A Specialist Periodical Report
Terpenoids and Steroids Volume 5
A Review of the Literature Published between Sep+embe...
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A Specialist Periodical Report
Terpenoids and Steroids Volume 5
A Review of the Literature Published between Sep+ember1973 and August 1974
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 J. R. Hanson, University of Sussex
D. N. Kirk, Westfield College, London T. Money, University of British Columbia, Vancouver, Canada
P. J. Sykes, University of Edinburgh A. F. Thomas, Firmenich SA, Geneva, Switzerland J. S. Whitehurst, University of Exeter
0 Copyright 1975
The Chemical Society Burlington House, London, W I V OBN
ISBN: 0 85186 296 9
ISSN: 0300-5992 Library of Congress Catalog Card No. 74-615720
Set in Times on Monophoto Filmsetter and printed offset by J . W. Arrowsmith Ltd., Bristol, England Made in Great Britain
Introduction
This Report covers the literature published between September 1973 and August 1974, except for the chapter on Steroid Synthesis, a topic omitted from Volume 4, which consequently reviews a two-year period from September 1972 to August 1974. The tight-rope economics of producing these Reports have unfortunately forced us to abandon our plan to include occasional reviews, which we had hopefully begun in Volume 4. We do include a list of selected Reviews on Steroid Chemistry 1969-1974, to complement the Reviews on Terpenoid Chemistry that appeared in Volume 4, and also a classified list, which just eluded the economic axe, of Terpenoid Structures determined by X-Ray Analysis. As always, comments, criticisms, and suggestions for future volumes will be heartily welcomed.
K. H. OVERTON
Contents Part I
Terpenoids
Chapter 1 Monoterpenoids
3
B y A. F. Thomas 1 Physical Measurements: Spectra etc. ;Chirality
3
2 General Chemistry
5
3 Occurrence, Biogenesis, and Biological Activity
7
4 Acyclic hlonoterpenoids Terpene Synthesis from Isoprene 2,6-Dimethyloctanes Artemisyl, Santolinyl, Lavandulyl, and Chrysanthemyl Derivatives
8 8 9
14
5 Monocyclic Monoterpenoids Cyclobutane Cyclopentanes, Iridoids p-Menthanes o-Menthanes m-Menthanes Tetramethy lcyclohexanes 1,4-Dimethyl-1-ethylcyclohexane Cycloheptanes
16 16 16 20 27 27 27 29 29
6 Bicyclic Monoperpenoids Bicyclo[3,1,O]hexanes Bicyclo[2,2,1]heptanes Bicyclo[3,1, ljheptanes Bicyclo[4,1,O]heptanes 7 Furanoid and Pyranoid Monoterpenoids
30 30 30 36 41 42
8 Cannabinoidsand other Phenolic Monoterpenoids
43
Chapter 2 Sesquiterpenoids By T. Money
46
1 Introduction
46 V
Terpenoids and Steroids
vi
2 Farnesanes
46
3 Bisabolanes
48
4 Cuparane, Laurane, Trichothecane, utc.
51
5 Acorane, Cedrane, etc.
53
6 Chamigrane, Widdrane, and Thujopsane
55
7 Sesquicamphane, PSantalane, Epi-Psantalane, etc.
57
8 Amorphane, Cadinane, Copaane, Copacamphane, Ylangocamphane, Sativane, etc.
59
9 Himachalane, Longipinane, Longica.-,phane, Longifolane, etc.
63
10 Humulane, Caryophyllane, Illudane, Hirsutane, etc.
65
11 Germacrane, Eudesmane, Eremophilane, Vetispirane, etc.
71
12 Guaiane, Pseudoguaiane, Seychellane, Aromadendrane, etc.
86
13 Mono- and Bi-cyclofarnesanes
90
Chapter 3 Diterpenoids By J. R. Hanson
93
1 Introduction
93
2 Bicyclic Diterpenoids Labdanes Clerodanes
93 93 98
3 Tricyclic Diterpenoids Naturally Occurring Substances Chemistry of the Tricyclic Diterpenoids
102 102 105
4 Tetracyclic Diterpenoids The Kaurene--Phyllocladene Series Beyeranes Gibberel lin s Other Tetracyclic Diterpenoids
108 108 111 112
5 Macrocyclic Diterpenoids and their Cyclization Products
116
6 Diterpenoid Synthesis
117
Chapter 4 Triterpenoids By J. 0. Connolly
122
115
1 SqualeneGroup
122
2 Fusidane-Lanostane Group
126
vii
Contents 3 Dammarane-Euphane Group Tetranor-tri terpenoids Quassinoids
130 133 135
4 Shionane Group
135
5 Lupane Group
136
6 Oleanane Group
137
7 UrsaneGroup
143
8 Hopane Group
144
Chapter 5 Carotenoids and Polyterpenoids By G. Britton
146
1 Introduction
146
2 Carotenoids New Natural Carotenoids Hydrocarbons Oxygenated Carotenoids Acyclic Monocyclic xanthophylls Bicyclic xanthophylls Isoprenylated Carotenoids Triterpenoid Carotenoids Degraded Carotenoids Stereochemistry ; Absolute Configuration C-6 c-3 c-2 Carotenoid Epoxides Isomytiloxanthin Degraded Carotenoids Conformation Car0tenoids Retinal and Derivatives Irone Synthesis Carotenoids Degraded Carotenoids Chemistry Carotenoids Degraded Carotenoids Physical Methods Separation Methods Electronic Spectroscopy Resonance Raman Spectroscopy
146 146 146 146 146 148 149 151 151 152 153 153 153 154 155 155 155 155 155 156 156 157 157 159 161 161 162 166 166 166 166
...
Terpenoids and Steroids
Vlll
Low-resolution Microwave Spectroscopy Infrared Spectroscopy N .M.R. Spectroscopy Mass Spectrometry Circular Dichroism X-Ray Crystallography 3 Polyterpenoids and Quinones Polyterpenoids Quinones
Chapter 6 Biosynthesis of Terpenoids and Steroids By D. V. Banthorpe and B. V. Charlwood
168 168 168 170
1 Introduction
170
2 Acyclic Precursors
170
3 Monoterpenoids
176
4 Sesquiterpenoids
178
5 Diterpenoids
183
6 Steroidal Triterpenoids
186
7 Further Metabolism of Steroids
190
8 Non-steroidal Triterpenoids
195
9 Carotenoids
195
10 Meroterpenoids
199
11 Polyterpenoids
203
12 Methods
203
Naturally Occurring Terpenoids whose Structures have been Determined by X - Ray Analysis
Part I/
166 166 166 167 167 168
206
Steroids
Chapter 1 Steroid Properties and Reactions By 0.N. Kirk 1 Structure, Stereochemistry, and Conformational Analysis
Spectroscopic Methods N. M.R. Spectroscopy Circular Dichroism Mass Spectrometry Miscellaneous
223 223 224 224 227 229 23 1
ix
Contents
2 Alcohols and their Derivatives, Halides, and Epoxides Substitution and Elimination Ring-opening of Epoxides Esters, Ethers, and Related Derivatives of Alcohols Oxidation Reduction Miscellaneous
231 23 1 235 235 237 238 239
3 Unsaturated Compounds Electrophilic Addition Epoxidation Miscellaneous Additions Reduction Oxidation Miscellaneous
239 239 24 1 242 243 244 245
4 Carbonyl Compounds Reduction of Ketones Other Reactions at the Carbonyl Carbon Atom Reactions of Enols and Enolate Ions Reactions of Enamines and Enol Derivatives Dehydrogenation and Oxidation Reactions of Oximes and Related Compounds Carboxylic Acids, Nitriles, and Aldehydes
246 246 248 25 1 254 256 258 259
5 Compounds of Nitrogen and Sulphur
26 1
6 Molecular Rearrangements Contraction and Expansion of Rings ‘Backbone’ and Related Rearrangements Aromatization of Rings Chromogenic Reactions Miscellaneous Rearrangements
264 264 266 268 27 1 272
7 Functionalization at Non-activated Positions
275
8 Photochemical Reactions Olefinic Compounds Carbonyl Compounds Miscellaneous
278 278 279 28 1
9 Miscellaneous
283
Chapter 2 Steroid Synthesis By P. J. Sykes and S. J. Whitehurst
285
1 Total Synthesis
285
2 Halogeno-steroids
296
Terpenoids and Steroids
X
3 Oestranes
300
4 Androstanes
304
5 Pregnanes and Corticoids
318
6 Seco-steroids
325
7 Cholestane and Analogues
330
8 Steroidal Insect and Plant Hormones
347
9 Steroidal Alkaloids
349
10 Sapogenins
352
11 Cardenolides
354
12 Bufadienolides
357
Reviews on Steroid Chemistry
36 1
Errata
367
Author Index
369
Part I TERPENOIDS
1 Monoterpenoids BY A.
F. THOMAS
There has been little increase in the volume of work published this year, but the space available for this Report is slightly reduced, so economy has been achieved in two ways. Papers not requiring any discussion, either because they are repetitive or because the minor point they make is evident from little more than the title, are placed at the end of each section. The number of formulae has been reduced, and more extensive use is made of names in the text. With these limitations, every effort has been made to quote all papers relevant to monoterpenoids.
1 Physical Measurements: Spectra etc. ;Chirality
'
Titanium tetrachloride is recommended as a useful shift reagent in assigning 3C n.m.r. frequencies, particularly in ag-unsaturated ketones such as carvone (1). which has a shift of - 5.83 Hz for the P-carbon frequency,compared with - 1.51 Hz using [Eu(fod),].' The 13Csignals of the bridge methyl groups of camphor (2) (C-9 and C-10) have been assigned using another new shift reagent, tris-[4,4,4-trifluoro-1-(2-thienyl)-1,3-butadiThe ene]europium(~~r),* and 3Cchemical shifts of substituted tricyclenes are discu~sed.~ importance of non-axial symmetry in interpreting lanthanide-induced shifts in ketones has special relevance for monoterpenoids, and Newman discusses the case of camphor (2).4 Shifts induced by [Eu(dpm),] in saturated 0- and p-menthone~,~ and its effect on the rotation of the isopropyl group in menthone and menthol have been measured.6 Some well known mass spectra of monoterpenoid alcohols have been published again7
'
-x
0
A
'
(1) (2) A. K. Bose, P. R. Srinivasan, and G. L. Trainor, J. Amer. Chem. SOC.,1974, 96, 3670; 9th International Symposium on the Chemistry of Natural Products, Ottawa, 1974, Abstracts 20B; A. K. Bose, personal communication. K. Beyer, Org. Magn. Resonance, 1974,5,471. E. Lippmaa, T. Pehk, and J. Paasivirta, Org. Magn. Resonance, 1973, 5 , 277. R. H. Newman, Tetrahedron, 1974, 30, 969. R. Enriquez, J. Taboada, I. Salazar, and E. Diaz, Org. Magn. Resonance. 1973,5, 291. K. Yamada, S. Ishihara, and H. Iida, Chem. Letters, 1973, 549. G . R. Rik and L. V. Kravchenko, Vestnik Sef'skokhoz. Nauki (Moscow),1973, 104 (Chern. A h . , 1973, 79, 70083).
Terpenoids and Steroids
4
The adsorption on a mercury electrode of borneol and adamantan-1-01 has been compared with that of camphor because of similar polarographic behaviour.' The chirality of alcohols, notably ( -)-linalool, ( - )-menthol, and cis-menth-2-enol(3) (the name in the text is different), is rapidly established by measuring the c.d. of the complex with copper hexafluoroacetylacetonate.9 Photodecomposition of racemic camphor with circularly polarized light occurs enantiomerically, the optical purity of recovered camphor theoretically rising to lOO:, at the end of the reaction. After 99% destruction of the (+)-camphor, the remainder has 20% optical activity."
( 5 ; R cis) (6; R [runs)
Notable examples of the induction of asymmetry by complexing with monoterpenoids are the resolutions of the iron complex (4)' and a titanium', complex. The menthyl( 5 ; R = PPh,) and neomenthyl- (6 ; R = PPh,) diphenylphosphines are epimeric, chiral ligands, suitable for asymmetric syntheses.' Another account has appeared of an attempt to induce asymmetry by cyclization of homogeranic ( -)-menthy1 ester. l 4 Various micro-organisms (Tridioderrnu, Absidia, etc.) hydrolyse some racemic acetates chirally ; thus a mixture of (+)-isopulegyl acetate [( +)-(7 ; R = COMe)] and (k)-neoisopulegyl acetate [( -k)-(8; R = COMe)] is converted into a separable mixture of (-)-isopulegol [( -)-[7 ; R = H)], (+)-isopulegyl acetate [( +)-(7; R = COMe)], and ( +)-neoisopulegyl acetate. Since interconversion with citronella1 (9) is easy, this represents a practical resolution of ( +)-citronellal.15 The acetates of menthol and carvomenthol undergo this reaction, but not those of the stable axial alcohols, neomenthyl
lo
"
'*
1
l4
'
'
S. L. Dyatkina and B. B. Damaskin, Elektrukhimiya, 1974, 10, 318. J . Dillon and K. Nakanishi, J. Amer. Chem. Soc., 1974, 96, 4056. G . Balavoine, A. Moradpour, and H . B. Kagan, J. Amer. Chem. Soc., 1974,96, 5152. C. T. Flood and D. L. Mills, J . Amer. Chem. Soc., 1973,95, 6460. H . Brunner and H . D . Schindier, J. Organometallic Chem., 1973, 55, C71. J. D . Morrison and W . F. Masler, J. Org. Chem., 1974, 39, 270. S. Kumazawa, T. Kato, and Y. Kitahara, Chern. Lc'tters, 1973, 633. T. Oritani and K. Yamashita, Agric. and Bid. Chern. (Japan), 1973, 37, 1687.
5
Monoterpenoids
acetate ( 5 ; R = OCOMe) and neocarvomenthyl acetate (10).l6 The further the acetate group is from the asymmetric centre, the lower is the optical yield.” New separation techniques for monoterpenoids are liquid chromatography on porous polymer (Hitachi gel 3010)’ and gas chromatography on graphitized carbon black for the notoriously delicate separation of the menthol isomers (although neomenthol and menthol are not cleanly separated).” 2 General Chemistry
Acid-catalysed isomerization of terpenoid hydrocarbons occupies much space in the literature, usually without the emergence of great novelty (see, however, pinenes). The use of mentha-2,8-diene as substrate2’ and other hydrocarbons on Ti0,-H2S0, catalysts is described.21 Liquid-phase rearrangements of pinene and limonene give results varying with acid strength,22and similar variations occur with basic strength in the base-catalysed rearrangement^.^^ By judicious choice of base, it is possible to prepare a particular menthene from one more a c ~ e s s i b l eRearrangement .~~ of limonene (1 1) in phosphoric acid was known to yield a bicyclic hydrocarbon ; 2 5 the latter is shown to be a mixture of three isomers (Scheme 1).26 Isomerization of a-pinene over ferric phosphate
A
+ menthadienes
(11)
Scheme 1
at 180-560 “C leads to rearrangements and ring-opening to men thane^,^' and heating terpenes with diethyl hydrogen phosphite yields phosphonates, also with rearranged skeletons ; pinenes give menthenes, camphene gives isocamphenyl ethylphosphonate, and limonene (1 1)gives a mixture containing a small amount of a bornyl phosphonate.28 Another paper on the hydration of monoterpenoids in the presence of an ion-exchange resin has appeared ( c j . Vol. 4, p. 13).29Treatment of linalool(l2) with chloranil results l6
‘’ Is l9
” ” 22
23 24 25 26
’’
29
T. Oritani and K. Yamashita, Agric. and Biol. Chem. (Japan), 1973,37, 1691, 1695.
T.Oritani and K. Yamashita, Agric. and Biol. Chem. (Japan), 1973,37, 1923. M. Nakayama, M. Hiraoka, A. Matsuo, and S. Hayashi, Nippon Kagaku Kaishi. 1973,2314.
V. B. Yakubovich and G. M. Petrov, Khim. Izmenchivost. Rust., 1972,95. 1. I. Bardyshev, Zh. F. Loiko, L. A. Popova, and L. V. Sionskaya, Doklady Akad. Nauk Beloruss. S . S . R . , 1973, 17,534. M. Dul and M. Bukala, Chem. Stosowana, 1973, 17, 19. R.Ohnishi, K. Tanabe, S. Morikawa, and T. Nishizaki, Bull. Chem. SOC.Japan, 1974,47,571. A. Ferro and Y.-R. Naves, Helv. Chim. Acta, 1974,57, 1152. A. Ferro and Y.-R. Naves, Helv. Chim. Acta, 1974,57, 1 141. V. N . Ipatieff, J. E. Germain, W. W. Thompson, and H. Pines, J. Org. Chem., 1952, 17,272. G. Accrombessy, M. Blanchard, F. Petit, and J.-E. Germain, Bull. SOC.chim. France, 1974, 705. V. V. Pechkovskii, Yu. P. Klyuev, L. S. Eschchenko, L. N. Shchegrov, V. M. Sycheva, and I. V. Petrashen, Izvest. Vyssh. Ucheb. Zaced., Les. Zhur., 1973, 16, 107 (Chem. Abs., 1974, 80, 48 172). R. L.Kennedy and G. S. Fisher, J. Org. Chem., 1974,39,682;Some related work is discussed in the bicyclo[3,1, Ilheptane section. Y. Matsubara, T. Fujiwara, and K. Tanaka, Yuki Gosei Kagaku Kyokai Shi, 1973, 31, 924.
Terpenoids and Steroids
6
(12)
(13)
(14)
(15) E
(17)
(16)
h a series of dehydrations and hydrations; myrcene (13), ocimene (14),and their hydration products are formed, but cyclization to menthadienes and subsequent hydration also occur. Geraniol (15), nerol (16), and linalool (12) are interconverted, and give similar products, nerol favouring the cyclized alcohol (17).30The claim that j3-pinene is among the dehydration products of linalool(l2)could not be confirmed using boron trifluoride or iodine as catalyst.31 Of particular relevance to monoterpenoids is the comparison of reaction parameters for triphenyl phospite ozonide (TPPO) formation and those of photosensitized oxygenation, where it has been shown that singlet oxygen cannot be a common active species for both types; limonene ( l l ) , for example, shows a very different product distribution in the two cases. TPPO oxidation occurs at lower temperatures than ozonide decomposition, and is in some cases, e.g. a-terpinene (18), more selective.32A general study of epoxidation of methylenecyclohexanes, closely related to monoterpenoids, includes a discussion of the epoxide conformation^.^^ Epoxidation of ally1 alcohols with t-nutyl hydroperoxide catalysed by vanadium or molybdenum complexes has enabled the new epoxides of geraniol(l9) and linalool(20) to be prepared.34 Oxidation of alcohols to ketones (menthol to menthone, borneol to camphor, etc.)generally occurs with N-chlorosaccharin, but limonene (11) gives a 4-chloro insertion product.35
(18)
(19)
(20)
Details of the highly stereoselective reductions of ketones, (mostly bicyclic monoterpenoids) with alkylboranes are published.36 A new method for alkylating methyl groups via 7r-ally1complexes3’ uses geranylacetone as a typical example ; this method tackles the general difficulty of making valuable higher terpenoids from cheap monoterpenoids. 3o 31
32 33
34 3s
” ”
S. Fujita, Y. Kimura, T. Iguchi, R. Suemitsu, and Y. Fujita, Nippon Kuguku Kuishi, 1972,2140. Y . Fujita, S. Fujita, and H. Okura, Nippon Kugaku Kaishi, 1974, 132. E. Koch, Anulyt. Chem., 1973,45, 2120. A. Sevin and J.-M. Cense, Bull. SOC.chim. France, 1974, 963, 969. K. B. Sharpless and R. C. Michaelson, J. Amer. Chem. Soc., 1973, 95, 6136. J. M. Bachhawat, A. K. Koul, B. Prashad, N. S. Ramegowda, C. K. Narang, and N. K. Mathur, Indian J . Chem., 1973, 1 1 , 609. H. C. Brown and V. Varma, J. Org. Chem., 1974, 39, 1631. B. M. Trost, T. J. Dietsche, and T. J. Fullerton, J. Org. Chem., 1974, 39, 737.
7
Monoterpenoids
3 Occurrence, Biogenesis, and Biological Activity A review has appeared on the distribution of terpenoids among different plant species, with sections on biosynthesis and m e t a b o l i ~ m . ~ ~ Some traditional monoterpenoid plant sources are becoming rarer, adding interest to the flourishing analytical work ;examples are the following species : Artemisia (several and Origanum (containing sabinene h~drate),~’ of which contain i s ~ t h u j o n e )Majurana ,~~ Citrus iyo peel oil (containing several rare oxygenated menthanes):’ and saffron.42The C,, substance (21) from Greek tobacco is possibly not monoterpenoid but derived from a d i t e r ~ e n e The . ~ ~ monoterpenoid hydrocarbon content of Cymbopogen oils varies widely with geographical source (large amounts from Ceylon, small from Java).44 A similar study has been made on the monoterpenoids of balsam fir.45
OMe (22)
A structure-activity correlation study of the substituted monoterpenoid type (22) of juvenile hormone attempts to show certain structural similarities with e c d y ~ o n eA. ~ ~ juvenile hormone antibody has been developed which binds specifically with the naturally occurring hormone, thereby distinguishing it from mimics such as the monot e r p e n o i d ~A. ~large ~ number of variants of the geranyl part of the monoterpenoid ether juvenoids, including cyclogeranyl, linalool oxide (tetrahydrofuryl), and reduced and oxidized types, have been tested for insecticidal Pharmacological activities are reported for but-2-ynamine derivatives of borneol and and of pinol and camphene.” The full paper on the repellant action of diethylthujamide against the yellow fever mosquito (Aedes aegypti) and other insects has appeared (Vol. 3, p. 38
39 40 41
42
43
44
45 46 47 48 49 50 51
H. J. Nicholas, in ‘Phytochemistry’, ed. L. P. Miller, Van Nostrand, New York, 1973, Vol. 2, p. 254. A. Matsuo, H . Hara, M. Nakayama, and S. Hayashi, Flavour Znd., 1973,4, 343. G . Marczal and M. V. Vincze, Gyogyszereszet, 1973, 17, 214 (Chern. Abs., 1973, 79, 149 277). M. Hiroi and D. Takaoka, Nippon Kagaku Kaishi, 1973, 1339. A. I. Akhmedov, Sh. K. Chogovadze, M. I. Goryaev, and A. D. Dembitskii, Masfob-Zhir. Prom., 1973, 26 (Chern. Abs., 1973,79,83 384). A. J. Aasen, J. R. Hlubucek, S.-0. Almquist, B. Kimland, and C. R. Enzell, Acra Chern. Scand., 1973, 27, 2405. R. 0. B. Wijesekera, A. L. Jayewardene, and B. D. Fonseka, Phytochemistry, 1973, 12, 2597. D. T. Lester, Canad. J. Forest Res., 1974, 4, 55. J. F. Grove, R. C. Jennings, A. W. Johnson, and A. F. White, Chern. and Ind., 1974, 346. R. C. Lauer, P. H. Solomon, K. Nakanishi, and B. F. Erlanger, Experientia, 1974, 30, 5 5 8 . B. D. Hammock, S. S. Gill, and J. E. Casida, J. Agric. Food Chern., 1974, 22, 379, 386. E. Mariani, M. Longobardi, P. Schenone, F. Bondavalli, and C. Bianchi, Chirn. thPr., 1973,8, 281. E. Mariani and P. Schenone, Educ. Sci., 1974, 29, 113. V. Hach and E. C. McDonald, Canad. J . Chern., 1973,51, 3230.
Terpenoids and Steroids
8 4 Acyclic Monoterpenoids
Terpenoid Synthesis from Isoprene.-Isoprene could be one substance affected by current raw material shortages, and its synthesis is vital for entry into the terpenoid field. Reactien of isobutylene with formaldehyde yields isoprene and 20% of a dioxan (23) which can be converted into a mixture of alcohols (Scheme 2) with oxalic acid, one of which (24) is produced i n d ~ s t r i a l l y . ~ ~
+
’ CH,O
--+
0
+
I\/cH20H
(COZWZ,
’
OH
0
+
(23)
&cH20H
L C H , O H
+
& OH (24)
Scheme 2
The thermodynamics of the Diels-Alder dimerization of isoprene are consistent with a one-step concerted m e ~ h a n i s m Dimerization .~~ of isoprene over certain palladium complexes yields only tail-to-tail-linked hydrocarbons (cf. Vol. 4, p. 1 1),54 and more has been published on the stannic chloride telomerization, giving a 61 % mixture of E- and 2-geranyl chlorides (25; R = H,) (besides tail-to-tail isomers),55the 2-isomer cyclizing to 8-chloromenthene under the telomerizing condition^.^^ Further work has appeared on the alkali-metal-catalysed dimerizations of isoprene using sodium naphthalene5’ or lithium and t-butylamine, the latter yielding head-to-tail and tail-to-tail products in equal amounts.58The dimer obtained in low yield using sodium in benzene is 92 myrcene (1 3).59 The chloride (25;R = 0)is available from the reaction between isoprene and senecioyl chloride (26) in the presence of stannic chloride. It has been converted into the ocimenones (27) and filifolone (28), and a similar route using isovaleroyl chloride instead of (26) leads to the tagetones (29).60 ,’;.”,
Isoprene
+ I , , , -) (26) 52
53 54
55
5b
” 58 59
6o
(25)
(27)
S. K. Ogorodnikov and Yu. M. Blazhin, Khim. Prom., 1974, 2 , 87; J. 0 . Turner and H. F. Peterson, Amer. Chem. Soc., Div. Petroleum Chem., Preprints, 1974, 19, 88. J . Rimmelin and G . Jenner, Tetrahedron, 1974, 30, 3081. A. D. Josey, J . Org. Chem., 1974, 39, 139. K. V. Laats, T. A. Kaal, I. A. Kal’ya, I. B. Kudryavtsev, E. A. Muks, M. A. Tali, S. E. Teng, and A. Yu. Erm, Zhur. org. Khim., 1974, 10, 159; K. V. Laats and E. A. Muks, ibid., p. 162. K. V. Laats, S. Teng, and T. 0. Savich, Zhur. org. Khim., 1974, 10, 164. T. Fujita, K. Suga, and S. Watanabe, Nippon Kagaku Kaishi, 1973, 2182. Y . Suga, S. Watanabe, and S. Tanaka, Jap. P., 28 403/1973(Chem. Abs., 1973,79, 145 948). J. Tanaka, T. Katagiri, and K. Takabe, Jap. P., 26 70611973 (Chem. Abs., 1973, 79, 66 610). D. R. Adams, S. P. Bhatnagar, R. C. Cookson, and R. M. Tuddenham, Tetrahedron Letters, 1974, 3197.
9
Mono terpenoids
(30)
(29)
Further syntheses with isoprene units are discussed in the next section.
2,6-Dimethyloctanes-Dehydroneryl isovalerate (30) [the formula (4 1) in Volume 4, p. 12, has wrong stereochemistry] has been synthesized from nerol(1Q6'One of the two coumarin monoterpenoids (3 1) in Capnophyllum peregrinum has been synthesized directly (Scheme 3) from the tetrahydropyranyl ether of linalool (12);62 the other is described in the furanoid section.
THP = tetrahydropyranyl
Reagents: i, SeO,; ii, PBr,; iii, 0
Scheme 3
The novel structure (32) reported from Psiada salvifolia is insufficiently supported (only mass and i.r. spectra).63 The two allo-ocimene isomers (33) from cz-pinene can be separated by allowing the Eisomer (more reactive) to form an adduct with methyl acrylate, leaving the pure Zisomer.64The reduced ocimene (34), formed by pyrolysis of pinane, can be converted into optically active citronellol (35) on hydroboration and oxidation [( +)-(35) from ( - p inane].^' Various cyclizations of the hydrocarbon (34) have been described (Scheme 4), formation of the palladium complex apparently occurring by sequential isomerization of the initially co-ordinated vinyl group, giving the strongly co-ordinated diene (36), which is reduced by available palladium hydride.66 61
62
63
" 65
66
F. Bohlmann and H.-J. Bax, Chem. Ber., 1974, 107, 1773. F. Bohlmann and D. Kornig, Chem. Ber., 1974, 107, 1780. R. Dennis, Phytochernistry, 1973, 12, 2705. Y . Fujihara, C. Hata, T. Noguchi, and Y. Matsubara, Nippun Kagaku Kaishi, 1973, 1802. K. Suga, S. Watanabe, and T. Fujita, Yukugaku, 1973, 22, 738. F. J. McQuillin and D. G. Parker, J.C.S. Perkin I, 1974, 809.
Terpeiioids and Steroids
10
6
CH,OH
(33)
(34)
(35)
I
(36) Reagents: i, PdC1,-CuC1,-DMF; ii, Hg(OAc),; iii, PdC1,-aq. acetone; iv, HC0,H-H,SO,.
Scheme 4
Reduction by diborane of the tricarbonyliron complexes of myrcene (13) and 2-ocimene (37) adds hydrogen across the isopropylidene double bond ; the a-phellandrene complex (see menthanes) was also e ~ a m i n e d . ~ Multistage ' syntheses of a-myrcene (38), myrcene (13), and a related alcohol have been published.68
Metal-catalysed addition of acetic acid to myrcene (13) yields mainly addition products to the conjugated diene system (cf. Vol. 4, p. 14).69Sensitized photo-oxygenation of the diene (34)70or linal0ol(l2)'~ results in the introduction of oxygen on the more 67
68 69 'O
-'
D . V. Banthorpe, H. Fitton, and J . Lewis, J.C.S. Perkin I, 1973, 2051. 0. P. Vig, B. Ram, U. Rani, and J . Kaur, J . Indian Chem. Soc., 1973,50, 329. K . Suga, S. Watanabe, T. Fujita, and K . Takeda, Yukugaku, 1973, 22, 321. D. V. Banthorpe, M. R. Young, and W. D. Fordham, Chem. and Ind., 1973, 901. H . Kjosen and S. Liaaen-Jensen, Acta Chem. Scand., 1973, 27, 2495.
Mon ot erpeno ids
11
substituted double bond, but autoxidation of myrcene is less specific. Upwards of 42 substances are formed by oxygegation, cyclization, disproportionation, and polymerization, including pinenes, linalool oxides, camphor, and carvone, besides expected corn pound^.^^ The pyrolysis of allo-ocimene peroxide (Vol. 1, p. 12) has been reinvestigated.73 Direct introduction of an amino-group into myrcene (13) occurs with diethylamine and sodium naphthalene, sodium acetate in acetic anhydride converting the products into geranyl acetate.74
Access to oxygenated 2,6-dimethyloctanes can also be achieved by ring-opening of oxygenated menthanes ; for example, Bayer-Villiger oxidation of ( - )-menthone (39), followed by metal hydride reduction to the glycol (40) and pyrolysis over potassium bisulphite, yields 60% of (+)-citronello1 [( + )-(35)], (+)-menthone similarly giving (-)citronellol of high optical The total synthesis of tagetonol (41) in five stages from isobutyl methyl ketone has been reported,76 and 2-methyl-6-methyleneocta-2,7dien-4-01 (42) was prepared following Scheme 5. Allylic rearrangement of (42) to the
Q
dcH2Br ___, Zn
HO
--bA
Scheme 5
alcohol (43),together with polymerization, occurs above 100 0C.77These total syntheses yield racemates, but Lefebvre et a!. have made (+)-dihydrotagetone (44)by photolysis of ( + )-3-methylcyclopentanone (49, followed by Grignard addition and oxidation. Natural tagetone was thus shown to be highly racemized [although some racemization occurred during irradiation of (45)].’
’’ R. H. Dieckmann and S. R. Palamand, J . Agric. Food Chem., 1974, 22,498. l 3
75 7b ”
78
I. P. Mash’yanov and G . L. Dranishnikov, Trudy Arkhangel’sk. fesotekh. Inst., 1972, 32, 60 (Chem. Abs., 1974,80,60 044). T. Fujita, K. Suga, and S. Watanabe, Austral. J . Chem., 1974, 27, 531. T. Shono, Y. Matsumura, K. Hibino, and S. Miyawaki, Tetrahedron Letters, 1974, 1295. 0. P. Vig, B. Ram, and B. Vig, J . Indian Chem. SOC.,1973, 50, 408. R. G. Riley, R. M. Silverstein, J. A. Katzenellenbogen, and R. S. Lenox, J . Org. Chem., 1974, 39, 1957. B. Lefebvre, J.-P. Le Roux, J. Kossanyi, and J.-J. Basselier, Compt. rend., 1973, 277, C,1049.
