Catalytic reduction to (15) followed by reaction with the anion of ( 5 ) yielded (6b; X = 0).Further elaboration produced dextrorotatory norgestrel (16). Monoalkylation of the diones (13) with 1,3-dichIorobut-2-ene yields6 the compounds (17) and then, after steps, the laevorotatory ketones (18).
@
0
0 (17)
(18)
When the racemic compound (19) in ether is treated4 with lithium in ammonia containing, as proton source, aniline (not t-butyl alcohol), followed by anhydrous formaldehyde at -78 "C, it undergoes aldol condensation to form (21), whose mesylate reacted with compound ( 5 )to give, after cyclization, (22) from which (*)~ - h o m o19-nortestosterone (23) was eventually obtained. The reaction is best conducted by trapping the intermediary enolate (20; R = negative charge) as the trimethylsilyl ether (20; R = Me,Si) and regenerating it with methyl-lithium before the addition of formaldehyde. Also starting from (19) the Michael addition of the a -silylated vinyl ketone (24) to the enolate (20) yielded' after cyclization compound OBu'
03
0
0
: H
CH,OH
(22)
(23)
(24)
(22). Beginning8 with compound (26), which is readily available by way of the diketone (25), the method yielded (27), which after reductive methylation, G. Sauer, U. Eder, G. Haffer, G. Neef, and R. Wiechert, Angew. Chem. Internat. Edn., 1975,14,417. U. Eder, G. Sauer, J. Ruppert, G. Haffer, and R. Wiechert, Chem. Ber., 1975,108,2673. G . Stork and J. Singh, J. Amer. Chem. SOC.,1974,96, 6181. R. W. Boeckmann, J. Amer. Chem. SOC.,1974,96,6179.
279
Steroid Synthesis
hydrolysis, and cyclization gave (28), a compound readily transformed into (*)progesterone.
I
&
0
'
H
In continuation' of the polyolefin cyclization approach" to steroids, the action of trifluoroacetic acid on (29) in the presence of isohexene yielded the compound (31)
by way of the ion (30). Moreover (Scheme 4), condensation of (32) (available in three steps from 2-methylfuran) and (33) (four steps from acrolein) furnished the acetylenic alcohol (34), which on lithium aluminium hydride reduction gave (35). This compound by three further steps produced compound (36) which with trifluoroacetic acid in trifluoroethanol formed (37) and, from this, (*)-ll a hydroxyprogesterone (38) (9.6% yield in 16 steps). (&)-Cortisol is obtainable from (38) in six stages. lo
W. S. Johnson, Chimia (Switz.), 1975,29,310(Lecture at Berne, April 18, 1975). Ref. 2, p. 294.
Terpenoids and Steroids
280
How' w
O x 0
0
Ill
0
(36)
1
(35)
(38)
Scheme 4
Details have been published of the pyridine-type molecule approach for the construction of carbocyclic compounds,' in particular ( )-D-homo-oestrone. Treatment of (39) with toluene-p-sulphonic acid in hot benzene for one minute gavel' compound (40) of the elusive A 8 ( 9 ) - ~ t r ~ ~further t ~ r e ; reaction led to the expected oestrapentaene (4 1) from which by suitable reduction procedures 8a H-, 9PH,14PH-, 8aH,14PH-, and 9PH-oestrone methyl ethers were obtained. The well known compound (42) on electrocatalytic r e d ~ c t i o n (palladinized '~ platinium
*
l2
l3
'Terpenoids and Steroids', ed. K. H. Overton (Specialist Periodical Reports), The Chemical Society, London, Volume 3, p. 413; S. Danishefsky, P. Cain, and A. Nagel, J. Amer. Chem. SOC.,1975,97,380. A. V. Platonova, S. N. Ananchenko, and I. V. Torgov, Bull. Acad. Sci. U.S.S.R.,1974, 1581. K . Junghans, Chem. Ber., 1974,107, 1391; 1973,106,3465; 1975,108,2824.
28 1
Steroid Synthesis
& @ &'
Me0 \
Me0 \ (39)
Me0
\
(41)
(40)
electrodes) in ethanol-sulphuric acid formed 8a H-oestradiol methyl ether almost exclusively. On oxidation with hydrogen peroxide in t-butyl alcohol-sulphuric acid it gave the equilenin compound (43) but with oxygen in a similar medium compound (44) (ca. 40%) was produced. The conversion of equilin (45) into equilenin (43; 17-CO) can be performed by sequences involving bromination or epoxidation. In a new method14 equilin derivatives were treated with
(44)
(45)
NaA1H2(0CH2CH20Me),in boiling toluene. Aromatization of ring B with production of hydrogen proceeds in 30-70% yield. Similar steroids with As- or A9(11)bonds do not undergo aromatization. Lithium aluminium hydride is virtually ineffective. The cyclization of (46) is known1' to give poor yields of (47). In a detailed study16 it was found that toluene-p-sulphonic acid in benzene gave 30% of (47) and 50% of (48). The mechanism for the formation of the latter is indicated by conversion of (49)
l4
l5 l6
(46) (47) J.-C. Hilscher, Chem. Ber., 1975, 108, 727; cf. the conversion of limonene into p-cymene by N lithioethylenediamine (L. Reggel, S. Friedman, and J. Wender, J. Org. Chem., 1958, 23, 1136). C. Rufer, H. Kosmol, E. Schroder, K. Kieslich, and H. Gibian, Annalen, 1967,702, 141. N. Makk, E. Tomorkeny, and G. Horviith, Tefrahedron Letrers, 1974,3271; N. Makk, G. T6th, and E. Tomorkeny, Steroids, 1975, 25, 611.
Terpenoids and Steroids
282
Me0
& '
into (50),the C-9 position for one of the deuterium atoms being established by mass spectrometry. When (46) was treated with 90% acetic acid at room temperature it yielded (70%)the A8(9)-isomeralong with (51; 8a-H,14p-OH) (4.5%) and (51; SpH,14a-OH) (0.5'/0). The main path from (46) to (47) is regarded as proceeding via the A8(9)-isomerand the yet unknown (52) rather than (51). An analogue of (49) (H in place of D; C-13 methyl) on brief treatment with hydrogen chloride in chloroform yields the As(9)-isomer.17
Reduction of one carbonyl group of the prochiral dione (53) with chiral reducing agents has produced mixtures of 'a-' (the OH groups at either C-14 or (2-17 a -oriented as the molecule is usually depicted) and ' p '-alcohols with disappointingly low discrimination. l8
1'
G. Langbein and S. Schwarz, Z. Chem., 1975,15, 105. G. Haffer, U. Eder, G. Sauer, and R. Wiechert, Chem. Ber., 1975,108,2665.
Steroid S y n d i esis
283
Condensation of the vinyl alcohol (54) with 2-ethylcyclopentane-1,3-dioneled to the expected product from which €3-noroestradiol was ultimately obtained. l 9 Of particular conformational interest is that the double bond in one of the intermediates (55) was not isomerized by acid to the A'(")-position despite the fact that the compound is a trans-hydrindane. The compound (56), prepared from rnmethoxyphenylethylmagnesium bromide and the corresponding cishydrindanedione, undergoes dehydration but not cyclization on treatment with
(57)
(56)
hydrogen chloride-aluminium chloride .20 Cyclization was induced by polyphosphoric acid but the product was the spiro-compound (57). Condensation (Scheme 5)
. .. I, I1 w
0
Me0 (58)
(59) iii-v
vi-viii t---
Reagents : KOBut-ButOH; ii, pMeC,H,SO,H; vi, 48 % HBr ; vii, A ; viii, MsC1-py.
iii, H,-Pd/C-benzene; iv, HCI-MeOH ; v, H,-Pd/C;
Scheme 5 l9 *O
G. S. R. Subba Rao, N. S. Sundar, K. S. Rao, and A. J. Birch, Indian J. Chem.,1975,13,644. D. K. Banerjee and S. D. Venkataramu, Indian J. Chern., 1974,12, 1119.'
Terpenoids and Steroids
284
of the vinyl ketone (58) with 2,3-bisethoxycarbonylcyclopentanoneproduced21 by way of (59) and (60) the racemic compound (61). The dextrorotatory form of (61) is an intermediate in the conversion2zof ( f )-oestrone into ( +)-18-hydroxyoestrone. The D-homo-analogue of (60) has also been ~ y n t h e s i z e d . ~ ~ 2 Halogeno-steroids
The replacement of OH by Fin aliphatic alcohols has been extended to The trimethylsilyl ether (62) of pregnenolone on treatment with PhPF, in methylene chloride produced as the sole isolated product (70%) the A5-3/3-fluoride (63). Pregnenolone acetate (64) reacted with a lead tetra-acetate-hydrogen fluoride mixture [Pb(OAc),-12HF] in methylene chloride at -50°C to yield the 5a,6adifluoride (65) (20%) and a product (66) of rearrangement ( ~ O Y O ) . ~ ~
~
(62) R (63) R
= =
(65)
Me,SiO F
o&EAc H-ACO
F F
H (66)
(67) R = H (68) R = CF, (69) R = CF,, 7,8-dihydro
Irradiation of the dienone (67) in pyridine-trifluoromethyl iodide furnished26as sole product the 4-trifluoromethyl derivative (68) which is readily hydrogenated to (69). Interestingly, the U.V.spectra of the last two compounds demonstrate that the trifluoromethyl group has no bathochromic effect relative to hydrogen. The compound (70) by epoxide ring-opening with hydrogen fluoride, followed by photocatalysed addition of acetylene to the A16-bond and lithium aluminium hydride reduction, gave (71). Protection of the 1,2-diol system in (71) as the acetonide followed by oxidation, dehydration, and regeneration of the diol grouping produced 21 22
23 24
25 26
D . K. Banerjee, S. D. Venkataramu, and P. K. Sen, Steroids, 1974,24, 627. J. E. Baldwin, D . H. R. Barton, I. Dainis, and J. L. C. Pereira, J. Chem. SOC.( C ) , 1968, 2283. S. Dutt, A. Banerjee, and P. K. Bhattacharyya, Indian J. Chem., 1974, 12,360. N. E. Boutin, D. U. Robert, and A. R. Cambon, Bull. SOC.chim. France, 1974; 2861; D. U. Robert, G. N. Flatau, A. Cambon, and J. G. Riess, Tetrahedron, 1973,29, 18.77. M. Ephritikhine and J. Levisalles, Bufl. SOC.chim. France, 1975, 339. G . H. Rasmusson, R. D. Brown, and G . E. Arth, J. Org. Chem., 1975,40,672.
Steroid Synthesis
*, 285
(72) as a mixture of 6 a - and 6P-epimers from which the 6a-compound was separated and then acetylated (at C-21), oxidized (at C-20), and hydrolysed to furnish (73).27 0
CH20Ac
Qf
CH,OH
I
=’\
HO
CHIOH I
F
OH
F (73)
The trienone (74), either by reaction with diazomethane and pyrolysis of the derived pyrazoline or by treatment with dimethylsulphoxonium methylide anion, yielded2*the 1a,2a -methylene derivative (75). Epoxidation followed by the action of hydrogen chloride gave (77). The methylene bridge was re-formed by the reaction of collidine, the product being (76). Halogenated steroids of use in determining the metabolic fate of 16-chloro-oestrone methyl ethers and of chlormadinone acetate have been ~ y n t h e s i z e d . ~ ~
R (75) R (74)
27
29
=H (76) R = Cl
CI (77)
J. Iriate, P. CrabbC, and J. Fried, Rev. SOC. Quim. Mexico, 1974,18, 219. L. S. Morozova, F. A. Lur’i, V. I. Maksimov, G. S. Grinenko, L. I. Lisitsa, A. I. Terekhina, and E. A. Rudzit, Khim. Farm. Zhur., 1975,9,7. T. Nambara and M. Nokubo, Chem. and Pharm. Bull. (Japan), 1974,22, 2455; T. Nambara and Y. Kawarada, ibid., 1975,23, 1613; T. Abe and A. Kambegawa, ibid., 1974, 22, 2824.
Terpenoids and Steroids
286
3 Oestranes Alkylation of A'-3-keto-steroids can be made to occur at either C-2 or C-4, according to the procedure adopted.30 The nor-steroid (78) in an aprotic solvent at low temperature with a strong base gives the enolate (79) which in the presence of methyl iodide (conditions of kinetic methylation) leads to compounds of type (80). Thus in THF-HMPA at -70 "C the product consists of (80) (Me axial) (7 1YO)and only 5% of the corresponding dimethyl compound (81). In the presence of a protic
(80) R' (78)
(79)
(81)
R'
= =
Me, R 2 = H R 2 = Me
solvent, proton transfer from the ketone to the kinetic enolate can generate the thermodynamic enolate. In 1 : 1 THF-Bu'OH at -30 "C, the product contains (80) ( 5 % ) ,the 4,4-dimethyI compound (82) (33%), and the tetramethyl compound (83) (15%). The ratio of base to ketone must be kept well above 1 : 1 because of ether formation from the methyl iodide present. The dienone (84) can be made to yield (85) (71 %) (kinetic enolate trapping conditions) or (86) (60%) (thermodynamic conditions). Under kinetic conditions (base added last) (84; gave (85; A' '(12)) ( 5 5 % ) , but under thermodynamic conditions (presumably owing to prolonged action of base) no methylation product could be obtained. OTHP
(86)
In the formation of the diethylene acetals of 1l-keto- and lla-hydroxy-19-norA4-3-ketones the A"-bond is shifted almost e x c l ~ s i v e l yto~ ~the 5,6-position, the 2o 31
L. Nedelec, J. C. Gasc, and R. Bucourt, Tefruhedron, 1974,30,3263; M. Tanabe and D. F. Crowe, J.C.S. Chem. Comm., 1973, 564. A. J. van den Broek, C. van Bokhoven, P. M. J. Hobbelen, and J. Leemhuis, Rec. Truv. chim., 1975,94, 35.
287
Steroid Synt izesis
amount of A5'""-product being less than 5%. The compound (87) with methyllithium produced (88) and this on formic acid dehydration formed the 1l-methylene compound (89; 3-C0, 17-CO). Moreover, (87) undergoes smooth Wittig reactions to yield (89) and (90; E configuration) (cf. the non-reaction of the C-13 methyl compounds). In the oestrane series (91) yielded (92) but this on formic acid treatment gave (95). However, the unconjugated 1l-methylene compound (94) was secured neatly by reaction of (91)with (trimethylsi1yl)methylmagnesiumchloride32 to yield (93), followed by hydrolysis with hydrochloric acid in acetone.
n
l----l
3
Me0
i o
(87) (88) (89) (90)
&
(91) (92) (93) (94)
R =0 R = P-OH,a-Me R = CH, R = CHMe
'
R =0 R = D-OHp-Me R = B-OH,a-Me,SiCH, R = CH,
Me0 (95)
with methyl Grignard reagent gave the expected The compound (96) on (97) and this on acetylation with acetic anhydride-calcium h ~ d r i d and e ~ ~thermolysis produced the ll-methylene compound (98). Acid treatment of (97) furnished the product (99) of Wagner shift. Dichlorodicyanobenzoquinone oxidation3' of (100) produces the 96-hydroxy-compound ( 6 5 % )by a reaction involving hydration of the intermediary quinone methide (101). The well known ring-c fission brought about
n
(96) R = 0 R = B-OH,cc-Me (98) R = CH, (97)
32 33 34 35
D. Peterson, J. Org. Chem., 1968, 33, 780. R. V. Coombs, J. Koletar, R. P. Dauna, and H. Mah, J.C.S. Perkin I, 1975, 792. R. V. Oppenauer, Monatsh., 1966,97,62. G. M. Buchan, J. W. A. Findlay, and A. B. Turner, J.C.S. Chem. Comm., 1975, 126.
288
Terpenoids and Steroids
by chromic acid oxidation of oestranes has been to proceed by way of 11-ketones and 9-hydroxy-11-ketones. The A7@)-bondin equilin (102) and its derivatives fails to react with the SimmonsSmith reagent. However, treatment37with methylene iodide in benzene containing triethylaluminium generated the methylene compound (103) (70%). The bridge is a-oriented as for the corresponding epoxides. Diazomethane in the presence of palladous acetate3' converts (104) into (105). The reaction is not stereoselective, the ratio of @-to a-isomer being 7 : 3.
a -Methoxyvinyl-lithium can be prepared from methyl vinyl ether and t-butyllithium. Reaction with oestrone methyl ether gave39(106) which on acid hydrolysis formed (107). Conditions4' have been found for the high-yield conversion of compounds such as (108) into (110) without involving the intermediacy of the corresponding bromides (111). In an interesting 1,3-alkylative carbonyl transposition4' oestrone methyl ether was treated with LiCMe=CH, to produce (109) (as 36 37
38
39 40
41
P. Aclinou and B. Gastambide, Compt. rend., 1975, 280, C, 1423. Y. Lefebvre, D. J. Marshall, and C. Revesz, J. Medicin. Chem., 1975,18,220; D. B. Miller, Tetrahedron Letters, 1964, 989. U. Mende, B. Raduchel, W. Skuballa, and H. Vorbriiggen, Tetrahedron Letters, 1975,629; P. Paulissen, A. J. Hubert, and Ph. Teyssie, ibid., 1972, 1465. J. E. Baldwin, G. A . Hofle, and 0. W. Lever, J. Amer. Chem. SOC.,1974,96, 7125. D. 0. Olsen and J. H. Babler, J. Org. Chem., 1975,40,255; see also W. Haefliger and D. Hauser, Helv. Chim. Acta, 1975, 58, 1629. B. M. Trost and J. L. Stanton, J. Amer. Chem. SOC.,1975,97,4018.
289
Steroid Synthesis OH
(106) R (107) R (108) R (109) R
H,CH,R
(110) R = OAc (111) R = Br
= C(OMe)=CH, = COMe
= CH=CH, = CMe=CH,
lithium salt) which with benzenesulphenyl chloride formed, by sigmatropic rearrangement of (112), the sulphoxide (113). The anion of (113) reacted with diphenyl disulphide to produce, by way of (114) and (115), the alcohol (116) which on hydrolysis with mercuric chloride in MeCN-H,O formed the aldehyde (1 17). Beginning with the a-and P-epoxides corresponding to (118) all four 16-amino-17hydroxy-stereoisomers have been ~ y n t h e s i z e d .Vinylmagnesium ~~ bromide in the presence of cupric acetate adds to the double bond of 19-nor-A4-3-keto-steroidsto yield SP-vinyl compounds, the reaction paralleling that of the addition of saturated Grignard
,sr
OSPh
CHSPh
Me
(113) R = H (114) R = SPh
(115) R = SPh (116) R = H
4 Androstanes
Two straightforward preparations of androstadienes have been described. When testosterone tosylhydrazone is treated with methyl-lithium in dimethyl digol, androsta-2,4-dien-17P-o1 is formed in 91Oh yield,44and when 5a-androst- 16-ene is sequentially brominated and dehydrobrominated the expected 5a -androsta- 14,16diene is Photo-oxidation of the latter diene in the presence of Rose Bengal afforded the hydroxyandrostenone (1 19). 42
43 44 45
B. Schonecker and K. Ponsold, Tetrahedron, 1975,31,1131. H. Mori and R. Oh-uchi, Chem. and Pharm. Bull. (Japan), 1975,23, 559. G. Phillipou and R. F. Seamark, Steroids, 1975, 25, 673. J. C. Beloeil and M. Fetizon, Compt. rend., 1974, 279, C, 347.
Terpenoids and Steroids
290 0
OH (1 19)
The synthesis of some androstane derivatives having an aromatic ring B has been Ergosterol was chosen as starting material for this work since it is easily photolysed to 19-norergosta-5,7,9(10),22-tetraen-3~-01 (neoergosterol) and this sterol contains the readily degradable A22-doublebond. Accordingly, ozonolysis of neoergosterol furnished a (20s)-aldehyde which was acetylated to give the 3pacetate (120), and this was in turn converted, using known routes, into 3P-acetoxy19-norpregna-5,7,9(lO)-trien-20-one and thence into the required 3P-acetoxy-19norandrosta-5,7,9( 10)-trien-17-one. Reaction at the 17-ketone with methylmagnesium iodide or acetylene and potassium t-butoxide led to the 17a-methyl and 17a -ethynyl derivatives respectively.
(120)
Methods for the construction of ring-c aromatic steroids containing an oxygen function at C-1 have been devised and take place according to Scheme 6.47 Bromination of the 3-ketone (121) is now shown not to give the previously described 2a-bromo-3-ketone derived from (121) but rather the 2a-bromo-3-ketone (122), where the 18-methyl group has undergone a Wagner-Meerwein shift. Dehydrobromination resulted in the expected A1-3-ketone (123) which was further converted into its la72a-epoxide(124) prior to reduction to the la-hydroxy-2,13-diene (125). Hydrogenation and benzoylation of (125) afforded the ring-A-saturated benzoate (126) which was aromatized by the bromination-dehydrobromination technique previously described.48Reduction of the triene (127) gave the alcohol (128) which by oxidation afforded the ketone (130) and thence the oxime (131); reduction of the latter gave exclusively the thermodynamically stable lcr-amino-17,17-dimethyl-18nor-5a-androsta-8,11,13-triene(129). Reduction of the 1-ketone (130) with sodium in propan-2-01 gave a mixture (3 : 1) of the 10-alcohol (128) and its 1P-epimer; the corresponding lp-amine could not be prepared. Ring-c aromatic steroids hydroxylated at C-7 have also been described.49Direct dehydrogenation of 3p -hydroxy- 17,17-dimethyl- 18-nor-5a -androst- 13-ene with 46
47 48 49
P. Kocovsky and Z. Prochazka, Coll. Czech Chem. Comm., 1974,39, 1905. C. L. Hewett, S. G. Gibson, J. Redpath, and D. S. Savage, J.C.S. Perkin I, 1974, 1432. C. L. Hewett, I. M. Gilbert, J. Redpath, D. S. Savage, T. Sleigh, and R. Taylor, J.C.S.Petkin I, 1974,897. C. L. Hewett, S. G. Gibson, I. M. Gilbert, J. Redpath, D. S. Savage, T. Sleigh, and R. Taylor, J.C.S. Perkin I, 1975, 336.
Steroid Synthesis
29 1
a H
0
(124)
1
vii
H (130) R (131) R
(127) R = OBZ
(128) R (129) R
= =
OH NH,
(130) -7 (131)
=
=
0 NOH
(129)
Reagents: i, Br,-NaOAc, H , O + ; ii, C a C 0 , - D M A ; iii, H,O,-NaOH; iv, N H , N H , ; v, H,-Pd/C; vi, PhCOCI- py ; vii, (bromination-dehydrobromination),;4* viii, LiAIH,; ix, Jones oxidation; x, NH,OH.
Scheme 6
selenium dioxide gave the 7a-hydroxy-derivative (132) in one step and this could then be further oxidized to its corresponding 3,7-dione. The diacetate of the diol (132) could also be obtained along with the epimeric 3&7P-diacetate from the reaction of 3P-acetoxy- 17,17-dimethyl- 18-nor-5a -androsta-7,13-diene with mercury(I1) acetate in acetic acid, but the latter diacetate could not be obtained pure. Further reaction of the same diol (132) or the corresponding diacetate (either
HO
Terpenoids and Steroids
292
7-epimer) with sulphuric acid gave good yields of 17,17-dimethyl-18-nor-5aandrosta-6,8,11,13-tetraen-3/3 -01. Three 5a -androst-6-ene derivatives have been recorded as intermediates for labelling with isotopic hydr~gen.~'Reaction of 3/3-acetoxyandrost-5-en-17-one with N-bromosuccinimide-perchloric acid followed by oxidation of the intermediate 5,6-bromohydrin gave the diketone (133; R' = Br, R2= H), which on treatment with
(133)
hydrogen bromide isomerized to the 7a-bromodione (133; R' = H, R2= Br). Borohydride reduction of this bromodione and subsequent reduction of the intermediate 7 a -bromo-6-alcohols with zinc dust gave 17P-hydroxy-5a-androst-6-en3P-yl acetate, from which the 3P,17P-diol was obtained by hydrolysis. The latter diol was converted by standard reactions into 17P-hydroxy-Sa-androst-6-en-3-one and into 3a-hydroxy-5a-androst-6-en- 17-one. The A6-bond in the 3&17P-diol, the 17P-hydroxy-3-one, and the 3a-hydroxy-17-ketone was reduced with deuterium to furnish the corresponding [6,7-2H,]-5a-androstane derivatives. A synthetic route to 7P -hydroxyandrost-4-ene-3,6,17-trioneis illustrated by the reaction of 6a,7a -epoxyandrost-4-en-3,17-dione with DMSO saturated with air at 100 0C;51the yield of 7P-hydroxy-6-ketone is 8 5 % . When a similar direct oxidation of 3P-acetoxy-l6a, 17-epoxypregn-5-en-20-one was carried out, 3P-acetoxy16a,17-epoxypregn-5-en-7,20-dioneresulted, but only in 20% yield. Three different procedures for the intramolecular alkoxyalkylation of 19hydroxytestosterone acetate have been described.52 Each method yields a chromatographically separable mixture of two products monoalkylated at C-2, C-4, or C-6 and in all cases the groups are introduced stereoselectively from the p-side. Thus reaction of 19-hydroxytestosterone with iodine-acetone led to a mixture of the 4~,19-oxidodimethylmethano-steroid (134; R = Me) and the 6p,19oxidodimethylmethano-derivative (135; R' = R2= Me); reaction with mercuric chloride and chlorodimethyl sulphide (ClCH,SMe) yielded the corresponding oxides (134; R = H) and (135; R' = R2 = H); reaction with trimethyl orthoformate and toluene-p-sulphonic acid afforded the oxides (135; R' = H, R2 = OMe), (135; R' = OMe, R2= H), and the 2P,19-oxide (136). Several 3P,19-oxido-steroids have been prepared commencing from variously substituted androstanes (137; R' and R2= H, halogen, alkyl, alkoxy, or acyloxy or R'R2 forms a double bond).53 Thus oxidation of So
1. Khattak and D. N. Kirk, J.C.S. Perkin I, 1974, 2010.
s51 M.
Kochr, L. Tomaszewska, K. Rafinska, and A. Kazabski, Bull. Acad. polon. Sci. Sir.Sci. chim., 1975,
23,223. 52 53
C . Luthy, H. R. Schlatter, and W. Graf, Helv. a i m . Acta, 1975, 58, 1120. H. Mori, K. Shibata, R. Ouchi, and N. Yarnakoshi, Japan Kokai 74/30 366 (Chem. A h . , 1974, 81, 49 921).
Steroid Synthesis
293
Sa,6/3-dichloro-3P-hydroxyandrostan-17-one (137;R' = R2= Cl) with lead tetraacetate in the presence of dibenzoyl peroxide produced the 3/3,19-oxide (138; R = H2)which on chromium trioxide oxidation gave the lactone (138; R = 0).
H
(134)
HO
R2
Sequential reaction of the spiro-epoxide (139), derived from 3-ethoxyandrosta3,5-dien-l7-one and Me,S'I-, first with chloranil to establish the A4'6-3-oxofunction and then with diethyl malonate, allowed the isolation of the spiro-steroid (140; R = C0,Me). Saponification and decarboxylation led to the derivatives (140; R = C0,H) and (140; R = H) r e ~ p e c t i v e l y .It~ ~has been demonstrated that the
(139)
(140)
reaction between hydrazoic acid and the epoxides 6 q 7 a -epoxyandrosta- 1,4-diene3,17-dione and the corresponding 176-acetate leads to the 7a-hydroxy-6pazidoandrostenes (141; R = 0 or P-OAc,H) re~pectively.~~ Jones oxidation of the 7a-aIcohoI (141; R = O ) leads to ring contraction and the formation of the 5pcyano-dione (142) which is readily converted into the 6,7-seco-steroid (143) by a trace of alkali. A similar ring contraction has been observed to take place when a refluxing benzene solution of 4-azido-4,6-androstadiene-3 ,17-dione is exposed to a photoflood lamp; the resulting A-nor-ketone (144) is formed in 74% yield. If a shorter wavelength is used in the irradiation step a 13a-epimer of (144) results.56 Again reaction of this 5p-cyanide with base leads smoothly to a seco-steroid, in this case the 4,5-seco-derivative (145). 54 55 56
J. Warnant and J. Jolly, Ger. Offen. 2404947 (Chem. A h . , 1974,81, 136383). M. K O C ~M. J , Gumulka, and W. Kroszczynski, Tetrahedron Letters, 1975, 165. E.M. Smith, E. L. Shapiro, G. Teutsch, L. Weber, H. L. Herzog, A. T. MacPhail, P. S. W. Tschang, and J. Meinwald, Tetrahedron Letters, 1974, 3519.
294
Terpenoids and Steroids R
&
MeO,C
0 CN
CN
Straightforward syntheses of the epoxides 4p,5p -epoxy-6a - hydroxy- and 2a,3a epoxy-6Plhydroxy-androstan-17p-yl acetate commencing from androst-5-en-17Pyl acetate and 6-oxoandrost-2-en- 17P-yl acetate respectively have been publ i ~ h e d . ' ~Reaction of the As-olefin with rn-chloroperoxybenzoic acid afforded a mixture of the 5 a 7 6 a - and SP,GP-epoxides which were oxidized with chromium trioxide to give 5a-hydroxy-6-oxoandrostan-l7~-yl acetate. Dehydration led to the known 6-oxoandrost-4-en-17P-yl acetate which was then reduced to the 6aalcohol prior to further epoxidation to yield a separable mixture (1 : 1) of 4p,5/3epoxy-6a -hydroxyandrostan- 17p -yl acetate and the 4a,5a -epimer. Sequential epoxidation of the A'-bond and oxidation of the 6-0x0-group transformed 6aceoxoandrost-2-en- 17p-yl acetate into 2a73a-epoxy-6~-hydroxyandrost-17~-y1 tate. Both the 4P,5P-epoxy-6a-alcohol and the 2a73a-epoxy-6~-a1coho1 described above were aromatized to 4-methyloestra-l,3,5( 10)-trien-17P-yl acetate on treatment with hydrobromic acid in glacial acetic acid. Another androgen which is readily aromatized is 2~-hydroxy-19-oxo-4-androstene-3,17-dione (150)? It is thought that this steroid may be the penultimate link in the androgen-oestrogen bioconversion, for it is transformed quantitatively into oestrone in the presence of water at neutral or basic pH. A synthetic route to this 19-aldehyde (150) is given in Scheme 7. Reaction of the A4-3,17-dione (146) with bromine led to the expected 6p-bromosteroid (147) which on acetolysis and concomitant rearrangement furnished the 2P,19-diacetate (148) accompanied by a small amount of the epimeric 2a,19diacetate. Hydrolysis of the 2P719-isomer led to the 2P,19-diol, which was selectively protected by partial silylation, and the resultant 19-alcohol (149) after oxidation and hydrolysis formed the required aldehyde (150). The epimeric 2a,19dihydroxy-4-androstene-3,17-dione was obtained via sulphuric acid rearrangement of 4P75P-epoxy-19-hydroxyandrostane-3,17-dione,itself obtained from alkaline peroxidation of the A4-en-3-one (146). 57
sR
D. Baldwin and J. R. Hanson, J.C.S. Perkin I, 1975, 1107. H . Hosoda and J. Fishman, J. Amer. Chem. SOC.,1974,96, 7325.
295
Steroid Synthesis
Br (147)
Reagents: I, NBS py; VI, ACL 7
.
