A Spec iaIist Period icaI Report
Terpenoids and Steroids Volume 4
A Review of the Literature Published between Septem...
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A Spec iaIist Period icaI Report
Terpenoids and Steroids Volume 4
A Review of the Literature Published between September 1972 and August 1973
Senior Reporter
K. H.
Overton, Department of Chemistry.
University of Glasgow Reporters C. Altona, Rijksuniversiteit, Leiden D. V. Banthorpe, University College, London G . Britton, University of Liverpool B. V. Charlwood, King's College, University of London J. D. Connolly, University of Glasgow R. A. G . de Graaff, Rijksuniversiteit, 1 eiden J. R . Hanson, University of Sussex H. J. C. Jacobs, Rijksuniversiteit, Leiden D. N. Kirk, Westfield College, University of London R. W. Mills, University of British Columbia T. Money, University of British Columbia C . Romers. Rijksuniversiteit, Leiden L. L. Smith, University of Texas, Medical Branch A. F. Thomas, Firmenich et Cie., Geneva
0 Copyright 1974
The Chemical Society Burlington House, London, W I V OBN
ISBN: 0 85186 2861 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
In tr oduc t ion
While following the pattern established in previous Reports of this series, we have this year added two chapters of a new kind. It seemed to us that areas of terpenoid and steroid chemistry not normally included in our coverage should be reviewed in occasional chapters. These will cover periods of about five years while otherwise preserving the detailed character of our annual Reports. The first results of this decision are Chapters 2 and 3 of Part I1 of this volume. In ‘Microbiological Reactions with Steroids’ Professor L. L. Smith gives a comprehensive account of the very large amount of work that has appeared in this field since the last review was published in 1967. The chapter ‘Steroid Conformations from X-Ray Analysis Data’ by Professor C. Romers and Dr. C Altona and their colleagues goes somewhat beyond the usual scope of Specialist Periodical Reports. The authors have in part used data recorded in the literature to recalculate equilibrium geometries for a large number of steroids. In their critical survey based on these geometries, they provide a most illuminating analysis of the way in which steroid conformations respond to functionality and configuration. This will be of interest to organic chemists and biochemists alike. Because of a change in authorship which we were not able to implement in time for this Report, the chapter on Steroid Synthesis has regretfully been held over for Volume 5, which will cover a two-year period. Finally, we have included a list of selected reviews of terpenoid chemistry that have appeared in the period 1968-1973, to fill what to us seemed a regrettable gap in the tertiary literature.
K. H. OVERTON
Contents Part 1 Terpenoids Chapter 1 Monoterpenoids By A. F. Thomas
3
1 Physical Measurements: Spectra etc.; Chirality
3
2 General Chemistry
6
3 Blogenesis, Occurrence, and Biological Activity
8
4 Acyclic Monoterpenoids Terpene Synthesis from Isoprene 2,6-Dimethyloctanes Artemisyl, Santolinyl, Lavandulyl, and Chrysanthemyl Derivatives
10 10 11
5 Monocyclic Monoterpenoids Cyclobutane Cyclopentanes, including Iridoids p-Menthanes rn-Menthanes Tetramethylcyclohexanes 1,4-Dimethyl-1-ethylcyclohexanes Cycloheptanes
22 22 23 26 37 37 40 41
6 Bicyclic Monoterpenoids Bicyclo[3,1,O]hexanes Bicyclo[2,2, llheptanes Bicyclo[3,1, llheptanes Bicyclo[4,1 ,O]heptanes
42 42 43 56 63
7 Furanoid and Pyramid Monoterpenoids
66
8 Canrtabidds and other Phenolic Monoterpenoids
69
Chapter 2 Sesquiterpenoids By R. W. Mills and T. Money 1 Introduction
19
77 77
V
vi
Terpenoids and Steroids 2 Famesane
77
3 Bisabolanes
87
4 Sesquicarane, Carotane, etc.
89
5 Cuparane, Laurane, Trichothecane,efc.
90
6 Acorane, Bazzanane, Cedrane,Zizaane, etc.
93
7 Chamigrane, Widdrane, and Thujopsane
96
8 Sesquipinane, Sesquifenchane, and Fumagillane
97
9 Sesquicamphane, &Santdane, a-Santdane, etc.
99
10 Amorphane, Cadinane, Cubebaw, Copaane, Copocamphane,
Ylangocamphane, Sativane, etc.
101
11 Himachalane, Longipinane, Longicamphane, Longifolane,
and Cyclolongicamphane
108
12 Humulane, Caryophyllane, etc.
112
13 Germacrane, Eudesmane, Eremophilane, etc.
114
14 Guaiane, Cyperane,Seychellane, Aromadendrane, and
Bourbonane 15 Mono- and Bi-cyclofarnesanes
Chapter 3 Diterpenoids By J. R. Hanson
133 139 145
1 Introduction
145
2 Bicyclic Diterpenoids
145
3 Tricyclic Diterpenoids Naturally Occurring Substances Chemistry of the Tricyclic Diterpenoids
150 150 154
4 Tetracyclic Diterpenoids
157 157
The Kaurene-Phyllocladene Series Beyeranes Gibberellins Grayanotoxins Diterpenoid A1kaloids
160 161 163 164
5 Macrocyclic Diterpenoids and their Cyclization Products
164
6 Miscellaneous Diterpenoid Substances
166
7 Diterpenoid Synthesis
167
Contents
vii
Chapter 4 Sesterterpenoids By J. R. Hanson
171
1 Introduction
171
2 Acyclic and Furanoid Sesterterpenoids
171
3 Gascardic Acid
174
4 ophiobori
176
5 Substances of Miscellaneous Structure
181
Chapter 5 Triterpenoids By J. D. Connolly
183
1 Reviews
183
2 Squalene Group
183
3 Fusidane-Lanostane Group
188
4 Dammarane-Euphane Group Tetranortriterpenoids Bicyclononanolides Quassinoids
197 202 204 206
5 Shionane-Baccharane Group
206
6 LupaneGroup
207
7 Oleanane Group
209
8 UrsaneGroup
218
9 HopaneGroup
219
10 Stictane-Flavicane Group
219
11 Serratane Group
220
Chapter 6 Carotenoids and Polyterpenoids By G.Britton
22 1
1 Introduction
22 1
2 Physical Metbods
22 1
3 New Natural Carotenoids Acyclic Carotenoids Monocyclic Carotenoids Bicyclic Carotenoids Aromatic Carotenoids
226 226 228 229 230
...
Terpenoids.and Steroids
Vlll
Carotenoid Glycosides Car0tenoproteins
23 1 23 1
4 Carotenoid Chemistry
23 1
5 Degraded Carotenoids Retinol and Derivatives Other Degraded Carotenoids Model Cyclizations
234 234 238 245
6 Polyterpenoids and Quinones Polyterpenoids Isoprenylated Quinones
246 246 247
Chapter 7 Biosynthesis of Terpenoids and Steroids By 0.V. Banthorpe and B. V. Charlwood
250
1 Introduction
250
2 Acyclic Precursors
25 1
3 Hemiterpenoids
260
4 Monoterpenoids
260
5 Sesquiterpenoids
264
6 Diterpenoids
267
7 Sesterterpenoids
27 1
8 Steroidal Triterpenoids
272
9 Further Metabolism of Steroids
282
10 Non-steroidal Triterpenoids
287
11 Carotenoids
288
12 Meroterpenoids
29 1
13 Polyterpenoids
296
14 Methods
296
15 Reviews
298
Reviews o n Terpenoid Chemistry
30 1
ix
Contents
Part // Steroids
Chapter 1 Steroid Properties and Reactions By D. N. Kirk
31 1
1 Conformational Analysis, Stereochemistry, and Spectroscopic Methods Spectroscopic and Chiroptical Methods N.M.R. Spectroscopy Mass Spectra
31 1 312 313 314
2 Alcohols and their Derivatives, Halides, and Epoxides Substitution and Elimination Ring-opening of Epoxides Esters, Ethers, and Related Derivatives of Alcohols Oxidation and Reduction Miscellaneous
315 315 322 325 327 329
3 Unsaturated Compounds Addition Reactions Epoxidation Reduction Oxidation Aromatic Compounds Alkynes and Cyclopropanes
330 331 332 338 340 343 345
4 Carbonyl Compounds Ketones : Reactions at the Carbonyl Group Reactions involving Enols and Enolate Ions Enolic Derivatives, Enamines, and their Reactions Reactions involving Oximes, Hydrazones, and Related Derivatives Carboxylic Acids, their Derivatives, and Aldehydes
348 348 354 359
5 Compounds of Nitrogen and Sulphur
367
6 Molecular Rearrangements Contraction and Expansion of Steroid Rings Backbone Rearrangements Aromatization of Steroid Rings Miscellaneous Rearrangements
369 369 373 376 379
7 Functionalhation at Non-activated Positions
383
8 Photochemical Reactions
386
9 Miscellaneous
392
362 364
Terpenoids and Steroids
X
Chapter 2 Microbiological Reactions with Steroids By L. L. Smith
394
1 Introduction
394
2 Hydroxylation Reactions
395
3 Hydroxy-steroid-Oxo-steroid Interconversions
453
4 Dehydrogenationand the Reduction of Carbon-Carbon
Double Bonds
470
5 Olefinic Bond Isomerization
486
6 Esterase, Amidase, and Hydrolase Reactions
489
7 Reactions involving Heteroatoms
494
8 Steroid Degradation Reactions
497
9 MiscellaneousMicrobial Reactions
523
Chapter 3 Steroid Conformations from X - Ray Analysis Data By C. Romers, C. Altona, H. J. C. Jacobs, and R. A. G. de Graaff
53 1
1 Introduction
53 1
2 Presentation of Results
534
3 The Perhydro-1,kyclopentanophenanthreneSkeleton
534
4 The Geometry of Ring A in 3-Oxo-A4-steroids
548
5 The AS3'-System
558
6 The Conformation of Ring B in Oestranes and A5-Compounds
562
7 Five-membered (D) Rings
565
8 Six-membered Boat Conformations
570
9 The Conformation of the Side-chain at C-17
573
10 Biological Activity at the Molecular Level
576
11 summary
578
12 Appendix
578
Errata Author Index
584 585
Part I TERPENOIDS
1 Monoterpenoids ~~
BY A. F. THOMAS
This year, the section on general chemistry has been enlarged, and some reactions that are not specific to monoterpenoids have been included. Physical methods are given a separate section. Unfortunately it must be noted that Chemicd Abstracts contains an increasing number of errors, as well as frequently citing insufficient information for the abstract to be useful. So far as possible, attention has been drawn to these points in each individual case. The abstracts of the Proceedings of the 4th Congress on Essential Oils (Tbilisi, 1968) have appeared, but much of this work is now out of date. 1 Physical Measurements: Spectra etc., Chirality The 3C n.m.r. spectra of citronellol, citronellal, and related substances have been discussed,' and a study of the shifts of the alkene signals induced by Ag' in the I3C n.m.r. spectra of a number of substances including the pinenes has been made.2 A very full discussion of the effect of shift reagents on the 'H and 13C n.m.r. spectra of borneol and isoborneol has shown that the complexes formed with the reagents are effectively axially symmetric, the magnetic axis being practically collinear with the oxygen-metal bond ;3 an estimate of the contact contribution has been made.4 Coupling constants in 7,7-dimethylnorborneols have been examined using the [Eu(dpm),] shift agent.5 In a study of the U.V.spectra of the complexes between boron trifluoride and unsaturated ketones, monoterpenoids are particularly unlucky : piperitone (1) does not fit the attempted correlation, and carvone (2) polymerizes under the conditions of measurement !6 The mass spectra of monoterpenoids have been di~cussed,~ and the loss of EtCONH, in the mass spectrum of (3) (a retro-Ritter reaction) has given rise to
'
A. K. Bose and R. J. Brambilla, J . Agric. Food Chem., 1972, 20, 1013.
' C. D. M . Beverwijk and J. P. C. M. van Dongen, Tetrahedron Letters, 1972, 4271.
'
G. E. Hawkes, D. Leibfritz, D. W. Roberts, and J. D. Roberts, J. Amer. Chem. Soc., 1973,95, 1659. G. E. Hawkes, C. Marzin, S. R. Johns, and J . D. Roberts, J. Amer. Chem. SOC.,1973, 95, 1661. K.-T. Liu, Tetrahedron Letters, 1973, 2747. J. Torri and M. Azzaro, Tetrahedron Letters, 1973, 3251. M. Sakaguchi, A. Hirakata, and H . Yamada, Koryo, 1972, No. 102, p. 41 (Chem. A h . , 1973, 78, 84 555).
3
Terpenoids and Steroids
4
speculations, without the support of labelling studies.' The Raman 'circular dichroism' of a number of optically active monoterpenoids has been examined. Circular intensity differentials (CID), A, = I! - I,"/(lt + I,"), where I!, I," are the scattering intensities with a-polarization in right and left circularly polarized incident light, have been measured in the low-frequency Raman spectra of (+)and ( -)-a-pinene, ( - )-P-pinene, (-)-borneol, and carvone.' The circular differential Raman spectrum of carvone has been reported elsewhere. *
Me
(4)
Monoterpenoids are the most common of the chiral agents used for inducing asymmetry. Measurement of the n.m.r. spectra of esters 'of camphanic acid, such as (4),has been used to find the enantiomeric purity and absolute configuration of a-deuteriated primary alcohols,' and separations of various alcohols and amines using esters of chrysanthemic acid are reported.I2 An interesting mutual resolution can be effected with ( k )-camphorsulphonic acid and a-( k )Me2NCH,CHMeCPh(OH)CH2Ph.13 ( )-Carvomenthol and chloroacetic acid give carvomethylacetic acid (9,which is useful for resolving alanine.14 Mislow et al. have used menthyl methylphenylthioarsenite (6) in an extension to arsenic of their earlier method (see Vol. 2, p. 28) of making optically active phosphine oxides.' Probably the most interesting work taking advantage of the chirality of monoterpenoids has involved the attempts to induce asymmetry in organic
+
* lo
I' l2
l3 l4
l5
S. Blum and S. Sarel, J . Org. Chem., 1972, 37, 3121. L. D . Barron and A. D. Buckingham, J . C . S . Chem. Comm., 1973, 152. M. Diem, J . L. Fry, and D . F. Burrow, J . Amer. Chem. SOC.,1973, 95, 253. H. Gerlach and B. Zagalak, J.C.S. Chem. Comm., 1973, 274. C. J . W. Brooks, M. T. Gilbert, and J. D. Gilbert, Anafyt. Chem., 1973, 45, 896. W. E. Thompson and-A. Pohland, Ger. Offen. 2 230 838. F. Rulko, K. Witkiewicz, and Z. Chabudzinski, Diss. Pharm. Pharmacol., 1972, 24, 297. J. Stackhouse, R. J. Cook, and K. Mislow, J . Amer. Chem. SOC.,1973, 95, 953.
Mono terpenoids
5
Me
’0-c
‘.-
“OCOCH,CC02 Et
I
OH (7)
(8)
(9)
synthesis. As a simple example, the rate of esterification of D-amino-acids with (-)-menthol is greater than that of L-acids, and this has led to a proposal for menthyl ester formation.16 The anion (8), obtained when menthyl acetate (7) is metallated, reacts with ethyl pyruvate to yield the menthyl ester of (S)-citramalic acid (9) in 26 % optical yield.I7 Kergomard et a/. found no asymmetric induction in the reaction between styrene, t-butyl hypobromite, and menthol [leading to (lo)].’* Oxidation of (+)-borne01 with (R)-(+)-menthy1 p-tolyl sulphoxide and dicyclohexylcarbodi-imide in the presence of phosphoric acid in benzene gave (-)-camphor in 7 % optical yield, l 9 and the cyclization of homogeranic ( -)menthyl ester with stannic chloride to cis-tetrahydroactinidiolide(1 1) occurred with only ca. 12 % optical yield, although this rose to 20.8% when the 1,2:5,6-di0-isopropyhdene-or-D-glucofuranoseester was used.*O Asymmetric reductions of diphenylmethyl alkyl ketones by complexes of lithium aluminium hydride and cis-pinane-2,3-diol and benzyl alcohol gave up to 20% optical yields,*’ but far more successful was the reaction of ethylene and cyclo-octa-1,3-diene [to (12)], catalysed by certain n-ally1 complexes of nickel where one ligand is a monoterpenoid phosphine, in which 70 % optical purity was achieved.’
King and Sim have described a useful method for demonstrating the presence of a reactive intermediate in reactions involving chiral diastereomeric transition l6
‘’ l9 2o 21
’*
T. Hayakawa, H. Yamamoto, Y. Murakami, Y.Yobiko, and S. Mitani, Bull. Chem. SOC.Japan, 1972, 45, 3556; see also Vol. 3, p.6. S. Brandange, S. Josephson, and S. Valltn, Acta Chem. Scand., 1973, 27, 1084. G . Dauphin, A. Kergomard, and A. Scarset, Bull. SOC.chim. France 11, 1973, 1104. M. H. Benn, P. Christensen, D . Kjersgaard, and C. Watanatada, Canud. J . Chem., 1973,51, 1977. T. Kato, S. Kumazawa, and Y. Kitihara, Synthesis, 1972, 573. R. Haller and H. J. Schneider, Chem. Ber., 1973, 106, 1312. B. BogdanoviC, B. Henc, B. Meister, H. Pauling, and G. Wilke, Angew. Chem. Znrernar. Edn., 1972, 11, 1023.
6
Terpenoids and Steroids
states; it provided a new piece of evidence for the intermediacy of a sulphene in the reaction between camphor-10-sulphonyl chloride and menth~lamine.,~ The Reporter is ill-placed to criticize a chapter on the synthesis of monoterpenoids in a recently published book on the total synthesis of natural products.23” However, a delay of three years between the latest reference quoted and publication of a book is deplorable. 2 General Chemistry
Sukh Dev has reviewed alumina- and silica gel-induced rearrangements, many of which involve m o n ~ t e r p e n o i d s .The ~ ~ Prins reaction of monoterpenoid hydrocarbons has also been reviewed.2s Microwave discharge of carbon dioxide can function as a singlet oxygen source ;photo-oxygenation by this means has been accomplished using limonene and y-terpinene as substrates.26 A two-phase solvent system is useful for epoxidizing sensitive olefins (e.g.6-methylhept-5-en-2-one) with rn-chloroperbenzoic acid, but limonene gave the same epoxide in the same yield as with the single-phase system., Several novel methods for the reduction and oxidation of oxygenated terpenoids have appeared. Potassium metal in graphite can be used to reduce camphor (a 60:40 exo:endo mixture is obtained), and oxidations of primary alcohols are effected by chromic oxide in graphite (citronellol yields 90 % of the aldehyde in 24h),28 but the preparation of the reagent can be dangerous.,’ Potassium metal in hexamethylphosphoramide, with or without a co-solvent, has also been used to reduce terpenoid ketones; with camphor, more endoproduct is formed than in the potassium-graphite reduction.,’ Hindered saturated secondary alcohols are oxidized by 2,3-dichloro-5,6-dicyano-1,4-benzoquinone; thus borneol and isoborneol are 96% and 95% oxidized in 8 h and neoisomenthol (i.e.the all-cis-isomer) and neoisocarvomenthol are 48 % and 40% oxidized in the same time, whereas the all-equatorial alcohols menthol and carvomenthol are hardly affected in this time.31 Reduction of camphor with various silanes (Ph,SiH,, PhSiH,, PhMeSiH,, and Et,SiH,) in the presence of tris(tripheny1phosphine)chlororhodiumgives 73-90 % of isoborneol ( e m ) , but triethylsilane gives only 30 % of isoborneol and phenyldimethylsilane does not reduce. Analogous results were obtained for m e n t h ~ n e , ~but , pulegone (13) presented some irregularities, mixtures of menthone (14) and pulegol (15) being J . F. King and S. K . Sim, J . Amer. Chem. SOC., 1973, 95, 4448. ”‘A. F. Thomas, in ‘The Total Synthesis of Natural Products’, ed. J. W. ApSimon, Wiley, New York, 1973, Vol. 2, p. 1 . 2 4 Sukh Dev. J. Sci. Ind. Res., 1972, 31, 60. 2 s J . Chlebicki, Wiadomosci Chem., 1972, 26, 629. 26 K. Gollnick and G . Schade, Tetrahedron Letters, 1973, 857. ” W. K . Anderson and T. Veysoglu, J . Org. Chem., 1973, 38, 2267. 2 8 J.-M.. Lalancette, G. Rollin, and P. Dumas, Cunud. J . Chem., 1972, 50, 3058. 2 9 Communication from the manufacturers, Ventron Corp., Beverly, Mass. 3 0 M. Larcheveque and T. Cuvigny, Bull. SOC.chim. France I I , 1973, 1145. * J. Iwamura and N . Hirao, Tetrahedron Letters, 1973, 2447. 3 2 I . Ojima, M. Nihonyanagi, and Y . Nagai, Bull. Chem. SOC.Japan, 1972,45, 3722. ”
Mono terpeno ids
c
7
/
+
/
OSi -
OSi -
\
\
P
+
0
(15)
(14)
produced in different amounts depending on the reagent.33 The rate of MeerweinPonndorf reduction (propan-2-01-aluminium isopropoxide) for a variety of terpenoid ketones is unexpectedly high. The half-life of camphor, for example, (the slowest of those measured) was 145.8min at 82 0C.34Triphenyltin hydride reduces the conjugated double bond of unsaturated aldehydes ; thus citral gives citronellal, but in the case of /?-cyclocitral(16),the reaction works less specifically, leading to a 1:l mixture of the saturated aldehyde (17) and the unsaturated alcohol (18).3 H + ~ O
~
(16)
H
+
a~;"" O
(17)
(18)
4-Dimethylaminopyridine is a useful catalyst in acylations ; an 80 % yield of linalyl acetate can be obtained (without rearrangement-see Vol. 3, p. 15) with its aid, using triethylamine as solvent and (presumably, for it is omitted from the experimental details!) acetic anhydride at room temperature for 14 h. Only catalytic amounts are needed, as was demonstrated by the preparation of menthyl m ~ n o p h t h a l a t e . ~Reaction ~ of aminomethylene ketones with 4-aminouracil (19; X = 0),the thio-analogue (20;X = S), or 2,4-diamino-6-hydroxypyrimidine (the enolized imino-analogue), yields '5-deazapteridines' ; those corresponding to menthone (20)and camphor (21) have been reported37 (see Vol. 3, p. 42).
(19) 33 34
3s
36 37
(20) X = 0,S, or NH
(21) X = S or NH
I. Ojima, T. Kogure, and Y. Nagai, Tetrahedron Letters, 1972, 5035. V. Hach, J . Org. Chem., 1973,38, 293. H. R. Wolf and M. P. Zink, Helv. Chim. Acta, 1973, 56, 1062. G. Hofle and W. Steglich, Synthesis, 1972, 619. E. Stark and E. Breitmaier, Tetrahedron, 1973, 29, 2209.
8
Terpenoids and Steroids
The preparation of monoterpenoid aldehydes from ketones (R,CHCHO in place of R,C=O) using the Grignard reagent EtOCH,MgCl is discussed.38 The Kondakov reaction is the reaction of crotonic anhydride with an olefin in the presence of zinc chloride. A number of monoterpenoid hydrocarbons react at their trisubstituted double bonds ; thus 2,6-dimethylocta-2,7-dienegives the ketone (22), car-3-ene gives (23), and menth-1-ene gives both cis- and transisomers.39 Double bonds react with chlorosulphonyl isocyanate to give compounds containing a four-membered heterocyclic ring ; camphene yields (24), and the products from a- and p-pinene and car-3-ene have also been de~cribed.~'
The reaction of vinylmagnesium bromide with unsaturated esters gives the corresponding divinylcarbinol ; ethyl mentha- 1,8-diene-7-carboxylate and ethyl pin-2-en-10-carboxylate have been treated in this way.41 A convenient method for the separation of terpenoid alcohols from mixtuies via the carbarnates is described.
3 Biogenesis, Occurrence, and Biological Activity A brief section on monoterpenoids is included in a review of biogenetic-like syntheses of t e r p e n ~ i d s .For ~ ~ the biosynthesis of monoterpenoids see Section 4 of Chapter 7, p. 260. Granger and Passet have carried out a chemotaxonomic study on Thymus uulgaris, L.44 This plant gives very diverse essential oils, and analysis of the monoterpenoids permits the assignment of a plant to its chemotype. Somewhat ~ of Juniperus similar is the approach of Banthorpe et aE. in an e ~ a m i n a t i o nof~oils and Thuja species. The juniper leaf oils consist of two types characterized by the presence of either predominantly pinene derivatives or thujane derivatives. 38
3y
40
41
42
43 44
45
M . de Botton, Bull. SOC.chim. France Ii, 1973, 2472. E. Klein and W. Rojahn, Dragoco Ber., 1972, 19,239; further examples of this reaction are in E. Klein, Ger. Offen., 2 120413 [Chem. Abs., 1973, 78, 84 555 has formula (22) incorrect]. T. Sasaki, S. Eguchi, and H. Yamada, J . Org. Chem., 1973,38, 679. S. Watanabe, K. Suga, and T. Fujita, Israel J . Chem., 1973, 11, 71. R. C . Gueldner, F. Y. Hutto, A. C. Thompson, and P. A. Hedin, Analyt. Chem., 973, 45, 376. T. Money, Progr. Org. Chem., 1973, 8, 29. R. Granger and J. Passet, Phytochemistry, 1973, 12, 1683. D. V. Banthorpe, H. ff. S . Davies, C . Gatford, and S . R. Williams, Plunta Med., 973, 23, 64.
Mono terpeno ids
9
Blue spruce (Picea pungens) can be identified by analysis of the cortical oleoresin m o n ~ t e r p e n o i d s . The ~ ~ genesis of monoterpenoids in the wood of common Russian conifers has been followed by direct analy~is.~’ Attention is drawn to the remarks on straightforward chemical analysis of plant and animal material made in Volume 3 (p. 8). Among analyses that are of interest for the monoterpenoid chemist are the following : Carphephorus odoratissimus (‘deertongue’, a tobacco additive),48 Cinnamomum reticulatum from Taiwan [containing a remarkable 96.8 % of ( - ) - l i n a l ~ o l ] , ~Crocus ~ s~tivus,’~ PassijZora edulis f. Jlauicarpa (passion fruit),’ Pelargonium tomentosum C86.9% ( - )-isomenthone, for which various possible stereochemical biogenetic routes and Pogostemon plectr~ntoides?~ are discussed],’ various Pinus spp. needle A very complete analysis of certain fractions of burley tobacco has given a plethora of substances, including many 1,1,3-trimethyl- and 1,1,2,3-tetramethyl-hexane derivatives and the novel isoprenoid (25).”
Secretions from the endocrine glands of staphylinid beetles, Bledius mandibularis and B. spectabilis, contain small amounts of citral and nera1.56 The full papers describing the preparation of the hypoglycaemically active arylsulphonylureido- and arylsulphonylamido-acyl derivatives of borneol and isoborneol (see Vol. 2, p. 7) have a ~ p e a r e d . ’ ~ Details of the preparation of the juvenile hormone compounds mentioned in Vol. 3, p. 10 have been p~blished,’~ and some more geranylanilines (with heterocyclic substituents in the aromatic
46
41
48 49 50
51
52 53
54
55 56
51
58
B. A. Rottink and J. W. Hanover, Phytochemistry, 1972, 11, 3255. Yu. A. Poltavchenko and G. A. Rudakov, Izvest. Nauch.-Issled. I n s t . Nefte-Uglekhim. Sin. Irkutsk. Univ., 1969, I 1 (part l), 39 (Chem. Abs., 1973, 78, 2056). K. Karlsson, I. Wahlberg, and C. R. Enzell, Acta Chem. Scand., 1972, 26,2837. Y. Fujita and S. Fujita, Bull. Chem. SOC.Japan, 1972, 45, 1243. A. I. Akhmedov, M . I. Goryaev, Sh. K. Chogovadze, and A. D . Dembitskii, Izoest. Akad. Nauk kaz. S.S.R., Ser. khim., 1972, 22, 56; see also the section on trimethylhexanes. M. Winter and R. Kloti, Helv. Chim. Acta, 1972, 55, 1916. F. W. Hefendehl, Planta Med., 1972, 22, 378. N . M. Joye, jun., A. T. Proveaux, and R. V. Lawrence, J . Chromatog. Sci., 1972, 10, 590. S. S. Nigam and M. Ramaiah, Riechstofle, Aromen, Korperpjlegem., 1972, 22, 378 el seq. E. Demole and D. Berthet, Helv. Chim. Acta, 1972, 55, 1866, 1898. J. W. Wheeler, G. M. Happ, J. Araujo, and J. M. Pasteels, Tetrahedron Letters, 1972, 4635. H. Bretschneider, K. Hohenlohe-Oehringen, and K. Grassmayr, Monarsh., 1972, 103, 1523; K. Hohenlohe-Oehringen, ibid., p. 1531 ; K. Hohenlohe-Oehringen, K. zur Nedden, and H. Bretschneider, ibid., p. 1534. C.-F. Chang and S. Tamura, Agric. and Biol. Chem. (Japan), 1972, 36, 2405.
10
Terpenoids and Steroids
part of the molecule) having juvenile hormone activity have been made.59 The section on chrysanthemic acid includes other compounds having juvenile hormone activity. Isobornyl chloroformate (26; R = COC1) is prepared from isoborneol and phosgene, and can be used as a protecting group for amino-acids which is removed by trifluoroacetic acid.60 Combined with propylenediamines, the amines (26 ; R = CONHCH,CH,CH,NR’R2) can be made which have local anaesthetic properties.6 I
0,’””
4 Acyclic Monoterpenoids
Terpene Synthesis from Isoprene.-The oligomerization of isoprene catalysed by nickel naphthenate and isoprenemagnesium in the presence of various phosphites as electron donors, known to give cyclic dimers (see Vol. 3, p. 12), has been reexamined.62 Oligomerization with cobalt chloride, sodium borohydride, and tripenylphosphine gives (27)as the main product when the ratio Ph,P :CoC1, < 1, but when this ratio is > 1 the tail-to-tail linked isoprenoid (28) and the 2,6-dimethyloctatriene (29) are the main products.63 Telomerization of isoprene by hydrogen chloride in the presence of stannic chloride is reported.64 Anionic telomerization with secondary amines in the presence of alkali-metal catalysts yields dimers having as their main components the ‘lavandulyl’ (30) and the ‘geranyl’ (31) structure^.^^ A similar report elsewhere66contains what appears
(27) 59
6o
61
62
6.3 64
65
“
(28)
(30)
(31)
Z . Arnold, J. Kahovcova, M. Pankova, M . Svoboda, M . Tichy, and F. Sorm, Coll. Czech. Chem. Comm., 1973, 38, 261; J. Kahovcova, Z. Arnold, and F. Sorm, ibid. p. 1165. M. Fujino, S. Shinagawa, 0. Nishimura, and T. Fukuda, Chem. and Pharm. B U N . (Japan), 1972, 20, 1017. G. Jaeger, R. Geiger, and R. Muschaweck, Ger. Often. 2 102 741. K. Suga, S . Watanabe, T. Fujita, and T. Shimada, J . Appl. Chem. Biotechnol., 1973, 23, 131. K. Takabe, K. Uata, T. Katagiri, and J. Tanaka, Nippon Kagaku Kaishi, 1972, 1695. K . Laats, T. Kaal, I. Kalja, I. B. Kudryavtsev, E. Miks, M . Tali, S . Teng, and A. Erm, Eesti N . S . V . Teadirste Akad. Toimetised, Keem., Grol., 1972, 21, 305; K. Laats and S . Teng, ibid., p. 314 (Chem. Abs., 1973, 7 8 , 97 819 is probably faulty). K. Takabe, T. Katagiri, and J. Tanaka, Tetrahedron Letters, 1972, 4009; Bull. Chem. SOC.Japan, 1973,46,218, 222. T . Fujita, K. Suga, and S . Watanabe, Chem. and Ind., 1973, 231.
Mono terpeno ids
11
to be the incorrect structure for geranyldiethylamine. The isoprene hydrochloride dimer [(32) or (33)j can be reduced with magnesium in tetrahydrofuran containing ethyl bromide ; treatment of the mixture with dry oxygen then yields lavandulol(34) and its isomers in >40% yield.67 The ‘regular’ geranyl skeleton is produced when isoprene is allowed to react with alcohols over a PdC1,-PhCN catalyst together with triphenylphosphine and sodium alkoxide. The main ethers thus formed have the skeleton (35).@‘ The geranyl triene (36)is also the main com-
ponent of the complex mixture obtained by treating isoprene and phenol with a sodium phenate-[PdBr,L,] (L = Ph,PCH,CH,PPh,) catalyst, the amount of phenol determining the composition of the mixture of produ~ts.~’With sodium hydride at 40°C under pressure isoprene yields myrcene (37) and the trimer (38).’* Hydrative dimerization of isoprene using a cation-exchange resin catalyst is described,71 and a review (in Japanese) on the oligomerization catalysed by lithium naphthalene has appeared.’,
e:
I:‘yMe Dienes react with B-keto-esters in the presence of P-phenyl-l-phospha-3methylcyclopent-3-ene and palladium chloride, and the addition product (39) from isoprene and methyl acetoacetate can be readily converted into methylheptenone (40).73
2,6-Dimethyloctanes.-The isovalerate of dehydronerol (41) has been isolated from the roots of Anthemis montana, L. ; this is the first report of a dehydronerol 67
68
69 ’O
”
’* 73
T. Kaal and K. Laats, Eesti N . S . V . Teaduste Akad. Toimetised, Kecm., Geol., 1973, 22, 180 (Chem. Abs., 1973,79, 32 133). W. Hoffmann, F. J. Muller, and K. von Fraunberg, Ger. Offen. 2 154 370. K. Takahashi, G. Hata, and A. Miyake, Bull. Chem. SOC.Japan, 1973,46, 2600. K. Takabe, T. Katagiri, and J. Tanaka, Bull. Chem. SOC.Japan, 1972, 45, 2662. T. Katagiri, 0. Nakachi, T. Suzuki, K. Takabe, and J . Tanaka, Bull. Inst. Chem. Res., Kyoto Univ., 1972, SO, 363. K. Suga, S. Watanabe, andT. Fujita, Koryo, 1972, N o . 102, p. 19. S. Watanabe, K. Suga, andT. Fujita, Canad. J . Chem., 1973, 51, 848.