Terpenoids and Steroids
12
A
(45)
(44)
Treatment of the dilithium salt (46) with an alkyl halide is equivalent to adding isoprene. The double-bond isomer (47) of geraniol was thus made, converted into the corresponding aldehyde and acid, and isomerized to the geraniol series.79The dianion (48) of methyl acetoacetate can replace (46), the additional methyl group being added to the en01 acetate (49)80to obtain a 1 : 10 mixture of 2 : E methyl geranates (50). Use of the enol benzoate, however, results (loo"//,!) in a 2 : E ratio of 5.8 : 1." The principle of activating a methylene group with a sulphone unit (Vol. 4,pp. 15,16) has been applied to couple a second geranyl group to geranyl sulphone.82 1
.+
0
.I
(50)
0
0
(49)
Conversion of linalool(l2) into geranyl, neryl, and a-terpinyl acetates with toluene-psulphonic acid in acetic anhydride83 is less interesting than the reverse rearrangement, which occurs on heating geranyldimethylamine oxide (51). Very pure linalool (12) is obtained from the substance (52) thus obtained after reduction with zinc in acetic acid, while heating (52) results in isomerization to the corresponding nerol and geraniol
isomer^.'^
'' "
'' 83
84
G. Cardillo, M . Contento, and S. Sandri, Tetrahedron Letters, 1974, 2215. C. P. Casey and D. F . Marten, Synth. Comm., 1973, 3, 321; c:f: S. N. Huckin and L. Weiler, Canad. J . Chem., 1974,52; 2157. C. P. Casey and D. F. Marten, Tetrahedron Letters, 1974, 925. P. A. Grieco and Y. Masaki, J . Org. Chem., 1974, 39, 2135. J. H. Babler and D. 0. Olsen, Terrahedron Letters, 1974, 351. V. Rautenstrauch, Helv. Chim. Acta, 1973, 56, 2492.
Mono t erpenoids
13
Base treatment of the sea hare monoterpenoid (Vol. 4, p. 12), a bromohydrin, yields the epoxide (53)” The fact that selenium dioxide introduces oxygen on the isopropylidene terminal carbon atom of geranyl compounds in exclusively the E geometry has been used to prepare E-1-chloro-2,6-dimethyloctanesfor further specific reactions.86
Cyclizations of carbonium ions derived from geranyl compounds are used as ‘biogenetic’ type models for polycyclic terpenoids. Using acetyl, crotonyl, and 2,6-dimethyl3-methoxybenzoyl chlorides and Lewis acids (Scheme 6), geranyl acetate (54)cyclizes to (55) or (56),but methyl geranate (50) does not cy~lize.~’ Citronellol, lacking the extra
Reagents: i, AICI,; ii, SnCl,; iii, LiCl-DMF. Scbeme 6
”
86 13’
M. R. Willcott, R. E. Davis, D. J. Faulkner, and M. 0. Stallard, Tetrahedron Letters, 1973, 3967. L. J. Altman, L. Ash, and S. Marson, Synthesis, 1974, 129. S. Kumazawa, Y. Nakano, T. Kato, and Y. Kitahara, Tetrahedron Letters, 1973, 3967.
14
Terpenoids and Steroids
double bond, gives the dimeric ether (57) with boron trifluoride etherate.’* A novel cyclization is discussed in the section on iridoids. Further relevant papers in this section (besides Cookson’s syntheses noted in the previous section) concern measurement of the triplet lifetime of a l l o - ~ c i m e n evarious ,~~ Diels-Alder reactions of allo-ocimene and homologues,90 the formation of hydrooxycitronellal and its ethers by hydration of citronella1 imines,” specific reduction of certain positions in gerani01~~ and ~ i t r awith l ~ ~different catalysts, epoxidation of geranyl chloride (25; R = H2),94and the preparation of (R)-6methylhexane from (-)-citronellol [( -)-(35)J9’
Artemisyl, Santolinyl, Lavandulyl, and Chrysanthemyl Derivatives.-A review of rearrangements in this series has appeared.96 Julia et al. have made artemisia ketone (58) from the sulphide (59) and lithium 3methylbut-1-yn-3-yl chloride [Li-(60)], the allene (61) resulting from the sigmatropic rearrangement being readily converted into the ketone (58). Alternatively, reaction of the sulphide (59) with (60) in aqueous sodium hydroxide gives the acetylene (62; R = C-CH)-not, apparently, by simple alkylation of the sulphide (59), which does not react with alkyl halides under these conditions. Sigmatropic rearrangement of the ylide
L
’
SMe
\*\* SMe
Reagents : i, Protonating solvent: ii, hydrolysis, HgCI,; iii, prolonged heat.
Scheme 7 89
92 93 94
’’ 96
K. Nagai, M. Nakayama, and S . Hayashi, Chem. Letters, 1973, 665. R. S. H . Liu, Y . Butt, and W . G. Herkstroeter, J.C.S. Chem. Comm., 1973, 799. Y . Matsubara, T. Kishimoto, M. Kasano, and W. Minematsu, Nippon Kagaku Kaishi, 1973, 972; Y . Matsubara, T. Kishimoto, Y. Imoto, and W. Minematsu, ibid., p. 1064; Y . Matsubara, T. Kishimoto, and W. Minematsu, ibid., p. 968. R . Ishino and J. Kumanotani, J . Org. Chem., 1974,39,108; P. Chabardes, Ger. Offen 2 262 740; Ogawa and Co., Ltd., Fr. P. 2 146 563 (Chem. Abs., 1973, 79, 78 997); CJ also Vol. 2, p. 11. Sou Phouti, Hua Hsueh, 1973, 72 (Chem. Abs., 1974, 80, 37 307). E. Mourier, Ger. Offen 2 322 584. J. H. H. Chan, U.S. P. (appl.) 219 866/1973. C. Carlini, D. Pini, 0. Bonsignori, and P. Neuenschwander, Gazzettu, 1973, 103, 1297. C. D. Poultier, J . Agric. Food Chem., 1974, 22, 167.
15
Monoterpenoids
anion (63) is proposed.97 The maximum enantiomeric purity of the artemisyl product (62; R = CH=CH,) from the sigmatropic rearrangement of the salt (64) using chiral bases was only 12%.98 Lavandulol(65; R = CH,OH) is produced (6 % yield) from the isoprene-magnesium . ~ ~nitrile (65 ; R = CN) complex (Vol. 2, p. 8) and prenyl chloride with air ~ x i d a t i o nThe smells of anise !loo Details have appeared of the preparation of chrysanthemic acids from carene ozonolysis (Vol. 3, p. 23)"' and of the pyrethrin crystal structure."' Photolysis of pyrethrin affects only the non-terpenoid portion. l o 3
.
R
= CH=NNHTs or CMe=NNHTs
*\
(64)
(65)
(66)
Thermal or photochemical decomposition of lithium salts of the tosylates (66) gives hydrocarbons of the artemisia and santolina series [690/,of santolinatriene (67)thermally], together with ring-expanded substances (cyclobutenes), the reaction proceeding via
II, 111 __*
NOH
(70) R = CH,CN (68) R = CH,OH Reagents: i, h v ; ii, Pd/C-H,; iii, C,H,ONO-t-amyl-K-dry C,H,; iv, N,H,-KOH; v, TiCl,; vi, PC1,-lutidine-ether; vii, KOH-triglyme-HOCH,CH ,OH ; viii, LiAIH,.
Scheme 8 97
98 99
loo lo'
lo'
Io3
D. Michelot, G. Linstrumelle, and S. Julia, J.C.S. Chem. Comm., 1974, 10; Cornpt. rend., 1974, 278, C , 1523. B. M. Trost and W. G. Biddlecom, J. Org. Chem., 1973, 38, 3483. H. E. Ramsden, Ger. Offen 2 311 068. H. Kappeler and J. Wild, Ger. Offen 1 817 925. W. Cocker, H. St. J. Lauder, and P. V. R. Shannon, J.C.S. Perkin Z, 1974, 194; see also the excellent modification by R. Sobti and Sukh Dev, Tetrahedron, 1974,30,2927, of the old Matsui synthesis, Agric. and Biol. Chem. (Japan), 1965, 29, 784; 1967, 31, 33. M. J. Begley, L. Crombie, D. J. Simmonds, and D. A. Whiting, J.C.S. Perkin Z, 1974, 1230. M. J. Bullivant and G. Pattenden, Tetrahedron Letters, 1973, 3679.
Terpenoids and Steroids
16
chrysanthemyl carbenes. 'O 4 Homologues of methyl chrysanthemate have been made by ozonolysis of chrysanthemate and Wittig rea~tion,'~' and other related materials, some of which are both more persistent and more photostable than the natural substances, have been described.lo6 5 Monocyclic Monoterpenoids
Cyc1obutane.--The synthesis of grandisol(68) from the eucarvone photoisomer (69) is shown in Scheme 8.'" The acid chloride (71) [from methylbutanolide (72)] reacts with isoprene and triethylamine in an autoclave to form the carbon skeleton of grandisol, but the synthesis failed when the halide (73) could not be converted into the alcohol.lo8 CH ,CH,Cl FfCI-SOCI,
I
Isoprene
CHCOCl
I
Me
(73)
A successful synthesis made use of the fact that if either four- or five-membered rings can be formed by cyclization of an epoxy-nitrile the cyclobutane is always preferred, the epoxide (74) giving the cyanocyclobutane (75) with lithium hexamethyldisilazane. Subsequently, the cyano-group was converted into methyl via the aldehyde, and the hydroxyl was removed by oxidation and a Wittig reaction.'"
OH (75)
Cyclopentanes, 1ridoids.-A new, antileukaemic iridoid lactone, allamandin (76) (dihydroplumericin), occurs with plumericin in Allarnandia cathartica.' l o Arornia mosdmfa, a Cerambycid of the Coleoptera, contains two iridodials (77).'11 From two Cornus spp. (dogwood), the new dihydrocornin (78 ; R' = Me, R 2 = R3 = H) has been isolated. The corresponding ketone, cornin, has long been known and is identical with 'verbanalin'; the latter name should be abandoned.' l 2 Other new iridoid glucosides are T. Sasaki, S. Eguchi, M. Ohno, and T. Umemura, J. Org. Chem., 1973, 38. 4095. K . Okada, K. Fujimoto, and M . Matsui, Agric. and B i d . Chem. (Japan), 1974, 38, 827. M . Elliott, A. W . Farnham, N. F. James, P. H . Needham. D . A. Pulman, and J . H . Stevenson, Nature, 1973,246, 169: 1974,248, 710; J. M. Barnes and R. D . Verschoyle, ibid., 1974,248,711 : K . Fujimoto, N . Itaya, Y . Okuno, T. Kadota, and T. Yamaguchi, Agric. and Biol. Chem. (Japan), 1973, 37, 2681. W. A. Ayer and L. M. Browne, Canad. J. Chem., 1974,52, 1352. J.-C. Grandguillot and F. Rouessac, Compt. rend., 1973, 277, C, 1273. G. Stork and J. F. Cohen, J. Amer. Chem. Soc., 1974, 96, 5270. S. M. Kupchan, A. L. Dessertine, B. T. Blaycock, and R. F. Bryan, J. Org. Chem., 1974, 39, 2477. G. Vidari, M. De Bernardi, M. Pavan, and L. Ragozzino, Tetrahedron Letters, 1973, 4065. S. R . Jensen, A . Kjaer, and B. J . Nielsen, Acra Chem. Scand., 1973, 27. 2581.
Io4
Io5
Io6
lo'
Io8 lo'
'lo
I I ' I 2
17
Mono terpeno ids
W H O
T C H O
lamiridoside (78; R' = R3 = OH, R 2 = Me) from the white dead-nettle (Larnium alburn),'13 durantoside (79; R = H) and two of its esters (79; R = methoxy- or dimethoxy-cinammoyl) from Duranta repens,' deutzioside (mentzeloside? cf. Vol. 4,p. 24) from Deutzia s ~ a b r a , 'and ~ ~ ajugol(80; R = H) and its acetate ajugoside (80; R = Ac) from Ajugu reptuns and other Labiatae. l 6 Ajugoside is very similar to leonuride, from Leonurus cardiaca.' l 7 Two new sweroside derivatives (81 ; R = /I-glucose esters)
' '
qo Ri:40
CH,OCOCH,CHMe,
C0,Me
H
O
G
o
MeFjo FI
I'
O-P-Glu
OR (81)
(82) R'
=
H or OH, RZ = HOC,H,CH,CH,
(83) R'
=
H, R 2 = (HO),C6H3CH,CH2
O-P-Glu (84)
have been isolated from Gentiana spp.,' and new secoiridoids (82 ;R = H or OH) from Ligustrum obtusifolium.l 1 Oleuropin (83), kingoside, and morronoside have been
I l3
'I4 'I6 'I7
'"
'I9
P. Eigtved, S. R. Jensen, and B. J. Nielsen, Acra Chem. Scand., 1974, B28, 8 5 . H. Rimpler and H. Timm, 2. Naturforsch., 1974, 29c, 1 1 1 . F. Bonadies, P. Esposito, and M. Guiso, Gazzetta, 1974, 104, 17. M. Guiso, T. Martini-Bettolo, and A. Agostini, Gazzetta, 1974, 104, 25. K. Weinges, P. Kloss, and W. D. Henkels, Annalen, 1973, 566. H. Inouye, S. Ueda, Y . Nakanmra, K. Inoue, T. Hayano, and H. Matsumura, Tetrahedron, 1974, 30, 571; H. Wagner and K. Vasirian, Phytochemistry, 1974, 13, 615. Y . Asaka, T. Kamikawa, T. Kubota, and H. Sakamoto, Chem. Letters, 1972, 615.
Terpenoids and Steroids
18
correlated with asperuloside ; I '' similar correlation of didrovaltrate and valerosidate (84)led to amendment of the structure of the latter.12' The structure of the hydrolysis product, elenolic acid (85), from oleuropin (83) has been established by converting it into ajmalicine (86).This showed that in the hydrolysis step the acyclic hydroxy-aldehyde system (87) undergoes conjugate addition of the ahydroxymethylene ester to the &unsaturated aldehyde.' 2 2
r2;q0 -
HO,C Y C CO,Me H O
C0,Me
(83)
+
OH
I
H0,C
--+ CHO (87)
OHC (85)
Me
1
Tryptamine (five steps)
A supposed difference between ( +)-boschniakin (88) and (+)-indicainz arose because the aldehyde group was converted into the acetal during recrystallization of the picrates ! The new cis,cis-nepetalinic acid (89) was prepared during full elucidation of the stereochemistries of all four acids.'24 The total synthesis of elenolic acid is shown in Scheme 9.12' Although only low yields of iridanes were obtained from cyclopentenaldehyde and ethyl 3-ethoxyacrylate,' 26 Tietze has made hydroxyloganin and hydroxyloganic acid from an intermediate (90) of the Buchi synthesis (Vol. 1, p. 20). Epimerization at C-6 in (91) gave a diacetate (92) which was glucosylated as in the Buchi synthesis.127The cis stereochemistry at C-1 and C-6 prevents cleavage of the ring by the dimethyl sulphoxide anion, but the trans-glycol monotosylate from (91) was cleaved to a mixture of the
'
12'
'''
124
127
H . Inouye, T. Yoshida, S . Tobita, K. Tanaka, and T. Nishioka, Tetrahedron, 1974, 30, 201 ; a preliminary note (Tetrahedron Letters, 1970, 2459) was omitted from these Reports, but full structures have been given with other papers from this group (Vol. 3, p. 28). H. Inouye, S. Ueda, S. Uesato, T. Shingu, and P. W. Thies, Tetrahedron, 1974, 30,2317. F. A. MacKellar, R. C. Kelly, E. E. van Tamelen, and C. Dorschel, J . Amer. Chem. Soc., 1973, 9 5 , 7 1 5 5 ; CJ recent conversion of secologanin into corynanthe-type alkaloids, R. T. Brown and C. L. Chapple, J.C.S. Chem. Comm., 1973, 886, and the total synthesis of elenolic acid ( 8 5 ) , below. D. Gross, W. Berg, and H . R. Schutte, Z . Chem., 1973, 13, 296. H . G. Grant and M. D. Sutherland, Austral. J . Chem., 1973, 26, 2183. R . C. Kelly and 1. Schetter, J . Amer. Chem. SOC.,1973, 95, 7156. L.-F. Tietze, Chem. Ber., 1974, 107, 2491. L.-F. Tietze, Angew. Chem. Internat. Edn., 1973, 12, 757; Chem. Ber., 1974, 107, 2499.
Mono terpeno ids
19 MeO,CCH,,
0
+ BrCH2C0,Me
Na
C H ,CO, Me
0
i."
x
/C02Me M
s
O
W
o
,
z
M
e
*I
I
'OH
HO
xO C O * M e CO,Me
-%
MsO
( 8 5 ) dimethylester
OH
Reagents: i, Citraconic anhydride; ii, H,O; iii, KClO,-OsO,; iv, acetone; v, electrolytic decarboxylation; vi, KMn0,-KIO,; vii, CH,N,; viii, NaBH,; ix, MsC1-py; x, 60 % H C 0 , H ; xi, HIO,; xii, py-H,O.
eo ,H
Scheme 9 C0,Me
C02Me
0
A c O - - e 0
H I
OMe
OMe
Ho2C
1
(90)
(91) IV, \.I, V I I
HOC
C0,Me
+ H
OMe
C0,Me
5 OMe
(92)
Hoq (81 ; R = Me)
i i - H tOYM0 e
Reagents: i, MeMgCO,; ii, NaBH,; iii, Ac,O-py; iv, B,H,; v, hydrolyse, then treat dimesylate with AcONEt,; vi, TsC1-py; vii, NaCH,SOMe.
Scbeme 10
Terpenoidsand Steroids
20
secologanin aglucone methyl ether (93), and the lactol of secologanic acid ether (94), from which sweroside methyl ether (81 ; R = Me) was obtained (Scheme 10). A postulated biogenetic path from the cis-loganin series, e.g. (92),is thus not realizable in vitro.' 2 8 A new type of geraniol cyclization occurs when either the E- or Z-isomer (15) or (16), cyclogeraniol (95; R = CH,OH), or irid-1-en-9-01 (96) is treated with fluorosulphonic acid in sulphur dioxide and carbon disulphide at - 78 "C.The presence of the oxonium ion (97)of the new iridoid (98)was demonstrated by n.m.r. spectrometry (Scheme 1l).'29
Scheme 11
p-Menthanes.-An excellent review of methods for synthesizing optically active menthol' 30 and one on pterpineol' have appeared. Addition of acetone to the dilithium salt of 4-methylcyclohex-3-enecarboxylicacid leads to a hydroxy-acid (99) which lactonizes with benzenesulphonyl chloride, the lactone (100)giving terpinolene (101)on heating.' 3 2 4-Methyl-2-hydroxycyclohexanone isomerizesduring reaction with 1-methyl-2-ethoxyethenyltriphenylphosphonium iodide, SO that two menthofurans (102) and (103) are oblained. Efforts to trap the single anion needed to form only (102)were not successful.' 3 3 Methyl 4-methylcyclohexa-l,4-dienecarboxylate is readily converted into mentha-l,4-dien-8-01 (104; R = OH), which is
'IR ""
13'
'"'"
L.-F. Tietze, J . Arne?. Chem. Soc., 1974, 96, 946. D. V. Banthorpe, P. A. Boullier, and W. D. Fordham, J.C.S. Perkin I , 1974, 1637. J . C. Leffingwell and R. E. Shackelford, Cosmetics and Perfumery, 1974, 89, 69. J . Verghese, Indian Perfumer, 1972, 16. 3 5 . A. P. Krapcho and E. G . E. Jahngen, jun., J . Org. Chem.. 1974, 39, 1322. M. E. Garst and T. Spencer, f . Org. Chem., 1974, 39, 584.
Monoterpenoids
21
readily oxidized by air to the aromatic alcohol. Claisen rearrangement of the vinyl ether (104; R = OCH=CH,) introduces a C2 unit at C-3.'34 The tricarbonyliron complexes (105) of ~+phellandrene~'.'~~ are isomerized by acid, subsequent removal of the iron (with Cu2+)giving mentha-2,4-diene.l 3 5 U.V. irradiation of a-phellandrene gives two isomers [(106); exo : endo = 5 : 13 arising from cyclization of triene (107).'36
Heptafluorinated menthanes and menthols (fluorine in the isopropyl group) have been made. 37 4-Chloromentha- 1,8-dienehas been noted above,3s trans-8-chloromenth2-ene is made by addition of hydrogen chloride to mentha-2,8-die11e,'~*and chlorination of menthone (39) and carvomenthone leads to substitution of the more substituted carbon atom adjacent to the carbonyl group.' 39 Carman and Venzke have prepared the 1,2,4,8-, 1,2,8,9-, and 1,4,7,8-tetrahaIogenomenthanesand have extended their work (Vol. 4,p. 31) by making optically active terpinolene tetrabromide (108)from (+)-or-terpineol (17).' 40 Bromination of ( - )-a-phellandrene and (- )-P-phellandrene [mentha-1(7),2diene] was examined ; the 1,2,3,7-tetrabromide from the latter showed greater stability than the limonene or terpinolene tetrabromides (108).14' Action of base on 1,4,8tribromomenthane, followed by bromination, gives the two tetrabromides (108)and (109) derived from terpinolene and mentha-l(7),4(8)-diene respectively. The tetrabromide of mentha-1(7),3-diene (p-terpinene) is also described. 42 In a discussion of halogenated
'
'
134 135
136 13'
13' 139
I4O 14' 14'
A. Hoppmann and P. Weyerstahl, Chem. Ber., 1974, 107, 1102. A. J. Birch, J . Agric. Food Chem., 1974, 22, 162. K. J. Crowley, K. L. Erickson, A. Eckell, and J. Meinwald, J . C . S . Perkin Z, 1973,2671. A. N. Blakitnyi, V. N. Boiko, E. V. Konovalov, Yu. A. Fialkov, and L. M. Yagupol'skii, Zhur. org Khim., 1974,10, 503; A. N. Blakitnyi, E. V. Konovalov, A. P. Sevast'yan, Yu. A. Fialkov, and L. M. Yagupol'skii, ibid., p. 509; cf: Vol. 2, p. 21. A. B. Booth, U S . P. 3 755 472. F. Yasuhara, Nippon Kagaku Kaishi, 1973, 1938. R. M. Carman and B. N. Venzke, Austral. J. Chem., 1973, 26, 2235; 1974, 21, 383. R. M. Carman and B. N. Venzke, Austral. J. Chem., 1974, 27, 441. R. M. Carman and B. N. Venzke, Austral. J. Chem., 1974, 27, 449.
Terpenoids and Steroids
22 CH,Br
Qr
---Br
menthones. it is suggested that some a,a'-dibromocyclohexanones can exist in boat form ( f 10) if there is an additional halogen-carbonyl i n t e r a ~ t i 0 n . l ~ ~ Photoinitiated auto-oxidation of l i m ~ n e n e ' ~ has ~''~ been ~ shown to involve 41 % unsensitized photo-oxidation by singlet oxygen, occurring concurrently with radical oxidation. 1 4 5 Limonene cis- and trans-monoepoxides can be separated by spinning-band distillation instead of the long route previously used (Vol. 1, p. 26); catalytic hydrogenation of the pure isomers has been studied.'46 The monoepoxide (1 11) of y-terpinene occurs in Origanum heracleoticum and was reported to be the sole product from epoxidation of the hydrocarbon with monoperphthalic acid,147which is surprising since peracetic acid148 and peroxybenzimidic acids' 49 yield both monoepoxides. a-Terpinene (18) also yields both monoepoxides,'50 and metal hydride reduction of all these substances has been investigated.'49*'5 o Ring-opening by ethanol in basic or acid media of limonene (11) 1,2epoxides and diepoxides has been studied ; the latter undergo 1,2-ring-opening with boron trifluoride etherate but 8,9-opening with base catalysis.' 5 1 The complete stereochemistry of (lS, 2S, 3R, 4S)-piperityl acetate epoxide (1 12) isolated from several Mentha spp. is established.'52
14' '44
145
146
14'
14'
' '
5o I
15*
R. M. Carman and B. N. Venzke, Austral. J. Chem., 1973,26, 1977. I . I . Bardyshev, V . S. Shavyrin, and V. V. Budylina, Sbornik, Trudov, (sent. nauchn.-issled. Proekt. Inst. lesokhim. Prom., 1971, NO.21, p. 25 (Chem. Abs., 1974, 80, 70 973). T. Sato and E. Murayama, Bull. Chem. SOC.Japan, 1974, 47, 715. A. Kergomard and H. Veschambre, Compt. rend., 1974, 279, C , 155. B. M. Lawrence, S. J. Terhune, and J. W. Hogg, Phytochemistry, 1974, 13, 1012. A. F. Thomas, unpublished work. S. A. Kozhin and E. I. Sorochinskaya, Zhur. obshchei Khim., 1974, 48, 944; cf- Vol. 4, p. 30. M. Zaidlewicz and A. Uzarewicz, Roczniki Chem., 1974,48,467. L. A. Mukhamedova, M. I. Kudryavtseva, R. R. Shagidullin, and Yu. Yu. Samitov. Izvesr. Akad. Nauk S . S . S . R . , Ser. khim., 1973, 1061; L. A. Mukhamedova, M. I. Kudryavtseva, and A. A. Martynov, ibid., 1974, p. 404. H . Shibata and S. Shimizu, Agric. and Biol. Chem. (Japan), 1973, 37, 2675.
Monoterpenoids
23
Hydroperoxides and other p-menthanes oxygenated at C-4 and C-8 are formed from menthan-4-01and hydrogen peroxide in acid.lS3A product of ene addition to isopulegol (8; R = H) dwing selenium oxide oxidation can be trapped as the selenino-lactone (1 13), thus supporting a step in the postulated mechanism of allyl alcohol oxidation (Vol. 4, p. 17). s4 Mercuric acetate and limonene (11) yield (after borohydride reduction) aterpineol (17) and menth-8-en-1-01. With less mercuric acetate, the 1,8-di0l (114) and 1,8-cineol (115) were found, together with (17),1 5 5 but possible dehydration of diols [e.g. (114)], known to occur on gas ~ h r o m a t o g r a p h y , was ' ~ ~ not taken into account. Dehydrocineol(ll6) has been isolated from Laurus nobilis, in which cineol (115) is the major constituent.' 5 7 Surprisingly, silver carbonate<elite oxidation of isopulegol (8 ; R = H) is slow and gives an unidentifiable mixture.15* Better stereoselectivity in the allyl oxidation by benzoyloxy-radicals of menth-2-ene is achieved by using copper octanoate as the catalyst (the radical attacking anti to the isopropyl group).'59
'
Nitration of p-cymene (117; R' = R 2 = H) has been known for well over a century to yield p-nitrotoluene by ips0 electrophilic attack (nitrodeisopropylation); now a novel mechanism, based on the idea of the C-1 position as that most active towards attack by nitronium ion, is supported by the isolation of up to 41 % of the ipso-adducts (1 18 ; cis and trans) and 41% of 2-nitrocymene (117; R' = H, R2 = NO,). Migration of the nitrogroup to C-2 masks the existence of the ipsu-products unless conditions allow their isolation, and their thermolysis leads to thymol acetate (117; R 1 = OAc, R2 = H).16' Esterification of 8-hydroxycuminic acid (119 ; R' = R 2 = H) with dry methanol and sulphuric acid gives the esters (119; R' = Me, R2 = H) and (119; R' = R2 = Me), but the presence ofmoisture results only in dehydration of the alcohol. Treatment with hydrochloric acid followed by methanol leads to the dimer (120).16' The protecting group (p-methylbenzyl ether) of perilla alcohol (121) was removed with perchloric acid in acetic acid after hydroboration of the 8,9-double bond.'62 This reaction might have been less successful if the double bond had still been present, owing to rearrangement in the acid conditions ( c j . Vol. 1, p. 23). 153
154 155
156
15'
Is8
I6O 161 16*
Yu. A. Ol'dekop, L. B. Beresnevich, and L. Ya. Shveidel, Vestsi Akud. Nauuk Belurusk. S . S . R . , Ser. khim. Nauuk, 1974, 50. D. Arigoni, A. Vasella, K. B. Sharpless, and H. P. Jensen, J . Amer. Chem. Soc., 1973,95, 7917. M. Bambagiotti A., F. F. Vincieri, and S. A. Coran, J . Org. Chem., 1974, 39, 680. L. Peyron, L. Benezet, D. de Dortan, and J. Garnero, Buii. Soc. chim. France, 1969, 339. J. W. Hogg, S. J. Terhune, and B. M. Lawrence, Phytochemistry, 1974, 13, 868. F. J. Kakis, M. Fetizon, N. Douchkin, M. Golfier, P. Mourges, andT. Prange, J . Org. Chem., 1974, 39, 523. A. L. J. Beckwith and G. Phillipou, Tetrahedron Letters, 1974, 69. R. C. Hahn and D . L. Strack, J. Amer. Chem. Soc., 1974,96,4335. J . Alexander and G. S. K. Rao, Indian J . Chem., 1973, 11, 619. G. Frages and H. Veschambre, Buli. SOC.chim. France, 1973, 3172.
24
Terpenoids and Steroids I
a-Terpinene (18) gives a nitro-oxime (122) with nitrous acid (the 'nitrosite' of W a l l a ~ h ) ; ' "oximes ~ (123) can also be obtained from y-terpinene (104; R = H) by addition of nitrosyl chloride, followed by treatment with amines. 164
Microbiological reduction of carvone (1) with Pseudomanas ovalis or Aspergillus niger occurs with inversion at C-4; the configuration at C-1 varies: (+)-carvone yields (-)isodihydrocarvone (124) and ( - )-isodihydrocarveols (125); ( - )-carvone gives ( + )dihydrocarvone (126)and ( -)-dihydrocarveols, the alcohols corresponding to (126)?
A
A
A
(124)
(125)
(126)
Rate measurements on the borohydride reduction of menthone (39) do not support epimerization before reduction, and the authors do not agree with Hach et al. (Vol. 2, p. 30) that 'extensive epimerization' occurs in dry propan-2-01.' 66 ( f)-Menthone is reduced to menthol with 29.2 % optical purity using chiral bis(cyclohexylmethy1-oanisy1phosphine)cyclo-octa-1,5-dienerhodium tetrafluoroborate and hydr~gen.'~'A thermoanalytical study of the menthol enantiomers has been carried out,'68 and con-
163
'64
16'
166
16*
R. M. Carman, B. Singaram, and J. Verghese, Austral. J. Chem., 1974, 27, 453; 0. Wallach, Annalen, 1887, 239, 33. R. M. Carman, B. Singaram, and J. Verghese, Austral. J. Chem., 1974, 27, 909. Y . Noma and C. Tatsumi, Nippon Nijgeikagaku Kaishi, 1973,47,705; Y . Noma, S. Nonomura, H. Ueda, and C. Tatsumi, Agric. and Biol. Chem. (Japan), 1974, 38, 735; Y. Noma and S. Nonomura, ibid., p. 741. D. C. Wigfield and D. J. Phelps, J. Amer. Chem. Sac., 1974, 96, 543. A. J . Solodar, Ger. Offen 2 312 924. M. Kuhnert-Brandstatter, R. Ulmer, and L. Langhammer, Arch. Pharm., 1974, 307,497.
Monoterpenoids
25
1
iii
Reagents: i, Anodic oxidation; ii, H,O,-OH-; iii, N,H,; iv, MnO,; v, Pd-H,. Scheme 12
version of (-)-menthone (39) into (+)-menthone (Scheme 12) was needed in a preparation of optically pure citronellols (above).75 Hydroxymethylation of menthone (39) gives a 5 : 1 mixture of cis : trans isomers (127) ;169based on the chemical shift of the enol proton, the formulation (127) is preferred to the alternative ( 128).170Reaction of these products with butenone reportedly gives (129) and (130), but the stereochemistry may be more complex than that described.17' Reformatsky reaction of (-)-menthone (39) leads to 80-90% equatorial entry of reagent, the presence of dimethyl sulphoxide increasing the amount of the other isomer.1 7 2 Preparation of the C-2 isomer by Reformatsky reaction of carvomenthone is also d e ~ c r i b e d . 'Variations ~~ in the proportion of axial : equatorial attack on menthone (39), depending on the metal atom, are noted with (131).17, Pulegone (132) and isopropylmagnesium chloride give a chloromagnesium enolate that reacts with p-substituted benzaldehydes (but not saturated ketones), yielding two of the four possible stereoisomers ( 1 33). s Reaction of carbon tetrachloride with limonene (1 1) is catalysed by benzoyl peroxide ; the product (134)can be hydrolysed to the corresponding acid, which was used to add a C, unit in synthesizing the sesquiterpenoid atlantone. 17' Hydroformylation of limonene in the presence of [CO(CO)~PR,],(R = Bu or Ph) or rhodium carbonyl complexes also results in addition to the isopropenyl group.177
'
16'
'-O
IT6
V . M. Potapov, G. V. Kiryushkina, 1. K. Talebarovskaya, N . N . Shapet'ko, and I. L. Radushnova, Zhur. org. Khim., 1973, 10, 21 34. C . Metge, P. Cuillier, and C. Bertand, Compt. rend., 1974, 278, C, 1141. G. D. Joshi, P. H. Ladwa, and S. N . Kulkarni, Indian J . Chem., 1973, 11, 824. J. Pansard and M. Gaudemar, Bull. Soc. chim. France, 1973, 3472. J . F. Ruppert and J. D. White, J . Org. Chem., 1974, 39, 269. N. Idriss, M. Perry, and Y . Maroni-Barnaud, Tetrahedron Letters, 1973, 4447. F. Ghozland,Y. Maroni-Barnaud, and P. Maroni, Bull. Soc. chim. France, 1974, 147, 155. J. Alexander and G. S. K. Rao, Indian J . Chem., 1973, 11, 859. K. Kogami, 0.Takahashi, T. Yanai, and J. Kumanotani, Yakagaku, 1973,22,316 (Chem. A b s . , 1973, 79, 92 400).