’
1
iii, iv
c; iii, K O H - M e O H ; iv, Bu‘Me,SiCl-imidazole-DMF; v, Cr0,-
Scheme 7
A general synthetic route has been proposed for the conversion of the readily available 3-ket0-A~,~-steroids into their 1a -hydroxy-As-analogues; the method is exemplified with androsta- 1,4-diene-3,17-dione, pregna- 1,4-diene-3,20-di0ne,’~ and cholesta- 1,4-dien-3-0ne.~’ Androsta-l,4-diene-3,17-dioneis first converted into its 17,17-ethylene acetal in order to protect the isolated ketone function through the strong-base deconjugation step which is used to obtain the intermediate 3-ketoA”’-steroid. The latter dienone is reduced with calcium borohydride in ethanol at a temperature below - 10 “C to produce the 2P-hydro~y-A’~’-steroid, obtained in 65-75% yield based upon the parent A134-3-keto-steroid.The last step in the procedure is hydroboration at the A’-bond followed by oxidation with alkaline hydrogen peroxide to yield a chromatographically separable mixture of the two isomeric 1a,3P- (15-20%) and 2a,3@-diols(20-25%). Removal of the acetal group from C- 17 then affords 1a - and 2 a -hydroxydehydroepiandrosteronerespectively. Many of the features of the above reaction sequence have also been used during the conversion of androst-1,4-diene-3,17-dioneinto the la-hydroxy- and 2P -hydroxy-derivatives of 3P-hydroxyandrosta-5,7-diene17,1’7-ethyleneaceta1.61 The 1,4-diene-3,17-dione was first converted by standard reactions into androsta1,4,6-triene-3,17-dione 17,17-ethylene acetal which was deconjugated with strong base, as before, prior to calcium borohydride reduction to afford an 80% yield of the A’,5,7-trien-3P-ol. This triene was protected with 4-phenyl-1,2,4-triazoline-3,5dione to give the 1,4-adduct (15 1) which on reaction with rn-chloroperoxybenzoic acid gave a separable mixture of the l a , 2 a - and lP,2P-epoxides. Separate lithium aluminium hydride reduction of each epoxide resulted in both the regeneration of the 5,7-diene function and the regioselective fission of the epoxide ring to yield the 5q
6o 61
C. Kameko, A. Sugimoto, S. Yamada, M. Ishikawa, S. Sasaki, and T. Suda, Chem. and Pharm. Bull. (Japan), 1974,22, 2101. C . Kameko, S. Yamada, A. Sugimoto, Y. Eguchi, M. Ishikawa, T. Suda, M. Suzuki, S. Kakuta, and S. Sasaki, Steroids, 1974,23, 75. H. Sakamoto, A. Sugimoto, and C. Kameko, Chem. and Pharm. Bull. (Japan), 1974,22,2903.
Terpenoids and Steroids
296
n
la73P-diol (152; R1= H, R2= OH) and the 2P73P-diol (152; R1= OH, R2 = H) respectively. Convenient and efficient sequences involving 3a75-cyclointermediates have been developed for obtaining 3,6- and 6,17-dioxygenated 5a-androstanes from the readily available sterol 3P-hydroxyandrost-5-en-17-one;these routes are summarized in Schemes 8 and 9.62Dehydroepiandrosterone was first converted into 3Phydroxyandrost-Sene (153) and thence into the cyclosteroid (154) which by stereoselective ring-opening readily afforded the 3P-hydroxy-6-ketone (155). In an alternative route to this hydroxy-ketone via the 3,6-diones (156) and (157), the last stage, partial reduction with borohydride, becomes difficult to control as the scale is increased. Complete reduction of the 3,6-dione (157) leads, as expected, to the 3P76P-diol (158). Selective acetalization of the 3,6-dione (157) to furnish the 3,3-acetal (159) is the key step in the route to the 6P-hydroxy-3-ketone (161). Under the usual homogeneous reaction conditions for acetal formation there was insufficient differentiation between the 3- and the 6-keto-groups, but the use of an insoluble ion-exchange resin as the acidic component led to a clean reaction at C-3 and an 81% yield of the monoacetal (159). Hydroboration of the A5-bond in the starting steroid (153) leads to the 3P76a-diol(162) (77% yield) which could then be oxidized selectively with Fetizon reagent (silver carbonate) to yield the 6 a -hydroxy3-ketone (163); the epimeric 3P76P-diol(158) could not be selectively oxidized in this manner. Scheme 9 outlines the routes to 6,17-dioxygenated androstanes. Dehydroepiandrosterone was first converted into the 3a75-cyclo-steroid (164) and thence by reduction, acetylation, and oxidation into the 6-keto-cyclo-derivative (165); reduction of the cyclopropane ring followed by alkaline hydrolysis furnished the 17P-hydroxy-6-ketone (166), which could be further oxidized to 5aandrostane-6,17-dione. Reaction of dehydroepiandrosterone with phosphorus pentachloride and then with ethylene glycol and an acid catalyst afforded the 3P-chlorosteroid (167) (65% yield), from which the chlorine could be removed to furnish the 6a-alcohol (168) after hydroboration. Hydrolysis of the acetal (168) gave the 6ahydroxy-17-ketone (169) which again was readily oxidizable to the corresponding 3,17-dione. A modified Treibs reaction has been used to convert dehydroepiandrosterone into 3P-acetoxy-6P-hydroxyandrost-5-en17-one; reaction is by means of mercury(I1) 62
Sir E. R. H. Jones, G. D. Meakins, J. Pragnell, W. E. Miiller, and A. L. Wilkins, J.C.S. Perkin I, 1974, 2376.
297
Steroid Synthesis
(153)4
HO
& '
4o@
111,
OH
H
i
OH
Reagents: i, p-MeC,H,SO,Cl-py; ii, KOAc-Me,CO-H,O, A ; iii, H,CrO,-Me,CO; iv, H2S0,-H20; v, H,CrO,-Me,CO ; vi, Zn-AcOH, A ; vii, NaBH,-CH,CI,-MeOH; viii, LiAlH(OBu'),, 0 "C; ix, HO(CH,),OH-C,H,-amberlite resin, A ; x, HCI-EtOH-H,O, 20 "C; xi, B,H,, then H,O,NaOH ; xii, Ag,CO,-celite.
Scheme 8
trifluoroacetate in methylene dichloride and the yield of 6P-alcohol is 40'/0.~~A short synthesis of two epimeric A-ring steroidal cyclopropanols has been publ i ~ h e d Treatment .~~ of 17P-hydroxy-Sa-androstan-3-one with bromine gave the known 2a,4a-dibromo-3-ketone which was reduced with borohydride to give a separable mixture of the epimeric 2a,4a-dibromo-3a, - and -3P-alcohols. Reaction of the dibromo-3~-alcoholwith a zinc-copper couple gave the 2p,4p-cyclo-3palcohol (170), and similar treatment of the dibromo-3a-alcohol furnished the same 63 64
G. Massiot, H. P. Hudson, and P. Potier, Synthesis, 1974, 722. J. F. Templeton and C. W. Wie, Canad. J. Chem., 1975,53, 1693.
Terpenoids and Steroids
298
Reagents : i, LiAIH(OBu'),. 0 " C ; ii, Ac,O --py; iii, H,CrO,-Me,CO ; iv, H,-Pd/AcOH ; v, KOH-EtOH ; vi, Na-Pr'OH. A : vii, B,H,, H,O,-NaOH; viii, HC1O,-THF-HzO, 20°C.
Scheme 9
cyclo-steroid (170) along with the epimeric 2p74~-cyclo-5a-androstane-3a, 17pdiol. The latter is shown to isomerize to the isomer (170) under the zinc-copper couple reaction conditions. The tosylate derived from (170) was found not to solvolyse, whereas the tosylate of the corresponding 3 a -alcohol solvolyses rapidly to a mixture of 17p-acetoxyandrost-2,4-diene, 4a,1 7 p-diacetoxy-5a -androst-2-ene, and 2a, 17j3-diacetoxy-5a -androst-4-ene.
(170)
A series of variously substituted chloro-androstanes (17 examples), bromoandrostanes (14 examples), and amino-androstanes (29 examples) prepared from the corresponding alcohols and oximes has been described.65 It was noted during the course of this work that all ring A, B, or C oximes were reduced by lithium aluminium hydride to yield over 90% of the corresponding axial amine, except at C-3 where 65% of the equatorial amine was isolated. This is in line with the lithium aluminium hydride reduction of 5a-cholestan-3-one where the equatorial hydroxy-steroid predominates. The observation was also made that when 3p-, 7p-, and 16ptosyloxy-5cr -androstanes are heated with tetra-n-butylammonium hydroxide in hs
D. B. Cowell, A. K. Davis, D. W. Mathieson, and P. D. Nicklin, J.C.S. Perkin I, 1974, 1505.
Steroid Synthesis
299
DMSO, the corresponding 3a-, 7a-, and 16a-hydroxy-50-androstanes are obtained in 90% yield without significant concomitant elimination. A series of steroidal phosphinic acid esters has been synthesized as possibly suitable derivatives for gas chromatography; in the evenf these derivatives turned out to be insufficiently volatile.66 For example, when 3a-hydroxy-5a-androstan17-one was treated with Me,P(O)NMe, a 99% yield of the 3a-ester (171; X = 0 ) was produced and similar reaction with Me,P(S)Cl-NEt, furnished the corresponding ester (17 1; X = s)in 97% yield. Spin-labelled esters of testosterone (172) and of cortisol have been prepared from 3-carboxy-2,2,5,5-tetramethylpyrrolidin1-yl oxyl free radical and the appropriate steroid using NN'-thionyldi-imidazole as the coupling reagent.67 Use of more conventional dehydrating agents failed to give the ester (172).
An improved route has been described for the degradation of cholesterol to dehydroepiandrosterone,68@ in which cholesterol is first acetylated and then brominated to give the 5a,6@-dibromide. This protected cholestane is then isomerized to the 5&6a-dibromide prior to chromium trioxide oxidation and zinc debromination. The yield of dehydroepiandrosterone (isolated from the reaction mixture as a 50.60-dibromide) is 20%. Reduction of steroidal dienones with lithium-ammonia complex has been used to obtain a 68% yield of the deconjugated ketone 17P-hydroxyandrost-5-en-3-one from the corresponding A476-dien-3-one.Reduction was achieved using Li(NH,), in THF containing 2-methylbutan-2-01.~' A similar, but not so useful, reduction of androst-1,4-dien-3-one led to androst-4-en-3-one in 46% yield. An interesting stereospecific reduction has been observed to take place between the apunsaturated iminium perchlorate (173), readily obtained by reaction of the corresponding dienamine with perchloric acid, and the Hantzsch ester (174). The reduction product, isolated in 70% yield, is the AB-cis-fused steroid 5p,6dihydrotest~sterone.~' The 1,4-dihydropyridine (174) is an NADH model, which confers on this reaction a degree of biological interest. A similar reduction of the iminium salt (175) furnished stereospecifically the corresponding ammonium salt (176) in 90% yield.72 h6
67 Ox 6y
70 71
72
K. Jacob, W. Vogt, 1. Fischer, and M. Knedel, Tetrahedron Letters, 1975, 1927. J. R. Dodd and A. J. Lewis, J.C.S. Chem. Comm., 1975, 520.
H. Sugihara, Y. Izuka, and S. Shirakawa, Japan Kokai 74/42 662 (Chem. A h . , 1974,81, 105 811). H. Sugihara, Y. Izuka, and S. Shirakawa, Japan Kokai 74/36 662 (Chem. Abs., 1974,81,49 922). V. 1. Melnikova and K. K. Pivnitskii, Zhur. org. Khim., 1974,10, 1014. U. K. Pandit, F. R. M. CabrC, R. A. Gase, and M. J. de Nie-Sarink, J.C.S. Chem. Comm., 1974, 627. U. K. Pandit, R. A. Gase, F. R. M. Cab& and M. J. de Nie-Sarink, J.C.S. Chem. Comm., 1975, 211.
300
Terpenoidsand Steroids OAc
Et0,C Me
fi
C0,Et
N
H
Me
( 176)
(175)
Some 2-deoxy-analogues of rubrosterone have been r e p ~ r t e d . 'The ~ synthesis commenced with a Bamford-Stevens reaction upon 3P, 17P-diacetoxyandrost-5-en'7-one tosylhydrazone to yield the corresponding 5,7-diene. Successive chromic acid and selenium dioxide oxidation of this diene furnished the 2-deoxyrubrosterones (177; R' = OAc, R2= H, R3= OH, X = 17p-OAc,H; 5a-H) and (177; R' = OAc, R2 = R3= H, X = 17P-OAc,H; 5a-H) respectively. Alkaline hydrolysis of the latter derivative afforded an A-homo-B-nor-steroid (178). The+rubrosterone(177; R' = R2 = R3= OH, X = 0; 5P-H), which possesses antidiabetic activity, has been prepared by oxidative degradation of the cholestene (179), itself obtained from ecdyster~ne.~~ X
H
HO
As ( 1 77)
The dienone-phenol rearrangement of androsta- 1,4,6-trien-3,11,17-trionehas been shown to lead to two major products, the AB-aromatic acetate (180; X = 0)and the corresponding 1la-01 (180; X = a-OH,H). Oxidation of the naphthol (180; 73
74
Zh. S. Sydykov, G. M. Segal, I. V. Torgov, and K. K. Koshoev, lzvest. Akad. Nauk S.S.S.R., Ser. khim., 1975,624. T. Takemoto and H. Hikino, Japan Kokai 73/42 872 (Chem. A h . , 1974,81,49 923).
301
Steroid S y ti thesis
X = 0;3-OH) with potassium nitrodisulphonate afforded the novel naphthaquinone (181) in 30% yield.7s Dienone phenol rearrangement of androsta- 1,4,6-triene3,16-dione with the hyperacid HF-SbFS at - 50 "C results in the formation of the conjugated phenol (182) rather than the classically rearranged phenol based on (180; X = H2).76
The preparation of nine 7sSe derivatives of steroids has been described; these labelled steroids have proved useful in assaying the comparative binding of prot e i n ~ Reaction .~~ of 75Se02with dehydroepiandrosterone yields a selenium derivative (183) which upon reduction with dithiothreitol or HSCH,CH,OH and then methylation furnishes the corresponding methylseleno-steroid.
(183)
Turning to recent syntheses which have involved the addition of extra carbon atoms to androstanes, an efficient sequence of reactions has been proposed for the The route is illustrated by conversion of a 17-keto-steroid into a 20-ket0-steroid.~~ the conversion of 3P-hydroxyandrost-5-en-17-oneinto the 20p-formyl intermediate (184; R = H) by means of methoxymethylenetriphenylphosphorane, followed by oxidation to the etianic acid (184; R = O H ) using silver oxide; it is
H (184)
unnecessary to protect the 3P-hydroxy-group through the oxidation. The acid (184; R = O H ) is then treated with methyl-lithium to yield the pregnenolone (184; R = Me) or indeed with isohexyl-lithium to yield the 20-0x0-21-norcholesterol [184; R = (CH,),CHMe,]. An interesting route has been explored which results in the 7s 76 77 78
S. M. Ali and A. B. Turner, J.C.S. Perkin I, 1974,2225. J . C. Jacquesy, R. Jacquesy, and U. H. Ly, Tetrahedron Letters, 1974, 2199. E. M. V. Chambers and A. L. M. Riley, Ger. Offen. 2 364 741 (Chem. Abs., 1974,81, 136 384). S. Danishefsky, K. Nagasawa, and N. Wang, J. Org. Chem., 1975,40, 1989.
Terpenoids and Steroids
302
transformation of 19-hydroxytestosterone acetate (185; R = H) into its 4,4dimethyl-5a -saturated analogue in high yield.7‘) Initial reaction of the 19-alcohol (185; R = H) with DMSO in acetic anhydride gave the 19-O-(methylthiomethyl)androstenone (185; R = CH,SMe) which on treatment with silver nitrate and N-bromosuccinimide afforded the 19-O-(rnethoxymethyl)steroid (185; R = CH,OMe). Successive methylation of the latter and hydrogenation of the As-bond gave as the major product the dimethylandrostane (186; R = CH,OMe) accompanied by some of the 5P-epimer, which with urea-hydrogen fluoride-propan-2-01 both gave the respective 19-hydroxy-4,4-dimethyl derivatives. Similarly, 17/3,19bis[(tetrahydropyran-2-yl)oxy]androst-4-en-3-one was methylated, hydrolysed, and then hydrogenated to yield the 3,19-oxide (187). The methyl-lithium-cupric
)iodide reagent has been used for the transformation of 1a-methylandrost-4-ene3,17-dione and la -methylandrost-4-en- 17p-01 into their respective lar,SP dimethyl derivatives (188); the compounds have proved useful as strong inhibitors of testes function and spermiogenesis.80 Another 3 3 -methyl steroid results from the alkylation of testosterone propionate with trimethylaluminium catalysed by nickel acetylacetonate; the product obtained in 35% yield is SP-rnethyl-3-oxo-Spandrostan-17P-yl propionate.*l
(188)
(189)
(190)
The combined action of lithium in liquid ammonia and carbon dioxide upon androst-4-en-3-one led to a synthesis of the P-keto-ester (189), after esterification of the intermediate acid; the reaction is one of reductive methoxycarbonylation.” Alkylation of the keto-ester (189) afforded a separable mixture of the 4P-methyl steroid (190) as the major product (55%) and the corresponding 4 a methyl epimer. Reduction of the steroid (190) led to 4a-hydroxymethyl-4Pmethyl-5a-androstan-3P -01. Finally in this section, it has been noted that vinylmagnesium bromide effects 1,4-addition to the @-unsaturated ketone 17phydroxy-5a-androst-l-en-3-oneto yield lu-vinyl-5a-androstan-3-on-17~-ol, which could be further reduced to the la-ethyl-3-ketone.*’ 79
HZ x3
H. R. Schlatter, C. Luethy, and W. Grad, Helv. Chim. Acta, 1974, 57, 1044. R. Philippson and H. Steinbeck, Ger. Offen. 2 253 087 (Chem. Abs., 1974,81, 6 3 879). L. Bagnell, A. Meisters, and T. Mole, Austral. J. Chem., 1975, 28, 817. M. R. Czarny, K. K. Maheshwari, J. A. Nelson, and T. A. Spencer, J. Org. Chem., 1975,40, 2079. H. Mori and R. Ohuchi, Chem. and Pharm. Bull. (Japan), 1975,23,980.
303
Steroid Synthesis
Turning now t o some of the more interesting heterocyclic derivatives of the androgens, chandonium iodide (191) (17a-methyl-3p-pyrrolidino-l7a-aza-~homoandrost-5-ene dimethiodide) and 4-methyl-1 7P-dimethylamino-4-aza-5aandrostane dimethiodide (192) have both been synthesized; the former is a powerful non-depolarizing neuromuscular-blocking agent of rapid action and short duration8" Using standard reactions, dehydroepiandrosterone acetate was converted into 17a-aza-~-homoandrost-5-en-17-on-3p -01 which was oxidized under Oppenauer conditions to the corresponding A"-3,17-dione. This was in turn converted into the enamine (193). Borohydride reduction of (193) followed by sodiumpentanol reduction of the intermediate 3P-pyrrolidino-As-l 7-one furnished the diamine, 3~-pyrrolidino-17a-aza-~-homoandrost-5-ene which formed the dimethiodide (191). The synthesis of the diaza-steroid (192) commenced by oxidation of androst-4-ene-3,17-dioneto the corresponding 3,5-seco-keto-acid which was converted directly into the dioxime 5,17-bishydroxyimino-4-nor-3,5secoandrostan-3-oic acid. The latter was reduced in one step to 17P-amino-4-aza5a-androstane which was further quaternized to yield the bis-onium salt (192). The reaction of 17a-methyl-l7a-aza-~-homoandrost-4-en-3-one with hydrazoic acid and boron trifluoride has been shown to afford 17a-methyl-3,17a-diaza-A,~bishomoandrost-4a-eno[3,4-d Jtetrazole (194),85whilst similar reaction of androst4-en-3,17-dione yields the diazabishomoandrostenobistetrazole ( 195).86 Other steroidal quaternary salts which have been reported to be fast-acting muscle relaxants are formed when the androstanes (196; R ' = H or Ac; R 2 = R 3 = piperidino) are treated with methyl or ally1 b r ~ m i d e . ~The ' route to these steroids commences with the epoiidation of 5a-androst-2-en- 16-one and ring-opening of +
(193) 84
85
86 87
(194)
H. Singh and D. Paul, J.C.S. Perkin I, 1974, 1475., H. Singh and D. Paul, Indian J. Chern., 1974, 12, 1211. H. Singh, R. K. Malhotra, and V. Parashar, Indian J. Chern., 1975, 13, 761. C. L. Hewett and D. S. Savage, Ger. Offen. 2 359 076 (Chern. Abs., 1974,81, 91 805).
Terpenoids and Steroids
304
bN*
R
)
/
y
7
p
R
3
N-N II
N,"
/ (196)
(195)
the resultant a-epoxide with piperidine to give 2P-piperidino-3a-hydroxy-5aandrostan- 1 6 - 0 1which ~ undergoes Leukart-Wallach reaction followed by acetylation to yield the required intermediate (196; R1= Ac, R2= R3 = piperidino). The Leukart reaction has also been used in the conversion of dehydroepiandrowhich on reduction sterone into 17p-formylamino-3~-formyloxyandrost-5-ene, with lithium aluminium hydride afforded 3P-hydroxy- 17p-methylaminoandrost-5ene. Acylation with isocaproyl chloride then furnished the N-methyl-N-isocaproyl steroid (197), after selective ester hydrolysis of the initially formed ON-diacyl derivative. The amide (197) was further converted into its 3,5-cyclo-6-ketone via the 3,5-cyclo-6~-alcoholand thence by reaction with hydrogen bromide into the corresponding 3p -bromo-5a-6-ketone which upon dehydrobromination furnished a A2-5a-6-ketone and ultimately the 2-monoacetate of the 2/?,3P-diol (198) after reaction with silver acetate and iodine. Hydrolysis to the 2@,3P-diol (198) gave a separable mixture of the 2P,3P-dihydroxy-Sa- and -5p-ketones.'' 0
(197)
(198)
Annelation of steroidal dienamines with substituted phenacyl bromides (7 examples) or with benzenediazonium salts (11 examples) has been shown to lead to the corresponding furano- and indolo-~teroids.~~ Thus the A3.5-dienaminederived from A4-androstene-3, 17-dione reacted with p-bromophenacyl bromide to yield the Asandrostano[3,4-b]furan (199) in 26% yield, and reaction of the same A3,5-dienamine with benzenediazonium fluoroborate at -45 "C led to formation of the hydrazone (200) which underwent Fischer-indole cyclization on treatment with phosphorus oxychloride to produce the A4-androstano[6,7-b]indole (201). The A3,5-dienamine derived from 17P-acetoxyandrost-4-en-3-one has been converted into the benz[4,5,6]-steroid (202; R' = Me, R2= H) by reaction with methyl vinyl ketone and into the analogous benzsteroid (202; R' = H, R2= Me) on treatment with crotonaldehyde." A route to the condensed pyrroline ring system (203) has been devised 89 90
Z. Mackova and V. &mL, Coll. Czech. Chem. Comm., 1974,39, 1091. M. S. Manhas, J. W. Brown, U. K. Pandit, and P. Houdewind, Tetruhedron, 1975,31, 1325. P. Houdewind, J. C. Lapierre Armande, and U. K. Pandit, Tetrahedron Letters, 1974, 591.
Steroid Synthesis
305
(202)
(203)
using Michael addition of nitromethane to 2-methyleneandrosta-4,6-dien17P-013-one followed by reductive cyclization of the intermediate 2 a -(p-nitroethyl)androsta-4,6-dien- 17p-01-3-0ne.~~ The fused pyrrole ring system (204) has been obtained by the reaction of 17Phydroxy-17-methylandrosta-1,4-dien-3-onewith tosylmethyl isocyanide in the presence of sodium hydride in DMS0,92 and 17~-hydroxy-17-methy1-7-oxa-5aandrostano-[3,2-c]- (205) or -[2,3-d]-isoxazoles (206; X = 0)have been prepared by treating 7-oxa-2-(hydroxymethylene)-17p-hydroxy- 17-methyl-5a -androstan%one with hydroxylamine h y d r ~ c h l o r i d e .In ~ ~the presence of pyridine, the isoxazole (206; X = 0)is formed, but when the reaction is catalysed by sodium acetate in acetic acid the isomeric steroid (205) results. Cycloaddition of hydrazine hydrate to the same 2-hydroxymethylene-7-oxa-steroidresults in the [3,2-c]pyrazole (206; X = NH). A similar addition is encountered in the reactions between 3P-hydroxy16-(hydroxymethylene)-5a-androstan-17-one and the substituted hydrazines RNHNH, (R = H, o-COC,H,NH, or p-COC6H4NH,) when the corresponding [ 17,16-c]pyrazoles (207) are formed after cyclization of the intermediate hydrazones .94
Hw‘ 0
(206) 91
92
93
94
(207)
M. Kodr, W. Kroszczynski,and B. Zultowska, Bull. Acad. polon. Sci. Sir. Sci. chim., 1974,22,8635. W. Krosznynski, Roczniki Chem., 1975,49, B13. R. W. Guthrie, R. W. Kierstead, and R. A. Le Mahieu, U.S.P., 3 869 467 (Chem. Abs., 1975, 83, 43 609). L. N. Volovel’skii, I. I. Kuz’menko, and-N. V.Novikova, Zhur. obshchei Khim., 1974,442577.
Terpenoids and Steroids
306 5 Pregnanes
In a remarkably simple synthesisY5of the corticosteroid side chain (Scheme 10) the oxime (208) was refluxed with acetic anhydride in pyridine to form the enamide (209) which with lead tetra-acetate in benzene under strictly anhydrous conditions gave the acetylimino-compound (210) (90%). Isomerization of (210) with acetic acidtrichloroacetic acid formed the enamide (21 1) (100%); further lead tetra-acetate oxidation gave the acetylimine (212) (84%). Compound (212) was quantitatively hydrolysed with aqueous acetic acid to the a-acetoxy-ketone (213) and thus led to a rapid synthesis of cortisone. These reactions are essentially ‘one pot’ syntheses.
IT?
1V
t-
Reagents: i, Ac,O-py (40 h, N,, A), chromatography, A1,0,; ii, Pb(OAc),-C,H,; AcOH-CCI,CO,H.
iii, AcOH-H,O; iv,
Scheme 10
A neat way of preparingg6 the system (215) (useful in bufadienolide synthesis) from (214) is illustrated for compound (216). Bromination to (217) followed by dehydrobrominationwith lithium bromide in DMF gave the dienone (218), which on triethylsilane reduction produced (2 19) and thence, by condensation with diethyl oxalate, (220). Methylthiotoluene-p-sulphonate in ethanol-potassium acetate now produced (22 1) whose oxidation with N-chlorosuccinimide in 2% methanolic sulphuric acid gave (223). A previous route to such compounds was by way of the aacetoxy-ketones (219) but suffers from a low yield at the acetoxylation step, (219) -+ (222). 95
96
R. B. Boar, J. F. McGhie, M. Robinson, and D. H. R. Barton, J.C.S.Perkin I, 1975,1242; R. B. Boar, F. K. Jetuah, J. F. McGhie, M. S. Robinson, and D. H. R. Barton, J.C.S. Chem. Comm., 1975, 748. E. Yoshi, T. Miwa, T. Koizumi, and E. Kitatsuji, G e m . and Pharm. Bull. (Japan), 1975,23,462.
307
Steroid Synthesis OHCYO
YI’
(218)
(219) (220) (221) (222)
R =H R = COC0,Et R = SMe R = OAC
(223)
A cortisone synthesis using remote functionalization at an unactivated carbon centre has been a~hieved.~’ Cortexolone (224) was converted into the 5a-H,3@-OH derivative (formation of the bismethylenedioxy-compound followed by lithiumammonia-ethanol reduction). Inversion98of 3 p - to 3 a -OH followed by esterification with rn-iodobenzoic acid produced (225), which on irradiation in methylene chloride containing phenyl iodide dichloride gave the 9a -chloro-derivative (not isolated). This was dehydrohalogenated and saponified by methanolic potash to yield (226) (75%) and thence, by further known steps, cortisone acetate.
(226)
In previous compound (227) was transformed into the C-2 1-acetoxyderivative (228) and from this to 18-hydroxycortexone (229) by the action of lead 97 9*
99
R. Breslow, R. J. Corcoran, andB. B. Snider, J. Arner. Chem. SOC.,1974, 94,6791, 6792. A. K. Bose, B. Lal, W. A. Hoffmann, and M. S. Manhas, TetrahedronLeners, 1973,1619. D. N. Kirk and M. S. Rajagopalan, J.C.S. Chem. Cornrn., 1974,145.
308
Terpenoids and Steroids
tetra-acetate. Compound (227) resists dehydration by the usual reagents and the lead tetra-acetate acetoxylation was considered to occur by way of the ion (230). It has now been foundloo that (227) is dehydrated by aluminium isoproproxide in toluene, the vinyl ether (231) being formed in ca. 90% yield, and this is readily hydroxylated either by osmium tetroxide or lead tetra-acetate to (229). In an alternative synthesis1oothe 20/3-alcohol (232) was treated with lead tetra-acetateiodine and then chromic acid to form (233) which was transformed by silver acetate in aqueous dioxan to (228) and the latter saponified to (227).
(227) R = H (228) R = OAC (229) R = OH
C\H,OAc
18-Oxocortexone (239), a potential metabolite of 11-deoxycorticosterone and biological precursor of aldosterone, has been synthesized'" (Scheme 11)beginning with the 20P-alcohol (234), itself readily available by reduction of pregnenolone acetate. Hypoiodite oxidation of C-18 to (235), followed by chromium trioxidepyridine furnished (236) as one of three products. The lead tetra-acetate oxidation of this gave (237) (10%) as a single isomer along with (238) (50%) as a mixture of epimers. Fortunately both (237) and (238) could be converted into 18oxocortexone, which exists as a mixture of the open and cyclic forms (239). In a new synthesisl'l of the starfish sapogenin asterone (241), the startingmaterial, 1l-oxoprogesterone, was first converted into its 3,5-dienol acetate. This was followed by protection at C-20 and then lithium aluminium hydride reduction to yield (240). Hydroboration and dehydration (carried out as a three-step process) then yielded asterone in 18% overall yield. Cortisol and its congeners can be converted into their 6p- and 6a-hydroxyderivatives by protection of the side chain (as a 17,21-acetonide) and of the A4-3100
lol
M. Biollaz, J. Kalvoda, and J. Schmidlin, Helv. Chim. Acta, 1975,58, 1424, 1433. J. W. ApSimon and J. A. Eenkhoorn, Canad. J. Chem., 1974,52,4113.