12
Terpenoids and Steroids
derivative in nature.74 The digestive gland of the sea hare, Aplysia californica, contains brominated and chlorinated monoterpenoids characterized by the presence of a terminal vinyl bromide group, e.g. (42) and (43). These compounds and other halogenated monoterpenoids have been found in the red algae, Plocarniurn coccineum, on which the sea hare is known to graze.75The structure of one compound (44)has been fully established by X-ray d i f f r a ~ t i o n .The ~~ p
.
B
r
/
y Br
Br
0
/
Br
c T l \ Br
\
c1
CI
c1 (42)
(41)
CHBr,
’*
*
CHBrz
(44)
(43)
three trienes (49, (46), and (47) have been isolated from Ledum p a l ~ s t r e ; ~ ~ one of them (46)has been previously identified in Pinus p o n d e r ~ s a A . ~nylnber ~ of
(47)
(46)
(45)
cppx$
bifunctional carbonyl compounds (48)-(53) have been isolated from lavandin oil. They all [excepting the aldehyde acetate (48)] can be obtained by the photooxygenation of linalyl acetate, and, apart from (48), they may well be artefact^.^'
OH CHO (481
\
‘0 (49)
(50)
(51)
(52)
(53)
An attempt to prepare photochemically mixtures of allo-ocimenes (54) with exclusive 2-configuration about the central double bond [(54a), (54b)l failed l4 ’5 ’6
”
’13
l9
F. Bohlmann and H. Kapteyn, Tetrahedron Letters, 1973, 2065. D. J . Faulkner and M. 0. Stallard, Tetrahedron Letters, 1973, 1171. D. J. Faulkner, M. 0. Stallard, J. Fayos, and J. Clardy, J . Amer. Chem. SOC.,1973, 95, 3413. M . von Schantz, K.-G. Widen, and R. Hiltunen, Acta Chem. Scand., 1973, 27, 551. R. M. Silverstein, J. 0. Rodin, D. L. Wood, and L. E. Browne, Tetrahedron, 1966, 22, 1929. B. D. Mookherjee and R. W. Trenkle, J . Agric. Food Chem., 1973, 21, 298.
Mono terpeno ids
13
with a variety of sensitizers, although some enrichment was noted.80 Vig et al. have synthesized myrcene (37) from the known ester ( 5 5 ; R = C0,Et) via the corresponding aldehyde (55 ; R = CHO),by a vinyl Grignard reaction, oxidation, and Wittig reaction.81 The pyrolytic conversion of a-pinene into allo-ocimene (54) is well known ;in order to trap the intermediate ocimene, it is necessary to cool the pyrolysate very rapidly.82
(54)
(55)
One method used to introduce oxygen into terpenoid hydrocarbons is by direct, acid-catalysed addition of water. With myrcene, water addition in the presence of Amberlite IR-120 gives a complex reaction mixture, consisting mostly of cyclized components; the hydrated products are mainly 1,8-cineol(56), mentha-1(7),2-dien-8-01 (57), and 2,6-dimethylocta-5,7-dien-2-01 (58).83 Acidcatalysed addition of acetic acid to ( + )-2,6-dimethylocta-2,7-diene [( + )-(59)] gives the tertiary acetate (60) initially, but refluxing for 6-43 h causes stereospecific cyclization to (61),together with formation of the two tetrahydroeucarvols (62).84 The rhodium(rI1) chloride-catalysed addition of ethanol to myrcene (37)
QoAc
'' 82 83 84
V. Ramamurthy, Y. Butt, C. Yang, P. Yang, and R. S. H. Liu, J. Org. Chem., 1973, 38, 1241. 0.P.Vig, M. S. Bhatia, A. S. Dhindsa, and 0. P. Chugb, IndianJ. Chem., 1973,11, 104. G. Rice and J. F. Pollock, U.S.P. 3 714 283. J. Tanaka, T. Katagiri, K. Takabe, and 0. Nakachi, Nippon Kagaku Kaishi, 1972, 1203. H. R. Ansari, Tetrahedron, 1973,29, 1559.
Terpenoids and Steroids
14
leads to oligomerization and isomerization, together with a mixture of the ethyl ethers [(63), (64),(65), and (66)] but none of the derivatives corresponding to those from the palladium-catalysed addition of methanol (see Vol. 2, p. 10).
Addition of acetic acid was also studied, but the mixture of acetates is more complex. Copper salts were less effective catalyst^.^^ Rienacker has used the octadienol ( - )-(59) and its antipode to make a-citronellol(67) by initially isomerizing the double bond to the terminal position (68),then hydroxyalumination, followed by oxygenation (air) and hydrolysis. Some of the isomer (69) is also formed.86
(-
1459)
-
p-r+F
A preliminary note has described the interesting double photo-oxygenation of 2,6-dimethylocta-2,6-diene (70) ; after reduction, two glycols [(71) and (72)] were obtained.87 OH
(70)
(71)
(72)
A new, mild method for making ally1 alcohols from epoxides has been applied to myrcene epoxide (73),thereby synthesizing the natural product (E)-2-methyl6-methyleneocta-3,7-dien-2-01(46) (Scheme 1). Other methods of base-catalysed epoxide-ring opening yield products resulting from attack on the methyl proton.88 85
86
88
R . J. H. Duprey, W . D . Fordham. J. F. Janes, D. V. Banthorpe, and M. R. Young, Chem. and Ind., 1973, 847. For comments on the unsatisfactory name ‘rhodinol’ used here, see ref. 230, p. 15. R. Rienacker, Chimia ( S w i t z . ) , 1973, 27, 97. J. Chaineaux and C. Tanielian, L’ActualirP chimique, 1973, 88. K. B. Sharpless and R . F. Lauer, J . Amer. Chem. Soc., 1973. 95, 2697.
Monot erpenoids
$ (73)
15
1L
Gh
-
(46)
LIH$OH] 0's
Ph
Reagents: i, Ph,Se, in abs. EtOH, then NaBH,; ii, H 2 0 2 .
Scheme 1
The ally1 mesitoate coupling reaction (see Vol. 3, p. 18)has been used to make the pheromone (74) of Ips confusus, and although the yield was only 10% using
lithium in tetrahydrofuran it rose to 52% when the lithium was replaced by zinc.89 Hotrienol (75) has been made from methylheptenone as in Scheme 2."
Reagents: i, KMnO,; ii, Pb(OAc),; iii, Ph,P=CHCMe=CH,;
iv, HC1; v, CH,=CHMgBr.
Scheme 2
Although circuitous, this type of route could be useful for isotopic labelling. Geranic acid (76), together with a small amount of lavandulic acid isomers (77), has been made by condensing prenyl bromide with an ethyl tiglate activated at the terminal methyl group by the presence of a phenylsulphone group (Scheme 3).'l Synthesis of the 2$-dimethyloctane system has also been achieved by reaction of methylmagnesium bromide with cyclopropylmethyl ketone and 89 90
9L
J. A. Katzenellenbogen and R. S. Lenox, J. Org. Chem., 1973, 38, 326. 0. P. Vig, J. Chander, and B. Ram, J. Indian Chem. SOC., 1972, 49, 793. M. Julia and D. Arnould, Bull. SOC.chim. France II, 1973, 743.
Terpenoids and Steroids
16
\
+
SO,Ph
1"
+Co2Et \
U
C
0
,
E
t
+SO,Ph C0,Et
++
C0,Et (76)
(77)
Reagents: i, KOBu'; ii, Na-Hg.
Scheme 3
condensation of the resulting bromide (78; X = Br) with methylated ethyl acetoacetate. Hydrolysis gave 'P-elgenone' (79).92 C0,Et
P C O M e
MeMgBr)
LcH,x UCO MeCO!;C02;I
1
(78)
U
C
O
M
,
(79)
A new synthesis of ally1 alcohols has been employed in the preparation of geraniol (80). The anion from the sulphoxide (81) reacts with alkyl halides, in particular with the iodide (78 ; X = I), to yield a derivative of the linalool type (82), which undergoes a [2,3] sigmatropic rearrangement to yield a 9 : 1 mixture of geraniol(80) and n e r 0 1 . ~The ~ stereoselectivity is reported to be high compared with other [2,3] rearrangements of this kind. (Further sigmatropic rearrangements in the 2,6-dimethyloctane series are discussed below.)
92
93
J . Kulesza and J . Gora, Mezhdunar 4th Kongr. Efirnym. Maslam, 1968 (published 1971), p. 48 (Chem. Abs., 1973, 78, 124 722 is incorrect; the synthesis described leads to a product lacking a methyl group). D. A. Evans, G . C. Andrews, T. T. Fujimoto, and D. Wells, Tetrahedron Letrers, 1973, 1385, 1389.
Monoterpenoids
17
The reduction of citral or citronella1 to the corresponding alcohols has been further examined. A culture medium or cell suspension of various microorganisms reduces (+)-citronella1 to a mixture containing 82 % of (-)-citronello1 and 18 % of ( + ) - c i t r ~ n e l l o l .Citral ~ ~ is reduced ‘quantitatively’at the aldehyde group (without attack on the conjugated double bond) by hydrogen over an iridium ~atalyst,~’and continuous hydrogenation of citral to citronellol, geraniol, and nerol has been de~cribed.’~ The deamination of geranylamine (31 ; R = H) and nerylamine has been compared with the hydrolysis of the corresponding chlorides, phosphates, and pyrophosphates ; the deamination reaction gives less cyclization in the case of the neryl compounds and less isomerization to linalyl compounds in the case of geranylamine.
’
NMe,
a
CH,SH NaOH-MeOH
There is little novelty in the discovery that geranyl dimethylthiocarbamate (83) rearranges on heating to linalyl dimethylthiocarbamate (84) or that the latter gives exclusively geraniol thiol (85) with methanolic base, linalol thiol requiring lithium aluminium hydride reducti~n.’~A mixture of digeranyl selenide and digeranyl diselenide (86) is formed when geranyl chloride reacts with sodium sulphide. The diselenide (86), on treatment with triphenylphosphine, has been found to undergo a [2,3] sigmatropic rearrangement [to geranyl linalyl selenide (87)] more rapidly than the analogous disulphide. The action of hydrogen peroxide on either the mono- or the di-selenide should lead to the selenic acid (88), but this rearranges directly, since only linalool (89) is obtained from this reaction.” (+)-Citronella1 can be converted into its dihydro-compound (go), whose methylation (uia the enamine) leads to 2,3,7-trimethyloctanal (91). The corresponding amine (92) on treatment with nitrous acid leads to various products (by migration of bonds a, b, or c). Migration of bond a gives the alcohol (93) (the formula of which is misprinted in the publication) without loss of optical 94
95
96
91 98
99
Takasago Perfumery Co., Jap. P. 16 191/1973. E. N. Bakhanova, A. S. Astakhova, Kh. A. Brikenshtein, V. G. Dorokhov, V. I. Savchenko, and M. L. Khidekel’, Izvest. Akad. Nauk S.S.S.R., Ser. khim., 1972, 1993. M. M. Paulose, A. J. Pantulu, K. V. Raghavan, and K . T. Achaya, Res. Ind. (New Delhi), 1972, 17, 1 1 . C. A. Bunton, D . L. Hachey, and J.-P. Leresche, J . Org. Chem., 1972, 37, 4036. R. E. Hackler and T. W. Balko, J . Org. Chem., 1973, 38, 2106. Closely similar work, together with relevant literature, unquoted by Hackler and Balko, may be found in V. Rautenstrauch, Helv. Chim. Acra, 1971, 54, 739. K. B. Sharpless and R. F. Lauer, J . Org. Chem., 1972,37, 3973; J . Amer. Chem. Soc., 1972,94,7 154.
Terpenoids and Steroids
18
(89)
(88)
activity, as shown by preparation of the ketone (94) from the alcohol (93) and from oxidation of the Grignard product of dihydrocitronellal(90). The retention of optical activity shows that partial bonding must exist during the migration of bond a.'" H LW
oxirne
QOMe
A (94)
A.
(93)
Oxidation of ( - )-(R)-dihydrolinalool (95) with potassium permanganate leads to a lactone (96), which has been used to prepare (-)-(S)-4-methylhexane1,4-diol (97).' O' Oxymercuration of geraniol results in cyclization to the tetrahydrofurans (100) (98) and (99), and oxymercuration of 2-methyl-6-methyleneoct-7-en-2-01 also gives cyclized products (101) and (102).'02 loo
lo' lo*
T. Shono, K. Fujita, and S . Kumai, Tetrahedron Letters, 1973, 3123. J . Jacobus, J . O r g . Chem., 1973, 38, 402. G . Brieger and E. P. Burrows, J . Agric. Food Chem., 1972, 20, 1010.
Mono t erpenoids
19 HO
Cyclization of cironellal and related substances is treated in the section on p-ment hanes. Artemisyl, Santolinyl, Lavandulyl, and Chrysanthemyl Derivatives.-An excellent review of this series, especially regarding the important biogenetic considerations, has been published by Epstein and P ~ u l t e r . " ~In this it is implied that 'isoartemisia ketone' [i.e. the unconjugated isomer (103)] is a natural product, but there is, in fact, no proof of this.'04 The similarity-between chrysanthemic acid (104) and presqualene alcohol also extends to their absolute configurations, which, contrary to earlier reports, are the same, i.e. R,R.loS The lavandulyl acetate aldehyde (105) has been identified in lavandin and a new santolinyl ester (106) in Artemisia tridentada.'06
Io3
lo4
lo'
Io6
W. W. Epstein and C. D. Poulter, Phytochemislry, 1973, 12, 737. There is also some confusion in other reviews about artemisia and isoartemisia ketone; see, e.g. D. V. Banthorpe, B. V. Charlwood, and M. J. 0. Francis, Chem. Rev., 1972, 72, 101. Much of this confusion arises because literature published prior to 1957 named the natural product, i.e. the conjugated ketone, 'isoartemisia ketone'. G. Popjak, J. Edmond, and S.-M. Wong, J. Amer. Chem. SOC.,1973,95, 2713. W. W. Epstein and J. Shaw, 166th A.C.S. Meeting, August, 1973, Abstracts AGFD, No. 5 5 .
20
Terpenoids and Steroids
Feeding experiments of labelled mevalonic acid to Chrysanthemum cinerariaefoliurn have been carried out, and preliminary analysis of the results indicates that the chrysanthemic acid (104) isolated is labelled only in the cyclopropane half of the molecule (see also the similar result with artemisia ketone, Vol. 2, p. 13).'07 The formation of the dicarboxylic acid, pyrethric acid, was shown to occur by oxidation of the chrysanthemic acid.'08
Rautenstrauch has extended earlier work on the sigmatropic rearrangements of dimethylallyl ethers and has shown that the corresponding quaternary ammonium salts (107)rearrange at - 73 "Cwith sodium amide in liquid ammonia, giving 80 % of the artemisia skeleton (108),together with some of the head-to-head and tail-to-tail linked isomers.'09 BogdanoviC has obtained both citral (109) and lavandulal (110) by reaction of prenyl bromide with the anion (111); the proportion of the products depends on solvent, ether favouring (110) and tetrahydrofuran favouring (109).1'0 Reaction of the precursor (112) of the anion (1 11) with the phosphorane (113)' yields, after hydrolysis, chrysanthemyl aldehyde ( 1 14) (Scheme 4). A new synthesis of yomogi alcohol (115) consists of addition of the lithium salt of 3,3-dimethylpent-l-en-4-yne(1 16) to acetone and reduction of the resulting acetylenic alcohol (117) with lithium aluminium hydride." The mass spectra of the pyrethrins [including that of chrysanthemic acid i104) and pyrethric acid (118)] have been discussed. All the derivatives of chrysanthemic acid, as well as the acid itself, produce a fragment at m/e 123,corresponding to the ion (119).' l 3 The lanthanide-shifted 'H n.m.r. spectra of chrysanthemic The absolute configuration esters and alcohols have also been discussed.' of the cyclopropane part of the natural pyrethrins was already known ; now an X-ray study of the six pyrethrins has established the absolute configuration of the whole molecules.'
''
'
'
lo' Io8
'09 lo
I I I
'I3 II4
I
G . Pattenden and R. Storer, Tetrahedron Letters, 1973, 3473. S. Abou-Donia, C. F. Doherty, and G. Pattenden, Tetrahedron Letters, 1973, 3477. V. Rautenstrauch, Helo. Chim. Acta, 1972, 55, 2233. B. Bogdanovic, personal communication. B. Bogdanovic and S. KonstantinoviC, Synthesis, 1972, 481. A. W. Burgstahler and H. W. Kroeger, Synth. Comm., 1973, 3, 21 I. G. Pattenden, L. Crombie, and P. Hemesley, Org. Mass Spectrometry, 1973, 7 , 719. L. Crombie, D. A. R. Findley, and D. A. Whiting, Tetrahedron Letters, 1972, 4027; T. Sugiyama, A. Kobayashi, and K. Yamashita, Agric. and Biol. Chem. (Japan), 1973, 37, 1497. M. J. Begley, L. Crombie, D. J. Simmonds, and D. A. Whiting, J . C . S . Chem. Comm., 1972, 1276.
Monoterpenoids
21
1 %CHO
U
C
H
O
Reagents: i, Bui,AIH; ii, LiNEt,; iii, Me,C=CHCH,Br; iv, H,O.
Scheme 4
Terpenoids and Steroids
22
Certain chrysanthemic phenyl esters carrying a methyl ester group in the p position (120) possess juvenile hormone activity in the pyrrhocorid bug (Dysdercus) only.'16 Because the main point of metabolic attack in both insects and mammals is on the E-methyl group of the isobutenyl side-chain of the chrysanthemates, Elliott et al. prepared pyrethrins where this group was not present, some of which (notably one with a butadienyl side-chain in place of isobutenyl) were much more potent insecticides,as well as being less toxic to mammals.'" Other modifications to pyrethrins to evaluate insecticidal activity have been made. l 8 Synthetic work in the chrysanthemic acid field includes the publication in full of the Glasgow synthesis (see Vol. 2, p. 14).11' A one-pot method for converting dihydrochrysanthemolactone (121) into ethyl cis-chrysanthemate with acidic ethanol, removing the water with molecular sieves or azeotropically, has been described.' 2 o Pyrolysis of pyrethrin-I (122) at 400°C yields chrysanthemic acid (104) and pyrocin (123),in addition to a hydrindanone (124) from the non-isoprenoid part of the molecule.
HA+
oco
-+ (104)
+
+ 0 (123)
(124)
Sugiyama et al. have published further work on the synthesis of allethrin metabolites (see Vol. 3, p. 23), in connection with the detoxication process.'22 5 Monocyclic Monoterpenoids
Cyc1obutane.-A monocyclic cyclobutane monoterpenoid (125) (not a conventionally head-to-tail linked isoprenoid) has been isolated from Juniperus
11'
11*
'I9 lZo
I2l 122
N . Punja, C. N. E. Ruscoe, and C. Treadgold, Nature New Biol.,1973, 242, 94. These authors d o not consider chrysanthemic acid derivatives to be terpenoid; neither does a reporter in Nature, 1973, 242, 159! In compensation Chemical Abstracts persistently classes compounds of the jasmone type (i.e. related to the non-isoprenoid part of the pyrethrins) as terpenoid! M. Elliott, A. W. Farnham, N. F. James, P. H. Needham, and D. A. Pulman, Nature, 1973, 244, 456. K. Sota, T. Amano, M. Aida, A. Hayashi, and I. Tanaka, Agric. and Biol. Chem. (Japan), 1973, 37, 1019. R. W. Mills, R. D. H. Murray, and R . A. Raphael, J . C . S . Perkin I , 1973, 133. A. Higo, N. Itaya, H. Hirai, and H. Yoshioka, Ger. Offen. 2 159 882. The preparation of the lactone and its conversion into chrysanthemic acid is described by H . Yoshioka, M. Matsui, Y. Yamada, and H. Sakimoto, Ind. Chim. (Bruxelles), 32 (Special number), Comptes rendus 36kme Congr. Internat. de Chimie Industrielle, 1967, Vol. 111, p. 890. Y. Nakada, Y. Yura, and K. Murayama, Bull. Chem. SOC. Japan, 1972,45,2243. T . Sugiyama, A. Kobayashi, K. Yamashita, and T. Suzuki, Agric. and Biol. Chem. (Japan), 1972.36, 2275.
Mono terpenoids
23
communis oil and synthesized from caryophyllene.’ 23 This substance (‘junionone’) is clearly derivable from a pinene skeleton. A stereoisomer of grandisol (126), called ‘fragranol’, with trans-substitution on the cyclobutane ring, has been isolated from Artemisia fragrens. A new synthesis of grandisol (126) constructs the cyclobutane ring by the dimerization of isoprene on a catalyst of bis-(1,5-cyclo-octadiene)nickeland tris-(2-biphenylyl) phosphite. The cyclobutane (127) formed (in 12-1 5 % yield, together with other compounds), was hydroborated with disiamylborane and alkaline peroxide then gave the monoterpenoid (126). 2 5 Mention is also made of a synthesis of (126) from P-pinene,’26 and another from eu~arvone,’~’ but details are not yet available.
& l
+ Isoprene-[Ni(cod),] TBP
1
i, (Siaj,BH-THF, 0 “C ii, H,O,-OH-
Cyclopentanes, including 1ridoids.-An account of work on the biosynthesis of iridoid and secoiridoid glucosides, and other aspects of iridoids, that was presented at the First International Congress of Pharmacognosy and Phytochemistry has appeared in print.’** A new cyclopentane terpenoid (25) from tobacco has been mentioned above.55
124
12’
28
A. F. Thomas and M. Ozainne, J.C.S. Chem. Comm., 1973, 746. F. Bohlmann, C. Zdero, and U. Faass, Chem. Ber., 1973, 106, 2904. W. E. Billups, J. H. Cross, and C. V. Smith, J. Amer. Chem. SOC., 1973, 95, 3438. P. D. Magnus, N. Bosworth, and P. D. Hobbs, 166th A.C.S. Meeting, August, 1973, Abstracts A G F D , No. 12. W. A. Ayer and L. M. Browne, 166th A.C.S. Meeting, August, 1973, Abstracts A G F D , No. 41. H. Inouye, in ‘1st International Congress o n Pharmacognosy and Phytochemistry’, ed. H. Wagner and L. Horhammer, Springer-Verlag, Berlin, 1971, p. 290; P. W. Thies, ibid., p. 41.
Terpenoids and Steroids
24
From Mentzelia decapetala, mentzeloside (128)"' and decaloside ( 129)130 are reported. H
(128) Glu
= P-glucose
(129)
Two biosynthetic studies are reported : the first deals with the incorporation of
4C02 into cispans-nepetalactone in Nepeta cataria.' 31 The other concerns the biogenetic route to genepin (130) in Genipa arnericana, and supports Inouye's postulate132 of the intermediacy of geniposidic acid (131) in the biosynthesis of iridoid glucosides having a hydroxylated C-10 group, the glucoside then being converted into the aglucone by methylation and deglu~osylation.'~~
(132) R = CH,CHMe,
(133)
Alcoholysis of didrovaltratum (132), isolated from Valerianu wallichii, in the presence of one equivalent of a hydrogen halide, HX, leads to compounds with the structure (133).'34 There is not complete agreement about the products from the treatment of the lactone (134) with potassium t-butoxide in dimethylformamide 129
130
'"
'
s4
T. J. Danielson, E. M. Hawes, and C. A. Bliss, Canad. J . Chem., 1973, 51, 760. T. J . Danielson, E. M. Hawes, and C. A. Bliss, Canad. J . Chem., 1973, 51, 1737. E. D. Mitchell, M. Downing, and G . R. Griffith, Phytochemistry, 1972, 11, 3193. H. Inouye, S. Ueda, and Y. Takeda, Tetrahedron Letters, 1970, 3351. R. Guarnaccia, K. M . Madyastha, E. Tegtmeyer, and C. J. Coscia, Tetrahedron Letters, 1972, 5 125. P. W. Thies and A. Asai, Chem. Ber., 1972, 105, 3491.
Mono terpenoids
25
____+
0 (135) 25xofeach isomer
( 1 34)
(136) 25xofeach isomer
followed by lithium aluminium hydride reduction. Andersen and Uh find approximately equal amounts of all the isomers [(135) and (136)],13' whereas Wolinsky and Eustace' 36 find primarily the all-cis isopropenyl isomer [cis-( 136)].
b \
/ + (+)-di-3-pinanylborane -D
HO
(138)
(139)
li
H-OH
H H
Me0,C
I!
'IJR)
CHO
(141) Aco-isa
H
OAc
C0,Me
(140)
1
ii
AcO--
+
+ AcO--
H C0,Me
H
C0,Me
-
(143) I iii
(142)
- - OAC
CH,OAc
AcO - H
C0,Me
Reagents : i, Et,NOAc; ii, h v ; iii. 2,3,4,6-tetra-0-acetyl-~-~-glucose.
Scheme 5 135 136
N. H. Andersen and H. Uh, Tetrahedron Letters, 1973, 2079. J . Wolinsky and E. J. Eustace, personal communication to the authors of ref. 1 3 5 ; see also, Vol. 2, p. 19 of these Reports.
26
Terpenoids and Steroids
The full account of Buchi’s loganin synthesis (cf:Vol. 1, p. 20) has appeared.I3’ Partridge et al. have described a short asymmetrically induced synthesis of loganin penta-acetate (137) from methylcyclopentadiene (138). The latter can be hydroborated in at least 95 optical purity, (+)-di-3-pinanylborane giving the (R,R)-isomer (139), which is converted into the (S,R)-cyclopentenyl acetate (140). Irradiation of the latter in the presence of methyl diformylacetate (141) gives the loganin aglycone derivative (142) regioselectively (Scheme 5)’ 38 Both papers discuss the difficulty of glucosylating the aglycone; this was effected in the presence of boron trifluoride, oia the unstable oxonium ion (143). p-Menthanes.-This year, synthesis of the skeleton will be treated first, followed by the properties, first of the hydrocarbons and halides and then of the oxygenated p-menthanes. New modifications of the Diels-Alder reaction for making p-menthanes continue to appear. The reactioq of chloroprene with methyl vinyl ketone was mentioned before (see Vol. 3, p. 49); the resulting ketone (144) has now been
6 $A 4
Q
>
+(8%Q
COMe (144)
jIV,.
Q (145)
Reagents:
I,
MeMgI; ii, Wittig; iii, Al,O,-py; iv, Li; v, Me,NCHO.
Scheme 6
converted (Scheme 6) into perilla aldehyde (143.‘ 39 Simple a-butenolides are not dienophiles, but the /I-carboxylated derivatives are ; thus with isoprene the butenolide (146) reacted in benzene after 3 days at 140-150°C to give the cisfused lactone (147), which was converted specifically into either (* )-menthone (148) or (+)-isomenthone (149) (Scheme 7).I4O 137
138
I39 140
G. Buchi, J . A. Carlson, J. E. Powell, jun., and L.-F. Tietze, J . Amer. Chem. SOC., 1973, 95, 540. J . J . Partridge, N . K . Chadha, and M . R. Uskokovic, J . Amer. Chem. SOC.,1973, 95, 532. Yu. S. Tsizin and A. A. Drabkina, Zhur. obshchei Khim., 1972, 42, 1852. S. Torii, T. Oie, H. Tanaka, J . D. White, and T. Furuta, Terrahedron Letters, 1973, 247 1 . The formula of one of the saturated lactones is misprinted in this paper.
Mono terpeno ids
27
j--Jco2H + 1 9 1 J$. --T -yo 0
H(147) l i , ii
19 %
75 % Jiii
1 v i . vii
I
b i , vii
1
b i i i , ix
Q, Reagents: i, H,-Pd; ii, distil; iii, LiAlH,; iv, Ac,O, 130°C; v, 14O-15O0C, PtO,; vii, NaOH; viii, pyrolysis of xanthate; ix, 0,. Scheme 7
3 h ; vi, H,-
Terpenoids and Steroids
28
The synthesis of menthone by Conia et al. depends on the fact that b-ethyleneketones cyclize thermally to cyclohexanones. Thus the P-keto-ester (150), readily obtained from ethyl acetoacetate, gives the cyclized P-keto-ester (151) as the main product after 16 h at 300 "C,whereas after 2 h at 350 "C, 50% of the product is a mixture of (+)-menthone and (-t-)-isomenthone (7 : 3). Cyclization of the ketone (152) without the ester group also gives the same mixture, but in lower yield, and under more vigorous conditions. 14' i, CH,=CHCH,CH,Br
MeCOCH ,CO,Et
-:1
ii, Me,CHI ________,
/
300°C. I6 h
C0,Et
In the preparation of isopulegols from (+)-citronella1 (153), the main product using tris(tripheny1phosphine)chlororhodium is ( + )-neoisopulegol (154). Stannic chloride cyclization, on the other hand, yields mostly (-)-isopulegol (155).142 Cyclization occurs when 3,7-dimethyloctane-1,7-diolis heated above 200 "C with an acid anhydride. The product is the pulegol ester (156).143The full paper
''I
'42 143
G. Moinet, J . Brocard, and J.-M. Conia, Tetrahedron Letters, 1972, 4461; J . Brocard, G. Moinet, and J.-M. Conia, Bull. SOC.chim. France II, 1973, 171 1 . K. Sakai and 0. Oda, Tetrahedron Letters, 1972, 4375. W. Hoffmann and W . Reif, Ger. Offen. 2 1 15 130.
Monoterpenoids
29
of Sukh Dev's preparation of the 1-vinylisopulegol (157) from geraniol vinyl ether (158) has appeared. 144
Formation of menthanes by ring-opening of pinanes is discussed in the section on bicyclo[3,l,l]heptanes. Addition of N,03 to ( - )-a-phellandrene (159)yields a crystalline nitro-nitrosocompound, now shown to be the dimer of (2R,4S,5S)-5-nitroso-2-nitromenth-6ene (160).145
(159)
It has been suggested that limonene might be used as a measure of the protonremoving power of 'superbases' ; for example, N-kalioet hylenediamine aromatizes limonene in 5 min at 25 "C (to p-cymene), whereas the lithium analogue requires > 2 h at 90°C.146 Further uses of metallated limonene include the reaction with formaldehyde, which leads to the alcohol (161 ; n = 1),147 and the homologue (161; n = 2) with ethylene oxide.'48 A study of the autoxidation of 2-substituted p-cymenes, in particular whether they react at C-7 or C-8,I4' includes previously published material.'50 The oxidation of limonene with hydrogen peroxide and catalytic amounts of selenium dioxide gives (162) as the main product. The structure of (162) was confirmed by catalytic reduction to a glycol (163). Several likely intermediates in the oxidation were examined, including the epoxide (164),with the results shown in Scheme 8.15' 145 146
14*
151
N. P. Damodaran and Sukh Dev, Tetrahedron, 1973,29, 1209. C. H. Brieskorn and H. H. Frohlich, Chem. Ber., 1972, 105, 3676. C. A. Brown, J . Amer. Chem. SOC.,1973,95, 982. R. J. Crawford, J . Org. Chem., 1972, 37, 3543. R. J. Crawford, U.S. P. 3 676 505. G. Bourgeois and R. Lalande, Bull. SOC.chim. France, 1972, 4324. A. F. Thomas, Helv. Chim. Acta, 1965,48, 1057. C. W. Wilson, tert. and P. E. Shaw, J . Org. Chem., 1973, 38, 1684.
30
Terpenoids and Steroids
(162)
1
( 164)
ii
decomposed Reagents: i , Pd:C - H 2 ;i i , H 2 0 , - S e 0 , .
Scheme 8
Epoxidation of y-terpinene (165) with peroxybenzimidic acid yields two epoxides (166) and (167) in 3 : 1 ratio, which are readily separable by d i ~ t i l l a t i o n . ' ~ ~
(165)
A
A
( 1 66)
(167)
Pure cis-menth-l-ene epoxide (168) was made by separation of the menthane1,2-diols (169)and (1 70), obtainable on treatment of menth-l-ene with performic acid, and hydrolysis of the 2-to~ylate.''~Both pure cis-menth- l-ene epoxide
'
57
A
A
A
(169)
(170)
(168)
S. A . Kozhin and E. I. Sorochinskaya, Zhur. obshchei Khim., 1973,43, 671. K . Piatkowski and A. Siemieniuk, Pracenauk. Inst. Chem. Org. i Fiz. Politech. Wroclawskiej, 1970,7 1 .
31
Monoterpenoids
(168) and the truns-isomer have also been made by the method used by Wylde and Teulon (cf Vol. 1, p. 26) for the limonene epoxides, separating the chlorohydrins through their p-nitrobenzoates. ''4 Continuing their work on brominated menthanes, Carman and Venzke have shown that bromination in light of trans-1,2,8-tribromo-cis-menthane (17 1) (see Vol. 3, p. 32) involves a bridged bromine radical and leads to a rearranged tribromide (172) and the two tetrabromides (173) and (174). The rearranged tribromide (172) is also formed in the dark reaction, which leads in addition to bromination in the 9-position (175).' " Br
I
Br
Br
Br
Br
Br
(174) Br
Buchi and Vederas have developed a method foF converting an unsaturated carbonyl compound into the allylic isomer that involves formation of an isoxazole (by using iodine oxidation of the oxime), followed by reductive ringopening. Whereas the technique worked well in the case of fl-ionone, the yield of carvone (176) from perilla aldehyde oxime (177) was only a few percent, because the isoxazole (178), even with sodium bicarbonate, yields the keto-nitrile (179) which undergoes further transformations.' 5 6 If the carbonyl group of cuminaldehyde (180) is protected as the imidazoline derivative (181), reduction with lithium in liquid ammonia readily gives the dihydro-compound from which the aldehyde (182), responsible for the flavour of cumin seeds, is obtained.I5' A molecular orbital study of the reduction mechanism ofp-mentha- 173-dien-7-al (183) with sodium in liquid ammonia has led to the conclusion that reduction 154
D. Sedzik-Hibner, H . Weinert-Orlik, and Z. Chabudzinski, Roczniki Chem., 1973, 47, 1249.
155
IS6 15'
R. M. Carman and B. N. Venzke, Austral. J . Chem., 1973, 26, 571. G . Buchi and J. C. Vederas, J . Amer. Chem. SOC.,1972, 94, 9128. A. J . Birch and K. P. Dastur, Austral. J . Chem., 1973, 26, 1363.