Terpenoids and Steroids
26
BU‘OC-.Q
1.:’
-
CHR M = metal (Mg, Zn, etc.)
’
A
(131)
CCI,
Ring contraction of the epoxide of (132) leads to cyclopentanes ; particularly interesting are the preparation of (1R,2R)-dimethylcyclopentane’ ” and the spirolactone (135). 7 9 C-Silylation (at C-6) occurs when carvone (1) is treated with trimethylchlorosilane in the presence of lithium in tetrahydrofuran.
I
+ ‘
0
(135)
The two diols (136) and (137) from hydroboration of (-)-piperitone (138), whose absolute stereochemistries have been confirmed, were used to check Nakanishi’s dibenzoate chirality rule.’ The conformation and reactions of cineolic acid (139), a product of the permanganate oxidation of cineol(ll5), have been studied.’ *
’’
(136)
(137)
(138)
( 139)
W. C. M. C. Kokke and F. A. Varkevisser, J . Org. Chem., 1974, 39, 1535. K. Hayashi, H. Nakamura, and H. Mitsuhashi, Chem. and Pharm. Bull. (Japan), 1973, 21,
‘‘I
2806. R. Calas, J. Dunogues, A. Ekouya, G . Merault, and N. Duffant, J. Organometallic Chem., 1974, 65, C4. J. I. Seeman and H. Ziffer, J. Org. Chem., 1974, 39, 2444. I. D. Rae and A. M. Redwood, Austral. J. Chem., 1974, 27, 1143.
27
Monoterpenoids
Other publications related to p-menthanes concern confirmation of two of the ‘carvelone’ structure^,'^^ selenium oxide-hydrogen peroxide oxidation of l i m ~ n e n e , ’ ~ ~ reaction of ( + )-pulegone (132) and benzoyl chloride, l 8 addition of carbene to carvone (l), piperitone (138), and pulegone (132),186addition of dibromocarbene to pulegone (132) and isopulegols (7; R = H) and (8; R = H) and conversion of the products into allene~,’~’and coupling of diazonium salts with menthadienes and of diazotized 3amino-p-cymene (117; R’ = NH,, R2 = H) with o-Menthane.-Spectra
of some o-menthenes have been studied.’ 89
rn-Menthanes.-Ficini has extended her stereospecific addition of an ynamine and an unsaturated ketone (Vol. 3, p. 39) to the rn-menthanes by using 5-methylcyclohex-2enone as substrate. The acids thus obtained were required in the juvabione synthesis.
Tetramethylcyclohexanes.4ne of the two new lactones from Avtemisia filifolia (Vol. 4, p. 38), (-)-filifolide-A (141), can be made from (-)-chrysanthenone epoxide ( l a ) , a rearrangement that is symmetry-forbidden if concerted. The stereochemistry at the aserisk
OR (142) (144)
R R
=
H
=
isopentyl
OAc
( 1 43)
Reagents: i, Pb(OAc),; ii, v. dil. NaOH in MeCN.
Scheme 13 J . Grimshaw and J. Trocha-Grimshaw, J.C.S. Perkin I , 1973, 2584; cJ Vol, 4, p. 33. I E 4 M. Sumimoto, T. Suzuki, and T. Kondo, Agric. and Biol. Chem. (Japan), 1974, 38, 1061. I M 5P. Crabbe, Recent Adc. Phytochem., 1973, 6, 1. I M 6F. Rocquet and A. Sevin, B u f f .Soc. chim. France, 1974, 888; cJ notes by these authors: Tetrahedron Letters, 1971. 1049; Compt. rend., 1971, 272, C , 417; and the (unquoted) work of M. Narayanaswamy, V. M. Sathe, and A. S. Rao, Chem. and Ind., 1969,921. l E 7M. Santelli and M. Bertrand, Bull. SOC.chim. France, 1973, 2326; B. Ragonnet, M. Santelli, and M. Bertrand, ibid., p. 3119. C. H. Brieskorn and H. H. Frohlich, Arch. Pharm., 1973, 306, 641.
19’
V. V. Bazyl’chik, I. I. Bardyshev, N. M. Ryabushkina, N . P. Polyakova, and P. I. Fedorov, Vestsi Akad. Navuk Belarusk. S . S . R . , Ser. khim. Navuk, 1973, 104. J. Ficini and A. M. Touzin, Tetrahedron Letters, 1974, 1447.
28
Terpenoids and Steroids
is consistent with that of lavandulol analogues from other Arternisia spp.19' Naturally occurring hydroxy-aldehydes (142) and (143) and the ester (144) have been synthesized (Scheme 13).192 Conversion of a-cyclogeraniol (95 ; R = CH,OH) into a-cyclocitral (95 ; R = CHO) without loss of optical activity requires careful modification of Oppenauer condit i o n ~ one ; ~ of ~ ~the corresponding saturated acids (145) (having a higher m.p.) is
identical with a naturally occurring acid from Californian crude oil.' 94 Some transformations of P-pyronene (146), available from pyrolysis of a-pinene, are described (Scheme 14),in the course of which dehydro-1,4-cineol(l48) is quoted [the analogous oxide (149)
HO
R
=
(147) R
=
(146)
Reagents: i, hv, O,-sensitizer; ii, LiAlH,; iii, HCrO, (two-phase); iv, NaBH,; vi, monoperphthalic acid.
Me CHO
V,
perbenzoic acid;
Scheme 14
was not encountered] however, the reference given196expresses doubt about its existence. a-Cyclogeranyl chloride (95 ; R = CH,CI) is conveniently made by cyclizing geranyl chloride (25; R = H,) with boron trifluoride etherate.197The action of lead tetra-acetate on P-cyclogeraniol(l50; R = C H 2 0 H )is less clean than that on a-cyclogeranisl(95; R = CH,OH), which yields a 50 : 30 mixture of the acetates (95; R = OAc) and (150; R = OAc).19*The vinyl ether (150; R = CH,OCH=CH,) gives a mixture containing 30"/; of the ketone (150; R = CH,COMe) and j?-cyclogeraniol (150; 19'
'92
S. J . Torrance and C. Steelink, J . Org. Chem., 1974, 39, 1068. F. Bohlmann and G. Weickgenannt, Chem. Bet-., 1974, 107, 1769;
CJ
Vol. 1, p. 36; Vol. 2, p.
35. 193
195 196
19' 19*
R. Buchecker, R. Egli, H. Regel-Wild, C. Tscharner, C. H. Eugster, G. Uhde, and G . Ohloff, Helv. Chim. Acta. 1973, 56, 2548. R. Buchecker and C. H. Eugster, Helv. Chim. Acra, 1973, 56, 2563. W . Cocker, K. J. Crowley, and K. Srinivasan, J.C.S. Perkin I, 1973, 2485. G. 0. Pierssn and 0. A. Rundquist, J. Org. Chem., 1969, 34, 3654. Y . Butsugan, K. Sahaki, T. Bito, and M. Muto, Nippon Kagaku Kaishi, 1973, 1804. J . Ehrenfreund, M. P. Zink, and H. R. Wolf, Helc. Chim. Acta, 1974, 57, 1098.
29
Monoterpenoids
R = CH,OH) with buty1-lithi~m.l~~ Safranal (147) is made by allylic bromination ( N bromosuccinimide of j3-cyclocitral(l50; R = CHO) followed by dehydrobromination, a-cyclocitral(95 ; R = CHO) decarbonylating under these conditions.200 Allyiic bromination of isophorone (151 ; R = H) yields the bromide (151 ; R = Br), reacting with sodium aryl sulphonates or sulphides to give the substitution products (152). Debromination of (151 ; R = Br) with zinc and chromium trichloride gives flisophorone (153)and isophorone (151; R = H) in the ratio 5 : 1.201 The ene reaction of isophorone (151; R = H) with tetracyanoethylene yields (154).’02
1,4Dimethyl- 1-ethylcyc1ohexane.-The methyl ketone has been improved.203
preparation of 1,4-dimethylcyclohex-3-enyl
Cycloheptanes-The eucarvone (155) ring-inversion energy barrier is 8.3 kcal mol- 1.204 The complexity of the products from photoisomerisation of eucarvone (155) is well known; a study in strong acids and methanolic solvents revealed the new product (156),probably formed from the protonated ketone ( 157).205
”’ V. Rautenstrauch, G. Biichi, and H. Wuest, J . Amer. Chem. SOC.,1974, 96, 2576. 2oo 20’ 202
203
W. M. B. Konst, L. M. van der Linde, and H. Boelens, Tetrahedron Letters, 1974, 3175. J. N . Marx, Org. Prep. Proc. Internat., 1973, 5, 45. A. Cornelis, P. Laszlo, and C. Pasquet, Tetrahedron Letters, 1973, 4335. W. Kreiser, W. Haumesser, and A. F. Thomas, Helv. Chim. Acta, 1974, 57, 164; cf. Vol. 4, p. 40.
204 205
E. Cuthbertson and D. D. MacNicol, Tetrahedron Letters, 1974, 2689. K . E. Hine and R. F. Childs, J . Amer. Chem. Soc., 1973, 95, 6116; cf. V O ~2,. p. 36; Vol. 3, p. 54.
30
Terpenoids and Steroids 6 Bicyclic Monoterpenoids
Bicycl~3,1,O]hexane~-The conformation of several thujanoi (1 58 ; unspecified stereochemistry) isomers is shown to be boat-like by both ‘H n.m.r.206and I3Cn.m.r. spectroscopy.207Nomenclature is not yet uniform : Norin (and this Report) uses ‘iso’ as with menthanes, to mean cis methyl and isopropyl groups,2o6 but Whittaker et a1.2 07.2 0 8 use the opposite convention. These authors have shown how transformations of the ion (159), derived from neothujanol (158) (which they call ‘neoisothujanol’) depend on the presence or absence of antimony pentafluoride.208
Bicyclo(2,2,l]heptanes.-A new synthesis of epicamphor (160; R‘ = Me, R2 = H2) not involving camphor has been effected (Scheme 15).*09 The fenchane (161) is obtained
4 n
CHCl
/ + I 1
f-3
-&
0
0
1
iv
/-I
r7 O@OH
O
k
O
Ht vi,ii,vii CHO
\
(+ isomer)
( 160) Reagents: i, hv; ii, acetalize; iii, Na; iv, B,H,-oxidation; v, deacetalize vii, LiAlH,; viii, NaH on tosylate.
+ retroaldol; vi, oxidize;
Scheme 15 206
207 208 209
T. Norin, S. Stromberg, and M. Weber, Acta Chem. Scand., 1973, 27, 1579. R. J. Abraham, C. M. Holden, P. Loftus, and D. Whittaker, Org. Magn. Resonance, 1974,6, 184. C . M . Holden and D. Whittaker, J.C.S. Chem. Comm., 1974, 3 5 3 . C. Boust and P. Leriverend, Bull. SOC.chim. France, 1974, 1201.
31
Monoterpenoids
by the action of stannic chloride on the cyclopropane (162).'" Full details of Money's camphor synthesis (Vol. 1, p. 39) have appeared.2' Mass spectrometric fragmentation of bornyl acetates and alcohols involves principally l 2 The molecular geometry of the fluorescent state of camphorci~-1,2-elirnination.~ quinone (160; R' = Me, R2 = 0)has been studied in the light of circularly polarized luminescence and c.d. meas~rements.~'C.d. measurments have also been carried out on the followingcompounds; (160; R' = 2H, R 2 = 0),214 (163; R = CF,, M = Co, n = 2),2'5 and (163; R = Me, M = Ru, n = 3).216 The chelate-forming ability of hydroxymethylene derivatives of camphor (2) has been examined2l 7 and the rotatory dispersion and c.d. of the copper chelates have been measured.218
&, GlM/n
M..O\X~\-J
Mec&
( 142)
(141)
(143)
Use of an algebraic model and a computer programme have enabled Johnson and Collins to solve problems such as the rearrangement of the lacton'e (164) in sulphuric acid ; they have confirmed Sorensen's idea that fenchyl ions in ultra-strong acid do not form sequentially, but seek out those structures which are thermodynamically most stable at a given temperature.*lg Olah and Liang were unable to detect non-classical ions of the dimethylnorbornyl type by n.m.r. spectroscopy, although they are not excluded as higher-energy species on solvolytic pathways.220 Camphene (165), tricyclene, and bornene all yield the same acetate mixture with acetic acid-sulphuric acid ; the kinetics of the reaction have been measured.221Re-calculation of data purporting to involve a small amount of endo-3,2-methyl shift during racemization of [8-' 3C]camphene (165) (Vol. 4,44) shows that this is not necessary.222The interconversion of
1641
210
2L1 212 213 214 215 216
218
220 221
222
P. A. Grieco and R. S. Finkelhor, Tetrahedron Letters, 1974, 527. J. C. Fairley, G. L. Hodgson, and T. Money, J.C.S. Perkin I, 1973, 2109. R. Robbiani and J. Seibl, Org. Mass Spectrometry, 1973, 7 , 1 1 5 3 . C. K . Luk and F. S. Richardson, J . Amrr. Chem. SOC.,1974,96, 2006. W. C. M. C. Kokke and L. J. Oosterhoff, J . Amer. Chern. SOC.,1973, 95, 7159. E. C. Hsu and G. Holzwarth, J. Amer. Chem. SOC.,1973, 95, 6902. G. W. Everett, jun., and R. R. Horn, J. Amer. Chem. SOC.,1974, 96, 2087. V. M. Potapov, G. V. Panova, N. K. Vikulova, and N. B. Kupletskaya, Zhur. obshchei Khim., 1973,43, 926, 930. V. M. Potapov, G. V. Panova, and N. K. Vikulova, Zhur. obshchei Khim., 1973,43,939. C. K. Johnson and C. J . Collins, J . Amer. Chem. SOC.,1974, 96, 2514; C. J. Collins, C. K. Johnson, and V. F. Raaen, ibid., p. 2524. G . A. Olah and G. Liang, J. Amer. Chem. SOC.,1974, 96, 189. Y . Castanet, F. Petit, and M. Evrard, Bull. SOC.chim. France, 1974, 1097. C. J. Collins and M. H. Lietzke, J. Amer. Chem. SOC.,1973, 95, 6842.
32
Terpenuids and Steroids
8-, 9-, and 10-homocamphene (165; +Me at positions indicated) under the same conditions as this racemization has been studied and a homotricyclene isolated.223 Re-examination of the thermal decomposition of borneol and isoborneol p-nitrobenzoates and urethanes has led to the detection of a small amount of pinene besides the known tricyclene, camphene, etc. 24 Rearrangement of bromonitrocamphane (166; R’ = Br, R 2 = NO2)to anhydronitrocamphane (167; R = Br) involves (i) loss of NO,, (ii) rearrangement of the cation, and (iii) recombination of NO,, the latter being postulated to occur by addition of H 2 N 0 2 +to 4-bromocarnpheney a precedent for this step being the addition of nitrous acid to camphene (165), which leads to anhydronitrocamphane (167; R = H).225
Rearrangements of the Wagner-Meerwein type occur if the amino-acid (166; R’ = NH,, R 2 = C 0 2 H )(made from camphor) is deaminated with nitrous acid,226and also on treatment of camphor (2) with isocyanides in the presence of acetic acid (Passerini reaction).227 Hydrogenolysis of bornylurea [166; R’ = H, R2 = Oc(NHC6Hl1)= NC6H is not easy because of steric hindrance, but the exu-isomer is hydrogenolysed in 20 h to the rearranged endu-isocamphene (168).228Similar rearrangements occur if exo-2,10-dibromobornane (169) is treated with bases (leading to o-bromocamphene), but not with silver nitrate, when substitution takes place.229Eliminations of bromoborneols with base take a different route from those of the tosylates (which form epoxides ; cf. Vol. 3, p. 68). syn-Elimination from 3-endu-bromoisoborneol(l70),yielding camphor, occurred with most bases except potassium t-butoxide in dimethylformamide, this course being followed exclusively with bromo-epi-borneol (1 71).230 Bromination of
camphor (Scheme 16) to endo-3,9-dibromocamphor (172) involves an exo-methyl migration, which Money et al. reasoned could be hindered by placing a bulky group (e.g. 223 224
22s 226
”’ 228
’”
230
W . R. Vaughan and D. M. Teegarden, J. Amer. Chem. SOC.,1974,96, 4902. P. Malkdnen and J. Korvola, Finn. Chem. Letters, 1974, 1, 19, 23. S. Ranganathan and A. H. Raman, Tetrahedron, 1974, 39, 63. Y. Maki, T. Masugi, and K. Ozeki, Chem. and Pharm. Bull. (Japan), 1973, 21, 2466. G. Minardi, E. Bottini, and A. Gallazzi, Farmaco, Ed. sci., 1973, 28, 1030. E. Vowinkel and I . Biithe, Chem. Ber., 1974, 107, 1353. G. Mehta, Indian J . Chem., 1973, 11, 843. K. Marks and M. Szkoda, Roczniki Chem., 1973,47, 2295.
Monoterpenoids
33
bromine) in the 3-exo-position (173; X = Br). Whether the actual mechanism is really a 2-endo-methyl migration is not clear, but the result is the formation of the desired 3,3,8-tribromocamphor (174)from the bromination of dibromocamphor (173;X = Y = Br). Zinc-acid reduction removes the secondary bromines, making either 8- or 9bromocamphor available.’ Dimmel has demonstrated that optical activity is lost in the bornyl sultone rearrangement (Vol. 4, p. 47), but there is almost no endo-3,2-methyl shift.23’ An exo-’H-labelled camphor was made by reduction of endo-bromocamphor (1 73 ; X = H, Y = Br) with sodium borohydride and rhodium t r i ~ h l o r i d e Arylidene.~~~ camphors are reduced in the presence of [RUC~,(PP~,),].”~ Although poor when applied to most ketones, incorporation of deuterium on quenching the reaction mixture of butyl-lithium and camphor tosylhydrazone with deuterium oxide reaches 95%.’3s Another anomaly is that the enol silyl ethers of camphor are not cleaved by ozone, but give 3-silyl ethers (175), probably uia the e p ~ x i d e . ~ ~ ~
Comparison of the action of Grignard and alkyl-lithium reagents on camphor (2) and on fenchone (176) has been made.237Prenyl-lithium reacts normally with fenchone
’’’ 232 233 34
235
236 23‘
C. R. Eck, R. W. Mills, and T. Money, J.C.S. Chem. Comm., 1973, 91 1. D. R. Dimmel and W. Y. Fu, J . Org. Chem., 1973, 38, 3778, 3782. C. J. Love and F. J. McGuillin, J.C.S. Perkin I, 1973, 2509. M. Dedieu and Y .-L. Pascal, Compr. rend., 1974,278, C , 9 ; they report that catalytic reduction is difficult, but see Vol. 3, p. 65. R. H. Shapiro and E. C. Hornaman, J . Urg. Chem., 1974, 39, 2302. R. D. Clark and C. H. Heathcock, Tetrahedron Lerters, 1974, 2027. J. Korvola, Suomen Kem. ( B ) , 1973, 46, 212, 262.
34
Terpenoids and Steroids
(176)(yielding only endo-product), but camphor is like other severely hindered ketones, giving more rearranged borneol (166; R' = OH, R2 = CMe2CH=CH2) than the product of direct addition (166; R' = OH, R 2 = CH2CH=CMe,).238 The Grignard addition product of 4-chloropent-3-enyl-lithium to the ketone (177) undergoes cyclization and rearrangement of a methyl group with formic acid, and the resulting product (178) is readily converted into the ketone (179), which is also obtainable from albene (180)(Vol. 3, p. 8), whose structure is thereby verified.239
(:76) R = Me (177) R = H
(178) R = Hor COMe (179) R = 0
(180) (181)
3-Bromocamphor (173; X = H, Y = Br) with phenylhydrazine yields the 3-phenylhydrazino-2-phenylhydrazone and the phenylhydrazone (18 1 ), with the diphenylhydrazone of camphorquinone (160; R' = Me, R 2 = 0)at higher temperature^.^^' Rate measurements on the iodination of the acid (173; X = H, Y = C 0 2 H )and the methyl ester have been made, but camphor reacts too slowly for reliable values to be obtained. 24' Highlights in a series of papers by Gream et al. on the carboxylic acids (182)and (166; R' = C 0 2 H , R 2 = H) include the behaviour on oxidation either with lead tetraacetate or anodically, a synthesis of (-)-camphene (165) of high optical purity from the tosylate (183) of campholenic alcohol, and a study of the opening of the cyclopropane ring of the main product (184) obtained from camphene (165) and (MeO),SiCH(OMe), .242
(182) R' = COZH, R 2 = H or R' = H, RZ = COzH (186) R' = H . R 2 = OTS
(183)
Carbocamphenilone (185), despite earlier conflicting statements, has a chair conformation (by X-ray crystallography and ~ . d . )Ring-expansion . ~ ~ ~ of the tosylate (186) is more difficult than with the unsubstituted homologue, and since release of ring strain A new was considered to be the same in both cases, an electronic effect was 238 239 240 241
24i
243 244
V. Rautenstrauch, Helc. Chirn. Acta, 1974, 57, 496. P. T. Lansbury and R. M. Boden, Terrahedron Letters, 1973, 5017. A. G. Giumanini, L. Caglioti, and W. Nardini, Bull. Chern. Soc. Japan, 1973, 46, 3319. R. P. Bell and M. I. Page, J . C . S . Perkin II, 1973, 1681. G . E. Gream and C. F. Pincombe, Ausrral. J . Chem., 1974, 27, 543, 589; G. E. Gream, C. F. Pincombe, and D. Wege, ibid., p. 603; G . E. Gream, D. Wege, and M. Mular, ibid., p. 567. B. Lee, J. P. Seymour, and A. W. Burgstahler, J . C . S . Chem. Cornm., 1974, 235. P. I. Meikle and D. Whittaker, J . C . S . Perkin I I , 1974, 322.
Monoterpenoids
35
ring-expansion involves N-bromosuccinimide bromination of the Grignard addition product (166; R' = OH, R 2 = CH2Ph) and reaction of the product (166; R' = OH, R2 = CHBrPh) with isopropylmagnesium bromide. The resulting complex gives the bicyclo[3,2,l]octanones (187) and (188) in benzene.245 Thermolysis of the cyclic endo-sulphite (189) yields camphor (2) and epicamphor (160; R' = Me, R2 = H2),but the more stable exo-isomer undergoes ring fission and rearrangement to the aldehyde (190).246Beckmann fragmentation of the oxime (191)has
been investigated (cf.Vol. 4,p. 51).247Microbial metabolism of camphor was claimed248 to produce a lactone (192; R = Me) with one carbon atom fewer. This lactone (192; R = Me) has now been shown to be a different substance, and the metabolic product is more likely to have retained all ten carbon atoms as in (193).249Some reactions of derivatives of camphanic acid (192; R = C 0 2 H ) are reported.250 Preparation of the ether (194; R = H2) from camphoric anhydride (194; R = 0) is described.251Ring fission to cyclopentanones and cyclohexanones accompanies chromic oxidation of the 1-hydroxybornanes ( 195).252
Thiocamphor (196) usually gives rearranged products (166 ; R ' = CHRCH=CH, , R 2 = SH) with ally1 Grignard reagents; heating converts these into cyclized sulphides (197) (cf. Vol. 4,p. 52).253Unlike camphor, thiocamphor (196) reacts readily with p benzylamines, giving nearly quantitative yields of the corresponding substituted i m i n e ~The . ~ ~dimer ~ (198) formed from thiocamphor with chloramine-T undergoes a hetero-Cope reaction, now shown to be a [3,3] sigmatropic antarafacial process, to give ( 199).25 Reaction of hindered thiones with hindered diazo-compounds gives A3-1,3,4245 246
"'
248
249 250
251 252 253 254
255
A. J. Sisti and G . M. Rusch, J . Org. Chem., 1974, 39, 1182.
R. F. J. Cole, J. M. Coxon, and M. P. Hartshorn, Austral. J . Chem., 1973, 26, 1595. D. Miljkovic, J. Petrovic, M. Stajic, and M. Miljkovid, J . Org. Chem., 1973, 38, 3585. T. Hayashi, M. Sakai, H . Ueda, and C. Tatsumi, Nippon Nogei Kagaku Kaishi, 1969,42, 670. J. Goldman, N. Jacobsen, and K . Torssell, Acta Chem. Scand., 1974, B28,492. V. SunjiC, F. Kajfez, M. OklobdZija, and M. Stromar, Croat. Chem. Acta, 1973, 45, 569. S. Wolff, A. B. Smith, tert., and W. C. Agosta, J. Org. Chem., 1974, 39, 1607. J. J . Cawley and V. T. Spaziano, Tetrahedron Letters, 1973, 4719. M. Dagonneau and J. Vialle, Tetrahedron, 1974, 30, 415. I. Shahak and Y. Sasson, Synthesis, 1973, 535. M. M. Campbell and a.M. Evgenios, J.C.S. Perkin I, 1973, 2866.
36
Terpenoids and Steroids
thiadiazolidines, and these can be pyrolysed to episulphides. Desulphurization of the latter with triphenylphosphine leads to the olefin, (166; R', R2 = =CR2) from camphor and analogous hydrocarbons from fenchone (176) being accessible in this way.256 \/
(196)
(197)
(198)
( 199)
Further papers of interest in the bicyclo[2,2,l]heptane series report the preparation of several new n.m.r. shift reagents from camphoric an investigation into the radical addition of thiols to bornene, yielding only e x o - a d d ~ c t sas , ~does ~ ~ addition to similar substrates of diphenylnitrilimine and benzonitrile oxide,, 59 exchange of the bromine atom in bromotricyclene (readily available) by a phenylsulphonyl group to activate the carbon atom carrying the functional group for metallation,260and addition from the less hindered side (endo)to camphor of trimethylsilyl cyanide in the presence of zinc iodide.261Methylation of camphor with methyl iodide fails in the presence of sodium t-butoxide, but succeeds with sodium amide.262Ethers of borneol and isoborneol have been made.263The reaction of camphorquinone (160; R' = Me, R 2 = 0)with aliphatic aldehydes has been re-investigated using CIDNP.264The stability of the Ni" complexes of camphorquinone dioxime have been investigated by 'H n.m.r.;265further papers on the geometry of the arylidenecamphors (Vol. 4, p. 50)266and on the condensation products of fenchene, camphene, and phenols in the presence of catalysts267 have appeared.
Bicycl@3,1,l]heptanes.-Further discussion of the conformation of pinane derivatives is supported by 'H n.m.r. spectra at 220 and 300 MHz268and an X-ray analysis of cispinocarveyl p-nitrobenzoate (200; R = 0 , C - C,H,N0,-p).269 The 'H n.m.r. spectrum of myrtenol(201; R = CH,OH) has been studied with a shift reagent.270 256
25'
258 259
260 26' 262
16'
264 265
266 26i
268
269 270
D. €1. R. Barton, F. S. Guziec, jun., and I. Shahak, J.C.S. Perkin I, 1974, 1794. M. D. McCreary, D. W. Lewis, D. L. Wernick, and G. M. Whitesides, J. Amer. Chem. SOC., 1974,96, 1038. M. J. Parrott and D. I. Davies, J.C.S. Perkin I, 1973, 2205. W . Fliege and R. Huisgen, Annalen, 1973, 2038. M. Julia and P. Ward, Bull. SOC.chim. France, 1973, 3065. D. A. Evans, G. L. Carroll, and L. K . Truesdale, J. Org. Chem., 1974, 39, 914. E. E. Aringoli and L. E. De Vottero, Rev. Fuc. Ing. yuim. Unit.. nac. Litoral, 1971-2 (publ. 1973), 40/41, 27 (Chem. Abs., 1974, 80, 70 974). K. Nagai, M. Nakayama, A. Matsuo, S. Eguchi, and S. Hayashi, Bull. Chem. SOC.Japan, 1974, 47, 1193. K. Maruyama and T. Takahashi, Chem. Letters, 1974, 467. S. B. Pedersen and E. Larsen, Acta Chem. Scand., 1973, 27, 3291. N. El Batouti and J. Sotiropoulos, Compt. rend., 1974, 278, C , 1109. V. I. Moskvichev and L. A. Kheifits, Zhur. org. Khim., 1973, 9, 1444, 2256; T. F. Gavrilova, 1. S. Aul'chenko, L. A. Kheifits, N. D. Antonova, and 0.A. Subbotin, ibid., p. 2260; cJ Vol. 4, p. 44. R. J. Abraham, M. A. Cooper, H. Indyk, T. M. Siverns, and D. Whittaker, Org. Magn. Resonance, 1973,5, 373. G. F. Richards, R. A. Moran, J. A. Heitmann, and W. E. Scott, J. Org. Chem., 1974,39, 86. J. Paasivirta, H. Hakli, and K.-G, Widen, Org. Magn. Resonance. 1974, 6, 380.
Monoterpenoids
37
CH,OTS
1
T
vi, vii
Reagents: i, Thioacetalize; ii, LiAlH,; iii, acetylate; iv, deacetalize; v, Me,CuLi; vi, O H - ; vii, TsC1-py ; viii, NaH-MeOCH,CH,OMe.
Scheme 17
Total syntheses of pinanes are rare enough to warrant a new one, based on a known cyclization of 5-to~yloxy-ketones,~~~ to be given in full (Scheme 17).272In order to avoid the difficult separation of nopinone (202) and its isomer (203), the scheme was modified by blocking the 6-position of the precursor with benzaldehyde, debenzalating the product with potassium hydroxide in hexamethylphosphoramide and 4-aminobutyric acid. Conversion of (202) into the pinenes followed conventional Whittaker's general piny1 carbonium ion scheme (Vol. 2, p. 50 and Scheme 18) has received much support. Products from the deamination of myrtanylamine (204 ;
(206)
(207)
(210)
(209)
i, Migration of a ; ii, migration of b; iii, removal of H X ; in ref. 260, X = Br.
Scheme 18
17' 272
K. B. Wiberg and G. W. Kline, Tetrahedron Letters, 1963, 1043; S . WolR and W. C. Agosta, J . C . S . Chem. Comm., 1973,771. M. T. Thomas and A. G. Fallis, Tetrahedron Letters, 1973, 4687.
38
Terpenoids and Steroids
X = NH,) are consistent with a ‘hot’ ion (205)273,274 and somewhat different from those arising from carbonium ions produced by the action of potassium hydroxide on pinanols. The unexpected production of the pinan-2-01 (206) in 28% yield from cismyrtanol (204; X = OH) and potassium hydroxide is explained by the capture of a hydroxide ion by the carbonium ion (207; R’ = R’ = H) so fast that the initial cis stereochemistry is retained. trans-Myrtanol yields mostly a-terpineol(17).’7 Substituted piny1 carbonium ions (207), prepared from the pinenes with the calculated amount of hydrogen bromide, rearrange to either bornanes (208) or fenchanes (209)(after dehydrobromination), according to whether the more substituted (a) or less the subtituted (b) bond of the ion (207)migrates, and this is highly dependent on the substituent R’ ; cissubstituents give mostly bornanes (208),whereas up to 100% fenchane (209) rearrangement can be achieved with trans-sub~titution.~~~ Differences in the relative migration of the (a) and (b) bonds have also been observed when the two pinan-2-01s are treated with acid, the one with a P-hydroxy-group [opposite to (206)] yielding more fenchol ion has been gener(210; R’ = R’ = H, X = OH).276The 6,6-dimethylnorpinan-2-yl ated (inter alia) by deamination of the amine (211), when it appeared to be of a highthe myrtanylamine case. energy classical type associated with a c ~ u n t e r i o nas , ~in~ ~ Catalytic reduction of optically active apopinene (201 ;R = H) occurs with racemization, the latter being faster than exchange when deuterium is the reducing agent ; a [1,3] sigmatropic shift is likely.’ 7 8 Catalytic reduction of the hydroperoxide yields pinan-2-01 (206), accompanying ring fission giving the by-product (212).’79
Contrary to the usual cis hydroboration-oxidation of P-pinene (200; R = H) leading to cis-myrtanol (204; R = OH), a large trans-substituent at C-3 causes the reaction to follow the opposite stereochemistry, the substituted pinene (213), for example, giving 85 ”/, of the corresponding trans-myrtanol.280The usual anti approach of the reagent leads to the thermodynamically less stable (cis) isomer, and Wilke et al. showed that reaction of P-pinene with tri-isobutylaluminium followed by oxidation gives cismyrtanol(204; R = OH) at lower temperatures, but trans-myrtanol at higher temperatures, when 2.2% of the diol(214; R = OH) was obtained, the latter leading to the first bridgehead-substituted pinane (214; R = H).,” 273 274
275 *16 277
278 279
28’
E. Chong-Sen, R. A. Jones, and T. C. Webb, J.C.S. Perkin II, 1974, 38. P. I. Meikle and D. Whittaker, J.C.S. Perkin IZ, 1974, 318. M. Barthelemy and Y. Bessiere-Chretien, Bull. SOC.chim. France, 1974, 1703. H . Indyk and D. Whittaker, J.C.S. Perkin ZI, 1974, 313. H. Indyk and D. Whittaker, J.C.S. Perkin I I , 1974, 646. G . V. Smith and D. S. Desai, Ann. New York Acad. Sci., 1973, 214, 20. L. A. Shutikova, V. G. Cherkaev, M. S. Erzhanova, and A. V. Alifanova, Maslob-Zhir. Prom., 1973,23 (Chem. Abs., 1973,79, 115 734). M. Barthelemy and Y. Bessiere-Chretien, Bull. SOC.chim. France, 1974, 600. H . Benn, J . Brandt, and G . Wilke, Annulen, 1974, 189.