309
Steroid Synthesis
l:::"::iH oG 7 L
0 (239) Reagents : i, Cyclohexane-Pb(OAc),-CaC0,-I,, hv; ii, Cr0,-py; iii, C H -MeOH-BF,,Et,O-Pb(OAc),; iv, MeOH-KOH; v, CrO,-CH,CI,-py ; vi, MeOH-KOH: Ri, PhMe-AI(OCHMe,),-cyclohexanone ; viii, HC10,-AcOH ; ix, dioxan-KOH.
Scheme 11
Terpenoids and Steroids
310
keto-system (as a 3,5-diene-3-methyl ether) (242), both operations being conducted in one step (refluxing 2,2-dimethoxypropane, DMF, and toluene-p-sulphonic acid),
A'."-Dien-3-ones are smoothly confollowed by photochemical autoxidation. verted (yields ca. 60%) by means of phosphorus pentasulphide into their corresponding thione A1-'-Dien-3-ones, the products of deconjugation of AlX4-dien-3-ones,are smoothly reduced to the corresponding 3P-alcohols by calcium borohydride. Diborane then attacks the A'-bond preferentially and leads by hydrogen peroxide oxidation to 2a,3P - and la,3P -diols in approximately equal amounts.'*4 The best conditions have been worked out for the conversion of androstenolone into pregnenolone'os and of progesterone into pregnenolone. lo6
6 Seco-steroids A route which makes available the 2,3-seco-steroid 17P-hydroxy-l7-methyl-2,3secoandrostan-2,3-dioic acid in a 60% yield from the corresponding 3-ketone has been p ~ b l i s h e d ; "fission ~ is effected by ozonolysis of the 2-benzylidene-3-ketone. Beckmann rearrangement of the oxime derived from 4,4-dimethylcholest-5-en-3one catalysed by toluene-p-sulphonyl chloride yields the 3,4-seco-nitrile (243),loS and reaction between the 4,5-epoxides derived from testosterone and toluene-psulphonylhydrazine has been shown to lead to the 4,5-seco-steroid (244).'09 Sodium borohydride reduction of the 5-ketone (244) furnished 5P, 17P-dihydroxy-4,5secoandrost-3-yne. This reaction has been extended to the synthesis of nine variously substituted 4,5-secopregn-3-yn-5-ones[245; R'-R2 = R3-R4 = OCH,O; R' = OH, R2R3= H, or 0; RZ= OH, R3 = H, R4 = OAc; or R1-R2 = OCMe,O; X = H,, Me,, or (CH,),; Y = H2 or 01 commencing from the 4,5-epoxides of the corresponding pregn-4-en-3-0nes.'~~ The various 3-yn-5-ones (244) and (245) may be cyclized by treatment with mercuric acetate to the parent A4-3-ketones. A seven-step sequence of reactions has been described for the conversion of oestradiol methyl ether into its 9,1l-seco-analogue,' l 1 as follows: oestradiol methyl A. Tsuji, M. Smulowtiz, J. S. C. Liang, and D. K. Fukushima, Steroids, 1974, 24, 739. D. H. R. Barton, L. S. L. Choi, R. H. Hesse, M. M. Pechet, and C. Wilshire, J.C.S. Chem. Comm., 1975, 557. C. Kaneko, A. Sugimoto, S. Yamada, M. Ishikawa, S. Sasaki, and T. Suda, Chem. and Pharm. Bull. (Japan), 1974,22,2101. In5 S. Danishefsky, K. Nagasawa, and N. Wang, J. Org. Chem., 1975,40, 1989. H. Hoellinger, N. H. Nam, and L. Pichet, Bull. Soc. chim. France, 1975, 233. S. Hara, Japan Kokai 74/39 674 (Chem. Abs., 1975,82, 171 293). E. Savva and T. E. Ryzhkina, Zhur. org. Khim., 1974, 10, 1997. M. Tanabe, U.S.P. 3 83.5 160 (Chem. Abs., 1975,82, 4476). M. Tanabe, U.S.P. 3 891 677 (Chem. Abs., 1975,83, 164439). 'I1 J. H. Dygos and L. J . Chinn, J. Org. Chem., 197.5,40,685. In3
311
Steroid Synthesis
X (245)
ether is first converted into 17~-hydroxy-3-methoxy-9-oxo-9,1 l-seco-oestra1,3,5(lO)-trien-ll-oic acid (246; R' = C 0 2 H , R2= Ac, X = 0) by a previously described route.' l 2 Hydrogenolysis over palladium charcoal was used to remove the C-9 ketone, giving the intermediate (246; R' = C 0 2 H ,R2= Ac, X = H2)which after hydrolysis and reaction with butyl vinyl ether gave the bis-addition compound (246; R' = CO,CH(Me)OBu", R2= CH(Me)OBu", X = H2). Reaction of the latter steroid with lithium aluminium hydride afforded a separable pair of diastereoisomeric butyl vinyl ethers (246; R' = C H 2 0 H , R2-=CH(Me)OBu", X = HJ, which on hydrolysis gave the same diol (246; R ' = C H 2 0 H , R 2 = H , X = H 2 ) or on tosylation the intermediates (246; R' = CH20Ts, R2 = CH(Me)OBu", X = H2). Displacement of the tosyl group by lithium aluminium hydride, followed by acid hydrolysis to restore the 17P-alcohol, gave the 9,ll-seco-oestrogen (246; R' = Me, R2= H, X = H2), whose 17-keto-analoguewas obtained by Jones oxidation. It has been noted that the 9,ll-seco-oesiratriene (246; R1= C 0 2 H , R2= H, X = 0)on reaction with toluenep-sulphonic acid is cyclized to the epoxyseeo-oestrapentaene (247) in 40% ~ i e 1 d . l ' ~
(246)
(247)
The abnormal Beckmann rearrangement displayed by the oxime of 17-0x0-5a androstan-3P-yl acetate (248) to yield the 13,17-seco-nitrile (249) has provided the key step in a synthetic route to 17-oxo-l8-nor-5a,13~-androstan-3~-yl acetate and its 13a-epimer.l14 The reaction sequence is shown in Scheme 12. The 17-ketone (248) was converted via its oxime into the seco-nitrile in a yield of 52%. Treatment of the oxime by the more conventional toluene-p-sulphonyl chloride reagent 112
R. C. Cambie and T. D. R. Manning, J. Chem. SOC. ( C ) ,1968,2603. Yu. P. Badanova and K. K. Pivnitskii, Zhur. obshchei Khim., 1974,44, 2089. J. C. Chapman and J. T. Pinhey, Austral. J. Chem., 1974, 27, 2421.
Terpenoids and Steroids
312
afforded the same seco-nitrile but in only 21% yield. Epoxidation of the olefin (249) gave a mixture of the C-13 epimeric oxirans (250) which were rearranged to yield the C-13 epimeric aldehydes (251) and by further oxidation and esterification the corresponding epimeric esters (252), separable by thin-layer chromatography. Dieckmann cyclization regenerated the D ring (253) and subsequent hydrolysis and decarboxylation gave the epimeric 18-nor- 17-ketones (254) which were separated by t.1.c. The route depicted in Scheme 12 has also been used to transform 1-oxo-Sa-
(249)
H O
H O
e-
CHO
CN
Reagents: i, NH,OH; ii, DCC-CF,CO,H; iii, rn-ClC,H,CO,H; iv, BF,-Et,O; v, Jones oxidation; vi, CHIN,; vii, K0Bu'-C,H,; viii, HCI-AcOH.
Scheme 12
androstan- 17p-yl acetate into l-oxo- 19-nor-5a,lO~-androstan-l7~-yl acetate in 91% yield from the seco-esters (255). OAc
(255)
Beckmann rearrangement of a 17-oxime has also been used to furnish A13(18)13,17-seco-5a-androstene-17-nitrile(249), which on methylation with methyllithium gave the ketone (256; R = H) and thence by hydride reduction the alcohol (257; R' = H, R2= OH, R' = Me).115Conversion of this alcohol into its tosylate and further hydride reduction furnished the exocyclic olefin A13(18)-13,17-seco-~homoandrostene (257; R' = R2= H, R' = Me). Reaction of the nitrile (249) with trideuteriomethyl-lithium gave the ketone (256; R = D) and conversion into the hydrocarbon as outlined above gave the olefin (257; R 1 = R 2 = H , R3=CD3). Reduction of the ketone (256; R = H) with lithium aluminium deuteride furnished the alcohol (257; R' = D, R2 = OH, R3 = Me) which could in turn be converted into "5
D. C . Marnato and G. A. Eadon, J. Org. Chem., 1975,40, 1784.
313
Steroid Synthesis
A13"8~-13,17-~e~~-5~-~-hom~[17,17-2Hz]androstene (257; R' = R2= D, R3 = Me).
(256)
(257)
The 13,17-seco-acid lactone (258), obtained from a Baeyer-Villiger oxidation of 5a -androstan- 17-one has been reduced to yield 13,17-seco-5a -androstan- 13a,17diol, whose diacetate on pyrolysis furnished the endocyclic seco-olefin (259; R = OAc) as the major reaction product. A minor product is the corresponding 01efin.l'~Hydrolysis of the acetate (259; R = OAc) to its alcohol (259; R = OH) and formation of the tosylate and the iodide (259; R = I), followed by reaction with lithium dimethylcuprate, afforded a route to A'3~'4-13,17-seco-5a-~homoandrostene (259; R = Me). The [17a,17a,17a-[2H3]androstene(259; R = CD,) was prepared by treating the iodide (259; R = I) with lithium perdeuteriodimethylcuprate.
Isomerization of the 9( 11)-double bond of the seco-oestratetraene (260; R' = H, RZ= OH) to the 8(9)-position has been accomplished in the presence of acid; the 140x0-derivative (260; R ' R 2 = 0 ) in the presence of the acid 2,5HO(SO,H)C,H,CO,H thus not unexpectedly cyclizes to 17p-hydroxy-3methoxyoestra- 1,3,5(10$,8(9),14-pentaene.' l 6
7 Cholestane and Analogues Many syntheses have been reported for variously hydroxylated cholestanes, the objective in many cases being the eventual conversion of these steroids into their hydroxylated vitamin D derivatives. 1 a -Hydroxycholest-5-ene has been synthesized by way of the epoxy-dienone (261), itself derived from cholesterol by successive 116
G. Langbein and S. Schwarz, Z. Chem., 1975,15, 105.
314
Terpenoids and Steroids
reaction with dichlorodicyanobenzoquinone and alkaline hydrogen peroxide.' l7 Hydride reduction of the epoxide (26 1) afforded 1 a,3P-dihydroxycholesta-4,6diene which upon further reduction with lithium in ammonia gave l a hydroxycholest-5-ene (262; R = H) directly in 60% yield. Alternatively, lithiumammonia reduction of the epoxide (261) followed by tosylation led to isolation of the la73P-diol 3-tosylate (262; R = OTs) which on hydride reduction again furnished
the required 1a-hydroxy-A5-sterol (262; R = H). 1a-Hydroxycholesterol itself has been prepared from 3P-acetoxycholesta- 1,5-diene by reaction of the latter with mercuric oxide and trifluoroacetic acid; subsequent addition of alkali followed by borohydride reduction afforded la-hydroxycholesterol (262; R = OH) in 30% yield.' l 8 A new synthesis of la-hydroxycholesterol has been accomplished using as starting material the 6-functionalized sterol 6~-acetoxycholest-l-en-3-one.l" Thus, reaction of the latter 6P-acetate with hydrogen peroxide led to the 1 a 7 2 a epoxide which on borohydride reduction gave a 4 : 1 mixture of la72a-epoxy-3Phydroxy-6P -acetoxy-5 a -cholestane and the corresponding 3a -epimer. Hydrolysis of the mixture followed by acetylation afforded la,2a-epoxy-3P-acetoxy-GPhydroxy-5a-cholestane which was sequentially dehydrated with phosphorus oxychloride and reduced with lithium aluminium hydride to give 1a-hydroxycholesterol. The epoxy-dienone (261) has also served as a starting material in a synthesis of 1a hydroxy-vitamin D, (263; R' = R3 = OH, R2= R4 = R5= R6 = H).l2OReduction with lithium in ammonia-THF gave cholesterol (15%), the A5-olefin(262; R = OH), and the corresponding A6-olefin, 1a,3P-dihydroxycholest-6-ene (45%). Sequential bromination and dehydrobromination, using HMPA containing 10% triethylmethylammonium dimethyl phosphate, gave a quantitative yield of the A577-and A476-dienes(1.3 : 1) separable by silver nitrate-impregnated silica gel dry-column chromatography. Irradiation of the 1a -hydroxy-7-dehydrocholesterol,followed by thermal equilibrium gave 1a-hydroxy-vitamin D3. A second routel*' to the latter vitamin commenced with the nitration of cholesterol, reduction and hydrolysis to the 6-keto-sterol, acetalization at C-6 followed by oxidation of the 3P-alcohol, and bromination of the resultant 3-ketone to furnish the intermediate (264; R'R2 = 0, R3 = Br, R4 = H, X = OCH,CH,O). Successive dehydrobromination, epoxidation, hydride reduction, and deacetalization gave the diol (264; R' = R3= H, R2 = R4 = OH, X = 0)which was converted into 1a,3P-diacetoxycholest-5,7-dieneby acetylation, borohydride reduction, dehydration, bromination, and dehydrobromination. M. N. Mitra, A. W. Norman, and W. H. Okamura, J. Org. Chem., 1974,39,2931. N. Ikekawa, M. Morisaki, and K. Bannai, Japan Kokai 75/69 059 (Chem. Abs., 1975,83, 114 757). N. Ikekawa, M. Morisaki, and K. Bannai, Japan Kokai 75/64 263 (Chem. Abs., 1975,83, 114 758). lZo D. Freeman, A. Acher, and Y. Mazur, Tetrahedron Letters, 1975,261. H. F. Deluca, H. K. Schnoes, M. F. Holick, andE. J. Semmler, U.S.P. 3 741 996 (Chem. Abs., 1975,82, 31 465). 118
315
Steroid Synthesis
Irradiation of the 5,7-diene gave the previtamin, which was isomerized and saponified to give 1a-hydroxy-vitamin D,. For the last synthesis of la-hydroxy-7dehydrocholesterol recorded here, cholesta-1,4,6-triene-3-onewas again used as starting steroid.122Deconjugation of this trienone with strong base followed by immediate reduction with calcium borohydride led to the unstable 3phydroxycholesta- 1,5,7-triene which, without isolation, was converted into the 1,4addition product (265) upon reaction with 4-phenyl- 1,2,4-triazoline-3,5-dione. R5
Epoxidation of the adduct (265) gave a mixture of the l a , 2 a - and 1@,2@-epoxides in the ratio 2 :3, separable by silica gel chromatography. Lithium aluminium hydride reduction of the 1a,2a -epoxide afforded 1a -hydroxy-7-dehydrocholesterol. An improved route to 2a-hydroxycholesterol has been devised as part of the preparation of 2a-hydroxy-vitamin D, (263; R' = R4= R5= R6= H, R2= R3 = OH).'23 Hydroxylation of the A'-bond of cholesta-1,5-dien-3P-o1 by means of 9-borabicyclo[3,3,1]nonane followed by reaction with alkaline hydrogen peroxide produced the 2-equatorial 2a,3a-diol in 70-80°/0 yield. The conventional fourstep sequence, acetylation, bromination, dehydrobromination, and hydrolysis, gave 2 a -hydroxycholesta-5,7-dien-3P-01 which was converted into 2 a -hydroxy-vitamin D3. The isomeric 2P-hydroxy-vitamin D3 has also been r e p 0 ~ t e d . lReaction ~~ of the lp,2p -oxide obtained by peroxidation of the adduct (265) with lithium aluminium hydride results in a mixture of 2/3,3P-dihydroxycholest-5,7-dieneand its lp,3pdihydroxy-epimer in the ratio 8 : 1. Irradiation of the former 5,7-diene furnished the expected previtamin, which on equilibration gave 2p -hydroxy-vitamin D3 (263; R ' = R 4 = R 5 = R 6 = H , R * = a - O H , R'=OH). By the use of well authenticated reactions, cholest-5-en-3&4a -did diacetate has been converted into its 7-dehydro-analogue and thence into 4a-hydroxy-vitamin D,
123
C. Kaneko, A. Sugimoto, Y. Enguchi, S. Yamada, M. Ishekawa, S. Sasaki, and T. Suda, Tetrahedron, 1974,30,2701. C. Kaneko, S. Yamada, A. Sugimoto, M. Ishikawa, T. Suda, M. Suzuki, and S. Sasaki, J.C.S. Perkin I,
124
C. Kaneko, S. Yamada, A. Sugimoto, and M. Ishikawa, Chem. and Pharm. Bull. (Japan),1975,23,1616.
122
1975,1104.
3 16
Terpenoidsand Steroids
(263; R' = R2= R5 = R6 = H; R3 = R4 = OH). The yield of the intermediate A5,'diene was disappointing (17'/0), owing probably to the considerable a -face repulsion by the 4a-acetate in the bromination Recent findings show that vitamin D, must be hydroxylated at C-25 by the liver and then at C-1 a by the kidney to 1cu,25-dihydroxy-vitamin D, before it can induce calcium transport. It is therefore not surprising to find several reports on the synthesis of both the 1a,25-dihydroxy-vitamin and 1a,25-hydroxycholesterol. In the first of these reported here the key intermediate epoxide (266; R = S0,Me) was prepared from 25-hydroxycholesterol in nine steps which include hydroboration of the As-bond to yield 3P,6(,25-trihydroxy-5(-cholestane, conversion of the 6(hydroxy-group to 6 p -stereochemistry followed by oxidation to the 3-ketone, and bromination and dehydrobromination to yield 6P,25-dihydroxy-Sa -cholest- 1-en-3one. Amalgam epoxide cleavage of the steroid (266; R=SO,Me) followed by borohydride reduction and elimination of methanesulphonic acid by means of lithium carbonate in DMF furnished la,25-dihydro~ycholesterol.'~~ A longer route (19 steps) to la,25-dihydroxycholesterol also commences from 25hydroxycholesterol.'27 This route passes through the intermediate 6 6 -acetoxy3P,25-diol and the epoxy-ketone (266; R = A c ) but at this stage the 25hydroxy-group has been lost, resulting in a mixture of C-17 side chains,
CH(Me)(CH,),CH=CMe, and CH(Me)(CH,),C(Me)=CH,. The 25-hydroxygroup was restored at the end of the synthesis. Successive acetylation, bromination, dehydrobromination, saponification, and irradiation when applied to 1a,25dihydroxycholesterol convert it either into la,25-dihydroxy-previtamin D,'28 or into a la,25-dihydroxy-vitamin D,, 129 depending on reaction conditions. The C- 15 epimeric 5a-lanost-8-en-3P,lS-diols have been ~ynthesized.'~' Cholesta-5,7-dien-3P-ol was first converted into 3P-hydroxy-5a-lanost-7-en-15one by a previously described route;13' hydride reduction of the 15-ketone yielded a chromatographically separable mixture of 3p, 15a-dihydroxy-5a-Ia~ost-7-ene and its 15P-epimer. Both 3P, 15-diacetates undergo nuclear double-bond rearrangement in the presence of hydrochloric acid to yield the corresponding As-3P,15-diols after hydrolysis. 125 126
127 12R 129 130 131
B. Pelc, J.C.S. Perkin Z, 1974, 1436. J. A. Iambelli, T. A. Narwid, and'M. R. Uskokovic, Ger. Offen. 2 453 648 (Chem. Abs., 1975, 83, 97 731). N. Ikekawa, M. Morisaki, and F. Rubio, Japan Kokai 75/64 264 (Chem. Abs., 1975,83, 114 759). D. H. R . Barton, R. H. Hesse, and E. Rizzardo, Ger. Offen. 2 400 931 (Chem.Abs., 1974,81,169 708). I. Mielczarek, Wiad.Chem., 1974,28, 813. G. F. Gibbons and K. Ramananda, J.C.S. Chem. Comm., 1975,213. R. B. Woodward, A. A. Patchett, D. H. R. Barton, D. A. J. Ives, and R. B. Kelly, J. Chem. Soc., 1957, 1131.
Steroid Synthesis
317
Stereospecific syntheses of (22R)-22 -hydroxycholesterol and (22R)-cholest a5,24-diene-3/3,22-diol take place according to Scheme 13. 132 Conversion of the known aldehyde (267) into the 24-norchol-22-ene derivative (268) was effected by a Wittig reaction in 65% yield. Bromination of the olefin gave three bromohydrins, the major being the (22S)-23-bromo-22-hydroxy-steroid (269); cyclization with base gave the (22S)-22,23-epoxide (270). The less polar (22R)-22,23-epoxide could be obtained by peroxy-acid oxidation of the olefin (268). Grignard reaction of the epoxide (270) furnished, in 70% yield, the (22R)-i-alcohol(271), from which could be generated (22R)-22-hydroxycholesterol. Reaction of the aldehyde (267) and isopentylmagnesium bromide furnished an epimeric (22S)-i-alcohol which was converted into (22S)-22-hydroxycholesterol. Similarly, the epoxide (270) was converted into the (22R)-i-alcohol (272), which after regeneration of the A5-3/3-ol system gave (22R)-cholesta-5-24-diene-3&22-diol, formed in an overall yield of 20% from the aldehyde (267). H
OMe (267) R = 0 (268) R = CH,
Reagents : i, NBS-THF--H,O ; ii, NaOH-MeOH ; iii, Me,CHCH,MgBr ; iv, Me,C=CHMgBr.
Scheme 13
The previously described (24S)-24,25-epoxycholesterylbenzoate has been reduced with lithium aluminium hydride-aluminium chloride to give a chromatographically separable mixture of 25-hydroxycholesterol ( 5 5 % ) and (24S)-24hydroxycholesterol (273),133 the configuration of which was determined by the modified Horeau method.135 It is interesting to note that cerebrosterol isolated from brain is (24S)-24-hydroxycholesterolwhereas natural 24,25-dihydroxy-vitamin D, J. P. Poyser and G. Ourisson, J.C.S. Perkin Z, 1974, 2061. N. Koizumi, M. Morisaki, N. Ikekawa, A. Suzuki, and T. Takeshita, Tetrahedron Letters, 1975, 2203. 134 C. J. W. Brooks and J. D. Gilbert, J.C.S. Chem. Comm., 1973, 194. 135 Y. Y. Lin and L. L. Smith, J. Labelled Compounds, 1974, 10, 541. 132 133
Terpenoids and Steroids
318
has the (24R) configuration. An improved route giving a 50% yield of 24ketocholesterol has been described,135and results of the action of isopropyl-lithium on 3P-hydroxychol-5-enic acid have been reported. Reduction of this ketone with and sodium borotritide gave a mixture of [24-3H]-(24S)-cholest-5-ene-3P,24-diol its (24R)-epimer, separable chromatographically as their 3P,24-dibenzoates. OH
Convenient syntheses of 25-hydroxycholesterol include the formation of the 24,25-epimeric epoxides of 3P-hydroxycholesta-5,24-diene(desmosterol), which upon lithium aluminium hydride reduction yield the required 3@,25-di01,~~~ and the degradation of the side chain of 24(28)-epoxyfucosterol (274; X = 0) to the 5,24diene by means of stannic chloride, followed by epoxidation and hydride reduction as before to yield 25-hydroxycholestero1. 137 Stigmasterol has also been converted by means of a ten-step sequence into 25-hydroxycholesterol.138The key steps are conversion of stigmasteryl tosylate into the cyclo-ether [275; R = CH= CHCH(Et)CHMe,] and the condensation of the derived i-pregnane (275; R = CH,OTs) with LiCsCCMe,OTHP to give the intermediate (275; R = CH,C-CCMe,OTHP). Finally, the cyclopregnane (275; R = 0)has been converted into a mixture of the ( E ) - and (2)-cyclonorcholestenones (276) by successive reaction with CH,=CHMgCl, dehydration with collidine, and reaction with diketen. Catalytic reduction of the olefin (276) followed by reaction of the 25-ketone with MeMgI and restoration of the 3P-hydroxy-A5-system gave (20R)-25hydroxycholesterol.1'9 An interesting method of forming 25-hydroxycholesta-4,6dien-3-one has come from the irradiation of 3P-acetoxy-5a-cholestane in the presence of peroxyacetic acid, when 3P,5,25-trihydroxy-5a -cholestane is .the first product to be isolated after saponification. 140 Partial oxidation with Jones reagent and successive dehydration and dehydrogenation gave the required 25-hydroxydienone.
As (267)
136
138 139
I4O
As (267)
N. Ikekawa and M. Morisaki, Japan Kokai 74/13 162 (Chem. A h . , 1974,81,25 860). N. Ikekawa and M. Morisaki, U.S.P. 3 846 455 (Chem. Abs., 1975,83, 10 610). J . J. Partridge and M. R. Uskokovic, U.S.P. 3 822 254 (Chem. A h . , 1974,81,78 157). T. A. Narwid and M. R. Uskokovic, U.S.P. 3 856 780 (Chem. A h . , 1975,82, 86 501). Y. Mazur and A. Rotman, Ger. Offen. 2 415 676 (Chem. Abs., 1975,82,4481).
319
Steroid Synthesis
A synthesis of both (24R)- and (24S)-24,25-dihydroxy-vitamifiD, has been reported. 1 4 ' Reaction of 24~,25-dihydroxycholesterolwith benzoyl chloridepyridine readily produces a mixture of the 3@,24-dibenzoates(277; R' = Bz, R2 = H) and (278; R'=Bz, R 2 = H ) and with difficulty the tribenzoates (277 and 278; R' = R2= Bz). The dibenzoates were converted into the corresponding 25trimethylsilyl ethers (277 and 278; R' = Bz, R2= TMS). The 38,24,25-tribenzoates and the 3/3,24-dibenzoate 25-TMS ethers could be resolved into their 24-epimeric components by silica gel chromatography; the structure (277; R1 = R2= Bz) was elucidatedt34as (24R )- 24,25 -tribenzo ylox ycholesterol. The dibenzoate TMS ethers were each separately transformed through established procedures into their vitamin D3 derivatives. Thus the trio1 (277; R'= R2 = H) furnished vitamin D, (263; R' = R2 = R4= H, R3 = R5= R" = OH). The same metabolite of vitamin D3 has also come from cholesta-5,24-dien-3P -yl acetate by successive osmic acid hydroxylation, acetylation, bromination, and dehydrobromination to give the intermediate 38,245diacetoxycholesta-5,7-dien-25-ol.which was photolysed to give 245,25dihydroxycholecalciferol.'42 Osmic acid oxidation has also been used to convert the olefins cholesta-5,24-dien-3 8 - 0 1 ' ~ ~and cholesta-5,25-dien-3P -01 acetate '43~144in high yields (7&90°/~) into 3&24&25-trihydroxy- and 3&25,26-trihydroxy-cholest5-ene acetate respectively. A synthesis of 25,26-dihydroxycholecalciferolhas been OR'
OR'
1
(277)
(278)
reported;145it commences with the conversion of 3P-hydroxy-27-norcholest-5-en25-one tetrahydropyranyl ether into the 5,25-diene by a Wittig reaction. Osmium tetroxide oxidation gave an inseparable mixture of the two epimeric cholest-5-ene3P,25(RS),26-triols, which were converted by standard reactions into a mixture of the A5*7-and A4'6-dienes,separable by fractional crystallization. The A5,7-dienewas subsequently converted into 25(RS),26-dihydroxy-vitamin D3 (279).
(279)
Syntheses of (24R)-Icw,24,25-trihydroxy-vitaminD, (263; R' = R3 = R5 = R6= OH; R2 = R4= H) and the corresponding (24s)-epimer have been devised starting M. Seki, N.Koizumi, M. Morisaki, and N. Ikekawa, TetrahedronLetters, 1975, 15. J. Redel, N. Bazely, Y. Calando, F. Delbarre, P. A. Bell, and E. Kodicek, J, Steroid Biochern., 1975,6, 117. 143 N. Ikekawa, M. Morisaki, J. R. Lightbourn, and M. Seki, Ger. Offen. 2 409 971 (Chem. A h . , 1975,82, 4480). 144 N. Ikekawa, M. Morisaki, R. Julieta, and M. Seki, Japan Kokai, 74/109 368 ( G e m . A h . , 1975, 82, 171 304). 145 J. Redel, P.A. Bell, N. Bazely, Y. Calando, F. Delbarre, and E. Kodicek, Steroids, 1974,24,463.