Terpenoids and Steroids
32
A n
n. .
proceeds through 1,6-biradical addition to the a/?,yd-unsaturated system.’ 5 8 An examination of the reduction of carvone over palladium or platinum catalysts has once again shown how platinum catalysts are more selective than palladium catalysts, platinum black yielding only carvomenthone (184), carvotanacetone (185), and carvomenthol (186); far more intermediates are found using 10% palladium on charcoal, whereas with palladium black, isomerization to carvacrol (187) occurs. 5 9 Wallach’s ‘dicarvelones’,formed by reduction of carvone (176)
(183) 158
i184)
(185)
(186)
(187)
H. Kayahara, Shinshu Daigaku Nogakubu Kiyo, 1972, 9, 83 (Chem. Abs., 1973, 79, 18 855).
E. I . Klabunovskii, L. F. Godunova, and L. K . Maslova, Izvest. Akad. Nauk S.S.S.R. Ser. khim., 1972, 1063.
Monoterpenoids
33
with zinc and have been shown to have the structures Wailach ascribed to them [(188),(189), and (190)].'61
i, 2HBr ii, KOH-MeOH
(176) +
(188) a
O W (190) 1'
Addition of bromine to carvone (176) gives, first, two tetrabromides (191) and (192); further bromination of the crystalline P-tetrabromide (191) yields a pentabromide (193). A discussion of the structures, and much information about other halogenated carvones, has been given by Carman and Venzke.'62 The Br
Br
Br
BrH,C'Br
0
CH,Br Br
0
Br Br
0
addition of bromine to carvone oxime occurs initially to the 8,9-double bond, then to the conjugated double bond, and both the dibromide (from the first addition) and the tetrabromide (from the second) can be reduced back to the oxime with zinc in alkali. Replacement of the tertiary bromine atoms by methoxy (with methanol) and replacement of the 8-bromo-atom by chlorine with nitrosyl chloride are also d i ~ c u s s e d . ' ~When ~ the carvone tribromides (194) and (195) react with methoxide or hydroxide anions (cf. Vol. 1, p. 31), methoxide gives I6O 161
'62 163
0. Wallach and H . Schrader, Annufen, 1894, 279, 377. R. M. Carman, G . N. Saraswathi, and J. Verghese, Austral. J . Chem., 1973,26, 883. R. M. Carman and B. N. Venzke, Austral. J . Chem., 1973, 26, 1283. E. G . Bozzi, C. Shiue, and L. B. Clapp, J . O r g . Chem., 1973, 38, 56.
Terpenoids and Steroids
34
products from the Favorskii rearrangement, trans-tribromocarvomenthone (195) yiclding the epoxide (196) in addition. Hydroxide gives fragmentation products, but the reactions depend on the nature of the base, the solvent, and the configuration of the bromine atom at C-6.1G4
(194) R'
=
R'
=
(195)
Br, R 2 = H H, R 2 = Br
(196)
Metal hydride reduction of carvone epoxide (197) is reported by Zaitsev and Kozhin to yield practically only trans-p-menth-8-ene-trans-2,6-diol (198)? The Russians used lithium aluminium hydride in ether, and their finding does not completely agree with the work of Piqtkowski, who reported a mixture of four glycols and isocarveol epoxide (199).'" The same author has examined the reduction of dihydrocarveol e p ~ x i d e 'and ~ ~ the diepoxide (200), the latter reportedly giving the glycol (201).16' The inaccessibility of the journal and the absysmal quality of the abstracts preclude full assessment of this interesting work. Glycols of the type (201), acetylated on the tertiary hydroxy-group,
A (200) 164
Ih5 Ihh
16'
16'
(201)
J . Wolinsky and R. 0. Hutchins, J . Org. Chem., 1972, 37, 3294. V. V. Zaitsev and S. A. Kozhin, Zhur. org. Khim., 1972, 8, 1841. K . Piatkowski. Pruce nuuk. Inst. Chem. Org. i Fiz. Politrch. Wvoduwskiej, 1970, 3. (Them. A h . , 1973, 78, 97 814); K. Piatkowski and A. Siemieniuk, ibid., p. 53 (Chem. A h . , 1973, 78, 97 820); see also Vol. 3, p. 37 of these Reports. K . Piatkowski and D. Mrozinska, Pruce nauk. Inst. Chem. Org. i Fiz. Politech. Wroduwskiej, 1970, 25 (Chem. Abs., 1973, 78, 97815). K . Piatkowski and D. Mroziriska, Prace nauk. Inst. Chem. Org. i Fiz. Politech. Wroduwskiej, 1970, 37 (Chem. Abs., 1973, 78, 97816).
Mono terpenoids
35
undergo transposition of the acetyl group to the secondary hydroxy when heated in sodium acetate.' 6 9 An introductory stereochemistry experiment for students involves determination of the relative and absolute configurations of (-)-menthol (202) and (+)neomenthol (203) by ( a ) equilibration and (b) reduction of menth~ne.'~' A discussion of columns for the separation of menthol and menthones by gas chromatography includes mention of the problem of interconversion of menthone and isomenthone on various columns. The classical Meerwein-PonndorfVerley reduction of pulegone (204) is known to be inefficient ;however, reduction occurs readily in the presence of a strong base (KOH) in propan-2-01 to yield a 1 : 1 mixture of menthol [( +)-(202)] and neomenthol [( +)-(203)].'72
'
Biological oxidation of piperitone (205) using a Fusarium species, Protoactinomyces roseus, or a local (Australian) species of Aspergillus niger yields in all cases mixtures in which the major component is 7-hydroxymenth- 1-en-3-one (206), accompanied by varying amounts of the 6-hydroxylated compound (207) (particularly with the P. roseus oxidation), and traces of an 8-hydroxylated piperitone (208)' 7 3
A publication by Nagell and Hefendehl 'establishes' the known structure of diosphenolene' 7 4 using much the same reasoning as the unacknowledged original work by Naves.' 7 5 W . Gary, U S . P. 3 676 487. J . Barry, J . Chem. Educ., 1973, 50, 292. D. G . Gillen and J. T. Scanlon, J . Chromatog. Sci., 1972, 10, 729. M . Calas, B. Calas, and L. Giral, Bull. Soc. chim. France II, 1973, 2079. 1 7 3 E. V . Lassak, J. T. Pinhey, B. J . Ralph, T. Sheldon, and J. J . H . Simes, Austral. J. Chem., 1973, 26, 845. "'A. Nagell and F. W. Hefendehl, Phytochemistry, 1972, 11, 3359. Y.-R. Naves, Helv. Chim. Acta, 1966, 49, 2012. lh9
36
Terpenoids and Steroids
Treatment with bromine of the product (209) from the reductive dimerization of (+)-pulegone results in aromatization of one of the cyclohexane rings (210); the stereochemistry of the various isomers has been discussed.' 7 6
(210) X = Br or H
(209)
A study of the alkylation of menthones has been p~blished.'~'It was known that pulegone (204)methylates predominantly in the 4-position, giving (21l), with sodium t-amylate and methyl iodide,'78 but it has now been found that if lithiumsecondary amide bases are used, the major product (212) is derived from the crossconjugated enol (Scheme 9)."'. The full paper on the methylation of (+)pulegone by Cox et a / . 8 o (preliminary communication ref. 178) has confirmed
Reagents: i,
56 "/,
23 %
(212)
(211)
(214)
N(Li)CHMe,-THF, 0 "C; ii, Me1 (excess), 25 " C .
Scheme 9
that ( - )-methylisopulegone (214) has the (1R,4S) configuration* in agreement with findings in the thujane series.'81 A comparison of the c.d. of (-)-methylisoJ. M. Font Cistero, Rev. Real Acad. Cienc. exactas,fis. natur. Madrid, 1972, 66, 455 [Chem. Abs., 1973,78,84 542 includes a n incorrect formula for (150)] Bull. Soc. chim. France I I , 1973, 1049. C. Djerassi, J. Osiecki, and E. J. Eisenbraun, J . Amer. Chem. Soc., 1961, 83, 4433; M. R. Cox, H. P. Koch, W. B. Whalley, H. B. Hursthouse, and D. Rogers, Chem. Comm., 1967,212. R. A. Lee, C. McAndrews, K. M. Patel, and W. Reusch, Tetrahedron Letters, 1973,
"' C. Metge and C. Bertrand,
17'
965.
M. R.Cox, H. P. Koch, and W. B. Whalley, J.C.S. Perkin I, 1973,174. T.Norin, Acta Chem. Scand., 1962,16,640.
* These publications do not use a nomenclature based on the menthane skeleton; this Report uses consistent numbering: thus (2 14) is (1 R,4S)-4-methylmenth-8-en-3-one.
Monot erpenoids
37
pulegone (214) with those of isopulegone and of saturated analogues includes a discussion about the relative dispositions of the double bond and the carbonyl group.*' 8 2 The n-allylpalladium compounds of piperitone (205) and pulegone (204) give the same mixtures of cyano-ketones (e.g. 1-cyanomenth-3-ones from piperitone) as are obtained from the parent crp-unsaturated ketones under similar conditions (KCN-NH,Cl in dimethylformamide at 100"C). The stereochemistry of the piperitone product was not assigned.l 8 Beckmann rearrangement of the oximes of menthone, carvone, and reduced carvones occurs with toluene-p-sulphonyl chloride in aqueous acetone containing sodium hydroxide. The structures and conformations of the lactams obtained have been discussed in the light of their n.m.r. spectra.' 84 Thymoquinone (215 ) reacts with piperylene in the Diels-Alder reaction, but the adduct (216) is not that of a naturally occurring sesquiterpenoid skeleton.'85
rn-Menthanes.-5-Hydroxy-rn-mentha-1,8-diene(217) (among other monoterpenoids) is reported as a constituent of Cannabis sativa resin. The study was an analytical attempt to determine what attracts dogs trained to detect hashish.' 86 However, the compound may not be a naturally occurring rn-terpenoid, but an artefact formed from a carene.
Tetramethylcyc1ohexaes.-The configuration at C-3 of picrocrocin (2 18; R = fl-glucose), the bitter substance of saffron (Crocus sativus) has now been established by correlation with the carotenoid xanthophyll, which was degraded S. Watanabe, Bull. Chem. SOC.Japan, 1973, 46, 1546. C. W. Alexander and W. R. Jackson, J.C.S. Perkin ZZ, 1972, 1601. "'A. Zabia, C. Wawrzenczyk, and H. Kuczydski, Bull. Acad. polon. Sci., Skr. Sci. chim., 1972,20,631 (Chem. Abs., 1972,77, 140 307). J. J . Sims and V. K. Honwad, Tetrahedron Letters, 1973, 2155. E. Stahl and R. Kunde, Tetrahedron Letters, 1973, 2841.
* See footnote o n previous page.
38
Terpenoids and Steroids
to ( - )-(R)-3-methoxy-P-ionone (219). The latter was obtained from picrocrock by saponification to the aglucone (218: R = H), methylation (Ag,O and MeI), and condensation with acetone to (219).18' Sandy sage (Arternisia Jil$olia) has been found to contain two lactones, (220) and (221).lgg Two other compounds, described as 'new' in the abstract, are, in fact, well known (filifolone and 2,6,6trimet hylcyclohex-2-ene-1,4-dione).
A novel cyclization procedure allows exclusively a-cyclocitral(222)to be made in 41 "/;) yield, The enamhe (223) (a mixture of cis- and trans-isomers), prepared from a mixture of the two citral isomers (109a)and pyrrolidine using a molecular sieve, is treated with 90 04 sulphuric acid at 0 "C and the resulting iminium salt (224) is converted (without isolation) into a-cyclocitral (222) by refluxing at pH 3---4.'89 When the same series of reactions is carried out on optically active enamines [ e g (225), obtainable from proli line], an optically active cyclocitral is obtained [(S)-a-cyclocitral (222a) from (2291.' Another type of cyclization
1 /
UHO
R. Buchecker and C. H. Eugster. H r l r . Chirn. Actu. 1973, 56, 1121. S. Torrance and C . Steelink, 166th A.C.S. Meeting, August, 1973, Abstracts A G F D , No. 54. I R 9S. Yamada, M . Shihasaki, and S . Terashima, Tetrahedron Letters, 1973, 377. 19" S. Yamada, M . Shibasaki. and S . Terashima, Tetrahedron Letters, 1973. 381.
I*'
39
Mono terpenoids
involves treatment of methyl geranate (226) with benzenesulphenyl chloride in nitromethane containing silver hexafluoroantimonate, and yields methyl a-cyclogeranate (227)
PhSC1-MeN0,-AgSbF,
In the hope of converting ethyl safranate (228) into a versatile intermediate for the synthesis of carotenoids, Biichi et al. have investigated its oxidation under various conditions. Selenium dioxide in acetic acid causes aromatization with migration of a methyl group to (229), but with dioxan as solvent the skeleton is maintained affording (230). Oxidation of the anion (231) with oxygen yields the mixture shown (Scheme
(231)
(230)
43 %
34 %
3%
Reagents: i, Se0,-HOAc; ii, Se0,-dioxan; iii, KOBu'; iv, 0,; v, heat.
Scheme 10
As usual, the C, substances related to isophorone (232) are included in this Report ; many such substances occur naturally together with safranate-like compounds. The epoxy-alcohol (233)derived from isophorone does not undergo the same ring contraction as unsubstituted cyclohexenol epoxide with lithium bromide in hexamethylphosphoramide.193Of the three possible enol acetates [(234), (235), and (236)] formed from isophorone with isopropenyl acetate, only
19'
192
193
M. T. Mustafaeva, M. Z . Krumer, V. A. Smit, A. V. Semenovskii, and V. F. Kucherov, Izvest. Akad. Nauk S . S . S . R . , Ser. khim., 1972, 2632. G. Buchi, W. Pickenhagen, and H. Wuest, J . Org. Chem., 1972, 37, 4192. G . Magnusson and S. Thoren, J . O r g . Chem., 1973, 38, 1380.
Terpenoids and Steroids
40
two, (234)and (235),undergo a Diels-Alder reaction with a-chloroacrylonitrile to yield bicyclo[2,2,2]octenes, (237) and (238).'94
CI 38 % (237)
62 % (238)
Reduction of the diketone (239)over platinum leads to reduction of the carbonyl group having adjacent methyl groups (240); this paper describes the preparation of a derivative of the other ketol(241; R = tetrahydropyranyl), related to grasshopper ketone.' 9 5
Cr EH
0
0
('39)
1,4-Dimethyl-l-ethylcyclohexanes.-A member of this class of compounds (242) has been found in the oil of Juniperus cornrnunis,but it is not certain that it is truly isoprenoid, since it could arise by biological methylation of a reduced p-methylacetophenone (although the latter could be a degraded isoprenoid, too!).'96
(242)
Iy4 I95
J. Daminao, S . Geribaldi, G . Torri, and M . Azzaro, Tetrahedron Letters, 1973, 2301. K . Mori, Tetrahedron Letters, 1973, 723. A . F. Thomas, Helc. Chim. Acta, 1973, 56, 1800.
Mono terpenoids
41
Cyc1oheptanes.-The Beckmann rearrangement of tetrahydroeucarvone oxime (243) has been di~cussed.'~'Treatment of karahanaenone epoxide (244) with sodium ethoxide results in ring contraction to the cyclohexanol (245), in which assignment of the endo configuration to the hydroxy-group is based on the
assumption supported by n.m.r. of a backside displacement of the epoxide oxygen at C-5 by the anion created at C-7, with inversion at C-5. The dehydration of the alcohol (245) (to the ketones in Scheme 1l), together with other reactions of the same alcohol, are described.' 98
Q
+
y-p=,b, 170
0
OH
(244)
(245)
-
180T
/
OH
KHSO, 170-I80
"C
Scheme 11
Conversion of eucarvone epoxide (246) into the two 1,1,4-trimethylcycloheptane-3,4-diols (247),with a view to examining the properties of the latter, has been described.' 99
197
198
199
A. Zabza, H . Kuczynski, Z . Chabudzinski, and G . Piotrowska, Bull. Acad. polon. Sci., SPr. Sci. chim., 1973, 21, 1 . Y. Gaoni, Tetrahedron, 1972, 28, 5533. Z. Chabudzinski, M. Skwarek, P. Molin, and I. Mielczarek, Roczniki Chem., 1 9 7 3 , 4 7 , 1407.
42
Terpenoids and Steroids
6 Bicyclic Monoterpenoids Bicyclo[3,1,0]hexanes.-Artemi.~iu herbu ulba, a Moroccan species, contains over 70 thuj-3-one (248) in its essential oil. This is the less commonly occurring isomer, called P-thujone by the authors, although there is no doubt which it is.2oo The epoxide of 4-isopropylidenecyclohexanone (249),0” treatment with alcoholic sodium hydroxide, yields a bicyclo[3,1,0]hexane(2%) in over 90 ”/, yield, which
(248)
(249)
(250)
is in principle readily convertible into thujane derivatives.201 Another synthesis of the .ring system involves preparation of the cyclopentanonylmethanol (251) in seven steps from (252); it can then be cyclized with dicyclohexylcarbodi-imide to sabinaketone (253).202
The acid-catalysed hydration of sabinene (254)and a-thujene (255)(Scheme 12) proceeds through a common carbonium ion (256); this work is similar to that of Norin (see Vol. 3, p. 57), but with a slight difference in reaction rate and formation of more menth-l-en-4-01 (257).203 Hach has examined the Meerwein-Ponndorf-Verley reduction of thujone (258) to the thujanols (259),204and converted the latter into the ~innamates.”~ Homoallylic alcohols can be readily dehydrated by photolysis of their thio2oo
202
*04
205
A. Cohen, J.-P. Lavergne, A. Leblanc, and Ph. Viallefont, Bull. S O C .Sci. nut. phys. Maroc, 1972, 52. 1 . Y . Gaoni, Tetrahedron, 1972, 28, 5525. C. Alexandre and F. Rouessac, Bull. Chem. SOC.Japan, 1972, 45, 2241. M . A. Cooper, C . M . Holden, P. Loftus, and D. Whittaker, J.C.S. Perkin If. 1973, 665. V. Hach, J . Org. Chem., 1973, 38, 293. V. Hach and H . G . Higson, Canad. P. 914 214 (the formulae are incorrect in Chem. Abs., 1973, 78,43 770); see also U.S. P. 708 521.
Monoterpeno ids
43
1; (254)
9 (255)
Scheme 12
I
(G93
benzoic 0-esters, although with two of the thujol isomers complex products were obtained.206
Bicyclo[2,2,l]heptanes.-In this Report, after the chemistry of monoterpenoids with this ring system, a section concerning the various rearrangements between bicyclo[2,2,l]heptanes and bicyclo[3,l,l]heptanes is included. The absolute configuration of ( )-fenchone (260) and ( + )-dehydrofenchone (261) using 0.r.d. has been discussed.207 A 3C-labelledcamphene (262)has been made conventionally in order to study its racemization in acid. It was found that there is little endo-methyl migration and tricyclene formation, Wagner-Meerwein 2,6-hydride rearrangement is ca.
+
’06
20’
D. H . R. Barton, M. Bolton, P. D. Magnus, K. G. Marathe, G . A . Poulton, and P. J. West, J . C . S . Perkin I , 1973, 1514. J. Korvola and P. J. Malkonen, Suornen Kern., 1972, B45, 381.
Terpenoids and Steroids
44
41%, and exo-3,2-migration is ca. 53%.208 Results from the dehydration of the camphanols (263) and related primary alcohols with polyphosphoric acid at 185 "C correspond to those from the acid isomerization of camphene, since the latter constitutes 46.5% of the products of the rapid dehydration of the cam-
p h a n o l ~ . ~A' ~kinetic study of the rearrangement in formic acid of cyclofenchene (264) and a-fenchene (265) has been shown to be'very complex (Scheme 13), but a-fenchene (265) is the most important early intermediate from cyclofenchene (264).21 Paasivirta has also examined the reaction of formic acid with tricyclene . , again.21
& (264)
Further products Scheme 13
In the publication about the reaction of phenol with a-fenchene, Gavrilova et al., having come close to plagiarism in earlier papers (see Vol. 2, p. 47), now reproduce exactly the work of Demole.21 208
209 210 21
'12
C . W. David, B. W. Everling, R. J. Kilian, J. B. Stothers, and W. R. Vaughan, J . Amer. Chem. SOC.,1973,95, 1265. E. Degny, F. Petit, M . Evrard, and M. Blanchard, Bull. SOC.chim. France, 1972, 4770. J . Paasivirta and P. Hirsjarvi, Acra Chem. Scand., 1973, 27, 1098. J. Paasivirta, Acra Chem. Scand., 1973, 27, 374. T. F. Gavrilova, I. S. Aul'chenko, and L. Kheifits, Zhur. org. Khim., 1973, 9, 89; see E. Demole, H e h . Chim. Acra, 1964, 47, 1766.
Mono t erpenoids
45
Acid-catalysed rearrangements of the anisyl compounds (266)2l 3 and (267),2l4 together with some other related have been discussed. The competition between Wagner-Meerwein rearrangement and intramolecular electrophilic substitution in the 3-diphenylmethyleneisobornyl system (268) is such that dehydration of the alcohol (268 ; R = H) with toluene-p-sulphonic acid below 60 "C gives only the Wagner-Meerwein products [(269)and (270)]whereas with potassium bisulphate, 2,6-hydrogen shifts and Nametkin rearrangement occur up to 130°C, with further complications at higher temperatures. The acetate (268 ; R = Ac) epimerizes at under 60 "C in acid.2'
P
O
M
e
Q
Earlier work216 on the reaction of N-bromosuccinimide with camphene (271) reported only an inseparable mixture in which the bromocamphene (272) was identified. Now Jefford and Wojnarowski have deduced (based on work with 2-methylnorbornene) that both geometrical isomers of (272)are formed, together with (probably) the tricyclene (273) and (possibly) (274).2l 7 Electrochemical
lL3 'I4 'I5
'I6 'l'
D. L. Adams and W. R. Vaughan, J . Org. Chem., 1972,37,3906. D. W. Kuehl, J. D. Nelson, and R. Caple, J . Org. Chem., 1973, 38, 2723 J. P. Morizur, B. Furth, and J. Kossanyi, J . Org. Chem., 1973, 38, 2698. J. D. Roberts and E. R. Trumbull, J . Amer. Chem. Soc., 1949,71, 1630. C. W. Jefford and W. Wojnarowski, Helv. Chim. Acta, 1972, 55, 2244.
46
Terpenoids and Steroids
reduction of the dibromobornanes (275)and (276)leads, in the case of the di-endoproduct (275), to tricyclene (277) as the primary product and bornane (278) as a secondary product, obtained uia the monobromide (279), which appears in the early stages of the reaction. The em-dibromide (276),formed by bromination of camphene, gives camphene (271) on electrochemical reduction [by solvolysis of the monobromide intermediate (280)], together with bornane (278), by stepwise
Br
Br
reduction of the bromine atoms.218 Formation of a tricyclene derivative (281) also occurs when 3,3-dibromocamphor (282) is reduced with diethylzinc, the initial camphor carbenoid formed (283)acting as an efficient internal trap (Scheme 14).2l 9 The reaction of the tricyclenone (281) with lithium dialkylcuprates leads to addition (284; R = Me) in the case of the dimethylcuprate, and reduction (284 ; R = H) with the di-n-butylcuprate.220
Scheme 14 2'k 'Iy
22v
Azizullah and J . Grimshaw, J.C.S. Perkin I , 1973, 425. L. T. Scott and W. D. Cotton, J. Amer. Chem. Soc., 1973, 95, 2708. L. T. Scott and W . D. Cotton, J.C.S. Chem. Comm., 1973, 320.
Monot erpenoids
47
Some further comments about the nitrous acid deamination of endo-fenchylamine have appeared.221 1 -NN-Dichloroaminoapocamphane (258),prepared by the action of t-butyl hypochlorite on 1-aminoapocamphane, yields the ringopened compounds of Scheme 15 on reaction with aluminium chloride at -75 "C, with only 10 % of the expected chloroamine (286).222
Scheme 15
The mechanism of the oxygen scrambling in the pyrolysis of benzoyl l-apocamphyl carbonate (287) has been discussed.223
H (289)
Borneo1 reacts with chlorodiphenylmethylium ion in t-butyl cyanide to give, by quenching after 5 min reaction time, the t-butyl amide (288 ; R = But). If, on the other hand, acetonitrile is added, the acetamide (288 ; R = Me) is obtained in addition, these reactions occurring via the oxonium ion (289).224The rearrangements occurring on pyrolysis of 10-isobornyl sultone (290), leading to endo- (291) and exo- (292) camphene sultones have been investigated.225 Pyrolysis of
*" 222
223
224 225
C. J. Collins and B. M. Benjamin, J. Org. Chem., 1972, 37, 4358; CJ W. Huckel and H.-J. Kern, Annalen, 1969, 728, 49. R. D. Fisher, T.D. Bogard, and P. Kovacic, J. Amer. Chem. SOC.,1972,94, 7599. S. Oae, K. Fujimori, and Y. Uchida, Tetrahedron, 1972,28, 5321 ; S. Oae, K. Fujimori, and S. Kozuka, ibid., p. 5321. D. H. R. Barton, P. D.Magnus, and R. N.Young, J.C.S. Chem. Comm., 1973, 331. D. R. Dimmel and W. Fu, 165th A.C.S. Meeting, April, 1973, Abstracts O R G N , No. 92. From this abstract, it is difficult to see the novelty beyond J. Wolinsky, D. R. Dimmel, and T. W. Gibson, J . Org. Chem., 1967, 32, 2087.
Terpenoids and Steroids
48
2-exo-bromo-2-endo-nitrobornane (293) gives 15% of the cyclopentene (294) and ca. 2 % of endo-bromocamphor (295).226 The proposed mechanisms, i.e. initial formation of campholenic nitrile (296) [the main product from pyrolysis at 300 “ Cin a sealed tube for 2 h of 2,2-dinitrobornane(297)],followed by bromination, would benefit from additional support.
15
+
Br
+ CN
H
Camphor deuteriated in the 9-methyl group (298) has been prepared.227The + )-camphorato]lanthanide(~r~)agents chiral tris-[3-t-butylhydroxymethylene-( LnT, are dimeric in dry CC14 solution for Ln = Pr, Nd, and Sm, at concentrations commonly used in n.m.r. shift work, unlike the later members of the series and unlike the dpm and fod shift agents.228
(298) R = CD, (299) R = Me
(300)
(3011
(302)
(303)
If any one of the three ketones camphor (299), endo-isocamphanone (300), or exo-isocamphanone (301) is heated at high temperatures with potassium tbut oxide in t-butyl alcohol all three are obtained, because of homoenolization [via the enolate (302)l. Homoenolization is also responsible for the fact that strong base-catalysed exchange of fenchone (303) (t-butyl [2H]alcohol and 226 ”’ 228
S. Ranganathan and H . Raman, Tetrahedron Letters, 1973, 41 1 . R. N. McCarty, Diss. Abs. ( B ) , 1973, 33, 3558. R. G . Denning, F. J. C. Rossotti, and P. J . Sellars, J . C . S . Chem. Comm., 1973, 381.
Mono terpenoids
49
potassium t-butoxide at 185°C) results in exchange of the protons at C-6 and
c-8.229 The long-known rearrangement of camphor to 3,4-dimethylacetophenone in sulphuric acid has received fresh attention. When camphor was specifically labelled at C-8 and C-9, the distribution of label in the acetophenone was as shown in Scheme 16.230 These findings were explained by a series of complex rearrangements, including an endo-2,3 hydroxyl shift, which the authors were reluctant to accept. Using a computer programme allowing enumeration of all possible intermediates in this reaction, it has been found that the observed results can be explained without this unprecedented rearrange men^'^
76 %
\J*
FOMe
0 Scheme 16
Reduction of (lR)-3-endo-aminocamphor(304) with aluminium chloride and tri-isobutylaluminium (i.e. AlC1,H) gives a 74.5 % yield of the endo-aminoborneol (305)rather than the i ~ o b o r n e o l ,reduction ~~~ from the em-side being the usual mode in the presence of the a m i n o - g r ~ u p .The ~ ~ ~mechanism of the
229
230 231
232 233
D . H . Hunter, A. L. Johnson, J . B. Stothers, A. Nickon, J. L. Lambert, and D. F. Covey, J . Amer. Chem. SOC.,1972, 94, 8582. 0. R. Rodig and R. J. Sysko, J . Amer. Chem. SOC.,1972,94,6475. C. J. Collins and C. K. Johnson, J . Amer. Chem. SOC.,1973, 95, 4766. H. Pauling, Ger. Offen. 2 153 819 (Chem. Abs., 1972, 7 7 , 114 599). A. H. Beckett, N . T. Lan, and G . R. McDonough, Tetrahedron, 1969, 25, 5689; A. Daniel and A. A. Pavia, Bull. SOC.chim. France, 1971, 1060.
50
Terpenoids and Steroids
dehalogenation of 3-bromocamphor by dimethylaniline has been shown to involve abstraction of a Br+ ion rather than thermal formation of bromine In order to prepare a molecule in which optical activity would arise only by virtue of replacement of l6O by l8O, and thereby shed light on the argument concerning the sense of twist in a-diketones (see Vol. 3, p. 68), Kokke and Oosterhoff have carried out a series of reactions on fenchone, shown in Scheme 17. The compound obtained showed a small but measurable effect in the c.d. of both low-intensity absorption bands in the region 25&520 nm.235
liv
Reagents: i , NH,OH,HCl; ii, Na-EtOH; iii, HNO,; iv, RuO,; v, N , H , ; vi, H , 1 8 0 - H + ; vii, Se0,-Ac,O.
Scheme 17
The arylidefle-epicamphors (306) exist in both stereoisomeric forms, the amount of each depending on the aryl substituent. Thus when aryl = Ph, only the E-isomer is present (see Vol. 3), but an o-chloro-substituent results in 10%of the 2-isomer and p-chloro in 80% of the Z - i ~ o r n e r . ’ ~ The ~ action of diazonium salts on 3-acyl- or 3-aroyl-camphors (307) results in initial endo attack (308), the other isomer (309) being formed on heating the first (308) in The action of phenylmagnesium bromide on camphor oxime (310) results in the cyclohexenylnitrile (311) (the nomenclature of which is incorrect in the paper) ; the mechanism is deduced to be as shown, since one deuterium atom from 3,3-dideuteriocamphor is removed in the reaction.238 The well-known Beckmann rearrangement of camphor oxime (310) has been re-examined using sodium hydroxide in aqueous acetone and toluene-p-sulphonyl chloride as catalyst. Camphenylone oxime (312) behaves in a similar way and yields ring-opened nitriles, together with ca. 30% of the amide (313). Fenchone oxime [probably having the oxime group syn to the gern-dimethyl group (31411 did not rearrange 234
2’5
236 23’
’”
A. G. Giumanini, ‘Proceedings of the International Symposium on Gas Chromatography Mass Spectrometry’, 1972, ed. A. Frigerio, p. 377 (Chem. Abs., 1973, 78, 124 736). W . C. M . C. Kokke and L. J . Oosterhoff, J . Amer. Chem. Soc., 1972,94, 7583; W. C. M . C. Kokke, J . Org. Chem., 1973, 38, 2989. F. Labruyere and C. Bertrand, Compr. rend., 1972, 275, C , 673. J.-C. Guillaumon, F. Labruyere, C. Metge, and C. Bertrand, Compt. rend., 1973, 276, c, 1 1 1 1 . R. Chaabouni and A. Laurent, Tetrahedron Letters. 1973, 1061.
Mono terpenoids
&
qR2 (306) R'
R'
R' aryl, R 2 = H = H, R 2 = aryl
COAr'
&COAr
Ar'N,;
OH
(307)
=
51
N=N \ Ar2
0 (308)
A-EtOY
v
Ar
/
0
AH
3PhMgB4 NOH
--+
&H CN
O
C
N
N-bOMgBr
(3 10)
(31 1)
& -+Go& N
NOH
'OH (312)
(313)
(314)
under these conditions.239 Beckmann rearrangements of the oxime (3 15) (available from camphor) and its syn- and anti-toluenesulphonates have been discussed by Fleming and Woodward, who used the lactam (316) to prepare methyl cis-P-(3-diazo-1,2,2-trimethylcyclopentyl)acrylate (317).240 The latter compound is of interest because in a dilute solution of sodium methoxide in methanol the major product is the bicyclo[2,2,l]heptene ester (318),241 but the reaction does not appear to be
239
240 241 242
A. Zabza, C. Wawrzenczyk, and H. Kuczynski, Bull. Acad. polon. Sci. SPr. Sci.chim., 1972, 20, 623. I. Fleming and R. B. Woodward, J.C.S. Perkin I , 1973, 1653. E. H. Billett and I. Fleming, J.C.S. Perkin I , 1973, 1658. E. H. Billett, I. Fleming, and S. W. Hanson, J.C.S. Perkin I , 1973, 1661.
52
Terpenoids and Steroids
3-Dimercaptomethylenecamphor (319) can be converted into a series of polysulphides (320), the configurations of which have been studied using dipole moment
SH (319)
6)" (320)
Irradiation of thiofenchone (321) or thiocamphor (322) gives the sulphur analogues of homoenols, (323) and (324), desulphurization with Raney nickel yielding the corresponding tricyclenes. Action of heat on the 'homothioenols' (323) and (324) results in homoketonization back to the starting materials (321) and (322), accompanied in the thiofenchone (323) case by 40% of endo-isothiofenchone (325).244 The action of Grignard reagents on thiofenchone (321) pro-
h
S
(322)
duces the radical (326), which is visible spectrally for several hours (the thiogroup is apparently endo);the products of the reaction are then the thiol(327) and the thioether (328). Thiocamphor (322) behaves similarly (although the radical is less stable) with higher Grignard reagents, but the thioenol ether (329) is formed additionally, and is, indeed, the major product with methylmagnesium bromide.245 A somewhat similar difference between thiofenchone (321) and the enolizable thiocamphor (322) is manifest in their behaviour with dimethyl-
SR (326) 243 244 245
SH (327)
SR (328)
3. Sotiropoulos and A.-M. Lamazouere, Compt. rend., 1973, 276, C,1 1 15. D. S . L. Blackwell and P. de Mayo, J.C.S. Chem. Comm., 1973, 130 M . Dagonneau, D. Paquer, and J . Vialle, Bull. SOC.chim. France I I , 1973, 1969; M. Dagonneau and J. Vialle, Tetrahedron Letters, 1973, 3017.