39
Mono terpenoids
Various additions of acrolein etc. to P-pinene have been described ; the reaction works at room temperature in the presence of aluminium chloride.282A preliminary report of the radical-induced cyclization of the acrolein adduct to the octalone (215) has ap~ e a r e dAlthough . ~ ~ ~ addition of acrylates to P-pinene does not yield c y c l o b ~ t a n e s , ~ ~ ~ addition of chloroketen gives (216)in 65 % yield.285Labelling studies have shown that the ene reaction between P-pinene and maleic anhydride occurs with transfer of the endoproton via the transition state (217), leading to a product (218) with R-chirality in the
(215 )
(216)
(2 17)
H
(218)
anhydride ring as the main isomer.286The ene reaction with benzyne (Vol. 4, p. 60) and methyl phenylglyoxylate is similar, and in the latter case, since the reaction is reversible, exchange of the product (219) with deuterium oxide followed by thermolysis gives a 8pinene stereospecifically labelled (220) at C-3.287
Afferdecomposition of P-pinene oxonide with dimethyl sulphide there was a violent explosion on distillation, thought to be due to the diperoxide (Vol. 4, p. 57), undecomposed by’this reagent.257The oxide (221) (Vol. 3, p. 64, refers to the methyl analogue) reacts with butyl-lithium and water to give an alcohol (222), or with butyl-lithium followed by methyl iodide to give the alcohol (223); these and other reactions are explained by the unusual concept of a carbodianion located on the carbon atom (C-10) carrying the phenylsulphonyl group.288 Rapid introduction to the 3,7,7-trimethylnorpinane series is by direct reduction of the hydroxymethylene derivative (224; R =
282
283 284
285 186
287 288
B. B. Snider, J . Org. Chem., 1974,39,255; cJ J. Matsubara, T. Kishimoto, H. Yamamoto, and W. Minematsu, Nippon Kagaku Kaishi, 1972, 669. M. M. Chatzopoulos and J. P. Montheard, Actual. chim., 1974, No. 5 , p. 56; CJ Vol. 1 , p. 46. From R. D. Sands, Synth. Comm., 1973,3, 81; such a reaction might appear possible, but the Reporter has found Sands’s work to be erroneous. W. T. Brady and A. D. Patel, J . Org. Chem., 1973, 38, 4106. R. K. Hill, J. W. Morgan, R. V. Shetty, and M. E. Synerholm, J . Amer. Chem. SOC.,1974, 96, 4201. V. Garsky, D. F. Koster, and R. T. Arnold, J. Amer. Chem. SOC.,1974,96, 4207. N. Bosworth and P. D. Magnus, J.C.S. Perkin I, 1973, 2319.
40
Terpenoids and Steroids
OH) catalytically to the 3-aldehyde, or the acetate (224; R = OAc) to the 3,7,7-trimethyln ~ r p i n a n eArylidenenopinones .~~~ (224; R = aryl) are all of E-ge~metry.'~' Photolysis of pinocarvone (225) gives products including the ketones (226)and (227); the mechanism was suggested to involve either a-p bond fission of the @-unsaturated ketone or (as appears more likely) ring-opening to 2-methyl-6-methyleneocta-2,7diene-5-0ne.~~ Photolysis of trans-verbenone epoxide (228) also gives ring-contracted ketones (229) and anhydrides (230).292Labelling has been used to investigate the verbenone-chrysanthenone photochemical rearrangement.293
Ring-opening of pinenes (to the menthane system) occurs with aliphatic aldehydes in the presence of cupric acetate ;294 with various aroyloxy-radicals in the presence of cupric salts, judicious choice of the aryl substituent enables the reaction to be directed towards ring-opening or removal of ally1 hydrogen ;295 ring-opening also occurs with phosphorous and phosporic acids and esters in the presence of peroxides or U.V.light296 and in the decomposition of myrtenal(201; R = CHO) semicarbazone with sulphuric acid (giving cuminaldehyde, p-is~propylbenzaldehyde).~~~ The radical-initiated photoaddition of N-nitrosopiperidine to a-pinene, in contrast, leads to menthanes only above 0 "C(Scheme 19). Below - 40 "C,addition of the nitroxide radical to the initially formed 289
290 291
292
293 294
295 296 29'
A. Yoshikoshi, Y . Takagi, and T. Akiyama, Jap. P., 91 04611973, 91 04711973. G. Feuillerat and J. Sotiropoulos, Compt. rend., 1974, 279, C, 71. T. D. R. Manning, Tetrahedron Letters, 1974, 2669. T. Gibson, J . Org. Chem., 1974, 39, 845. G. W. Shaffer and M. Pesaro, J . Org. Chem., 1974, 39, 2489. M. G. Vinogradov, G. P. Il'ina, and G. I. Nikishin, Zhur. org. Khirn., 1974, 10, 1153. M. Julia and D. Mansuy, Bull. SOC.chim. France, 1974, 1678. H. FranCois and R. Lalande, Compt. rend., 1974, 279, C, 117. M. Villarrubia de Martinez and F. Gonzalo de Venditti, Arch. Bioquim. Quim. Farm., 1971,17, 61 (Chem. A h . , 1973,79, 91 723).
Man oterpeno ids
41
a-pinene
li
n
A Reagents : i, N-Nitrosopiperidine-H +-piperidine (pip)-MeOH, hv; ii, N O ; iii, air; iv, H ,-Pt.
Scheme 19
piny1 radical (231) occurs before ring-opening, but the resulting nitroso-compound undergoes proton transfer with ring-opening to the cyclobutane oxime (232).298 Further papers on the pinane system concern ring-opening of a-pinene epoxide in the presence of S 0 3 2 - (which does not give addition products like ~ a r e n e and ) ~ ~the ~ following known reactions : acid-catalysed addition to phen01,~" reactions of pinonic acid a m i d e ~ , ~ "rearrangement of 2-hydroxypinocamphone,302 ring contraction of pinane-2,3-diol 3-t0sylate,~'~ and reaction with N-bromosuccinimide.304
Bicyclo[4,l,O]heptanes.-The 220 MHz n.m.r. spectrum of car-3-ene (233) supports a planar cyclohexene ring.305 Thermolysis of either cis- or trans-carane at 400°C produces the other isomer, besides many p - and rn-rnenthane~.~'~ The ring-opening by hydrogen chloride on carane is de~cribed,~"and further work of no great novelty concerns the ring-opening of carene epoxides3'* and the direct hydroxylation of ~ a r - 3 - e n e . ~ ' ~ 298 299
300 301
302
303 304
305
306 307
308
309
H. H. Quon, T. Tezuka, and Y. L. Chow, J.C.S. Chem. Comm., 1974,428. E. MySliriski, Roczniki Chem., 1973, 47, 1755; cf: Vol. 4, p. 65. V. I. Moskvichev and L. A. Kheifits, Zhur. org. Khim., 1973, 9, 2256. Z. Bore, F. Avotins, and E. Gudriniece, Latv. P.S.R. Zinar. Akad. Vestis, Kim. Ser., 1973, 583 (Chem. Abs., 1974,80,60 045). T. J. De Pasqual, I. Sanchez Bellido, T. Egido, and M. Grande Benito, Anales. de Quim., 1973, 69, 687; cf: Vol. 2, p. 54, Vol. 4, p. 63. Z. Chabudzidski, Z. Rykowski, and K. Burak, Roczniki Chem., 1973,47, 2505. C. A. N. Catalan, D. J. Merep, and J. A. Retamar, Anafes. SOC.cient. Argentina, 1973, 196, 35. R. J. Abraham, M. A. Cooper, and D. Whittaker, Org. Magn. Resonance, 1973,5, 51 1. I. I. Bardyshev, E. F. Buinova, and B. G. Udarov, Zhur. org. Khim., 1973,9, 1670. I. I. Bardyshev and E. F. Buinova, Vestsi Akad. Naouk Befarusk. S.S.R., Ser. khim. Naouk, 1974, 94 (Chem. Abs., 1973,79, 105 422). B. A. Arbuzov, Z. G. Isaeva, and V. A. Shaikhutdinov, Doklady Akad. Nauk S.S.S.R., 1973, 210, 837; B. A. Arbuzov, Z. G. Isaeva, and E. Kh. Kazakova, Imest. Akad. Nauk S . S . S . R . , Ser. khim., 1973, 2554; Doklady Akad. Nauk S.S.S.R., 1974, 215, 113 (see Vol. 4, p. 64). B. A. Arbuzov, Z. G. Isaeva, R. R. D'yakonova, and G. A. Bakaleinik, Izvest. Akad. Nauk S.S.S.R., Ser. khim., 1973, 2543, 2549 (see Vol. 4, p. 64).
42
Terpenoids and Steroids OH
Acetolysis of the tosylates of the alcohols (234), made by reduction of the ozonolysis products of car-3-ene, led to the suggestion that the cis- but not the trans-tosylate forms a non-classical ion (235).31 Various heterocyclic rings fused to caranes have been ~ r e p a r e d . ~ '
'
7 Furanoid and Pyranoid Monoterpenoids Both rose oxides (236) have been found in an insect."' Cantharidin (237; R = Me) and (+)-cantharic acid (238)have been related to palasonin (237; R = H), isolated from Butea Ji.ondosa, the absolute configurations being determined by the Horeau method. Unsuccessful experiments destined to incorporate precursors into palasonin were r e p ~ r t e dl .2~
Full papers on the lilac alcohols (239) and aldehydes have appeared,313and a specific oxidation of dehydrated linalool oxide (240)with 9-borabicyclo[3,3,1]nonane to give a lilac alcohol (239) has been
(239) R' = H, R2 = CH,OH (240) R ' , R Z = CH2
'lo
(24 1)
M. Walkowicz, C. Walkowicz, and H. Kuczynski, Bull. Acad. polon. Sci., ScJr.Sci.chim., 1973, 21, 343.
311
3'2
313
3'4
F. Bondavalli, P. Schenone, and M. Longobardi, Farmaco, Ed. sci., 1974, 29,48. M. G. Peter, G. Snatzke, F. Snatzke, K. N. Nagarajan, and H. Schmid, Helv. Chim.Acta, 1974, 57, 32. S. Wakayarna, S. Narnba, K. Hosoi, and M . Ohno, Bull. Chrrn. Soc. Japan, 1973, 46, 3183; S. Wakayarna and S. Narnba, ihid., 1974, 47, 1293. S. Akutagawa and S. Watanabe, Jap. P., 61 46811973.
Monoterpenoids
43
Dioxins are converted mainly into furans by base, and the method has been applied to the synthesis of perillene (241).3l 5 The dioxin (242) obtained from dehydrolinalool is converted by aluminium oxide into a mixture of the furan (243)and an alcohol (244), which can be readily oxidized to the corresponding lactone and thence to the coumarin (245) from Capnophyllum peregrinum.62
1
three steps
8 Cannabinoids and other Phenolic Monoterpenoids Marihuana chemistry3l 6 and the syntheses of tetrahydrocannabinol (THC), its metabolites, and the a z a - a n a l ~ g u e s ~ have ’ ~ been reviewed. Marihuana might be useful in cancer therapy. l 8 Cannabicitran (citrylidene-cannabis)(246)has been isolated from Lebanese hashish3l 9 (it was not known to be naturally occurring). The relative amounts of certain cannabinoids have revealed three phenotypes of Cannabis.320Contrary to the results with rhesus monkeys, cannabinol(247) can produce a ‘high’ in man, but at much higher doses than Al-THC (248).321 I
I
(246) 315
316 317
31B
319 320 321
(247)
(248)
K. Kondo and M. Matsumoto, 9th I.U.P.A.C. Symposium on Natural Products, Ottawa, 1974, Abstracts, p. 27A. For preparation of dioxins from dienes cf: K. Kondo and M. Matsumoto, J.C.S. Chem. Comm., 1972, 1332; E. Demole, C. Demole, and D. Berthet, H e f v . Chim. Acta, 1973,56, 265. R. Mechoulam, ‘Marihuana’, Academic Press, New York, 1973. D. Bieniek, W. Bau, and F. Korte, Naturwiss., 1974, 61, 117. Chem. and Eng. News, 1974, Aug. 26, p. 6. C. A. L. Bercht, R. J. J. C. Lousberg, F. J. E. M. Kiippers, and C. A. Salemink, Phytochemistry, 1974, 13,619. E. Small and H . D. Beckstead, Nature, 1973, 245, 147. M.Perez-Reyes, M. C. Timmons, K. H. Davis, and E. M. Wall, Experientia, 1973, 29, 1368.
Terpenoids and Steroids
44
A determined attack on methods of detection and purification has made it possible to detect 100 pg ml- of A'-THC as the heptafluorobutyrate with an electron capture detector3,' and as little as 2 ng ml- plasma as the phosphate ester using flame-photometric detection.323 It is possible to predict the retention times of the cannabinoids from those of substituted r e s o r ~ i n o l sMass . ~ ~ ~and n.m.r. spectra of many hydroxylated cannabinoids have been quoted to facilitate the identification of In the mass spectrum of A'-THC, it seems that double-bond isomerization to A6-THC and transfer of the phenolic proton are important before f r a g m e n t a t i ~ n . ~Pyrolysis ,~ of cannabidiol (249; R = H) gives two compounds of molecular weight 314 (C21H3002), the major product being one of the two isomers of decarboxylated cannabielsoic acid (250),327which has been made from cannabidiolic acid (249; R = C0,H) by photooxidation or with manganese
'
R (249)
CO,H (250)
Conditions for the synthesis of A'-THC from mentha-2,8-dienol and olivetol can now be adjusted so that isomerization to A6-THC is prevented or so that the reaction stops at the cannabidiol (249; R = H) stage.329 14C-Labelled A'- and A6-THC have been made from suitably labelled 01ivetol.~~' The full paper on the pyridine-catalysed reaction of unsaturated aldehydes or acetals with phenols (Vol. 4, p. 75) has appeared.331 Epoxidation and photo-oxidation of A6-THC have been investigated. Reduction of the hydroperoxides gives the expected alcohols, the acetates of one pair (251)rearranging to the primary acetate (252; R = CH,OAc) on heating.332 The corresponding acid (252; R = C0,H) is a urinary metabolite of A6-THC and is formed when the alcohol (252; R = CH'OH) is fed to rabbits. The methyl ester (252; R = C0,Me) was made from the aldehyde (252; R = CHO), a selenium oxide oxidation product of A6-THC.333 Reaction of limonene (11) or a-pinene with orcinol in 50% formic acid leads to the same type of cannabinoid structure as prepared by Merlini et al. from piperitol (Vol. 3, 322 323 324 325 326 321
328 329
330
33 1
332 333
D. C. Fenimore, R. R. Freeman, and P. R. Loy, Analyt. C h ~ m .1973,45, . 2331. N. K. McCallum, J. Chromatog. Sci.,1973, 11, 509. K. Bailey, D. Legault, and D. Verner, J. Chromatog., 1973. 87, 263. M. Binder, S. Agurell, K. Leander, and J.-E. Lindgren, Helv. Chim. Acta, 1974, 57, 1626. T. B. Vree and N. M. M. Nibbering, Tetrahedron, 1973, 29, 3849. F. J. E. M. Kuppers, R. J. J. C. Lousberg, C. A. L. Bercht, C. A. Salemink, J. K. Terlouw, W. Heerma, and A. Laven, Tetrahedron, 1973, 29, 2797. A. Shani and R. Mechoulam, Tetrahedron, 1974, 30,2437. R. K. Razdan, H. C. Dalzell, and G. R. Handrick, J. Amer. Chem. SOC.,1974, 96, 5860. Nguyen-Hoang-Nam, J. P. Beaucourt, H. Hoellinger, and L. Pichat, Bull. SOC.chim. France, 1974, 1367. D. Clarke, L. Crombie, and D. A. Whiting, J.C.S. Perkin I, 1974, 1007. T. Petrzilka and M. Demuth, Helv. Chim. Acra, 1974. 57, 121. R. Mechoulam, Z. Ben Zvi, S. Agurell, I. M. Nilsson, J. L. G. Nilsson, H. Edery, and Y. Grunfeld, Experientia, 1973, 29, 1193.
45
Mono terpeno ids
p. 89; Vol. 4, p. 75); the reaction has also been carried out with sesamol (methylene-3,4dioxyphenol), which yields isomers of (253).334At 200 "C,geraniol and triphenyl phosphite give a mixture similar to that obtained from geraniol and phenol in the presence of phosphoric acid (Vol. 2, p. lo), but without the hydrogenated ~ a n t h e n e s . Nor-THC ~~' (252; R = H) has been prepared.336
(253)
Condensation of citral with nitrogen-containing phenols (e.g. hydroxyacridones and hydroxycarbazoles) gives citrylidene compounds similar to the cannabinoid type. In particular, ( f)-mahanimbine (254) and currayazolidine (also known as cyclomahanimbine and curryanine) (255), two alkaloids from Murrayu koenigii, have been made from 2-hydroxy-3-methylcarbazole.Mahanimbine (254) is converted into the cyclic compound with Dowex 50 in benzene.337
334
335
K. L. Stevens, L. Jurd, and G. Manners, Tetrahedron, 1974, 30, 2075. Y.Shigemasa, H. Kuwamoto, C. Sakazawa, and T. Matsuura, Nippan Kuguku Kuishi, 1973, 2423.
R. S. Wilson and E. L. May, J. Medicin. Chem., 1974, 17, 475. W. M. Bandaranayake, M. J. Begley, B. 0. Brown, D. G. Clarke, L. Crombie, and D.A. Whiting, J.C.S. Perkin I , 1974, 998; D. P. Chabraborty, P. Bhattacharayya, and A. R. Mitra, Chem. and Ind., 1974,260.
2 Sesqu iterpenoids BY T. MONEY
1 Introduction The structural classification of sesquiterpenoids outlined in the previous volume’ is used again in this Report, which covers the literature during the period August 1973August 1974.A new review summarizing current biosynthetic theory has been published.2 2 Farnesanes Additional confirmation of the structure of sesquirosefuran (4)has been provided by simple syntheses involving the condensation of geranyl bromide (1) with 2-lithio-3methylfuran (2)3or 2,2’-bis-(3-methylfuryl)mercury(3).4
(3)
J
An interesting feature of a recent synthesis of freelingyne (6)is the coupling reaction between 3-furanylcopper and the iodoalkyne (9.’ In an alternative route,6a flash vacuum pyrolysis ofthe tertiary acetate (8) provided a mixture from which ( k )-freelingyne (6) could be isolated by preparative t.1.c. Dihydrofreelingyne (lo), which also occurs in the heartwood of Eremophilafreelingii, has been synthesized from the same acetylenic ester (9) (Scheme 1).6h
’
R. W. Mills and T. Money, in ‘Terpenoids and Steroids’, ed. K. H. Overton (Specialist Periodical Reports), The Chemical Society, London, 1974, Vol. 4, p. 77. Angew. Chem. Internat. Edn., 1973. 12, 793. Y. Gopichand, R. S. Prasad, and K. K. Chakravarti, Tetrahedron Letters, 1973, 5177. S. Kumazawa, K. Nishihara, T. Kato, Y . Kitahara, H . Komae, and N. Hayashi, Bull. Chem. Soc. Japan, 1974, 47, 1530. D. W. Knight and G . Pattenden, J.C.S. Chem. Cnmm., 1974, 188. C . F. Ingham, R. A. Massy-Westropp, and G . D. Reynolds, ( a ) Austral. J . Chem., 1974, 27, 1477; ( b ) ibid., p. 1491.
‘ G . Rucker,
‘
’
46
47
Sesquiterpenoids
I
(7) R = H (8) R = COMe
vii. viii
I
A
Reagents: i, Bu”Li-CuBr; ii, MnO,; iii, 0A p p h 3 r : vi, A; vii, LiAiH,; viii, PBr,; ix, LiAIH,-THF;
iv, Ph,P=CHCOMe; v, Zn-THF; C r 0 3 . 2 p q ; xi, Ph,P=CMeCO,Et:
X,
Bu, P Scheme 1
The use of vanadium acetylacetonate-t-butyl hydroperoxide [VO(acac),-Bu‘OOH] to epoxidize the known diol (11) stereoselectively is the key feature of a new synthetic route (Scheme 2) to C , , Cecropia juvenile hormone (13)’“
’ (a) S. Tanaka, H. Yamamoto, H. Nozaki, F. B. Sharpless, R. C. Michaelson, and J. D. Cutting, J . Amer. Chem. Soc., 1974, 96, 5254; ( b ) E. J. Corey, J. A. Katzeneilenbogen, N. W. Giiman, S. A. Roman, and B. W. Erickson, ibid., 1968, 90. 5618.
Terpenoids and Steroids
48
c/ ref 7h
ii. Me,CuLi; iii, Me,NCf-I(OMe),; iv. Ac,O. 130 " C ; v,
Reagents: i, VO(acac),-Bu'OOW; HCIO,.
Scheme 2
3 Bisabolanes A revised structure (15) for caespitol [previously (14)'"l has been proposed on the basis
of its chemical correlation with isocaespitol (16).9 Both compounds co-occur with the intercsting e' 1 2 metabolite furocaespitane (17)*' in the marine alga Laurencia caespitosa Larnx. The spectroscopic properties reported" for furocaespitane are also consistent with the alternative structure (18).
Br'
&c,
u%cl
B%Br
C1
Br
Rr (14)
(15)
(16)
Br (17) A. G . Gonzfilez, J. Darias, and J. D. Martin, ( a ) Tetrahedron Lerters, 1973, 2381; ( h ) ihid., p. 3625.
Sesquiterpenoids
49
Three new sesquiterpenoids have been isolated from Douglas fir and identified as dihydropseudotsugona1(19), dihydropseudotsugonol(20),and nr-todomatuic acid (21).'"
A
A
(19) R = CHO (20) R = CHZOH
(21)
Alternative synthetic routes to ( & )-ar-turmerone (22)' ' (Scheme 3), ( k )-a-atlantone (23)12(Scheme 4),and (+)-(E)-nuciferol (24)13have been reported. The synthesis of the keto-acid (25)'& from cyclohexanone has recently been integrated into a stereospecific synthesis of (+)-juvabione (26) (Scheme 5.)14"
Reagents: i, p-MeC,H,CHO:
ii, MeMgI-CuC1: iii, A.
Scheme 3
lo I' I* l3 l4
A. G. Gonzalez, J. Darias, J. D. Martin, and C. Perez, Tetrahedron Letters, 1974, 1249. T. Sakai and Y. Hirose, Chem. Letters, 1973, 825. T.-L. Ho,Synlh. Comm., 1974, 4, 189. J. H. Babler, D. 0. Olsen, and W. H. Arnold, J . Org. Chem., 1974, 39, 1656. J.-C. Depezay and Y. Le Merrer, Tetrahedron Letters, 1974. 2755. (a) J. Ficini and A. M. Touzin, Tetrahedron Letters, 1972, 2093, 2097; ( b )J. Ficini, J. d'Angelo, and J. Noire, J , Amer. Chem. Soc., 1974, 96, 1213.
50
Terpenoids and Steroids
(23) Reagents: i, H,C=CHLi; ii, AcOH-H'; NaO Me-MeOH.
iii, KOH: iv, Cr0,,2py; v, H,C=CMeCH,MgCl;
vi,
Scheme 4
OH
p .':1:3 V
t-
0
RO
A Reagents: i, H,C=CHOEt-H ; ii, LiAlH,: iii, CBr,-Ph,P-py; iv, Me,CHC-(0R)CN(Me,N),PO; v, H'-MeOH; vi, (CH,OH),-H + ;vii, CrO,,py; viii, (MeO),CO-NaH; ix, NaBH,; x, TsC1-py; xi, NaOMe; xii, H,O-H'. +
Scheme 5
51
Sesquiterpenoids
A new method of constructing the isopropylidene group, by thermolysis of p-lactones, has been used in a recent synthesis of (-t)-curcumene (27) (Scheme 6).15
HO
/t\
CO, H
Reagents: i, Me,CHCO,H-LiNPr';;
(27) ii, PhS0,Cl-py; iii, 140 "C.
Scheme 6
4 Cuparane, Laurane, Trichothecane, etc.
A short synthesis of ( k )-cuparene (29), involving BF,-catalysed rearrangement of the epoxide (28), has been published.I6 The related compound b-cuparenone (30) can be obtained by treating the diazo-ketone (31) with anhydrous copper sulphate (Scheme 7)." Cuparene derivatives isolated from plants and fungi generally have R- and S-
%-"/:o-.
HO,C
... .
111,
1v
(29) R (30) R
=
H,
=
0
(31)
Reagents: i, BF,-Et,O-C,H,;
ii, NH,NHCONH,; iii, SOCI,; iv, C H , N , ; v, CuSO,.
Scheme 7
'' l6
A. P. Krapcho and E. G. E. Jahngen, J. Org. Chem., 1974, 39, 1322. C. W. Bird and Y . C. Yeong, Synthesis, 1974, 27. R. B. Mane and G. S. K. Rao, J.C.S. Perkin I , 1973, 1806.
52
Terpenoids and Steroids
configurations respectively. However, the liverworts (Hepaticae) are unique among plants since they produce antipodal sesquiterpenoids (cf. p. 63), and the recent isolation of (S)-2-hydroxycuparene from Marchantia polyrnorpha Linn. is consistent with this genera! observation.’ A non-epimerizing method of ketone methylenation” is the prominent feature of a recent synthesis2’ of ( )-laurene (33) from the known bicyclic alcohols (32)(Scheme 8).21
(33) Reagents: i, BH,-THF; ii, H,O,-NaOH; iii, CrO,,py; iv, PhSCH2Li; v, (PhCO),O; vi, Li-NH,.
Scheme 8
The use of 13Cn.m.r. spectra in biosynthetic studies continues to increase and in the sesquiterpenoid area this technique has recently been used effectively to provide further details regarding the biosynthesis of trichothecanes and helicobasidin.22 Details of these studies are provided in the Specialist Periodical Report dealing with bio~ynthesis.~ Several toxic strains of Fusariurn culrnorum are associated with cereal crops, and a recent has shown that a toxic extract derived from one of these strains contains a trichothecane sesquiterpenoid (34; R = 0)which is closely related to 15-de-0-acetylcalonectrin (34 ; R = H2).Complete details of the first total synthesis of (+) trichoder-
Is
l9 *O
22
23 l4
B. J. Hopkins and G . W. Perold, J.C.S. Perkin I, 1974, 32. R. L. Sowerby and R . M . Coates, J. Amer. Chem. Soc., 1972, 94, 4758. J . E. McMurry and L. A. von Beroldingen, Tetrahedron, 1974, 30, 2027. T. Irie, T. Suzuki, Y.Yasunari, E. Kurosawa, and M. Masamune, Tetrahedron, 1969, 25, 459. ( a ) J. R. Hanson, T. Marten, and M. Siverns, J.C.S. Perkin I, 1974, 1033; (b) R. Achini, B. Muller, and C. Tamm, Heft>.Chim. Acta, 1974,57, 1442; (c) M. Tanabe, K. T. Suzuki, and W. C. Jankowski, Tetrahedron Letters, 1973, 4723. J. R. Hanson in ‘Biosynthesis’, ed. J. D. Bu’Lock (Specialist Periodical Reports), The Chemical Society, London, Vol. 4, in the press. M. M . Blight and J. F. Gr0ve.J.C.S. Perkin I, 1974, 1691.
53
Sesqu it erpeno ids
min (35;R’ = H,, R2 = COMe) have been p~blished.’~ Since allylic oxidation to the corresponding 8-0x0-compound (35; R’ = 0, R 2 = Ac) has previously been accomplished, the synthesis of trichodermin constitutes a synthesis of trichothecolone (35 ; R’ = 0, R2 = H) and trichothecin (35; R’ = 0, R2 = COCH=CHMe). Various synthetic approaches to the trichothecane nucleus have been reported in preliminary form.26 The isolation of a-barbatene (36) and p-barbatene (37) from various liverworts (Barnilophozia species) has been de~cribed.~’ P-Barbatene (37) is identical with a hydro-
K carbon previously isplated from the liverwort Gyrnnornitrion obtusurn.**It is interesting to note that a-pompene, a metabolite of the liverwort Bazzania pornpeana, has been assigned the novel structure (38).29However, the chemical and spectroscopic evidence does not exclude the alternative a-barbatene structure (36): indeed, the chemical shift values for a-pompene and a-barbatene are almost identical. 5 Acorane, Cedrane, etc. An alternative synthetic approach to the acorane-type sesquiterpenoids has recently been used in a new total synthesis of ( )-P-acorenol(39) and ( )-P-acoradiene (40).30As shown in Scheme 9, the spirocyclic skeleton was constructed by a thermal intramolecular ene reaction. Cationic cyclization, involving chloroalkene groups, is a notable feature of a new The required spiro-ketone (43) synthetic route to (+ )-a-cedrene (45) (Scheme was obtained by formolysis of (41) and the subsequent regioselective introduction of alkene functionality into (43) was accomplished by an intramolecular dehydrohalogenation reaction involving alkoxide (44).
+
E. W. Colvin, S. Malchenko, R. A. Raphael, and J. S. Roberts, J.C.S. Perkin I, 1973, 1989. (a) D. J. Goldsmith, A. J. Lewis, and W. C. Still, Tetrahedron Letters, 1973, 4807; (6) Y. Fujimoto, S. Yokura, T. Nakamura, T. Morikawa, and T. Tatsuno, ibid., 1974, 2523; ( c ) N. Masuoka, T. Kamikawa, and T. Kubota, Chem. Letters, 1974, 751. *’N. H. Anderson, C. R. Costin, C. M. Kramer, Y. Ohta, and S. Huneck, Phytochemistry, 1973, 12, 2709. 2 8 J. D. Connolly, A. E. Harding, and I. M. S. Thornton, J.C.S. Chem. Comm., 1972, 1320. 2 9 A. Matsuo, Y. Maeda, M. Nakayama, and S. Hayashi, Tetrahedron Letters, 1973, 4131. 3 0 W. Oppolzer, Helv. Chim. Acta, 1973, 56, 1812. 3 ’ P. T. Lansbury, V. R. Haddon, and R. C. Stewart, J. Amer. Chem. Sor., 1974, 96, 896. 25
26
Terpenoids and Steroids
54
@&bLb+ C'0,Et
C0,Et
C0,Et
1
C0,Et
111
b&+J =_.I, h?&k5h \
C0,Et
C0,Et
OCH,OMe
0
COzEt
I
\
6 OH
/t\
OH
A
(39)
(40)
Reagents: i, H,C =CHCH,CH,Br-LiN(C,H, ,)CHMe,; ii, 280 "C; iii, Na,CrO,-AcOH-Ac,O; iv, MeLi; v, ClCH,OMe; vi, 195 "C; vii, Na-NH,-EtOH; viii, Al,O,-py.
Scheme 9
u
I'
Ac1
Reagents: i, HC0,H-Ac,O; ii, PhICI,; iii, MeLi; iv, H C 0 , H .