141 14*
320
Terpenoidsand Steroids
from 24&25-dihydro~ycholesterol.~~~ The latter 24,25-diol was converted into 24~,25-dihydroxycholest-174,6-trien-3-one and thence into la,24&,25-trihydroxycholesterol via the intermediate la,2a -epoxide. After resolution of the C-24 epimers, each was converted into the vitamin D3 derivative using the standard reaction sequence. Other derivatives of vitamin D3 prepared recently include C-19-acetoxyprecalciferol,*473-deoxy-~-homo-vitamin D3,148and 3deoxy-la-hydroxy-vitamin D,.149 The first was prepared from 19acetoxycholesteryl acetate by allylic oxidation to the intermediate As-6-ketone and thence by reaction of the derived tosylhydrazone with lithium hydride to 3P,19diacetoxycholest-5,7-dieneand so to the vitamin D by the usual route. The second a itself obtained vitamin D analogue148was derived from ~ - h o m o - S -cholest-6-ene, from the reaction of diazomethane and 5a-cholest-6-en-3-one with subsequent removal of the 3-carbonyl function. The previously reported epoxy-ketone (264; R1R2= 0,R’R4 = 0,X = OCH,CH,O) was used as an intermediate in the synthesis of 3-deoxy- la-hydroxy-vitamin D3.14’ Reaction of the epoxy-ketone with hydrazine hydrate followed by catalytic reduction of the intermediate A2-olefin afforded the la-hydroxy-derivative (264; R’R2 = H2, R3 = H, R4 = OH, X = OCH,CH,O) from which the 6P-alcohol was prepared and dehydrated to yield l a acetoxycholest-5-ene. Conversion into the A5.7-diene, irradiation, and alkaline equilibration gave the 3-deoxy-1 a-hydroxy-vitamin. Turning now to the reactions of cholestanols, it has been shown that when dilute solutions of non-activated carboxylic esters such as 3P-acetoxy-5a-cholestane are irradiated at 254 nm in aqueous HMPA the corresponding alkanes are formed in high ~ie1ds.l~’ A useful method which allows for the specific oxidation of secondary hydroxygroups in the presence of primary alcohols has been r e p ~ r t e d . ”Oxidation ~ of 5acholestan-3~,19-diolwith chlorine in pyridine gave a 62% yield of 5a-cholestan-19ol-3-one, and the corresponding 5P-diol furnished 5~-cholestan-19-01-3-onequantitatively. Similar oxidation of 5a-cholestane-3P,.5,6P-triol gave Sa-cholestane3P,S-diol-6-one (73%). A convenient route to steroidal aryl ethers has been exemplified by the reaction of 5a-cholestan-3P-01 with phenol or p-bromophenol in the presence of triphenylphosphine and diethyl azodicarboxylate. lS2 The products are 3a -phenoxy- and 3a -p-bromophenoxy-5a -cholestane respectively in yields of 65--80%. Reaction proceeds with inversion of configuration except in the case of cholesterol which furnishes As-3P-ethers owing to the intervention of i-steroid intermediates. The same neighbouring-group participation has been observed during the stereospecific reaction of cholester01’~~ or cholesteryl trimethylsilyl etherlS4with phenylfluorophosphorane where 3P-fluorocholest-5-ene is formed in 146
147 148 149
lSo ls1 152
Is3
154
N. Ikekawa, M. Morisaki, N. Koizumi, Y. Kato, and T. Takeshita, Chem. and Pharm. Bull. (Japan), 1975, 23, 695. R. M. Moriarty, H. Paaren, and J. Gilmore, J.C.S. Chem. Comm., 1974, 927. S. M. Sine, J. E. Conklin, and W. H. Okamura, J. Org. Chem., 1974, 39, 3797. H. Y. Lam, B. L. Onisko, H. Schnoes, and H. F. Deluca, Biochem. Biophys. Res. Comm., 1974,59,845. H. Deshayes, J . P. Pete, C. Portella, and D. Scholler, J.C.S. Chem. Comm., 1975, 439. J. Wicha and A. Zarecki, Tetrahedron Letters, 1974, 3059. M. S. Manhas, W. H. Hoffman, B. Lal, and A. K. Bose, J.C.S. Perkin I, 1975, 461. Y. Kobayashi, I. Kumadaki, A. Ohsawa, M. Honda, and Y. Hanzawa, Chem. and Pharm. Bull. (Japan), 1975, 23, 196. N. E. Bontin, D . U. Robert, and A. R. Cambon, Bull. SOC.chim. France, 1974,2861.
Steroid Synthesis
321
yields of 25% and 80% respectively. In the former reaction a 64% yield of dicholesteryl ether was also recorded. Similar fluorination of Sa-cholestan-3P-01 and the -3a-01 leads to the isolation of the 30- and 3P-fluoro-5a-cholestanes re~pectively.'~~ Another inversion reaction of interest has been observed in the formation of 5a-[3P-2H]cholestan-3a-ol from the [3~x-~H]-3P-ol by isomerization of the 3P-mesylate in aqueous collidine or by treating the 30-01with benzoic acid in the presence of triphenylphosphine and diethyl azodi~arboxylate.'~~ No loss of deuterium from C-3 was observed in either reaction. The ring-A/B moiety (286) of the naturally occurring C,, steroidal lactone withaferin A has been incorporated into cholestane as outlined in Scheme 14.'56 Hydride reduction of the epoxide (280) gave the diol (281) which reacted stereospecifically with peroxy-acid to yield the a-epoxide (282), and this was in turn converted into the epoxy-enone (283). The yield of (283) based upon the epoxydienone (261) is 70%. Ring-opening of the oxide (283) afforded the Sa-alcohol (284) which was dehydrated to the A2?'-diene (285). The As-bond was then epoxidized stereoselectively and quantitatively to the 5Q-oxide (286). Ring A of this 5P-oxide was shown to be in the boat conformation.
- (3 v111, ._.I.X
OI-
I OH
OAC.
(285) iiil
OH (286) Reagents : i, H,-Pd/CaCO, ; ii, LiAlH,; iii, peroxy-acid; iv, acetylation; v, oxidation (at (2-1); vi, elimination (A1203);vii, H+-H,O; viii, SOCI,-py; ix, hydrolysis.
Scheme 14 155
J. E. Herz, L. A. MBrquez, and J. Sjovall, J.C.S. Perkin I, 1974, 1438.
156
M. Weissenberg, E. Glotter, and D. Lavie, Tetrahedron Letters, 1974, 3063.
322
Terpenoids and Steroids
A method of converting steroidal monoketones into the corresponding 1,3diketones has been exemplified by reaction of the cholestanone enol esters (287; R = Ph or But, X = H2) with sodium chromate in acetic acid-acetic anhydride-CC1,. The 1-0x0-derivatives (287; R = Ph or But, X = 0)are hydrolysed to 5a-cholestanA new general reaction of ketoximes has been described,I5*which 1,3-di0ne.*~~ results in their transformation in excellent yields into enamides. Thus, refluxing 5acholestan-3-one oxime with acetic anhydride for 10 h gave a black solution from which the enamide (288; R = H), 3-acetylamino-5a-cholest-2-ene, could be isolated by alumina chromatography in 93% yield. If the crude reaction product was purified by crystallization or by silica gel chromatography a new product, the enimide (288; R = Ac) was obtained. Both the enamides and enimides proved less reactive than the corresponding enamines.
K
The first case of the exclusive introduction of bromine at a site unfavourable for enolization has been reported. 159 Reaction of methyl 3-0x0-5P-cholanate with two equivalents of iodine monobromide can be seen to take place in two distinct stages; after 2 h the expected 4P-bromo-derivative can be isolated, but after 5 days the only product isolated is the equatorial methyl 2~-bromo-3-oxo-5~-cholanate, resulting from debromination at C-4 and rebromination at C-2. The deoxygenation of some 3-0x0-steroids has been investigated;'60the reagent is chlorotrimethylsilane and zinc. The major product from 5a-cholestan-3-one was 5a-cholest-2-ene (70%) and from 5a-cholestan-3,6-dione was 5a-cholest-2-en-6one (6 1"/o). Deoxygenation at C-7 of 3P-acetoxycholest-5-en-7-one,prepared by direct oxidation of cholesteryl acetate by chromic anhydride-pyridine, has been accomplished by treating its derived tolyl-p-sulphonyl hydrazone with lithium hydride (Bamford-Stevens reacfion).l6l The reaction product (93%) is 7dehydrocholesteryl acetate. A high-yield (85%) route to 2-methyl-5a-cholest-2ene has also been published.lh2 5a-Cholestan-3P-01 tosylate was converted into cholest-2-ene which then was treated with iodine and potassium iodate in acetic acid to afford the 2P-acetoxy-3a-iodo-derivative, hydride reduction of which furnished 2P -hydroxy-5a -cholestane. Jones oxidation, Grignard addition of methylmagnesium iodide, and subsequent dehydration finally yielded 2-methyl-5a -cholest-2ene. lS7 15H
lSy
Ih0
lh2
R. Mechoulam, K. Luchter, and A. Goldblum, Synthesis, 1974, 363. R. B. Boar, J. F. McGhie, M. Robinson, D. H. R . Barton, D. C . Horwell, and R. V. Stick, J.C.S.PerkinI, 1975, 1237. Y. Yanuka and G . Halperin, J. Org. Chem., 1974,39, 3047. P. Hodge and M. N. Kahn, J.C.S. Perkin I, 1975, 809. E. V. Yablonskaya and M. G. Segal, Khim. prirod. Soedinenii, 1973,6,739. M. Adinolfi, M. Parrilli, G. Barone, and G. Laonigro, Steroids, 1974, 24, 135.
323
Steroid Synthesis
Viable routes to 5a -cholesta-7,24-dien-3@-01 and 5 cy -cholesta-5,7,24-trien-3/3 01 have been described.’63 Ergosteryl benzoate was selectively hydrogenated in the presence of tris(tripheny1phosphine)rhodiurn to give the diene (289; R = Bz), which is also reported to be the product (289; R = Ac) from the hydrogenation of ergosteryl acetate using Raney nickel in ethyl acetate with added dimethylaniline. 164 Ozonolysis163of the diene gave the aldehyde (290; R = CHO) which was reduced to the corresponding alcohol and thence by reaction with carbon tetrabromide and triphenylphosphine to the 22-bromo-steroid (290; R = CH,Br). Coupling of the latter bromo-derivative with y, y -dimethylally1 bromide by means of magnesium gave 5a -cholest-7,24-dien-3fi-ol. In a second reaction sequence, 26-norcholest-5en-25-on-3P-01 was brominated and dehydrobrominated to give 26-norcholesta5,7-dien-25-on-3P-o1 which reacted with methylmagnesium iodide to give the intermediate A5”-3P,25-diol; after acetylation at C-3 and dehydration it was transformed into cholesta-5,7,24-trien-3fi-ol, separable by chromatography from its A25-isomer.’63
R
O H
W
(290)
(289)
The acid-catalysed decomposition of the adducts (291) and (292; R = 0)derived from the parent steroidal 5,7-dienes furnishes a novel route to 4,4-dimethylcholesta5,7,14(15)-trien-3-one (90’/0) and cholesta-4,6,8( 14)-trien-3-one respectively.’6s It has also been noted that reaction of the adduct (292; R = P-OAc,H) with boron trifluoride etherate gives an oxidative rearrangement to the anthrasteroid (293)
Aco,*v 163
164
(293)
J. P. Moreau, D. J. Aberhart, and E . Caspi, J. Org. Chem., 1974, 39, 2018. W. Tadros and A. L. Boulos, Helv. Chim. Acta, 1975, 58, 668. J. Brynjolffssen, A . Emke, D. Hands, J. M. Midgley, and W. B. Whalley, J.C.S. Chem. Comm., 1975, 633.
324
Terpenoidsand Steroids
whose structure was determined by X-ray diffraction. 166 Reaction of sterol acetates containing A7, As(14),or A14(15)unsaturation with anhydrous hydrogen chloride at which is readily -60 "C yields 3~-acetoxy-14-chloro-5a,l4~,17a-cholestane dehydrochlorinated to yield 3P-acetoxy-Sa, 1 7 a - c h o l e ~ t - 1 4 - e n e .The ~ ~ ~ reaction thus provides a ready synthesis of l7a-sterols. Conversion of 3P-acetoxy-4Pmethylcholest-5-ene into 4P-methy1-5a-cholest-8-en-3~-01has been described.16' Allylic bromination followed by dehydrobromination Of the A5-olefin gave the A577-dienewhich upon treatment with acid rearranged to the 8,14-diene, whose catalytic reduction furnished the required As-sterol. Allylic bromination of 4methylcholest-4-en-3-one gives the expected 6P-bromo-derivative, which upon hydride reduction with a large excess of reagent provides an 84% yield of 4 a methylcholest-5-en-5~-01.'~~ Reduction of the same 6P -bromo-A4-3-ketone with lithium aluminium deuteride gave [3a,4P-2H2]-4-methylcholest-5-en-3-ol. A partial synthesis of pollinastanol (294; R = H) commencing from cycloartanol (294; R = Me) has been publi~hed.'~'Successive tosylation, isomerization, and ozonolysis of cycloartanol furnished an intermediate A-nor-ketone (295 ; R1 = Ac, R2= H) which was epimerized to (295; R1 = H, R2= Ac). Subsequent BaeyerVilliger oxidation, alkaline hydrolysis of the resultant acetate, and chromic acid oxidation gave the ketone (295; R1R2= 0),methylenation of which furnished the olefin (295; R1R2= CH,). Ring expansion was achieved by treating this olefin with cyanogen azide and lithium perchlorate to give a separable mixture of pollinastanone Hydride and isopollinastanone (1 4a-rnethyl-9,19~-cyclo-5a-cholestan-4-one). reduction of pollinastanone gave the 3P-alcohol (294; R = H). Two stereoisomers, (22S, 23S, 24s) and (22S, 23S, 24R), of demethylgorgosterol (296) have been prepared from stigmasterol. 17' The usual degradation reaction sequence applied to stigmasterol afforded the unstable aldehyde (275; R = CHO), which was immediately treated with the phosphorane Ph,PCHCOCHMe, to yield 3a,5-cyclo6~-methoxy-5a-cholesta-22-en-24-one. Reaction of this ketone with oxosulphonium methylide led to methylenation of the double bond and production of a trans-cyclopropyl ketone, itself converted into (22S,23S)-6P-methoxy-3a,5-cyclo22,23-methylene-5a-ergost-24(28)-ene (297) by the action of methylenetriphenylphosphorane. Hydroboration of the olefin (297) led to a 1: 1 mixture of the two isomeric primary alcohols, easily separable by t.1.c. and convertible via hydride H
166
167
168 169
170 171
H
N. Bosworth, J. M. Midgley, C. J. Moore, W. B. Whalley, G. Ferguson, and W. C. Marsh, J.C.S. Chem. Comm., 1974,719. G. Rossi and A . Scala, J. Org. Chem., 1975,40, 2006. F. F. Knapp, S. T. Trowbridge, and G. J. Schroepfer, J. Amer. Chem. SOC.,1975,97, 3522. F. F. Knapp and G. J. Schroepfer, J. Org. Chem., 1974, 39, 3247. A. Bekaert, M. Devys, and M. Barbier, Helu. Chim. Acta, 1975, 58, 1071. G. D. Anderson, T. J. Powers, C. Djerassi, J. Fayos, and J. Clardy, J. Amer. Chem. SOC.,1975,97,388.
325
Steroid Synthesis
(297)
(298) (22S,23S,24R)
reduction of their mesylate8 into the (24R)-methyl steroid (298) and its (24s)epimer. Restoration of the 3/3-hydroxy-A5-function gave the required isomers of demethylgorgosterol. The first member of the class of C,, marine sterols resulting from methyl migration in the side chain has been isolated from Asterias amurensis; it is 22-trans-27-nor(24S)-24-methyl-5a-cholesta-7,22-dien-3/3-01 (299)”, and it has been synthesized from (20S)-3/3-acetoxy-5a-bisnorchol-7-en-3~-ol-22-al (300; R = CHO). Reaction of the latter aldehyde with the phosphonium ylide derived from the bromination product of (-)-2-methylbutan-1-01 gave amusterol acetate (299). The Wittig reaction between the ylide Ph,P=CHCOEt and 3/3-acetoxy-23,24-bisnorchol-5-en-22a1 (300; R = CHO) followed by hydrogenation of the intermediate unsaturated ketone gave the intermediate, 3/3-acetoxy-27-norcholest-5-en-24-one (300; R = CH,CH,COEt), which was converted into stigmasta-5,24-dien-3p-ol in the following manner.’73 Reaction of the 24-ketone with isopropenylmagnesium bromide gave the tertiary alcohol (301), which underwent allylic rearrangement on reaction with phosphorus tri-iodide to yield the iodo-steroid (302; R = I), and reduction
finally gave stigmasta-5,24-dien-3P-ol (302; R = H). 5a -Stigmasta-7,24-dien-3p01 was similarly prepared commencing from 3~-acetoxy-27-nor-5a-cholest-7-en2 4 - 0 n e . I ~Syntheses ~ of the compounds 5a-stigmasta-22,25-dien-3/3-01(312), 5astigmast-22-en-3/3-01 (313), and 5a-stigmastan-3/3-01 (3 14) and their 24-epimers 172 173
M. Kobayashi and H. Mitsubashi, Tetrahedron, 1974,30, 2147. W. Sucrow, M. Slopianka, and P. Larny, Chern. Ber., 1975, 108, 754.
Terpenoids and Steroids
326
take place according to Scheme 15.'74 Reaction of 3P-acetoxy-5~~-(20S)-pregnan20-carboxaldehyde (303) with 1-butynylmagnesium bromide gave the 22-epimeric butynyl carbinols (304) and (305) separable by alumina chromatography. Each was
(305 (22R)
(304) (22s)
\ \
CONMe,
+ (307) (24S,25S)
(308) (24S,25R)
I
, 1 1 1
(306) (22R)
+ (31 I ) (24R,25S)
(312) (24R)
(310) (24R,25R)
(313) (24s)
(309) (22s)
(314) (24R)
Reagents: i, EtC-CMgBr; ii, H,-Lindlar catalyst; iii, MeCH=C(OMe)NMe,; iv, LiAlH,; v, H,O,; vi, Cope rearrangement; vii, H,-(Ph,P),RhCI ; viii, H,-Pt.
Scheme 15
separately reduced to the olefins (306) and (309) and each olefin underwent Claisen rearrangement to yield the chromatographically separable 24,25-isomeric stigmastenamides (307 and 308) and (3 10 and 3 11).Sequential hydride reduction, peroxide oxidation, and Cope elimination applied to the amide (311) furnished the 22,25diene (312) which could be reduced in stages to the AzZ-stero1(313) and the saturated 174
W. Sucrow, M. Slopianka, and P. P. Caldeira, Chern. Ber., 1975,108, 1101.
Steroid Synthesis
327
analogue (314). A similar reaction sequence applied to the isomeric amide (308) afforded 5a -poriferasta-22,25-dien-3P-ol (3 12; but 24S), again reducible to 5aporiferasta-22-en-3p -01 (313; but 24R) and eventually 5a -poiiferastan-3P-ol (314; but 24s). Repetitive Wittig reactions between 3/3 -acetoxy-5,8-epidioxy-22,23-bisnorchol6-en-24-a1 and the phosphoranes Ph,P=CHOMe and Ph,P=CHCO,Me gave the epidioxyhomocholene (3 15).175 Further hydragenation, epidioxy-ring cleavage, tosylation, and detosylation led eventually to a synthesis of methyl 3 p acetoxyhomochola-5,7-dien-25-oate.An interesting synthesis of the allenic analogues of fucosterol(3 16) and desmosterol(3 17) has been published.’76 Reaction of 24-oxocholesterol tetrahydropyranyl ether with sodium acetylide gave the ethynyl alcohol (3 18) which upon hydride-aluminium chloride reduction afforded stigmasta5,24(28),28-trien-3/3-01 (3 16) along with saringosterol (319). The second allene
(317)
(3 19)
(3 17) was prepared from 3-acetoxybisnorcholenic acid which was converted (five steps) into the tosylate (300; R = CH,OTs) prior to being coupled with lithium 2methylbut-3iyn-2-01 tetrahydropyranyl ether to yield the propargyl alcohol (300; R = CH,CrCCMe,OH). Hydride-aluminium chloride reduction furnished the allylic alcohol (300; R = CH,CH=CHCMe,OH) and the allene (317), the latter in only 13% yield. The allene (316) was found to be a specific inhibitor of sterol metabolism in the silk-worm. Another example of a fucosterol derivative which acts as a metabolic inhibitor in insects is 24,28-iminofucostero1(274;X = NH);I7’ it can by synthesized by reaction of fucosterol with silver isocyanate and iodine to give an intermediate 24-isocvanato-25-iodo-derivative which on hydride reduction and base-catalysed cyclization is transformed into the required iminofucosterol. A method for the degradation of the side chain of bile acids or lanosterol has been described.17*Cholanic acid or lithocholic acid were first converted into the phenyl N. A. Bogoslovskii, Sh. Levi, R. R. Evstigqeeva, and G. I. Samokhvalov, Zhur. obshchei Khim., 1975,45, 925. 176 M. Morisaki, N. Awata, Y. Fujimoto, and N. Ikekawa, J.C.S. Chem. Comm., 1975,362. 177 N. Ikekawa, M. Morisaki, and Y. Fujimoto, Japan Kokai 75/50 356 (Chem.Abs., 1975,83,131 843). 178 M. Fetizon, F. J. Kakis, and V. Ignatiadou-Ragoussis, Tetrahedron, 1974,30, 3981. 175
Terpenoids and Steroids
328
ketones (320; R = H or OAc) respectively, which under the influence of molecular oxygen in a basic medium were degraded by two carbon atoms to give the 23,24bisnor-steroids (300; R = C0,Me) in overall yields of 60-70%. Further degradation to the 20-keto counterparts of these steroids is described. 0
A number of syntheses have been devised which lead to heterocyclic derivatives of cholestanes. 4-Aza-5a-sitostane (321; R = H, X = H2) and its N-methyl derivative (321; R = Me, X = H2)have been prepared by way of oxidative opening of ring A of 4-sitosten-3-one to give a 3,5-seco-5-oxo-3-oic acid which was cyclized by reaction with ammonium hydroxide or methylamine to give A5-enamine lactams; these upon hydrogenation gave the lactams (321; R = H or Me, X = 0) respectively. Hydride reduction completed the route to the required 4-a~a-steroids.'~~ Cholesterol has been converted into both 4-thia-5a- and -5p-cholestanes; the oxides and dioxides of these thia-steroids are also described and the work is summarized in Scheme 16.180 The seco-ester (322), derived from cholesterol, was converted into the 5-benzylthio-ether (323), which on desulphurization furnished the A5-olefin (324), reducible to the unsaturated alcohol (325). Reaction of the 3-methanesulphonate (326) with tetrabutylammonium thioacetate gave the corresponding 3-acetylthio-steroid (327) which upon reduction and irradiation of the intermediate 3-thiol(328) gave 4-thia-5p-cholestane (329) by intramolecular addition of the 3-thio-radical to the A5*6-do~ble bond. The yield of the thia-steroid (329) was 36%, based upon cholesterol. Oxidation of the thian (329) led to the sulphone (330) which could be isomerized with base to its 5a-isomer (331). Milder oxidation of the same thian (329) gave a mixture of the 4p-oxide (332) and the 4a-oxide (333) in yields of 93% and 2% respectively; when, however, the oxidizing agent was changed from peroxydodecanoic acid to t-butyl hypochlorite the mixture of oxides was recovered in yields of 27% (332) and 44% (333). Treatment of the 4P-oxide (332) (equatorial oxygen) with base gave an equilibrium mixture of (332) and the 5a-epimer (334), in which the oxygen is axial. Under basic conditions the corresponding (5p) 4 a -oxide (333) is quantitatively isomerized to 4-thia-5a -cholestane 4a-oxide (335). A direct stereospecific synthesis of the 4a-oxide (333) is reported in which the sulphenic acid (338), prepared via the t-butyl sulphide (336) and the corresponding sulphoxide (337), is stereospecifically added to the A596-doublebond. A short and stereoselective route'to 6-thiacholestanes has been published."' 179
181
H. Y. Aboul-Encin and N. J. Doorenbos, J. Heterocyclic Chem., 1974, 11, 557. D. N. Jones, D. A. Lewton, J. D . Msonthi, and R. J. K. Taylor, J.C.S. Perkin I, 1974, 2637. W. N. Speckamp and H. Kesselaar, Tetrahedron Letters, 1974, 3405.
329
Steroid Synthesis
\
CH2Ph (323)
(324)
iiil
I (327)
lii
HS
m '
& ' q
I
ix
,viii
11
II
0
0
(334)
(336)
(337)
(338)
Reagents: i, Toluene a-thiol; ii, Raney N i ; iii, LiAlH,; iv, MeS0,Cl; v, Bu,NSCOMe; vi, irradiation; vii, rn-CIC,H,CO,H; viii, base; ix, peroxydodecanoic acid or Bu'OCI; x, Bu'S-; xi, boiling xylene; xii, spontaneous cyclization.
Scheme 16
Reduction by diborane of the sodium salt of 3 p -t-butyloxy-5,7-seco-~norcholestan-5-on-7-oic acid gave the 5PH lactone (339) which could be further reduced to the corresponding 5a,7-diol. Conversion into the 5a,7-dimesylate was followed by reaction with sodium sulphide to give 6-thiacholestanol butyl ether
330
Terpenoids and Steroids
(340). Similarly, the 5 a H lactone corresponding to (339) was converted into 6-thiaSP-cholestanol butyl ether. Each ether was converted into the corresponding alcohol, which was oxidized to the 3-ketone, and the 6-sulphones and sulphoxides were also prepared.
(339)
(340)
The tetrazole analogue (341) of 7-oxocholest-5-en-3p-yl acetate has been prepared'*' by reaction of the ap-unsaturated ketone with hydrazoic acid and boron trifluoride etherate; hydrolysis of the 3-p-acetate and oxidation of the resultant Cycloaddialcohol furnished 7a-aza-~-homocholest-4-eno[7a,7-d]tetrazol-3-one. tion of ethylenediamine to 2a -bromo-5a-cholestan-3-one has furnished a simple one-s tep route to 5 a -cholestane[ 2,3- e]dihydro-2,3-pyrazine (342). Analogous cycloaddition has been achieved using 16a -bromoandrostan- 17-ones.
(342)
(341)
The azanorcholesterol (343) has been synthesizedlx4 by condensation of 2methylpropionaldehyde with 20a -aminopregn-5-en-3P-o1 and subsequent reduction of the intermediate by borohydride. The azahomocholesterol(344) was derived from reaction between the tetrahydropyranyl ether of 20a -aminopregn-S-en-3P-o1 and 4-methylpentanoyl chloride followed by hydride reduction and hydrolysis of the protecting group.
Y
NH(CH,),CHMe,
(343) fl = 1 (344) n = 3
8 Steroid Insect and Plant Hormones Because compounds (345)-(348) show the same biological activity it was that compound (349) (2,25-dideoxy-a-ecdysone)should also exhibit maximum 182
H. Singh, R. K. Malhotra, and N. K. Luhadiya, J.C.S. Perkin I , 1974, 1480.
P. Catsoulacos and E. Souli, J. Heterocyclic Chem., 1975, 12,193. R, Counsel1 and M. C. H. Lu, U.S.P. 3 818 055 (Chem. A h . , 1974,81,78 158). M. N. Galbraith, D. H. S. Horn, and J. A. Thomson, Experientia, 1975,31, 873.
33 1
Steroid Synthesis
biological activity. This compound has been synthesized starting from the aldehyde (350) (obtainable from ergosterol) by what are now standard methods. The compound had only half the activityof P-ecdysone (347). All four stereoisomers of (351) have been synthesized.'86 Bamford-Stevens reaction on the toluene-p-sulphonyl hydrazone of (352) yielded the corresponding A5?'-diene. This compound on oxidation with chromic acid and then selenium dioxide furnished the 2deoxyrubrosterone derivatives (353)R = H or OH.lX7 R3
R' (345) H (346) H (347) OH (348) OH (349) H
RZ H OH OH OH H
H
R 3 R4 OH OH OH OH OH OH OH H OH H
(350)
&&
HO
H
(351)
(353)
9 Steroidal Alkaloids Verazine (358), the steroidal alkaloid of Viscurn album, has been synthesized,"' starting from the pregnadiene ketone (354) (Scheme 17), itself available by a hydrazine reduction (Wharton-Bohlen reaction) of the 16a,17cu-epoxide of 16dehydropregnenolone. Condensation of (354) with (2S)-methyl-5-nitropentanoate (355) gave a mixture of C-22 epimers from which the (C-22S)-compound (356) was ls6
Is8
H. Hikino. T. Okuyama, S. Arihara, Y. Hikino, T. Takemoto, H. Mori, and K. Shibata, Chem. and Pharm. Bull. (Japan), 1975,23, 1458. Zh. S. Sydykov, G. M. Segal, I. V. Torgov, and K. K. Koshoev, Bull. Acad. Sci. U.S.S.R., 1975, 624. S. V. Kessar, A. Sharma, M. Singh, and R. K. Mahajan, Indian J. Chem., 1974, 12, 1245.
332
Terpenoids and Steroids
secured. The nitro-group in the C-16-dithioacetal of (356) was reduced and the dithioacetal group in the derived lactam removed with Raney nickel. The lactam carbonyl of (357) was reduced with lithium aluminium hydride and the product converted into its N-chloro-derivative which was treated with sodium methoxide in methanol to effect transformation into natural verazine (358). v ti 0 2 N Y H c o 2 * I e
1
111
HO
(355)
/
IV-
VI
(357)
(358)
Reagents : i. Michael reaction ; ii. AczO py ; iii, chromatography ; iv, HSCH,SH-HCI ; v, Zn-AcOH ; V I , Ni(WZ)-EtOH; vii, MeOH-K,CO,; viii, LiAIH,-THF; ix, N-chlorosuccinimide-CHZC1,; x. NaOMe--MeOH.
Scheme 17
The conversions shown in Scheme 18 interrelate a number of alkaloids and in conjunction with optical circular dichroism evidence establish the structure of spiropachysine (3591, a major alkaloid in the leaves of Pachysandra terminalis Sieb. et Zucc. (Buxaceae), unique in possessing a five-membered spirolactam Spiropachysine (359) was reduced by lithium aluminium hydride to the deoxocompound (360), whose dimethiodide on Hofmann degradation yielded two materials, the more strongly basic being a mixture of two olefins (361) which both afforded on hydrogenation the compound (362). The last compound was also prepared from 189
T. Kikuchi, T. Nishinaga, M. Inagaki, M. Niwa, a n d K. Kuriyama, Chem. and Pharm. Bull. (Japan), 1975, 23,416.
Steroid Synthesis
333
(359)
Me,
+--IV
H
CN (363)
(364)
Reagents: i, LiAIH,--THF; ii, Mel-MeOH; iii, K0Bu'-Bu'OH; iv, H,-Pt0,-AcOH; v, Ca-NH,; vi, HC0,H-Ac,O; vii, CNBr-C,H, ; viii, LiAlH,-THF; ix, N-chlorosuccinimide-CHZClz ; x, NaOMe-MeOH, H,O; xi, PhCH,NMe,-LiBu; xii, HOCH,CH,OH-HCI.