Mono terpeno ids
53
sulphoxonium methylide, thiofenchone giving the thiirans (330), and thiocamphor the S-methyl-enethiol (329; R = Me).246 The thiirans (330) are 65% of the S-endo-isomer and 35 % of the S-exo-isomer, 2-Diazopropane yields only the thermal decomposition product (33 l).247
The reaction between diazomethane and the intermediate sulphene produced by treatment of (1s)-camphor-10-sulphonyl chloride with triethylamine gives a thiiran dioxide;248 both isomers of this compound (332) have now been ~haracterized.~~’ Notwithstanding the work of Kirmse (see Vol. 3, p. 60), the conversion of bornanes into pinanes has not been easy. Following Scheme 18, Paukstelis and Macharia have converted camphor (299) into nopinone (333). The vital step, rearrangement of the mesylate (334), depends on the fact that the migrating bond must be anti-periplanar to the mesylate group. The scheme shows the best conditions found for making nopinone [in 40% yield from the known 1-trichloroacetoxycamphene (335)], but several other routes to (334) were considered and two others were used.250 The same authors have converted camphor (299) via the known chloro-alcohols (336) into the bicyclo[2,l,l]hexane system (337). 2 5 1 As usual, most of the literature on pinane-bornane rearrangements concerns passage from pinanes to bornanes. The Wagner-Meerwein rearrangement finds new examples every year ; thus verbenone (338) yields 6-chloroepicamphor (339) with gaseous hydrogen chloride, and the chloroepicamphor can be converted into bornane-2,Sdione (340) ; 2 5 2 chrysanthenone (341) behaves ~imilarly.~ 53 Nopadiene (342) or its isomer homoverbenene (343) gives a variety of dichlorohomobornanes (Scheme 19), but it is curious that the maleic anhydride adduct of despite the fact that it nopadiene (344) does not react with hydrochloric does react with hydrogen bromide (see Vol. 1, p. 46),255and the corresponding ester (345 ; R = C0,Et) and alcohol (345 ; R = CH,OH) react normally.254 Wolinsky has already reported the reaction of camphene with sulphur trioxide (see above), and now finds that a-pinene reacts with sulphur trioxide to yield a 246 247
248
249 250 251 252
25 254 255
D . Lecadet, D . Paquer, and A. Thuillier, Compt. rend., 1973, 276, C , 875. J . M. Beiner, D . Lecadet, D . Paquer, A. Thuillier, and J. Vialle, Bull. SOC.chirn. France ZI, 1973, 1979, 1983. N. Fisher and G . Opitz, Org. Synth., 1968, 48, 106. T. Kempe and T. Norin, Acta Chern. Scand., 1973,27, 1452. J. V. Paukstelis and B. W. Macharia, Tetrahedron, 1973, 29, 1955. J. V. Paukstelis and B. W. Macharia, J . Org. Chem., 1973, 38, 646. 0. A. Arpesella, D . I. A. De Iglesias, and J. A. Retamar, Essenze Deriu. Agrurn., 1972, 42, 48 (Chem. Abs., 1972, 77, 164 852). D. J. Merep and J. A. Retamar, Anales SOC.cient. Argentina, 1972, 193,3. B. Bochwic and S. Markowicz, Roczniki Chem., 1973,47, 1083. C. Arcupas and W. S. Roach, Chem. Comm., 1969, 1468.
Terpenoids and Steroids
54
&+&
c1,ccoo
PhC'H,O
,O
I
P h C H&H ,O
0
OH
ii
-t- P h C H & Hl O
OH
(334)
(333)
Reagents: i, NaH-PhCh,Cl; ii, NaBH,; iii, MsC1-py; iv, Pd/C-H,; v, Bu'OK-Bu'OH.
Scheme 18
(299)
5
jf$)
++ $ - $H
+ Hof/$ H
HO (336)
~N~oH-DMF
CHo (337)
(338)
(339)
CO,H
(340)
(341)
55
Mono terpeno idi
(343)
6 'Q"1 n
/ HCI
+ HCI
+ cl..&H2c'
(342)
R
R (344)
(345)
Scheme 19
so2-0 (346)
bornane derivative (3461, albeit in only 7.3 % yield.256 The reaction of chlorosulphonyl isocyanate with a-pinene (347)4072 leads ultimately to a similarly bridged bornane (348) at room temperature, the four-membered-ring adduct (349)being formed at - 70 "C.
''
4
SO2CI
CISO,NCO+ - 70 "C
&O
+ 4
(347)
(349)
&
0
/
CISO,
(348) 256
*"
J . Wolinsky, R. L. Marhenke, and E. J. Eustace, J . Org. Chem., 1973, 38, 1428. G . T. Furst, M . A . Wachsman, J. Pieroni, J. G. White, and E. J. Moriconi, Tetrahedron, 1973,29, 1675.
Terpenoih and Steroids
56
The conversion of the pinane ether (350) into fenchane glycol derivatives (351 ; = Ac or Ts, R2 = Ts or Ac) in the presence of the mixed toluene-p-sulphonicaceticanhydride reagent(see Vol. 3,p. 64)has been thesubject o f c o n t r ~ v e r s y ? ~ ~ ~ ~ ~ ~ Bosworth and Magnus have further developed the products from this type of reaction for the preparation of cyclopentanes suitably substituted for possible sesquiterpenoid syntheses [e.g. (352)].260
R'
Bicyclo[3,1,l]heptanes.-For the first time trans-chrysanthenyl acetate (353) has been described ; it was isolated, together with chrysanthenone (353), from Chrysanthemum shiwogiku, 2 6 1 and also from C .japonese var. debile.262
(353)
(354)
(355)
(356)
The structure of /3-pinene (354), as determined by electron diffraction, agrees with the results of conformational calculations.263 The acid-catalysed rearrangement of the pinenes is thought to start by proton attack on the double bond rather than on the cyclobutane ring,264 and a mechanism for the dimerization of a-pinene with phosphoric acid to give (355) starts similarly.265 A study of the catalytic hydrogenation of pinene derivatives has been made.266 The hydroboration of a-pinene to isopinocampheol(356) in 85 % yield has now appeared in Organic Syntheses.267 Oxidation of P-pinene with oxygen in the
'" 259
O'' 16'
262
263 264
265
266 267
N. Bosworth and P. D. Magnus, J . C . S . Perkin I, 1972,943. C. Grison and Y . Bessiere-Chretien, Bull. Soc. chirn. France, 1972, 4570. N . Bosworth and P. D . Magnus, J . C . S . Perkin I, 1973, 76. A. Matsuo, Y . Uchio, M. Nakayama, and S. Hayashi, Bull. Chem. SOC.Japan, 1973,46, 1565. A. Matsuo, M . Nakayama, T. Nakamoto, Y . Uchio, and S. Hayashi, Agric. and Biol. Chem. (Japan), 1973, 37, 925. V . A. Naumov and V. M. Bezzubov, Zhur. strukt. Khirn., 1972,13,977. G. A . Rudakov and L. S. Ivanova, ref. 92, p. 285 (Chern. Abs., 1973,78, 124 737). N . K . Roy, B. S. Rathore, and G. B. Butler, J . Indian Chem. Soc., 1972, 49, 1221. W. A. Boyd, D i s s . Abs. (B), 1973, 33,4185. G . Zweifel and H . C . Brown, Org. Synth., 1972,52, 59.
Mono terpeno iak
57
presence of t-butyl nitrite gives a mixture of pinocarvone (357) and the pinocarveols (358),this reaction being effected by the peroxynitrite radical, Bu'N
/ \
0 0-0
not by singlet oxygen.268 Using t-amyl hydroperoxide in the presence of hexacarbonylmolybdenum, the oxidation of a-pinene yields epoxides at 40 "C, and a
(357)
(358)
mixture of hydroxypinocamphone (359) and campholenic aldehyde (360) (presumably from an a-pinene epoxide intermediate) at 80 0C.269 Chromyl chloride oxidation of or-pinene yields270a complex mixture containing products of acid-catalysed rearrangement (bornyl chloride, borneol, dipentene), allylic
(359)
(360)
oxidation (myrtenol, myrtenal, verbenone), and oxidative addition and rearrangement [pinocamphone, pinocarveol, campholenic aldehyde, and pinol (36 l)]. Anodic oxidation of a- and fl-pinenes in acetic acid or methanol, with tetraethylammonium toluene-p-sulphonate as the supporting electrolyte, yields p-menthane
derivative^.^^ '
Ozonolysis of a-pinene gives a small amount of isomeric crystalline diperoxides, one isomer of which (362) is readily purified.272 Sabinene (254) gives a similar diperoxide of m.p. 154 0C.273
268
269 270
2'2
273
J . A. Maassen and Th. J. de Boer, Rec. Trau. chim., 1972, 91, 1329. G. A. Tolstikov, U . M. Dzhemilev, and V. P. Yur'ev, Zhur. org. Khim., 1972,8, 1190. F. W. Bachelor and U. 0. Cheriyan, Canad. J . Chem., 1972,50,4022. T. Shono and I. Ikada, J . Amer. Chem. SOC.,1972,94,7892. K . H. Overton and P. Owen, J . C . S . Perkin I , 1973, 226. A. F. Thomas, unpublished work.
Terpenoih and Steroids
58
Further work about the radical additions to p-pinene includes the use of ethylene glycol derivatives. Ethylene glycol itself does not react, possibly because of poor miscibility, but the diacetate and other derivatives give the usual 7substituted m e n t h - l - e n e ~ , ~as’ ~do d i ~ x a l a n s . ~The ~ ’ main products from the radical-initiated addition of t-butyl hypochlorite to a-pinene are myrtenyl (363) and verbenyl (364) chlorides, together with 10% of 2,6-dichlorobornane and about 10% of other d i ~ h l o r i d e s . ~ ~ ~ A conventional method277for the preparation of 6-pinene (365) in 36 % overall yield from cr-pinene requires the preparation, first, of apopinene (366), then reaction of the latter with N-bromosuccinimide, followed by Grignard coupling of the bromide (367). MeMgBr
I LI 2cucI,)
+
(366)
(367)
@.. .
(365)
The reaction between the pinenes and iodine azide has been published once by Bochwic and O l e j n i c ~ a k ,and ~ ~ twice (almost identical papers) by Ranganathan et a1.279 Using acetonitrile as solvent, a-pinene yields a mixture of ring-opened
Scheme 20 273 275 276
2”
278 2’9
M. Cazaux, B. Maillard, and R. Lalande, Compt. rend., 1972, 275, C , 1133. B. Maillard, M. Cazaux, and R . Lalande, Bull. SOC.chim. France I I , 1973. 1368. I. Uzarewicz and A. Uzarewicz, Roczniki Chem., 1973, 47, 921. D. Joulain, C. Moreau, and M. Pfau, Tetrahedron, 1973, 29, 143. The preliminary communication was submitted one month later than the full paper, to J.C.S. Chem. Comm., 1972, 1 1 10. B. Bochwic and B. Olejniczak, Roczniki Chem., 1973,47, 315. S . Ranganathan, D. Ranganathan, and A. K. Mehrotra, Tetrahedron Letters, 1973, 2265 : Synthesis, 1973. 356.
Mono terpeno ids
59
products, particularly the tetrazole (368), the acetonitrile taking part in the reaction as in Scheme 20. In addition to giving the 7-azido-isomer of the tetrazole (368), fi-pinene yields bornanes ; in dimethylformamide solution, the bornane (369) is the sole product in the reaction of c r - ~ i n e n e . ~Azides ’~ are also produced in the reaction of the pinenes with lead acetate-azide, the initial product (370) from pinene rearranging at 6 0 ° C in acetic acid to the verbenyl azide (371).280 Y
N3 I (369)
I370)
(37 1)
(372)
\\
tY
N-N
(373)
With this reagent, /?-pinene always gives skeletal-rearrangement products, 45 % being the azide (372), with 14 % of the tetrazole (373).280
(374)
(375)
COR (376)
0-
0-
Further work on the addition of carbenes to pinenes includes the full paper of an earlier note (see Vol. 2, p. 50) that reported that trans-6-pinene (365) does not react with carbene, whereas the cis-isomer gives only insertion to (374); orthodene (375) and apopinene (366) behave normally.28 The dibromocarbene reaction products with the pinenes have been described for the fourth (?) time!282 Hatem and Waegell have succeeded in removing a single chlorine atom from the dichlorocarbene adduct of a-pinene without the earlier ring-opening (see Vol. 2, p. 50).283 280 281 282
283
A. Stiitz and E. Zbiral, Annalen, 1972, 765, 34. See also the earlier reports quoted in Vol. 3, Part I, Ch. 1 , refs. 273 and 355. D. Joulain and F. Rouessac, Bull. SOC.chim. France I I , 1973, 1428. G . Mehta and S. C. Narang, Indian J . Chem., 1972, 10, 1057. J. Hatem and B. Waegell, Tetrahedron Letters, 1973, 2019, 2023.
Terpenoidr and Steroids
60
The reductive cyclopropane ring-opening of carbene addition products (376) of the pinene ketones occurs with fission of the ring in such a way that there is maximum overlap with the carbonyl n-orbitals, and, in the absence of steric factors, the most stable carbanion is formed. Thus with (376; R = Me), there is 25% formation of (377; R = Me) and 75% of (378; R = Me), but the proportion changes with increasing steric requirements of R until with (376; R = But) the sole product is (377; R = B u ‘ ) . ~ ~ ~ The reaction of P-pinene with an enophile should be stereoselective if it occurs via a cyclic transition state, approach from the methylene-bridge side being strongly favoured. In the reaction with benzene, 2-a-deuterio-P-pinene (379) transfers deuterium to phenyl (380) to the extent of at least 95%.285
(380)
(379)
(38 1)
The stereochemistry of a number of oxygenated pinanes has been discussed in the light of n.m.r. measurements286and 0.r.d. and ~ . d . ” Thioverbenone ~ (381) can be prepared in 5 5 % yield by treating verbenone (338) with a mixture of hydrogen sulphide and hydrogen chloride at 0 0C.288Electrochemical reduction of apoverbenone (382) leads to dimerization, the dimer formed by reaction on the less hindered side of both halves (383) predominating; some dimer (384) is formed from a less hindered-more hindered combination, but none where both halves involve the more hindered side.*”
+y]=t
?-iJ O H
(382)
(383)
(384)
The selenium dioxide oxidation of chrysanthenone (341) leads to chrysanthenonal (385),253the vinyl methyl group being oxidized as in the case of ver284 285
286 2a’ 288 z89
M. M. El Gaied and Y. Bessiere-Chretien, Bull. Soc. chim. France 11, 1973, 1351. R. T. Arnold, D. Koster, and V. Garsky, 165th A.C.S. Meeting, April, 1973, Abstracts ORGN No. 6. T. Hirata, Bull. Chem. SOC.Japan, 1972, 45, 3169. T. Hirata, Bull. Chem. SOC.Japan, 1972, 45, 3458. P. Metzner and J. Vialle, Bull. SOC.chim. France, 1972, 3138. J. Grimshaw and H. R. Juneja, J . C . S . Perkin I , 1972, 2529.
Mono terpenoids
61
benone (338) (see above). Per-acid oxidation of chrysanthenone (341) takes place from the side opposite to the gem-dimethyl group, leading to the trans-epoxide (386).290 The earlier preparation of this epoxide did not specify the stereochemistry.291 In view of these recorded precedents, it is surprising that Bachelor and Cheriyan had hoped to cleave the cyclobutane ring in a Baeyer-Villiger reaction of ~ h r y s a n t h e n o n e . ~ ~ ~ When pinocarveol (358) is heated with ethyl vinyl ether in the presence of phosphoric acid, the rearrangement product (387) is isolated directly.293 CHO
(385)
/
(386)
F C H O
(387)
Pyrolysis of 2-oxygenated pinanes is well known to give a variety of products, mostly ring-opened, but if the acetate is pyrolysed in pyridine, only c(- and ppinenes are The full paper on the pyrolysis of verbanone has appeared.295 A novel synthesis of the bicyclo[3,3,l]nonane system involves a Cope reaction of the enol of the piny1 ketone (388 ;R = Me). This reaction occurs when the ketone (388; R = Me) is heated above 15OoC,but at higher temperatures (above 200°C) a retro-Claisen rearrangement leads to the vinyl ether (389) (Scheme 21). The corresponding aldehyde (388; R = H) gives only the retro-Claisen reaction. 96 A reinvestigation of the reaction of pinane-2,3-dio1(390)with acetic anhydride has shown that the products are all ring-opened, trans-carveyl acetate (391) and trans-sobrerol mono- and di-acetates (392) constituting the majority.297 on the photoisomerization of cisSome anomalies in the earlier verbanone (393)were the incentive for a study which confirmed that there are two products, (394) and (395), formed in the ratio of 7 : l.299
290
291 292
293 294
295
296
297 298 299
B. A. Arbuzov, A. N. Vereshchagin, N. I. Gubkina, I . M. Sadykova, and S. G. Vul'fson, Izvest. Akad. Nauk S . S . S . R . , Ser. khim., 1972, 1288 (Chem. Abs. 1972, 77, 101 911 gives an incorrect structure for the epoxide). Y . Bessiere-Chretien and J.-A. Retamar, Bull. SOC.chim. France, 1963, 884. F. W. Bachelor and U . 0. Cheriyan, 166th A.C.S. Meeting, August 1973, Abstracts AGFD, No. 30. J. B. Hall, Ger. Offen. 2 065 172. T. N. Pisareva, L. S. Ivanova, A. G . Borovskaya, and G. A. Rudakov, Izvesf. nauch.issled. Inst. Nefte-Uglekhim. Sin. Irkutsk. Uniu., 1969, 11, 41 (Chem. Abs., 1972, 77, 152 361). J. M. Coxon, R. P. Garland, and M. P. Hartshorn, Austral. J. Chem., 1972, 25, 2409. Y . Bessitre-Chrktien and C. Grison, J.C.S. Chem. Comm., 1973, 549. There is a precedent for Cope rearrangement of an enol: S. J. Rhoads and C. F. Brandenburg, J . Amer. Chem. SOC.,1971,93, 5805. Z. Rykowski and M. Skwarek, Roczniki Chem., 1973, 47, 1555. T. Matsui, Tetrahedron Letters, 1967, 3761. A. G . Fallis, Tetrahedron Letters, 1972, 4573.
62
Terpenoids and Steroids OH e
\
OH
1
0
A (390)
(391)
koR (392)
R
=
H or Ac
,CHO
(393)
(394)
(395)
Treatment of pinonic acid (396) with 50% sulphuric acid leads to the lactone (397).300 Other pinonic acid derivatives (398) have been treated with methyllithium, and a number of other substituted cyclobutanes were prepared from the alcohols (399) thus obtained.301 300
F. Avotins and I . E. Savochkina, Laro. P . S . R . Zinat. Akad. Vestis, Kim. Ser., 1972, 483 (Chem. Abs., 1973,78,4558).
301
K . P. Sivaramakrishnan, L. H. Brannigan, and C. S. Marvel, J . Org. Chern., 1972, 37, 4206.
Mono terpeno ids
63 ,COMe
Work already well documented that has received further attention includes the rearrangement of ( + )-2-hydroxypinocamphone in oxalic acid302 and the ring contraction of cis-pinane-cis-2,3-di013-tosylate~~~ (see Vol. 2, p. 54 for both these reactions).
Bicycl~4,1,O]heptanes.--The incorrect numbering of the carene skeleton perpetrated until recently by Russian authors and frequently by Chemical Abstracts (both following logical rather than international numbering) penetrated into Volume 3 (see Errata). The reaction of car-3-ene (400) with lead tetra-acetate leads to a mixture of ringopened products, mainly (4O1J3O4
Further investigation (see Vol. 2, p. 56) of the ring-opening of car-3-ene a-epoxide (402)with hydrogen chloride shows that the stepwise low-temperature reaction gives the two chlorohydrins (403) and (404),which subsequently undergo cyclopropane ring-opening to give the corresponding menth-8-ene chlorohydrins, 302
303
304
T. Hirata, J . Sci. Hiroshima Univ., Ser. A-2, 1971,35, 239; T. J. De Pascual, I . Sanchez Bellido, and M . Grande Benito, Anales de Quim., 1973,69, 217. T. Hirata and T. Suga, Yuki Gosei Kagaku Kyokai Shi, 1972, 30, 1050. A publication omitted from earlier Reports is R. C. Carlson and J. K. Pierce, Tetrahedron Letters, 1968, 621 3 , who described this ring contraction independently of the Japanese work. B. A. Arbuzov, V . V. Ratner, and Z . G . Isaeva, Izvest. Akad. Nauk S . S . S . R . , Ser. khim., 1973, 45.
Terpenoids and Steroids
64
together with some m-menthene c h l ~ r o h y d r i n . ~Ring-opening ~' of the epoxide (402) with acetyl bromide in acetic anhydride gives mostly the cis-adduct (405), with minor amounts of trans-adduct (406).305 Treatment of this cis-adduct (405) with alcoholic potassium hydroxide yields the three substances (407), (408),and (409) in the ratio 3 : 1 : 5,305 whereas similar treatment of the trans-adduct gives car-3-ene fl-epoxide (410).307These reactions are summarized in Scheme 22.
+
..OH
+
4--
Scheme 22
Acid-catalysed hydration of car-3-ene a-epoxide (402) yields a diol of m.p. 137 " C ,previously assigned the structure caran-3P,4fl-diol (411). The latter has now been made by several routes, e.g. mercuration-demercuration of the acetates of alcohols (408)308or (409),309or directly from car-3-ene by treatment with silver 305
306
307
308
3 09
B. A. Arbuzov, Z. G. Isaeva, G. Sh. Bikbulatova, and N. I . Semakhina, Doklady Akad. Nauk S.S.S.R., 1972,207,853. I n this paper, Arbuzov draws attention to the I.U.P.A.C. convention for numbering the carane ring. B. A. Arbuzov, E. Kh. Kazakova, and Z. G. Isaeva, Izvest. Akad. Nauk S.S.S.R., Ser. khim., 1972, 1681. Z . G. Isaeva, E. Kh. Kazakova, and R. R. D'yakonova, Sbornik Nekot. Probl. Org. Khim., Muter. Ncuch. Sess., Inst., org.$z. Khim. Akad. Nauk S . S . S . R . ,ed. A. N. Vereshchagin, 1972, p. 40 (Chem. Abs., 1973, 7 8 , 30007). B. A. Arbuzov, Z. G. Isaeva, R. R. D'yakonova, V. A. Shaikhutdinov, and E. Kh. Kazakova, Izvest. Akad. Nauk S . S . S .R., Ser. khim., 1972, 1680. B. A. Arbuzov, V. A. Shaikhutdinov, and Z. G. Isaeva, Izvest. Akad. Nauk S.S.S.R., Ser. khim., 1972, 2124.
65
Monoterpenoids
acetate and iodine in aqueous acetic acid (followedevery time by hydrolysis of the acetates); the diol (411) has m.p. 42 0C.308 The structure was confirmed by inverting the configuration at C-4 of the diol of m.p. 89-90 "C (412) by acetolysis of the tosylate of (412), giving (411) and the bicyclo[3,1,0]hexane (413).309 Car3-ene epoxides (402) and (410) are also opened by sodium bisulphate or sodium
sulphate. Bisulphate yields only glycols, but sulphate yields a mixture containing 27 % of the sulphonate (414) from the or-epoxide (402) and 64 % of the sulphonate (415) from the P-epoxide (410).310
+ (412)
+
+
(411)
A further communication about the stereochemical course of the photolysis of 3-methylcar-4-en-2-one (416) (see Vol. 3, p. 83) in the presence of methanol, leading to (417),confirms that the earlier course311is correct, but only because the stereochemicalassignments for the methyl groups in both educt and product must be rever~ed.~ * Beckmann rearrangement of the caranone oximes (418) and (419) leads, respectively, to the amides (420) and (421), using toluene-p-sulphonyl chloride in basic 310
311
*
E. MySliriski and E. Michal'ek, Roczniki Chem., 1973, 47, 2 8 5 . These authors seem to have been unaware of Arbuzov's work308 and have the configurations of two of the carandiols (of m.p. 137 and 30 "C-the latter probably the same as Arbuzov's glycol of m.p. 42 "C) opposite to those of the Soviet workers. J. E. Baldwin and S. M. Krueger, J . Amer. Chem. Soc., 1969, 91, 2396. A. J. Bellamy and W. Crilly, J . C.S. Perkin 11, 1973, 122.
Terpenoids and Steroids
66
aqueous acetone, but the unsaturated oxime (422: R = H) gives only the tosylate (422; R = Ts) under these condition^.^'^
(420)
I
(422)
A synthesis of chamic acid methyl ester (423) and chaminic acid (424) starts from dimethyl 5-hydroxyisophthalate (425) (Scheme 23). The key step is the cyclization of the chloro-ketone (426) to give 42% of the trans-ester (427) and 28 7; of the cis-ester (428). The double bond is then introduced into (427) under conditions which do not epimerize the ester group.314 A further double-bond isomer of these acids was synthesized as the ester (429) by allowing the cyclohexadiene ester (430) to react with diphenylsulphonium isopropylide (431), when the esters (429) and (432) were obtained, in amounts that varied with the solvent used. Conformations and hydrogen-bonding in the carene derivatives (433) and (434) have been discussed in terms of their i.r. spectra.316
'
7 Furanoid and Pyranoid Monoterpenoids A new synthesis of -?-substituted furans has been applied to making perillene (435). Methylheptenone is converted into the n-butylthiomethylene derivative (436) of its a-formyl derivative and this is then treated with dimethylsulphonium
"' 'I s 'I5 'I6
A . Zabia. C. Wawrzenczyk, and H . Kuczynski, Bull. Acad. polon. Sci., SPr. Sci. chim., 1972, 20, 521.
W. J. Gensler and P. H . Solomon, J. O r g . Chern., 1973, 38, 1726. C. S. F. Tang and H. Rapoport, J. Org. Chern., 1973,38,2806. I . P. Povodyreva, R. R. Shagidullin, and T. N . Ivaseva, Izvest. Akad. Nauk S . S . S . R . , S r r . kkim., 1972, 2618. The numbering is incorrect here, and also in Chern. A h . , 1973, 78. 8 4 5 5 2 .
Mono t erpeno ids
vi, vii
67
1
Reagents: i, Rh/AI,O,-H,; ii, hydrolysis; iii, AcCl; iv, MeMgCl; v, c. HC1; vi, esterify; vii, oxidize; viii, KOBu'; ix, [PhNMeJBr,; x, NaBH,; xi, Zn-MeOH; xii, alkali.
Scheme 23
Terpenoids and Steroids
68
(433)
(434)
methylide, when a 55 % yield of perillene (435)is obtained, together with recovered n-butylthiomethylene derivative (436).3l 7
The absolute configuration at C-2 of the oxides (437)--(440) from Liliurn rnakinoi is the same as that of the congeneric linalool, which is therefore presumed to be a biosynthesic p r e c u r ~ o r .*~
A new synthesis of the lilac alcohols (441) as an isomeric mixture has been carried out by Vig et al. by cyclizing the ester (442)with sodium hydride in benzene, then reducing the ester group with lithium aluminium h ~ d r i d e . ~ ”
(442)
”’ 3‘8 319
(44 11
M . E. Garst and T. A. Spencer, J . Amer. Chem. SOC.,1973, 95, 250. T. Okazaki, A. Ohsuka, and M . Kotake, Nippon Kakaku Kaishi, 1973,359 (Chem. Abs., 1973, 7 8 , 136 423). 0. P. Vig, R. S. Bhatt, J . Kaur, and J . C. Kapur, J . Indian Chem. SOC.,1973, 50, 37.
Mono terpenoids
69
8 Cannabinoidsand other Phenolic Monoterpenoids The name ‘meroterpenoid’has been suggested for compounds arising from mixed bi~genesis,~ 2o and phenolic terpenoids belong to this class. The isolation of alliodorin (443) from Cordia alliodora lends some support to occurring in C. millenii arise by the idea321that the cordiachromes [e.g. (a)] condensation of a benzenoid precursor with geranyl pyrophosphate and subsequent oxidative cyclization of an ally1 methyl group. Alliodorin (443) represents a stage along such a
OH
I
I
0
(443)
(444)
Linalool or myrcene produce the cation (445), which reacts with hydroquinones to produce a mixture of chromans (Scheme 24).323 OH
OH
(445)
R’ = H, RZ = Me, Bu‘, or t-octyl, R3 = H ; or R’
=
RZ = R3 = Me
Scheme 24 320 J21
322 323
J. W. Cornforth, Chem. in Britain, 1968, 4, 102. M. Moir, R. H. Thomson, B. M. Hausen, and M. H. Simatupang, J.C.S. Chem. Comm., 1972, 363. K. L. Stevens, L. Jurd, and G. Manners, Tetrahedron Letters, 1973, 2955. M. H. Stern, T. H. Regan, D. P. Maier, C. D. Robeson, and J. G. Thweatt, J. Org. Chem., 1973, 38, 1264.
Terpenoids and Steroids
70
Sukh Dev’s group has isolated the phenolic terpenoid (446)from Psoralea corylifolia and has established the absolute configuration I
I
Another review of the cannabinoids has a ~ p e a r e d . ~ ’ It has been stated that thin-layer chromatography is preferable to gas chromatography in the analysis of the constituents of cannabis;326 nevertheless gas chromatography takes a prominent place in much of the work described below. An analysis of the headspace over cannabis essential oil [using gas chromatography-mass spectrometry (g.c.-m.s.)] yielded only common monoterpenoids as positively identified.327 One report3’* stated that it was not yet possible to measure the level of tetrahydrocannabinol (THC) in blood using g.c.-m.s. coupling, at about the same time that a prominent manufacturer of g.c.-m.s. equipment was advertising just that ! 3 2 9 A new cannabidiol monomethyl ether (447) has been isolated from hemp leaves of a Japanese variety,330 and from South African Cannabis satiua a new acid, A’-tetrahydrocannabivarolicacid (448).33
’
1’
3 24
325
326 327
328 329 330
33 1
I
G . Mehta, U. R . Nayak, and Sukh Dev, Tetrahedron, 1973,29, 1 1 19; A. S. C. P. Rao, V . K. Bhalla, U. R. Nayak, and Sukh Dev, ibid., p. 1127. R. K. Razdan in ‘Progress in Organic Chemistry’, Vol. 8, ed. W. Carruthers and J. K. Sutherland, Butterworths, 1973. M. R. Paris and R . R. Paris, Bull. SOC.chirn. France 11, 1973, 118. L. V. S. Hood, M. E. Dames, and G. T. Barry, Nature, 1973,242,402; see also ref. 186 for analytical work on hashish smell. Nature, 1973, 244, 3 . Advertisement for LKB in Chem. and Ind., 1973, July 7, p. vi. Y. Shoyama, K. Kuboe, I . Nishioka, and T. Yamauchi, Chem. and Pharm. Bull. (Japan), 1972,20,2072. M. Paris, C. Ghirlanda, M. Chaigneau, and L. Giry, Compr. rend., 1973, 276, C , 205.
71
Monoterpenoids
The metabolism of A'-THC [(449), using normal monoterpenoid numbering] by a liver microsomal fraction of the squirrel monkey, Saimiri sciureus, has resulted in the isolation of two new metabolites, the 6-ketone (450) and the epoxide (451) (the configuration of the latter was not established on the isolated material, but synthetic work referred to below has shown it to be as drawn), and three new metabolitites (5-0x0-A"-THC, 5p- and Sa-hydroxy-A6-THC) were identified from A6-THC metabolism.332 After oral administration of A'-THC (449), the following were isolated from human blood plasma: A'-THC, 7-hydroxy-A1-THC (452), and 6~,7-dihydroxy-A'-THC, together with tentative
identification of 6p- and 6 a - h y d r o ~ y - A l - T H C .Some ~ ~ ~ of these metabolites show activity, and there are suggestions that some cannabis effects are due to them.334 Tested separately, 7-hydroxy-A1-THC has about the same potency as A1-THC, GP-hydroxy-A'-THC is less potent, and the 6a-hydroxylated material is inactive.33 Cannabidiols (453) and cannabinol (454)are inactive in man.336 The marihuana activity of various A'-THC and A6-THC substituted in the aromatic ring at C-3' and C-5', and having various side-chains at C-4', has been examined.337
ho
OH
(453) 332 333
334
335
336 337
(454)
(455)
0. Gurny, D. E. Maynard, R. G . Pitcher, and R. W. Kierstead, J . Amer. Chem. SOC.. 1972, 94, 7928. M . E. Wall, D. R. Brine, C. G . Pitt, and M . Perez-Reyes, J . Amer. Chem., SOC.,1972, 94, 8579. L. Lemberger, J. L. Weiss, A. M . Watanabe, I . M. Galanter, R. J. Wyatt, and P. V. Cardon, New England J . Med., 1972, 286, 685. Many other papers attest to this, including all those on the synthesis of metabolites quoted below. M . Perez-Reyes, M. C. Timmons, M . A. Lipton, H . D. Christensen, K. H . Davies, and M . E. Wall, Experientia, 1973,29, 1009. L. E. Hollister, Experientia, 1973, 29, 825. H. Edery, Y . Grunfeld, G . Porath, 2. Ben-Zvi, A. Shani, and R. Mechoulam, Arzneim.Forsch., 1972, 22, 1995.
Terpenoidr and Steroids
72
(456)
(460)I %
(461) 14%
Reagents: i, SOC1,-py, 0 " C , 16 h ; ii, SO,Cl,; iii, AgOAc.
Scheme 25
Much synthetic work this year has concerned the metabolites of A'-THC. Oxidation with selenium dioxide of A'-THC gives the 6-ketone (450),and epoxidation of A'-THC yields the epoxide (451),the configuration of which was established by conversion with boron trifluoride into the ketone (455), in which the methyl group has to have the same configuration as the epoxide, and which was shown to be in the unfavourable cis-configuration by isomerization with base to the trans-isomer. Finally the 5-oxygenated A6-THC compounds were made by t-butyl chromate oxidation of A6-THC acetate to give the 5-oxo-compound, which was reduced with lithium aluminium hydride to the corresponding alcohols.33* A convenient synthesis of the 7-hydroxy-metabolite from A1(')THC (450), announced briefly last year (see Vol. 3, p. 87), has been improved in the full paper by carrying out an osmium tetroxide oxidation on the acetate of (456) and dehydrating the product (457) with thionyl chloride in pyridine, when the two THC acetates (458; R = Ac) and (459; R = Ac) are obtained in the 378
R. Mechoulam, H. Varconi, Z. Ben-Zvi, H. Edery, and Y. Grunfeld, J . Arner. Chern. S O C . ,1972. 94, 7930.
Mono t erpenoids
73
ratio of 2 : More directly, 7-acetoxy-A1-THC(459; R = H) can be made by treatment of A’-THC with sulphuryl chloride followed by silver acetate, the 6-acetoxy-compounds (460; R = Ac) and (461; R = Ac) being formed at the same time (Scheme 25).340 The same paper reports a new route to 7-hydroxy-A1-THC (452) from the ketone (462), which is outlined in Scheme 26.340
l i i . iii
A (4 52)
A
Reagents: i, 0
NH-Cl,CCO,H ; ii, HC1-ZnC1,,2H20-CHC1,; iii, Et,COK-toluene; L J iv, EtOH-KOH; v, LiAIH,.