Scheme 10
55
Sesquiterpenoids
6 Charnigrane, Widdrane, and Thujopsane Halogenated sesquiterpenoids having a chamigrane or rearranged chamigrane skeleton are common constituents of algae of the marine genus Laurencia. The isolation and structural elucidation of several new compounds of this type have recently been reported : these include acetoxyintricatol (46)32(L. intricata), glanduliferol (47)33"and co-metabolites (48)-(50)33b (L. gianduli$era), and nidificene (51) and nidifidiene (52)34(L. nidifica). OH
6Ac
i
Br
%
B
r
a
:
A new synthesis of (*)-a-chamigrene (55) has been described35 in which the spiro ring system is constructed by a method which should be of general applicability. As shown in Scheme 11 the crucial step in the synthetic sequence is an intramolecular carbene-insertion reaction. Subsequent reduction of the tricyclic product (53) provides an intermediate (54) which can be easily converted into ( f)-a-chamigrene (55). Postulated biogenetic relationships between sesquiterpenoids are often supported by their co-occurrence in nature. In addition it seems reasonable to expect that certain compounds of predictable structure will eventually be found to co-occur with known metabolites of a particular plant or mi~ro-organism.~~ A recent report37supports this viewpoint. Examination of the minor hydrocarbon constituents of Hiba wood oil
32 33 34
'' 36 37
J. A. MacMillan, I. C. Paul, R. H. White, and L. P. Hager, Tetrahedron Letters, 1974, 2039. M. Suzuki, E. Kurosawa, and T. Irie, ( a ) Tetrahedron Letters, 1974, 1807; ( 6 ) ibid., 1974, 821. S. M. Waraszkiewicz and K. L. Erickson, Tetrahedron Letters, 1974, 2003. J. D. White, S. Torii, and J. Nogami, Tetrahedron Letters, 1974, 2879. G. L. Hodgson, D. F. MacSweeney, and T. Money, J.C.S. Perkin I, 1973, 21 13. S. Ito, K. Endo, and H. Narita, Tetrahedron Letters, 1974, 1041.
Terpenoids and Steroids
56
1
i\ -\i
Reagents: i, N a - N H , ; ii, 3 % HCI; iii, ( C H , O H ) , - H i ; iv, NaH-C,H,; v, ( C O c I ) , ; V i , M e C H , N 2 ; vii, Cu": viii, Li-NH,; ix, LiAlH(OBu'),; x, MeSO,CI-py; xi, Me,SO, 60 " C ; xii, HCI0,-THF; xiii, MeLi; xiv, Me,SO, 80 "C. Scheme 11
(57)
1
1
1
(29)
Scheme 12
Sesquiterpenoids
57
(Thujopsis dolobrata) has resulted in the isolation of P-chamigrene (57) and (+)-apseudowiddrene (58).37 These compounds are co-metabolites of thujopsene (59), cuparene (29), and cuprenenes (56) and have structures which are consistent with current biogenetic theory (cf. Scheme 12). A new efficient procedure for converting y-keto-acids into aP-unsaturated ketones has been successfully incorporated into a recent synthesis of (+ )-mayurone (61)and ( & )thujopsadiene (62) (Scheme 13).38 The basic tricyclic framework [cf. (60)] of these compounds was constructed by means of a known intramolecular a-ketocarbene-olefin insertion reaction. Hydrolysis of the product (60) followed by treatment with lead tetra-acetate in the presence of cupric ion provided (+)-mayurone (61), which was subsequently converted into ( k )-thujopsadiene (62) in the usual way. CHO
C0,Me
CO Me VI1 +
Y. VI
0 (60)
Reagents: i, Ag,O; ii, K,CO,-Mel; iii, LiN(C,H, ,)CHMe,-H,C =CHCH,Br; iv, NaI0,-OsO,; v, (COCI),; vi, CH,N,; vii, Cu-CuSO,; viii, NaOH-EtOH; ix, Cu(OAc),- Pb(OAc),py: xi, MeLi; xii, NH,CI.
Scheme 13
7 Sesquicamphane, fi-Santalane, Epi-fi-Santalane, etc. The potential of commercially available (+)-camphor (63) or (-)-camphor (64) as a starting material in sesquiterpenoid synthesis has been exploited in a general synthetic scheme (Scheme 14) which provides (-)-campherenone (68), (-)-camphereno1 (70; endo-OH), ( - )-P-santalene (72), ( + )-epicampherenone (67), ( + )-isoepicampherenol (69 ; exo-OH), ( + )-epi-B-santalene (71), and tricyclic sesquiterpenoids described in J. E. McMurry and L. C. Blaszczak, J . Org. Chem., 1974, 39, 2217.
Terpenoids and Steroids
58
1
i, iii,
5
iv
ii- iv
IsBr
"P-
1
x or
methyl ketones > cyclopentanones) allow selective reductions of androstane-3,17-diones and pregnane-3,20-diones at C-3. The 0x0-group is presumably activated to reduction by protonation, for ketones are rather unreactive to NaBH,CN in neutral media.' 5 4 The reduction of a series of cholestenones with NaBH,CN has also been examined. Both 1,2- and 1,4-addition of hydrogen were observed, in proportions depending upon the particular enone and the pH of the solution.' A new reducing agent, lithium dimesitylborohydride bis(dimethoxyethane), shows remarkable stereoselectivity for the reduction of cyclohexanones to axial alcohols, as well as widely differing reaction rates according to steric hindrance.'56 The stable crystalline reagent offers interesting possibilities in steroid chemistry. 'Disiamylborane', and other highly hindered dialkylboranes reduce cycloalkanones with high 5aselectivity for approach from the more exposed side of the carbonyl Cholestan-6-one gave only the 6P-alcohol, whereas the 3a,Sa-cycl0-6-ketone gave the 6a-alcohol. Stereochemical control reported for 2-alkylcyclohexanones implies that other suitable steroid ketones should afford the less stable of the possible alcohol products. Further study of the reduction of ketones by either ethanol or propan-2-01, with soluble iridium complexes as catalysts, has shown varied stereoselectivity according to the associated ligands and other factors. Experiments with 5a-cholestan-3-one, using amines or DMSO as ligands, afforded up to 69% of the axial but for preparative purposes none of these modifications equals the original method for preparing the axial alcohol, by use of trimethyl phosphite. 5 9 Sa-Cholestan-3-one is reduced in the presence of various precipitated metals, with water as hydrogen donor. The 3ccand 3P-ols are formed in ratios dependent upon the metal and solvent system, the axial (3a) alcohol predominating in some cases.' 6 o Aminoiminomethanesulphinic acid (thiourea SS-dioxide) is another reducing agent for 3-0x0-%steroids. In a strongly alkaline solution (sodium n-propoxide-n-propanol) it gives the 3P-alcohols as major products. 5a-Pregnane-3,20-dione was reduced only at C-3.I6'
'
153
15' 155 156
15'
159
I6O 16'
L. E. Conteras, D. de Marcano, L. Marquez, M. Molina, and L. Ternpestini, J . Org. Chem., 1974, 39, 1550. M.-H. Boutigue and R. Jacquesy, Compt. rend., 1973, 276, C , 437. M.-H. Boutigue, R. Jacquesy, and Y. Petit, Bull. SOC.chim. France, 1973, 3062. J . Hooz, S. Akiyama, F. J. Cedar, M. J. Bennett, and R. M. Tuggle, J. Amer. Chem. Soc., 1974, 96, 274. H. C. Brown and V. Varma, J. Org. Chem., 1974, 39, 1631. Y. M. Y. Haddad, H. B. Henbest, J. Husbands, T. R. B. Mitchell, and J. Trocha-Grimshaw, J.C.S. Perkin I , 1974, 596. Y. M. Y. Haddad, H. B. Henbest, J. Husbands, andT. R. B. Mitchell, Proc. Chem. Soc., 1964, 361 ; D. N. Kirk and P. A. Browne, J. Chem. SOC.(0,1969, 1653. M. Ishige, M. Shiota, and Y. Ideno, Canad. J. Chem., 1973, 51, 3923. J. E. Herz and L. A. de Marquez, J.C.S. Perkin I , 1973, 2633.
248
Terpenoids and Steroids
A new procedure for deoxygenation of ketones to give olefins may find applications in steroid chemistry : the ketone is stirred in ether with chlorotrimethylsilane and zinc dust. 1 6 2 The mechanism of reduction of the sapogenin side-chain (a masked 22-oxo-compound) with LiAID,-AlCI, has been elucidated : 6 3 the resulting dihydrosapogenin (86) contained one deuterium atom, specifically at the C-22-position in the (22R)configuration.
Other Reactions at the Carbonyl Carbon Atom.--The Wittig reaction of 5wcholestan3-one with ethylidenetriphenylphosphoranegives a mixture of (2)-and (E)-3-ethylideneSa-cholestanes [ ( S ) and (6);see p. 2281, which were separated by fractional crystallization and chromatography on activated charcoal. Configurations were assigned on the basis of hydroboration-oxidation and a c.d. study of the acetates and o-nitrobenzoates of the derived alcohols (87).33 The characteristic olefinic c.d. curves of the 3-ethylidene isomers are discussed on p.228. Suitable Wittig reagents have been used to convert the bisnorcholan-22-a1 (88) into mixed cis- and trans-isomers of the corresponding cholest-22-ene (89) and its 24-nor-analogue (90), re~pectively.'~~
\ CH =C H ( C H 1°CHM e
(89) n = 1 (90) n = 0
A 21-hydroxypregnan-20-onereacts with 0-ethoxyvinyltriphenylphosphoniumsalts (or suitable precursors) in the presence of a base to give the furan (91).'65 A review of
applications of organic phosphonate carbanions (Wittig-Homer reaction) includes a
Ih2 lh3
'
b4 I b 5
W. B. Motherwell, J . C . S . Chem. Comm., 1973, 935. A. H. Albert, G . R. Pettit, and P. Brown, J . Org. Chem., 1973, 38, 2197. A. Metayer. A. Quesneau-Thierry, a n d M. Barbier, Tetrahedron Letters, 1974, 595. M. E. Garst and T. A. Spencer, J . Org. Chem., 1974, 39, 584.
t
Steroid Properties and Reactions
249
number of steroidal examples, including conversions of the types \
' /c=o 1 , /------C=CHCo2Et
/C=CHCN
and applications of the products in synthesis'66 The immonium salt (92), formed by reaction of 17P-hydroxy-5a-androstan-3-0ne with 3-pyrrolinium perchlorate, is converted by diazomethane into the spiro-salt (93); butyl-lithium causes fragmentation of the latter compound to give the 3-methylenederivative (94)in 82 yield, a significant improvement on yields claimed from the Wittig reaction. Other ketones and aldehydes react similarly.' 6 7
x)
(92)
(93)
(94)
Tosylmethyl isocyanide (TsCH,NC) adds onto ketones under basic conditions to give oxazolines or derived products. Use of thallium(]) ethoxide as base gave a 4-ethoxy-2oxazoline, which was readily hydrolysed by acid to give an a-hydroxy-aldehyde. Applied to 5a-cholestan-3-one, the two-step process afforded the 3a-hydroxy-3Baldehyde (99,which was found to exist partly in dimeric form.'68 Trimethylsilyl cyanide is an efficient reagent for the conversion of ketones into the trimethylsilyl ethers (96) of cyanohydrins, even in cases where hydrogen cyanide addition to the ketone is unsuccessful. The cyanohydrin ether (96) may be reduced and hydrolysed to give the aminomethyl alcohol (97). 69 Although no steroidal examples have yet been described, the importance of aminomethyl alcohols (97) for Demjanov ring expansion "O suggests applications in steroid chemistry.
(95)
n-(2-Methoxyallyl)nickel bromide (98),a new and reasonably stable reagent, converts ketones (e.g. 5a-cholestan-3-one) into 3-hydroxy-3-(2-oxopropyl) derivatives (99).'
'
166
16' i68
lh9
J. Boutagy and R. Thomas, Chem. Rev., 1974, 74, 87. Y. Hata and M. Watanabe, J. Amer. Chem. SOC.,1973, 95, 8450. 0. H. Oldenziel and A. M. van Leusen, Tetrahedron Letters, 1974, 167. D. A. Evans, G . L. Carroll, and L. K. Truesdale, J. Org. Chem., 1974, 39, 914. Ref. 80, pp. 323, 324; Ref. la, 1971, Vol. 1, p. 353; ibid., 1974, Vol. 4, p. 370. L. S. Hegedus and R. K. Stiverson, J. Amer. Chem. SOC., 1974, 96, 3250.
250
Terpenoids and Steroids
(99)
(98)
Steroidal 19-methyl 3.19-diketones (100) readily undergo internal cyclization with (101),a compound belonging to the bicyclobase to give the 3,lO-(2'-oxoethano)-system [2,2,2]octanone class. Huang-Minlon reduction under forcing conditions removed the oxo-group. C.d. data are reported for compounds of the type (101).'72
H -
H
In continuation of study of A'(")-unsaturated 5,10-seco-5-oxo-steroids (102), the trans-isomer has been shown to react with hydroxylamine or N-methylhydroxylamine to give cyclized derivatives (isoxazolidines) (103) or (104), respectively. The cis-isomer of (102) failed to react, apart from simple formation of the 5-oximino-derivative.' 7 3
R (103) R = H (104) R = Me
Steroidal nitrones [e.g. (105) and (106)]have been prepared by treating suitable aldehydes and ketones with N-alkylhydroxylamine salts and sodium bicarbonate : the products were stable crystalline solids. i 4
17*
F. M. Hauser, A. Philip, and F. I . Carroll, J. Org. Chem., 1973, 38, 3696. M. Lj. Mihailovic, Lj. Lorenc, Z. Maksimovic, and J. Kalvoda, Tetrahedron, 1973, 29, 2683. P. M. Weintraub and P. L. Tiernan, J . Org. Chem.. 1974, 39, 1061.
25 1
Steroid Properties and Reactions
I
CH=N
Me
\
t 105)
R
Reactiom of Enols and Enolate Ions.-Although all previous work involving enolization of 1l-oxo-steroids (107) has indicated the 9(1 1)-en-11-01 structure, lithium di-isopropylamide gives the kinetically controlled product, the 1 l-en-11-01,which was trapped as its trimethylsilyl ether (108). Use of lithium as cation minimizes rearrangement to the more stable 9(11)-enol. The lithium A' '-enolate reacted with perchloryl fluoride to give the 1 2 ~ and l2p-fluoro-ketones (109). Similar reactions in the 9~-fluoro-l l-oxo-series (110) proceeded through the A' '-en01 (1 1 1) to give the novel 9~,12\j-difluoro-(1 12) 75 and 9~!,12,12-trifluoro-ketones.' F
(107) R = H
(108) R = H
(110) R
(111)
=
F
R
=
F
(109) R (112)
R
= =
H F
Methylation of the 1l-oxo-oestrone derivative (113) gave the 9cr-methyl compound (1 14); the stereochemistry of alkylation was confirmed by an independent synthesis, involving aromatization of a 9a-methylandrosta-l,4-dien-3-one derivative. 7 6
'
(113) R = H
(114) R
=
Me
The hemiacetal form (115) of an 18-hydroxypregnan-20-onereacts smoothly with lead tetra-acetate in acetic acid to give the 21-acetoxy-derivative (116),or with sources of electrophilic bromine (e.g. Ph,Me,N+ Br, -) to give the 21-bromo-hemiacetal (117).
176
D. H. R. Barton, R. H. Hesse, M. M . Pechet, a n d T. J . Tewson, J . C . S . Perkin I , 1973, 2365. R. V. Coombs. J. Koletar, R . D a n n a , H. Mah, a n d E. Galantay, J.C.S. Perkin I , 1973, 2095.
Tcrpenoids and Steroids
252
R R (117) R (119) R (115) (116)
=
H
= = =
OAC
Br OH
These reactions. like the rapid substitution of hydrogen at C-21 by deuterium when the hemiacetal was treated with deuterioacetic acid, suggest the rapid and reversible formation of the vinyl ether (118) in acidic media, allowing electrophilic attack at C-21. These reactions led to the first convenient synthesis of 18.21-dihydroxypregn-4-ene3,20-dione, which exists in the hemiacetal form (1 19).17’ Boron trifluoride was found to be an effective catalyst for the bromination of methyl 3a,7a-diacetoxy-12-oxo-5~-cholanate (120) with bromine and acetic acid.’ 7 8 The 1 la-bromo-derivative (121) was formed in high yield, although reaction was only slight when HBr was used as the catalyst, even at 70 “C. This situation contrasts with the ready bromination of the corresponding 12-oxo-derivative lacking a 7a-acetoxysubsti tuen t .
H
(120) (121)
R R
= =
H Br
The 2-acetoxylation of 4-en-3-ones with lead tetra-acetate is improved by using a four-fold excess of reagent at 6&70 0C.30Stereospecific bromination of the 4-en-3-one at the 6P-position with N-bromosuccinimide requires intensively dried solvent for optimum yields.30 4.4-Dimethyl 5a-steroidal 2-ones undergo acetoxylation, bromination. or formylation at C-3; the latter reaction is slow and ineffi~ient.”~The 2a.3fi-diol (1 22), a metabolite of ‘chlormadinone acetate’. the corresponding 4.6-dien-3-one. has been obtained along with the 2/1,3[Gisomer by acetoxylation at C-2 [Pb(OAc),], followed by reduction with sodium borohydride. Both diols form acetonides.’ 80 Ring-D bromination of the steroid-like 17-oxocyclopenta[a]phenanthrene (123) has been studied.’ The lithium A3-enolate obtained by reduction of testosterone with lithium-ammonia reacts with l-iodo-3-trimethylsilylbut-2-eneto give the 4-alkylated derivative (124). ”’
‘‘I
D. N . Kirk and M . S. Rajagopalan, J.C.S. Chem. Camm., 1974, 145. Y. Yanuka and G . Halperin. J. Org. Chem., 1973, 38, 2587. A. D. Boul, R . Macrae, and G. D. Meakins, J.C.S. Perkin I, 1974, 1138. T. Abe and A. Kambegawa, Chem. and Pharm. Bull. (Japan), 1973, 21, 1295. M . M. Coombs. M.Hall, and C. W. Vose, J.C.S. Perkin I, 1973, 2236.
253
Steroid Properties and Reactions
(1 23)
Epoxidation and treatment with acid converted the vinylsilane component into the 4-(3’-oxobutyl)derivative (125), a suitable intermediate for construction of an additional ring.’82 Reductive alkylation (Li-NH,, then MeI) of cholesta-4,6-dien-3-one gives 4,4-dimethylcholest-5-en-3-one rather than a 4-monomethyl derivative. 8 3
Enolizable ketones (or aldehydes) react with phenylselenenyl chloride in ethyl acetate at room temperature to give a-phenylseleno-derivatives. Oxidation in situ with H,O,, peracetic acid, or sodium metaperiodate is followed by spontaneous elimination of the selenoxide to give the ap-unsaturated ketone or aldehyde. 5aCholestan-3-one gave the 1-en-3-one in high yield, with only minor contamination by the 4-en-3-one and 1-4-dien-3-0ne.l~~ A kinetic study of the enzyme-modelled isomerization of cholest-5-en-3-one by phenol-triethylamine mixtures has revealed complex behaviour, interpreted in terms of a transition state (126) involving a mole of the phenol and a phenol-triethylamine complex. rn-Nitrophenol was the most effective of a series of substituted phenols investigated.
\
ArO-H’
i:&c:-
,.o
H
c?.,..H--NEt,
o&
0I
A1
G . Stork and M . E. Young, J. Amer. Chem. SOC.,1974, 96, 3682. K . P. Dastur, Tetrahedron Letters, 1973, 4333. lE4 K . B. Sharpless, R. F. Lauer, and A. Y. Teranishi, J. Amer. Chem. Sac., 1973, 95, 6137. 1 8 5 A . Fauve, A. Kergomard, and M. F. Renard, Tetrahedron, 1973, 29. 2903. 18’
183
254
Terpenoids und Steroids
The well-known enolization-protonation procedure has been employed to deconjugate cholesta-l,4,6-trien-3-one,giving the 1,5,7-trien-3-one (127), which was found to be very unstable. Reduction with Ca(BH,), gave the 1,5,7-trien-3P-ol,which was used in a new synthesis of la-hydroxy-7-dehydrocholesterol.' 86 The concept of stereoelectronic control of deprotonation of a ketone, first proposed to account for the reactions of a 7-oxo-steroid, receives new support from a demonstrated kinetic preference for deuterium exchange of 2-axial protons in 4-t-butylcyclohexanone. 8 7 Steroidal 7-en-6-ones may be converted into their 6,8(14)-dien-6-01acetates (128) without change of configuration at C-5. The n.m.r. spectra of these derivatives provide reliable evidence of the C-5 configuration, depending upon the presence or. absence of allylic coupling between the C-5 and C-7 protons.'88
'
Reactions of Enamines and Enol Derivatives.-3-Pyrrolidino-3.5-dienes ( 1 29) react with formaldehyde to give 6-hydroxymethyl-4-en-3-ones (1 30) as major products.'89 Depending upon the reaction conditions, the product may be predominantly in the 6a- or the 6P-configuration, but both isomers are dehydrated by acid to give the 6methylene-4-en-3-one (13 l), a known intermediate for the preparation of 6-methylated s t e r ~ i d s . ' ' ~Dienamines of the 19-nor and 9P,10a ('retro') series react in a similar manner. 189
The dienamine (129) reacts with either crotonaldehyde or methyl vinyl ketone to give the benz[4,5,6]-steroids (1 33) or (134), respectively, after hydrolysis and chromatography. Condensation probably proceeds through a Michael-type addition at C-6, to give the keto-enamine (132),followed by electrophilic attack by the carbonyl group at C-4. A dehydrogenation step, required to aromatize the initial cyclohexadiene,
"'
'" I9O
C. Kaneko, A. Sugimoto, Y. Eguchi, S. Yamada, M. Ishikawa, S. Sasaki, and T. Suda, Tetrahedron, 1974, 30, 2701. G. B. Trimitsis and E. M. Van Dam, J.C.S. Chem. Comm., 1974, 610. W. B. Smith and G. P. Newsoroff, Steroids, 1974, 23, 579. F. Schneider, A. Boller, M. Muller, P. Muller, and A. Fiirst, Hefv. Chim. Acta, 1973, 56, 2396. D. Burn, G. Cooley, M. T. Davies, J. W. Ducker, B. Ellis, P. Feather, A. K. Hiscock, D. N. Kirk, A. P. Leftwick, V. Petrow, and D. M. Williamson, Tetrahedron, 1964, 20, 597.
255
Steroid Properties and Reactions
(133) R' (134) R'
(1 32)
= =
H, R 2 = Me Me, R2 = H
may occur by air oxidation, or possibly through disproportionation, since yields never reached 50 %.' Dichlorocarbene generated by thermolysis of sodium trichloroacetate converted 3-pyrrolidyl-3,5-dienes (129) directly into 4-chloro-~-homo-4(4a),5-dien-3-ones(1 35). Chlorofluorocarbene gave the corresponding 4-fluoro-derivative.' 9 2 O-Carboxymethyl-oximes (1 36) of steroidal 4-en-3-ones, required for binding to proteins for
H02CCH20N
c1
( 136)
(135)
radioimmunoassay studies, are readily prepared from monoketones, but selective condensation of 0-(carboxymethy1)hydroxylamine at C-3 in progesterone and its oxygenated derivatives has required indirect routes, to avoid formation of the 3,20bis-oxime derivative. The 3-pyrrolidyl-3,5-diene (129), which is formed selectively from progesterone with pyrrolidine in methanol, has been found to react with 0(carboxymethy1)hydroxylamine preferentially at C-3, giving the required C-3 derivative (1 36) in acceptable yield.' 9 3 Attempts to deconjugate 4-en-3-ones by careful protonation of the 3-pyrrolidyl dienamine derivative (129) gave poor results except in the case of oestr-9(11)-ene ~~ analogues, which afforded the 5( 10),9(1 l)-dien-3-ones in reasonable ~ i e 1 d s . I A detailed study of the hydrolysis of a 3-pyrrolidino-3,5-dienehas revealed an unexpectedly complex mechanism ;195 the transition state for protonation of enamines is thought to be more reactant-like than for the corresponding reaction of enol ethers.' 96
H
i137) 19* 193 194
i138)
i139)
P. Houdewind, J. C . L. Armande, and U. K. Pandit, Tetrahedron Letters, 1974, 591. S. A. G . de Graaf and U. K. Pandit, Tetrahedron, 1974, 30, 1 1 15. A. H. Janoski, F. C. Shulman, and G . E. Wright, Steroids, 1974, 23, 49. R . Bucourt and J. Dube, Bull. SOC.chim. France, 1974, 479. P. Bolla and M. Legrand, Bull. SOC.chim. France, 1973, 2143. P. W. Hickmott and K. N. Woodward, J.C.S. Chem. Comm., 1974, 2 7 5 .
256
Terpenoids and Steroids
An androst-15-en-17-one (137) is most effectively converted into the A' 4-compound (139) by reduction of the enol acetate (138)with sodium borohydride.' 9 7 17,!?-Acetoxy-3-methoxyoestra-2,5(10)-diene (140) reacts with perchloryl fluoride to give a 2-fluoro-5(10)-en-3-one(141). The configuration at C-2 is considered likely to be ,!? on the basis of some reactions of derivatives.19*
(1 40)
(141)
The enol acetates of cyclohexanone and cyclopentanone react with phenylselenenyl bromide and silver trifluoroacetate to give the 2-phenylselenoketones. Oxidation with NaIO, affords the 2-en-l-one7 by smooth collapse of an intermediate selenoxide, suggesting a potentially useful route for the regioselective dehydrogenation of steroidal ketones, when the required enol acetates are available (c$ p. 253).' 99 Alkylations and formylations of enol ethers with the Vilsmeier reagent have been reviewed.200 Dehydrogenation and Oxidation.-The dehydrogenation of a 4-en-3-one with dichlorodicyanobenzoquinone (DDQ) has been known for many years to give the 1,4-dien-3one, invariably contaminated by some 15% of 1,4,6-trien-3-one. Removal of the trienone from the residues left after direct isolation of as much dienone as possible has been achieved by selective reaction of the trienone with sodium metabisulphite to give a water-soluble adduct. The trienone could be recovered by decomposition of the complex with alkali2' The p-nitrophenylhydrazones of 5a-cholestan-3-one and lanost-8-en-3-one are dehydrogenated by iodine and potassium t-butoxide to give the corresponding 1,4-diene (142), requiring two molar proportions of reagent, and the 1-ene (143),requiring one mole of reagent, respectively.202 Nitrobenzene, or more conveniently p-nitrobenzoic acid, is a useful alternative to iodine as the oxidant. Yields are excellent (85-92"/,), so these processes will be seen as attractive alternatives to
(142)
(143)
DDQ or selenium dioxide if the p-nitrophenylhydrazone groups can be removed with equal efficiency to give the 174-dien-3-oneand 1-en-3-one: this requirement has not yet been discussed. Mechanisms are considered, a point of additional interest being the formation of the (E)-isomer of the A'-compound (143)by use of iodine, or the less stable G. H. Rasmusson a n d G. E. Arth, Steroids, 1973, 22, 107. J. Pataki, Tetrahedron, 1973, 29, 4053. lYY D. L. J. Clive, J . C . S . Chem. Comm., 1973, 695. D. Burn, Chem. and Ind., 1973, 870. 201 A. K. Lala a n d A. B. Kulkarni, Steroids, 1973, 22, 763. 2 0 2 D. H. R. Barton, J. C. Coll, J. F. McGarrity, a n d D. A. Widdowson, J.C.S. Perkin I, 1973, 1565. I"
lY8
Steroid Properties and Reactions
257
(2)-isomer when a nitroaryl oxidant was employed.202 A new method for the introduction of unsaturation ap to an ester group comprises generation of the a-carbanion by means of lithium N-cyclohexyl-N-isopropylamide, a-sulphenation by reaction with dimethyl disulphide, oxidation of the 01-methylthio-ketoneto the sulphoxide, and final pyrolysis of the latter at ca. 120 0C.203Yields are high, and ketone enolates are unaffected, allowing the selective conversion illustrated in Scheme 3. Diphenyl disulphide is more reactive than the dimethyl reagent, offering an analogous route to ag-unsaturated ketones. Lactones can also be dehydrogenated by these procedures (cc similar reactions using phenylseleno-ketones as intermediates, pp. 253 and 256).
0
C0,Me
1 0 H Scheme 3
A Nocardia species can be used either to reduce a 4-en-3-one to give the 501 saturated ketone or to dehydrogenate the enone, giving the 1,4-dien-3-one, according to the incubation conditions.204 Enzymic conversion of oestr-4-ene-3,17-dione into oestrone proceeds through loss of the 2P-proton, as revealed by tritium labelling.205
'03 '04 '05
B. M. Trost and T. N . Salzmann, J . Amer. Chem. SOC., 1973,95, 6840. G. Lefebvre, F. Schneider, P. Germain, and R. Gay, Tetrahedron Letters, 1974, 127. T. Nambara; T. Anjyo, M. Ito, and H. Hosoda, Chem. and Pharm. Bull. (Japan), 1973,21, 1938.
Terpenoids and Steroids
258
Autoxidation of 5a-cholestan-3-one in t-butyl alcohol with potassium t-butoxide proceeds beyond the known 2,3-dione by hydroperoxide attack on (2-4 (144) and loss of the C-3 carbon atom ; the product, the aldehyde-carboxylate (145), was reduced by sodium borohydride and afforded the lactone (1 46). Comparable reactions converted Sfl-cholestan-3-one into the lactones (147)and ( 148).206 A1(9)-Octal-2-oneand A '(*'-indan-2-one have been used as models for a detailed study of the Baeyer-Villiger oxidation: they can be regarded as bicyclic analogues of steroidal 4-en-3-ones and ~-nor-3(5)-en-2-0nes.~'~ Reactions of Oximes and Related Compounds.-A reaction sequence recently developed for the selective removal of a methyl group from 4,4-dimethyl steroids has now been adapted for the preparation of 18-nor-17-0x0-steroids. Abnormal Beckmann fission of the oxime (149) was followed by epoxidation of the unsaturated nitrile (150) and cyclization of the epoxide (151) with BF, to give the ketone (152). The product was assigned the 13P-configuration from n.m.r. evidence.208
The Beckmann cleavage of an cehydroxy-ketoxime (153) has been used to open ring reaction with tosyl chloride-pyridine gave the unstable cyano-aldehyde (154).209 The 5-hydroxy-6-acetoximino-5a-cholestane(1 5 5 ) undergoes Beckmann fragmentation under exceptionally mild conditions, or even on storage, to give the cyano-ketone (1 56),210 whereas the corresponding h i t r i t e is converted by alumina into a mixture of products.21 D:
OH
(155)
( I 56)
Further studies on Schmidt and Beckmann rearrangements have concerned 6-0xo-, ~-oxo-,and A5-7-0x0-steroids2l 2 and oestrone.21 The oxime of an a$-epoxy-ketone is fragmented by hydroxylamine-0-sulphonic acid in alkaline solution to give an acetylenic ketone214(cf:the analogous tosylhydrazone ?06 207 208 'OY
210
"'
2 L 2
R. Sandmeier and C . Tamm, Helv. Chim. Acta, 1973, 56, 2238. A. DeBoer and R . E. Ellwanger, J. Org. Chem., 1974, 39, 77. M. M. Coombs and C . W. Vose, J.C.S. Chem. Comm., 1974, 602. D. MiljkoviC, J. Petrovic, M. Stajic, and M. Miljkovic, J. Org. Chem., 1973, 38, 3585. C . R . Narayanan and M. S. Parkar, Chem. and Ind., 1974, 163. M. Onda and K. Takeuchi, Chem. and Pharm. Bull. (Japan), 1973, 21, 1287. B. Matkovics and Z . Tegyey, Acta Chim. Acad. Sci. Hung., 1974, 80, 21 1. B. Matkovics, B. Tarodi, and L. Balaspiri, Acta Chim. Acad. Sci. Hung., 1974, 80, 79. P. Wieland and H . Kaufmann, Helv. Chim. Acta, 1973, 56, 2044.
259
Steroid Properties and Reactions
C
I
H
cleavage215). The new reaction has been applied to the oxime of a 9a,lla-epoxy-12ketone, a compound which is resistant to the tosylhydrazone method of cleavage. A 4,5-epoxy-3-ketone gave the 4,5-seco-3-yn-5-one(157), which reacted with 4N-H2S04 in dioxan, undergoing ring closure to give the 4-en-3-0ne.~l 4 The mechanism of hydrolysis of the 3-oxime of 17cr-acetoxy-6cr-methylpregn-4ene-3,20-dione, and some derivatives, has been studied.2l 6 The reaction of hydrazoic acid and boron trifluoride with a 4-en-3-one to form a tetrazole has been extended to a
(158)
R
N GN,
= I
,.’