Scheme 18
Terpenoidsand Steroids
334
epipachysamine-A (363), which was deacetylated with calcium in ammonia, N formylated, and then treated with cyanogen bromide to form (364). Lithium aluminium hydride reduction of this produced the alkaloid dictyophlebine (365). Ruschig degradation then gave funtumafrine-C (366).l9' Condensation of (366) with o-lithio-N-dimethylbenzylaminefollowed by dehydration produced the olefin mixture (361), hydrogenated as before to compound (362). Reduction'"' of the imine (367) with diborane followed by a catalytic hydrogenation produced 20a(20S)- and 20P(20R)-amines, (370) and (371), in the ratio 55 : 45. Reduction employing (+)-di-3-pinanylborane gave a similar mixture. However, when chirality was introduced into the imine as in (368) [prepared from (S)-phenylethylamine] diborane reduction yielded uniquely the 20a -amine (370) (funtuphyllamine A). The imine (369), prepared from (+)-(R)-phenylethylamine, gave (370) (8%) and (371) (92%). Me
I
(367) R = PhCH, (368) R = PhCHMe(S) (369) R = PhCHMe(R)
(370) 20s (371) 20R
Treatment of the conanine (372) with bromine-aqueous sodium carbonate yields'"' (100%) the conenium salt (375) which is readily converted into (376) (80%). Compound (376) is also formed starting from (373). When C-20 is substituted by two methyl groups as in (374) the product is (377). The conanine (373) is photo-~xygenated,'"~ in the presence of methylene blue, to (376). The nitrone (378) is quantitatively deoxygenated by triphenyl phosphite; with trimethyl phosphite the reaction is more complex.'94 Me I R2
H (372) R ' = R 2 = H (373) R' = Me, R 2 = H (374) R ' = R 2 = Me 190
Me I+
Br-
Me
-r3 (377)
(378)
Q. Khuong-Huu, X . Monseur, M. Truong-Ho, R. Kocjan, and R. Goutarel, Bull. Soc. chim. France,
1065,3035. G. Demailly and G . Solladie, Tetrahedron Letters, 1975, 2471, I y 2 A. Picot and X. Lusinchi, Synthesis, 1975, 109. l Y 3F. Khuong-Huu, D . Herlem, and Y. Hubert-Brierre, Tetrahedron Letters, 1975, 359. I y 4 P. Milliet and X. Lusinchi, Compt. rend., 1975, 280, C, 1319. Iy1
Steroid Synthesis
335
10 Sapogenins A method for the stereoselective oDening of ring E of furostan sapogenins has been described;lg5the route leads to 16,22R,26-trihydroxy-steroids. For example, reduction of (25R)-Sa-spirostan with lithium aluminium hydride-aluminium chloride affordsthe alcohol (379; R = CH,OH), which can be oxidized with Jones reagent to the acid (379; R = C02H) and this in turn converted into a separable equimolar mixture of the olefinic lactones (380) and (381). Oxidative hydroboration of the olefin (38 1) furnished quantitatively the trio1 (382) which after Jones oxidation and methylation formed the diketo-ester (383). The reaction sequence described above was also applied to the benzyl ether of tigogenin, and compounds analogous to (379)-(383) were obtained. A method giving access to various 16-substituted
sapogenins has been p ~ b l i s h e d ; these ' ~ ~ derivatives can be further converted into the corresponding 16-alkylpregn-16-en-20-ones using known routes.196 Thus when 9 a , l l a-epoxytigogenin acetate was oxidized with chromium trioxide in moist acetic acid 9a, 11a-epoxytigogenic acid (384) was formed and subsequent reaction with ethylmagnesium bromide furnished, after reacetylation, the 6-lactone 9a,11aepoxy-16a-ethyl-26-oxotigogeninacetate (385) in 35% yield. Diosgenin has been converted into (25R)-Sa-spirost-7-ene-3P,5,14a-triol-6one, an analogue of ecdysone. 197 Successive hydroxylation, partial oxidation, acetylation, and bromination gave the intermediate bromo-ketone (386) which underwent dehydrobromination and hydroxylation at C-14 with selenium dioxide to give the required ecdysone analogue. Iy5
196 197
A. G. Gonzhlez, C. G. Francisco, R. Friere, R..HernBndez, J. A. Salazar, and E. Suhrez, Tetrahedron Leners, 1974,4289. D. H. R. Barton and P. G. Sammes, B.P. 1372 688 (Chem. Abs., 1975,82, 73 316). I. L. Novosel'skaya, M. B. Gorovits, and N. K. Abubakirov, Khim. prirod. Soedinenii, 19.75,11,258.
Terpenoids and Steroids
336 0
0
5c0
A CO
(384)
11 Cardenolides The synthesis of 6a -methyldigitoxigenin acetate (394) has been reported according was converted into its 6a-methyl to Scheme 19.'98 Pregn-4-en-21-01-3,2O-dione derivative (387) using a previously described five-step reaction sequence; biological hydroxylation furnished the 14a,12-diol (388) and reduction of the derived 21acetate gave the SP-dihydro-steroid (389). Dehydration furnished the AI4-olefin (390) which was converted into the 21-mesylate and thence into the lactone (391) by reaction with the monoethyl ester of malonic acid. The crude lactone was decarboxylated, reduced to the 3/3-alcohol(392), and converted into the bromohydrin (393) via its 3P-acetate and thence by debromination into 6cw -methyldigitoxigen 3-acetate (394). A reaction sequence has been published for the transformation of pregnenolone acetate into 18-acetoxy-3P -hydroxy-l4a -carda-5,20(22)-dienolide (39S).'99 Key steps in this sequence are the hydrolysis of the oxime (396) to give the epoxypregnenol (397) and chromium trioxide oxidation of the diacetoxypregnenol (398) to give the pregnenone (399), which underwent a Reformatsky reaction with bromoacetic ester to give the required cardenolide (395). Pregnenolone acetate has also been used as starting material for the synthesis of the 19-oxygenated cardenolides corolaucigenin acetate (408) and corotoxigenin acetate (409);200 the reactions are outlined in Scheme 20. Pregnenolone acetate was first converted into the 20P-alcohol prior to formation of the 19-hydroxy-4,6-dien-3-0ne(400) using
U. Valcavi, B. Corsi, S. Innocenti, and P. Martelli, Farmaco, Ed. sci., 1975, 30, 597. E. Baumgartner, U. Buffo, T. Guentert, H. Handschin, E. Hauser, H. H. A. Linde, M. Ragab, L. Sawlewicz, S. Spengel, and A. Tanner, Pharm. Acta Helv., 1974,49, 31. G. Kruger, Canad. J. Chem., 1974,52,4139.
Iyx
lYy
Steroid Synthesis
337 YH,OAc
Me
H i
liv 0 S-0
CH,OAc
& (390)
HO
H : (392)
\'
::?
XI
----*
OH Br (393)
(394)
Reagents : i, Mucorgriseo-cyunus ATCC 1207a ( +), incubation; ii, acetylation; iii, H,-Pd/BaSO,; iv, KHS0,Ac,O; v, K,CO,-H,O; vi, mesylation; vii, EtO,CCH,CO,- K + - D M F ; viii, p-TsOH-collidine; ix, H,IrC1,,6H20-(MeO),P0; x, N-bromoacetamide; xi, Raney nickel.
Scheme 19
0
HO
338
Terpenoids and Steroids $H,OH
H
(397)
(398)
(399)
the previously described route as applied to the synthesis of 19-hydroxy- 17ppivaloxyandrosta-4,6-dien-3-0ne.~~' The dienone (400) was further dehydrogenated to the trienone (401) prior to sequential borohydride and catalytic reduction to
&p'vLo&L&
0
(400)
HO
H
(402)
(401)
& 0
1 , -.I
CH,OCOCH,P(O)(OEt), 0
$6
x
XLI
t-----
AcO
(405)
H
(403)
\
Reagents: i, NaOMe-DMSO, D D Q ; ii, NaBH,; iii, catalytic H , ; iv, pyridinium bromide perbromide; v, dihydropyran ; vi, bis(methoxyethoxy)aluminium hydride ; vii, Cr0,-py ; viii, AcOH-H,O ; ix, acetylation ; x, Pb(OAc),-BF, ,Et,O ; xi, KOH-MeOH ; xii, (diethy1phosphono)acetic acidDCC; xiii, KOH-H,O; xiv, AcOH-Zn; xv, Ac,O; xvi, Zn-HC0,H-H20; xvii, N-bromoacetamide: xviii, Raney nickel ; xix, KOH-H,O; xx, t-butyl chromate.
Scheme 20 *01
G. Kruger, J. Org. Chem., 1971, 36, 2129.
339
Steroid Synthesis
the A8(14)-01efin(402). Oxidation then furnished the 8,19-oxide, which was converted into the corresponding 3-pyranyl ether before the 20P-hydroxy-group was restored (reagent vi) and then oxidized to give the 8,19-oxido- 14-en-20-one (403), after acetylation at C-3. Further oxidation led to the 21-acetate, which upon selective hydrolysis afforded the corresponding 3P-acetoxy-2 1-hydroxy-20-ketone and this was further converted into the phosphonoacetate (404) and the cardenolide (405). Hydrogenolysis of this cardenolide gave the expected 19-alcohol convertible into the diacetate (406), identical with,P-anhydrocorolaucigenin diacetate. Further reaction of the same cardenolide (405) with zinc in formic acid afforded the 19-alcohol and then the 19-formate which on oxidation of the AI4-bond led to an intermediate bromohydrin convertible into the 19-formyloxy- 14P-hydroxyderivative (407). Selective hydrolysis allowed isolation of the corresponding 19alcohol (408), which upon oxidation gave the 19-aldehyde (409), identical with corotoxigenin 3-acetate. Some derivatives of 3-deoxydigitoxigenin have been synthesized and are reported to show much less cardiotonic activity than their 30 -hydroxy counterparts.202 3-Deoxydigitoxigenin (410; X = H,) was dehydrated with thionyl chloride to yield the A14-olefin which was converted into 14P,15P-oxido-5P,14P-card-20(22)enolide by the N-bromoacetamide route. Catalytic hydrogenation of the AI4-olefin using palladium on barium sulphate gave 5P,14a-card-20(22)-enolide, but the corresponding cardanolide (411; 20R or 20s) was obtained when the catalyst was changed to platinum. Hydrogenation of the cardenolide (410; X = H,), followed by dehydration of the 14-alcohol, allowed the isolation of 5P-card-14-enolide, again as a mixture of the (20R)- and (20s)-epimers. 3-Alkylidene derivatives of the carthey are denolide (410; X = 0) have been reported as useful cardiac prepared by reaction of the 3-ketone with appropriate Wittig reagents. The two examples quoted are the derivatives (410; X = CH,) and (410; X = CHMe); the corresponding bufadienolides were also prepared.
AS (410; X = H , )
I
A partial synthesis of syriogenin (412; R'=P-OH,H; R2=OH: S a - H ) has been reported204 commencing from digoxigenin (412; R1 = P-OH,H; R2 = OH; 5P-H).Digoxigenin was first converted into the A4-3-ketone by oxidation to the 3-ketone (412; R' = 0, R2 = OH; 5P-H)using oxygen-platinum and selenium dioxide dehydrogenation. Hydrogenation (hydrogen-palladium charcoal) yielded 202
203 204
T. R. Witty, W. A. Remers, and H. R. Besch, jun., J. Pharm. Sci., 197564, 1248. H. P. Albrecht, Ger. Offen. 2 254 980 (Chem. Abs., 1974,81, 37 737). C. Casagrande, F. Ronchetti, and G. Russo, TetrahedronLetters, 1974, 2369.
340
Terpenoids and Steroids
the expected mixture of 5aH-3-ketone and SPH-3-ketone7and borohydride reduction furnished a chromatographically separable mixture of 3P, 12P714P-trihydroxy5a-card-20(22)-enolide (syriogenin) and 3a, 12p,14@-trihydroxy-SP-card-20(22)enolide. The nitration of digoxin using concentrated nitric acid in acetic anhydri.de at -10 "C results in the formation of digoxin pentanitrate which on standing with methanolic hydrochloric acid undergoes partial hydrolysis to give digoxigenin 12-nitrate (412; R1= P-OH,H, R2= ONO,; 5p-H).205
R' H (412)
A new method has been published206for the direct conversion in high yield of the cardiac glycoside digitoxin into 3/3-acetoxy-14-dehydrodigitoxigenin(413) without the need to isolate the intermediate 14P-alcohol; the reagent of choice is toluene-psulphonic acid in acetic acid-acetic anhydride. Further reaction of the olefin (413) with iodine and silver acetate gave 3P, 15~-diacetoxy-14~-hydroxy-5~-card20(22)-enolide (414; R' = OH, R2= H), which upon hydrolysis completed a synthetic route to 15P-hydroxydigitoxigenin. A series of cardenolides (414; R' = OAc, R2= F, N,, O N 0 2 , OAc, SOCMe, or MeO) has been prepared by the reaction of (414; R' = OAc, R2= Br) with AgF, AgN,, AgNO,, KOAc, KSOCMe, and MeOHAgC10, re~pectively,~'~ and digitoxigenone oxime (410; X = NOH) has been reduced by aluminium amalgam to give the aminocardenolide (410; X = P-NH,, H), which was itself condensed with ethylene oxide to give an intermediate convertible into the oxazolidine (415) on reaction with phosgene.208 0
As (41 3 )
205
206
207
20x
lYR2
(415 )
R. Megges. B. Streckenbach, G. Karnmann, and K. R. H. Repke, Austrian P. 319491 (Chern. A h . , 1975,83, 10611). Y. Karnano, M. Tozawa, and G. R. Pettit, J. Org. Chem., 1975,40, 793. R. Megges, H. Timm, P. Thiernann, F. Dittrich, P. Franke, H. Portins, and K. Repke, Ger. (East) P. 109622 (Chem. Abs., 1975,83, 59 166). K. Meyer, Swiss P., 559 219 (Chern.Abs., 1975, 83, 28 459).
34 1
Steroid Synthesis
12 Bufadienolides A simple two-step synthesis of the a-pyrone ring has been applied to the synthesis of bufadienolides.210 Reaction of the known ap -unsaturated aldehyde (416) with the dimethyl acetal of chloroketen [ClCH=C(OMe),] gave a 57% yield of the intermediate 2,2-dimethoxy-3 &chloro-3,4-dihydropyran (4 17) which on reaction with sodium methoxide in DMSO afforded the a-pyrone (418) directly in 64% yield. CHO
ISH2
(417)
(418)
Syntheses of marinobufagin (419; R = H) and marinobufotoxin have been published.21' The route to these compounds commences with the selective removal of the 14P-hydroxy-group from telocinobufagin (420) by treatment of the trio1 with hydrochloric acid in methanol. The resultant 14-dehydrotelocinobufagin was selectively acetylated to give the 3P-acetate prior to reaction with hypoiodous acid; this afforded the 14P-hydroxy- 15a-iodo-derivative which on reaction with base gave the 14p715P-epoxide, marinobufagin acetate (419; R = Ac). Reaction of dehydrotelocinobufagin with m -chloroperoxybenzoic acid gave the isomeric 14a,15a epoxide. By condensing marinobufagin with suberic a -anhydride, the corresponding 3-suberate ester [419; R = CO(CH,),CO,H] was obtained which was converted into a mixed anhydride by reaction with isobutyl chloroformate prior to addition, in the cold, to L-arginine monohydrochloride. This reaction sequence constitutes a synthesis of marinobufotoxin [419; R = CO(CH,),CONHCH(CO,H)(CH,),NHC(=NH)NH,]. An efficient synthesis of ISP-hydroxybufalin (421) has 0
RO
209 21O 211
OH
A. Belanger and P. Brassard, Canad. J.. Chem., 1975, 53, 195. A. Belanger, P. Brassard, G. Dionne, and Ch. R. Engel, Steroids, 1974,24, 377. G. R. Pettit and Y. Kamano, J. Org. Chem.,1974,39, 3003.
Terpenoidsand Steroids
342
been described;212it is achieved by treating 14-dehydrobufalin with iodine and silver acetate under the conditions for Woodward cis-hydroxylation. Acid-catalysed hydrolysis of the 15P-acetate affords the required triol (421). The 3P-acetate of the triol (421) could be oxidized to give 3P-acetoxy- 14P-hydroxy-15-oxo-5~-bufa20,22-dienolide. Two partial syntheses of bufotalin (426) have been described,213 and are summarized in Scheme 21. The 16P-acetoxy-group of cinobufagin (422) 3-acetate was hydrolysed and oxidized to yield the 3-acetoxy- 16-ketone (423) which on reduction of the epoxide ring furnished a chromatographically separable mixture of the 14P-alcohol (424) and the AI4-olefin (425). The former could be converted into the latter by treatment with acid. Reduction of the 16-ketone and hydrolysis of the 3-acetate provided bufotalin (426). In an alternative route the unsaturated ketone (425) was reduced to the alcohol (427) and via the iodohydrin (428) was converted into the required bufotalin. R R R
(423)
(424)
\,vi
6 R
OH
(427)
Reagents: i. KHC0,-H,O; ii, CrO,; iii, Cr”(OAc),; iv, H + ; v, Urushibara nickel A; vi, HCI-MeOH; vii, N-iodosuccinimide-Me,CO-H;O.
Scheme 21
Cinobufagin (422) has also been used as starting material in a synthesis of the methyl ester of a newly isolated novel bufotoxin [429; R = CO(CH,),CO,H] from *I2 *I3
Y. Kamano, G. R. Pettit, M. Tozawa, Y. Komeichi, and M. Inone, J. Org. Chem., 1975,40,2136. Y. Kamano, G. R. Pettit, and M. Inone, J. Org. Chem., 1974,39, 3007.
Steroid Synthesis
343
the Japanese toad Bufo vulgaris forrnosus Boulenger.,14 Reaction between cinobufagin, methyl hemiadipate, and DCC affords the required ester [429; R = CO(CH,),CO,Me] in one step. The same reaction has also been used to convert bufalin into the corresponding 3-hemiadipate methyl ester.
214
K. Shirnada,Y. Fujii, E. Mitsuishi, and T. Nambara, Chem. and Pharm. Bull. (Japan),1974,22,1673.
ERRATA
Vol. 5,1975 Page 135. Structure (95) should have a methyl group at C-10. Page 141, structure (137).
For
@
Read
0
Page 142, structure (141).
Page 241, end of first paragraph. The reference number should be 114, not 113.
Author Index
Aasen, A. J., 47, 112 Abdallah, M. A,, 118 Abdel-Baset, Z., 218 Abe, H., 29 Abe, K., 26, 29 Abe, T., 201, 285 Abeln, G. J . A., 201, 202 Aberhart, D. J., 323 Aboul-Encin, H. Y., 328 Abraham, P. M., 32 Abubakirov, N. K., 225, 335 Achenbach, H., 65 Acher, A., 234,314 Achini, R., 64, 212, 213 Aclinou, P., 288 Adam, G., 110, 1 1 1 Adams, D. R., 27,58 Adams, J. B., 206 Adarns, M. R., 97, 187 Adarns, R. G., 165 Adinolfi, M., 234, 235, 322 Adler, G., 202 Adolf, W., 11 3 Aexel, R. T., 198 Agami, C., 243 Agarwal, S. K., 132, 133 Agata, A., 15 Agatsuma, K., 76 Agnew, W., 119 Agostini, A., 23 Aguiar, J . M., 65, 182 Aguilar-Martinez, M., 145 Ahlers, B., 204 Ahmad, M. S., 84. 253, 255 Ahn, B. Z., 24 Ahrens, E. H., 169 Ahrens, H. M., 163, 2 1 1 Ajami, A. M., 187 Akhtar, M., 193, 203, 234 Akita, H., 105 Akiyama, T., 123 Albone, E. S., 47 Albrecht, H. P., 339 Alcalde, A., 198 Alchalel, A., 165 Alder, A. P., 35 Alekseev, E. V., 165 Aleshina, V. A., 45 Alexander, J.. 3 1
Alexander, K., 12, 193 Alexandre, G., 31 Ah, S. M., 301 Allam, A. M., 204 Allen, C. M., 213 Allinger, N. L., 6, 105, 225 Almqvist, S.-O., 47 Alper, H., 10 AI-Rawi, J. M., 202, 223 Altman, K., 201 Alvarado, F., 140 Alvarez, M. i., 210 Ambles, A., 263 Arnbrus, G., 202 Amos, J., 247 Arnouyal, E., 168 Ananchenko, S. N., 280 Anastasia, M., 193, 266 Anchel, M., 73, 106 Anderson, A. B., 107 Anderson, G. D., 324 Anderson, L. M., 201 Anderson, N. H., 63 Ando, N., 15 Andreoni, A., 232 Andrewes, A. G., 148 Andrews, G . C., 69 Aneja, R., 226 Ansari, H. R., 18 Anteunis, M., 15, 16 Antomova, N. D., 4 , 4 1 Aoshirna, K., 120 Aoyagi, R., 136 ApSimon, J. W., 223, 308 Aratani, T., 21 Araujo, H. C., 8 Arbuzov, B. A., 46 Archer, R. A., 48 Arhart, R. J., 229 Arigoni, D., 67, 203, 234 Arihara, S., 101, 331 Armstrong, D. J, 214 Armstrong, V. W., 251 Arnett, J. F., 35 Arnold, W., 223 Arora, P., 158 Arth. G. E.. 271. 284 Arthur, H. R., 122 Arthur, J. R., 201
345
Asahara, T., 17 Asaka, Y., 26 Asako, T., 265 Asato, A. E., 153 Ashby, E. C., 38 Aso, S., 40 Astruc, M., 177 Atallah, A. M., 198, 200 Atta-ur-Rahman, 133 Atuma, S., 163 Audouin, M., 250 Aul’chenko, I. S., 4, 41 Auterhoff, H., 29 Avigan, J., 173 Avotins, F., 4 Awata, N., 197, 198, 327 Ayer, W. A., 108, 109 Azerad, R., 165, 216 Azzaro, M., 40 Baba, S., 217 Raba, Y.,2 17 Babiak, Z., 209 Babin, D. R., 111 Babler, J. H., 21, 228, 288 Bachmann, J.-P., 83 Back, D. J., 201 Back, T. G., 40 Badanova, Yu. P., 31 1 Bagaturova, E. M., 233 Bageenda-Kasujja, D., 115 Bagnell, L., 31, 302 Bailey, J. A., 80 Bailey, R. B., 194 Bailleul, F., 24 Baillie, T. A., 201, 216 Bakaleinik, G. A,, 46 Baker, F. C., 184 Baker, J. D., jun., 256 Baker, J. F., 232 Bakker, H. J., 110, 188 Balasubramaniarn, S., 204,206 Baldwin, D., 265, 294 Baldwin, J. E., 284, 288 Baldwin, S. W., 66 Ball, J. H., 108, 109 Ball, P., 202 Ballio, A., 115 Banerjee, A., 116, 132, 284
346 Banerjee, D. K., 283, 284 Banerjee, S. K., 274 Banerji, N., 130, 132 Bang, L., 62,90, 182 Binhidai, B., 246 Bannai, K., 314 Banner, B. L., 238, 277 Bannikova, G. E., 233 Bannister, L. H., 202 Banthorpe, D. V., 11, 177 Baran, J. S., 17 Barbier, M., 12 1, 324 Bard, M., 193 Bardyshev, I. I., 31, 32, 45, 46 Barone, G., 235, 322 Barr, R. M., 2 11 Barrack, E. R., 217 Barrett, A. G. M., 269 Barron, D., 5 Barron, L. D., 36 Barron, R., 225 Barrow, K. D., 97, 115 Barta, I., 202 Bartlett, L., 224 Barton, Sir D. H. R., 10, 40, 115, 118, 176, 193,227,248, 254,260,269,284,306,3 10, 3 16,322,335 Bartschot, R., 218 Bartter, F. C., 205 Baskevitch, N., 243 Baskevitch, Z., 128 Bateson, J. H., 110, 111 Bathurst, E. T. J., 262 Batta, A. K., 121 Battaglia, R., 203, 234 Battersby, A. R., 216 Batzold, F. H., 204, 241 Bauer, L., 12 Baumgartner, E., 336 Bax, H.-J., 52 Baxter, R. L., 102, 113, 114 Bazely, N., 319 Bazyl’chik, V. V., 45 Beames, D. J., 116 Bearder, J. R., 109, 188, 189 Becker, J., 162 Becker, K., 210 Becker, R. S., 32, 164, 165 Beckett, A. H., 38 Beckett, B. A., 109 Beckett, G. J., 202 Beckey, H. D., 225 Beckhaus, H., 246 Bedoukian, R. H., 33 Beedle, A. S., 198 Beeley, L. J., 109 Beeman, C. P., 37 Begley, M. J., 75 Behare, E. S., 78 Behl, R., 185 Beier, J., 215 Beierbeck, H., 223 Bekaert, A,, 121, 324
Author Index Bekker, A. R.,18 Belanger, A., 341 Bell, A. A., 66 Bell, C.L., 12 Bell, P. A., 319 Bellamy, A. J., 34 Bellavita, V., 139 Bellesia, F., 183 Bellino, A., 106 Beloeil, J.-C., 240, 289 Ben-Aziz, A., 210 Bender, B. E., 49 Bensasson, R., 165, 168 Benschop, M., 179 Benson, A. M., 204, 217 Benveniste, P., 194 Bercht, C. A. L., 50 Bercovici, T., 27 1 Berenger, G., 121 Berenson, G. S., 200 Berenson, L. M., 200 Berger, S., 5, 32, 164 Bergot, B. J., 187, 206 Berman, E., 222 Berman, M. L., 201 Bernays, E. A., 170 Berndt, J., 173 Bernhard, K., 149 Bernstein, H. J., 165 Berrier, C., 263 Bertin, J., 10 Bertram, H., 29 Besch, H. R.,jun., 339 Bessihe, Y., 44 Betz, G.. 205 Beugelmans, R.,270,272 Bey, P.,129 Beyer, C., 201 Bhacca, N. S., 222 Bhakuni, D. S., 147 Bhandaru, R. R., 200 Bhat, S. V., 101 Bhathena, S. J., 173 Bhatnagar, P. K., 10, 216 Bhatnagar, S. P., 27, 58 Bhattacharyya, P. K., 284 Bhatwadekar, S. V., 182 Bianw, A., 23,24 Bible, R. H., jun., 268 Bickelhaupt, F., 111 Biellmann, J. F., 203 Bikle, B. D., 202 Bimpson, T., 194 Biolaz, M., 251, 308 Birch, A. J., 283 Birrell, G. B., 274 Bjorkhem, I., 204,205 Blackburn, T. F., 8 Bladon, P., 239 Bland, J., 240 Blankespoor, R. L., 34 Blanton, C., 207 Blaszczak, L. C., 84 Blatz, P. E., 165