Scheme 26
Another paper has been published about the preparation of tritium-labelled cannabinoids from labelled olivetol;341it includes a very similar route to that mentioned earlier (see Vol. 3, p. 88). Some reactions of A6-THC have been carried out by Mechoulam’s group. The epoxide (463), on treatment with boron trifluoride etherate, gives two compounds, the ketone (464) and the ring-contracted aldehyde (465), depending on whether bond a or b migrates (see formula). Hydroboration of A6-THC leads to a mixture of the alcohols (466) and (467)and the B-oriented alcohol (467)can be 339 340
341
R. K. Razdan, D. B. Uliss, and H. C. Dalzell, J . Amer. Chem. SOC.,1973,95, 2361. C. G. Pitt, F. Hauser, R. L. Hawks, S. Sathe, and M. E. Wall, J . Amer. Chem. SOC., 1972,94, 8758. S. Agurell, B. Gustafsson, T. Gosztonyi, K. Hedman, and K. Leander, Acra Chem. Scand., 1973, 27, 1090.
Terpenoids and Steroids
74
dehydrated (uiu the tosylate) to As-THC (468), which is devoid of marihuana
C5H1
1
Some analogues of A6-THC with nitrogen in the pentyl side-chain have been prepared,343and some of A’-THC with nitrogen in the menthane ring.344 There are some papers on more general aspects of reactions of terpenoids with phenols. The full paper of the citric acid-catalysed condensation of orcin and s42
743
344
R . Mechoulam, Z. Ben-Zvi, H . Varconi, and Y . Samuelov, Tetrahedron, 1973, 29, 1615. T. Petrzilka and W . G. Lusuardi, Helu. Chim. Acta, 1973, 56, 510: T. Petrzilka, M . Demuth, and W. G. Lusardi, ibid., p. 519. M . Cushman and N. Castagnoli, jun., J . Org. Chem., 1973, 38, 440. We hope that this paper, using a more appropriate numbering system, presages a change of heart by the American Chemical Society!
75
Mono t erpenoids
monoterpenoid alcohols (see Vol. 3, p. 88) contains a discussion about the formation of the dihydrobenzofurans (469) and (470), formed respectively from menth4-en-3-01 (471) and pulegol (15).345 Crombie’s group has suggested how the
H
I
(15) --+ -+
, o orientation of chromenylation in reactions between phenols and certain aldehydes (catalysed by pyridine) may be governed by the possibility for chelation throughout the reaction sequence, a simple example being illustrated in Scheme 27.
xt:
-0
Scheme 27
For examples of such reactions, see the literature and also Vol. 2, p. 62. A condensation of this nature, between citral (109) and pinocembrene (472), was already known to occur in the presence of pyridine (see Vol. 2, p. 63). Now Montero and Winternitz have effected347a kind of biological synthesis 345 346 347
B. Cardillo, L. Merlini, and S. Stefano, Gazzerra, 1973, 103, 127. D. G. Clarke, L. Crombie, and D. A. Whiting, J.C.S. Chem. Comm., 1973, 580, 582. J. L. Montero and F. Winternitz, Tetrahedron, 1973,29, 1243.
76
Terpenoids and Steroids
by carrying out the reaction in the presence of a pseudo-alkaloid,anibine (derived from nicotinic acid), when they obtained ( & )-rubranine (473) in higher yield than when pyridine was the catalyst. -
HO
Ph (472)
+
--*
k WPh (473)
2 Sesq u iterpenoids BY
R. W. MILLS AND
T. MONEY
1 Introduction The large number of publications which appear each year on the structure, synthesis,’ biosynthesis,2 and natural occurrence of sesquiterpenoids reflects the widespread interest in this group of natural products. This high level of research activity has been maintained during the period covered by the present Report. The excellence of previous Reports3 in this series was largely due to the organized way in which new information was presented. Sesquiterpenoids were classified into structural groups based on biosynthetic consideration^^"-^ and, to some extent, on the number of carbocyclic rings in the basic structure. The present Reporters have adopted a similar classification with minor modifications and, for convenience, skeletal representations of the various structure types are shown in Table 1. Most of the biosynthetic investigations described in the present Report make excellent use of substrates specifically labelled at an appropriate prochiral centre and rely heavily on the pioneering, authoritative studies of the CornforthPopjak group. A new review describing some of these studies has appeared recently. 2 Farnesanes
Current biosynthetic theory assumes that the biosynthesis of all sesquiterpenoids4” involves appropriate modification of the pyrophosphate esters of trans,-
’ C. H. Heathcock, in ‘Total Synthesis of Natural Products’, ed. J. W. ApSimon, Wiley, New York, 1973, Vol. 2. J. R. Hanson, in ‘Biosynthesis’, ed. T. A. Geissman (Specialist Periodical Reports), The Chemical Society, London, 1972, Vol. 1, p. 41. J. S. Roberts, in ‘Terpenoids and Steroids’, ed. K. H. Overton (Specialist Periodical Reports), The Chemical Society, London, ( a ) 1971, Vol. 1 , p. 5 1 : (b) 1972, Vol. 2, p. 65 ; ( c ) 1973, Vol. 3, p. 92. ( a ) W. Parker, J. S. Roberts, and R. Ramage, Quart. Rev., 1967,21, 31 1 and references cited; (6) L. Ruzicka, Experientia, 1953, 9, 357; (c) J. H. Richards and J. B. Hendrickson, ‘Biosynthesis of Steroids, Terpenes, and Acetogenins’, Benjamin, New York, 1964, p. 225; (d)T. A. Geissman and D. H. G . Crout, ‘Organic Chemistry of Secondary Plant Metabolism’, Freeman, Cooper and Co., San Francisco, 1969, p. 269; ( e ) J. W. Cornforth, Angew. Chem. Internat. Edn., 1968, 7 , 903; Quarr. Rev., 1969, 23, 125; (f)W. B. Turner, ‘Fungal Metabolites’, Academic Press, 1971, p. 219. J. W. Cornforth, Chem. SOC.Rev., 1973,2, 1 .
77
Terpenoids and Steroids
78
/-+
Ill
W
E
79
Sesquiterpenoids
>h Ek
“6
Terpenoids and Steroids
80
?d
k‘ Y’
d
.-
-Y
LL
Ill
I
3
t
Monocyclofarnesane
Bicy clofarnesane (Drimane)
Bourbonane
Aromadendrane
a-,
Pseudoguaiane
/
Guaiane
Maaliane
CYPerane
lshwarane
Pre-Seychellane
Aristolane
Seychellane
82
Terpenoids and Steroids
trans-farnesol (l),cis,trans-farnesol(3),or nerolidol(2). The formation of cis,transfarnesol could involve direct biosynthesis from mevalonic acid or isomerization of the trans,trans-isomer (1) (e.g. via nerolidol). Recent studies using [ l,l-2H2]trans,trans-farnesol or [1,l -2H2]-trans,trans-2,3-epoxyfarnesolhave shown that Helrninthosporiurn satiuurn can convert these compounds into the corresponding cispans-compounds via the aldehyde intermediates (4) and (5) (Scheme 1).6
A (31
E
C
H
O
(4)
Scheme 1
(5)
A similar study, using a cell-free system from Andrographis panicdata and appropriately labelled mevalonate as substrate, has also demonstrated that the isomerization of trarqtrans- (1) to cis,trans-farnesol (3) involves aldehyde inter(6) and mediates.' A total loss of 3H label from [2-'4C,(4S)-4-3Hl]mevalonate complete retention from [2-14C,(4R)-4-3H,]mevalonate (9) was found in both (1) and ( 3 ) (Scheme 2).7*8Using [2-14C,5,5-3H,]mevalonate there was total retention of tritium in trans,truns-farnesol (1) but loss of one-sixth of the tritium in the cis,trans-isomer (3) (cf. p. 92). It has also been shown' that cell-free extracts of Citrus sinensis (orange) flavedo can convert geranyl (1 1) and isopentenyl pyrophosphate ( 7 ) into a mixture of farnesols and farnesals. A redox Y . Suzuki and S . Marumo, Tetrahedron Letters, 1972, 1501.
' K. H. Overton and F. M. Roberts, J.C.S. C h m Cornrn., 1973, 378. Cf. E. Jedlicki, G . Jacob, F . Faini, and 0.Cori,.Arch. Biochem. Biophys., 1972,152,590. L. Chayet, R. Pont-Lezica, C. George-Nascimento, and 0. Cori, Phytochemistry, 1973, 12, 95.
Sesquiterpenoids
83
mechanism (cf. Scheme 1) for the isomerization of the farnesols is supported by the fact that farnesyl pyrophosphate could not be isomerized by the cell-free extract. It is also significant that NAD+ favours the isornerization and that neryl pyrophosphate (12) cannot substitute for the trans-isomer (1 1) in the biosynthetic process.' For further discussion of biosynthetic studies see Chapter 7, p. 254.
-
T H
HT y HOH,C
q C0,H
--+
(1)
+ (3)
Scheme 2
Further studies on the sesquiterpenoid constituents of the stock-poisoning shrub, Myoporium deserti A. Cunn, have revealed the presence of (-)-epingaione (1 3), ( - )-dehydrongaione (14), ( - )-dehydroepingaione (1 5), and ( - )-deisopropylngaione (16)" The same group of investigators has also established the stereochemistry of ( - )-myoporone (17) and ( - )-dehydromyoporone (18), which occur in various myoporium and eremophila species' (monocyclic metabolites of this plant are described on p. 143). Dendrolasin (21) has been syn-
'
lo
"
W. D. Hamilton, R. J. Park, G. J . Perry, and M. D. Sutherland, Austral. J . Chern., 1973, 26, 375. I . D. Blackburne, R. J. Park, and M . D. Sutherland, Austral. J . Chem., 1972, 25, 1787.
84
R
3
Terpenoids and Steroih
2
0
(13) (15 ) 2,3-dehydro-( 1 3)
0
(14) R = CH,COCH=CMe,
(17)
(16) R = CH,COMe
(18) 2,3-dehydro-( 17)
Po+ Q?@
thesized from ketone (19)by a synthetic route which should be generally applicable to a variety of furanoid sesquiterpenoids. l 2
0
S(CH d3Me (19)
(20)
(21)
A recent structural elucidation'3.'4 of gyrinal (27), a nor-sesquiterpenoid isolated from the 'whirligig' beetle (cf: p. 143) has been followed by two stereowhich are virtually identical (Scheme 3). The synthesisI6 selective syntheses' ' 9
'
OHC O -R
&OR (22) R
=
0
COMe
(23) R = CO
(24) ki,
111
J L . A - b * R "
OAc
(25)
0
CHO 0 (27) Reagents: i, SeO,; ii, MeCH(0Li)C GCLi-THF; iii, Ac,O-py; iv, Na-NH,; v, LiAlH,; vi, MnO,.
Scheme 3
l 3
l4
''
l6
M. E. Garst and T. A. Spencer, J. Amer. Chem. SOC., 1973,95,250. H. Schildknecht, H. Neumaier, and B. Tauscher, Annalen, 1972, 756, 155. J. Meinwald, K. Opheim, and T. Eisner, Proc. Nat. Acad. Sci. U . S . A . , 1972, 69, 1208. J. Meinwald and K. Opheim, Tetrahedron Letters, 1973, 281. C. H. Miller, J. A. Katzenellenbogen, and S. B. Bowlus, Tetrahedron Letters, 1973,285.
85
Sesquiterpenoidr
which uses geranyl mesitoate (23) as starting material and LiA1H4 to cleave the ester function and reduce the triple bond is reputed to be more efficient. Considerable effort has been expended on the structural elucidation, synthesis, and physiological properties of the juvenile hormone (28) of Hyulophora ce~ropiu.~"' A new stereoselective synthesis (Scheme 4) of this compound
i, iii
lv lviii
J
\
0
Reagents: i, BuLi-DABCO; ii, SOC1,-py; iii, +OTHP;
iv, BuLi-DABCO-/(1
;
c1 v, hydrolysis, Li-EtNH,, -70 " C ;vi, Li-EtNH,, -20 "C;vii, Jones oxidation; viii, acetylation, Ra-Ni; ix, (EtO),PCH ,CO,Me.
It
0
Scheme 4
Reviews: B. M. Trost, Accounts Chem. Res., 1970, 3, 120; J . B. Sidall, 'Chemical Energy', ed. E. Sondheimer and J . B. Simeone, Academic Press, New York, 1970, p. 282.
Terpenoids and Steroids
86
employs an elegant reaction sequence based on the condensation of dihydrothiopyrans.'* An alternative synthesis, based on the Claisen rearrangement of vinyl ally1 etherslg has also been described (Scheme 5).20 A probable biosyn-
r
I
I A
v
C
0
2
1 OH
0
OH Reagents: i,
OMe ; ii, TsC1-py; iii, NaOMe-MeOH.
Scheme 5
thetic precursor of juvenile hormone (28) is bishomofarnesyl pyrophosphate (32), and the formation of this compound by incubating cis-3-methylpent-2-enyl pyrophosphate (29), 3-ethylbut-3-enyl pyrophosphate (30), and isopentenyl pyrophosphate (31)with farnesyl pyrophosphate synthetase has been reported.21
Lop, + + L
(39)
18
2o
''
O
(30)
P
2
L
O P (31)
,
K. Kondo, A . Negishi, K . Matsui, D. Tunemoto, a n d S. Masamune, J . C . S . Chem. Comm., 1972, 1311. W . S. Johnson, T . J . Brocksom, P. Loew, D. H . Rich, L. Werthermann, R. A. Arnold, T. Li, a n d D. J. Faulkner, J . Amer. Chem. SOC.,1970, 92, 4463. D. J . Faulkner and M . R. Petersen, J . Amer. Chem. SOC.,1973.95, 553. T. Koyama. K . Ogura, and S . Seto, Chem. Letters, 1973, 401.
87
Sesquiterpenoids
3 Bisabolanes A recent general method**for the synthesis of bisabolane-type sesquiterpenoids has been used in the synthesis of (-)-cryptomerion (34) from (-)-carvone (33).23 It has also been notedz3that irradiation of cryptomerion provides photocryptomerion (35) in a reaction which is analogous to the photocyclization of carvone (33) to carvonecamphor (36) (Scheme 6). The [2,3]-sigmatropic rearrangement of
0 (33) 1vii
J
(36)
(34)
(35)
Reagents: i, Zn-NaOH; ii, (HOCH,),CMe,-H ; iii, BuLi-TMEDA-Me,C =CHCH ,C1; iv, H+-Me,CO; v, [PhN+Me,]Br,-; vi, py. A ; vii, hv. +
Scheme 6
I
i-0-
BPLi ___+
p \p -
PhS--MeOH
Ar\ OL/
CH,OSAr
(37)
(38)
1
'* 23
(39) R. J. Crawford, W. F. Erman. and C. D. Broaddus, J. Amer. ChPm. SOC.,1972, 94, 4298. G. L. Hodgson, D. F. MacSweeney. and T. Money, J.C.S. Chern. Cornrn., 1973, 236.
Terpenoids and Sterolds
88
allylic sulphoxides [e.g. (37)] to allylic sulphenates [e.g.(38)] forms the basis of a new synthesis of ( )-(E)-nuciferal (39)240(natural nuciferal possesses the 2 configuration). The same group has also described a two-step synthesis (Scheme 7) of (-t )-ar-turmerone (42) using regiospecific alkylation of the dianion (41) of the P-ketophosphonate ester (40).24b 0
0
P
0
A (42)
Reagents: i , N a H - T H F ; ii, BuLi; iii, NaH-dimethoxyethane; iv, M e 2 C 0 .
Scheme 7
Pseudotsugonal (43), ar-pseudotsugonal (44),( + )-methyl todomatuate (45),2 and ( - )-dihydroepitodomatuic acid (46)24 have been isolated from Douglas fir grown in British Columbia and assigned the R,R configuration. The biological activity of these compounds may be interesting since similar metabolites of balsam fir, juvabione (47) and (+)-dehydrojuvabione (48), have been shown to possess insect juvenile hormone activity. Spectroscopic evidence has been provided for the structure of deodarone (49), a component of the essential oil of Cedrus deodoru Loud.”
24 25 26
2,
P. A. Grieco and R . S. Finkeihor, ( a )J. O r g . Chem., 1973, 38, 2245; ( b ) ibid.,p. 2909. T. Sakai and Y . Hirose, Chem. Letters, 1973, 491. I . H . Rogers and J. F . Manville, Canad. J . Chem., 1972,50, 2380. R . Shankaranarayanan, S. Krishnappa, S. C. Bisarya. and S. Dev, Tetrahedron Letters, 1973. 427.
Sesquiterpenoih
89 H
0P
C
O
2
0@C02Me
H
A (47)
0@C02Me
4 Sesquicarane, Carotane, etc.
A new sesquiterpenoid diol, jaeschkeanadiol (50), has been isolated from the roots of Ferula jaeschkeana Vatke.28 Sequential ring-expansion and ring-
(50)
contraction techniques have been used in a recent synthesis of (+)-daucene (51),29and the low-yield conversion of this compound into (+)-carotol(52) and (-)-daucol(53) has also been described (Scheme 8).29
Scheme 8 (continued overleaf) 28
M . C. Sriraman, B. A. Nagasampagi, R. C. Pandey, and S. Dev, Tetrahedron, 1973,29, 885.
29
H. de Broissia, J . Levisalles, and H. Rudler, Bull. Soc. chim. France, 1972, 4314.
Terpenoids and Sterolds
90
iii,
iv
Reagents: i, C H , N , ; ii, PCl,; iii, per-acid; iv, Li-EtNH,; v, p-O,NC,H,CO,H.
Scheme 8
5 Cuparane, Laurane, Trichothecane, etc. Detailed descriptions of recent studies on the biosynthesis of the trichothecane group of sesquiterpenoids have been provided.2,30-34,36-40 Th e structures of these compounds are based on the 12,13-epoxytrichothec-9-enenucleus (62) and the cumulative efforts of various research groups have provided evidence which supports the proposed biosynthetic route shown in Scheme 9. Incorporation experiments, using mevalonic acid (54),geranyl pyrophosphate ( 5 3 , and farnesyl pyrophosphate (56) specifically labelled with 14Cand/or 3H, have shown that trichothecin (65) is derived from three molecules of mevalonic and that cispans-farnesyl pyrophosphate (56)30 is an intermediate on the biosynthetic pathway. Incorporation of tritium from [2-3H]geranyl pyrophosphate (55) into position 2 of the trichothecane nucleus3’ and an e ~ a m i n a t i o nof~the ~ precursor activity of y-bisabolene (57)exclude the latter compound as a precursor of trichothecin (65).* Further support for the biosynthetic proposals outlined in Scheme 9 has been provided by the isolation of trichodiene (59),36trichodiol (60),3“,? 12,13-epoxytrichothec-9-ene(62),3 and 4,8-dihydroxy-12,13-epoxytrichothec-9-ene (68)3 from Trichothecium roseum and by the demonstration that radioactivity from tritiated trichodiene (59) can be incorporated into t richot hecolone (66).
’
”
B. A. Achilladelis, P. M. Adams, and J. R. Hanson, J.C.S. Perkin I , 1972, 1425 and references cited therein.
.’’ Y . Machida and S. Nozoe, Tetrahedron, 1972, 28, 5 1 13. ’’ E. R. H. Jones and G . Lowe, J. Chem. S O C . ,1960, 3959.
R. Achini, B. Muller, and Ch. Tamm, Chem. Comm., 1971, 404. J . M. Forrester and T. Money, Canad. J . Chem., 1972, 50, 3310. 1 5 P. M. Adams and J . R. Hanson, J . C . S . Perkin I , 1972, 586; S. Nozoe, M. Morisaki, and H. Matsumoto, Chem. Comm., 1970, 926. 3 6 S. Nozoe and Y . Machida, Tetrahedron Letters, 1972, 28, 5105. ” Y. Machida and S. Nozoe, Tetrahedron Letters, 1972, 1969. ’* R. Evans, A. M. Holtom, and J. R. Hanson, J . C . S . Chem. Comm., 1973, 465. ’’ S. Nozoe and Y . Machida, Tetrahedron Letters, 1970, 1177. 4 o P. M. Adams and J. R. Hanson, Chem. Comm., 1970, 1569. 3 S
* y-Bisabolene (57) has also been excluded as an intermediate in the biosynthesis of the cuparane-type sesquiterpenoid helicobasidin (7 I). t The ‘trichodiol’ (61) previously described39 is an artifact produced from trichodiol during saponification. 3 6
91
Sesquiterpenoids OH
(63) R = M (64) R = COMe
(65) R (66) R
= =
COCH=CHMe H
(67) R = COCH=CHMe
Scheme 9
Trichodiene (59) and cis,trans-farnesol [c$ (5611 are also formed when trans, trans-[1,1,5,5,9,9-3H,,4,8,12-'4C3]farnesyl pyrophosphate is incubated with a cell-free extract of T. r ~ s e u r n The . ~ ~ loss of one tritium label during the formation of (59) and (56) is readily explained by isomerization of the precursor to the cis,
Terpenoids and Steroids
92
trans-form (56) by a redox mechanism (cf: p. 82), followed by cyclization to trichodiene (59). Comparative experiments using [2,2-3H, ,2-' 4C]mevalonate (54) as precursor demonstrated that trichothecolone (66) (from T. roseurn) and trichodermol(63) (from Trichoderrna sporulosurn)contained four and five [2-3H]mevalonoid labels re~pectively.~'One of the incorporated tritium atoms in trichothecolone (66) was located at position 7 (exchanged with base) and this has prompted the suggestion3' that crotocin (67),which co-occurs with trichothecin, may be an intermediate in the biosynthetic route. Rearrangement of crotocin (67) to trichothecin (65) could involve a 1,2-hydride shift, and this would explain the labelling results described above. When trichodermol (63), containing five [2-3H]mevalonoid labels (positions 4,8, and 14), was fed to T. roseurn the trichothecin (65)and trichothecolone (66)isolated contained only three tritium atoms.40 This evidencejustifies the inclusion of trichodermol(63) as an intermediate in the biosynthetic route to trichothecin etc. Studies on the stereochemistry of trichodermol(63) have shown that epoxidation occurs on the p-face of the m~lecule.~'With verrucarol (15-hydroxytrichodermol) some reaction occurs on the a-face owing to the directing effect of the C- 15 hydroxy-group. Two new trichothecanes, calonectrin (69) and 15-deacetylcalonectrin (70), have been isolated from culture filtrates of Calonectria n i u ~ E i s . ~ ~ The absence of oxygen functionality at C-4 differentiates these compounds from other members of the trichothecane group of fungal sesquiterpenoids.
(69) R = COMe (70) R = H
Gymnomitrol (72 ; R = OH) and its congeners, (72 ; R = OAc), (73 ; R = H2), and (73 ; R = H, P-OAc), have been isolated from the liverwort Gyrnnornitrion
obtusum (Lindb) Pears.43 The structural assignments are based on chemical and spectroscopic evidence and it has been suggested that the biosynthesis of this 41
42 43
P. M . Adarns and J. R. Hanson, J.C.S. Perkin I, 1972, 2283. D. Gardner, A . T. Glen, and W. B. Turner, J.C.S. Perkin I, 1972, 2576. J . D. Connolly, A . E. Harding, and I . M. S. Thornton, J.C.S. Chem. Comm., 1972,1320.
Sesquiterpenoids
93
interesting group of tricyclic sesquiterpenoids could involve cyclization of trichodiene (59) or a closely related compound. The co-occurrence of the tricyclic hydrocarbon (72; R = H) provides indirect support for this proposal.43 Methylenation of the known bicyclic intermediate (74)44is the key feature of a recent synthesis of ( & )-debromolaurinterol (77).45 The 3 : 1 mixture of epilaurinterol methyl ether (76; R = Me) and laurinterol methyl ether (75; R = Me) obtained in this reaction could not be demethylated without prior removal of the bromine substituents. Debromolaurinterol (77) has previously been converted into laurinterol (75 ; R = H), aplysin (79), and d e b r ~ m o a p l y s i n . ~ ~
B
f
l
’
OMe
(74)
6 Acorane, Bazzanane, Cedrane, Zizaane, etc.
A stereospecific synthesis of (-)-cr-acorenol (81) and (+)-P-acorenol (82) from ( + )-(3R)-methylcyclohexanone(80)has been described47 and is shown in Scheme 10. These compounds should be of interest in studies associated with the biosynthesis of the cedrane, allocedrane, and zizaane classes of sesquiterpenoids. ( + )-2,5-Diepi-B-cedrene (83) has been isolated from Sciadopitys verticillata Sieb. et Zucc. and its absolute configuration established by X-ray crystallographic analysis.48 The key feature of an elegant new synthetic route (Scheme to (+)-cedrol(86) and (-t-)-cedrene (87) is a cation-olefin cyclization process 44
4s 46 47
48
K. Yamada, H. Yazawa, D. Vemcera, M. Toda, and Y. Hirata, Tetrahedron, 1969, 25, 3509. R. J . Fentrill, R. N . Mirrington, and R. J. Nicholls, Austral. J . Chem., 1973, 26, 345. T. hie, M. Suzuki, E. Kurosawa, and T . Masamune, Tetrahedron Letters, 1965, 3619. I . G . Guest, C. R. Hughes, R. Ramage, and A. Sattar, J . C . S . Chem. Comm., 1973, 526. T. Norin, S. Sundin, B. Karlsson, P. Kierkegaard, A.-M. Pilotti, and A.-C. Wiehager, Tetrahedron Letters, 1973, 17.
Terpenoidr and Steroids
94
Jvi-viii
1 1
Reagents: i, CH, =CHCN-Triton B; ii, hydrolysis and esterification; iii, Na-C,H,; iv, LiI-DMF; v, Ph,P=CH,-BuOH; vi, p-MeC,H,.SO3H-Me2CO; vii, Ph,CLi-C5H, ,ONO; viii, chloramine; ix, hv.
Scheme 10
involving cyclopropyl ketone (84).49 The cationic enol ester intermediate (85) was implicated in a previous cedrene synthesis." Complete details of the isolation of ( + )-do-cedrol (89) from Juniperus rigida and evidence supporting its structure and absolute configuration have been 49 50
E. J . Corey and R. D. Balanson, Tetrahedron Letters, 1973,9153. E. J. Cotey, N. N. Girotra, and C. T. Mathew, J . Amer. Chem. Soc., 1969,91, 1557
95
Sesquiterpenoidr
a i?r"
H
c-
H
H
r e p ~ r t e d . ~ "The ? ~ cyclization of P-acoradiene (88) to (+)-allo-cedrol(89) and the subsequent rearrangement of the brosylate of (89)to ( - )-prezizaene (90)were also described (Scheme 12). Similar transformations in the antipodal series have been
H
A
iii,
i, i:
,
~;"r
H
Reagents: i, H C 0 , H ; ii, KOH; iii, BrC,H,.SO,Cl-py.
Scheme 12
postulated to account for the biosynthesis of (+)-prezizaene (91)and (+)-zizaene (92).52 An interesting epimerization occurs when (+)-prezizaene (91), (+)zizaene (92), or epizizaene (93) is treated with formic acid.53 The same mixture of alkenes [(94) and (96)] is obtained in each case and intermediate (95) has been proposed to account for the epimerization occurring at a centre remote from the original alkene linkage. 5 1
52
"
B. Tomita and Y . Hirose, Phytochemistry, 1973, 12, 1409. N. H. Andersen and M. S . Falcone, Chem. and Ind., 1971, 61 and references cited; N. H. Andersen and D. D. Syrdal, Tetrahedron Letters, 1972, 899. N . H. Andersen, S. E. Smith, and Y. Ohta, J.C.S. Chem. Comm., 1973,447.
Terpenoidr and Sterozih
96
t-
Experimental details have been provided for the ~ y n t h e s i sof ~ ,epizizanoic ~~ acid (98) and for the isolation55 of this compound and zizanoic acid (97) from vetiver oil.
R'
&
(97) R' (98) R'
= =
C 0 2 H , R2 = H H, R2 = C 0 2 H
7 Chamigrane, Widdrane, and Thujopsane
Interest continues to be focused on the occurrence of novel halogenated sesquiterpenoids in marine algae. The isolation of prepacifenol (99) from Laurencia jifiIiforrnis has been reported,56 and its conversion into pacifenol (100) demonstrated in the laboratory. The original claim that pacifenol (100) occurs in L. pacijica has been retracted since silica gel chromatography employed in the initial separation was shown to produce (100) as an artifact from prepacifenol (99). More cautious separation techniques led only to the isolation of the latter compound. Pacifenol (loo), however, occurs naturally in L. tasrnanica whereas caespitol (101), a possible biosynthetic precursor of prefacifenol (99), has been isolated recently from L. c ~ e s p i t o s a . ~ ~ In the course of studying the behaviour of the cyclopropylmethyl cation in non-aqueous acidic media, the action of anhydrous hydrogen chloride on (-)thujopsene (102) at temperatures between - 10 and + 40"Chas been investigated 54 55
56 57
F. Kido, H. Uda, and A. Yoshikoshi, J . C . S . Perkin I , 1972, 1755. N. Hanayama, F. Kido, R. Tanaka, H. Uda, and A. Yoshikoshi, Tetrahedron, 1973, 29, 945. J . J. Sims, W. Fenical, R. M. Wing, and P. Radlick, J . Amer. Chem. SOC.,1973,95,972. A. G. Gonzalez, J. Darias, and J. D . Martin, Tetrahedron Letters, 1973, 2381.
Sesquiterpenoiak
97
Br (99)
using n.m.r. s p e c t r o ~ c o p y .The ~ ~ initially formed product (103), on warming to 20°C, rearranged to the 1,4-addition product (104). Further heating to 40°C afforded compound (105) whose structure was readily comparable with that of widdrol (106). The final thermodynamic product (107) was obtained after 20 h at 40°C.
8 Sesquipinane, Sesquifenchane, and Fumagillane The structures9and synthesis6' of sesquifenchene (114), the root oil hydrocarbon of Valerianu waalichi, have been reported. Treatment of the cyclic ether (108)61 with acetic anhydride and boron trifluoride gave a mixture of hydroxy-acetates 58
59
6o 61
A. R. Hochstetler and G. C. Kitchens, J . Org. Chem., 1972,37, 2750. S. K. Paknikar and J. K. Kirtany, Chem. and Ind., 1972,803 ; cf. E. J. Corey, D. E. Cane, and L. Libit, J . Amer. Chem. SOC.,1971,93, 7016. Y. Bessiere-Chretien and C. Grison, Compt. rend., 1972, 275, C , 503; Bull. SOC.chim. France, 1972,4570. T. W. Gibson and W. F. Erman, J . Amer. Chem. SOC.,1969,91,4771.
98
Terpenoids and Steroids
(109) and (1 10). Rearrangement of the tosylate (1 11) provided 9-acetoxy-afenchene ( I 12), and the corresponding iodide (1 13) was converted into sesquifenchene (1 14) using the Corey coupling procedure.62 In an attempt to effect a simple synthesis of a-cis-bergarnotene (1 16), it was found that treatment of the ether (108) with acetic anhydride and pyridine chlorohydrate gave a 70% yield of 9-acetoxy-a-pinene (1 15);6 the latter compound, however, could not be converted into a-cis-bergamotene (1 16) using the procedure described above.
1
Ac,O BF, Lt,O
(109) R' = OAC,R 2 = OH (110) R ' = OH, R 2 = OAC ( I 11) R' = OTS,R 2 = OAC
Ovalicin, a fumigallane-type sesquiterpenoid isolated from Pseudeurotium ovalis, has been assigned structure (1 17) on the basis of chemical and spectroscopic evidence.63
'' ''
E. J . Corey and M. F. Semmelhack, J . Amer. Chem. SOC.,1967, 89, 2756. P. Bollinger, H . - P . Sigg, a n d H.-P. Weber, H e f v . Chim.A c t a , 1973, 56, 819.
Sesquiterpeno ids
99
9 Sesquicamphane, fMhtalane, or-Santalane, etc. The synthesis (Scheme 13) of (+)-campherenone (118) and its use as a key intermediate in a general synthetic route to a group of structurally related sesquiterpenoids have been Compounds included within the scope of the general scheme are divided into groups whose members are sesquiterpenoid
1.
/JyC’ “1,--x
,
iv, H ’ ; v , isopropenyl acetate-pvii, (CH,OH),-H ; viii, Nal-Me,CO;
Reagents: i, BuLi-TMEDA; ii, L O ; iii, CC1,-Ph,P; MeC,H,.SO,H; vi, BF,-dH,Cl2; ix, Ph,P; x, dimsylsodium-Me,CO.
+
Scheme 13
analogues of camphor, borneol (isoborneol), camphene, and tricyclene. The success of the general scheme has been illustrated recently by the total synthesis of ( f)-campherenone (118), ( f)-epicampherenone (119), ( f)-p-santalene (12l), ( f)-a-santalene (123), and ( f)-epi-8-santalene (125) (Scheme 14). Furthermore, the synthesis of ( -t)-copacamphor, (+)-ylangocamphor, and ( k)-sativene has also been ~ o m p l e t e dand ~ ~ is, ~described ~ later in this Report (p. 106). A related study6’ has resulted in the synthesis of (-)-campherenone (118), (-)-p-santalene (121),(+)-epicampherenone (1 19),and (+)-epi-p-santalene (125) from ( + )-camphor (1 26) and provides evidence to establish or confirm the absolute 64 65
66 6’
T. Money, Progr. Org. Chem., 1973,8,29. G . L. Hodgson, D. F. MacSweeney, and T. Money, J.C.S. Perkin I, 1973, 2113. G . L. Hodgson, D. F. MacSweeney, and T. Money, Tetrahedrori Letters, 1972, 3683. G. L. Hodgson, D. F. MacSweeney, R. W. Mills, and T. Money, J.C.S. Chem. Cornm., 1973, 235.
Terpenoids and Steroid\.
100
Reagents: i, LiAl(OMe),H; ii, p-MeC,H.SO,Cl-py; iii, HgO-MeOH, A.
Scheme 14
configuration of these naturally occurring enantiomers. In the original report6' describing the synthesis of (-)-campherenone (118) etc., the conversion of (+)camphor (126) into the acetal(131) of ( -)-8-iodocamphor was accomplished in 12 steps using a combination of known reaction sequences. Recent investigations, however, have resulted in the development of a simple stereospecific conversion of camphor into 8-bromocamphor which can be accomplished in three steps.68 These syntheses are summarized in Scheme 15. Thus, the synthesis of (-)- or (+)-campherenone can be accomplished in a simple and'efficient manner from ( -)- or ( + )-camphor respectively and the sesquiterpenoids derived from campherenone (Schemes 14 and 19) are now readily available in either enantiomeric form. C. R . Eck, R. W . Mills, and T. Money, J.C.S. Chem. Comm., 1973,911.