N
0’
T, Me
(159) R = NHCOMe
5-en-7-one and to progesterone. Reactions with the 20-0x0-function afforded two recognizable products, the bis-tetrazole (158) and the acetamido-tetrazole ( 159).2l 7 The phenylhydrazones (160) of 5cr-cholestan-3-one or cholest-4-en-3-one react with arsenic trichloride to give the corresponding arsadiazole derivatives (1 61).2
Carboxylic Acids, Nitriles, and Aldehydes.-A novel degradation of the lanosterol sidechain (162) has provided the corresponding pregnan-20-one derivative (1 66) without damage to the sensitive A8-olefinic system. Selective ozonolysis of a lanosteryl ester first provided the trisnor-acid (163). Two routes were then developed for further degradation : (a) bromination of the acid ester at C-23 via the enolate anion, followed by dehydrobromination, gave the ap-unsaturated ester (164), which isomerized in a
*l5 217
M. Tanabe, D. F. Crowe, R. L. Dehn, and G. Detre, Tetrahedron Letters, 1967, 3739. R. E. Huettemann and A. P. Shroff, J. Pharm. Sci.,1974, 63, 74. H. Singh, R. K. Malhotra, and N. K. Luhadiya, J.C.S. Perkin Z, 1974, 1480. G. Markl, H. Baier, and C. Martin, Tetrahedron Letters, 1974, 1977.
Terpenoids and Steroids
260
basic medium to the fill-unsaturated (A20(22))ester (165),and a second selective ozonolysis generated the required 20-0x0-group (166); (b)the acid chloride (167) was converted by means of lithium diphenylcuprate into the phenyl ketone (168), which underwent photochemical cleavage to give the 20-methylenepregnane (169); again the degradation was completed by selective ozonolysis.2
(163) R (167) R
= =
OH C1
7a-Cyanotestosterone acetate (1 70), prepared by reaction of the 4,6-dien-3-one with HCN and Et,Al, was incompletely hydrolysed by methanolic HC1, the amide intermediate being trapped by conjugate addition on to the 4-en-3-one to give the lactam (171). Suitable conditions were found for completion of the hydrolysis uia the N-nitroso-lactam (172), to give 7a-carboxytestosterone acetate (173). Sulphur tetrafluoride converted the carboxy-group into a trifluoromethyl group (174)without damage to the enone system.220
(170) R (173) R (174) R
= = =
CN CO,H CF,
(171) R = H (172) R = N O
Methyl deoxycholate and esters of other steroidal acids are readily hydrolysed by enzymes present in potato tubers. Several other plants, including apple and pineapple, contain similar esterases, although potatoes exhibited the highest activity. A crude cell-free extract of the enzyme was also effective.221The iodo-aldehyde (175) underwent a remarkable reductive cyclization when its hexane-benzene solution was passed through chromatographic alumina, giving the oxepan (176). The same product was *lo 220
3.Ganem and M. S. Kellogg, J . Org. Cham., 1974, 39, 515. G. H. Rasmusson, A. Chen, and G . E. Arth, J. Org. Chern., 1973, 38, 3670. N. G. Chan and Z . Prochazka, Coll. Czech. Chern. Comrn., 1973, 38, 2288.
Steroid Properties and Reactions
26 1
formed from the iodo-aldehyde by reduction with NaBH, in boiling THF, or with NaBH, in methanolkther at room temperature followed by passage through alumina. In the absence of any other obvious reducing agent in the direct cyclization on alumina, it is suggested that the reacting steroidal species is able to abstract a hydride ion from the hydrocarbon solvent.2 2 2
Titanocene (from the dichloride and sodium) deoxygenates aldehydes, esters, and epoxides to hydrocarbons with the same carbon skeleton : methyl 5P-cholanate gave SP-~holane.~~~ 5 Compounds of Nitrogen and Sulphur
The 22-tosylates of 22R- and 22s-hydroxycholesteryl 3-benzoates gave 22-azides of inverted configuration with sodium azide in HMPA : the corresponding 22-aminocholesterols were obtained by reduction of the azides. No difficulty was encountered in converting 22-oxocholesterol into its oxime, which afforded the mixed amines on reduction.224The amino- and acetamido-derivatives at (2-3, C-4, C-6, C-7, C-1 1, C-16, and C-17 in the Sa-androstane series have been prepared by conventional methods, and their configurations have been assigned from n.m.r. spectra.64 2-Azido- and 4-azidoderivatives of oestrogens have been prepared from the corresponding phenolic amines by diazotization and reaction with sodium azide, and the diazoacetates of oestradiol and oestrone were obtained by reaction with the tosylhydrazone of glyoxylic acid chloride (TsNHN=CHCOC1).22s Reaction of some 17P-acetamido-androstanes with nitrous acid gave the 17pacetoxy-derivatives in only low yields. a/?-Unsaturated E-lactams merely gave the N nitroso-lactams, and enamine-lactams [e.g. (177)] suffered nitrosation to give oximinolactams (1 78).226
222 223 224 225
226
H. Suginome and K . Kato, Tetrahedron Letters, 1973, 4143. E. E. van Tamelen and J. A. Gladysz, J. Amer. Chem. SOC.,1974, 96, 5920. Q. Khuong-Huu, Y. Letourneux, M. Gut, and R. Goutarel, J. Org. Chem., 1974, 39, 1065. J. A. Katzenellenbogen, H. N. Myers, and H. J. Johnson, jun., J . Org. Chem., 1973, 38, 3525. M. Kobayashi and H. Mitsuhashi, Chem. and Pharm. Bull. (Japan), 1973, 21, 1069.
262
Terpenoids and Steroids
The reaction between p-carboxybenzenesulphonyl azide and a 16-diethylaminomethylene- 17-ketone [e.g. (179)] provides a synthesis of the 16-diazo-17-ketone (1 80) which is claimed to be superior to the more usual chloramine oxidation of the oximinoketone. Photolysis of the diazo-ketone (180)gave a mixture of isomeric 16-carboxy-~nor-1 3a-androstane derivatives ( 181).227
(179) X = CHNEt, (180) X = N,
(181)
A 16-aminomethy1ene-17-oxo-steroid(182), obtained by ammonolysis of the 16methoxymethylene derivative, condenses with 4-aminouracils (183) to give the novel heterocyclic structures ( 184).228
& X
CHNH, +
0 H-NH, N (182)
(183) X
=
NH
~
0. S, or N H
1
/
( 184)
The water-soluble steroidal imidazole (1 85) has been studied as a model for an enzyme system, and is found to catalyse the hydrolysis of esters of 3-arylpropionic acid and related compounds229and of phenolic acetates.230 Hydrophobic interaction between the ester molecule and the body of the steroid (cc-face)is thought to stabilize the transition state for attack of the imidazole residue on the ester group. The related imidazolyldiamine with C-3 and C-17 substituents interchanged is even more effectiveas a catalyst for hydrolysis of aryl esters.231 H
I
H, N
22’
228 229 230
231
J. Meinwald and A. J. Taggi, J . Amer. Chem. SOC.,1973, 95, 7663. G. Bouchon, H. Pech, and E. Breitmaier, Chimia (Swirz.), 1973, 27, 212.. J . P. Guthrie and Y. Ueda, J.C.S. Chem. Comm., 1973, 898. J. P. Guthrie and Y. Ueda, J . C . S . Chem. Comm., 1974, I 1 1 . J. P. Guthrie and Y. Ueda, Canad. J . Chem., 1973, 51, 3936.
263
Steroid Properties and Reactions
The oxidation of pseudosolasodine diacetate, as a key step in the degradation of has received a detailed study leading solasodine to 3/I-acetoxypregna-5,16-dien-20-one, to the identification of intermediates and b y - p r o d u ~ t s . ’ Criteria ~~ for the assignment of stereochemistry to steroidal indolizidines (186) have been reported; the rate of quaternization with methyl iodide is more useful than spectroscopic methods.233
( 186)
A kinetic and product study of the ally1 sulphoxide-sulphenate rearrangement (Scheme 4) in the steroid series indicates that the reaction is a normal suprafacial [2,3] sigmatropic process. Rate differences were used to assign configurations at sulphur in the sulphoxides, on the basis of the degree of steric strain in the transition state for rearrangement. 234
@
7 L
...
04s
o,..
SMe
The 2cr,3cr-anti-(R)-episulphoxide(187) reacts with acidified alcohol to give the bissteroidal disulphide S-mono-oxides (188) ; reactions leading to assignment of configuration at sulphur in these products are described.235
( 187)
232 233
* 34 23s
S
H
(188) G . G . Malanina, L. I. Klimova, L. M. Morozovskaya, 0. S. Anisimova, L. M . Alexeeva, and N. N. Suvorov, Khim. Farmatseot. Zhur., 1974, 8, 18. V. M . Kolb and M. StefanoviC, Tetrahedron, 1974, 30, 2233. D. N. Jones, J. Blenkinsopp, A. C . F. Edmonds, E. Helmy, and R. J. K . Taylor, J.C.S. Perkin I , 1973, 2602. M. Kishi, S. Ishihara, and T. Komeno, Tetrahedron, 1974, 30, 2135.
264
Terpenoids and Steroids
5a-Cholestan-3-one 2a-ethylxanthate reacted with HCl in benzene to form the novel heterocycle (189), although in ether the product was the 3-0x0-2a-thiol. Either the xanthate or the thiol, with malononitrile and a catalytic amount of morpholine, afforded the thiophen derivative ( 190).236 Steroidal thiophenylacetates are desulphurized by deactivated Raney nickel to give jj-phenylethenyl ethers.237
6 Molecular Rearrangements Contraction and Expansion of Rings.-A new homologation procedure comprises the addition of difluorocarbene on to an enol acetate, followed by hydrolysis of the resulting difluorocyclopropyl acetate; some of the many examples are outlined in Scheme 5.
1
Scheme 5
Difluorocarbene is readily produced by pyrolysis of sodium chlorodifluoroacetate. Mechanisms for opening of the difluorocyclopropane ring are
’”
”’ 23x
S. K . Roy, J . Org. Chem., 1973, 38, 4211. J . Ellis and R. A. Schibeci, Austral. J . Chem., 1974, 27, 429. P. Crabbe, A. Cervantes, A. Cruz, E. Galeazzi, J. Iriarte, and E. Velarde, J . Amer. Chem. Soc., 1973, 95, 6655.
Steroid Properties and Reactions 265 Cyanogen azide (hazard warning !) reacts with alkylidenecycloalkanes to give, after hydrolysis, ring-expanded cyclic ketones. Examples in the steroid field include the conversion of a 3-methylene-5a-steroid (191) into A-homo-ketones (192) and (193), or of a 3-ethylidene-A4-compound into mixed methyl-enones with an enlarged ring. The
proposed mechanism is very similar electronically to the Tiffeneau and diazomethane reactions, which afford comparable mixtures of ring-enlarged ketones.239 Solvolytic rearrangements of D-nor-steroids in the 13a-series are interpreted on the basis that a leaving-group at the 16a- or 16b-position has the quasi-equatorial c ~ n f o r m a t i o n . ~ ~ ’
No special strain is involved in the 16a-series (194), but a 16b-substituent appears to force a boat-like conformation on ring c (195). The reader is referred to the original
OH Reagents: i, Li(Bu‘O),AlH; ii, H + ;iii, Jones’ reagent
Scheme 6 239
J. E. McMurray and A. P . Coppolino, J . O r g . Chem., 1973, 38, 2821.
266
Terpenoids and Steroids
paper for details of the complex reactions undergone, which appear to involve nonclassical cationic intermediates. Diagrams (194) and (195) illustrate only the initial geometries of the reactants. Reactions of the 5a.7a-cyclo-~-homo-4-ketone(196) and related compounds exhibit interesting features. some of which are illustrated in Scheme 6.240 ‘Backbone’ and Related Rearrangements.--The ‘backbone’ and ‘Westphalen’ rearrangement products (198) and ( 199) from 4~-acetoxy-5-hydroxy-5cc-cholestane ( 197) with D2S04-DOAc-Ac20 contained no detectable deuterium, 2 4 1 showing that
AcO
AcO
the rearrangement under these conditions occurs without the intermediacy of olefinic or cyclopropane-like structures. This finding contrasts with evidence for some analogous reactions, including the backbone rearrangements (in H2S04) of the steroidal amines holamine (200) and methylholaphylline (201). Reaction of samples bearing 8P-deuterium labels resulted in extensive but not total loss of deuterium, indicating that the stage involving conversion of a C-9 into a C-8 carbonium ion proceeds mainly uia deprotonation to a A’-olefin, followed by reprotonation. Direct hydride shift (8p --+9p) occurs to a small extent. The authors comment briefly on the unresolved features of this mechanistic
R d (ZOO) P R C= E-NH, O M (201) R
=
e
fi-NHMe
A new example of the backbone rearrangement appears at first sight to contravene the accepted principle of thermodynamic equilibration of products.243The 2a-hydroxyA8-unsaturated compound (202), with the 14P-configuration, rearranged with formic acid in refluxing dichloromethane to give, after removal of formate groups, a mixture containing the A5- and A4-unsaturated isomers (203) with the 1 4 a - c o n f i g ~ r a t i o n . ~ ~ ~ Although some examples of ‘retro-Westphalen’ rearrangements (5P-Me -P 10P-Me) 240 241
242
243 244
L. Kohout and J. FajkoS, Coll. Czech. Chem. Camm., 1974,39, 1613. E. T. J. Bathurst and J. M. Coxon, J . C . S . Chem. Comm., 1974, 131. J.-C. Thierry, F. Frappier, M. Pais, and F.-X. Jarreau, Tetrahedron Letfers, 1974, 2149. Ref. la, 1972, Vol. 2, pp. 304, 305; 1973, Vol. 3, pp. 378-381. A. Ambles, J.-C. Jacquesy, and R. Jacquesy, Bull. Soc. chim.France, 1973, 2865.
Steroid Properties and Reactions
267
(203) A4 or As
(202)
are known,245the simultaneous isomerization from the 148- to the 14a-configuration is unprecedented. Without the 2a-hydroxy-substituent, a full backbone rearrangement would occur, leading to a A'3('7)-isomer [cf: (198)], so the 2a-hydroxy-group seems to be responsible for the unusual reaction. Two points may be noted: (a) the 2a-OH (or OCHO) group is originally axial, but becomes equatorial in the products ; (h) the 17p-side-chain in cholestane derivatives has been said to stabilize the 14a- more than the 14fl-configuration,by virtue of torsional interaction across the C-13-C-17 bond.Z46 Nevertheless, the apparent absence of any 14p-or A13(l')-product is not readily explained. Further examples of backbone rearrangement under thermodynamic control have been reported for compounds of the euphol series.z47 The 6~-cyano-Sa-hydroxy-compound (204) gives a normal 'Westphalen' product (205), the cyano-group being similar to a 6P-fluoro-substituent in its effect on the rate of reaction. A 6P-azido-group (206), however, leads to the unrearranged 3,5-diacetate as major product, behaviour which indicates neighbouring-group participation by the azido-group attacking C-5 (207) in the initial step.248
(204) R' (206) R'
= =
Me, R2 = CN Ac, RZ = N,
(205)
The 5a-hydroxy-7-en-6-one (208) rearranges with acid to give dienones (209) and (210) and minor third compound, probably the lOP-isomer of (210). The reactions
AcO
245
246
247
*"
0
Ac 0
E.g. Ref. la, 1972, Vol. 2, p. 303. Ref. la, 1971, Vol. 1, p. 362. J. L. Zundel, G. Wolff, and G. Ourisson, Buff. SOC.chim. France, 1973, 3206. B. A. Marples, B. M. O'Callaghan, and J. L. Scottow, J . C . S . Perkin I , 1974, 1026.
Terpenoids and Steroids
268
are of 'Westphalen' type, but remarkable in that the saturated hydroxy-ketone corresponding to (208) is inert under similar conditions.249 A partial backbone rearrangement occurs when a C-9 carbonium ion (212) is generated in 5P-pregnane-3,20-dione by the action of concentrated sulphuric acid on either the 9(1 1)-ene (211) or its 1 la-hydroxy precursor.250 Conjugation in the 13(17)-en-20-one (213) probably accounts for the stability of the product. Epoxidation of the olefinic bond, followed by reaction of the epoxide (214) with formic acid, reversed the migration of C- 18 to give 17a-hydroxy-9p-pregn-8(14)-ene-3,20-dione (215). Using known methods, the pregnane side-chains of compounds (213) and (215)were degraded to afford the corresponding 17-oxoandrostane derivatives.25o
(2 15)
Aromatization of Rings.-Some further interesting isomerizations in the hyperacidic solvent HF-SbF, imply that both dienon-phenol and phenol-dienone interconversions are possible. Androsta- 1,4,6-triene-3,17-dione(2 16) is aromatized to give a 'pura' phenol, while also being isomerized at C-14 and suffering double-bond migration, to give the compound (217). This reaction, and a similar isomerization of androsta1,4-diene-3,17-dione, requires backbone rearrangements to explain the inversion at C-14 and probably occurs through transient dearomatization of the initial product of a normal dienone-phenol rearrangement.2
249 250
251
R. Hanna, Tetrahedron Letters, 1973, 3349. J. Schmitt, A. Hallot, P. J . Cornu, and A. Costes, Bull. Soc. chim. France, 1973, 2035. J.-C. Jacquesy, R. Jacquesy, and Ung Hong Ly, Tetrahedron Letter.$, 1974, 2199.
Steroid Properties and Reuctions
269
A further group of steroids with functional groups equivalent to triple unsaturation in rings A and B has been shown to give a 4-methyloestra-l,3,5(10)-triene on reaction with HBr-AcOH. The 3- and 6-monoacetates (218) and (219) of a 4-ene-3P,6P-diol, however, gave the 4-en-6-one (220) and 4-en-3-one, respectively, although the 3,6diacetate aromatized normally.252 The mechanism of enone formation has not yet been defined in detail, but seems likely to involve initial elimination of acetic acid to give the dienol corresponding to the product enone.
(218) R' = A c ; R 2 = H (219) R' = H ; RZ = AC
(220)
Other examples of the aromatization of steroids with triple functionality in rings A and B include 3,4,5- and 3,5,6-triol derivatives.253A 3~-acetoxy-4ct,5a-epoxyandrostane was similarly aromatized in HBr-AcOH via a spiro-cation intermediate, but the corresponding oestrane derivative aromatized without skeletal rearrangement, as revealed by use of 3a-deuterio-labelled material. When C-4 was blocked by a methyl substituent, the androstane derivative (221) aromatized to give mainly the 1P-dimethyloestratriene (222), accompanied by a little of the 3,4-dimethyl derivative. The 1,4dimethyl product arises by a simple migration of the C-19 methyl group to C-1. The effect of 2,2-dimethyl substitution on the aromatization was also The 5,6-epoxyandrostan-7-01~ (223) were unexpectedly found to give the 4-methyloestraA ~kinetic study of the dienone-, 1,3,5(10)-triene on heating with H B ~ - A c O H . ~ ~ phenol rearrangement of androsta-1,4-diene-3,17-dione, and other model dienones, includes measurements of their basicities.' 56
2~-Hydroxy-3,17-dioxoandrost-4-en19-a1 (224), prepared by a novel sequence of conventional reactions, is converted rapidly and quantitatively into oestrone in neutral aqueous The hydroxy-aldehyde is suggested as the immediate biosynthetic precursor of oestrone, implying that the final step in uiuo may not require enzymic assistance. 252
253 254
255 256
257
D. Baldwin, J. R. Hanson, and A. M . Holtom, J.C.S. Perkin I, 1973, 1704. D. Baldwin, J. R. Hanson, and A. M. Holtom, J.C.S. Perkin I, 1973, 2687. J. R. Hanson and H. J. Wilkins, J.C.S. Perkin I, 1974, 1388. D. Baldwin and J. R. Hanson, J.C.S. Chem. Comm., 1974, 21 1 . M. J. Hughes and A. J. Waring, J.C.S. Perkin I / , 1974, 1043. H. Hosoda and J. Fishman, J.C.S. Chem. Comm., 1974, 546.
270
Terpenoids and Steroids
Reduction of the adduct (225) with LiAlH, gave the aromatic steroid analogue (226). The suggested mechanism of this unusual reaction involves the intermediate reduced compound (227), which appeared (n.m.r.) to be formed under mild conditions. The aromatization step may involve deprotonation at nitrogen and expulsion of a lithiumco-ordinated methyl carbanion, as illustrated. The A8(I4)-isomerof (225) afforded a 7,7’-dimericsteroid under similar reaction conditions.’
(228)
(229)
The reaction between the 7p-hydroxylanost-8-en-11-one (228) and toluene-psulphonyl chloride in pyridine also proceeded in part by ejection of the C-19 methyl ~ reaction, ~ ~ under ionizing group, giving the product (229) with an aromatic ring B . This conditions, is in sharp contrast to the more usual formation of anthrasteroids when ring B is aromatized. 17,17-Disubstituted-18-norandrost13-enes have been aromatized in ring c by brominationdehydrobromination to give the 7,13-diene, followed by a repetition of these two steps.260 Other steroid analogues with a phenolic ring c (231) have been obtained by treating l7~-hydroxy-l7cr-methylandrost-8-en-ll-ones [e.g. (230)] with formic acid. Dehydration at C-17, with Wagner-Meerwein migration of the 13pmethyl group to C- 17, provides the necessary third unsaturated linkage. Treatment of the 1 1-acetate (232) with DDQ gave the corresponding 1,4-dienone,accompanied by 258
*”
H. de Nijs and W. N. Speckamp, Tetrahedron Letters, 1973, 3631. J . R. Dias, J . O r g . Chem., 1974, 39, 1767. C . L. Hewett, I. M . Gilbert, J. Redpath, D. S. Savage, J. Strachan, T. Sleigh, and R. Taylor, J.C.S. Perkin I, 1974, 897.
27 1
Steroid Properties and Reactions H+
0
AcO
(230)
(231) R (232) R
= H = AC
(233)
the phenanthrene derivative (233), resulting from dienone+phenol rearrangement and further dehydrogenation.26 Chromogenic Reactions-The essential structural features for a positive Kober reaction have been closely defined from study of a wide variety of steroids: a steroidal ring system with a phenolic ring A is necessary, together with unsaturation or an oxygen function in ring D, an angular methyl group at C-13, and angular hydrogen atoms (rather than unsaturation or substitution) along the ‘backbone’ of the molecule. Several of the products of the Kober reactions of oestradiol and oestrone 3-methyl ether have been identified as 17-methyl-18-noroestrane derivatives, with varying levels of unsaturation up to and including that of a phenanthrene derivative.262 Further indicate that benzylic cations of the type (234), resulting from cationic migration from ring D, are key intermediates in the Kober reaction sequence. A series of papers describes new studies of the chromogenic reactions between steroids and strong acids. A solution of testosterone in 70 % perchloric acid deposits a crystalline 1 : 1 complex of its components within 30 minutes, but heating a chloroform solution of testosterone (235) and the with the acid affords isomeric 17-methyl-18-norandrost-4-en-3-ones corresponding 4,13(14)- (236) and 4,13(17)-dien-3-ones (237). Colour development appears to be associated with cationic species [e.g.(238)]derived from these die none^."^
(235) Ring D saturated (236) A13 (237) A r 3 ( 1 7 )
Epitestosterone (l7a-OH) generates the same dienones in formic acid. The KagiMiescher reaction (HOAc-H,SO,, then Br,-HOAc) of epitestosterone appears to 261
C . L. Hewett, S. G . Gibson, I. M. Gilbert, J. Redpath, and D. S . Savage, J.C.S. Perkin I , 1973, 1967.
262
263 2h4
M. Kimura, M. Kawata, K. Akiyama, K. Harita, and T. Miura, Chem. and Pharm. Bull. (Japan), 1973, 21, 1720, 1741. M. Kimura, K. Akiyama, and T. Miura, Chem. and Pharm. Bull. (Japan), 1974, 22, 643. M. Kimura and K . Harita, Chem. and Pharm. Bull. (Japan), 1973, 21, 1205.
272
Terpenoids and Steroids
involve formation and further reactions of similar cations derived from the dienones to generate the characteristic c o l o ~ r The . ~ ~absorption ~ spectra of products resulting from the chromogenic reactions of testosterone depend upon the particular acidic species employed. Sulphuric, phosphoric, or perchloric acids and the Lewis acids SbCI,, SbCl, , ZnCI,, or AlC1, all give distinguishable spectra, as well as characteristic gas-chromatograms of isolated products.266 Miscellaneous Rearrangements-The hydrolysis of Sfl-pregnane-3a,20a-diol20sulphate with boiling hydrochloric acid causes elimination with rearrangement to give the olefinic product (239), in contrast to the 208-isomer which gives ‘uranediol’, a D-homoandrostane d e r i ~ a t i v e . ~These ~’ rearrangements follow the pattern already recognized in the solvolysis of the corresponding 2O-tosylo~ypregnanes.~~~
(239)
Concentrated sulphuric acid transforms 2 1-acetoxypregnan-20-ones (240) into rearranged products, either the 17P-methyl-18-nor-17a-pregn-13-en-20-0ne (243) or the 13-hydroxy-derivative (242), which readily dehydrates to give the 13-ene on heating.26’ Although similar rearrangements are well known to occur in 17%-hydroxypregnane derivative^,^^' the present reaction requires an unusual preliminary step to generate a C- 17 carbonium ion. Allylic displacement of the 21-acetoxy-substituent from the enol (241) is proposed.269 CH,OAc CO
P FH,-OAc
iH2
SH 1
265
‘‘’‘ 2h7
2hX
‘‘’ ‘’O
M. Kimura and K . Harita. Chem. and Pharm. Bull. (Japan), 1973, 21, 1235. M. Kimura and K. Harita, Chem. and Pharm. Bull. (Japan). 1973, 21, 1261. 1. Yoshizawa, T. Miura, M. Kimura, K. Anzai, and S. Matsuda, Chem. and Pharm. Bull. (Jupun), 1973, 21, 1622. H. Hirschmann, F. B. Hirschmann, and A. P. Zala, J . Org. Chem.. 1966, 31, 375. J . Schmitt, A . Hallot, P. J. Cornu, A. Costes, and P. Comoy, Bull. SOC.chim. France, 1973,2032. Ref. 80, p. 271.
27 3
Steroid Properties und Reactions
Pregnane-3,20-diones (244) are isomerized by the hyperacidic media HF-SbF, or HS03F--SbF, to give mixtures containing the 13a,17a- (246; major product), 130,17a-, and 13aJ 7P-analogues. The simultaneous equilibration of configurations at both C-13 and C-17 is thought to proceed through the 13,17-ssco-enol(245),for samples labelled with deuterium at C-17 and C-21 lost none of the
0 ti
The 9a,l la-epoxide (247) rearranged with boron trifluoride to give the related 9,B-11ketone and the novel 9-methyl- 19-nor-9P-pregn-5(10)-en-11a-01 derivative (248).27 This result contrasts with a recent report273of rearrangement of 9a,l la-epoxy-5aandrostane-3,17-dione to give 1la-hydroxy-90-androst-8( 14)-ene-3,17-dione.,Evidently the nature of substituents at C-3 and/or C-17 controls the reaction path. Epoxidation of the A5(l')-olefin (248) gave first the SP,lOP-epoxide,which rearranged in the presence of acid to give the Sa,lla-epoxy-lO[j-oI (249), a compound of curious and unprecedented structure which owes its existence to the unusual proximity of C-5 and C-1 1 permitted by the 90-configuration. Further simple transformations of the 5a,l la-epoxy-compound afforded the 90-methyl product (250) with a phenolic ring A.272
21 1 272 273
J.-C. Jacquesy. R. Jacquesy, S. Moreau, and J.-F. Patoiseau, J.C.S. Chem. Comm., 1973, 785. A. C. Campbell, C . L. Hewett, M. S. Maidment, and G. F. Woods, J . C . S . Perkin 11974, 1799. J. W. ApSimon, R. R. King, and J. J. Rosenfeld, Canad. J . Chem., 1969,47, 1989.
274
Terpenoids and Steroids Me
Me
(255)
-+ (253)
(2541
The curious reactions whereby the 20a- and 20j-acetoxy- 16417a-epoxypregnanes (251) and (253) react with methylmagnesium iodide to give the isomeric 20-methyl-l6a,20-diols (252) and (254) are explained by a mechanism [see (255)] involving hydride transfer (20 -+ 17), as revealed by deuterium labelling. The stereochemistry of hydride migration in each isomer depends upon the side-chain conformation required to bring the C-20 and C-16 oxygen substituents into close proximity, for complexing with magnesium.274 The Serini reaction (rearrangement of a diol monoacetate by zinc dust-toluene) occurs in ring D with suitably alkylated derivatives. A 16a-alkyl 16P,17j-diol 17acetate (256) gave the 16~-alkyl-17-ketone(257) in good yield. A similar trans-diol derivative failed to react, in accordance with the suggested involvement of an orthoacetate of the diol. The l6a-vinyl compound (258) reacted to give the (Z)-16-ethylidene17-ketone (259) in high yield. Reactions with 17a-deuteriated diol derivatives showed that a hydride migration step is involved.275
(256) R = Et, Ph. etc. (258) R = CH=CH,
(257)
(259)
The reactions of 5,6cc-dibromo-5~-cholestan-3~-ol and of its Sa,6j-isomer with aqueous silver fluoride give complex mixtures including small amounts of rearrangement products, apparently resulting from initial ionization of the C-5-Br bond in each case.27 h Aluminium chloride catalyses the isomerization of a 3-methoxyoestra-2,5(10)diene to the 3,5(6)-diene.277 Mechanistic details of the formation of 5a- and SP-azidoderivatives from 5a-pregnan-6/50] (with HN,-BF,) have been elucidated by deuterium labelling. A key feature is hydride migration from C-5 to C-6, which is followed by T. V. Ilyukhina, A. V. Kamernitzkii, a n d I. I. Voznesenskaya, Tetrahedron, 1974, 30, 2239. G. Goto, K . Yoshioka, a n d K . Hiraga, Tetrahedron, 1974, 30, 2107. 2 7 h A. Kasal a n d A. Trka, Coll. Czech. Chrm. Comm., 1974, 39, 603. "' A. J. Birch a n d K . P. Dastur, J.C.S. Perkin I, 1973, 1650. 274
275
Steroid Properties and Reactions
275
kinetically controlled formation of the 5a-azide, later converted into an equilibrium mixture of 501- and 5 f l - i ~ o m e r s .The ~ ~ ~step involving electrophilic addition of the elements of hydrazoic acid across an olefinic bond has been demonstrated in a series of separate experiments with a variety of steroidal 0 1 e f i n s . ~ ~ ~ Buffered acetolysis of the 19-mesyloxy-3-thioacetal (260) gave the 5,19-cyclo-3,5dieno[3,4-b]dithian (261), with migration of sulphur following attack of the A4-olefinic bond upon C-19.Desulphurization of the dithian gave the 5,19-cyclo-A3-derivative (262).28 o
7 Functionalization at Non-activated Positions
A detailed study of ‘remote oxidation’ by photochemically excited benzophenone groups has shown the scope and limitations of the method.281 Suitable esters of 5acholestan-3a-01, 5a-androstan- 17/3-01, and 5/3-cholan-24-01gave oxidation products, but esters of 5a-cholestan-3P-01and 5IJ-cholestan-3a-01 (with equatorial OH groups) failed to react. Benzophenone 3- and 4-carboxylic acids and some of their homologues were employed for esterification. In general, oxidation by the excited benzophenone will occur if the benzophenone carbonyl oxygen can easily contact remote hydrogens on the steroid; photographs of space-filling models illustrate the shape of a reactive molecule, 5a-cholestan-3a-yl benzophenone-4-propionate, where the carbonyl oxygen can reach the 7a-, 12a-, and 14a-hydrogen atoms, and also that of the benzophenone-4carboxylate, which is a V-shaped molecule, so that the necessary proximity of the benzophenone carbonyl group and a remote hydrogen atom cannot be attained. Reactive esters show strong circular dichroism, induced in the benzophenone by the adjacent chiral steroid. whereas unreactive esters show only weak c.d. effects. Phosphorescence lifetimes are also a sensitive indicator of molecular packing. The products of ‘remote oxidation’, some of which have been described in earlier Reports,282comprise olefins and also macrocyclic benzophenone-steroid insertion products which can be converted into olefins at the point of benzophenone insertion.281 Many of the products are not readily accessible by other methods. The principle of ‘remote oxidation’ at tertiary centres, directed by proximity effects, has been combined with that of chlorination of steroids at the 5a-, 9a-, and 14a-positions with iodobenzene d i ~ h l o r i d e by , ~ ~employing ~ the iododichloride (263) derived from 278
219
280 28 1
282
283
Q. Khuong-Huu, A. Pancrazi, and I. Kabore, Tetrahedron, 1974, 30, 2579; CJ ref. la, 1973, Vol. 3, p. 369. A. Pancrazi and Q . Khuong-Huu, Tetrahedron, 1974, 30, 2337. J. R. Williams and G. M. Sarkisian, Tetrahedron Letters, 1974, 1109. R. Breslow, S. Baldwin, T. Flechtner, P. Kalicky, S. Liu, and W. Washburn, J . Amer. Chem. SOC.,1973, 95, 325 1. Ref. la, 1971, Vol. 1, p. 390; 1972, Vol. 2, p. 317; 1973, Vol. 3, p. 396; 1974, Vol. 4, p.386. Ref. la, 1973, Vol. 3, p. 396.