Bledsoe, J. O., 46 Blickenstaff, R. T., 232 Bloch, K., 176 Bloxham, D. P., 170 Boar,R.B., 118, 121,176,190, 216,254,306,322 Bochwic, B., 39 Bodea, C., 153 Bodenstein, 0. F., 13 Boeckman, R. K., 87 Boeckmann, R.W., 278 Boelens, H., 84, 158 Bognounou, Q., 24 Bogoslovskii, N. A., 327 Bogri, T., 111 Boguslawski, W., 201 Bohlmann, F., 32, 52, 53, 56, 5 8 , 59, 85, 89, 93, 100, 133 Bohme, K. H., 203 Boid, R.,207 Boll, M., 173 Bollert, B., 204 Bolognesi, M., 266 Bombardelli, E., 133 Bompiani, A., 204 Bonati, A., 133 Bond, F. T., 7 Bonet, J.-J., 272 Bontin, N. E., 320 Bonting, S. L., 2 11 Boon, A., 49 Booth, R., 172 Borch, G., 148 Bordner, J., 129 Borowiecki, L., 37, 39 Borienova, N. V., 160 Bosch, T., 31 Boschung, A. F., 38 Bose, A. K.,4,5,216,222,226, 307,320 Bosworth, N., 265, 324 Botham, K. M., 205 Botta, L., 179 Bouchier, F., 165 Boulos, A. L., 240, 323 Bourbonniere, R.A., 207 Bourgeois, M.-J., 44 Bournot, P., 201, 217 Boussac, G., 44 Boutin, N. E., 227, 284 Bowden, B. F., 133 Bower, D. H., 106, 110 Bowins, B., 49 Box, V. G. S., 60 Boy, M., 199 Boyd, G. S., 201,202 Bozzato, G., 83 Bracke, J. W., 179 Brady, L. E., 32 Braekman, J. C., 112 Bramley, P. M., 163, 209 Brand, J. M.,179 Brannan, P. G., 173 Braselton, W. E., 203
347
Author Index Brassard, P., 341 Breidenbach, R. W., 188 Breitmaier, E., 5 Bremser, W., 164 Breslow, J. L., 172 Breslow, R., 268, 269, 307 Brewer, H. W . , , l l l Bridges, A. J., 9 Brieger, G., 6, 14 Brien, C. J., 184 Brieskorn, C. H., 241 Briggs, D. E., 188 Briggs, L. H., 13, 105 Britten-Kelly, M. R.,40 Britton, G., 209 Britton, R.W., 128 Brockmann, H., 5 Brooker, J. D., 172 Brooks,C. J. W., 184,234,317 Brophy, P. J., 206 Broughton, J. M., 236 Brown, D. G., 13 Brown, D. J., 209 Brown, H. C., 30, 37 Brown, J. W., 253, 304 Brown, M. S., 170, 172, 173 Brown, R. D., 206,271,284 Brown, S. A., 214 Browne, L. E., 179 Brownie, A. C., 201 Brunelle. D. J., 87 Brunschede, G. Y., 173 Bryan, R. F., 102 Brynjolffssen, J., 323 Bryson, T. A., 69 Brzezinka, H., 152 Buchan, G. M., 240,287 Buchecker, R., 146, 147, 153 Buckingham, A. D., 36 Buckingham, J., 3 Bucourt, R., 221, 249, 268, 286 Budd, D. L., 222 Buddrus, J., 149 BudESinskf, M.,131, 134 Budzikiewin, H., 77, 152 Buchi, G., 6, 53 Buffo, U., 336 Buinova, E. F., 45, 46 Bulgrin, V. C., 155 Bull, J. R., 248 Bu’Lock, J. D., 97, 148, 187 Burak, K., 44 Burden, R. S., 80 Burger, B. V., 14 Burgers, P. C., 49 Burka, L. T., 180 Burke, R. W., 241 Burlingame, A. L., 191 Burnett, R. D., 221 Burov, V. N., 14 Burova, L. E., 159 Burreson, B. J., 20, 65, 88, 97, 179
Burstein, S., 201 Busch, U., 23 Bms, V., 225 Buttrick, P. A., 35 Cabaret, D., 6 Cabeza, M., 201 CabrC, F. R. M.,254, 299 Cacchi, S., 244 Cagnoli-Bellavita, N., 96, 187 Cahiez, G., 9 Cain, P., 280 Caine, D., 78 Calando, Y ., 3 19 Caldeira, P. P., 326 Callender, R. H., 165 Calzada, J. G., 15 Cama, H. R., 21 1 Cambie, R. C., 102, 103, 104, 105, 133,236,311 Cambon, A. R., 227,284,320 Cameron, A. F., 126 Cameron, E. H. D., 203 Campbell, H. M., 109 Campbell, I. M., 217 Campbell, 0. A., 176 Campbell, R.V. M., 119, 150 Campello, J. de P., 101 Campillo, A. J., 165 Cane, D. E., 181 Canonica, L., 19 1 Cant, P. A. E., 42 Caputo,R., 125, 133, 134,235, 244 Caranto, M., 241 Carey, S. T., 47, 177 Cargill, R. L., 21 Carlisle, C. H., 269 Carlisle, T. L., 209 Carlstrom, K., 203 Carmon, M., 147 Casagrande, C., 339 Casida, J. E., 13 Casinovi, C. G., 115 Caspi, E., 10, 191, 192, 194, 196, 197,216,229,247,266, 323 Cassal, J.-M., 277 Castagnino, E., 248 Castognoli, N., jun., 50 Castro, B., 247 Catalan, A. N. C., 35 Catsoulacos, P., 260, 330 Caughlan, C. N., 85 Cavill, G. W. K., 25 Cebubka, Z., 40 Ceccherelli, P., 96, 187 Cech, F., 239 Cerda-Olmedo, E., 210 Cerfontain, H., 157, 161 Cerng, V., 250,304 Cesar, A., 35 Chaabouni, R.,31 Chabudzinski, Z., 44
Chadwick, D. J., 222,225 Chain, Sir, E., 1I S Chakrabarty, S., 116 Chakrabarty, P. N., 116 Chakravarti, D., 133, 274 Chakravarti, K. K., 21,58, 182 Chakravarti, R. N., 132, 133, 274 Chambers, E. M. V., 301 Chambers, J., 225 Chan, J. A., 10, 216 Chan, J. T., 193 Chan, W. R., 60, 114 Chandrasekhar, B. P., 256 Chang, C. J., 101,102 Chan-Santos, E., 163 Chapman, J. C., 2 5 5 , 3 11 Chapman, R. F., 170 Chari, V. M., 121 Chatterjee, A., 132 Chaudhry, Z. H., 255 Chaudhuri, N., 228 Chaudhuri, R. K., 47 Chavez, P. I., 218 Chen, H. W., 172, 200 Chen, S.-M. L., 224 Chen, Y. P., 113 Cheng, Y. S., 100 Chetyrina, N.-S., 135 Cheung, H. T., 122 Chevallier, F., 191 Chevli, D. M., 230 Chiang, S., 14 Chichester, C. O., 209, 210 Chinn, L. J., 241, 310 Chishti, N. H., 150, 251 Cho, H., 29 Choay, P., 249 Choi, L. S. L., 260, 310 Chong, A. O., 6 Chong, K.-F., 129 Chorvat, R. J., 268 Chou, S., 273 Chow, J. C., 173 Christa, 2.. 100 Christie, W. M., 204 Christophersen, C., 65 Christy, K. J., 6 Chu, J. Y. C., 274 Chugh, 0. P., 18 Chuit, C., 9 Chujo, R.,164 Chuman, T., 27 Cimino, G., 92,93 Clardy, J., 88, 100, 106, 112, 114, 115, 121, 122,324 Clark, R.,18 Clark, R. D., 83 Claus, P., 38 Clifford, K. H., 120, 191 Clinkenbeard, K. D., 170, 171 Cloke, C.. 106, 110 Clower, M. G., 6 1 Coates, J., 12
Author Index
348 Coates, R.M., 9 Cocker, W., 21, 32 Cody, V., 221 Cohen, B. I., 200,206 Cohen, C. F., 198 Cohen, G. M., 28 Cohen, N., 238,276,277 Cohen, N. C., 221 Colby, H. D., 205 Cole, R. J., 112, 115 Collins, D. C., 201, 202 Collins, R. P., 13 Collins, W., 203 Colquhoun, A. J., 185 Conia, J. M., 237 Conklin, J. E., 320 Conner, R. L., 198 Connolly, J. D., 63, 98, 125, 126 Conway, W. P., 9 Cook, 1. F., 107, 110, 188 Cooke, B. A., 200 Cookson, R. C., 27, 58 Coombe, B. G., 68 Coombs, R. V., 245,287 Coppell, S. M., 150 Corbella, A., 95, 181 Corbett, R. E., 104, 141 Corbier, B., 18, 28 Corcoran, R. J., 268, 269, 307 Cordell, G. A., 190 Corey, E. J., 8,9,233, 257 Cornforth, J. W., 10, 170, 216 Corsi, B., 336 Coscia, C. J., 179 Costin, C. R., 63 Couch, E. F., 207 Counsell, R., 330 Court, W. A., 273 Cowan, R. A., 204 Cowell, D. B., 298 Cox, R. H., 112 Coxon, D. T., 80 Coxon, J. M., 37.42, 262 Crabbe, P., 285 Craney, B., 240 Crastes de Paulet, A., 177 Crawford, M., 139 Crews, P., 20, 33 Crilly, W., 34 Critchfield, W. B., 97 Croft, K. D., 107 Crombie, L., 5, 49, 119, 150, 164 Crombie, W. M. L., 49 Cronholm, T., 191, 206 Crosby, G. A., 9 Cross, B. E., 104, 110, 111 Crowe, D. F., 286 Crowley, K. J., 32 Crozier, A., 189 Culter, H. G., 112 Cunningham, I. M., 234
Curtis, R. F.,,80 Cushman, M. S., 6, 50 Czarny, M. R., 250, 302 Czarny, R. J., 129 Daemen, F. J. M., 21 1 Dagonneau, M., 40 Dahlgren, R., 23 Dahm, K. H., 56, 186 Dainis, I., 284 d’Alessio, V., 115 Dalling, D. K., 32, 164 Daloze, D., 112 Dalzell, H. C., 49, 50 Damico, J. N., 225 Damps, K., 118, 176, 216 Dana, S. E., 172 d’Angelo, J., 277 Danielsson, H., 204, 206 Danishefsky, S., 257, 280,301, 310 Danna, R. P., 245 Darias, J., 115 Darnley-Gibbs, R., 217 Das, K. G., 137 Das, K. K., 155 Dasgupta, S. K., 229 Dauben, W. G., 71,82, 157 Dauna, R. P., 287 Dauphin, G., 16 Davies, A. P., 226 Davies, B. H., 163, 209, 216 Davies, L. J., 188, 189 Davis, A. K., 298 Davis, B. R., 102 Dawes, C. C., 248 Dawidar, A. M., 225 Dawson, M. J., 129 De Bernardi, M., 74 Deb Nath, N. B., 133 Debrauwere, J., 13 De Camp, W. H., 111 Decorzant, R., 157 Decouzon, M., 40 Degenhart, H. J., 201, 202 de Hertogh, A. A., 179 Deighton, M., 81 de Klerk, W. A., 200 De Koning, B., 165 Delaveau, P., 24 Delbarre, F., 319 De Leenheer, A. P., 154 de Leeuw-Boon, H., 201 Della Casa de Marcano, D. P., 115 Delle Monache, F., 138 DeLuca, H. F., 163, 205, 21 1, 314,320 Demailly, G., 259, 334 De Marco, A., 95 de Mayo, P., 62 Demde, E., 155 Dence, J. B., 4 Den Engelsen, D., 165
de Nie-Sarink, M. J., 254, 299 Dennis, D. T., 174 Dennis, F. G., 109, 189 Dennison, N. R., 59, 107 Denny, W. A., 103 de Quesada, T. G., 102, 106, 109 Derfer, J. M., 46 de Rosa, M., 119,208 De Rossef, A. J., 41 De Ruyter, M. G. M., 154 Desai, B. N., 241 Desalbres, X., 41 Descomps, B., 177 Deshayes, H., 273,320 Deshchits, G. V., 46 Deshpande, N., 204 De Smet, A., 15, 16 de Souza, J. P., 9 de Souza, N. J., 101 De Stefano, S., 92, 93 de Szoes, J., 140 Dev, S., 70 de Villiers, D. J. J., 14 Devon, T. K., 13 Devys, M., 121, 324 Deyrup, C. L., 213 Dhar, M. H., 97,98 Dhavlikar, R. S., 184 Dhingra, V. K., 147 Diamondstone, B. I., 241 Dick, K. F., 8 Dickson, L. G., 193 Dietsche, T. J., 9 Dietschy, J. M.,170, 200 Dighe, S. S., 47 Dijkstra, G., 49 Dionne, G., 341 di Sanseverino, L. R., 49 Dittrich, F., 340 Djarmati, Z., 97, 111 Djerassi, C., 122, 324 Dobbs, F. R., 38 Dodd, J. R., 34, 299 Doisy, E. A., 206 Do Khac Manh Duc, 98, 117 Dominguez, X.A., 133 Doorenbos, N. J., 328 Dorffling, K., 185 Doria, G., 232 Dorn, F., 67 Doskotch, R. W., 75 Dossena, A,, 213 Downing, M. R., 179 Doyle, P. J., 193 Draoi, E., 232 Drake, D., 148 Drawert, F., 15, 215 Dresbach, C., 2 11 Dreyer, M., 208 Duax, W. L., 203, 221,266 Dubini, R., 29, 55 Ducruix, A., 105 Dugan, R. E., 172
349
Author Index de Manoir, J . R., 10 Duncan, G. R., 266 Duncanson, F. D., 126 Durley, R. C., 189 Dutky, S. R., 208 Dutta, N . L., 130, 133 Dutta, P. C., 116 Dutta, P. R., 116 Dutta, S., 132, 284 D'yakonova, R. R., 46 Dyer, A., 217 Dykos, J. H., 310 Dzhernilev, U. M., 44 Dziadkowiec, I., 201 Dzizenko, A. K., 135 Eadon, G. A., 225,312 Eber, J., 109 Eberhart, N. L., 174 Ebersole, R. C., 197, 229 Eck, C. R., 10, 39,60,216 Eder, U., 278, 282 Edrnond, J., 172,173 Edwards, 0. E., 273 Eechaute, W., 201 Eenkhoorn, J. A., 308 Eger, G., 221 Eggerer, H., 170 Eguchi, Y., 241,295 Ehrenfreund,'J., 159, 162 Ehret, C., 47 Eichel, W. F., 238, 277 Eignerova, L., 244 Einarsson, K., 201 Eisfeld, W., 273 Eisner, T., 13 Ekong, D. E. U., 125 Ekundayo, O., 1 1, 177 Elahi, M., 210 El Attar, T. M. A., 201 Elder, D. L., 126 El-Feraly, R.-S., 75 El Gaied, M. M., 44 El-Carnal, M. H. A., 134 El Hachimi, Z., 165, 216 El-Kady, I. A., 204 Elkin, Y. N., 135 Elks, J., 244 Elliott, M., 13 Elliott, W. H., 202, 205, 206 Ellis, B. E., 214 Ellis, R. F., 14 Ellis, W. D., 218 Ellison, R. A., 10, 216 Ellyard, R. K., 206 Els, H., 223 El-Sernrnan, E.-H., 41 El-Tawil, B. A. H., 134 Elvidge, J. A., 202, 223 Elyakov, G. B., 135 Elze, H., 202 Emke, A., 323 Ernrnerich, H., 208 Enda, T., 24
Engel, Ch,R., 341 Engel, L. L., 201, 203, 217 Engelhardt, G., 222 Enger, A., 271 Enggist, P., 155 Englert, G., 223 Engovatov, A. A., 165 Enguchi, Y., 315 Enornoto, S., 20 Enzell, C. R., 47, 112 Ephritikhine, M., 236, 284 Epstein, S., 20 Epstein, W. W., 12 Erickson, K. L., 64 Eriksson, H., 201, 206 Erinson, J. L. E., 201 Errnan, W. F., 45 Ernstbrunner, E. E., 223 Ernster, L., 206 Eslava, A. P., 210 Eugster, C. H., 101, 146 Evans, F. J., 113 Evans, P. J., 166 Evans, R., 64,97, 188 Evans, R. B., 170 Evstigneeva, R. P., 154, 327 Fakunle, C. O., 125 Fales, H. M., 225 Falk, A. J., 12 Falke, H. E., 202 Falkiner, M. J., 102 Fallis, A. G., 41 Fallon, W. E., 223 Farges, G., 30 Farmer, R. W., 200 Farthing, J., 34 Fattorusso, E., 89 Faulkner, D. J., 20, 33, 57, 64 Faux, A. J., 102 Fayez, M. B. E., 134,225 Fayos, J., 100, 122, 324 Fehlhaber, H.-W., 95, 101 Feigenbaum, A., 271 Feldman, M., 246 Feliziani, F., 238 Femino, A. M., 202 Fenical, W., 64, 94 Ferguson, G., 99,125,265,324 Ferreira, G. A. L., 8 Ferro, A., 27 Fesenko, D. A., 31 Fetizon, M., 8, 98, 117, 120, 233,240,254,289,327 Fiecchi, A., 266 Filippova, T. M., 18, 159 Filler, R., 8 Findlay, J. W. A,, 240, 287 Findley, D. A. R., 119, 150 Finer, J., 88, 121 Finkel'shtein, E. I., 165 Firth, M.R., 104 Fischer, E., 271 Fischer. I., 233, 299
Fischer, R., 14 Fisher, M. M., 165 Fishrnan, J., 265, 294 Flake, R. H., 217 Flament, J. P., 117 Flatau, G. N., 284 Flemrning, K., 205 Floor, J., 248 Flynn, G. A., 28 Fogelman, A. N., 172, 173 Fong, R. W., 241 Fonken, G. S., 62 Fonseca, S. F., 101 Font-Cistero, J. M., 31 Forest, J. C., 206 Forne, E., 31 Forsen, K., 4, 218 Foster, D. W., 200 Fotherby, K., 190 Fowler, M. S., 50 Francisco,C. G., 138,199,257, 335 Franke, P., 340 Franz, J. A., 229 Frasnelli, H., 246 Fratiello, A., 223 Fratini, L., 139 Frayha, G. J., 216 Fredericks, M.,200 Freeman, D., 222,234,314 Freidlin, L. Kh., 160 Freire, R., 138, 199, 257, 335 Fried, J., 285 Friedman, S., 28 1 Friedrich-Fiechtl, J., 48 Froborg, J., 73 Fronza, G., 74 Fryxell, P. A., 66 Fuchs, P. L., 82 Fiirst, A., 223,277 Fujihara, Y., 42, 43 Fujii, S., 265 Fujii, Y., 343 Fujirnori, T., 148 Fujirnoto, T., 142, 143, 218 Fujirnoto, Y., 198, 327 Fujita, E., 99, 189, 218 Fujita, K., 97, 188 Fujita, S., 18, 180 Fujita, T., 17,99, 189, 218 Fujita, Y.,18. 180 Fujiwara, H., 15 Fukui, K., 103 Fukunaga, T., 29 Fukunishi, K., 14 Fukushirna, D. K., 310 Fulke, J. W. B., 125 Furuichi, K., 25, 26 Furukawa, H., 89 Furusaki, A., 272 Furuya, T., 202 Gaare, G., 260 Gabai, M., 147
Author Index
350 Gabetta, B., 133 Gadola, M., 157 Gafner, G., 164 Gagosian, R. B., 207 Gaio, P., 232 Galbraith, M. N., 207, 330 Gal’chenko, G. L., 45 Galli, G., 193 Galli-Kienle, M., 193 Gambacorts, A., 119 Camper, N. M., 14 Gandhi, R. P., 272 Gandolfi, C., 232 Ganeon, B., 9,233 Ganguly, S. N., 109 Gaoni, Y., 162 Gara, R. I., 218 Garbarino, J. A., 10, 227 Garbers, C. F., 14 Garg, S., 272 Gariboldi, P., 95, 181 Garlaschelli, L., 74 Garrett, E. R., 50 Gasc, J . C., 249, 286 Case, R. A,, 254, 299 GaSik, M. J., 16 Gaskin, P., 109, 188 Gastarnbide, B., 28, 288 Gaughan, L. C., 13 Gautsthi, F., 157 Gavrilova, T. F., 4, 41 Gawad, D. H., 60 Gawienowski, A. M., 21 1 Gay, R., 202 Gedye, R. N., 158 Geiger, H., 41 Geipel, R., 95 Geluk, H. W., 161 Gennings, J. N., 202 George, R., 173 Germain, P., 202 Gervais, H.-P., 41 Gesson, J.-P., 264 Geuns, J. M. C., 194 Ghatak, U. R., 116 Ghisalberti, E. L., 100, 107, 112, 115 Ghosal, S., 47 Ghosh, S. K., 116 Ghraf, K.,200 Giannini, D. D., 222 Giannoli, B., 244 Gibb, W., 203, 244 Gibbons, G. F., 120, 192, 193, 206.3 16 Gibbs, J. J., 104 Gibbs, R. D., 10 Gibian, H., 281 Gibson, S. G., 265, 290 Gielen, J., 204 Gilbert, I. M., 265, 290 Gilbert, J. D., 317 Gilbertson, G., 10 Giles, C. A,, 204
Gilgen, P., 38 Gillette, J. R., 205 Gilmore, J., 320 Girard, C., 237 Girault, Y., 40 Girigavallabhan, M., 23 1 Glass, R. W., 210 Glomset, J. A., 202 Glotter, E., 321 Goad, L. J., 121, 190, 194, 196, 198 Godtfredsen, W. O., 197 Goetz, N., 14 Goldblurn, A., 322 Goldstein, J . L., 172, 173 Goldzieher, J . W., 202 Golfier, M., 8, 233 Gomulka, M., 261 Gonplves de Lima, O., 138 Gondlez, A. G., 65, 115, 138, 182, 199,257,335 Goodwin,T. W., 144,190, 196, 198,207,209 Gopichand, Y., 21, 58 Gordon, G. C., 201 Gore, M. C-., 170 Gorovits, M. B., 225, 335 Goryunova, T. G., 45 Goto, T., 3, 96, 170 Gottlieb, H. E., 128 Could, R. G., 171 Goulston, G., 121, 194 Goutarel, R., 334 Cower, D. B., 190, 202,206 Goy, R. W., 201 Grad, W., 302 Graebe, J . E., 188 Graf, W., 129, 251, 263, 292 Graham, C. E., 201 Granchelli, F. E., 5 1 Grandi, R., 75, 183 Grandolini, G., 115 Grant, D. J. W., 140 Grant, D. M., 32, 164 Grant, J. K., 204 Grant, P. K., 97 Gravestock, M. B., 69 Gray, R. T., 10 Green, B., 239 Green, 0. C., 201 Green, T. R., 174 Greengrass, C. W., 70 Gregg, C. T., 2 16 Gregory, K. W. 172 Gregson, M., 15 Greiner, G., 241 Greiner, J. W., 205 Grenz, M., 32, 53, 85, 133 Grieco, C., 273 Grieco, P. A., 15, 60, 83 Griffin, J . F., 266 Griffin,J. R., 218 Griffith, 0. H., 274 Grigor, B. A., 102
Grimrne, L. H., 210 Grimsrud, E. P., 9 Grinenko, G. S., 285 Grisebach, H., 65 Groman, E. V., 217 Gross, J., 147 Grover, S. H., 5 Gruber, L., 226 Grunwald, C., 190 Grutzner, J. B., 4 Guarnaccia, R., 179 Guenard, D., 272 Guentert, T., 336 Guenther, E., 10 Guerriero, A., 92 Guest, I. G., 81 Guilhem, J., 121 Guiso, M., 23, 24 Gullo, V. P., 126 Gumulka, M., 293 Gunatilaka, A. A., 193, 194 Gunn, P. A., 109, 125 Gupta, P. K., 247 Gur’yanova, L. F., 160 Gusakov, V. N., 45 Gustafsson, J. A., 201, 206 Gut, M., 204, 222, 228, 229 Guthrie, J. P., 232 Guthrie, R. W., 305 Guttel, H. W., 199 Guziec, F. S., 40 Gvinter, L. I., 160 Haas, B. M., 201 Haefliger, W., 288 Haffer, G., 278, 282 Hagaman, E. W., 16,55, 128 Hagan, C. P., 28 Hahn, W. E., 40 Hajos, Z. G., 238, 266, 276 Hakli, H., 4 Hakozaki, M., 201 Hakozaki, S., 8 * Halbert, T. R., 274 Halirn, A. F., 13 Hall, M. S., 186, 187, 206 Halperin, G., 251, 322 Halsall, T. G., 115 Hammer, E., 14 Hamon, D. P. G., 39,41 Hamonniere, M., 105 Handa, V. K., 18 Handjieva, N., 25 Handrick, G. R., 49 Hands, D., 323 Handschin, H., 336 Hanni, R., 126 Hannus, K., 165 Hansbury, E., 190 Hansen, H.-J., 38 Hanson, J. R., 64, 71, 96, 97, 182, 188,216,222,236,265, 294 Hanson, S. W., 139
351
Author Index Hanus, L., 48 Hanzawa, Y., 227, 320 Hara, S., 310 Harada, N., 224 Harayama, T., 29 Harding, A. E., 63, 126 Harding, 1. M. S., 63 Harding, K. E., 8 Harding, R. W., 210 Harman, J. G., 206 Harney, D. W., 246 Harries, W. B., 197 Harrington, C. A., 200 Harris, T. M.,180 Harrison, C. R., 236 Harrison, D. M., 110 Harrison, F. A., 202 Hart, D. J., 82 Hart, P. A., 84 Hartmann, M. A., 194 Hartshorn, M. P., 42, 228, 262 Hartung, W., 185 Harva, O., 42 Hasan, M. U., 37 Hase, T., 132 Hasegawa, T., 180 Haseltine, R. P.. 36 Hasenhuettl, G., 78 Hashimoto, H., 72 Haslanger, M. F., 9 Hasnain, S., 204 Hata, C., 42, 43 Hatanaka, M., 143 Hattori, H., 45, 67 Hauser, D., 288 Hauser, E., 336 Haven, G. T., 200 Haxo, F. T., 146 Hayakawa, Y., 33 Hayashi, J., 8 Hayashi, K., 30 Hayashi, N., 218 Hayashis., 35,63,89,90, 184 Hayashi, T., 135 Hayashi, Y., 73, 102 Hayman, E. P., 209,210 Hayward, R. C., 102, 104, 105 Heap, R. B., 202 Heathcock, C. H., 83 Heckel, E., 77 Hecker, E., 113 Hedden, P., 188 Hedin, P. A., 179 Heerma, W., 49, 50 Heftmann, E., 169, 190, 199 Hegedus, L. S., 248 Heimgartner, H., 38 Heinstein, P., 213 Heller, R. A., 171 Helton, E. D., 202 Hemming, F. W., 166 Henc, B., 41 Henderson, M. S., 125 Hendrickson, J. B., 233
Henkels, W.-D., 23 Henry, H. L., 205,206 Hergenhahn, M., 113 Herin, M., 112 Herlem, D., 121, 334 Hernandez, R., 138, 199, 257, 335 Herz, J. E., 201, 216, 321 Herz, W., 76, 88,89,97 Herzog, H. L., 260, 293 Hesse, R. H., 260, 310, 316 Hethelyi, E., 218 Hewett, C. L., 265, 266, 290. 303 Heys, J. R., 118, 176 Hicks, K., 13 Hidai, M., 15 Higashi, T., 200 Higgins, M.J. P., 173 Higuchi, T., 102 Hikino, H., 76, 207, 208, 223, 300,331 Hikino, Y., 331 Hilgard. S., 134 Hill, H. M., 170 Hill, R. K., 42 Hillman, J. R., 185 Hilscher, J. C. 242, 281 Hiltunen, R., 218 Hinman, D. F., 274 Hiraga, K., 110, 11 1, 265 Hirai, H., 41 Hirata, T., 11, 124, 178 Hirata, Y., 68, 77, 113, 119, 214, Hirayanagi, S., 15 Hiroi, K., 83, 252 Hirose, Y.. 7 1 Hirota, H.. 130, 131 Hirotani, M., 202 Hirotsu, K., 102 Hirth, C. G., 203 Hiyama, T., 31 Hlubucek, J. R., 47 Ho, C. M.,83 Ho, T.-L., 256 Hobbelen, P. M. J., 244, 286 Hobbs, P. D., 21 Hochberg, R. B., 246 Hodge, P., 236, 254, 322 Hodgson, G. L., 60 Hodler, M., 152 Hofle, G. A., 288 Hoellinger, H., 310 Hoff, H. G., 200 Hoffman, W. H., 226,307,320 Hoffmann, E. G., 41 Hoffmann, J. A., 208 Hohne, E., 110 Holden, C. M. Y., 35,41 Holick, M. F., 314 Holmlund, C. E., 209 Homberg, E. E., 197 Honda, M., 227, 320
Honig, B., 165 Honma, S., 202 Hooz, J., 15 Hopkins, H. P., 38 Hopley, S. M., 218 Hoppen, H. O., 202 Hoppmann, A., 94 Horhold, C., 203 Horibe, I., 4, 76 Horie, T., 137 Horn, D. H. S., 207, 330 Hornaman, E. C., 7 Homing, E. C., 203 Hornung, R., 4 Horrocks, D. L., 217 Horster, H., 218 Horvath, A., 140 Horvath, G., 202, 28 1 Horwell, D. C., 254,322 Hosoda, H., 223,265, 294 Hosoya, E., 51 Hosozawa, S., 100 Hotchandani, S., 165 Hotta, Y., 121 Houdewind, P., 253, 304 Houghton, E., 25 Houminer, Y., 234,244 Hovenkamp-Obbena, R., 210 Howard, B., 80 Howard, B. M., 64 Howell, C. R., 66 Howes, J. F., 49 Hrutfiord, B. F., 218 Hrycay, E. G., 206 Hsieh, W.-C., 37 Hsuing, H. M., 192 Hsu, H. Y., 113 Huang, E., 36 Huang, F.-C., 10, 216 Haung, H.-C., 75 Hubbell, J. P., 71 Hubert, A. J., 288 Hubert-Brierre, Y., 334 Hudec, J., 223, 224, 225 Hudson, A. M., 200 Hudson, H. P., 297 Huffmann, J. W., 104 Hufford, C. D., 75 Hughes, C. R., 81 Hughes, D. L., 80 Hughes, P. R., 13, 180 Huhtaniemi, I., 206 Hui, W. H., 113, 133, 138 Hulcher, F. H., 204 Huneck, S., 63 Hung, H. K., 109 Hung, Ph. D., 110 Hurley, J. C., 85 Husson, H.-P., 249 Hutchings, M.G., 30 Hutchins, R. O., 9 Hutchinson, S. A., 184 Hyer, R. C., 165 Hylemon, P. B., 204
Author Index