Sesquiterpenoa
1-111
...
I
101
(119) -+ (124) -+
(125)
/
o&Br
Reagents i, Br, (1 mole); ii, Br,-CIS0,H;
iii, Zn-HBr; iv, Br, (2 moles);
10 Amorphane, Cadinane, Cubebane, Copaane, Copacamphane, Ylangocamphane, Sativane, eic. The original structure (132)69assigned to khusinol [a metabolite of Vetiveria zizanoides (L) Nash] was recently revised to ( 133),70and subsequent synthetic studies have confirmed that neither of the C-3 epimers of (132)is identical with the natural product7' The C-2 epimer of khusinol has also been isolated recently 69
70
71
A. A. Rao, K. L. Surve, K. K. Chakravarti, and S. C. Bhattacharyya, T e t r a h e d r o n , 1963, 19, 233. S. V. Tirodkar, S. K. Pakinkar, and K. K. Chakravarti, Science a n d C u l t u r e , 1969, 35, 27. R. B. Kelly and J. Eber, Canad. J . Chern., 1972, 50, 3272.
Terpenoih and Steroids
102
from vetiver C.d. measurements and chemical condensation with known amorphenes have established the structure and absolute configuration of zonarene (134) and l o - e ~ i z o n a r e n e .A~ ~new sesquiterpenoid lactone, arteannuin B, has been isolated from Artemisia annua L. and assigned structure (135) on the basis of spectroscopic evidence.74
Hofi & "i HO
10
3 \
\
#
\
8
H :
\
O.'O'
H :
A
A
\ O (135)
( 134)
(133)
(132)
established the structure of cubebol (138), the Although previous stereochemistry at C-4 and C-10 remained in doubt. A recent synthesis of cubebol (138), a-cubebene (139), and p-cubebene (140) from ( -))-trans-caran-2-one (136) has established the absolute configuration of these The key intermediate, norcubebanone (137), was synthesized by an intramolecular carbene insertion process and its stereochemistry deduced from c.d. data.
5. (F --+
'P
t 136)
A (137 72 7 .3
74 1 5 76
-.+
'P
&IOH 'P I
A t 138)
(139)
(140)
P. S. Kalsi, J . C. Kohli, and M . S. Wadia, Indian J . Chem., 1972, 10, 1127. N. H. Andersen, D. D. Syrdal, B. M . Lawrence, S. J. Terhune, and J . W. Hogg, Phytochemistry, 1973, 12, 827. D. Jeremic, A. Jokic, A. Behbud, and M . Stefanovic, Tetrahedron Letters, 1973, 3039. F. Vanasek, V. Herout, and F. Sorm, Coll. Czech. Chem. Comm., 1960, 25, 919. A. Tanaka, R. Tanaka, H. Uda, and A. Yoshikoshi, J.C.S. Perkin i, 1972, 1721.
I03
Sesquiterpenoids
Some interesting transformations of santonic acid (141) have been discovered as a result of attempts to utilize this compound as starting material in a projected synthesis of copaene (142).77 A summary of the various rearrangements is shown in Scheme 16. An alternative synthesis of ( +)-a-copaene (142) and ( +)-a-ylangene
Me0,C
:
CO,H
+
CO,H
0
(141)
Reagents: i, H,O,-OH-; ii, Na-Hg; iii, Ac,O; iv, KOBr.
Scheme 16
(143) has been reported,78 and although the synthetic plan is similar to that previously used7' a notable feature of this synthesis is the selectivity of the initial Diels-Alder reaction (cf. occidentalol synthesis p. 119). P-Copaene (145) and P-ylangene (146) were also synthesized from the intermediate dienone (144). These syntheses are summarized in Scheme 17. An elegant stereoselective total synthesis of (- )-ylangocamphor (153), ( - )ylangoborneol (154), and ( -)-ylangoisoborneol (155) has been reported and is shown in Scheme 18.80 Octalone (147) was converted into the keto-ester (149) 77
78 79
8o
A. G . Hortmann and D. S. Daniel, J . Org. Chem., 1972, 37, 4446. E. J . Corey and D . S. Watt, J . Amer. Chem. SOC.,1973,95, 2303. C. H . Heathcock, R. A. Badger, and J . W. Patterson, J . Amer. Chem. SOC.,1967, 89, 41 13. E. Piers, M. B. Geraghty, F. Kido, and M. Soucy, Synth. Comm., 1973, 3 , 39.
I 04
Terpenoids and Steroids
1
C0,Me
CH,OR
I
vii, viii
Reagents: i, LiAlH,; ii, Ac,O-DMSO; iii, Li-NH,; iv, TsC1-py; v, H + ;vi, MeSOCH,Na; vii, Mg-MeOH: viii, LiAIH,Bu';; ix, TsNHNH,; x, LiAlH.; xi, Zn-HOAc; xii, Na-Me,CHOH; xiii, TsCI-py; xiv, H +; xv, MeSOCH,Na.
Scheme 17
105
Sesquiterpenoids
(147) R = H, (148) R = CHOH
AcOCH
0 Jiv-vi
(' I 50)
MeOCH+
(149)
H
(153) R', R2 = 0 (154) R' = H, R2 = OH (155) R' = O H , R 2 = H Reagents : i, DDQ; ii, Me,CuLi, iii, MeCOCl; iv, 0,; v, H,O,-OH-; vi, CH,N,; vii, NaN(SiMe,),; viii, NaN(SiMe,),-Me,CHBr; ix, MeOCH=PPh,; x, H +-H,O; xi, K,CO,-MeOH; xii, CH, =PPh,; xiii, disiamylborane-THF; xiv, MsCl; xv, NaN(SiMe,),-(MeOCH,), . Scbeme 18
which underwent intramolecular Claisen condensation in the presence of sodium bis(trimethylsily1)amideto provide (150). Selective formation of the monoenol ether (15 l), followed by appropriate modification of the bridged ketone, provided a mixture of aldehydes, from which the desired keto-mesylate (152) could be obtained. The final cyclization step in the synthesis was accomplished in 84% yield by treating the keto-mesylate (152) with sodium bis(trimethylsily1)amidein dimethoxyethane. Conversion of (- )-ylangocamphor(153) into the correspond-
106
Terpenoih and Steroids
ing alcohols (154) and (155) was accomplished using Ca-liquid NH3 and LiAlH, respectively. Copacamphor ( 1 56), ylangocamphor (1 53), sativene (1 58), and copacamphene (159) have also been synthesized (Scheme 19) as part of a general synthetic
;Scheme
1
I
B...f (155)
(158) R' = H , R 2 = Pr' (159) R' = Pr', R2 = H
(1 57)
Reagents: i, Bu'OK-Bu'OH; ii, SOC1,-py; iii, Pt-H,; iv, LiAlH,; v, MeS0,Cl-py.
Scheme 19
approach to s e s q ~ i t e r p e n o i d s ~(cf: ' . ~p. ~ 99). Since the synthetic route illustrated in Scheme 15 (p. 101)provides the key intermediate, campherenone (118), in either enantiomeric form,67,68the synthesis of any of the enantiomers of copacamphor,
107
Sesquiterpenoids
ylangocamphor, copacamphene, and sativene is now a comparatively simple procedure. The structure of v.ictoxinine (164), a metabolite of Helrninthosporiurn oictoriae and H . satiuurn, has been confirmed by synthesis from prehelminthosporol (160) (Scheme 20)." Other metabolites of H. victoriae include (162) and the trycyclic ether (163),which can also be obtained from (162)by treatment with acid.
Reagents: i, H + ; ii, MeS0,Cl; iii, H,NCH,CH,OH.
Scheme 20
The total synthesis of dendrobine (165), a picrotoxane-type alkaloid isolated ~~,~~ from Dendrobiurn species, has been reported by two research g r o ~ p s . One synthesis,8 involving the separation of isomers at several stages, is summarized in Scheme 21. In the other synthesiss3 (Scheme 22) the tricyclic intermediate (1 67) was formed from (1 66) by intramolecular Michael additions4 followed by aldol condensation. 'I
'* 83
84
F. Dorn and D. Arigoni, J.C.S. Chem. Comm., 1973, 1342. Y. Inubushi, T. Kikuchi, T. Ibuka, K. Tanaka, 1. Saji, and K. Tokane, J.C.S. Chern. Comm., 1972, 1252. K. Yamada, M. Susuki, Y. Hayakawa, K. Aoki, H. Nakamura, H . Nagase, and Y . Hirata, J. Amer. Chem. SOC.,1972,94, 8278; Tetrahedron Letters, 1973, 331. W. S. Johnson, S. Shulman, K. I. Williamson, and R. Pappo, J . Org. Chem., 1962,27, 201 5 .
Terpenoih and Steroidr
108
11 Himachalane, Longipinane, Longicamphane, Longifolane, and Cyclolongicamphane
Acid-catalysed cyclization of the keto-triene (168) to the bicyclic keto-alkene (169) is the key feature of a recent synthesis of a- (170) and P-himachalene (172) (Scheme 23).85 A new synthesis of (+)-a- and (k)-P-longipinene, (177) and (178), has been achieved by photocyclization of the triene (173) followed by ring expansion of the derived ketone (175) (Scheme 24).86 A second total synthesis of ( )-longifolene (184) has been reported.87 Cyclization of the keto-epoxide (179) yielded a tricyclic ketol (180) which was converted into (182) by treatment with dibromocarbene followed by silver ion-assisted ring enlargement. Reductive
lxv
-
xix, x x
xvi-xviii
I
CN
$5
'r
0
0
0
(165) Reagents: i, TsCl; ii, NaCN-DMSO; iii, H,-5% Pd/SrCO,; iv, Br,; v, -HBr; vi, (CH ,OH),-H ; vii, KOH-(CH ,OH) ,-H ,O; viii, HCl-H ,O ; ix, MeNH,HCl; x, Pr'MgBr; xi, KHSO,,A; xii, I,-AgOAc; xiii, KOH-MeOH; xiv, Cr0,-py; xv, EtzAICN; xvi, NaBH,; xvii, KOH-H20; xviii, HCl-H,O; xix, Et,O+BF,- ; xx, NaBH,-glyme. +
Scheme 21
85
B6
''
E. Wenkert and K. Naemura, Synth. Comm., 1973, 3, 45. M. Miyashita and A. Yoshikoshi, J.C.S. Chem. Comm., 1972, 1173. J . E. McMurry and S. J. Isser, J. Amer. Chem. SOC.,1972, 94, 7132.
Sesquiteipeno ib
109
Reagents: i, K0Bu'-HOBu'; ii, CH,N,; iii, Ac,O-H'; iv, 0,;v, NN-carbonyldi-imidazole; vi, MeNH 2-H20-glyme; vii, pyridine bromide perbromide; viii, NaH-glyme ; ix, (CO,H),; x, NaH-glyme; xi, NaBH,; xii, H'; xiii, Et,O+BF,-; xiv, NaBH,glyme.
Scheme 22
(171) Reagents: i, AlCl,, A; ii, Ph,P+CH2Br--PhLi; iii, MeLi; iv, POC1,-py.
Scheme 23
( 1 72)
Terpenoih and Sterods
110
( 1 73)
( 1 74)
6% iii. iv
'ii
1
VI,
vii
( 1 77)
(178)
Reagents: i, hv; ii, Me,S=CH,; iii, NaN,-DMF; iv, Pt-H,-HOAc; v, NaN0,-H,O-H+ ; vi, MeLi; vii, POCl,-py.
Scheme 24
elimination of bromine followed by Collins oxidation provided the tricyclic ene-dione (183), which was converted into longifolene (184) by the sequence of reactions shown in Scheme 25. Recent studiess8 on isolongifolene epoxide (186) and the derived ketone (187) have provided additional support for the revised configurations assigned to these corn pound^.^^ Deuteriated samples of these compounds were prepared from longifolene, and n.m.r. evidence established the stereochemistry of ketone (187) and indicated that epoxidation had occurred at the or-face of isolongifolene. Additional support for these stereochemical assignments has been provided by the results of hydrogenation studiesg0 which show that hydrogenation of (190)and (191)occurs at the ct-face (endo)to yield (192)and (193) respectively. The rearrangement of isolongifolene to the substituted tetralin (194) occurs in trifluoroacetic acid at room temperature." A total " '9
''
G. Mehta and S. K . Kapoor, Tetrahedron Letters, 1973, 497. E. H . Eschinasi, G. W. Shaffer, and A. P. Bartels, Tetrahedron Letters, 1970, 3523. D . V. Banthorpe, A. J. Curtis, and W. D. Fordham, Tetrahedron Letters, 1972, 3865. G . Mehta, Chern. and Ind., 1972, 766.
Sesquiterpenoidr
111
Reagents: i, MeSOCH,Na+-DMSO; ii, H 2 S 0 4 ; iii, Br,CH-KOBu'; iv, AgClO,; v, Na-NH,; vi, Cr0,-py; vii, Me,CuLi; viii, NaBH,-MeS0,CI-NEt,; ix, KOBu'; x, [(Ph,P),RhCl]-H,; xi, MeLi; xii, SOC1,-py.
Scheme 25
&
'0 +-
-go
t
112
Terpenoids and Steroid3
synthesis of (+)-longicyclene (197) has finally been achieved by a route (Scheme 26) in which the construction of the cyclopropane unit was achieved by an intramolecular carbene insertion process [(195)-+( 196)].92 An unsuccessful attempt to use the homo-Diels-Alder reaction in the construction of longicyclene has also been described. 12 Humulane, Caryophyllane, erc.
As part of an intensive study of the biosynthesis of mono- and sesqui-terpenoid constituents of peppermint (Mentha piperita L.) it has been shown94 that caryophyllene (201) is biosynthesized from three molecules of mevalonic acid (MVA) (198) in accordance with biosynthetic theory (Scheme 27).4 Although caryophyllene and other sesquiterpenoids constitute less than 2 % of peppermint oil they incorporate label from [2-I4C]MVA (198) much more efficiently than the monoterpenoids which constitute the bulk of the oil. This low incorporation of label from MVA into monoterpenoid constituents of peppermint oil is probably characteristic of plants with distinct oil gland^.^^*^^ Degradation of labelled caryophyllene (201) demonstrated that the distribution of radioactivity could be 92 93 94 95
96
S. C. Welch and R. L. Walters, Synth. Comm., 1973, 3, 15. T. R . Kelly, Tetrahedron Letters, 1973, 437. R. Croteau and W. D. Loomis, Phyrochemisfry, 1972, 11, 1055. D. V. Banthorpe, B. V. Charlwood, and M . J . 0. Francis, Chem. Rev., 1972, 7 2 , 115. W . D. Loomis, in 'Terpenoids in Plants', ed. J. B. Pridham, Academic Press, New York, 1967, p. 59.
113
Sesquiterpenoih
1
v-viii
(195)
Reagents: i, BuiAlH-THF; ii, HC1; iii, MsCI-NEt,; iv, collidine, A ; v, Ph,P=CHOMeDMSO; vi, HCI0,-H,O-Et,O; vii, K,CO,-MeOH; viii, Cr0,-Me,CO; ix, (COCI),; x, CH,N,; xi, Cu-THF, A; xii. BuiAIH-THF; xiii, MsCI-NEt,; xiv, LiAlH,.
Scheme 24
represented by the asterisks shown in structure (201),and it is interesting to note that the gem-dimethyl group, containing label from dimethylallyl pyrophosphate (200), is considerably less active than the positions derived from isopentenyl pyrophosphate (199).94 A similar effect has been noted in the monoterpenoid s e r i e ~ ~and ~ * may ~ ’ be due to an endogenous dimethylallyl pyrophosphate pool in the plant or to compartmentalization effects. The biosynthesis of illudin M (204) in CIytocybe illudens has been studied using doubly labelled m e v a l o n a t e ~ . ~ ~ Incorporation of three [2,2-3H,]- and one [4(R)-4-3H,I-mevalonoid labels and the loss of a [2,2-3H,] label from the cyclopropane ring suggests that humulene (202) cyclizes to the illudene skeleton (203) in a non-concerted manner (Scheme 27). An interesting new sesquiterpenoid, velleral (206), has been isolated from Lactarius vellerens and L.pergamenus.” It is presumably related biosynthetically to isovelleral(205),which is found in the same source. 97
98 99
D . V. Banthorpe, B. V. Chariwood, and M. R. Young, J.C.S. Perkin I , 1972, 1532 and references cited therein. J. R. Hanson and T. Marten, J.C.S. Chem. Comm., 1973, 171. G. Magnusson, S. Thoren, and T. Drakenberg, Tetrahedron, 1973, 29, 1621.
Terpenoids and Steroids
114
1
*";
(202)
0
Scheme 27
13 Germacrane, Eudesmane, Eremophilane, etc. Considerable interest is being shown in the conformational analysis of sesquiterpenoids containing ten-membered rings (germacranes, germacranolides). The variable-temperature n.m.r. spectrum of deuteriated hedycaryol (206) has been used to demonstrate the existence of specific conformers of this molecule, and
Sesquiterpenoids
115
has provided experimental basis for current biosynthetic theory4 associated with the cyclization of germacradiene-type intermediates.'" A similar study' on germacra-l(10),4,7(1l)-trienyl-9-acetate (208) has shown that in solution at 30 "C this compound exists as two n.m.r.-distinguishable conformers in a ratio of 92 : 8. The interpretation of intramolecular nuclear Overhauser effects (NOE) (cf: ref. 3) indicates that the major conformer is represented by (209). NOE's have also been used to demonstrate that the major conformers of bicyclogermacrene and isobicyclogermacrene in solution are represented by (210) and (211) respectively.lo2 OAc
H
1
The structures of many new germacranolides have been determined recently ; these include cupaserrin (212) and deacetylcupaserrin (213) (Eupatorium semiserratum DC),'03 eupacunin (214), eupacunoxin (215), eupatocunin (216), eupatocunoxin (217), and eupatocunolin (218) (Eupatorium cuneifolium),'O4 provincialin (219) (Liatrisprovincialis Godfrey),'05 deacetyl-laurenobiolide (220) and specioformin (221) (Arternisia tridentata),' O6 alatolide (222) (Jurinea d a t a Cass.),'07 lipiferolide (223) (Liriodendron tulipifera L.),'08 punctatin (224)(Liatris lo' lo*
Io4
lo6
lo'
P. S. Wharton, Y . - C .Poon, and H. C. Kluender, J. Org. Chem., 1973, 38, 735. 1. Horibe, K. Tori, K. Takeda, and T. Ogina, Tetrahedron Letters, 1973, 735. K. Nishimura, I. Horibe, and K. Tori, Tetrahedron, 1973, 29, 271. S. M. Kupchan, T. Fujita, M. Maruyama, and R. W. Britton, J. Org. Chem., 1973, 38, 1260. S. M. Kupchan, M. Maruyama, R. J. Hemingway, J. C. Hemingway, S. Shibuya, and T. Fujita, J. Org. Chem., 1973, 38, 2189. W. Herz and I. Wahlberg, J. Org. Chem., 1973, 38, 2485. F. Shafizadeh and N. R. Bhadane, Phyfochemistry, 1973, 12, 857; cf. R . G . Kelsey, M. S. Morris, N. R. Bhadane, and F. Shafizadeh, ibid., 1973, 12, 1345. D. Drozdz, Z. Samek, M. Holub, and V. Herout, Coll. Czech. Chern. Comm., 1973,38, 727. R. W. Doskotch, S. L. Keely, jun., and C. D. Hufford, J.C.S. Chem. Comm., 1972, 1137; cf. R. W. Doskotch, C. D. Hufford, and F. S. El-Feraly, J. Org. Chem., 1972, 37, 2740.
Terpenoids and Steroids
116
p u n c t ~ t a ) , 'novanin ~~ (225) (Artemisia nova),' l o molephantin (226) (Elephantopus mollis),' and liatrin (227) (Liatris chaprnanii).' l 2 Many of the compounds listed
'
above exhibit interesting antileukaerni~'~~*' l 2 or cytotoxic proper tie^.'^^^'^^^'^^
HO..
w'
(OR OQOR
3
0
0
(214) R' = H, R 2 = Ac,
(212) R = COMe (213) R = H
R3 = COCMe=CHMe 0
(215) R 1 = H, R2 = Ac, R3 = COCL'CHMe
1
Me R2
OR' 0 (216) R' = COCMe=CHMe, R2 = H
AcOQ
CH2R1
R2CH2
(218) R'
=
0 H, R2 = OH
0 (217)
R'
= H, R 2 = COCcCHMe
I
Me
Ace*
OR
k---!+
0
CH,OH (219) R
= COC-CH20C0
II
CHCH,OH log 'lo
'I2
I
'CHMe
W. Herz and I. Wahlberg, Phytochemistry, 1973, 12, 1421. M. A. Irwin and T. A. Geissman, Phytochemistry, 1973, 12, 875. K.-H. Lee, H. Furukawa, M. Kozuka, H.-C. Huang, P. A. Luhan, and A. T. McPhail, J.C.S. Chem. Comm., 1973, 476. S. M. Kupchan, V. H . Davies, T. Fujita, M. R. Cox, R. J. Restivo, and R. F. Bryan, J. Org. Chem., 1973, 38, 1853.
Sesquiterpenoids
117
Wo
&,
OCOCH Me,
,
OH
qc 0
(223)
HOCH, QR 0
Ro
(224) R
AcO
0 =
COC=CHMe
I
CH,OH
(225)
7H2OH OCOC=CHMe
X-Ray crystal-structure analysis has shown that the configurations of mikanolide (228) and miscandenin (230)are in accordance with their postulated formation from the epoxy-diene (229).'l 3 A [3,3] sigmatropic rearrangement can be invoked to account for the formation of miscandenin (230). I
' ''
P.J.
Cox, G . A. Sim,
J. S. Roberts, and W. Herz, J.C.S. Chem. Comm., 1973, 428.
Terpenoih and Steroids
118
According to biosynthetic theory4 the eudesmane group of ssquiterpenoids is derived by cyclization of a germacrane derivative (232) formed from trans,transfarnesyl pyrophosphate (231). The successful duplication of the second step in the sequence has been elegantly demonstrated in the laboratory' l 4 and recent reports represent further examples of these cyclization processes.' 5 , 1 l 6 Thermal
'
cyclization of elemol (235) produces a mixture of hedycaryol (236) and starting material which undergoes silver ion-catalysed rearrangement to a- (237) and Elemol and the eudesmols co-occur in the citronella oil P-eudesmane (238).
q OH
(Ceylon variety) and this may indicate that a biosynthetic relationship exists between them. fl-Elemen-9fl-ol (240) and a new germacrane derivative, agerol (239), have been shown to co-occur in Achillea ageratum L., and the proposed
I'
'I5
T. W. Sam and J . K . Sutherland, Chem. Comm., 1971, 970 and references cited therein. T. C. Jain and J. E. McCloskey, Tetrahedron Letters, 1972, 5139.
Sesquiterpenoids
119
biosynthetic relationship between them is supported by the thermal conversion (239)+(240).’l 6 Similarly acoragermacrone (241), which co-occurs with shyobunone (242) in Acorus calarnus L., can be cyclized to (242) and (243).”’ OH
OH
The obvious difficulties associated with attempts to duplicate the first step, (231)+ (232), in the proposed biosynthetic route to eudesmanes prompted an alternative proposal involving a six-membered-ring intermediate (233).3c,’ A biogenetic-type synthesis of (+)-junenol (244) was based on this hypothesis.3c.’l 8 Acolamone (245) and isoacolamone (246), which are closely related to junenol(244), have recently been isolated from Acorus calarnus L.’
Several synthetic routes to (*)-occidentalol (252) have been reported recently.3c”20’121 In one of these (Scheme 28) a cis-fused decalin system (249) containing the required homoannular 1,3-diene functionality was constructed in 2 5 - 4 0 % yield by Diels-Alder reaction between 3-methoxycarbonyl-2-pyrone (247) and the enone (248)l2’ (cf. Scheme 17, p. 104). An additional feature of this synthesis was the use of an appropriate thioether (250) to construct the inter116
117
118 119
120
R. Grandi, A. Marchesini, U. M . Pagnoni, and R. Trave, Tetrahedron Letters, 1973, 1765. M. Iguchi, M . Niwa, A. Nishiyama, and S. Yamamura, Tetrahedron Letters, 1973, 2759. M. A. Schwartz, J. D. Crowell, and J. H. Musser, J. Amer. Chem. SOC.,1972,94,4361. M. Niwa, A . Nishiyama, M . Iguchi, and S. Yamamura, Chem. Letters, 1972, 8 2 3 . D. S. Watt and E. J . Corey, Tetrahedron Letters, 1972, 4651.
Terpenoidrs and Steroid
[& C02Me
Reagents: i, LiAlH,-THF; MeLi.
ii, (EtO),P(O)CH(SMe)Me-HMPA;
iii, HgC1,-H,O;
iv,
Scheme 28
mediate ketone (25 1) which was subsequently converted into ( +)-occidentalol (252). The other synthesis12' which appeared during the period under review was based on the suggestion'22 that the biosynthesis of (+)-occidentalol (257)'23 and related compounds involves cyclization of dehydrohedycaryol (259) (cf: Scheme 30). Thus irradiation of the trans-decalin derivative (254) (Scheme 29) provided an intermediate cyclodecatriene (255)which underwent thermal cyclizaI
I
I 22
A . G. Hortmann, D. S. Daniel, and J. E. Martinelli, J. Org. Chem., 1973, 38, 728. A. G. Hortmann, Tetrahedron Letters, 1968, 5785; cJ E. J. Corey and A. G. Hortmann, J. Amer. Chem. SOC.,1965,87, 573'6. Further support for the stereochemistry of (+)-occidentalol (257) has been provided by T. Suga, K. lnamura, T. Shishibori, and E. von Rudloff, Bull. Chem. SOC.Japan, 1972,45, 3502; CJ A. G. Hortmann and J. B. DeRoos, J. Org. Chem., 1969,34, 736.
Sesquiterpenoib
121
Reagents: i, hv; ii, MeLi; iii, 250°C; iv, h v ; v, -70°C.
Scheme 29
tion to the synthetic precursors of 7-epi-(-)-occidentalol(256) and ( + )-occidentalol(257). Using (- )-trans-occidentalol(258) instead of (254)in the photofissionthermal cyclization sequence gave (256) and (257) directly and provided experimental support for the suggested intermediacy of a suitably substituted cyclodecatriene [e.g. (259)] in the biosynthesis of ( + )-occidentalol. The relative yield (3 : 2) of (256) and (257) in the thermal cyclization of (259) is similar to the relative abundance of ( + )-occidol(260)and (+)-occidentalol(257) in T.occidenta!is and T. koraiensis and it has been suggestedI2l that 7-epi-(-)-occidentalol(256)
122
Terpenoids and Steroih
the biosynthetic precursor of ( +)-occidol (260). The epoxide (261) of triene (259) has been proposed'24 as a probable intermediate in the biosynthesis (Scheme 30) of ( + )-occidenol (262) [cf. (229)J and the stereochemistry of 7-epi(-)-occidental01 (256) has led to its implication in the biosynthesis of dehydrochamaecynene (264) and chamaecynone (263)' IS
i
T
OH
(264)
Scheme 30
124
B. Tomita and Y . Hirose, Tetrahedron Letters, 1970, 2 3 5 .
Sesquiterpenoic?..
123
Recent synthetic studies and appropriate spectral comparisons have shown that paridisiol, a component of grapefruit oil, is identical to intermedeol (265). 2 5 Related compounds, longlilobol(266) and pygmol(267) have been isolated from Artemisin longilohn' 2 6 and A . p v g m ~ e u 'respectively. ~~ The isolation and structural elucidation of several eudesmanolides have been described recently : these iriclude arbusculin-B (268) and isomers (269) and (270) (Frullania tamarisci),' 28 iasolide (271) (Luser trilohum),*2 9 graveolide (272) (Inula gruveolens).' 3 0 arbusculin-D (273) (Artemisia arbus~ulu),'~~ and ridentin-B (274) ( A . tripnrtita).132
'
H0
125
126 121 128
I29 130 13 I
132
J. W. Huffman and L. H . Zalkow, Tetrahedron Letters, 1973, 751. F. Shafizadeh and N. R. Bhadane. Tetrahedron Letters, 1973, 2171. M. A. Irwin and T. A. Geissman, Phytochemistry, 1973, 12, 849. J. D. Connolly and I . M . S. Thornton, Phytochemistry, 1973, 12, 631. M . Holub and Z. Samek, Coll. Czech. Chem. Comm., 1973, 38, 1428. G. S. d'Alcontres, M . Gattuso, M . C. Aversa, and C. Caristi, Gazzetta, 1973, 103, 239. M. A. Irwin and T. A. Geissman, Phytochemistry, 1973, 12, 8 5 3 . M . A. Irwin and T. A . Geissman, Phytochemistry, 1973, 12, 871.
124
Terpenoih and Steroids
Naturally occurring eudesmanolides having cis- or trans-fused cc-methylene, y-butyrolactone rings have been made more accessible as a result of recent synthetic studies.'33 In the cis-fused bromination and dehydrobromination steps convert cis-cc-methyl-lactones [e.g. (275)] into cis-fused CImethylene-lactones (276) (Scheme 31). Benzoylation followed by thermal
(275) Reagents: i, Ph,CLi-dimethoxyethane;
ii, BrCH,CH,Br ; iii, DBN-MePh, A.
Scheme 31
elimination of benzoic acid produces the corresponding conversion in the trans series, and the use of this in the synthesis of (+)-arbusculin-B (268) (Scheme 32)
q., QOCOPh
O
O
n o
0 (268)
Reagents: i, Ph,CLi-dimethoxyethane;
ii, (PhCO),-dimethoxyethane, 5 "C; iii, -450 "C.
Scheme 32
has been described.'33b The nature of the trichloride (279),formed when santonin (277) is treated under a variety of conditions (PC1,-CHCl,, PC1,-HOAc, or SOCl,), has been determined and the monochloride (278) has been shown to be an intermediate in this t r a n s f ~ r m a t i o n . 'The ~ ~ change in reduction state accompanying formation of (279) is very similar to that previously noted in the conversion of pyrosantonin (280) into (28l).' s
,
0 (277)
'33
134
13*
(278)
(279)
A. E. Green, J.-C. Muller, and G. Ourisson, ( a ) Tetrahedron Letters, 1972, 2489; ( b ) ibid., p. 3375. A. Frohlich, K. Ishikawa, and T. B. H. McMurry, Terrahedron Lerters, 1973, 995. T. B. H . McMurry and D . F. Rane, J . Chem. SOC.( C ) , 1971, 3851.
Sesquiterpenoids
125
0 (280)
(281 )
Further studies on the structural elucidation and reactions of eudesmane-type alkaloids have been Wilfordine (282) and alatamine (283) are components of Euonymus a l u m forma striutus (thumb.) ma kin^,'^^ and the corresponding desoxy-compounds, euonine (284), evonimine (285), and evonine (286), have been isolated from seeds of Euonymus Sieboldiana B l ~ m e . ' ~ ' - ' ~All ~ of these alkaloids may be regarded as derivatives of a- and P-agarofuran (287). The synthesis of (+)-norketoagarafuran (288) has been de~cribed.'~'A full account of the structural elucidation and synthesis of rishitinol (289) [cf: (+)occidol(260)], a metabolite of diseased white potato tubers, has been r e ~ 0 r t e d . I ~ ~ This compound is presumably derived from a eudesmane precursor by 1,2-methyl shift and it is interesting to note that it co-occurs with the noreudesmane sesquiterpenoid rishitin (290). A new method for the synthesis of spiroannelated cyclohexenones from enol ethers of cyclic 1,3-diketones has been elegantly used in a simple stereospecific OAc
PhCOO X*..
AcO
(282) X
I oAc
=
16%) yields into (81) but although the ergostane skeleton was incorporated intact no unambiguous direct pathway could be picked out: rather a grid of multiple pathways was indi~ a t e d . 'Non-artefactual ~~ (82) was detected in the culture media'56 but it has been suggested elsewhere that this is formed by pigment-sensitized photooxidation of ergosterol.' 5 7
Two mechanisms are extant for the introduction of A5 into ergosterol : one involves direct elimination of the hydrogens from C-5 and C-6, and the other requires a hydroxylation-dehydration.Previous tracer work had favoured the former, but evidence for the latter is the incorporation of [28-14C]-(78) into specifically labelled (83) by aerobically growing yeast.lS8 It seems likely that both routes can co-occur or that either can predominate in different conditions. Other studies pertaining to the transformations of ergosterol and its near relatives have been reported.159y160 154
M . Freyberg, A . 0. Oehlschlager, and A. M. Unrau, Biochem. Biophys. Res. Comm., 1972,48, 593.
155 156
Is' 15'
15'
L. Atherton, J . M . Duncan, and S. Safe, J.C.S. Chem. Comm., 1972, 882. J. D. White, D. W. Perkins, and S. 1. Taylor, Bioorg. Chem., 1973, 2, 163. J. Arditti, R. E. M. H. Fish, and B. H. Flick, J.C.S. Chem. Comm., 1973, 1217. M. Freyberg, A. 0: Oehlschlager, and A. M. Unrau, Biochem. Biophys. Res. Comm., 1973, 51, 219. C. G. Anderson, Diss. A h . (B), 1973, 33, 4643. J . R. Lenton, L. J. Goad, and T. W. Goodwin, Phytochemistry, 1973, 12, 1135.
278
Terpenoids and Steroids
One pathway to phytosterols in higher plants requires the opening of the cyclopropyl ring of the precursor skeleton at the stage of either cycloartenol(71), its 24-methylene derivative, or cycloeucalenol (84), all of which are ubiquitous plant products. An enzyme from cultures of bramble so cleaved the last substrate, but was much less effective with the 4,4-dimethyl-~terols.~~~ Demethylation of the latter sterols is known to proceed via loss of the &-methyl group with the 4P-methyl epimerizing into the 4cx-position in the product. The fate of the 4p-hydrogen during the following final demethylation has been ascertained in the conversion of [2,2,4-3H,]obtusifoliol (85), enzymically derived from (84), into poriferasterol(86). About 30 % of the axial 4P-hydrogen was inverted to the 4%-positionin (86), and the low retention may either represent an experimental artefact in the preparation of labelled precursor or be the result of exchange of the C-4 hydrogens (via enolization of a 3-0x0-compound) during demethylation. h 2
(85) ‘‘I
162
(86)
E. Heintz, T. Bimpson, and P. Benveniste, Biochem. Biophys. Res. Comm., 1972, 49, 820. F. F. Knapp, L. 3. Goad, and T. W. Goodwin, J.C.S. Chem. Comm., 1973, 149.