276
Terpenoids and Steroids
5a-cholestan-3a-yl p-i~dophenylacetate.~~~ The reagent delivered chlorine selectively to the 14a-position, giving the AI4-unsaturated derivative in 53 yield after dehydrochlorination. The dichloro-derivative of the rn-iodobenzoate attacked C-9 in preference to C-14, affording a route to the A9(' ')-isomer. As in the analogous reactions with benzophenone derivatives, the site of attack is predictable from the geometry of the steroid ester.284
'Remote oxidation' has also been achieved by the use of a photoexcited nitrobenzene derivative.285 Sa-Androstan-3cc-yl P-(p-nitropheny1)propionate (264), irradiated in Pyrex, gave a mixture which was subjected to the action of iodine-acetic acid to dehydrate any tertiary alcohols formed. 5a-Androst- 14-en-3-one was isolated in 26 % yield after Jones oxidation of the products. The residue contained a little of the 3,12dione, indicating that the excited nitro-group can abstract hydrogen from either C- 12 or C-14, which are roughly equidistant from C-3.285 Direct hydroxylation at tertiary centres can be achieved by irradiation of a cholestane derivative and peracetic acid in acetic acid. 3/l-Acetoxy-5a-cholestane gave the 5ahydroxy- (30 ",) and 25-hydroxy- (37.5"6)derivatives, along with small amounts of the 14-, 17-, and 20-hydroxycholestan-3[~-yl acetates. Use of 5a-cholestan-3/l,5-diol 3acetate gave the 5a,25-diol, transformed in three steps into 25-hydroxycholester01.~~~ k variation of the Barton reaction (photolysis of a nitrite287)provides a nitrate instead of the usual oxime.288When oxygen was bubbled through an irradiated solution of the 7%-nitrite(265) in benzene, the 7~,32-diol32-nitrate (266) resulted. The nitrate group could be reduced by Zn-AcOH as a convenient route to the 32-alcohol. The suggested mechanism of formation of the nitrate involves capture of an alkyl radical by oxygen and reaction of the peroxyl radical with nitric oxide (Scheme 7). Sa-Pregnane-3fi,4fi,20/l-triol 3,20-diacetate was converted by lead tetra-acetate into the 4/3.19-epoxy-derivative(267);further transformations led to 19-norproge~terone.~~~ R. Breslow, R. Corcoran, J. A. Dale, S. Liu, and P. Kalicky, J . Amer. Chem. SOC.,1974, 96, 1973. Z H 5 P. C. Scholl and M . R. van de Mark, J . Org. Chem., 1973, 38, 2376. A. Rotman and Y. Mazur, J.C.S. Chem. Comm., 1974, 15. "' Ref. 80, p. 398. 2 8 M J. Allen, R. B. Boar, J. F. McGhie, a n d D. H. R. Barton, J . C . S . Perkin I , 1973, 2402. 2 8 9 R. E. Gall. J. E. Nemorin, a n d L. Tarasoff, J . C . S . Perkin I , 1974, 881.
284
277
Steroid Properties and Reactions
+ NO Scheme 7
Irradiation of the N-iodo-derivative (268) of a cholan-24-amide afforded the 24,20lactones (269), epimeric at C-20.290
The furost-25-ene (270), prepared by application of conventional reactions to the furostan-26-01, has been hydroxylated (OsO,) and acetylated to give the diol monoacetates (271); the hypoiodite-photolysis process [ Pb(OAc),-I, , hv] transformed these products into isomeric 22,25-epoxyfurostan-26-01 derivatives (272).291
Thermolysis of the 1 1-0xo1anostan-7a-yl azidoformate (273) gave the oxazolidinone (274) resulting from nitrene insertion into the 6a-CH bond. The Sa-CH insertion 290 291
P. Hodge, G . M. Perry, and M. Pollard, Steroids, 1974, 24, 79. A. G. Gonzalez, C. G. Francisco, R. Freire Barreira, R. Hernandez, J. A. Salazar, and E. Suarez, Tetrahedron Letters, 1974, 2681.
278
Terpenoids and Steroids
*cOJ$YY
A c Op OCN, S H N d H
0
(274)
(273)
product was also formed, but none of the desired 9a-CH insertion compound was obtained. The 7(3-yl azidoformate similarly gave products of nitrene attack at C-6 and at the 8/?-po~ition.’~~ The 6-0x0, 7-0x0, 11-0x0, and ll-oxo-9(3-derivatives have been isolated in small amounts from among the products of oxidation of 3fl-acetoxy-5a-androstan-17one with chromium trioxide in acetic A possible clue to the mechanism of 15a-hydroxylation of deoxycholic acid by iron(r1) ions and oxygen or H , 0 2 2 9 4 comes from the observation that cyclohexanol affords a mixture of diols. An oxidized iron species bound by the hydroxy-group of cyclohexanol is considered to effect the hydroxylation : binding by the 12a-hydroxy-group may serve to direct hydroxylation to the 1 Sa-position in the steroid.295 8 Photochemical Reactions
Olefinic Compounds.--Quantum transformation yields have been estimated for the reversible reactions indicated in Scheme 8.29hThe effect of wavelength on the production of previtamin D, has been evaluated ; 2 9 7 methods are described for the thinlayer,298gas,299and column chroma tog rap hi^^^^ separation of the various isomers ,olqA
Toxisterol, A
Lumisterol,
Scheme 8
produced by the irradiation of ergosterol. U.V. spectra are reported for the various products obtained by photoisomerization of vitamin D, . 3 0 1 Irradiation of 7-dehydrocholesterol in the presence of eosin gave a mixture of isomeric 7,7’-dimers, the separate 292
293 294
295 29h 297
298 299
300 30’
0. E. Edwards and Z . Paryzek, Canad. J . Chem., 1973, 51, 3866. J . Jovanovic, M. Spiteller-Friedmann, and G . Spiteller, Annalen, 1974, 693. Ref. la. 1971, Vol. 1, p. 391; 1974, Vol. 4, p. 385 J. T. Groves and M. Van Der Puy, J . Amer. Chem. Soc., 1974,96, 5274. R. Mermet-Bouvier and E. Abillon, J . Pharm. Sci.,1973, 62, 891. E. Abillon and R. Mermet-Bouvier, J . Pharm. Sci., 1973, 62, 1688. R. Mermet-Bouvier, J . Chromatog., 1971, 59, 226. R. Mermet-Bouvier, J . Chromatog. Sci.,1972, 10, 733. R. Mermet-Bouvier, Analyt. Chem., 1973, 45, 584. R. Mermet-Bouvier, Bull. SOC.chim. France, 1973, 3023.
279
Steroid Properties and Reuctions
components having either the 5,8(9)- or 5,8(14)-diene structure.302 The chemistry of the Vitamin D series of compounds has been reviewed briefly.302" Cholest-5-ene is partially isomerized on irradiation in t-butyl alcohol with water and o-xylene (as sensitizer) to give a 7 : 3 mixture of the 4-ene and 5-ene, accompanied by the 5a- and 5p-01s. Use of deuterium oxide instead of water gave products with inclusion of from one to four deuterium atoms.303 Phatochemical cycloadditions of ethoxycarbonylnitrene to olefinic bonds of tesgave the aziridines (275) and tosterone acetate and 3~-acetoxypregna-5,16-dien-20-one (276), re~pectively.~'~
"\
C0,Et
(276) (two isomers)
U.V. irradiation of the 18,18-dimethoxypregn-16-en-20-one (277) gave a mixture of the cyclic ether (278) and the rearranged product (279).305 Acetone-sensitized photolysis of a 6-en-5a-01 (280) ruptured the 5,6-bond, giving the 5-oxo-5,6-seco-steroid (281). Other conditions for the irradiation were ineffective.306
Carbonyl Compounds.-Photoisomerization of the 14p,17a-pregnan-1 1-one derivative (282) proceeded normally to give the 11,19-cyclo-compound(283),but lead tetra-acetate 302
F. Boomsma, H. J. C . Jacobs, E. Havinga, and A. van der Gen, Rec. Tratl. chim., 1973,92,1361.
302
( a ) E. Havinga, Experientia, 1973, 29, 1181.
303 304
305 306
J. A. Waters, Steroids, 1974, 23, 259. R. P. Gandhi, S. Garg. and S . M. Mukherji, J. Indian Chem. Soc., 1974, 51, 324. F. Marti, H. Wehrli, and 0. Jeger, Helv. Chim. Acta, 1973, 56, 2698. H. A. C . M. Keuss and J. Lakeman, J . C . S . Chem. Comm., 1973, 480.
Terpenoids and Steroids
280
7
H
oxidation of the latter gave the unusual 9.1 l-seco-ether (284),along with the 19-hydroxy14p,17a-pregnan-11 Photolysis of the 23,24-diphenylcholan-24-onesystem (285) in t-butyl alcohol gave the corresponding 20-methylenepregnane derivative (286) (Norrish Type TI process). Ozonolysis of the product (286) completed a novel degradation of cholanic acids to give pregnan-20-ones (287).308 An analogous degradation was successful in the lanostane series309(see also p. 259).
(285)
(286) R (287) R
= =
CH, 0
Photolysis of 5-vinyl-~-nor-5cc-cholestan-3-one (288) in t-butyl alcohol gave the 5P-isomer (289) as the only product detected. The biradical(290) is envisaged as the key intermediate. The 5-vinyl compound also resulted from irradiation of the A-homoenone (28l), through cc-cleavage (3,4-bond) to give the biradical (290).310
‘A Chapter on Ketone Photochemistry’, in the Van’t Hoff-Le Be1 commemorative issue of Tetrahedron, includes reviews of a variety of reactions drawn from the steroid fieid.311 307
308 309
3‘0 311
P. Gull, Y . Saito, H . Wehrli, and 0. Jeger, Helt.. Chim. Acta, 1974, 57, 863. M. Fetizon, F. J. Kakis, and V. Ignatiadou-Ragoussis, J. Org. Chem., 1973, 38, 4308. M . Fetizon, F. J. Kakis, and V. Ignatiadou-Ragoussis, J. Org. Chem., 1974, 39, 1959. J. I. Seeman and H. Ziffer, Tetrahedron Letters, 1973, 4409. K. Schaffner and 0. Jeger, Tetrahedron, 1974, 30, 1891.
Steroid Properties and Reactions
28 1
Miscellaneous.-Photosensitized oxidation of cholesterol affords the 6a- and 6phydroperoxy-A4-compounds (292) in 1-2 % yields, along with the known 5a-hydroperoxy-6-ene (293). Reaction with singlet oxygen by the ene mechanism seems likely to account for all the p r o d ~ c t sl .2~
Photo-oxygenation (singlet oxygen) converted the 5( 10),9( 11)-diene (294) first into 5a- and 5~-hydroperoxy-l(lO),9(1l)-dienes(295), and then into a mixture of isomeric
'
5-hydroperoxy- 1,ll-epidioxy-9-enes (296).3
\
NOH
(30 1) Scheme 9 312
313
M. J. Kulig and L. L. Smith, J . Org. Chem., 1973, 38, 3639. M. Maumy and J. Rigaudy, Bull. SOC.chim. France, 1974, 1487
282
Terpenoids and Steroids
The demethylation of dimethylamino-steroids and other tertiary amines by photosensitized oxidation has been ~ t u d i e dl 4. ~ The photo-Beckmann rearrangements of androsterone and 13a-androsterone oximes give product mixtures (Scheme 9) which have not yet been fully explained. The formation of both 13p and 13a isomeric lactams from the 13P-oxime (297) seems to imply separation of C-13 from C-17 before C-13-N bonding occurs, but the 13aoxime (300) afforded no detectable 13P-lactam, giving instead the isomeric 13a-lactams (299) and (301),both of which could be envisaged as rearrangement products from an intermediate oxaziridine (302).3' A version of the hypoiodite reaction (irradiation in the presence of HgO and I,) converted cholesterol or its 3a-epimer into a mixture of products which included the 3,4seco-4-iodo-3-aldehyde (303), as well as two oxetans (305) derived by photoaddition of the aldehyde group to the 4,5-olefinic bond in intermediate products (304)."'
(304) 6a
(303)
+ 6p
(305) 6a
+ 68
Photolysis of the 19-nitrite (306) caused elimination of the angular 10P-substituent, giving a mixture of the 6-oximino-5(10)-ene (307) with a lesser amount of the 1(10),5diene (308).3l 7
(306)
Cholesteryl O-thiobenzoate gave cholesta-3,5-diene on photolysis, with stereospecific removal of the (cis) 4P-hydrogen atom. Prolonged irradiation caused readdition of the thiobenzoic acid to the diene to give a mixture of the 3a- and 3P-S-
c> H
WCH (309)
'14
3'5 3'6 3 ' 7
I
OH ( 3 10)
D Herlem, Y . Hubert-Brierre, F. Khuong-Huu, and R. Goutarel, Tetrahedron, 1973, 29, 2195. H. Suginome and T. Uchida, Bull. Chem. SOC.Japan, 1974, 47, 687. H. Suginome and K. Kato, Tetrahedron Letters, 1973, 4139, 4143. Y. Watanabe and Y. Mizuhara. J . C . S . Chem. Comm., 1973, 7 5 2 .
283
Steroid Properlies and Reactions
’
(309) in propan-2thioben~oates.~ Irradiation of a 17r-ethynyl-17P-hydroxy-steroid 01 gives the cis- and trans-adducts (310j.319
9 Miscellaneous The search for cholesteric mesophases with low transition temperatures has led to with transition temperatures some long-chain alkanoates of 5a-cholest-8(14)-en-3~~-ol, 30 “C lower than those of the corresponding cholesteryl esters. The transition temperatures of the decanoate, for example, to the smectic, cholesteric, and isotropic phases, are 44.4,58.9, and 71.8 “C,re~pectively.~~’ The smectic phases of cholesteryl nonanoate and myristate have been characterized as ‘type A’ by miscibility studies with known smectic liquid ~rystals.~”p-Methoxycinnamates of a series of 17/?-alkyl-5a-androstan3p-01~give cholesteric me so phase^.^^^ A cholesteric mesophase comprising cholesteryl chloride and nonanoate (2 : 3) confers optical activity on dissolved hexacarbonylmolybdenum. 3 2 Plates of silicic acid impregnated with iron(Irr), nickel(II), or chromium(m) salts, which were originally developed for the separation of prostaglandins, have received limited study for steroids. 3,7,12-Trioxocholanic acid is more strongly retarded by iron(m) plates than by untreated or silver nitrate plates, but ergosterol was only slightly more retarded than cholesterol. It would seem to follow that iron(rI1) interacts with ketones and so may prove useful for the separation of polar ~ t e r 0 i d s . jBenzoylation ~~ of hydroxy-steroids to confer U.V.absorption is a useful aid to detection in high-resolution liquid c h r ~ m a t o g r a p h y . ~ ~ ~ Solubilities of some steroids in water and in saline have been determined by use of l4C-labe1led materials.326Lecithin has been shown to retard the dissolution of cholessterol in bile acid The steroidal nitroxide radical (311) forms a gel on dissolution in c y ~ l o h e x a n e . ~ ~ ~ The stereochemistry of oxazolidinyloxy-radicalsattached to a steroid at C-3 has been established.329 0. I
318
31y
320 321 322 323
324 325
326 327 328
329
S. Achmatowicz, D. H. R. Barton, P. D. Magnus, G . A. Poulton, and P. J. West, J.C.S. Perkin I , 1973, 1567. L. M. Kostochka, E. P. Serebryakov, and V. F. Kucherov, Zhur. org. Khim., 1973, 9. 1611. J. Y . C . Chu, J.C.S. Chem. Comm., 1974, 374. D. Coates and G. W. Gray, J . C . S . Chem. Comm., 1974, 101. J. Malthiete, J. Billard, and J. Jacques, Bull. Soc. chim. France, 1974, 1199. S. F. Mason and R. D. Peacock, J.C.S. Chem. Comm., 1973, 712. R. L. Spraggins, J. Org. Chem., 1973, 38, 3661. F. A. Fitzpatrick and S. Siggia, Analyt. Chem., 1973, 45, 2310. D. K. Madan and D. E. Cadwallader, J . Pharm. Sci., 1973, 62, 1567. W . 1. Higuchi, S. Prakongpan, V. Surpuriya, and F. Young, Science, 1972, 178, 633. R. Ramasseul and A. Rassat, Tetrahedron Letters, 1974, 2413. P. Michon and A. Rassat, J . Org. Chem., 1974, 39, 2121.
284
Terpenoids and Steroid
20R-p-Tolylpregn-5-ene-3[j,20-diol has been used as an alternative substrate for studies on the biosynthetic degradation of cholesterol to pregnenolone, with positive results.330 A review of the uses of potassium t-butoxide in synthesis includes many examples of applications in the chemistry of steroids and other alicyclic molecules : reactions include the base-catalysed alkylation or nitrosation of ketones, eliminations, condensations, and rearrangement^.^ 3 1 Further to last year’s warning, methyl iodide and benzyl chloride are added to the list of potentially carcinogenic alkylating agents, which already includes dimethyl sulphate and other reagents with applications in steroid chemistry : precautions against skin contact or inhalation of the vapour are strongly re~ommended.~
330 331
332
R. B. Hochberg, P. D. McDonald, M. Feldman, and S . Lieberman, J . Biol. Chem., 1974, 249, 1277. D. E. Pearson and C. A. Buehler, Chem. Ret.., 1974,14, 45. G. W. Gribble, Chem. in Britain, 1974, 10, 101.
Steroid Synthesis BY P. J. SYKES AND J. S. WHITEHURST
1 Total Synthesis Much skill and ingenuity continues to be displayed in the synthesis of steroids. Oestrone has been synthesized' (Scheme 1) starting from 6-methoxy-l-vinyl-3,4dihydronaphthalene (1). The key reaction is the Diels-Alder addition of (1) to 2,6dimethylbenzoquinone (2), which is directed by boron trifluoride etherate to give as the major product the desired intermediate (3) (69yd) and relatively little (1404)of the undesired compound (4). However, the undesired compound is the only product isolated in the purely thermal addition of (1) and (2). Isomerization of ( 3 ) to ( 5 )followed by conversion of the two carbonyl groups into methylenes, ring fission [to (13)], and alkaline re-closure yielded compound (14); Beckmann rearrangement of its oxime gave racemic oestrone methyl ether (15). 19-Nor-steroids have been synthesized from glutaraldehyde by way of the lactones (16),2which by the action of vinylmagnesium chloride give the ketones (17) from which the Mannich bases (18; X = NR', or NHR') or the ketones (19) can be obtained. under mildly acid Condensation of (18) or (19) with 2-methylcyclopentane-1,3-dione conditions yields the dienol ethers (20),readily transformed into the unsaturated ketones (21). Catalytic reduction of these can be induced stereoselectively to give either the aor the fl-configuration at C-9 (steroid numbering), the final products being 19-norsteroids with stereochemistry 9a,lOP or 9P,lOc~.~ In extending this approach to form oestrone, m-methoxyacetophenone was converted by three steps into the nitrile (22) which was resolved4 The dextrorotatory lactone (23; Ar = m-methoxyphenyl),however, consumed two moles of vinyl Grignard reagent [cf: (16)]; the difficulty was overcome by reduction of (23) to (24),followed by reaction of the latter with vinylmagnesium chloride (Scheme 2). Manganese dioxide oxidation of the product (25) (preferential oxidation of the allylic hydroxyl) in the presence of diethylamine gave (26). Condensation of this with 2-methylcyclopentane-1,3-dione yielded a diketone (27) rather than a dienol ether [cJ (1 S)]. Dehydration of (27) followed by partial catalytic reduction produced (28), a compound which is readily converted into oestrone methyl ether. The racemic form of (27) was transformed into racemic equilenin methyl ether. Compounds such as
' *
R . A . Dickinson, R . Kubela, G . A. McAlpine, Z. Stojanac, and Z . Valenta, Canad. J . Chem., 1972,50,2377. 'Terpenoids and Steroids', ed. K . H . Overton (Specialist Periodical Reports), The Chemical Society, London, 1973, p. 409. J. W. Scott, E. Widmer, W. Meier, L. Labler, P. Muller, and A. Furst, J . Org. Chem., 1972,37, 3183. N. Cohen, B. L. Banner, J. F. Blount, M. Tsai, and G . Saucy, J . Org. Chem., 1973, 38, 3229.
285
Tcrpcnoids and Steroids
286
(9)
(6) R = OH
I
iv: (7) R = OMS V:
(8) R
=
vii
H
R = H
H
(10) R = OH viii: (11) R = OAC ix: (12) R = H
I
Me0
&
0
Reagents: i, Ether-BF, etherate: ii, NaHC0,-MeOH ; iii, LiAIH(OBu'),-THF: iv, MsCI-py; v, Zn-MeOH; vi, H,-PdiCaCO,; vii, NaAIH,(OCH,CH,OMe),; viii, Ac,O-py: ix, Li-THF-NH,; x, Os0,-py; xi, Pb(OAc),-THF: xii, 5 aq. HCI-THF; xiii, Beckmann rearrangement.
Scheme 1
Steroid Synthesis
287
0
0 OH
H (20)
(21)
(17) react with thiourea in glacial acetic acid to form the compounds (29); however, these substances are inferior to the Mannich bases (18) in their condensation with 2-methylcyclopentane-1,3-dioneto form the dienol ethers (20).5 In a study of the
Reagents: i, Acid phthalate-(R)-( + )-a-methylbenzylamine; ii, hydrolysis; iii, AIH(Bu’),-toluene; iv, C H , =CHMgCl; v, Mn0,-benzene-Et,NH; vi, 2-rnethylcyclopentane-1,3-dionetoluene-AcOH ; vii, toluene-p-sulphonic acid-toluene ; viii, H ,-Pd/C-toluene.
Scheme 2
N . Cohen, B. L. Banner, J. F. Blount, G. Weber, M. Tsai, and G. Saucy, J . O r g . Chem., 1974, 39, 1824.
Terpenoids und Steroids
288
R2
non-reductive methylation of (30) (R1 = suitable ring A precursors: R2, various) the best ratio of [j- to a-face methylation was achieved6 by use of THF as solvent at - 78 "C. The asymmetric ( i e . unilateral) cycli~ation'.~ of the ketone (31 ; n = 5 ) by (S)-proline in acetonitrile at room temperature has produced (97.373 the ketol (32; n = 5); dehydration of this by toluene-p-sulphonic acid in benzene gave (99 :(,) the dione (33 ; n = 5 ) of 87",, optical purity.8 The homologue (31 ; n = 6) the compound (33; n = 6) in 83 ",, yield and 71 y o optical purity. The compounds (33; n = 5 or 6) are obviously attractive intermediates for the total synthesis of steroids. Compound (33; n = 6) by the successive action of lithium acetylide and hydrogen-palladium yielded the vinyl alcohol (34), which with phosphorus tribromide formed the allylic bromide (35; X = Br). This condensed' with the sodium salt of 2-methylcyclopentane1,3-dione to form (+)-(36). However, cyclization to (37) was only slightly stereoselective, the product being a mixture of C-13 epimers. Interestingly too, neither the
0
(36)
0
(37)
' J. W . Scott, P. Buchschacher, L. Labler, W . Meier, and A . Furst, Helv. Chim. Acta, 1974,57, '
1217. U . Eder, G. Sauer, and R. Wiechert, Angew. Chrm. Internat. Edn., 1971, 10, 496. Z . G. Hajos and D. R. Parrish, J . Org. Chem., 1974, 39, 1615. J. Ruppert, U . Eder, and R. Wiechert, Chem. Ber., 1973, 106, 3636.
Steroid Synthesis
289 + alcohol (34) nor the isothiouronium salt [35; X = S=C(NH,), -OAc] could be induced to react with 2-methylcyclopentane-1,3-dione. The bromide derived from 6-methoxy-1-tetralone by the successive action of vinyl Grignard reagent and phosphorus tribromide has an endocyclic double bond; it is therefore a substituted ethyl bromide and not an analogue of (35) as had been assumed in earlier work." The racemate (38) has been converted" into (+)-19-nortestosterone (42) by the reactions shown in Scheme 3. The stereoselective hydrogenation of (39) to (40)doubtless
(39)
(39a)
I
I
i"
v-
i
C02Et
VI-viii
Reagents: i, NaH-DMSO; ii, - D M S O ; iii, Et,O-CO,; iv, H,-Pd/BaSO,-EtOH; v, H C H O aq.piperidine, HCl-DMSO; vi, NaOMe-MeOH-(41); vii, HCl aq.-MeOH; viii, toluene, reflux ; ix, H ,-Pd/C-EtOH-NEt ; x, HCl-MeOH.
Scheme 3
proceeds through the dienol (39a). Decarboxylation produces a negatively charged carbon at the site of the carboxy-group, thereby selectively directing electrophilic attack to this centre. Compound (38) has also been transformed into compound (45) (Scheme 4),which is of value in the synthesis of fusidic acid (46).12 The stereoselective methylations are notable, as is the Westphalen-type rearrangement (43) -+ (44). lo l1
M. H. Tankard and J. S. Whitehurst, J.C.S. Perkin I, 1973, 615. Z. G. Hajos and D. R. Parrish, J. Org. Chem., 1973,38, 3239, 3244; cf. G . S. Grinenko, E. V. Popova, and V. I. Maximov, Zhur. obshchei Khim., 1971,7,935; G . Nomine, G. Amiard, and V. Torelli, Bull. SOC.chim. France, 1968, 3664. W. G. Dauben, G. Ahlgren, T. J. Leitereg, W. C. Schwarzel, and M. Yoshioko, J . Amer. Chem. SOC.,1972, 94, 8593.
290
Terpenoids and Steroids OBu'
0
(38) bi-iv
OBu'
(ii-viii
0
I&= O
A 0
'
0 0 H
o & ' /
(43)
(44)
(45)
Reagents: i, NaH--DMSO; ii, Bu'OK-Mel; iii, aq. M e C O , H ; iv, Triton B; v, KOH-Bu'OH-MeI; vi, N a O H : vii, (COCl),; viii, LiCuEt,; ix. Triton B ; x, m-chloroperbenzoic acid; xi. BF,.Et ,O; xii, toluene-p-sulphonic acid-benzene: xiii, Li-NH ,-Bu'OH.
Scheme 4
The well-known oestrone intermediate (47)on partial reduction and optical resolution gave the enantiomers (48) and (49).13 Compound (48) on cyclization formed the ether (50) and thence, via (51), natural oestrone. A neat way of converting the 'unnatural' isomer (49) into natural oestrone (apart from oxidation and re-cycling) is conversion l 3
C. H . Kuo, D. Taub, a n d N . L. Wendler, J . Org. Chem., 1968.33, 3126; H . Gibian, K. Kieslich, H.-J. Koch, H . Kosmol, C . Rufer, E. Schroder, and R. Voslich, Terrahedron Letrers, 1966, 2321.
29 1
Steroid Synthesis
0
m OH
"0
Me0
-0
Me0
OAc
1
into the acetate and sodium borohydride reduction. The product (52) on treatment with toluene-p-sulphonic acid in benzene yielded (53), which by hydrolysis and oxidation produced (50).14 Compound (47)on peracid oxidation gives a mixture of the compounds (54) and (55). Treatment of this mixture with triethyloxonium fluoroborate has given the compounds l4
T. Asako, H . Hiraga, and T. Miki, Chem. and Phurm. Buff. (Japan), 1973,21, 107, 697, 7 0 3 .
292
Terpenoids and Steroids 0
0
0
0
H
Me0
Me0
OH
\
(56) (ca. 2596) and (57) (ca. 75‘1~3’~ (C-9 epimers in both cases). Compound (57) was transformed into ( +)-13-isoestrone methyl ether. A stereoselective total synthesis of oestrone by a cationic olefin cyclization method has been achieved16(Scheme 5). Condensation of the aldehyde (58) with (59) followed by sequential treatment with acid and base gave (60: R’ = H, R2 = 0). Reduction to the alcohol followed by stannic chloride-methylene chloride cyclization at - 100 “C produced the racemic compounds (63) (major component) and (64). The proportions of these compounds depended on several factors and varied strikingly according to the nature of R’, R2, and the cyclizing agent and conditions. The a-epoxide (65) was obtained from (63) by way of the chlorohydrin and was rearranged to oestrone (67). Direct epoxidation of compound (63) gave the unwanted P-epoxide (66). Johnson’s group has also synthesized natural progesterone (Scheme 6) by a cationic cyclization route.” Starting from Hagemann’s ester (68) the acid (69) was obtained in racemic as well as in both optically active forms (resolution by a-methylbenzylamine) and these in turn provided the corresponding forms of (70). Wittig coupling of this with the acetylenic aldehyde (71) produced compound (72). Release of the carbonyl group” followed by its reduction gave an epimeric mixture of alcohols (73) from all three forms of (72). Cyclization of the alcohols (73) formed an 85 : 15 mixture of the 17j3- and 17%-epimersof (74), the 17P-epimer being secured in 95% optical purity. Elaboration to progesterone (75)was carried out on the racemic form by two oxidations (t-butyl chromate to introduce the C-3 carbonyl group and DDQ to introduce a A4-double bond) and a homogeneous catalytic reduction. (+-)-Testosterone was also obtained” from compound (73). Cyclization with trichloroacetic acid in 2-nitropropane formed the oxime ether (76). Lithium aluminium l5 l6 I’
A. R . Daniewski, M. Guzewska, and M . Kocor, J. Org. Chem., 1974, 39, 2193. P. A . Bartlett and W . S. Johnson, J. Amer. Chem. Soc., 1973,95, 7501. R . L. Markezich, W. E. Willy, B. E. McCarry, and W. S. Johnson, J . Amer. Chem. SOC.,1973, 95, 4414, 4416. M . Fetizon and M . Jurion, J.C.S. Chem. Comm., 1972, 382. D . R . Morton, M . B. Gravestock, R . J . Parry, and W . S. Johnson, J. Amer. Chem. SOC.,1973, 95, 4417, 4419.
293
Steroid Synthesis
Ph,; I(58)
I
/
R2
0
1
R'O (60) R = H, R2 = 0 i v : (61) R' = H, R 2 = H,OH v : (62) R' = Me& R 2 = H,OH
I
(59)
H
HO
I H
HO
\
viii.
IX
H
HO
Reagents: i, PhLi-ether, MeOH; ii, MeOH-H,SO,; iii. aq. N a O H ; iv, NaAlH,(OCH,CH,OMe),; v, CF3CON(SiMe3)~;vi, SnC14-CH2C12 ( - 100 "C); vii, MeOH; viii, p TsNC1,; ix, Me,NOH-Me,CO; x, BF,,Et,O.
Scheme 5
hydride reduction gave the glycol (77), which on sodium periodate cleavage produced the ketone (78), which was transformed into testosterone benzoate. Interestingly, the cyclization'' of compound (79) does not give a 17-isopropenyl-steroid. Instead, the product is the olefin (80);in this connection Japanese workers have found that compound (81) rearranges to (82) on treatment with hydrochloric acid.21 2o
"
K . A. Parker and W . S. Johnson, J . Amer. Chem. SOC.,1974,96, 2556. I . Yoshizawa, T. Miura, M. Kimura, K . Anzai, and S. Matsuda, Chem. and Pharm. Bull. (Japan). 1973, 21, 1622.
Terpenoids and Steroids
294
viii-xi
I
xv
(72)
(73)
1
XVI
Reagents: i , HOCH,CH,OH-H +,LiAlH,; i i , HC1-THF; iii, CH,(CO,Me),-MeOH-NaOMe; iv, MeC0,H-HC1; v, MeOH-H ; vi, HSCH,SH-BF,,Et,O-CHCl,; vii, KOHM e O H ; viii, NaAlH,(OCH,CH,OMe),-THF; ix, TsC1-py; x, NaI-Me,CO-Pr;NEt ; xi, PPh,-MeCN-Pr',NEt ; xii, PhLi-ether; xiii, MeI-DMF-H,O-CaCO,; xiv, NaAlH ,(OCH ,CH,OMe),-THF; xv, C F , H Me-ethylene carbonate-CF,CO,H ; xvi, ButOCrO,OH-C1,C =CCl,-AcOH-Ac,O; xvii, DDQ-toluene; xviii, H ,-Rh(PPh,),It oluene-Et OH. +
Scheme 6
Steroid Synthesis
295
.d
-_.I-:’
HO-’ HO.’