352 Iacobelli, J. A., 316 Iavarone, C., 23, 24 Ibuka, T., 7 5 Ichihara, A., 72 Ichikawa, N., 20 Ignasiak, T., 218 Ignatiadou-Ragoussis, V., 120, 254, 327 Iitaka, Y., 121, 123, 124 Ikeda, A,, 8 Ikekawa, N., 197, 198, 221, 241,314,316,317,318,319, 320,327 Imai, K., 56, 175 Imai, S., 103 Imaizuma, F., 15 Imaizurni, S., 4 0 Imakura, Y., 135 Imamura, T., 10 Immirzi, A,, 9 5 Inagaki, M., 332 Inano, H., 204 Inayama, S., 5 1 Ingleman-Sundberg, M., 206 Innocenti, S., 336 Inone, M., 342 Inoue, S., 7, 167 Inoue, Y., 164 Inouye, H., 24, 25 Inubushi, Y., 29, 143 Ioffe, N. T., 165 Ireland, C., 20, 6 4 Ireland, R. E., 6, 129 Iriate, J., 285 Irikawa, H., 119 Isaeva, 2. G., 46 Isakov, V. V., 135 Isherwood, F. A., 156 Ishida, M., 105 Ishida, T., 202, 205 Ishiguro, T., 114 Ishihara, M., 202 Ishihara, T., 153 Ishikawa, M., 241, 295, 310, 315 Ishiwatari, H., 15 Ishiyama, J., 4 0 Isihara, M., 32, 48, 158 Island, D. P., 206 Isobe, K., 142, 143, 218 Isobe, T., 107 Israel, H. W., 217 Ito, M., 29 Itoh, M., 18, 204, 21 1 Ito, S., 3, 96, 112, 170 Ito, Y. L., 163, 21 1 Ives, D. A. J., 316 Iwata, N., 124 Izuka, Y., 299 Izumi, G., 10 Jackson, B., 38 Jacob, J., 32, 133 Jacob, K., 233. 299
Jacquesy, J.-C., 263, 264, 267, 301 Jacquesy, R., 263, 264, 267, 301 Janes, N. F., 13 Jarman, T. R., 118, 176, 193, 194 Jarolim, V., 13 Jaswal, S. S., 11 1 Jautelat, M., 4 Jeanloz, R. W., 166 Jefferies, P. R., 100, 107, 110, 112, 115, 188 Jeffery, E. A., 31 Jeffery, J., 203, 244 Jefford, C. W., 38 Jeger, O., 162,271 Jennings, P. W., 8 5 Jennings, R. C., 56, 186, 187, 206 Jennings, W. H., 165 Jensen, H. P., 29 Jensen, S. R., 2 3 Jentzsch, K., 199 Jetuah, F. K., 306 Jin, H., 207 Johansen, J. E., 146, 151, 153 Johannes, B., 152 Johnson, A. L., 4 0 Johnson, J. H., 37 Johnson, P., 198 Johnson, R. A., 62 Johnson, R. C., 191, 200 Johnson, R . C., 200 Johnson, W. E., 46 Johnson, W. S., 69, 279 Jolly, J., 293 Joly, G., 263, 264 Jommi, G., 95, 181 Jones, A. J., 37 Jones, B. E., 148 Jones, C. A., 177 Jones, D. N., 238,328 Jones, Sir E. R. H., 233, 296 Jones, J. G., LI., 247 Jones, J. P., 191 Jones, R. B., 97 Jones, S. B., 218 Joshi, B. S., 60, 138 Joshi, G. C., 41 Joshi, K. C., 23 Joshi, P. P., 147 Judy, K. J., 56, 186, 1 8 7 , 2 0 6 Julieta, R., 319 Jung, D. H., 241 Junghanns, J. U., 24 Junghans, K., 239,280 Junker, A,, 1 5 Juonen, S., 218 Junod-Busch, U., 23 Kabalka, G. W., 256 Kabuto, C., 103 Kacher, M., 9
Kagami, M., 6 Kagan, H. B., 10 Kahn, M.N., 322 Kaiser, F., 199 Kajtar, M., 202 Kakis, F. J., 120, 254 Kakisawa, H., 137 Kakuta, S., 241, 295 Kalkman, M. L., 200 Kallos, J., 111 Kalvoda, J., 251, 308 Kalyanaraman, P. S., 89, 101 Kamano, Y., 3 4 0 , 3 4 1 , 3 4 2 Kambegawa, A., 201,285 Kamikawa, T., 26 Kammann, G., 340 Kampare, R., 4 Kan, K. W., 201 Kandasamy, D., 9 Kandutsch, A. A., 172,200 Kaneko, C., 241,295,3 1 0 , 3 1 5 Kaneko, H., 148 Kapadi, A. H., 11 1 Kapil, R. S., 27, 147 Kaplanis, J. N., 208 Kapoor, S. K.,4 0 , 6 9 Kaposi, P., 218 Karavolas, H. J., 201 Karlmar, K. E., 205 Karlson, P., 208 Karlsson, B., 8 8 Karlsson, R., 112 Karplus, M., 165 Karstens, T., 225 KarvaS, M., 271 Kashman, Y.,112 Kasprzyk, Z., 202 Kasuga, R.,148 Katagiri, T., 15 Katayama, C., 113 Katayama, T., 64 Kates, M., 165 Kato, K., 272 Kato, N., 100 Kato, T., 28, 200 Kato, Y., 241, 320 Katoh, Y.,130 Katsui, N., 80 Katsuki, H., 193 Katzenellenbogen, J. A., 6 Katzman, P. A,, 201 Kaur, J., 18 Kawahara, F. S., 201 Kawahara, N., 261 Kawai, K., 265 Kawai, K.-I., 123, 124 Kawarada, Y., 202, 285 Kawase, Y., 200 Kazabski, A., 292 Kazakos, A,, 243 Keeley, D. E., 21 Keely, S. L., 7 5 Kellie, G. M.,3 4 Kelly, R. B., 109, 316
Author Index Kelner, L., 225 Kergomard, A., 27, 30,37, 4 1 Kerr, V. N., 216 Kessar, S. V., 331 Kesselaar, H., 328 Khalil, A. H., 158 Khan, M. A., 133 Khan, M. N., 254 Khanra, A. S., 21 Khare, A., 145 Khattak, I., 264, 292 Kheifits, L. A., 4 , 4 1 Khmelnitskaya, V. V., 46 Kho, E., 2 0 , 3 3 Khong, P. W., 133,140 Khristoforov, V. L., 154 Khukhryansky, V. G., 251 Khuong-Huu, F., 1'21,334 Khuong-Huu, Q., 222, 249, 258,334 Kienzle, F., 152, 161 Kierstead, R. W., 305 Kieslich, K., 281 Kikuchi, K., 265 Kikuchi, T., 137,332 Kim, P. A., 201 Kim, R. S., 202 Kimland, B., 47 Kimpara, K., 143 Kimura, T., 151 Kimura, Y., 110 King, J. F., 10 King, R. W., 5, 119, 150, 164 Kinghorn, A. D., 113 Kingsford, M., 13 Kinuyama, Y., 201 Kirdani, R. Y., 202 Kirk, D. N., 203,221,224,228, 244,262,264,292,307 Kirkup, M., 1 0 Kirksey, J. W., 115 Kirsten, E. S., 172 Kise, H., 17 Kishimoto, T., 18 Kitadani, M., 103 Kitagawa, I., 99, 122, 135, 141 Kitagawa, Y., 118 Kitahara, T., 153 Kitahara, Y., 28, 103 Kitatsuji, E., 306 Kitazawa, K., 141 Klein, J., 243 Klein, P. D., 198 Klimek, J., 201 Kliment, M., 134 Klimov, A. N., 202 Klinot, J., 134 Kloss, P., 23 Kluge, A. F., 13 Klyne, W., 3 Knaggs, J. A., 226 Knapp, F. F., 190, 192, 234, 324 Knedel, M., 233,299
353 Knight, D. W., 53, 55 Knoll, W., 59, 212 Knox, J. R., 107, 110, 188 Knox, S. D., 238 Knuppen, R., 202 KO, P. D. S., 122 Kobayashi, M., 218, 325 Kobayashi, S., 17 Kobayashi, T., 28 Kobayashi, Y., 217, 227, 320 Koch, H. J., 129 Kochakian, C. D., 204 Kocienski, P. J., 10 Kocjan, R., 334 Kocor, M., 261, 292, 293, 305 Kocovsky, P.,290 Kodama, M., 112 Kodama, J., 9 6 Kodicek, E., 319 Koenig, R. T., 10 Konst, W. M. B., 158 Kohl, H., 101 Kohler, B., 204 Koike, S., 113 Koizumi, N., 221, 241, 317, 319,320 Koizumi, T., 306 Kojima, M.,267 Kok, J. G. J., 161 Kokami, K., 30 Koker, M. E. S., 139 Koletar, J., 245, 287 Kolleck, M., 6 2 Kollman, P. A., 222 Kollman, V. H., 165, 216 Komae, H., 218 Komatsu, T., 165 Komeichi, Y., 342 Komeno, T., 222 Konda, Y., 236 Kondo, K., 1 6 , 5 8 Kondo, N., 124 Kondon, Y., 114 Kone, M., 9 8 Konishi, T., 217 Konno, C., 7 6 , 2 2 3 Kooiman, P., 24 Koolman, J., 208 Kopp, B., 199 Koren, E., 210 Kornel, L., 201 Kornig, D., 5 9 Kosela, S., 21 1 Koshoev, K. K., 300, 331 Kosmol, H., 281 Kotze, J. P., 200 Koudogbo, B., 24 Kovanen, P. T., 200 Kowallik, W., 21 1 Kowalski, C. J., 129 Kozhin, S. A,, 30 Kozikowski, A. P., 157
Kozina, M. P., 4 5 Kozlov, E. I., 165 Kraaipoel, R. J., 201 Kramer, C. M., 63 Kramer, H. F., 4 9 Kramer, R. E., 205 Krecek, V., 131 Krejci, Z., 48 Kresze, G., 31 Kriedemann, P. E., 184 Krimer, M. Z., 14 Kritchevsky, D., 204 Krivoshchekova, 0. E., 14 Kroszczyfiski, W., 261, 293, 305 Kriiger, C., 41 Kruger, G., 336,338 Kruger, G. J., 132 Krupa, S., 169 Krymskaya, E. B., 4 , 4 1 Krzemien, J. R., 200 Kuball, H.-G., 225 Kubelka, W., 199 Kubik, A., 46 Kubota, K., 157 Kubota, T., 26, 107, 139 Kuchin, A. V., 4 3 Kuczynski, H., 3 1 , 4 3 , 4 6 Kuder, J. E., 274 Kiinstler, K., 2 3 Kiippers, F. J. E. M., 50 Kuhl, H., 233 Kuhnert, L., 180 Kuksis, A., 202 Kulig, M. J., 217, 240, 275 Kulkarni, A. B., 47 Kulkarni, A. K., 4 Kulshreshtha, D. K., 123 Kumadaki, I., 227, 320 Kumamoto, J., 15 Kumar, N., 130 Kumazawa, S., 28 Kummel, H. W., 210 Kun-She Low, 9 7 Kupchan, S. M., 102, 113, 114, 128 Kurihara, H., 112 Kuriyama, K., 122,224,332 Kurozumi, S., 252 Kushi, Y.,6 3 Kusumi, T., 137 Kuswik, G . , 39 Kuwata, M.,29 Kuz'menko, I. I., 305 Kuznetsova, G. A., 218 Kuzovkina, I. N., 218 Kwart, L. D., 16 Labovitz, J. N., 141 Lacadie, J. A., 128 Lacroix, E., 201 Lajsic, S. D., 97, 111 Lakshmanan, M. R., 172 Lal, B., 226,307, 320
354 Lalande, R., 44 Lallemand, J. Y., 44 Lam, H. Y., 320 La Mar, G. N., 222 Lamazoukre, A. M., 35 Lamy, P., 325 Lan, N. T., 38 Land, E. J., 165, 168 Landrey, J. R., 198 Lane, G. A., 105, 225 Lane, M. D., 170, 171 Lang, S., 223 Langbein, G., 282, 31 3 Lang-Feulner, J., 210 Lanthier, A., 201 Laonigro, G., 234,322 Lapierre Armande, J. C., 304 Larson, D. B., 35 Lassak, E. V., 12 Lauder, H. St. J., 21 Laurent, A., 31 Laurie, R. N., 14 Lavie, D., 122, 124, 127, 321 Lawrence, L., 218 Lax, E. R., 200 Layne, D. S., 203 Lazare, S., 117 Leblanc, R. M., 165 Lee, K.-H., 75, 89 Lee, L. F. H., 10, 216 Lee, T., 210 Lee, Y. C., 138 Leemhuis, J., 244, 286 Leets, K. V., 14 Lefebvre, G., 202 Lefebvre. Y., 288 Leferink, J. G., 201 Le Goff, M.-T., 270 Lehoux, J. G., 206 Le Mahieu, R. A., 305 Lernoine, G., 221 Lernpa-Krzymien, L., 203 Lenkey, B., 199 Lenton, J. R., 190, 196 Lentz, C. M., 87 Lenz, G. R., 270 Lesins, K., 218 Letourneux, Y., 204,222,228 Leusen, I., 201 Leveille, G. A., 190 Lever, 0. W., 288 Levi, Sh., 327 Levin, R. H., 181 Levisalles, J., 236, 243, 250, 252,284 Levy, s., 49 Lewis, A. J., 299 Lewis, H. P., 201 Lewis, K. G., 133, 140 Lewis, M. K., 190 Lewton, D. A., 328 Li, M.-M., 113, 133 Liaaen-Jensen, S., 145, 146, 147, 148, 151, 152, 153
Author Index Liang, J. S. C., 310 Liang, X. T., 47 Liau, H. T. L., Y7 Libertini, L., 225 Lichtenthaler, H. K., 210 Liddle, G. W., 206 Lieberman, S., 246 Liepins, E., 4 Lifshitz, A,, 147 Lightbourn, J. R., 319 Limacher, J., 157 Lin, G. H. Y., 64 Lin, K. C., 100 Lin, T. J.. 213 Lin, Y,. Y., 216, 221, 317 Lincoln, D. N., 223 Linde, H. H. A., 336 Lindley, P. F., 269 Lindner, H. J., 95 Lindquist. J., I63 Lion, F., 21 1 Lipinski, C. A,, 129 Lipnicka, U., 44 Lischewski, M., 11 1 Lisitsa, L. I., 285 Lisy, J. M., 106 Liu, D.-W., 239 Liu, J. J., 100 Liu, K.-T., 37 Liu, R. S. H., 153, 161 Liu, W.-C., 112 Lloyd-Jones, G. J., 207 Lo, M. M. L., 228 Lockley, W. J. S., 198, 207 Loder, J. W., 102 Loeser, B. K., 201 Loev, B., 49 Lofland, H. B., 204 Lomax, J. A., 21 1 Lombardi, P., 160 London, R. E., 216 Longcope, C., 202 Longevialle, P., 258 Lookhart, G. L., 155 Loomis, G. L., 78 Loomis, W. D., 11, 174, 216 Losman, D., 112 Lothrop, D. A., 172 Louis, J.-M., 8, 233 Lousberg, R. J. J. C., 50, 175 Loveys, B. R., 184 Low, J., 206 Low, L. K., 50 Lowel, M., 173 Lower, E. S., 275 Lu, M. C. H., 330 Luche, J. L., 10 Luchter, K., 322 Luthy, C., 251, 263, 292, 302 Luhadiya, N. K., 330 Lui, H. J., 35 Luk, K., 133 Lukacs, G., 96, 121, 187,222 Lundstrom, K., 163
Lur’i, F. A,, 285 Lusinchi, X., 334 Lutsky, B. N., 1’92 Ly, U. H., 301 Lyons, C. W., 125 Lysenkov, V. I., 3 1 Maatschappij, B. V., 21 Mabry, T. J., 41, 75, 218 McAlees, A. J., 106, 108, 109 McCallum. N. K., 49 McCarry, B. E., 69 McChesney, J. D., 101 McCrindle, J., 106, 107 McCrindle, R., 99, 108, 109, 125, 126 McDerrnott, J. C. B., 209 Macdonald, I. A., 204 McDonald, P. D., 246 McDonough, G. R., 38 Mace, M. E., 66 McGarry, J. D., 200 McGhie, J. F., 254, 306, 322 McGlynn, S. P., 35 MacIntyre, J., 110 McKenzie, T. C., 129 McKillop, T. F. W., 72 Mackova, Z., 304 McMartin, C., 200 McMillan, C., 218 MacMillan, J., 106, 109, 110, 188, 189 McMillan, J. A,, 70 McMurry, J. E., 84, 256 McPhail, A. T., 13,75,89,260, 293 Macpherson, A. S., 49 MacSweeney, D. F., 60 Madhosingh, C., 200 Maeda, M., 267 Maeda, T., 63 Magno, S., 89 Magnus, P. D., 10,2 1,227,248 Magnusson, G., 73 Magot, T., 191 Mah, H., 245,287 Mahajan, D. K., 206 Mahajan, J. R., 8 Mahajan, R. K., 331 Mahato, S. B., 132, 133 Mahdi, H., 203, 244 Maheshwari, K. K., 250, 302 Mahoney, T. J., 107 Mahony, D. E., 204 Maillard, B., 44 Mairanovskii, V. G., 165 Maiti, B. C., 132 Majumder, P., 130 Makhubu, L. P., 266 Makino, S., 33 Makk, N., 281 Maksimov, V. I., 285 Malhotra, R. K., 260, 303, 330 Mallaby, R., 170
355
Author Index Mammato, D. C., 225, 3 12 Manabe, Y., 14 Manchand, P. S., 100, I14 Mandal, K., 164 Mander, L. N., 68, 116 Mangoni, L., 125, 133, 134, 234,235,244 Manhas, M. S., 226, 253, 304, 307,320 Mann, J., 11, 177 Manning, T. D. R., 31 1 Manukov, E. N., 32 Marazano, C., 258 Marchelli, R., 213 Marchesini, A., 75, 183 Marekov, N., 25 Marhenke, R. L., 38 Mariano, P. S., 45 Marini-Bettolo, G. B., 138 Marini-Bettolo, R., 2 3 Markovetz, A. J., 179 Markwell, R. E., 104 Marquez, L. A., 321 Marr, D. H., 5 Marriott, T. B., 274 Marroquin, J., 133 Marsh, W. C.,99,125,265,324 Marshall, D. J., 258 Marshall, D. R., 129 Marshall, J. A., 28, 73, 81, 83, 90 Martelli, P., 336 Marti, F., 271 Martin, G. C., 109, 189 Martin, H. F., 205 Martin, J., 72 Martin, J. C., 229 Martin, J. D., 65, 115, 182 Marumo, S., 56,67, 175 Marx, J . N., 61, 156 Masaki, N.. 137 Masaki, Y.,6 0 Masamune, T., 29 Mashio, F., 14 Massiot, G., 297 Massy-Westropp, R. A,. 41 Masuda, H., 103 Masuda, M., 261 Masuya, H., 265 Matern, S., 206 Mathews, R. J., 5 Mathieson, D. W., 298 Mathubara, Y., 41 Matsubara, Y., 18, 29, 35, 42, 43 Matsui, A., 42 Matsui, M., 14, 153, 201 Matsuki, Y., 9 6 Matsumoto, K., 201 Matsumoto, M., 16 Matsumoto, T., 72, 103, 272 Matsunaga, A., 8 0 Matsuo, A., 35,63,89,90,184 Mattice, W. L., 35
Mattox, J., 34 Matwiyoff, N. A., 216 Maudsley, D. V., 217 Maume, B. F., 201, 217 Maumy, M., 237 May, E. L., 49 May, L. M., 8 Mayer, H., 152 Mayol, L., 8 9 Mazur, Y., 222, 234, 271, 314, 318 Meakins, G. D., 233, 296 Mechoulam, R., 49, 322 Megges, R., 340 Mehrotra, A. K., 3 9 Mehta, G., 7, 38, 40, 69, 8 8 Meier, A., 223 Meier, W., 277 Meinwald, J., 13, 260, 293 Meister, W., 223 Meisters, A., 31, 246, 302 Mellor, J . M., 97 Mellows, G., 115 Melnikova, V. I., 299 Melvin, L. S., 9 Menard, R. H., 205 Mende, U., 237,288 Mendelsohn, R., 165 Menini, E., 204 Menis, O., 241 Menn, J. J., 14 Mercer, E. J., 121, 194, 197 Mercker, H.-J., 9 5 Merlini, L., 4 9 Meshulam, H., 122, 124, 127 Messner, B., 170 Meteshkina, L. P., 4 5 Metzner, K., 225 Meyer, K., 340 Meyer, R., 246 Meyers, R. F., 6 9 Mezzetti, T., 139 Micheli, R. A., 238, 276 Middleditch, B. S., 201 Middleton, E. J., 207 Midgett, R. J., 205 Midgley, J. M., 265, 323, 324 Mielnarek, I., 316 Miettinen, T. A.. 200 Migicovsky, B. B.. 200 Mihashi, S., 105 Mikhalkovich, K. A., 3 2 Miki, T., 265 Milborrow, B. V., 91,149,156, 185 Milborrow, M., 144 Miles, D. H., 6 9 Miller, D. B., 288 Miller, R., 154 Miller, R. B., 78 Miller, R. W., 1 3 Milliet, A., 121 Milliet, P., 334 Mills, J. S., 9 8
Mills, R. W., 39, 60, 81, 108 Milne, G. W. A., 225 Milner, J . A., 216 Minale, L., 92,Y 3,94,119,208 Minato, H., 6 4 Mincione, E., 238 Minder, R. E., 161 Minemathu, W.,41 Miropol’skaya, M. A., 18, 159, 160 Mirrington, R. N., 59, 107 Misiti, D., 244 Misra, T. M., 164 Missen, A. W., 105 Mitchell, E. D., 179 Mitlin, N., 179 Mitra, M. N., 274, 314 Mitra, R. B., 21 Mitropoulos, K. A., 192, 193, 204,206 Mitschelen, J . J. 217 Mitsubashi, H., 325 Mitsuhashi, H., 261 Mitsui, T., 27 Mitsuishi, E., 343 Mittal, R. S. D., 10, 216 Miura, I., 126 Miwa, T., 25, 26, 27, 306 Miyabo, S., 201 Miyakado, M., 4 1 Miyakoshi, T., 14 Miyamoto, M., 9 7 Miyamoto, R., 34 Miyauchi, M., 142 Miyaura, N., 18 Miyoshi, Y., 164 Mizutani, S., 201 Mohler, J . H., 165 Mole, T., 31, 246, 302 Mompon, B., 83 Monaco, P., 125, 133, 134, 244 Money, T., 39, 55, 60, 8 1 Mongiorgi, R., 49 Monneret, C., 249 Monseur, X., 334 Monteiro, H. J., 9 Monti, S. A., 75 Mooney, R. A., 170 Moon Li, M., 138 Moore, C. J., 265, 324 Moore, R. E., 20, 179 Moore, R. J., 203 Morales, F., 133 Moran, V. C., 10 Morand, P., 203 Moreau, J. P., 192, 194, 266, 323 Morgan, E. D., 233 Mori, H., 237, 289, 292, 302, 33 1 Mori, K., 14, 15, 18 Mori, M., 210 Moriarty, R. M., 320
Author Index
356 Morii, S., 7 Morikawa, A., 7 Morimoto, A,, 142, 143 Morin, R. J., 202 Morisaki, M., 197, 198, 221, 241,314,316,317,318,319, 320,327 Moriyama, T., 261 Moriyama, Y., 86, 130 Morozova, L. S., 285 Morris, D. G., 4, 3 6 Morrison, G. A., 230 Morrison, J. D., 5 Morton, D. R., 6 9 Mosbach, E. H., 200, 206, 217 Moser, J.-F., 129 Moskvichev, V. I., 4, 4 1 Moss, G. P., 145, 149 Motl, O., 6 Mott, R. L., 217 Mouk, R. W., 261 Msonthi, J. D., 328 Mudd, A., 262 Miiller, B. L., 157 Mueller, K. H., 6 Miiller, W. E., 233, 296 Mui, M. M., 202, 205 Mukai, T., 34 Mukaiyama, T., 7, 17 Mukerjee, S. K., 147 Mukherji, S. M., 272 Muks, E. A., 14 Mulheirn, L. J., 225 Muller, B., 64, 212, 213 Mummery, R. S., 2 18 Munakata, K., 100 Munns, T. W., 201 Murae, T., 113 Murai, N., 214 Muraleedharan, N. V., 32 Murata, T., 225 Murofushi, N., 97, 110, 189 Murphy, G. J . P., 188 Murphy, R. C., 241 Murray, A. M., 4, 3 6 Murray, R. D. H., 108 Musamune, T., 8 0 Muscio, 0. J., 12 Mushfiq, M., 253 Musser, J. H., 84 Mustich, G., 133 Myant, N. B., 204, 206 Mynderse, J. S., 20, 33 Naf, F., 91, 157 Nagai, Y., 6 Nagano, H., 86 Nagao, Y.,189, 218 Nagasampagi, B. A., 267 Nagasawa, K., 257, 301, 310 Nagasawa, T., 13 Nagase, T., 2 1 Nagato, K., 139 Nagel, A., 280
Nagel, M., 177 Naik, C. G., 77 Nair, M. S. R., 47, 73, 177 Naito, I., 14 Nakachi, K., 165 Nakamoto, T. 8 9 Nakamura, E., 9 9 Nakanishi, K., 3, 96, 126, 170, 223,224 Nakatani, N., 7 5 Nakatani, Y., 157 Nakayama, M., 35, 63, 89, 90, 184 Nam, N. H., 3 10 Nambara, T., 202, 223, 285, 343 Nambudiry, M. E. N., 38 Nanasi, P., 199 Narayanan, C. R., 4, 267 Narwid, T. A., 3 16, 3 18 Narzollaev, A. S., 11 1 Nasini, G., 100 Natori, S., 3, 96, 120, 170 Naves, Y. R., 19, 27 Naya, Y., 20 Nayak, V. R., 7 0 Nearn, R. H., 102 Nedelec, L., 249, 286 Neef, G., 278 Neeman, I., 112 Neeman, M., 230 Nelson, J. A., 250. 273, 302 Nenzil, R. W.. 4 1 Nepokroeff, C. M., 172 Nervi, F. O., 200 Nes, W. R., 198 Ness, G. C., 172 Nestrick, T. J., 6 Neumiiller, 0.-A., 273 Newkorne, G., 35 Newman, M. S., 228 Ng, K. K., I13 Ngan, H.-L., 119, 173 Nicholas, H. T., 191, 198, 200 Nicholas, J. C., 217 Nicholas, T. E., 201 Nicholson, W. E., 206 Nicklin, P. D., 298 NicoarP, E., 153 Nicolau, G., 217 Nielson, A. J., 102 Nielsen, B. J., 23 Nigg, H. N., 208 Nikiforova, A. A., 202 Nikkila, E. A., 200 Nishi, A., 210 Nishiguchi, I., 28 Nishimura, H., 24 Nishinaga, T., 332 Nishioka, T., 25 Nishizawa, M.. 73 Nitsche, H., 146 Nitta, K., 267 Nitta, M., 28
Niwa, H., 119 Niwa, M., 137,332 Noble, T., 20 Noda, Y., 6 3 Node, M., 218 Noguchi, M., 27, 148 Noguez, J. A., 8 3 Nokubo, M., 285 Nolte, H. J., 225 Noma, Y., 12 Nomine, C., 204 Nommik, H., 218 Nonomura, S., 12 Nordstrom, J. L., 2 17 Norman, A, W., 205, 206,314 Norman, L. R., 6 1 Normant, J. F., 9 Norte, M., 65, 115, 182 Norton, S. J., 13 Novak, W., 207 Novikova, N. V., 305 Novosel’skaya, I. L., 335 Nowak, N. V., 201 Nowock, J., 208 Noyori, R., 33 Nozaki, H., 7, 20, 31, 52, 63, 118 Nozoe, S., 3, 96, 170 Nucea, R., 2 17 Nukina, M., 67 Nuretdinova, 0. N., 4 6 Nybraaten, G., 145 Nyfeler, R., 71, 182 Oba, K., 173 Obermann, H., 105 Ochi, M., 139 Ochiai, K., 139 Ofner, P., 201 Ogawa, H., 267 Ogihara, Y., 123 O’Grodnick, J. S., 191, 229, 230 Ogura, K., 174 Ohizumi, Y., 208 Ohloff, G., 91, 157, 160, 162 Ohnishi, R., 42 Ohnishi, Y., 6 Ohno, A., 6 Ohno, N., 41 Ohsawa, A., 227,320 Ohta, Y., 63 Ohtsuka, Y., 97, 105 Oh-uchi, R., 237, 289,302 Ojima, I., 6 Okamura, W. H., 314,320 Okita, T., 33 Okogun, J. I., 125 Okuda, T., 113 Okukado, B. V., 144 Okukado, N., 151 Okumura, Y., 119 Okura, H., 18 Okuyama, T., 223, 331
357
Aitrilor Index Okjnictak, €3.. 39 Olesen, W. H., 204 Olguin, L. M., 133 Olin, C . R., 274 Olsen, D. O., 228, 288 Olson, R. E., 167 Omichi, H., 14 Onan, K. D., 75,89 Onda, M., 236 Onisko, B. L., 320 Ono, T., 276 Onozawa, K., 15 Opliger, C. E., 167 Oppenauer, R. V., 287 Orgiyan, T. M., 99 Oritani, T., 6, 149 Orr, J. C., 201, 203, 236 Orsini, F., 95 Ortiz, A., 201 Osawa, Y., 202, 203, 221 Oseroff, A. R., 165 Oshima, K., 20, I18 OSianu, D., 153 Osman, A. M., 139 Ott, D. G., 216 Ottersen, T., 49 Ottolenghi, M., 165 Ouchi, R., 292 Ourisson, G., 62, 90, 96, 182, 194,317 Overton, K. H., 56, 174, 234 Ozainne, M., 55 Paaren, H., 320 Paasivirta, J., 4 Pachaly, P., 24 Padieu, P., 217 Padolina, W. G., 75, 218 Pagnoni, U. M., 75, 183 Paisley, J. K., 255 Paknikar, S. K., 77, 182, 184 Pak-tsun Ho, 112 Pallos, F. M., 14 Palumbo, G., 125, 244 Pancrazi, A., 258 Pande, L. M., 41 Pandit, U. K., 253, 254, 299, 304 Panizo, F. M., 1OY Panveliwalla, D. K., 169 Paquer, D., 40 Parashar, V., 303 Parekh, A. C., 241 Parker, W.. 72 Parks, L. W., 194 Parnell, J. C., 133 Parrilli, M., 235, 322 Parrish, D. R., 238, 276, 277 Parry, R. J., 69 Pars, H.G., 51 Partridge, J. J., 73, 318 Pascard-Billy, C., 105 Pascual, J., 31 Pasechnik, G. S., 105
Passannanti, S., 100 Patchett, A. A., 316 Patel, K. M.,249, 256, 261 Paternostro, M. P., 100 Patoiseau, J.-F., 267 Pattenden, G., 11, 53, 55, 75, 119, 150, 178 Patterson, G. W., 193, 198 Patterson, R., 188 Patterson, R. B., 274 Patwardhan, V. V., 201 Paul, D., 303 Paul, D. P., 201 Paul, I. C., 70 Pauling, H., 41 Paulissen, P., 288 Paust, J., 164 Pavanasasivam, G., 130 Payne, T. G., 100 Payne, W. W., 15 Peach, C. M., 264 Pechet, M. M., 260,310 Pedersen, R., 148 Pelc, B., 316 Pelletier, S. W., 97, 111 Petter, A., 30 Pemberton, P. W., 97 Penasse, L., 204 Pendlebury, M. H., 269 Pensar, G., 165 Pentegova, V. A., 100 Pepin, Y., 249 Pereira, J. L. C., 284 Perelman, D., 243 Pereyre, M., 6 Perez, A. E., 201 Perez-Palacios, G., 201 Perkins, J., 49 Persicaner, P. H. R., 10 Pertsemlidis, D., 169 Pesaro, M.,83 Pete, J,.-P., 271, 273, 320 Peter, M. G., 56, 186 Peterson, D., 287 Peterson, P. E., 230 Pettit, G. R., 340, 341, 342 Pettler, P. J., 198 Petrow, V., 244 Peytremann, A,, 206 Pfaffenberger, C. D., 30 Pfander, H., 152 Pfenninger, H., 129 Pfoertner, K. H., 154 Pharis, R. P., 189 Philippson, R., 302 Phillipou, G., 256, 289 Phillips, G. T., 120, 191 Phillips, I., 97 Phillips, L., 269 Phillips, L. R., 18 Phinney, B. O., 109, 188, 189 Piancatelli, G., 248 Piatkowski, K., 31, 46 Pichet, L., 310