Biosynthesis of Terpenoids and Steroids
279
Studies on the functionalization of the side-chain of sterols continue. One important finding is that a pro4R hydrogen of MVA occupied the pro-24S position in tigogenin (87) biosynthesized by Digitalis lanata. 163 Unless some
unlikely stereochemical change occurred after saturation of the A24-bondof the precursor, this implies that reduction occurred with trans stereospecificity (cf ref. 152). The 27-methylene group of the related convallamarogenin from Conuallama majalis was derived from C-2 of MVA,’ 6 4 i.e. stereospecific oxidation of one of the terminal methyls occurred. Administration of [2-14C, 4R-4-3H,]MVA (3H : 14C = 1 : 1) to the alga Ochrimonas malhamensis gave cycloartenol (3H : 14C = 1 : 1) and poriferasterol (3H : 14C = 3 : 5 ) with the patterns in (88) and ( 89)165that are consistent with a hydride shift from C-24 to C-25 duringalkyla-
represents 14C; T represents 3 H
tion of the side-chain. [Me-2H3]Methionine was incorporated into poriferasterol to give four atoms of tracer per molecule and this implicated a 24-ethylidene intermediate (90) and was consistent with the previously proposed scheme, Such a scheme had not been experimentally demonstrated in Scheme higher plants, and feeding Larix decidua with the same doubly labelled precursor and measuring the isotope ratio in sitosterol (91) and 28-isofucosterol(92) indicates that although a A24(25)-intermediatemay have been involved, a shift of lh3
h4 Ih5
L. Canonica, F. Ronchetti, and G . Russo, J.C.S. Chem. Comm., 1972, 1309. F. Ronchetti and G . Russo, J.C.S. Chem. Comm., 1973, 184. A. R. H . Smith, L. J . Goad, and T . W. Goodwin, Phytochemistry, 1972,11, 2775.
Terpenoids and Steroids
280
L
f Scheme 10
r-
/
hydrogen from C-24 to C-25 did not now occur.166 Studies on a Trebouxia algal species using [Me-2H,]methionine and labelled phytosterols as precursors suggested that side-chain alkylation to form poriferasterol and related compounds could involve a A25-intermediateas outlined in Scheme 1 l.'67 The A24(28)-bond
Scheme I1 J. Randall, H. H. Rees, and T. W. Goodwin, J.C.S. Chem. Comm., 1972, 1295. ' ' P. L. J . Goad, F. F. Knapp, J . R. Lenton, and T. W. Goodwin, Biochem. J., 1972,129,2 19.
Ih6
Biosynthesis of Terpenoids and Steroids
28 1
of 24-methylenecholesterol was not reduced in uivo as in liver preparations from rats, although the A24(25)-~onds of other sterols were reduced. Hence rats lack the appropriate reductase that is widely distributed in plants. 16' Many phytophagous and omnivorous insects can dealkylate C28 and C29 sterols to obtain cholesterol. The hydrogen at C-25 of 28-isofucosterol was retained during such a process in a mealworm species, and the route in Scheme 12
Scheme 12
(93)
168
,'
(94)
:-I:::: (95)
W. R.Nes, J . W. Cannon, N. S . Thampi, and P. A. G. Malya, J . Biol. Chem., 1973,248,
484.
Terpenoids and Steroids
282
has been ~uggested."~This process is basically the reverse of the route of biosynthesis of the phytosterol, but a more complex situation obtained in a silkworm. Here fucosterol-24,28-epoxide(95)was detected as a possible intermediate in the degradation of sitosterol (93) and this, fucosterol (94), and 24-methylenecholesterol (97) were converted into cholesterol in yields of 15, 10, and 3",/, respectively. Fucosterol and desmosterol(96) were known from previous work to be intermediates en roule from sitosterol to cholesterol and the route shown in Scheme 13 was deduced in which the direct dealkylation route was of minor importance.' 'O 9 Further Metabolism of Steroids
An interesting review' ' discusses the implications from recent work which indicates that certain phytosterols that have been considered secondary metabolites actually may play some fundamental physiological role. This conclusion is based on analyses of complex mixtures which enable non-random metabolic processes (i.e. those that can selectively involve particular components of the mixture) to be identified and assigned either as specifically co-ordinated reactions or as involving metabolic grids. The nature and significanceof these non-random processes is, however, quite obscure. Previous work had indicated that tumour-bearing rats formed 'phytosterols' as judged by incorporation of deuterium from [,Me-2H,]methionine into the components of a certain fraction that was absent in controls. More rigorous studies have disproved this ; the 'phytosterol' fraction was shown to be mainly cholesterol, and incorporation of deuterium into this occurred in both experimental animals and in controls, presumably as a consequence of degradation of the p r e c ~ r s o r . ' ~ ~ Much, mainly inconclusive, work has been concerned with the degradation of the cholesterol side-chain and modification of the resulting products. Although it is established that such degradation to form bile acids commences with C-26-hydroxylation, the stage at which this occurs was not clear. It is now claimed' 7 3 that 5,!?-cholestane-3a,7cr,12cr-trio1 and 5~-cholestane-3a,7a-diolare the main substrates for C-26-hydroxylases of rat liver microsomes and mitochondria and minor pathways involving other substrates have been outlined. On the other hand, the intermediacy of 26-hydroxycholestero1 on the pathway from cholesterol to lithocholic acid in rat liver mitochondria has been proposed on the basis of tracer incorporation and the effects of added quantities of cold 24-hydroxycholestero1on the specific activities of products formed from labelled Ih"
'" I"
'" ".'
P. J . Randall, J . G . Lloyd-Jones, I . F. Cook, H . H . Rees, and T. W . Goodwin, J.C.S. Chem. Comm., 1972, 1296. M. Morisaki, H. Ohtaka, M. Okubayashi, N. Ibekawa, Y . Horie, and S. Nakasone, J.C.S. Chem. Comm., 1972, 1275. B. A . Knight, Chem. in Britain, 1,973, 9, 106. J . G. Lloyd-Jones, P. Heidel, B. Yagen, P. J. Doyle, G. H. Friedell, and E. Caspi, J . Biol. Chem., 1972, 247, 6347. I . Bjorkhem and J. Gustafsson, European J . Biochem., 1973,36, 201.
Biosynthesis o j Terpenoids and Steroids
283
precursors ;l 7 4 alternatively 7a-hydroxylation of cholesterol has been considered as a rate-limiting step for the sequence.' 7 5 The cholesterol-7a-hydroxylaseof rat liver has been purified and shown to be a typical mixed-function oxidase with requirement for NADPH, cytochrome C-reductase, and cytochrome P45O.I 6 , Sterol carrier protein (see Section 8) from liver also stimulated cleavage of the side-chain of cholesterol to form steroid hormones'88 and bile acids.'79 A similar, closely related factor that is either a protein or is associated with one occurs in bovine adrenal mitochondria and increased the formation of pregnenolone up to ten-fold. This factor was heat-stable and remained active after heating had inactivated the cytochrome P450 enzyme system: it was thought to be implicated in the transport of cholesterol within the cell as well as in the cleavage reaction and it may act as a solubilizing agent by the formation of cholesterolphospholipid micelles.' A similar factor isolated from serum proteins stimulated the formation of progesterone and deoxycortisone by solubilized enzymes from adrenal microsomes.'8 ' [4-14C,17a-3H]Pregnen~lone (98) yielded progesterone (99), 17-hydroxyprogesterone, 17-hydroxypregnenolone, and testosterone (100) on incubation 799180
(98)
(99) R (100) R
= =
COMe OH
erepresents 14C
with minced ovarian tissue.'82 The 3H tracer was retained at C-17 in (99) but the other compounds were devoid of this activity and it was concluded that testosterone was formed along established pathways involving C-17-hydroxylation of C , , precursors rather than by direct insertion of oxygen between C-17 K. A. Mitropoulos, M. D . Avery, N . B. Myant, and G . F. Gibbons, Biochem. J . , 1972, 130, 363. S. Balasubramaniam, K. A. Mitropoulos, and N. B. Myant, European J . Biochem., 1973, 34, 77. l i 6 G. S. Boyd, A. M. Grimwade, and M. E. Lawson, European J. Biochem., 1973,37,334. '" J. Robinson and P. M. Stevenson, F.E.B.S. Letters, 1972, 23, 327. K . W. Kan and F. Ungar, J. Bioi. Chem., 1973, 248, 2868. G . A. Grabowski, M. E. Dempsey, and R . F. Hanson, Fed. Proc., 1973,32, 520 (abs.). K . W. Kan, F. Ungar, J . C. Y. Hsiao, R. Gunville, and D. T. Maghane, Fed. Proc., 1973, 32, 519 (abs.). M. A. Hamilton, R. W. McCune, and S. Roberts, J . Endocrinoi., 1972,54, 297. l E 2 L. Milewich and L. R. Axelrod, Arch. Biochem. Biophys., 1972,153, 188. lid
Terpenoids and Steroids
284
and C-20. A number of other studies of the metabolism of pregnenolone, testosterone, and their derivatives in animals and plants have a ~ p e a r e d . ' ~ ~ - ' ~ ~ A large number of studies have also been made on enzymic modifications to the steroid skeleton, although many are fragmentary, some follow well-trodden pathways, and others are inconclusive. However, recent work on ecdysterone (101 ; R = OH), an insect moulting hormone, certainly falls into none of these classes, for, contrary to the situation in animals and some plants, it was demonstrated that oxidation of C-3 is not obligatory for formation of the Cis-A-B ring junction. Administration of [4-'4C,3-3H]cholesterol to seedlings of Tuxus baccatu yielded [14C]ecdysterone containing at least 70% of the 3H tracer retained at C-3.' 9 7 The presumed precursor( 101 ;R = H) was sequentially hydroxylated at the time of puparium formation in a blow-fly species to give ecdy~ t e r 0 n e . I In ~ ~another double-labelling study it was demonstrated that the hydrogens at C-2 of MVA were incorporated with retention of configuration at C-22 of fusidic acid (102), and so the intermediate formation of a product with a
R
183 1n 4
I85 I86 187 188
I89 190 191 1Y2
1q.3
I94
19s 196
197 198
S. J . Stohs and M. M. El-Olemy, Phytochemistry, 1972, 11, 2409. T. Furuya, K. Kawaguchi, and M. Hirotani, Phytochemistry, 1973, 12, 1621. B. P. Lisboa, H. Brewer, and E. Witschi, Z . physiol. Chem., 1972, 353, 1907. B. P. Lisboa, and J. C. Plasse, Steroids Lipids Res., 1972, 3, 142. P. V. Maynard and E. H . D. Cameron, Biochem. J., 1973, 132, 283. W. R. Mayle, Y . C. Kong, and J. Ramachandran, J . Biol. Chem., 1973, 248, 2409. H. J . Lee and C . Monder, Fed. Proc., 1973, 32, 479 (abs.). W. C . Schwarzel, W. C. Krugyel, and H. J . Brodie, Endocrinology, 1973, 92, 866. T. Tabei and W. L. Heinrichs, Endocrinology, 1972, 91, 969. G. J. Van der Vusse, M . L. Kalkman, a n d H. J . Van der Molen, Biochim. Biophys. Acta, 1973, 297. 173. T. A. Van der Hoeven, Diss. Abs. ( B ) . 1972, 33, 1934. T. Katkov, W . D. Booth, and D. B. Gower, Biochim. Biophys. Acta, 1972, 270, 546. I . H . White and J. Jeffery, Biochim. Biophys. Acta, 1973, 296, 604. H . Oshima, K . Ochiai, N. Niizato, and A . Tamaki, Biochim. Biophys. Acta, 1973, 306, 227. J . G. Lloyd-Jones, H. H. Rees, and T . W. Goodwin, Phytochcmistry, 1973, 12, 569. M. N . Galbraith, D. H. S. Horn, E. J. Middleton, and J . A. Thomson, J . C . S . Chem. Comm., 1973, 203.
285
Biosynthesis of Terpenoids and Steroids
A20(22)-bondwas excluded. 199 When digitoxigenin and digoxigenin were formed in Digitalis lanata from [8-3H,4-14C]cholesterol,all the tritium was retained : this could indicate that neither A7-, A8-,nor A8(14)-intermediate~ were involved in cardenolide biosynthesis2" if the assumption is made that no migration of hydrogen occurred during this process. The route from cholesterol (103) to 5a-cholest-7-en-3P-01 (105) in mammals has been shown to involve cholest-4-en-3-one (106). A similar pathway was claimed to exist in two species of starfish from the observation that (104)and (105) together with (103) were labelled when [4-I4C]-(106) was fed, and from the loss of most of the 3H tracer when (104) was biosynthesized from [4-'4C,3a-3Hl]-(103): this was consistent with the route shown in Scheme 14.''' (106) is also thought to be an intermediate in the conversion of cholesterol into its 5P-epimer by intestinal micro-organisms, and the 3-0x0-A4-steroid SP-reductase of such a system has been partially purified and its mode of action investigated.202
(105)
Scheme 14
Several studies of the enzyme systems involved in these and related reactions have appeared. The 3-oxo-A4-steroid 5P-reductase of yeast transfers hydrogen from the A-position of NADPH to the SP-position of the steroid whereas the corresponding 5a-reductase involves hydride shift from the B-position of the coenzyme.203 The reduction of the 3-0x0-group of various steroids by cortisone reductase always resulted in transfer from the B-position of NADH whether the final product was 3a- or 3/l-hydro~ylated,2~'and this same hydrogen was involved when the same enzyme reduced the 20-0x0-group of pregn-4-ene-3,20lg9
201
2oz 203 204
E. Caspi, R. C. Ebersole, W. 0. Godtfredsen, and S . Vangedal, J.C.S. Chem. Comm., 1972, 1191. D. J . Aberhart, J . G. Lloyd-Jones, and E. Caspi, Phytochemistry, 1973,12, 1065. A . G . Smith, R . Goodfellow, and L. J. Goad, Biochem. J . , 1972,128, 1371. I. Bjorkhem, J . Gustafsson, and 0. Wrange, European J. Biochem., 1973, 37, 143. Y. J. Abul-Hajj, Steroids, 1972, 20, 215. W. Gibb and J. Jeffery, European J. Biochem., 1973,34, 395.
286
Terpenoids and Steroids
dione. This presumably means that the reductase can only bind NADH in such a manner that the 4B-hydrogen is available for transfer. Several different 3a- and 3p-hydroxy-steroid dehydrogenases in rat liver also showed this same stereospecificity towards NADH.205 The properties of other A4- and Asreductases,206-’ O8 As -+A3-keto-steroid is om erase^,^^^.^'^ 17p- and 7ahydroxy-steroid dehydrogenases,2 l 4 7a-hydroxylases,’ and other modih ave been studied, as have products of metabolism of fying enzymes2 6-2 steroids with mixed enzyme systems in v i t r ~ . ’ ~ ~ - ’ ~ ’ Evidence for the intermediate formation of hydroperoxides in the 17a-hydroxylation of progesterone has been obtained.228 Cytochrome P450 acted as a microsomal peroxidase in rat adrenal and as this was inhibited by several steroids this system may contribute to the regulation of hydroperoxide decomposition. Pregnan-l7a-hydroperoxidewaz also implicated in the formation of other adrenocortico-hormones.229~230 Preparations of rat liver microsomes converted various neutral 16-dehydro-C19-steroids into 16,17-dihydroxy metabolites, possibly uia a 16,17-epoxide,again with the involvement of cytochrome P450.23 Conversion of taurodeoxycholic acid into cholic acid via 7a-hydroxylation in rat
’-’
I . Bjorkhem, H. Danielsson, and K. Wikvall, European J . Biochem., 1973,36, 8. H. J . Eyssen, G. G. Parmentier, F. C. Compernolle, G . DePauw, and M. PiessensDenef, European J . Biochem., 1973,36, 41 1. ’Oi I . Bjorkhem and I . Holmberg, European J . Biochem., 1973, 33, 364. * 0 8 P. Germain, G . Lefebvre, B. Bena, and R. Gay, Compt. rend. Soc. Biol., 1972, 166, 1123. 2 ” y J . B. Jones and K. D. Gordon, Biochemistry, 1973, 12, 71. 2 1 0 R. J. Martyr m d W. F. Benisek, Biochemistry, 1973, 12, 2172. R. Ghraf, M . Raible, and H . Schriefers, Z . physiol. Chem., 1973, 354, 299. * I 2 J . J. O’Rangers, Diss. Abs. ( B ) , 1972, 33, 1004. 2 L 3 M. A. Chernyavskava, G . M. Segal, and I . V. Torgov, Izuest. Akad. Nauk S . S . S . R . , Ser. biol., 1972, 588 (Chem. Abs., 1972, 77, 123298). ‘I5 I . A. MacDonald, C. N. Williams, and D. E. Mahony, Biochim. Biophys. Acta, 1973, 309, 243. 2 1 5 D. Mayer, F. W. Koss, and A. Glasenapp, Z . physiol. Chem., 1972, 353,921. ‘I6 P. Geynet, J . Gallay, and A. Alfsen, European J . Biochem., 1972,31, 464. ’ ’ W. Voigt and S. L. Hsia, J . Biol. Chem., 1973, 248, 4280. 2 1 8 J. W. Chu and K . Kimura, J . Biol. Chem., 1973,248, 5183. 2 1 q C. Monder and P. T. Wang, J . Steroid Biochem., 1973, 4, 153. 2 2 0 L. A. R. Sallam, A. H . El-Refai, S. Nada, and A. F. Abdel-Fattah, J . Gen. Appl. Microbiol., 1973, 19, 155. *” J . Ramseyer and B. W. Harding, Biochim. Biophys, Acta, 1973, 315, 306. 222 M . Maugra, P. Savigny, and J. LeMatre, Compt. rend., 1973, 276, D,3221. * 1 3 A . S. Goldman and K. Sheth, Biochim. Biophys. Acta, 1973, 315, 233. 2 2 4 J. Van Cantfort, Life Sci., 1972, 11, 773. 2 2 5 1. Bjorkhem, K. Einarssonn, J. A. Gustafsson, and A. Somell, Acta Endocrin., 1972,71, 569. 2 2 6 W. E. Braselton, J . C. Orr, and L. L. Engel, Analyt. Biochem., 1973,53, 64. 227 R . Tschesche and J. Leinert, Phytochemistry, 1973,12, 1619. 2 2 8 E. Hrycay and P. J. O’Brien, Arch. Biochem. Biophys., 1972, 158, 480. *” E. Hrycay, P. J. O’Brien, J . E. Vahnier, and G . Kan, Arch. Biochem. Biophys., 1972, 153, 495. 2 3 0 E. Hrycay and P. J. O’Brien, Arch. Biochem. Biophys., 1973, 157, 7. 231 C. von Bahr, K. Brandt, and J . A. Gustafsson, F.E.B.S. Letters, 1972,25, 65. ’05 20h
287
Biosynthesis o j Terpenoids and Steroids
liver microsomes was also deduced to involve cytochrome P450, and the kinetics of the process were a n a l y ~ e d . ~ ~ ~ Contrary to previous reports, the vitamin D, -C-25-hydroxylase of the chick is not restricted to the liver, but also occurs in the kidney and intestine: neither is it strongly subject to product inhibition, nor affected by the vitamin D status of the bird.233 Since the kidney appears to be the unique site of C-25-hydroxyvitamin D,-1-hydroxylase, renal homogenates are capable of completely converting vitamin D, into its 1,25-dihydroxy-derivative,which is the hormonal form. The latter enzyme is affected by the vitamin D and calcium status and may be involved in the regulation of the hormonal form. All the oxygen utilized in la-hydroxylation of 25-hydroxy-vitamin D, by chick kidney arose from the air, not from water : consequently the enzyme is a mixed-function o x i d a ~ e . ~ , ~ An attempt has been made to elucidate the stereochemistry at C-1 of wortmannin (107), a metabolite of Peniciflium wortmannii, by feeding [2-’4C,2S-3HI]0
MVA and its (2R)-isomer to the fungal cultures. Although incorporations of 1 4 % were achieved, the results were not conclusive as substantial and unexplained loss of tritium (relative to I4C) occurred from both precursors. Nevertheless, the greater retention of tritium from the (2R)-precursor suggested a stereochemistry (as shown) opposite to that deduced from crystallographic st~dies.’~~.~~~ 10 Non-steroidal Triterpenoids
A full account of the cyclase from Ononis spinosa root that converted 2(3),22(23)dioxidosqualene into a-onocerin ( 108) has appeared.23 The properties differed in several respects from those of other oxidosqualene c y ~ I a s e s and ~ ~ *the enzyme may be the first truly soluble enzyme of the class ; consequently differences in susceptibility to inhibitors may be due to differences in structural organization
’
232
233 234 235
236 237
238
D. Trulzsch, H. Greirn, P. Czygan, F. Hutterer, F. Schattner, H . Popper, D. Y . Cooper, and 0. Rosenthal, Biochemistry, 1973, 12, 76. G . Tucker, R. E. Gagnon, and M. R. Haussler, Arch. Biochem. Biophys., 1973,155,47. J. C. Ghazarian, H. K. Schnoes, and H . F. DeLuca, Biochemistry, 1973, 12,2555. J . MacMillan, T. J. Simpson, and S. K. Yeboah, J . C . S . Chem. Comm., 1972, 1063. T. J. Petcher, H . P. Weber, andZ. Kis, J.C.S. Chem. Comm., 1972, 1061. M. G. Rowan and P. D. G. Dean, Phytochemistry, 1972,11, 31 1 1 . P. D. G . Dean, Steroidologia, 1972, 2, 143.
288
Terpenoids and Steroids
rather than in mode of action. The cyclase required both epoxide groups of the substrate to effect cyclization and there was some evidence for an intermediate product in which only one 'end' of the substrate was cyclized. Under conditions where 2,3-oxidosqualene was converted into P-amyrin (109) in 13 yield, an homogenate of pea tissue converted (1 10) into the same It seems very compound in 0.0060~yield without randomization of the unlikely that (110) is a mandatory intermediate for P-amyrin, but the result ()/;
illustrates the ability of the cyclase(s) to generate a normal product from an artificial substrate via a short-cut process which reduces its function to the formation of only three rings. Although tissue cultures of Tylophora indica had lost their ability to produce alkaloids they could synthesize P-amyrin and phyto~terols.~~' A novel product, lup-20(29)-ene-3P,llg-diol (111) was synthesized de nouo in the shrub Dodonea ~ t t e n u a t a .Pentacyclic ~~~ triterpenoids of this type are very rare in bacteria but (112)was formed from [l-'4C]acetate and [2-I4C]MVA in Bacillus acidocaldarius : however, no degradations to locate tracer were carried 11 Carotenoids
Earlier work on the stereochemistry of elimination during double-bond formation in carotenoids was hampered by loss of stereospecificity of label during the 13'
140
2J2
M. Horan, J . P. McCormick, and D. Arigoni, J.C.S. Chem. Comm.,1973, 73. B. D . Benjamin and N . B. Mulchandani, Planta Med., 1 9 7 3 , 2 3 , 394. E. L. Ghisalberti, P. R. Jefferies, and M. A. Sefton, Phytochemistry, 1973, 12, 1125. M. DeRosa, A . Gambacorta, L. Minale, and J . D . Bu'lock, Phytochemistry, 1973, 12, 1 1 17.
Biosynthesis of Terpenoids and Steroids
289
&
HO
long incubation times that were necessary. This has been overcome by employing a preparation from Flauobacterium capable of efficiently synthesizing lycopene, ruboxanthin, zeaxanthin, and others without randomization of tracer.243 The hydrogens lost from C-7, C-11, C-7', and C-11' of phytoene during its conversion into the unsaturated carotenoids arose from the 5-pro-R hydrogen of MVA, whereas those from C-8, C-12, C-8', and C-12' came from the 2-pro-S hydrogen. This corresponds to trans-elimination in the formation of each double bond. The inhibition of carotenogenesis has received considerable attention. Rhodopseudomonas species grown in the presence of nicotine accumulated neurosporene (113) at the expense of spheroidene (116) and hydroxyspheroidene (117): on removal of the inhibitor, the pool of (1 13) rapidly diminished and (116) and (117) were formed.244 These results were held to provide evidence for the pathway in Scheme 15 involving chloroxanthin (114) and demethylated spheroidene (1 15). R2
(113) R' = a , R 2
=
L. L. G.
e
h...
(114) (115) R' R 1 = b, c, R2 R2 = = ee
(116) R' (117) R '
= =
d, R2 d,R2
= =
e f
a
b
..
:
d
C
.*.-
-:.
(113)-
(114)-
(115)-
(116)-
(117)
e
f
OH
Scheme 15 243 244
J. C. B. McDermott, G. Britton, and T. W. Goodwin, Biochem. J . , 1973,134, 1 1 15. R. K . Singh, A . Ben-Aziz, G. Britton, and T. W. Goodwin, Biochem. J . , 1973, 132, 649.
290
Terpenoids and Steroids
Nicotine also inhibited cyclization of carotenoid glucoside esters in Myxococcus fulcus, and the acyclic ester that accumulated underwent monocyclization on removal of the alkaloid from the culture medium. Inhibition of hydroxylation at C-1' occurred at higher concentrations of nicotine,245and 2-(4-chlorophenylthio)triethylamine h y d r o ~ h l o r i d e , ~ ~ ~amongst - ~ ~ * other corn pound^,^^^-^^ also prevented cyclization of acyclic carotenoids :in all these experiments lycopene and its derivatives accumulated, and removal of inhibitor caused cyclization. Carotenogenesis was completely inhibited in other micro-organisms by substituted benzophenones,2" and diphenylamine stopped the oxidation of hydroxygroups to carbonyl.2'2 It is generally accepted that hydroxylation occurs at a late stage in carotenoid biosynthesis ; however, the isolation of 3-hydroxy-Pzeacarotene from the green alga Scenedesmus obliquus indicates that cyclization and hydroxylation can occur at the neurosporene level of d e s a t ~ r a t i o n . ' ~ ~ Several mutants of tomatoes are known in which the carotenoid content of the fruit is markedly altered from that in the standard varieties in that lycopene or 6, b, and 5-carotenes are present. Use of I4C-labelled IPP, phytoene, and lycopene as additives for soluble enzyme systems revealed some unexpected enzymic activities : systems from all mutants had synthetase activity for phytoene and for the formation of p-carotene from lycopene. The apparent lack of some of these activities in the various fruits may be due to the presence of specific inhibitor^.^'^ Other studies of the formation of carotenoids in bacteria, algae, and other organisms are a ~ a i l a b l e . ~ The " ~ ~fossil ~ ~ spore-wall components sporapollenins, which are polymers of units such as (1 18) and (119),appear to be formed by
L4h 247
248
H. Kleinig and H. Reichenbach. Biochim. Biophys. Acta, 1973, 306, 249. P. P. Batra, R . M. Gleason, and J . W. Louda, Phytochemistry, 1973,12, 1309. W. J . Hsu, H . Yokoyama, and C. W. Coggins, Phytochemistry, 1972, 11, 2985. M . Elahi, T. H. Lee, K . L. Simpson, and C. 0.Chichester, Phytochemistry, 1973, 12, 1633.
249 250 251
'
253
M . Elahi, C. 0. Chichester, and K. L. Simpson, Phytochemistry, 1973, 12, 1627. N. F. Lewis and U . S. Kumta, F.E.B.S.Letters, 1973, 30, 144. R . Herber, B. Maudinas, and J. Villoutreix, Phytochemistry, 1972, 31, 3461. 0. G. Sassu, Phytochemistry, 1972, I I , 3 195. F. J. Levenberger, A. J. Schocher, G. Britton, and T. W. Goodwin, F.E.B.S. Letters, 1973, 33, 205.
254
255
15'
C. Papastephanou, F. J . Barnes, A. V. Briedis, and J . W. Porter, Arch. Biochem. Biophys., 1973, 157, 415. G. N. Lutsenko and V . S. Saakov, Fiziol. Biokhim. Kul't. Rast., 1972, 4, 608 (Chem. Abs., 1973, 79, 50 769). M . B. Gochnauer, S. C. Kushwaha, M. Kates, and D. J . Kushner, Arch. Mikrobiol., 1972, 84, 339 (Chem. A h . , 1972, 7 7 , 149 484).
Biosynthesis of Terpenoids and Steroids
29 1
with in vitro model oxidative polymerization of c a r ~ t e n o i d s . ~Experiments ~ systems support the hypothesis that damascones [e.g. P-damascone (1 20)] are derived in vivo by degradation of c a r ~ t e n o i d s . ~ ~ ~ . ~ ’ ~
Carotene 15,15’-dioxygenase, which oxidizes carotene to retinal, has been purified 200-fold from rabbit intestine preparations and the kinetics and parameters of the enzyme have been reported.260 12 Meroterpenoids
This convenient term (Cornforth, 1968) covers compounds of partly terpenoid origin. Only topics in which the biosynthesis of the terpenoid moiety is involved are included. Mycophenolic acid ( I 21) has a terpenoid side-chain. Isolation of 6-farnesyl-5,7dihydroxy-4-methylphthalide from the culture medium of Penicillium brezlicompactum and the high incorporation of this into (121) indicate that the most important route for the formation of the side-chain is the introduction of a C I S chain followed by oxidative degradation at the appropriate double bond.26
The stereochemistry of the A-B ring junction in a group of phytotoxic diterpenoid alkaloids occurring in Aconitum and Delphinium species is similar to that in gibberellins. This suggested that these compounds might inhibit the action or biosynthesis of gibberellic acid but a detailed study showed that although the alkaloids inhibited certain gibberellin-mediated responses (a-amylase synthesis and stem-node elongation) they did not consistently mimic the effect of either abscisic acid or the drug AMO-1618 (known inhibitors of gibberellin action and 257 256
259
260 261
G . Shaw, Proceedings of the Symposium on Sporapollenins, 1971 (publ. 1972), p. 305. G. Ohloff, V. Rautenstrauch, and K. H. Schulte-Elte, Helv. Chim. Acta, 1973, 56, 1503. S. h o e , S. Katsumura, a n d T . Sakan, Helv. Chim. Acta, 1973,56, 1514. M. R. Lakshmanan, H. Chansang, and J . A. Olson, J . Lipid Res., 1972,13,477. L. Canonica, W. Kroszczynski, B. M. Ranzi, B. Rindone, E. Santaniello, and C. Scolastico, J . C . S . Pirkin I , 1972, 2639.
292
Terpenoids and Steroids
biosynthesis respectively). Effects of the alkaloid on gibberellin transport or on uptake by target cells seemed more likely.262 Feeding experiments with [2-14C]-,[5-14C]-,and [4-3H,]-MVA have shown263 that daphniphylline (122) is formed in Daphniphyllurn macropodurn from six MVA molecules oia a squalene-like intermediate, and [14C]squalene was incorporated in low (O.OOSO,,) yield. Degradation made it possible to suggest a biosynthetic pathway. Partial degradation of daphniiactone-B (l24), biosynthesized in fruit of Daphniphyllunz teijsmunni, indicated that four MVA moieties were incorporated per molecule and a plausible route was suggested whereby (123) was an intermediate which was degraded with loss of eight carbon atoms to yield the product.’ h 4
Tomatine [a glucoside of tomatidine (1 25)] was formed in excised tomato root cultures but addition of MVA or the steroid inhibitor SKF-7997-A3 caused
(1Xj 262 263
264
R . H. Laurence and G. R. Waller, Fed. Proc., 1973, 32, 521 (abs.). K . T. Suzuki, S. Okudo, H . Niwa, M . Toda, Y . Hirata, and S. Yamamura, Tetrahedron Letters, 1973, 799. H. Niwa, Y .Hirata, K. T. Suzuki, and S. Yamamura, Tetrahedron Letters, 1973, 2129.
Biosynthesis of Terpenoids and Steroids
293
reduction in the rate of its synthesis and also of root Tomatine was broken down by tomato fruits to form (126) in a combined (probably glucoside)
H
from,266although tomatidine was metabolized by Nocardia restrictus such that 174-dien-3-oneswere formed and the side-chain was left intact.267 [2-14C]MVA was reported to be incorporated intact by Claviceps purpurea into the ergoline moiety of ergotamine.268 Feeding experiments with (5R)-and (5S)-[5-3H,]MVA have confirmed (see Vol. 2, p. 198) that elymoclavine, agroclavine, and chanoclavines are all formed in Claviceps strains with loss of pro-5R and retention of pro-5S hydrogen of m e ~ a l o n a t e . ~ ~Thermodynamic ' considerations of the biosynthesis of the ergot alkaloids are available.270 The enzyme from Aspergillus oirnstelodarni that prenylates cyclo-L-alanyl-Ltryptophanyl(l27) to yield (128)has been partially p ~ r i f i e d . ~The ~ ' ,product ~ ~ ~ is believed to be an intermediate on the pathway to echinulin (129)and its [3H , 14C]0.
(127) R' = RZ = H (128) R' = H , R 2 = CMe,CH=CH, (129) R' = CH,CH=CMe,, RZ = CMe,CH=CH,
labelled form was incorporated into the latter by the mould in 5-14% yield. Echinulin was not degraded to establish the tracer pattern but the preservation of the isotope ratio of precursor in the product implied that intact uptake had 265
266
'" 268 269
270 27'
'"
J. G . Roddick and D. N. Butcher, Phytochemistry, 1972, 11, 2991. E. Heftmann and S. Schwimmer, Phytochemistry, 1972, 11, 2783. I. Belic and H. Sock, J . Steroid Biochem., 1972, 31, 843. R. A. Bassett, E. B. Chain, and K. Corbett, Biochem. J., 1973,134, I . C. I. Abou-Chaar, H. F. Guenther, M. F. Manuel, J . E. Robbers, and H . G . Floss, LIoydia, 1972, 35, 272. Z. Rehacek, P. Sajdl, and A. Kremen, Biotechnol. Bioeng., 1973, 15, 207. C. M. Allen, Biochemistry, 1972, 11, 2154. C. M. Allen, J . Amer. Chem. SOC.,1973, 95, 2386.