H
H (80)
(81)
H
(82)
Starting from cyclopentane 1,3-diones having suitable substituents at the 2-position (e.g. ally1 and ethoxycarbonylmethyl), aromatic and 19-nor-gonanes have been syn-
thesized.22 Also, starting from cyclopentanones, analogues of 16-methyloestrone and 16-methyl-19-nortestosterone have been ~ynthesized.’~The compound (83) by addition of rn-methoxyphenylethylmagnesium bromide yielded the lactone (84). When this was cyclized (AIC13-HCI in benzene) the product was the racemic 9PH-marrianolic acid derivative (85) from which ( +)-9P-oestrone was ~ r e p a r e d . ’ Likewise, ~ the action of rn-methoxyphenylethylmagnesium bromide on (86) followed by cyclization, hydrolysis, and oxidation yielded racemic 9P,13a-oe~trone.’~Triethylsilane-trifluoroacetic acid is a useful variant of the known methods for the reduction of the compound (87) (or its 8PH-A9(’‘)-isomer) to the 8P,9a-dihydro-c0mpound.’~
”
23 24
25
K . Yoshioka, T. Asako, G. Goto, K . Hiraga, and T. Miki, Chem. and Pharm. Bull. (Japan), 1973, 21, 2195, 2202, 2427; M. Harnik, R. Szpigielman, Y . Lederman, J. Herling, and Z . V. I. Zaretskii, J . O r g . Chem., 1974, 39, 1873. D. K . Banerjee and P. R . Srinivasan, Indian J . Chem., 1972, 10, 891. V. A . Andryushina, E. V. Popova, 0. S. Anisimova, and G . S. Grinenko, Zhur. org. Khim., 1974, 10, 222; V. A. Andryushina and G . S. Grinenko, ibid., p. 519. T. A. Serebryakova, S. N. Ananchenko, and I. V. Torgov, Izuest. Akad. Nuuk S.S.S.R., Ser. khim., 1973, 1917.
Terpenoids and Steroids
296 ,CO,Me
0
H
CH,CO, Me Me0
(83)
(84)
OAc
2 Halogeno-steroids Methods for introducing fluorine adjacent to carbonyl are being actively pursued. With the aim of preparing 12-fluoro-corticosteroids26 the bis-methylenedioxy-compound (88; R ' = F) was treated with sodium bistrimethylsilylamide in THF and the enolate quenched with trirnethylsilyl chloride or benzoic anhydride. However, neither of the products (89; R' = F, R2 = H, X = SiMe,) and (89; R' = F, R2 = H, X = Bz) could be induced to react with trifluorofluoro-oxymethane (CF,OF). Attention was turned to the use of metal enolates. The sodium enolate (89; R' = F, R 2 = H, X = Na) reacted violently with CF,OF but quite smoothly with perchloryl fluoride to form (90 ; 12p-F) (equatorial fluorine). For large-scale preparations the necessarily longer reaction times militate against the use of sodium enolates as these tend to equilibrate with unreacted ketone: the problem was solved by the use of lithium enolates, best prepared from the sodium enolates by exchange with lithium chloride in THF. Compound (88 ; R' = H) could be smoothly converted into (88 ; R' = F). However, if the base was lithium di-isopropylamide, (88; R' = H) was converted into the 11,12-enolate (89; R' = H, R2 = H, X = Li), which with perchloryl fluoride produced the 12fluoro-ketones (90: 12P-F) (65 and (90; 1 2 ~ - F(23 ) %). The nature of the base used is therefore of paramount importance in deciding whether the product is formed kinetically or thermodynamically.
x)
26
D. H. R. Barton, R. H. Hesse, M . M. Pechet, and T. J. Tewson, J . C . S . Perkin I , 1973, 2365.
St ero id Synthesis
297
The addition of difluorocarbene to a variety of steroid enol acetates and enol ethers has been studied27(see p. 313). ~ - N o r - s t e r _ o i d ssuch ~ ~ -as ~ ~(91) undergo reaction to form (92; X = Y = F), readily transformed by hydrolysis, oxidation, and treatment with base into the fluoro-ketone (93). Interestingly, chlorofluorocarbene, CClF (generated from PhHgCC1,F) adds to (91) to give both the compounds (92; X = C1, Y = F) and (94; X = F, Y = Cl), whereas dichlorocarbene yields only (94; X = Y = C1).28 The addition of difluorocarbene to side-chain unsaturated linkages has been used to generate, ultimately, steroids containing allenic substituents, as well as orally active progesterone analogues.
The action of perchloryl fluoride in aqueous dioxan on compound (95) has given the highly unstable 2P-fluoro-compound (96), which readily loses hydrogen fluoride, 27
28 29
P. Crabbe, A. Cervantes, A. Cruz, E. Galeazzi, J. Iriarte, and E. Velarde, J . Amer. Chem. SOC., 1973,95, 6655. P. Rosen, A. Bovis, and R . Karasiewicz, J . Medicin. Chem., 1974, 17, 182. P. Crabbe, H . Carpio, E. Velarde, and J. H. Fried, J . Org. Chem., 1973, 38, 1478; H . Carpio, P. Crabbe, and J. H . Fried, J.C.S. Perkin I , 1973, 227.
Terpenoids and Steroids
298
generating an aromatic ring A . ~ ’ Much use has been made of the epoxide (98) of the ketone (97) as a source of fluorine- and bromine-containing ring-a aromatic steroids.3 1 Epoxide opening of (98) by HBr leads to the corresponding 4-bromo-ketone (99; X = H, Y = Br) whereas HF yields the 2a-fluoro-ketone (99; X = F, Y = H), which was transformed into 2-fluoro-oestrone. Perchloryl fluoride in methanol introduced a 4-fluoro-substituent into the pyrrolidine enamine of a 19-n0r-A~-3-ketone,~~ which was converted into 4-fluoro-oestrone.
(95)
0
0 0’
I[:”
0 Y
(97)
(99)
Much of the interest in halogeno-steroids centres on their use as progestational agents. Even a brief survey shows the concentration of effort made to produce 6possessing a 17a-acetoxyhalogeno-A4-3-keto- or 6-halogeno-A4~6-3-keto-systems pregnan-20-one system or 17fi-hydroxy-17a-ethynyl unit. Additional structural elements that have been added include a 16-methylenegroup and a la,2a-cyclopropane unit. The appropriate papers should be consulted for these compounds.33 In a new synthesis34 of the potent progestational agent chlormadinone acetate (104) (see also p. 252) the starting material (100) (available from the 16a,l7a-epoxide or 16-dehydropregnenolone acetate) was treated with N-bromosuccinimide and the 7a-bromo-derivative produced was converted, by treatment with potassium hydroxide in methanol, into the acid-sensitive 7a-methoxy-compound (101). Alkaline hydrolysis gave the 3-hydroxy-derivative, which on perbenzoic acid oxidation formed the epoxide (102), itself transformed by hydrogen chloride in water-free solvents into the chlorohydrin (103). Chromic acid oxidation and treatment with lithium chloride-hydrogen 30 31
32
33
34
J . Pataki, Tetrahedron, 1973, 29, 4053. M. Neeman, T. Mukai, J. S. O’Grodnick, and A. L. Rendall, J.C.S. Perkin I , 1972, 2300: M. Neeman, J. S. O’Grodnick, and K . Morgan, ibid., p. 2302; M. Neeman and J. S . O’Grodnick, Tetrahedron Letters, 1972, 4847; M. Neeman, Y. Osawa, and J. Mukai, J.C.S. Perkin I , 1973,1462; M. Neeman and J. S. O’Grodnick, Canad. J . Chem., 1974,52,2941. M. Neeman, Y . Osawa, and T. Mukai, J . C . S . Perkin I , 1972,2297; M. Neeman and Y . Osawa, Tetrahedron Letters, 1963, 1987. E . g . , A . L. Johnson, J . Medicin. Chem., 1972, 15, 854; S. J. Halkes and J. Hartog, ibid., p. 1288; J. Hartog, J. J. G . M. Wittelaar, L. Morsink, and A . M. de Wachter, ibid., p. 1292; E. L. Shapiro, L. Weber, G. Teutsch, H . Harris, R. Neri, and H . L. Herzog, ibid., 1973, 16, 649; R. Mickova, Coll. Czech. Chem. Comm., 1973, 38, 2492. G. Langbein, E. Menzer, M. Meyer, and R. Weseman, J . prakt. Chem., 1973, 315, 8.
299
Steroid Synthesis
AcO &Me
e
M
:HO &
HO C1
fl
0
C1
chloride in DMF gave 17~-acetoxy-6-chloropregna-3,5-diene-3,2O-dione (chlormadinone acetate) (104). The metabolism of this compound has been studied in the rabbit and one of the urinary compounds is a 2,3-dihydroxy-compound. The configuration of this has been e ~ t a b l i s h e d .Lead ~ ~ tetra-acetate oxidation of (104) led to the 2a- and 2~-acetoxy-compounds(105). These were distinguished from each other by the conversion of one into the other by the action of potassium acetate in acetic acid. The stable epimer, therefore, was the equatorial 2rx-compound. On sodium borohydride reduction this produced the expected 2a,3P-dio1(106),identical with naturally produced material. Interestingly, although the compound is a trans-diol, it gave an acetonide (see also p. 252). 35
T. Abe and A. Kambegawa, Chem. and Pharm. Bull. (Japan), 1973, 21, 1295.
300
Terpenoids and Steroids
3 Oestranes The synthesis of 9-methyl-19-nor-steroids has received attention. 3 6 , 3 7 11-0x0-oestrone methyl ether (107) on reaction in methyl iodide solution with potassium t-butoxide in t-butyl alcohol yielded stereoselectively the 9cc-methyl derivative, which was readily converted into 9a-methyloestrone (108). This was also obtained by methylation of the 1 l - e n ~ l a t eof ~ compound ~’~~ (109) and reductive removal of the C-10 methyl group by lithium-biphenyl-diphenylmethane and of the C- 1 1 carbonyl group by Wolff-Kishner reduction. Compound (108) was converted into 9a-methyl-19-norprogesterone(1 10). The stereochemistry at C-10 was settled unequivocally by X-ray analysis. 9P-Methyl steroids were prepared from the totally synthetic optically active compounds (1 1 1). Compound (1 1 la) underwent m e t h ~ l a t i o nby ~ ~ lithium dimethylcuprate to form, stereoselectively, the 9P-methyl compound (112a). Though a cis-2-decalone, this underwent further alkylation at position 6 (steroid numbering). Perforce the requisite side-chain had to be introduced by alkylation of the pyrrolidine enamine to form (111b) : this was then followed by conjugate addition of methyl to form (112b). Lithium dimethylcuprate also converted37 (1 1lc) into (112c). Subsequent cyclization gave, from both 0
Me0
R
@
R
&p
0 (111) a ; R = H
b; R
=
MeCCI=CHCH,
c ; R = MeC(-OCH,CH,O-)CH,CH, 3h 37
38
”
(112) a ; R = H b ; R = MeCCl=CHCH, c ; R = MeC(-OCH,CH,O-)CH,CH,
J. R. Bull and A. Tuinman, Tetrahedron, 1973, 29, 1101. R . V. Coombs, J. Koletar, R. Danna, H. Mah, and E. Galantay, J . C . S . Perkin I , 1973, 2095. M.Tanabe and D. F. Crowe, Chem. Comm., 1969, 1498. D. H. R . Barton, R . H . Hesse, G. Tarzia, and M. M. Pechet, Chem. Comm., 1969, 1497.
30 1
Steroid Synthesis OH
(112b) and (112c),the 19-nor-steroid (113), which had 9P,lOa-stereochemistry (as in the cucurbitacins). Conjugate addition of cyanide to (11lc) yielded the 9a-cyano-deri~ative~~ (112c; 9a-CN in place of 9P-Me). Lithium dimethylcuprate induced (114) to form a 5-methyl rather than a 9-methyl compound.36 Some of the most fascinating reactions being discovered in the steroid field involve the use of superacids. Oestrone, its methyl ether, and its acetate on treatment with HF-SbF, are all smoothly converted into oestra-4,9-diene-3,17-dione (1 15) in ca. 80% yield.40 With FS0,H-SbF, the products are compounds (116) (62%) and (115) (ca. 10%). 19-Norandrostenedione (117) in contact with HF-SbF, for 10 minutes at 0°C produced the isomer (117; 14P-H) in 75% yield.41 Using the system DF-SbF,, up to 12 deuterium atoms could be incorporated into the molecule. In the androstane series some highly unsual products have been obtained by using HF-SbF, to promote dienone-phenol rearrangement^.^^
&*
0
’
H
(115)
HO \
H
(116)
& *
/
( 1 17)
The methylation of 19-nor-A4-3-keto-steroids (118 ; R = H) to produce 2a-methyl derivatives (118 ; R = Me) has been made possible by the action of lithium hexamethyldisilazane and the trapping of the A2~4-enolatewith methyl iodide.43 5aH- 19-Norketones of type (119) very readily undergo conjugate addition of methyl (coppercatalysed Grignard reagent) to give the la-methyl compounds, even in the presence of an 1lP-hydroxy-group which might have been expected to induce P-attack of the reagent by complex f0rmation.4~ In 19-nor-steroids (118; R = H) ring A becomes aromatized and C-6 oxidized by the action of oxygen in DMS0.45 The products, 3-hydroxy-6-ketones, are formed by
40 41
42 43 44 45
J. P. Gesson, J.-C. Jacquesy, and R . Jacquesy, Bull. SOC.chim. France, 1973, 1433. J.-C. Jacquesy, R. Jacquesy, and G. Joly, Tetrahedron Letters, 1972, 4739. J.-C. Jacquesy, R . Jacquesy, and Ung Hong Ly, Tetrahedron Letters, 1974, 2199. M . Tanabe and D. F. Crowe, J.C.S. Chem. Comm., 1973, 564. C. C. Bolt and F. J. Zeelan, Rec. Trav. chim., 1973, 92, 1267. H. Hofmeister, H. Laurent, and R. Wiechert, Chem. Ber., 1973, 106, 723.
Terpenoids and Steroids
302
(1 18)
(1 19)
sequential oxygenation at C-6 followed by aromatization and not in the reverse order. 2~-Hydroxy-3,17-dioxoandrost-4-en19-a1(12l), which is quite possibly the penultimate steroid in the androgen-oestrogen bioconversion, has been ~ y n t h e s i z e dfrom ~ ~ (120; R' = R2 = R3 = H, R4 = OAc). N-Bromosuccinimide introduced a 6P-bromine atom, to afford (120; R 1 = R 2 = H, R3 = Br, R4 = OAc), and the action of glacial acetic acid-potassium acetate on the latter replaced the bromine with rearrangement ; one of the products (120; R' = R4 = OAc, R2 = R3 = H) on hydrolysis and treatment with dimethyl-t-butylsilyl chloride-imidazole yielded (120; R 1 = OSiMe,Bu', R 2 = R 3 = H, R4 = OH), which on oxidation and hydrolysis formed (121). Compound (121) in a phosphate buffer at pH 7 was converted rapidly and quantitatively into oestrone. If indeed (121) is the penultimate link in the biological sequence, the last step might well be non-enzymatic. 0
0
I
R3
The a-epoxide (122) gave the 10P-hydroxy-compound (123) when treated with either potassium t-butoxide or lithium di-is~propylamide.~~ The or-epoxide (124) by contrast yielded compound (125) with potassium t-butoxide (loss of the 12-axialproton) and (126) with lithium di-isopropylamide. These results have been rationalized in terms of orbital symmetry.48 Compound (125) was quantitatively converted on deacetalization into (127). The ketone (128) on peroxidation with rn-chioroperbenzoic acid gave the l0a-hydroxy-compound (129) in addition to the known 10~-compound.30 Compounds of type (130) have been and have contraceptive properties. On catalytic hydrogenation they produce 9PH-compounds, but on metal-ammonia reduction the normal 9ctH-stereochemistry ensues. A three-step procedure for converting 17-keto-steroids into their 18-nor-derivatives has been worked out in the oestrane series (see p. 258).51 Dehydroabietic acid has been 46 4'
48 49 50
5L
H . Hosoda and J . Fishman, J.C.S. Chem. Comm., 1974, 546. G . Teutsch and R . Bucourt, J . C . S . Chem. Comm., 1974, 763. J. Mathieu, Bull. SOC.chim. France, 1973, 807. H . J. Kooreman, D. van der Sijde, and A. F. Marx, Rec. Trav. chim., 1972,91, 1095. D. van der Sijde, H . J . Kooreman, K. D. Jaitly, and A. F. Marx, J. Medicin. Chem., 1972, 15, 909; 1973, 16, 1302. M. M. Coombs and C. W. Vose, J.C.S. Chem. Comm., 1974, 602; cf. R . Anliker, M. Miiller, M. Perelman, J . Wohlfahrt, and H. Heusser, Helv. Chim. Acta, 1959, 42, 1071.
Steroid Synthesis
303
304
Terpenoids and Steroids
transformed into the 14a-methyl-19-nor-compound( 131).52 The best route so far known to A14-17p-olsis that of sodium borohydride reduction of the 14,16-diene-17acetates (132).5 3 Compound (1 33) on reaction with Grignard reagent, acetylation, and treatment with zinc in toluene (Serini-type reaction) produced in high yields the 168alkyl compounds (134)? Starting from the 16-hydroxy-17-keto-isomer of (133) the products were the 17~-alkyl-16-ketones.Methods for the construction of ethers of type (135) have been devised;55 the compounds are orally active oestrogens, the 17cycloalkenyl ether grouping being a variant of the more usual 17a-ethynyl-typegrouping. OAc
I
Me0
p \
(133)
(135)
4 Androstanes
A new synthesis56 of A2-steroids is exemplified by the conversion of 17D-acetoxy-5aandrostan-3-one into 17P-hydroxy-5a-androst-2-ene. Initial conversion of the 3-ketone + into its 2a-hromo-derivative is accomplished by reaction with PhNMe, Br, - ; reaction of the bromo-ketone with triethyl phosphite affords the enolate [136; R = (EtO),P(O)O], which on reduction with lithium in ammonia-propan-2-01 yields the olefin (136; R = H). The remote oxidation of unactivated C-H bonds by photoexcited nitrobenzene derivatives has been r e p ~ r t e d , ~and ’ the procedure is illustrated by the conversion of 5a-androstan-3a-ol into 5cc-androst-14-en-3-one. Ring-D dehydrogenation is accomplished by irradiation of the P-(pnitropheny1)propionate ester [137; R = 0,C(CH2),C,H,N0,-p] ; saponification and chromatography of the resultant neutral fraction yields a mixture of 5a-androstan-3cc-01and 5a-androstan-14-en-3a-o1? which is oxidized to the respective ketones for ease of separation. A 26% yield of the 52
T. Wirthlin, H . Wehrli, and 0. Jeger, H e h . Chim. Acta, 1974, 57, 368.
54
G. Goto. Y . Yoshioka, K . Hiraga, and T. Miki, Chem. and Pharm. Bull. (Japan), 1973. 21,
’’ G. H . Rasmusson and G. E. Arth, Steroids, 1973, 22, 107. 55 56
5’
1393; Tetrahedron, 1974, 30, 2107. R . Gardi, R. Vitali, G. Falconi, and A. Ercoli, J. Medicin. Chem., 1973, 16, 123. M . Fetizon, M . Jurion, and A . Nguyen Trong, Org. Prep. Proced. Internat., 1974,6, 31. P. C. Scholl and M . R. Van der Mark, J. Org. Chem., 1973,38, 2376.
Steroid Synthesis
305
H (1 37)
A14-3-ketone can be achieved. The yield of well defined remote-oxidation product is, however, lower by this method than that reported58 for the photolysis of the benzophenone derivatives ( 1 38). Irradiation of androsterone 3wtrifluoroacetate (137 ; R = O,CCF,) in the presence of PhICI, yields a product which upon dehydrochlorination and saponification is shown5' to be androst-9(1l)-en-17-one (49 %) (see also p.275). Interest has continued in reactions which lead to aromatization in steroids, and it is reported that the action of hydrogen bromide on 17~-acetoxy-4P,5a-dihydroxyandrost2-ene, 5a,6a- and 5cr,6P-dihydroxyandrost-2-en-l 7-one, and 4P-acetoxy-3P-hydroxyandrost-5-en-17-one is to convert them into their respective 17-substituted-4-methyloe~tra-l,3,5(10)-trienes.~~ SimiIar treatment of 6~,17P-diacetoxy-3P-hydroxyandrost4-ene gives a mixture of 17P-acetoxy-4-methyloestra-1,3,5( 10)-triene and testosterone acetate. Selective ring-c aromatization has been accomplished by treating 17P-hydroxy17-methylandrost-4,6,9(1l)-trien-3-one with refluxing formic acid.6' The reaction furnishes 17,17-dimethy1-18-norandrosta-4,8,1 lJ3-tetraen-3-one (139; R = H) in 45';/,, yield ; dehydrogenation of this tetraene gives the corresponding A4,6,8,' -pentaene. The formic acid rearrangement reaction has also been used to convert 3P-acetoxy-17Phydroxy-17-methyl-5c-androst-8-en-ll-one and 9cc-bromo-l7~-hydroxy-l7-methylandrost-4-ene-3,ll-dione into 3P-acetoxy-1l-hydroxy-17,17-dimethyl-l8-nor-5a-androst8,11,13-triene and 1l-hydroxy-l7,17-dimethyl-18-norandrosta-4,8,11,13-tetraen-3-one (139; R = OH) respectively.62 Application of this aromatization procedure to 38acetoxy-l7~-hydroxy-l7-methyl-5~-androst-9( 1l)-en-12-one in an attempt to obtain the corresponding 12-phenol resulted only in the formation of 3P-acetoxy-17-methyl-
59
(139) R. Breslow, S. Baldwin, T. Flechtner, P. Kalicky, S. Liu, and W. Washburn, J . Amer. Chem. SOC.,1973, 95, 3251. R. Breslow, R. Corcoran, J. A. Dale, S. Liu, and P. Kalicky, J . Amer. Chem. SOC.,1974, 96, 1973.
6o 61 62
D. Baldwin, J. R. Hanson, and A. M. Holton, J.C.S. Perkin I, 1973, 1704. A. B. Turner, Chem. and Ind., 1972, 932. C. L. Hewett, S. G . Gibson, I. M. Gilbert, J. Redpath, and D. S. Savage, J . C . S . Perkin I , 1973, 1967.
306
Trrpenoids and Steroids
5a-androsta-9(1 1),16-dien-l2-one, presumably since aromatization of ring c would involve an unstable tertiary carbonium ion adjacent to the C-12 carbonyl group. The scope of the available reactions to ring-c aromatic steroids has been extended to include a route via bromination and dehydrobr~mination~(Scheme 7). Initial bromination of the A ' 3-steroids (140) followed by dehydrobromination leads to the 7,13-dienes (141) as expected; these on further bromination yield, in the main, the dibromides (142),of which (142b and c) were sufficientlystable to be isolated. Dehydrobromination of the crude dibromides (142) results in the direct formation of the 8,11,13trienes (143), generally in good yields. This aromatization procedure has also been and the correapplied to 3a-benzoyloxy-17,17-dimethyI-18-nor-S~-androst-l3-ene, sponding SP-ring-c-aromatic steroid was isolated in good yield. , J H 2 RMe 2 ,&H2R2
Br
I
(140) a : R ' = Ac, R 2 = H b : R' = Rz, R 2 = H C : R ' = Bz, R 2 = OBZ d : R ' = Ac. R 2 = Ph e : R ' = Bz, R 2 = Ph
Po-
J.
&Ll
iii
4
H (143)
Reagents: i , B r ? . - 6 0 ° C ; ii. N a I L M e 2 C O ; iii, B r ? , - 6 0 ° C ; iv, stir with silica in benzene.
Scheme 7
4,4-DimethyI-Scc-androstan-2-one has been prepared for the first time.64 The into its synthesis commences with the conversion of 4,4-dimethyl-5a-androstan-3-one 2-arylidene derivative by reaction with p-methoxybenzaldehyde ; the 3-keto-group is then reduced and acetylated prior to ozonolysis of the 2-arylidene group. The resulting 3[$acetoxy-2-ketone on treatment with zinc in acetic acid affords the required 2-ketone. Conversion of the 3-ketone directly into the 2a-acetoxy-3-ketone by lead tetra-acetate seems to offer a shorter route, but the subsequent isomerization (2a-OAc.3-C=0 -+ 3P-OAc,2-C=0) results in the formation of an equilibrium mixture of both steroids. Thus although the route first described is longer, the overall yield of 2-ketone is higher. The preparation of four D-homoandrostanes has been d e s c r i b ~ d(Scheme ~~ 8), via the ring expansion of the intermediate amino-alcohols (144). Subsequent oxidation of C . L. Hewett, I. M. Gilbert, J. Redpath, D. S. Savage, J. Strachan, T . Sleigh, and R. Taylor, J . C . S . Perkin I . 1974, 897. "'A . D. B o d . R. Macrae. and G . D. Meakins, J . C . S . Perkin I , 1974, 1138. h5 L. E. Contreras, J. M. Evans, D. de Marcano, L. Marquez, M. Molina, a n d L. Tempestini, J . O r g . Chem., 1974, 39, 1550.
63
Steroid Synthesis
a ; R' b ; R' C ; R' d ; R'
= =
= =
307
1
iv
a-OH, R 2 = H b-OH, R 2 = H H, RZ = p-OH H, RZ = b-OH, As
c>
Reagents: i. Trimethylsulphonium ylide; ii, NaN,-boric acid; iii, Zn-HCI; iv, NaN0,-HCl; v, Huang-Minlon reduction.
Scheme 8
the D-homo-alcohol (145c) furnished the 3-keto-derivative and this was converted into 2-keto-~-homoandrostaneby a group-transposition sequence similar to that outlined Oxidation of the alcohol (145d) allowed above for 2-keto-4,4-dimethyl-5a-androstane. which was reduced to the A4-~-homo-steroid, the isolation of the ~-homo-A~-3-ketone, and this in turn on hydroboration and oxidation furnished a route to ~-homo-Scxandrostan-4-one. Oxidation of either of the derivatives (145a) or (145b) provided a simple way to ~-homo-5cx-androstan-l -one. A novel route to D-homoandrostanes has been described, based upon the reaction of the trio1 (146) with base.66 The reaction involves elimination of the acetylene with consequent ring-D homologation to form 3p, 1 7afi-dihydroxyandrost-5-en17-one.
( 1 46)
( 1 47)
The published route67 from Sa-androstan-17-one to the corresponding 15-ketone has been improved and adapted to large-scale preparations of this hitherto not readily with available ketone.68 Reaction of 16a-bromo-17,17-ethylenedioxy-5a-androstane base yields a A' 5-acetal which on hydrolysis affords the A' 5-17-ketone; peroxidation h6 67
68
H . Chwastek, R . Epsztein, and N . LeGoff, Tetrahedron Letters, 1973, 179. C. Djerassi, G . von Mutzenbecker, J. FajkoS, D. H. Williams, and H . Budzikiewicz, J . Amer. Chem. SOC.,1965,87, 817. I . M. Clark, W . A . Denny, E. R . H . Jones, G . D. Meakins, A. Pendlebury, and J. T. Pinhey, J . C . S . Perkin I , 1972, 2765.
308
Terpenoids and Steroids
then affords the keto-epoxide (147). The key step in this improved synthetic route is the reaction of the epoxide (147) with hydrazine and toluene-p-sulphonic acid in the presence of air to yield 5%-androstan-15P-01. Surprisingly, if this latter reaction is carried out in nitrogen, the allylic alcohol 5a-androst-16-en-15P-ol is obtained. Oxidation of the saturated 15fi-alcohol affords the desired 15-keto-steroid. A convenient high-yield conversion of androst-5-ene-3P, 17P-diol into the 3P-hydroxyA5- 17-ketone (dehydroisoandrosterone) has been devised, in particular for small-scale radioactive preparation^.^^ The method depends on selective reaction at the C-3 hydroxy-group between the 3fi~7P-dioland dimethyl-t-butylsilyl chloride in the presence of imidazole : androst-5-ene-3P,17P-diol3-dimethyl-t-butylsilyl ether is formed in 71 yield. Oxidation at C-17 is then accomplished with chromium trioxidepyridine and cleavage of the protecting group is carried out with aqueous acetic acid. The reaction of formaldehyde with a series of dienamines (148) and (149) has been shown to establish a synthesis of the corresponding 6-hydroxymethyl-steroids (150) and (151)respectively. 'O The latter could be dehydrated to their 6-methylene analogues and thence by palladium-carbon isomerization to their 6-methyl-A4~6-derivatives. ''()
R
R2
Me, R2 = 0 R2 = P-Ac,r-H c: R' R2 = B-Ac,cr-OAc d : R ' = H.R2 = 0 e : R' = H, R 2 = B-OH,cr-Me
(148) a ; R' b : R'
=
= Me, = Me,
(149) a ; R b; R C:
R
d; R
= =
0 P-Ac,a-H
= B-Ac,u-OAC ==
P-OH,a-Me
A route to 6P-methyi derivatives of €3-norandrostanes has been illustrated by the reaction of 3fi-acetoxy-~-nor-5x-androsta-6,17-dione with methylmagnesium bromide.' The initial dimethylated steroid can be dehydrated to 3P-hydroxy-6,17~ dimethyl-~-nor-androst-5-en-l7-01, which on oxidation yields the corresponding 6P-methyl-A4-3-ketone; the preparation of the corresponding 6/3-methyl-~-norcholest4-en-3-one is also described. A procedure for the 2-alkylation of A4-3-keto-steroids h9
'O
"
H . Hosoda, D. K . Fukushima, and J . Fishman, J . Org. Chem., 1973, 38, 4209. F. Schneider, A . Boller, M. Muller, P. Muller, and A . Furst, Helu. Chim. Actu, 1973,56, 2396. J . Joska, J . FajkoS, and F. Sorm, Coll. Czech. Chem. Comm., 1973,38, 2121.
Steroid Synthesis
309
via the corresponding 2,4-dienolate ion has been p~blished.~,Thus when the 17tetrahydropyranyl ether of testosterone or 19-nortestosterone is treated with lithium hexamethyldisilazane, the 2,4-dienolate ion is produced in high yield and can be trapped as the hitherto unknown ring-A homoannular 2,4-dienol silyl ether (152 ; R = Me or H) by reaction with t-butyldimethylchlorosilane. Alkylation of the dienol ether (152 ; R = Me) with methyl iodide in hexamethylphosphoramide gave an 800/0 conversion into a mixture of the 2a- and 2P-methylated-A4-3-ketones, which on base equilibration gave the 2a-methyl-steroid. Acid-catalysed removal of the C- 17 protecting group afforded 2a-methyltestosterone. Michael addition of nitromethane to 17/?-propionyloxyhas been shown to yield the or 17fi-hydroxy-l7-methylandrosta-l,4,6-trien-3-one corresponding la-(nitr~methyl)-dienones~~ (153; R = CH,NO,). Reduction of the nitromethyl group with titanous chloride yields the la-formyl derivative (153; R = CHO), whilst hydrogenation of the nitromethyl steroid affords la-(nitromethyl)-17Ppropionyloxy-5~-androstan-3-one.
Me (1 53)
(152)
An improved route to a-diazoketo-steroids has been published. 7 4 Formylation of the 17-ketone (154: R = H,) with ethyl formate and sodium hydride gave the 16-formyl derivative (154; R = CHOH), which on reaction with diethylamine was converted into the enamine (154; R = CHNEt,). Reaction of the latter with p-carboxybenzenesulphonyl azide afforded the diazo-ketone (154; R = N,) in an overall yield of 627; based upon the 17-ketone. This method avoids the erratic results encountered in the chloramine oxidation of oximino-ketones. Irradiation of the diazo-ketone (90 ; R = N,) and -1 68gave a mixture of two acids, 3P-hydroxy-~-l3a-norandrost-5-ene-l6acarboxylic acids. 0
154)
Benzyl alcohol has been used as a hydrogen donor in the selective hydrogenation of unsaturated steroid^'^ with heterogeneous catalysts such as 10 Pd-C. Seven examples are given amongst which are the reduction of 17fi-hydroxy-5a-androst-1-en-3-one to the saturated 5a-androstan-3-ketone (quantitative) and 17P-hydroxy-1,4-androstadienl2
l3
74
l5
M . Tanabe and D. F. Crowe, J.C.S. Chem. Comm., 1973, 564. M . Kocor, M . Gumulka, and T. Cynkowski, Bull. Acad. polon. Sci., Ser. Sci. chim., 1973, 21, 721. J. Meinwald and A. J. Taggi, J. Amer. Chem. Soc., 1973, 95, 7663. R . Vitali, G. Caccia, and R. Gardi, J. Org. Chem., 1972, 37, 3745.
Terpenoids and Steroids
310
3-one to a mixture of 17P-hydroxy-S/?-androstan-3-one (25 %) and 17p-hydroxyandrost4-en-3-one (72 ?