Pickenhagen, W., 157 Picket, J. A,, 12 Picot, A,, 334 Piestert, G., 199 Pietrzyk, D. J., 163 Pigott, H. D., 9 Pilette, J. F., 248 Pilgrim, H., 202 Pillai, N. K., 255 Pilotti, A.-M., 88 Pinhey, J. T., 255, 31 1 Piozzi, F., 100, 106 Pipithakul, T., 41 Piraux, M., 248 Pitt, C. G., 50 Pitton, G., 55 Pitzele, B. S., 17 Pivnitsky, K. K., 241, 299, 31 1 Platonova, A. V., 280 Plattier, M., 28 Plettman, S. G., 218 Ploner, K. J., 17 Plotti, G., 204 Pochan, J. M., 274 Pochini, A., 213 Podratz, K. C., 201 Poisson, J., 105 Pokrywiecki, S., 221 Pollow, B., 204 Pollow, K., 204 Polonsky, J., 96, 128, 187 Polyakova, N. P., 45 Pomponi, M., 138 Ponsold, K., 227,23 1,258,289 Poole, C. F., 283 Popa, D. P., 97,99, 105 Popjak, G., 119, 172, 173 Poplawski, J., 88 Popli, S. P., 27 Popov, S., 24, 25 Popova, N. V., 251 Popplestone, C. R., 11, 178 Portella, C., 273, 320 Porter, J. W., 172 Portins, ti.,340 Portland, L. A., 238,276 Posner, G. H., 78,87 Potier, P., 249, 297 Pottier, E., 29 Poucher, W. A., 10 Poulter, C. D., 12 Pouzar, V., 131 Powell, G. P., 224 Powers, T. J., 324 Poxton, I. R., 21 1 Poyser, J. P., 317 Pradhan, D. K., 132 Pradhan, S. K., 23 1 Pragnell, J., 233, 296 Prakash, L., 23 Prakash, S. R., 267 Pratt, G. E., 187 Preedy, J. R. K., 202 Prestwich, G. D., 141
358 Previtera, L., 133, 134, 235, 244 Price, G. M., 208 Price, K. R., 80 Priegnitz, J. W., 41 Prince, E. C., 114 Prochazka, Z., 244, 290 Prost, M.,201 Przybylska, M.,112 Pugmire, R. J., 32, 164 Pui-Suen Wong Tschang, 260 Pulman, D. A., 13 Puntervold, O., 152 Purushotharnan, K. K., 98 Pusset, J., 270 Rabanal, R. M., 107 Radhakrishnarnurthy, B., 200 Radics, L., 202, 226 Radlick, P., 94 Radiichel, B., 237, 288 Radwan, M. A., 218 Rae, D. R., 239 Rae, I. D., 37 Rafinska, K.. 292 Ragab, M., 336 Ragsdale, N. N., 194 Rahm, A., 6 Raicht, R. F., 200, 206 Railton, I. D., 189 Raj, K., 27 Rajagopalan, M.S., 307 Raldugin, V. A., 100 Ram, B., 18 Rarnage, R., 70, 81, 150, 251 Ramamurthy, V., 153, 161 Ramananda, K., 120,3 16 Ramasarma, T., 173, 214 Ramm, P. J., 192, 194 Ramsey, R. B., 191, 198,200 Ramstad, E., 213 Randazzo, G., 115 Randrianjohany, E., 24 Ranganathan, D., 39 Ranganathan, S., 39, 214 Ranganayakulu, K., 36 Rangaswami, S., 12 1 Rani, U., 18 Rank, W., 273 Rao, G. S. K., 31, 38 Rao, K. S., 283 Rao, M. M., 122, 124, 127 Rao, N., 56 Rao, Y. S., 8 Raphael, R. A., 72 Rapoport, H., 167 Rappaport, L., 188, 189 Rashkes, Y. V., 225 Raskin, P;; 200 Rasmussen, H., 202 Rasmussen, R. A., 9, 177 Rasrnusson, G. H., 27 1, 284 Rassat, A., 4 Rastogi, R. P., 123, 132, 133
Author Index Rau, W., 210 Rauchschwalbe, G., 45 Raval, G., 202 Ravikumar, P. R., 10, 216 Razdan, R. K., 49, 50, 51 Reap, J. J., 83 Redel, J., 319 Redpath, J., 265, 266, 290 Reed, R. C., 174 Reed, W. D., 170, 171 Reeder, S. K., 85 Rees, A. F., 163, 216 Rees, H. H., 198,207 Reeve, D. R., 189 Reeves, B. E. A., 206 Reggel, L., 281 Reid, D. M., 189 Reinbold, A. M., 99 Reinhard, E. 177, 199, 202 Rembiesa, R., 201 Remers, W. A., 339 Renson, J., 204 Repke, K. R. H., 340 RepollCs, J., 272 Restivo, R., 125 Retamar, J. A., 35 Reusch, W., 249,256,261 Revesz, C., 288 Rey, P., 4 Rhstama, K., 42 Riccio, R., 94 Richards, D., 202 Richer, J.-C., 243 Richtr, V., 134 Riddle, M. C., 202 Riess, J. G., 284 Riew, C. K., 6 Riley, A. L. M., 301 Rilling, H. C., 174 Rimpler, H., 24, 27 Ring, S. G., 156 Rios, A., 191 Ripperger, H., 122 Risch, N., 5 Rivett, D. E. A., 10 Rizzardo, E., 316 Robaye, B., 204 Robbins, W. E., 208 Robert, D. U., 227, 284, 320 Roberts, F. M., 56, 175 Roberts, J., 49 Roberts, J. D., 4 Roberts, J . S., 72 Robichaud, C. S., 196 Robinson, C. H., 204, 241 Robinson, J . A., 201 Robinson, M. S., 254,306,322 Rodriguez, B., 97. 102, 106, 107, 108, 109 Rodwell, V. A., 217 Rogenmoser, E., 23 Rogers, L. J., 170 Rohmer, M., 194 Rohrer, D., 203
Rornanyuk, M. G., 18 Romeo, A., 236 Rorner, A., 77 Rorner, C. R., 121, 190 Romer, F., 208 Rommerts, F. F. G., 200 Romsos, D. R., 190 Ronchetti, F., 191, 199, 215, 339 Roof, A. A. M., 157 Rosback, D. H., 16 Rose, E., 252 Rosenberg, H., 190, 199 Rosenfeld, J. J., 49 Rosenfeld, T., 165 Rosenqvist, E., 49 Rosini, G., 256 Ross, F. P., 10, 216 Rossi, C., 115 Rossi, G., 266, 324 Rossi, O., 238 Rothbacher, H., 179 Rotman, A., 3 18 Rotmans, J. P., 2 1 Rouessac, F., 31 Rouillier, P.. 28 Rowan, R., 163, 64 Rowe, K., 30 Rua, L., 9 Rubio, F., 316 Rudney, H., 173 Rudra, K., 116 Rudzit, E. A., 285 Ruedi, P., 101 Rufer, C., 281 Ruis, H., 199 Runge, W., 204 Ruokonen, A., 206 Ruppert, J., 278 Russell, D. W., 172 Russell, G. A., 34 Russell, G. B., 208 Russell, R. A,, 269 Russell, S. M., 194 Russo, G., 191, 199, 215, 339 Ryback, G., 225 Rykowski, Z., 44 Ryzhkina, T. E., 310 Rzheznikov, V. M., 241 Saat, Y.A., 202 Sabatka, J. J., 199 Sachder, H. S., 257 Saeva, F. D., 274 Saffran, J., 201 Sahu, N. P., 132 Saigo, K., 7 St. Pyrek, J., 261 Saito, K., 167 Saito, S., 14 Sakai, H., 12 Sakai, K., 103 Sakai, M., 33 Sakakibara, J., 121
359
Author Index Sakakibara, K.,200 Sakamoto, H., 241, 295 Sakan, F., 72, 73 Sakan, T., 102 Sakata, I., 27 Sakuda, Y., 30 Sakuma, S., 15 Salazar, J. A., 138, 199, 257, 335 Salei, L. A., 97 Salemink, C. A., 49, SO, 175 Salvador, J., 203 Sammes, P. G., 335 Samokhvalov, G. I., 18, 159, 160, 165,327 Samuel, O., 165,216 Samuels, L. T., 206 Sanada, S., 124,200 Sandberg, A. A., 202 Sangare, M., 121 Sano, T., 142, 143, 218, 273 Santacroce, C., 89 Sanyal, M. K., 201 Saraswathi, G. N., 32 Sarma, A. S., 116 Sasaki, K., 113 Sasaki, S., 241, 295,310,315 Sassa, T., 115 Sathe, S., 50 Sato, K., 7, 167 Sato, S., 89.90, 184 Sato, T., 10, 17, 86 Satoh, H., 13 Satoh, J. Y., 229 Sattar, A., 81 Saucy, G., 238, 277 Sauer, G., 278,282 Saunders, J. K., 223 Savage, D. S., 265, 266, 290, 303 Savarese, J. J., 216 Savidan, L., 29 Savona, G., 96,216 Savva, E., 310 Sawa, A., 51 Sawada, H., 31 Sawaya, H. S., 78 Sawlewicz, L., 336 Sazanov, A. P., 14 Scala, A., 193, 266, 324 Scallen, T. J., 190 Scarpati, M. L., 24 Scettri, A., 248 Szhade, W., 23 1 Schafer, B., 27 Schaffer, A. M., 165 Schaffner, K., 271 Schenck, G. O., 273 Scheuer, P. J., 65, 88, 97 Schiaffella, F., 139 Schick, H., 228 Schiller, H. P. K., 197 Schilling, G., 23 Schinke, R. T., 217
Schlatter, H.-R., 251,263,292, 302 Schlegel, J., 227 Schlosser, M., 14, 45 Schmid, H., 38 Schmid, H. H. O., 190 Schmidlin, J., 25 1, 308 Schmidt, R., 113 Schmit, J. P., 248 Schneider, G., 111, 222,227 Schneider, H.-J., 4 Schnoes, H. K., 84,314,320 Schollkopf, U., 246 Schonecker, B., 227,258,289 S&oller, D., 273, 320 Schooley, D. A., 56, 186, 187, 206 Schreiber, K., 111 Schreier, P., 15 Schreiner, M. E., 173 Schrieters, H., 200 Schriider, E., 281 Schroepfer, G. J., 192,234,324 Schroth, G., 41 Schubert, K., 203, 227 Schulte-Eke, K. H., 157 Schultz, R. M., 217 Schumann, D., 93 Schwartz, J., 8 Schwartzman, S. M., 233 Schwarz, H., 52,56, 93 Schwarz, S., 282, 313 Sciamanna, W., 238,276 Scopes, P. M., 224 Scora, R. W., 15 Scott, A. I., 13,216, 222 Scott, J. A., 6 Scott, M. A., 238, 276 Seager, J., 172 Seamark, R. F., 256,289 Seetharam, B., 190 Segal, G. M., 300,322,33 1 Segiet-Kujawa, E., 43 Seidel, I., 110 Seifert, K., 122 Seitz, D. E., 83 Seki, M., 221, 319 Sellens, A. M., 218 Sembdner, G., 111 Semmler, E. J., 314 Sen, M., 137 Sen, P. K., 284 Senda, Y.,40 Sengupta, P., 137 Sengupta, S., 137 Seno, M., 17 Seo, S., 133, 134, 139, 208 Septe, B., 121 Skquin, U., 216, 222 Serantoni, E. F., 49 Serebrennikova, G. A., 233 Servera, F., 272 Seshadri, T. R., 130, 147 Seto, S., 174
Setton, R., 10 Seydewitz, V., 205 Shafiullah, 253 Shah, J. N., 118 Shah, S. N., 191,200 Shamshurin, A. A., 14 Shanbhag, M.N., 112 Shannon, P. V. R., 21 Shapiro, D. J., 217 Shapiro, E. L., 260,293 Shapiro, R. H., 7 Shapiro, S. L., 165 Sharanin, Y. A., 40 Sharanina, L. G., 40 Sharma, A., 331 Sharma, R. P., 76, 88,97 Sharma, S. C., 97, 98 Sharpe, F. R., 12 Sharpe, P. E., 274 Sharpless, K. B., 6, 29 Sharpless, N., 165 Shavyrin, V. S., 45 Shaw, J., 20 Shaw, P. E., 29 Shechter, I., 175 Shefer, S., 200, 217 Sheldrake, P. W., 216 Sheppard, P. N., 107, 115 Sherrod, J. A,, 204 Sheta, A. E., 139 Sheves, M., 222 Shibasaki, M., 32, 158 Shibata, H., 28 Shibata, K., 203, 292, 331 Shibata, S., 123, 124 Shibata, Y., 200 Shiga, M.,23 Shigematsu, Y ., 157 Shigemoto, H., 4 Shimada, A,, 102 Shimada, K., 343 Shimagaki, M., 117 Shimaoka, A., 133 Shimazu, K., 45 Shimizu, B., 28 Shimizu, I., 193 Shimizu, S., 28 Shimizu, Y.. 223, 261 Shine, W. E., 11, 174 Shingu, T., 25 Shinka, T., 174 Shintari, S., 265 Shirahama, H., 72 Shirakawa, S., 299 Shirasaki, H., 136 Shishibori, T., 11, 211 Shizuri, Y., 77 Shoeb, A., 27 Shoji, J., 124, 200 Sholiton, L. J., 201 Sholl, S. A., 201 Shono, T., 8, 28 Shonowo, 0. O., 5 Shukla, Y.N., 98
360 Shvartsman, I. G., 165 Sica, D., 89 Sickles, B. R., 113 Siddall, J. B., 186, 206 Sidwell, W. T. L., 121 Siefermann, D., 2 11 Siegfried, C. M., 206 Siemieniuk, A.. 31 Sigel, C. W., 128 Sigg-Gruetter, T., 17 Sih, C. J., 216 Sih, J., 10 Siirala-Hansen, K., 248 Silver, S. M., 87 Silvestri, M., 256 Simmons, D. L., 11 1 Simpson, K. L., 209, 2 10 Sims, C., 241 Sims, J. J., 64, 94 Sine, S. M., 320 Singaram, B., 32 Singh, A., 11 1 Singh, A. K., 47 Singh, B. P., 7, 38, 88 Singh, H., 21 1, 260, 303, 330 Singh, J., 278 Singh, L. B., 23 Singh, M., 33 1 Singh, N., 11 1 Siperstein, M. D., 172 Sircar, S. M.,109 Sisti, M., 181 Siverns, M., 96, 97, 216, 222 Sjovall, J., 191, 201, 206, 216, 32 1 Skalaban, T. D., 154 Skalhegg, B. A., 203 Sklarz, B., 147 Skoog, F., 2 14 Skorianetz, W., 160 Skuballa, W., 237, 288 Sleigh, T., 265, 290 Sliwowski, J., 194, 196 Slopianka, M., 325, 326 Small, V. R., 233 Smirnov, A. M., 2 18 Smit, A., 161 Smit, D. B., 14 Smith, A. G., 198, 234 Smith, E. M., 260, 293 Smith, G. D., 85 Smith, G. W., 140 Smith, K., 30 Smith, L. L., 216, 217, 221, 240,275,317 Smith, 0. W., 201 Smith, P. M., 102 Smith, R. A., 4 Smith, T., 203, 234 Smith, W. B., 207 Smolanoff, J., 13 Smolenski, S. J., 12 Srnuckler, E. A., 202 Srnulowitz, M., 3 10
Author Index Snajberk, K., 2 18 Snatzke, G., 148 Snider, B. B., 268, 269, 307 Snieckus, V. A., 3 Snowden, R. L., 225 Snyder, C. D., 167 Snyder, W. R., 90 Sodano, G., 94, 208 Solladik, G., 259. 334 Solomon, P. H., 223 Sonka, B., 185 Sonnenbichler, J., 77 Sood, A., 129 Sorensen, T. S., 36 Sorm, F., 13 Sorochinskaya, E. I., 30 Sorrentino, M., 115 Sotiropoulos, J., 35 Souli, E., 260, 330 Southern, A. L., 201 Southwell, I. A., 12, 31, 180 Spaulding, D. E., 172 Speckamp, W. N., 328 Spencer, H. K., 42 Spencer, T. A., 250, 273, 302 Spengel, S., 336 Spiteller, G., 48, 105 Spohn, K. H., 5 Springer, J. P., 112. 114, 115 Squatrito, D., 94 Srikantaiah, M. V., 190 Srinivasan, A., 89 Srinivasan, P. R., 4, 5, 222 Srinivasan, S. R., 200 Srivastava, S. C., 50 Stacewicz-Sapuncakis, M., 21 1 Stallard, M. 0..64 Stanton, J. L., 246, 288 Stavely, H. E., 201 Steinbeck, H., 302 Steinman, D. H., 17 Stemke, J. E., 7 Stenhouse, I. A., 98 Sterling, J. J., 87 Stevenson, D.. 204 Stevenson, J. R., 72 Stevenson, R., 136 Steward, F. C., 217 Sticher, O., 23, 24 Stick, R. V., 254, 322 Stilbs, P., 4 Still, J., 173 Stipanovic, R. D., 66 Stockis, A., 45 Stoessl, A., 80, 184 Stohs, S. J., 190, 199 Stojanac, N., 129 Stojanac, Z., I29 Storer, R., 11, 178 Stork, G., 15, 277, 278 Story, J. A,, 204 Stothers, J. B., 5, 40, 80, 184 Stover, C. S., 223 Streckenbach, B., 340
Strege, P. E., 9 Strickler, H., 157 Strigina, L. I., 135 Stripp, B., 205 Strong, F. M., 84 Stuart, A. D., 59 Su, K. L., 190 Suan, R.,62 Suarez, E., 138, 199, 257, 335 Subba-Rao, G., 173 Subba Rao, G. S. R., 283 Subbiah, M. T. R., 202 Sucrow, W., 325,326 Suda, T., 241, 295, 310,315 Suga, K., 17 Suga,T., 11, 124, 178, 211 Sugano, N.. 210 Sugawara, T., 122 SUBS, J. W., 8, 233 Sugihara, H., 299 Sugimoto, A., 241, 295, 310, 315 Suginome, H., 255, 272 Sugiura, K., 77 Sugiura, M., 5 Sugiyama, T., I7 1 Sultarbawa, M. U. S., 130 Sundar, N. S., 283 Sung, W. L., 156 Sunthankar, S. V., 256 Suokas, E., 132 Suruda, A. J., 204, 2 17 Suteu, F., 179 Sutherland, I. W., 21 1 Sutphin, H. D., 165 Suzuki, A., 18, 317 Suzuki, H., 141, 165, 173 Suzuki, K. T., 181 Suzuki, M., 68, 241, 295, 315 Svec, W. A., 146 Svoboda, J. A., 208 Svonkova, E. N., 154 Swain, T., 217 Sweeny, J. G., 113 Swenton, L., 268 Sydykov, Zh. S., 300,331 Sykes, B. D., 163, 164 Symalla, D., 34 Szarka, E., 202 Tabacik, C., 177 Tachibana, K., 130, 137 Tachibana, Y., 116 Tada, M., 86 Tadros, W., 240, 323 Tagami, H., 18 Taguchi, H., 24 Tahara, A., 105, 117 Tahara, R., 157 Tahara, T., 30 Takabe, K., 15 Takagi, Y., 30 Takahashi, A., 164 Takahashi, H., 255
36 1
Author Index Takahashi, K., 29, 122 Takahashi, N., 97, 110,
11,
188, 189
Takahashi, S., 225 Takahashi, T., 86, 130,
31.
136, 137
Takahashi, T . T., 229 Takam, J.-M., 22 Takani, M., 122 Takao, S., 189 Takasaka, N., 17 Takeda, K., 76 Takeda, T., 225 Takeda. Y.. 24 Takemoto, T., 76, 114, 207, 208,223,300,331
Takeshita, T., 241, 317, 320 Takeuchi, N., 204 Talalay, P., 204, 217 Talapatra, B., 132 Talapatra, S. K., 132 Tamaoki, B., 204 Tamm, C., 59, 64, 121, 126, 191,212,213
Tan, C. T., 5,40 Tan, W. L., 122 Tanabe, K., 42,45 Tanabe, M.,181,286,310 Tanahashi, Y., 86, 130, 131 Tanaka, E., 15 Tanaka, J., 15 Tanaka, K., 2Y Tanaka, O., 105, 124 Tanaka, S., 7, 52, 200 Tanaka, Y., 205,211 Tandon, J. S., 97,98 Taneja, S. C., 24 Tange, K., 11, 178 Tani, T., 99 Tanner, A., 336 Tanno, T., 143 Tantisewie, B., 24 Tardivat, J. C., 37,41 Taubert, H.-D., 233 Taurog, J. D., 203 Tavernier, D., 16 Taylor, B. B., 201 Taylor, D. A. H., 126 Taylor, D. R., 125 Taylor, G. F., 39 Taylor, R., 265, 290 Taylor, R. F'., 163, 216 Taylor, R. J. K., 328 Tchistiakova, A. M., 202 Teisseire, P., 18, 28,47 Telang, S. G., 256 Templeton, J. F., 202, 297 Teng, J. I., 217 Tepper, S. A., 204 Terao, S., 273 Terashima, S., 32, 158 Terekhina, A. I., 285 Terlouw, J. K., 49, 50 Tetenyi, P., 199, 218
Teuscher, E., 202 Teutsch, G., 260, 268, 293 Teyssie, Ph., 288 Thackeray, M. M., 164 Thiemann, P., 340 Thies, P. W., 25 Thomas, A. F., 29, 55 Thomas, G., 213, 214 Thomas, P. W., 236 Thomas, R., 202,223 Thommen, H., 152 Thommen, W., 55 Thompson, M. J., 208 Thompson, R. M.,203 Thompson, W. R., 51 Thomson, J. A., 207,330 Thortn, S., 73 Thorin, J., 218 Threlfall, D. R., 213, 214 Tietz, D., 185 Tilley, J. W., 129 Timm, H., 340 Tiwari, H. P.. 24 Tkatchenko, I.. 252 Tobe, S. S., 187 Toda, M.,119 Tomorkeny, E., 281 Tomoskozi, I., 226 Toft, P., 201 Toh, N., 113 Toia, R. F., 112 Tokito, Y., 164 Tolstikov, G. A., 43, 44 Tomaszewska, L., 292 Tomesch, J. C., 66 Tomita, Y., 133, 134, 139, 208 Torgov, I. V.. 280, 300, 331 Tori, K., 4, 64, 76, 133, 134, 139,208,222
Tori, T., 137 Torii, S., 32, 48, 158 Torrini, I., 236 Tbth, G., 149, 281 Totty, R. N., 224 Toubiana, M. J., 83 Toubiana, R., 83 Tozawa, M., 340,342 Trager, L., 204 Trave, R., 75, 183 Traynor, S. G., 32 Troetschler, R. G., 187 Trogolo, C., 23,24 Trost, B. M., 9, 21, 45, 246, 252,288
Trowbridge, S, T., 192, 324 Trumpower, B. L., 167 Truong-Ho, M., 334 Trus, B. L., 129 Truscott, T. G., 165 Trust, R. l., 129 Tsai, L. B., 198 Tsai, P., 205 Tsai, T. Y. R., 112 Tsau, J., 50
Tschang, P. S. W., 293 Tschesche, R., 95, 132, 199 Tsuda, Y., 142, 143,218 Tsuji, A., 310 Tsujimura, T., 201 Tsukamoto, Y., 12 Tsukanaka, M., 31 Tsuneya, T., 13 Tsuyuki,T., 130,131,136,137 Tsuzuki, K., 72 Tuddenham, R. M., 27,58 Tuinman, A., 248 Turnbull, J. K., 107 Turnbull, K. W., 11, 177 Tunemoto, D., 58 Turner, A. B., 240,287,301 Turner, B. L., 2 17 Turner, J. V., 68, 116 Tursch, B., 112 Tustin, G., 153 Uchida, I., 99, 224 Uchida, K., 204 Uchida, Y., 15 Uchio, Y., 35 Udarov, B. G., 31.46 Ueda, K., 13 Ueda, M., 200 Ueda, S., 25 Ueda, Y., 232 Uemura, D., 113 Uesato, S., 25 Ueyama, M., 76 Ukai, A., 143 Uliss, D. B., 49, 50 Umehata, Y., 27 Umenoto, K., 4, 13 Uneyama, K., 32,48, 158 Ungar, F., 201 Uno, E., 113 Uprety, H., 98, 147 Urata, M., 29 Urban, J., 134 Uritani, I., 173 Uskokovic, M. R., 3 16,3 18 Uto, S., 89 Uzarewicz, A., 43 Uzarewicz, I., 43 Valadon, L. R. G., 218 Valcari, U., 336 Valdez, V., 133 Valenta, Z., 129 Valverde, S., 97, 102, 106, 107, 108, 109 van Beek, V., 201 van Bokhoven, C ., 244,286 van Broekhoven, L. W., 175 van Cantfort, J., 204 van den Broek, A. J., 244,286 Vandenheuvel, F. A., 274 Van der Gen, A,, 84 Van der Linde, L. M., 84, 158 van der Molen, H. J., 20
362 van der Vusse, G. J., 200 Van der Wielen, F. W. M., 157 Vangedal, S., 197 van Maarschalkerweerd, M. W., 175 Van Noort, P. C. M., 157, 161 van Rheenen, J. W. A., 198 van Schalkwyk, T. G. D., 132 van Tamelen, E. E., 118, 176 Van Wageningen, A., 157, 161 van Winsen, M. P. I., 200 Vasanth, S., 98 Vass, A., 222 Vedejs, E., 252 Veerman, A., 148 Veierov, D., 271 Velapoldi, R. A,, 241 Velgovi, H., 250 Vena, R. L., 201 Venkataramu, S. D., 283,284 Venturella, P., 106 Verbit, L., 274 Verghese, J., 32 Verma, A. L., 165 Verzele, M., 13 Veschambre, H., 27 Vidari, G., 74 Vietmeyer, N. D., 71 Vig, A . K., 18 Vig, 0. P., 18 Vihko, R., 206 Villieras, J., 9 Vincent, G. G., 80 Viotti, A . 217 Visagie, H. E., 14 Visser, H. K. A,, 201, 202 Viswanathan, N., 138 Vita Finzi. P., 74 Vittek, J., 201 Vogt, W., 233,299 Voigt, B., 110 Voisin, D., 28 Voitekhovskaya, G. I., 32 Volkmann, R. A., 69 Volovel’skii, L. N., 25 1, 305 von Carstenn-Lichterfelde, C., 97, 109
von Gross, B., 95 von Rudloff, E., 10, 217, 218 von Schantz, M., 218 Vooght, P. A., 198 Vorbriiggen, H., 226, 237, 288 Vuillerme, J. P., 37, 41 Vyrodov, V. A., 45 Vystrcil, A., 131, 134
Author Index Walba, D. M., 129 Walters, R. L., 69 Wang, H. C., 21 1 Wang, N., 257, 301, 310 Waraszkiewicz, S. M., 64 Ward, E. W. B., 80 Warnant, J., 293 Warneboldt, R. B., 255 Warren, C. D., 166 Warshel, A., 165 Wasserman, H. H., 273 Watanabe, S., 17 Waterman, E. L., 248 Watson, D., 45 Watson, J. A., 172 Watson, y. G., 118, 176 Watts, D. J., 101 Wawrzennyk, C., 43,46 Waymouth, C., 200 Weakley, R., 205 Weaver, M. L., 199 Weber, L., 45, 260, 293 Weedon, B. C. L., 145, 149 Weeks, C., 203 Weete, J. D., 176 Wehrli, P. A., 238, 276 Wei, R., 84 Weigand, E. F., 4 Weight, M. J., 200 Weight, N., 200 Weiler, L., 255 Weiner, B.-Z., 49 Weinges, K., 23 Weinreb, S. M., 106 Weinshenker, N. M., 9 Weisflog, A., 23 Weiss, K., 165 Weissberger, E., 45 Weissenberg, M., 321 Weisz-Vinne, I., 222, 227 Welch, S. C., 69 Wells, J. M., 115 Welmar, K., 95 Welniak, M., 39 Wels, C. M., 189 Welvart, Z., 6 Wender, J., 28 1 Wenkert, E., 16, 55, 101, 102, 128
Wentzel, M., 204 West, C. A,, 174 Westberg, H. H., 9 Weyerstahl, P., 94 Whaley, T. W., 216 Whalley, W. B., 265, 323, 324
Wada, K., 202,205 Wagner, H., 77 Wagner, S. D. 248 Wahlberg, I., 88 Wahlborg, A., 35 Waisser, K., 134 Wakelyn, P. J., 66 Wakselman, C., 10, 216
Wheeler, J. W., 5 White, G. W., 13, 105 White, J. D-, 100, 156 Whiting,D.A.,5,119,
Whittaker, D., 35,41 Whitten, C. E., 87 Whittle, P. R., 34 Wicha, J., 320
150, 164
Widdowson, D. A., 118, 176, 193,269
Wie, C. W., 297 Wiechert, R., 278, 282 Wiehager, A.-C., 88 Wiesner, K., 111, 112, 269 Wild, J., 17 Wilder, P., jun., 37 Wilke, G., 41 Wilkie, J. S., 207 Wilkins. A. L. 104, 141, 233, 296
Wilkinson, J. B., 230 Willhalrn, B., 55 Williams, C . N., 204 Williams, D. H., 32, 222 Williams, D. J., 60 Williams, D. L., 50 Williams, J. G., 202 Williams, K. I. H., 202 Williams, M. C., 202 Williamson, D. G., 203, 204 Wilshire, C., 260, 310 Wilson, B. J., 180 Wilson, C. W., 29 Wilson, J. D., 203 Wilson, M. A., 264 Wilson, R. S., 49 Wilson, S. R., 18 Wilton, D. C., 193 Wing, R. M., 64, 94 Wing-Cheung Liu, 1 12 Winkler, H. U., 225 Winkler, J., 3 1 Winskill, N., 148 Winstanley, D. J., 148 Witteween, J. G., 84 Wittstruck, T., 229, 266 Witty, T. R., 339 Wunderwald, M., 231 Wodzki. W., 37 Wolf, H., 62 Wolf, H. R., 35, 159, 162 Wolff, M. E., 222, 260 Wolfhugel, J. L., 271 Wolinsky, J., 33, 38 Wolinsky, L. E., 57 Wong, C. M., 256 Wong, J. Y., 9 Woo, W. S., 133 Wood, D. L., 179 Wood, E. W. B., 184 Woodgate, P. D., 102 Woods, R. A., 193 Woodward, R. B., 316 Woolard, F. X., 20, 179 Worth, G. K., 112 Wray, V., 223 Wright, B.J., 202,223 Wright, B. W., 21 Wuest, H., 6, 53 Wuffli, F., 157 Wulff, G., 132 Wychick, D., 274
363
Author Index Xue, Z., 47 Yablonskaya, E. V., 322 Yabuki, R., 236 Yagen, B., 49, 191 Yagi, H., 15 Yahara, S., 105 Yakovlena, M. Y., 251 Yakovleva, T. 0..43 Yamada, K., 2 9 , 6 8 , 7 7 Yamada, S., 32, 137, 225, 241, 295,310,315 Yamada, S.-I., 158 Yamaguchi, I., 97, 188 Yamaguchi, M., 144, 151 Yamaguchi, R, 167 Yamakoshi, N., 292 Yamamoto, H., 7, 20, 52, 118 Yamamoto, H. Y., 21 1 Yamamura, S., 1 1 9 , 2 1 4 Yamamura, Y., 204 Yamane, H., 97, 11 1, 189 Yamao, N., 141 Yamaoka, T.. 165 Yamasaki, K., 105 Yamashha, K., 6, 149, 223 Yamazaki, K., 121 Yamazaki, M., 265 Yanuka, Y., 251,322
Yasuda, A.. 7, 52 Yasue, M., 12 1 Yasui, A., 14 Yates, J., 204 Yau, C. C., 153 Yogev, A., 271 Yokokawa, Y., 24 Yokota, T., 110 Yokoyama, A., 120 Yokoyama, H., 209 Yokoyama, T., 2 8 Yoneyoshi, Y., 21 Yoshi, E., 306 Yoshida, A., 210 Yoshida, T., 113 Yoshihara, K.,71 Yoshihara, M., 99 Yoshikawa, M., 135 Yoshikoshi, A., 103 Yoshioka, H., 41, 7 5 Yosioka, I., 99, 122, 135, 141 Younes, M. E.-G., 139, 140 Young, R. N., 1 0 , 3 9 , 2 2 7 Younglai, E. V., 201 Yunusov, M. S., 11 1 Yunusov, S. Y., 11 1 Yur’ev, V. P., 4 3 , 4 4 Zabza, A., 43, 46
Zadock, E., 112 Zakharova, N. I., 18, 159 Zalkow, L. H., 61 Zameonik, J., 109 Zanati, G., 260 Zandee, D. I., 198 Zanno, P. R., 126 Zarecki, A., 320 Zaretskii, V. I., 225 Zatsny, I. L., 225 Zavarin, E., 218 Zawadzki, J. F., 241 Zbiral, E., 239 Zdero, C., 32, 52, 53, 58, 85, 89,93 Zelewski, L., 201 Zelnik, R., 124, 127 Zen’ko, R. I., 32 Zetterberg, C. T., 110 Ziegler, M. F., 102, 128 Ziegler, R., 121 Zietz, R., 201 Zile, M., 163, 21 1 Zilkha, A., 49 Zimmerly, V., 11 3 Zimmerrnan, W. T., 157 Zink, M. P., 159 Zoltowska, B., 305 Zontova, V. N., 241