294
Terpenoids and Steroids
occurred. The pathways from p-hydroxybenzoate to the ubiquinones in bacteria are well established, where the first step is the formation of 4-carboxy-2-polyprenylphenol. In higher plants the situation is less certain but the appropriate transferase activity has been demonstrated in preparations from bean root and yeast. Such cell-free systems synthesized ( I 30) from p-hydroxybenzoate and either CO,H I
I PP or protein-bound polyprenyl pyrophosphate. The mitochondria contained all of the transferase activity but were unable to construct the side-chain from IPP, possibly owing to damage of the organelles during p r e p a r a t i ~ n . ~ ’ ~ The transferase from E . Coli catalysing coupling of DMAPP to RNA to form a N6-(A2-isopentenyljadenosinelink in the latter has been purified 500-fold, and was found only to accept substrate that lacked the isoprenyl modification normally present in ~ i u o The . ~ enzyme ~ ~ had a molecular weight of 55000 dalton and required reduced SH groups and bivalent metal ions for full Labelled farnesol, geranylgeraniol, dolichols, and ubiquones were isolated after administration of [2-14C]MVA to aerated cultures of the fungus Phytophthoru cactorum whereas the last were not formed in the absence of aeration. Studies with [4R-4-3H,]MVA and its (4s)-isomer gave the stereochemistry of hydrogen loss expected from previous work on these classes of compound: formation of trans-A-bonds in all products except the dolichols resulted from stereospecific loss of the pro-4S hydrogen, whereas the latter contained several cis-A-linkages formed with the loss of the epimeric hydrogen.276 Transmethylation from [Me-2H3]methioninehas been demonstrated into isoprenoid quinones (ubiquinones, rhodoquinones, phytoquinones, etc.) of Euglena g r a ~ i l i s and ,~~~ a pathway for the biosynthesis of ubiquinones in E . coli has been proposed based on genetic analysis and isolation of intermediates (such as 2-octaprenyl-6methoxyphenol and 2-octaprenylphenol) that accumulated in mutants with blocked pathways.278 The proposal that cardiachromes, a novel group of quinones [e.g.(131j], arise by condensation of a benzenoid precursor with geranyl
zi3 2’4
275 276
”’ 278
G. Thomas and D. R.Threlfall, Biochem. J., 1973, 134, 81 1 . N . Rosenbaum and M. L. Gefter, J. Biol. Chem., 1972,247, 5675. J. K . Bartz and D. Soll, Biochemie, 1972, 54, 31. J . B. Richards and F. W. Hemming, Biochem. J., 1972, 128, 1345. D. R. Threlfall, Biochim. Biophys. Acta, 1972, 280, 472. I. G . Young, P. Stroobant, C. G. MacDonald, and F. Gibson, J. Bacteriol., 1973, 114, 42.
Biosynthesis of Terpenoids and Steroids
29 5
0
pyrophosphate and oxidative cyclization is supported by the isolation of alliodorin (132) from heart wood of Cordia alliodora.279~280 OH
Other oxygenated meroterpenoids are cochlioquinones A and B from Cochliobolus miyabeanus, which are formed by the introduction of a C unit [rings A, B, and c in (133)] into an aromatic precursor.281 A group of interesting furanoterpenoids with C, , C,, , C,, , and C, linear chains or truncated C, and C, chains occurs in marine sponges.282 Linear C Z 1compounds closely related to the C,, class occur in the same source and this suggests that the former are degraded sesterterpenoid~.~
,
The role of long-chain isoprenols in the formation of peptidoglycan of bacterial cell walls has been investigated284and reviewed.28 27q
280
281
282
283 284
285
K. L. Stevens, L. Jurd, and G. Manners, Tetrahedron Letters, 1973, 2955. M. Moir, R. H. Thomson, B. M. Hausen, and M. H. Simatupang, J.C.S. Chem. Comm., 1972, 363. L. Canonica, B. M. Ranzi, B. Rindole, A. Scala, and C. Scolastico, J.C.S. Chem. Comm., 1973,213. G. Cimino, S. De Stefano, L. Minale, and E. Trivellone, Tetrahedron, 1972,28,4761. G. Cimino, S. De Stefano, and L. Minale, Tetrahedron, 1972, 28, 5983. J. L. Strominger, Y. Higashi, H. Sandermann, K. J. Stone, and E. Willoughby, Proceedings of the Symposium on the Biochemistry of the Glucosidic Linkage, 1971, ed. R. Piras and H. G. Portis, Academic Press, New York, p. 135. J. Baddiley, ref. 284, p. 337.
296
Terpenoids and Steroids
13 Polyterpenoids Derivatives of C, , - i ~ o p r e n o are l ~ ~of~ importance as lipid-bound intermediates that carry activated sugar fragments for the biosynthesis of peptidoglycan of bacterial cell walls. Kinetic analyses had revealed that the activity of CSsisoprenol phosphokinase, a butanol-soluble enzyme involved in this process, could be manifested if the aqueous interface of mixed micelles consisted of the lecithin cofactor, the prenol, and the apoprotein of the enzyme. Preparation of such a complex and addition of ATP indeed generated full enzymic The phosphokinase was isolated from Staphylococcus aureus288 and the C-55isoprenyl phosphate ester itself accumulated in Micrococcus lysodeikticus cells that had been treated with bacitracin before harvesting.289 The dephosphorylating enzyme for the substrate was located in the membrane of the latter bacteria290and purified.291 Reviews of this work are a ~ a i l a b l e . ~ ~ ~ ~ ~ ~ ’ 14 Methods
Useful methods for the preparation of [1-3H]DMAPP,292[1-’4C]-2,3-oxido~ q u a l e n e and , ~ ~[’~4C]gibberellic have appeared. A timely warning has been given concerning the widespread tendency to assume chemical and radiochemical purity of compounds isolated by g.1.c. or t.1.c. after feeding of 14C-labelled precursors to plant systems, and using the apparent incorporations to construct biosynthetic schemes. For example, camphor was isolated by g.1.c. from various plant species with apparently very significant radioactivity after feeding [2-14C]MVAbut the tracer content decreased to zero when the product was repeatedly re~rystallized.~~ Similar observations have been made on several other occasions (but have been ignored by the majority of workers in the field) in studies involving the isolation of a wide range of terpenoids. It seems that background activity is spread over practically the whole range of the g.1. or t.1. chromatograin in products obtained from both in vivo and in vitro systems. The simplest explanation is probably that highly radioactive products (polyols, epoxides?) are formed (perhaps by salvage mechanisms) on feeding a non-physiological excess of the precursor and break down during the process of separation to give very highly labelled moieties which contaminate any fractions that are collected. Another factor that may introduce artefacts is the much higher labelling of squalene’ (or sesquiterpenoids and carotenoids) than of monoterpenoids biosynthesized by the same in vivo systems. Thus contamination of the monoterpenoid fraction by components of these classes 286
J. N . Umbreit and J. L. Strominger, J . Bucteriol., 1972, 112, 1306.
’” H . Sandermann, F.E.B.S. Letters, 1973, 29, 256. 288 289
290 291 292 293
294
H . Sandermann and J. L. Strominger, J . Biol. Chem., 1972, 247, 5123. K. L. Stone and J. L. Strominger, J . Biol. Chem., 1972, 247, 5107. E. Willoughby, Y. Highasi, and J . L. Strominger, J . Biol. Chem., 1972, 247, 5113. R. Goldman and J. L. Strominger, J . Biol. Chem., 1972, 247, 5116. E. Cardemil and 0. Cori, J . Labelled Compounds., 1973, 9, 15. J . Bascoul, D. Nikolaidis, A. Crastes de Paulet, and L. Pichat, Bull. SOC.chim. France I I , 1973, 2318. J. R. Hanson and J. Hawker, Phytochemistry, 1973, 12, 1073.
Biosynthesis of Terpenoids and Steroids
297
may cause spuriously high incorporation of tracer, and the widespread practice (especially in studies using cell-free systems) of assaying the tracer in the 'hexanesoluble' fraction and considering this fraction equivalent to the tracer in monoterpenoids is absolutely unjustified. An excellent review of the methods (and the difficulties) involved in the study of biosynthesis of terpenoids in higher plants is available295and an interesting discussion (applied to the incorporation of amino-acids into alkaloids but applicable to the field under consideration) concerns the use of D- and L-precursors as metabolites;296it is suggested that the efficienciesof incorporation of each isomer are not per se necessarily suitable measures as to which isomer is metabolized, and the incorporation of doubly labelled enantiomorphs is favoured. A magisterial essay on the logic of working with enzymes has a ~ p e a r e d . ~ ' A study of the incorporation of late intermediates into the meroterpenoid strychnine has application in a wider field. It was shown that although insignificant incorporation of tetra- and hexa-cyclic intermediates occurred in 5 days after administration to Strychnos nux vornica, feeding, repotting, and assaying after 100 days led to 0.2--1.6 incorporation of the presumed intermediate without significant degradation : 2 9 7 incorporations were also detected at shorter times by autoradiographic t.1.c. of the plant extracts. Mevalonate was little catabolized to carbon dioxide (< 0.05 %) after administration for 160 h to various plants where de nouo synthesis of monoterpenoids from exogenous precursors had occurred. Geraniol and C, precursors derived from MVA were degraded to only a small extent (ca. 3 %) whereas acetate and 3'3-dimethylacrylate were extensively (ca. 20 %) broken down.64 An approach to chemical phylogeny of plants based not on the isolation of individual components but upon branching of pathways from particular precursors has been outlined.298and biogenetic speculations based on variations of the monoterpenoid composition and content of various organs during development have been made.299 Reviews and articles on instrumental methods in biosynthetic st~dies,~" the application of 13Cn.m.r.301 and 'H n.m.r.302 to such problems, counting the techniques for I4C and 3H,303-308 general methods of inve~tigation,~'~ solubilization of membrane-enzymes and other aspects of their p~rification,~
''
295 296 297 298
299 '0° 301 302 '03 '04
305 '06
307
308 '09
310 3"
S. A. Brown and L. R. Wetter, Progr. Phytochem., 1972,3, 1 . E. Leistner, R . N. Gupta, and I. D. Spenser, J. Amer. Chem. SOC., 1973,95,4040. S. I. Heimberger and A. I. Scott, J.C.S. Chem. Comm., 1973, 217. A. J . Birch, Pure Appl. Chem., 1973, 33, 17. Y . A. Poltavchenko and G . A. Rudakov, Biol. Nauki, 1972,15,95. H. G . Floss, Lloydia, 1972, 35, 399. J. B. Grutzner, Lloydia, 1972, 35, 375. L. J. Mulheirn, Tetrahedron Letters, 1973, 3175. R. Tykva, Coll. Czech. Chem. Comm., 1973,38, 503. R. M . McKenzie and R. K. Gholson, Analyt. Biochem., 1973,54, 17. R. L. Boeckx, D. J. Protti, and K . Dakshinamurti, Analyt. Biochem., 1973,53, 491. L. Csernay, Acta Med. Acad. Sci. Hung., 1973, 29, 131. W. E. Braselton, J. C. Orr, and L. L. Engel, Analyt. Biochem., 1973,53, 64. A. G . Lacko, H. L. Rutenberg, and L. A. Soloff, Clin. Chim. Acta, 1972,39, 506. J. R. Quayle, Methods Microbiol., 1972, 6B,157. J. L. Gaylor, Adv. Lipid Res., 1972, 10, 89. A. Szewczuk, Wiad. Chem., 1973, 27, 289 (Chem. Abs., 1973,79, 62 972).
298
Terpenoids and Steroids
tissue-culture technique^,^', and the extraction of enzymes from plants in the presence of endogenous phenols3 have appeared.
15 Reviews This section contains a list of reviews that have been published in the year August 1972 to August 1973 (Part A) concerning terpenoid and steroid biosynthesis, and details of the more important reviews in the field published since 1967 (Part B). A. Reviews Published August 1972-August
1973
Reviews are available on : General. The biogenetic isoprene rule ;314 the stereochemical aspects of enzyme action ;3 1 , 3 1 5 the stereochemistry of biogenetic-type cyclizations of olefins ;316 chemistry and biosynthesis of insect attractant^,^'^ terpenoid pheremones and hormones ;318,319the C,--C,, terpenoids ; 3 2 0 the triterpenoids, steroids, and car~tenoids.~~' Methods. General methods employed in the determination of biosynthetic pathways ; 2 9 5 * 3 2 2 , 3 2 3 for details of specific methods applicable see Section 14. Acyclic Precursors. The properties and kinetics of I P P - i s ~ m e r a s e . ~ ~ ~ Monoterpenoids. The chemistry and biosynthesis, in part, of thujane and its derivat i ~ e s . ~ Sesquiterpenoids. Biosynthetic pathways to t ~ t i n and ~ ' ~abscsiic acid."' Diterpenoids. Biosynthesis and chemistry of the cyclic d i t e r p e n ~ i d sand ~ ~the ~.~~~
gibber ell in^.^ 3 0
G. Teuscher, Pharmazie, 1973, 28, 6. G. A. Buzan, Uspeki, biol. Khim., 1972, 13, 102. '14 L. Ruzicka, Ann. Rec. Biochem., 1973, 42, 7. 'I5 J. W. Cornforth, in 'Biosynthesis and its Control in Plants', ed. B. V. Milborrow, Academic Press, 1973, p. 17 1. ' I h K. E. Harding, Bioorg. Chem., 1973, 2, 248 (36 references). 3 1 ' D. A. Evans and C. L. Green, Chem. SOC.Rev., 1973, 2 , 75 (72 references). 3 1 8 H. Z. Levinson, Naturwiss., 1972, 59, 477 (126 references). '19 J. G. MacConnell and R. M. Silverstein, Angew. Chem. Internat. Edn., 1973, 12, 644 (208 references). 32 J. R. Hanson, in 'Biosynthesis', ed. T. A. Geissman (Specialist Periodical Reports), The Chemical Society, London, 1972, Vol. 1, p. 41 (104 references). 32 H. H. Rees and T. W. Goodwin, ref. 320, p. 59 (302 references). 3 2 2 S. A. Brown, ref. 320, p. 1 (162 references). 3 2 3 E. G . Paoletti, A n n . Isr. Super. Sanira., 1972, 8, 244. 3 2 4 P. W. Hollaway in 'The Enzymes-, ed. P. D. Boyer, 3rd. edn., Academic Press, 1972, p. 565. j 2 ' D. Whittaker and D. V. Banthorpe, Chem. Rev., 1972, 72, 305 (1 15 references). 3 2 6 G. Jommi, Cron. Chim., 1972, 20. j Z 7 D. Gross, Pharmazie, 1972, 27, 619. 3 2 8 J. R. Hanson, Fortschr. Chem. org. Naturstofle, 1971, 29, 395 (64 references). 3 2 9 J. R. Hanson, Progr. Phytochem., 1972, 3, 231 (214 references). 3 3 0 C. A. West in ref. 315, p. 143. 312
'13
Biosynthesis oj. Terpenoids and Steroids
299
Triterpenoids and Steroids. Biosynthesis of cholesterol and enzyme systems associated therewith;331- 3 3 3 biosynthesis of plant sterols;334*335 steroidal sapogenins and pentacyclic triterpenoid sapogenins ; 3 3 6 , 3 3 7 the biosynthesis of steroids in fungi;338,339 the properties of As-3-keto-steroid i~omerase.~~’ Carotenoids. Recent advances in the study of the biosynthesis of carotenoids ;341,342 studies of the biosynthesis of carotenoids in micro-organisms in genera1,343,344 in b a ~ t e r i a , ~and ~ ’ ,in~ ~ ~ Meroterpenoids. Biosynthesis of various terpenoid alkaloids ;348-3 biosynthesis of ~biquinones.~ ”, 3 5 2 Two books have appeared which include aspects of these t o p i ~ s . ~ ’ ~ , ~ ~ ~
B. Reviews Published 1967-1972 Amongst the numerous reviews available are : General. The alkylation of olefins in biosynthe~is~~’ and the biosynthesis of insect hormones.3s6 Reviews of the biosynthesis of the various classes of terpenoids are to be found in the Proceedings of conferences held under the auspices of the Phytochemical and Biochemical S~cieties.~ 5 9
”-’
331 332
333 334 335 336
337
338 339 340 341
342
343 344
345 346
347 348 349
350 351
352 3s3 354
355
356 357
”
359
J. W. Cornforth, Labo-Pharma-Probl. Tech., 1972, 20, 51. R. B. Ramsey, Biochem. SOC.Trans., 1973, 1, 341 (58 references). J. L. Gaylor and C. V. Delwiche, Ann. New York Acad. Sci., 1973, 212, 122. L. J. Goad and T. W. Goodwin, Progr. Phytochem., 1972,3, 113 (448 references). L. J. Mulheirn and P. J. Ramm, Chem. SOC.Rev., 1972, 1, 259 (99 references). K. Takeda, Progr. Phytochem., 1972, 3, 287 (147 references). R. Tshesche and G. Wulff, Fortschr. Chem. org. Naturstofle, 1973,30, 461. J. D. Weete, Phytochemistry, 1973, 12, 1843 (181 references). J. D. Bu’Lock, Pure Appl. Chem., 1973, 34, 435 (77 references). P. Talalay and A. M.Benson, ref. 9, p. 591. T. W. Goodwin, Biochem. J., 1972, 128, 11P (7 references). T. W. Goodwin, in ‘Phytochemistry’, ed. L. P. Miller, Van Nostrand-Reinhold, New York, 1973, Vol. 1, p. 112. S. Liaaen-Jensen, Ann. Rev. Microbiol., 1972, 26, 225 (1 56 references). E. P. Feofilova, Uspekhi Mikrobiol., 1972, 8, 159. J. C. B. McDermott, A. Ben-Aziz, R. K. Singh, G. Britton, and T. W. Goodwin, Pure Appl. Chem., 1973, 35, 29 (48 references). T. W. Goodwin, ‘Proceedings of the 2nd International Congress on Photosynthesis’, ed. G . Forti, Junk N.V., The Hague, 1971, Vol. 3, p. 2437. B. H. Davies, Pure Appl. Chem., 1973, 35, 1 (69 references). E. Leete, ref. 320, p. 158 (103 references). R. Thomas and R. A. Bassett, Progr. Phytochem., 1972, 3, 47 (215 references). R. Gabelta, Fitoterapia, 1973, 44,3. F. Gibson, Biochem. SOC. Trans., 1973, 1, 317 (20 references). W. Yamamoto, Farumashia, 1973, 9, 29. H. Metzner, ‘Biochemie der Pflanzen’, Enke, Stuttgart, 1973, 376 pp. N. M. Packter, ‘Biosynthesis of Acetate-derived Compounds’, Wiley, Chichester, 1973, 203 pp. J. W. Cornforth, Angew. Chem. Internat. Edn., 1968, 7, 903 (19 references). C. E. Berkoff, Quart. Rev., 1969, 23, 372 (115 references). ‘Perspectives in Phytochemistry’, ed. J. B. Harborne and T. Swain, Academic Press, 1969. ‘Aspects of Terpenoid Chemistry and Biochemistry’, ed. T. W. Goodwin, Academic Press, 1971. ‘Natural Substances Formed Biologically from Mevalonic Acid., ed. T. W. Goodwin, Academic Press, 1970.
300
Terpenoids and Steroids
Methods. The preparation of biosynthetic intermediates and of enzyme systems of terpenoid biosynthesis ; 3 6 0 the use of asymmetrically labelled and multiply labelled substrates in enzyme studies ; 3 6 1 ? 3 6 2techniques of plant tissue culture.363 Monoterpenoids. The biosynthesis of r n o n o t e r p e n o i d ~ . ~ ~ ~ Sesquiterpenoids. Biosynthetic pathways to sesq~iterpenoids.~~ Diterpenoids. The biosynthesis of the gibber ell in^.^^^ Triterpenoids and Steroids. The biosynthesis of limonoids and quassinoids ;36 the chemistry of sterol and acylic terpenoid epoxides ; 3 6 8 biosynthesis and biochemistry of sterol^,^^^-^^* pregnane derivatives,373 steroidal oestrogens, adrenal corticosteroids ;376376 bile Carotenoids. Biosynthesis of carotenoids and vitamin A.378 Meroterpenoids. Terpene alkaloid biosynthesis ; 3 7 9 , 3 8 0 biosynthesis of vitamins E and K ;381 the distribution, function, and biosynthesis of p h y t o q ~ i n o n e s . ~ ~ ~ Other Terpenoids. The biosynthesis of r ~ b b e r8 .3 ~
36" 361 362 363 364
365 366 367
368
369 370 371 372
373 374
375
376
378 379
380 381 382
383
'Methods in Enzymology', ed. R. B. Clayton, Academic Press, 1969, Vol. 15. J. W. Cornforth, Quart. Reu., 1969, 23, 125 (26 references). J . R. Hanson, Ado. Steroid Biochem. Pharm., 1970, 1, 51 (82 references). E. J. Staba, Adv. Steroid Biochem. Phurm., 1970, 1,75 (274 references). D. V. Banthorpe, B. V. Charlwood, and M. J. 0. Francis, Chem. Retl., 1972, 72, 115 (537 references). W. Parker, J. S. Roberts, and R. Ramage, Quart. Rev., 1967, 21, 331 (203 references). B. E. Cross, Progr. Phytochem., 1968, 1, 195 (78 references). J. D. Connolly, K. H. Overton, and J. Polonsky, Progr. Phytochem., 1970, (146 references). E. E. van Tamelen, Accounts Chem. Res., 1968, 1, 1 1 1 (37 references). I. D. Frantz and G . J. Schroepfer, Ann. Rev. Biochem., 1967,36, 691 (181 references). J. L. Gaylor, Adv. Lipid Res., 1972, 10, 89 (128 references). E. Lederer, Quart. Reu., 1969, 23, 453 (1 18 references). C. J. Sih and H. W. Whitlock, Ann. Rev. Biochem., 1968, 37, 661 (196 references). S. Burstein and M. Gut, Adv. Lipid Res., 1871, 9, 291 (302 references). P. Morand and J. Lyell, Chem. Rev., 1968, 68, 85 (472 references). B. W. Harding, J. J. Bell, L. D. Wilson, and J. A. Whysner, Adu. Enzyme Regulut., 1969, 7, 237 (51 references). E. Griffiths and E. H. D. Cameron, Adu. Steroid Biochem. Pharm., 1970, 2, 223 (132 references). 'Bile Acids', ed. P. P. Nair, Plenum, New York, 197 1 . 'Carotenoids', ed. 0. Isler, Birkhaeuser, Basel, 1971. A. 1. Scott, Accounts Chem. Res., 1970, 3, 151 (33 references). E. Leete, Adv. Enzymol., 1969, 32, 373 (279 references). D. R. Threlfall, Vitamins and Hormones, 1971, 29, 153 (213 references). J. C. Wallwork and F. L. Crane, Progr. Phytochem., 1970, 2, 267 (198 references). B. L. Archer and B. G . Audley, Ado. Enzymol., 1967, 29, 221 (130 references).
Reviews on Terpenoid Chemistry
The following list of reviews on terpenoid chemistry covers the period 1968-1973 and is arranged according to the chapter titles of Part 1. 1 Monoterpenoids
General. A. R. Pinder, ‘The Chemistry of the Terpenes’, Wiley, New York, 1970. T. K. Devon and A. I. Scott, ‘Handbook of Naturally Occurring Compounds’, Vol. 2, ‘Terpenes’, Academic Press, New York, 1971, p. 3. D. Whittaker, in ‘Chemistry of Terpenes and Terpenoids’, ed. A. A. Newman, Academic Press, London, 1972, p. 11. A. F. Thomas, in ‘The Total Synthesis of Natural Products’, ed. J. W. ApSimon, Wiley, New York, 1973, Vol. 2, p. 1. J. Verghese, ‘Chemistry ofa-Terpinene’, Flavour Ind., 1972,3,252 (109 references). D. Whittaker and D. V. Banthorpe, ‘The Chemistry of Thujane Derivatives’, Chem. Reo., 1972, 72,305 (115 references). W. Cocker, ‘A Review of Some Investigations of the Chemistry of Carene’, J . Soc. Cosmetic Chemists, 1971, 22, 249 (63 references). N. E. Bean, ‘Camphora-Curriculum Vitae of a Perverse Terpene’, Chem. in Britain, 1972, 8, 386. Iridoids. J. M. Bobbitt and K.-P. Segebarth, in ‘Cyclopentanoid Terpene Derivatives’, ed. W. I. Taylor and A. R. Battersby, Marcel Dekker, New York, 1970, p. 1. G. W. K. Cavill, in ‘Cyclopentanoid Terpene Derivatives’, ed. W. I. Taylor and A. R. Battersby, Marcel Dekker, New York, 1970, p. 203. V. Plouvier and J. Favre-Bonvin, ‘Les Iridoides et Seco-iridoides : Repartition, Structure, Proprietes, Biosynthese’, Phytochernistry, 1971, 10, 1697 (317 references). H. Inouye, in ‘1st International Congress on Pharmacognosy and Phytochemistry’, ed. H. Wagner and L. Horhammer, Springer-Verglag, Berlin, 1971, p. 290. R. Hegnauer, ‘Pflanzenstoffe und Pflanzensystematik’, Naturwiss., 1971, 58, 585 (88 references).
30 1
302
Terpenoids and Steroids
P. W. Thies, in ‘1st International Congress on Pharmacognosy and Phytochemistry’, ed. H. Wagner and L. Horhammer, Springer-Verlag, Berlin, 1971, p. 41 (iridoid alkaloids). Cannabinoids. R. Mechoulam, ‘Marihuana Chemistry’, Science, 1970,168, 1 159 (87 references). T. Petrzilka, ‘Chemistry of Synthetic Hashish Derivatives’, Bull. Schweiz. Akad. Med. Wiss., 1971, 27, 22 (20 references). C . R. B. Joyce and S. H. Curry, ‘Botany and Chemistry of Cannabis’, Churchill, London, 1970. H. G. Pars and R. K. Razdan, ’Tetrahydrocannabinol and Synthetic Analogs’, Ann. New York Acad. Sci., 1971, 191, 15 (22 references). R. K. Razdan, in ‘Progress in Organic Chemistry’, ed. W. Carruthers and J. K. Sutherland, Butterworths, London, 1973, Vol. 8. W. D. M. Paton and J. Crown, ‘Cannabis and its Derivatives’, Oxford University Press, London, 1972. R. Mechoulam, ‘Marijuana Chemistry, Pharmacology, Metabolism, and Clinical Effects’, Academic Press, New York, 1973. Biogenesis. D. V. Banthorpe, B. V. Charlwood, and M. J. 0 . Francis, ‘The Biosynthesis of Monoterpenes’, Chem. Rev., 1972, 72, 115 (527 references). W. W. Epstein and C. D. Poulter, ‘A Survey of Some Irregular Monoterpenes and their Biogenetic Analogies to Presqualene Alcohol’, Phytochemistry, 1973, 12, 737 (30 references). Mass Spectrometry. C. R. Enzell, R. A. Appleton, and I. Wahlberg, in ‘Biochemical Applications of Mass Spectrometry’, Wiley, New York, 1972, p. 351. Photochemistry. P. G. Sammes, ‘Photochemical Reactions in Natural Product Synthesis’, Quart. Rev., 1970, 24, 37 (120 references). M. Pfau. ‘Photochemistry in the Field of Monoterpenes and Related Compounds’, Flavour Ind., 1972, 3, 89 (87 references). Perfumes and Flavours. Y.-R. Naves, ‘Progress in the Synthesis of Perfumes Based on Pinenes’, Rum. Chem. Rev., 1968, 37, 779 (specifically pinenes) (1 19 references). G. Ohloff, ‘Chemistry of Odoriferous and Flavouring Substances’, Fortschr. chem. Forsch., 1969, 12, 185 (418 references). Resolution. P. H. Boyle, ‘Methods of Optical Resolution’, Quart. Rev., 1971, 25, 323 (132 references).
Reviews on Terpenoid Chemistry
303
2 Sesquiterpenoids General. J. S. Roberts, in ‘Chemistry of Terpenes and Terpenoids’, ed. A. A. Newman, Academic Press, New York, 1972, p. 88. R. Bryant, ‘Mono- and Sesqui-terpenoids’, Interscience, New York, 1969. T. K. Devon and A. 1. Scott, ‘Handbook of Naturally Occurring Compounds’, Vol. 2, ‘Terpenes’, Academic Press, New York, 1971, p. 55. Sesquiterpenoid Lactones. J. Romo, ‘Recent Studies on Sesquiterpenes’, Pure Appl. Chem., 1970, 21, 123 (33 references). T. A. Geissman and M. A. Irwin, ‘Chemical Contributions to Taxonomy and Phylogeny in the Genus Artemisia’, Pure Appl. Chem., 1970, 21, 167 (54 references). S. M. Kupchan, ‘Recent Advances in the Chemistry of Terpenoid Tumor Inhibitors’, Pure Appl. Chem., 1970, 21, 227 (24 references). F. Sorm, ‘Advances in Terpene Chemistry’, Pure Appl. Chem., 1970, 21, 263 (20 references). S. C. Bhattacharyya, ‘Some Interesting Sesquiterpene Lactones’, J. Indian Chem. SOC.,1970, 47, 299 (19 references). W. Herz, ‘Recent Advances in Phytochemistry’, ed. T. J. Mabry, North-Holland Publishing Co., Amsterdam, 1968, Vol. 1, p. 229. W. Herz, G. Anderson, S. Gibaja, and D. Raulais, ‘Sesquiterpene Lactones of Some Ambrosia Species’, Phytochemistry, 1969, 8, 877 (12 references). Sesquiterpenoid Ethers. K. Takeda, ‘Sesquiterpenes Having a Five-membered Ether-ring in the Molecule’, Pure Appl. Chem., 1970, 21, 181 (26 references). Insect Juvenile Hormone. B. M. Trost, ‘The Juvenile Hormone of Hyalophora cecropia’, Accounts Chem. Res., 1970, 3, 120 (29 references). Y. S . Tsizin and A. A. Drabkina, ‘The Juvenile Hormone of Insects and its Analogues’, Russ. Chem. Rev., 1970, 39, 498 (134 references). Biosynthesis. J. R. Hanson, ‘Biosynthesis of Terpenoid Compounds: C,-C,, Compounds’, in ‘Biosynthesis’, ed. T. A. Geissman (Specialist Periodical Reports), The Chemical Society, London, Vol. 1, 1972, p. 41 (104 references); Vol. 2, 1973, p. 1 (77 references). G. P. Moss, ‘The Biogenesis of Terpenoid Essential Oils’, J. SOC.Cosmetic Chemists, 1971, 22, 231 (67 references). Synthesis. C. H. Heathcock, in ‘Total Synthesis of Natural Products’, ed. J. W. ApSimon, Wiley, New York, 1973, Vol. 2, p. 197.
304
Terpenoids and Steroid
S. E. Danishefsky and S. Danishefsky, ‘Progress in Total Synthesis’, AppletonCentury-Crofts, Meredith Corporation, New York, 1971, Vol. 1, p. 1 10.
3 Diterpenoids General. R. McCrindle and K. H. Overton, in ‘Rodd’s Chemistry of Carbon Compounds’, 2nd Edn., Elsevier, Amsterdam, 1969, Vol. IIC, Ch. 14. E. Fujita, ‘The Chemistry on Diterpenoids in 1966’, Bull. Inst. Chem. Res., Kyoto Univ., 1967, 45, 229 (181 references); ‘The Chemistry on Diterpenoids 1967’, ibid., 1969, 47, 522 (180 references); ‘The Chemistry on Diterpenoids in 1968’, ibid., 1970,48, 11 1 (200 references); ‘The Chemistry on Diterpenoids in 1969’, ibid., 1970, 48, 294 (220 references). J. R. Hanson, in ‘Chemistry of Terpenes and Terpenoids’, ed. A. A. Newman, Academic Press, New York, 1972. T. Devon and A. I. Scott, ‘Handbook of Naturally Occurring Compounds’, Vol. 2, ‘Terpenes’, Academic Press, New York, 1972, p. 185. Nomenclature. J. W. Rowe, ‘The Common and Systematic Nomenclature of Cyclic Diterpenes’, U.S. Dept. of Agriculture, Forest Products Laboratory, Madison, Wisconsin, 1968. Bicyclic Diterpenoids. J. R. Hanson, ‘The Bicyclic Diterpenes’, Progr. Phytochem., 1972, 3, 231 (214 references). Resin A cids. D. F. Zinkel, L. C. Zank, and M. F. Wesolowski, ‘Diterpene Resin Acids’ (a compilation of i.r., m.s., n.m.r., and U.V.spectra), U.S. Dept. of Agriculture, Forest Products Laboratory, Madison, Wisconsin, 1971. Tetracy clic Diterpeno ids. J. R. Hanson, ‘The Chemistry of the Tetracyclic Diterpenes’, Pergamon Press, Oxford, 1968. J. R. Hanson, ‘Recent Advances in the Chemistry of the Tetracyclic Diterpenes’, Progr. Phytochem., 1968, 1, 161 (1 27 references).
Gibberellins. B. E. Cross, ‘Biosynthesis of the Gibberellins’, Progr. Phytochem., 1968, 1, 195 (78 references). A. Lang, ‘Gibberellins: Structure and Metabolism’, Ann. Rev. Plant Physiol., 1970, 21, 537 (205 references). C. A. West, M. Oster, D. Robinson, F. Lew, and P. Murphy, ‘Biochemistry and Physiology of Plant Growth Substances’, ed. F. Wightman and G. Setterfield, Runge Press, Toronto, 1970, p. 313. J. MacMillan, in ‘Advances in the Chemistry and Biochemistry of Terpenoid Substances’, ed. T. W. Goodwin, Academic Press, London, 1971, p. 153.
Reviews on Terpenoid Chemistry
305
J. MacMillan, in ‘Phytochemistry’, ed. L. P. Miller, Reinhold, New York, 1971, Ch. 6. Diterpene Alkaloids. S. W. Pelletier and K. H. Lawrence, in ‘Chemistry of the Alkaloids’, ed. S. W. Pelletier, van Nostrand-Reinhold, New York, 1970. Biosyn thesis. J. R. Hanson and B. Achlladelis, ‘The Biosynthesis of the Diterpenes’, Perfumery and Essential Oil Record, 1968, 59, 802 (31 references). J. R. Hanson, ‘The Biosynthesis of the Diterpenes’, Fortschr. Chem. org. Naturstofle, l971,29, 395 (64 references). Chemotaxonomy. R. C. Cambie and R. J. Weston, ‘Chemotaxonomy of the New Zealand Podocarpaceae’, Chem. in New Zealand ( J . New Zealand Inst. Chem.), 1968, 32, 105. T. Norin, ‘Some Aspects of the Chemistry of the Order Pinales’, Phytochemistry, 1972, 11, 1231 (69 references).
4 Sesterterpenoids L. Canonica and A. Fiecchi, ‘Structure and Biosynthesis of Ophiobolins’, Rec. Progr. Org. Biol. Med. Chem., 1970, 2, 51.
5 Triterpenoids General. T. K. Devon and A. I. Scott, ‘Handbook of Naturally Occurring Compounds,’ Vol. 2, ‘Terpenes’, Academic Press, New York, 1972, p. 281. M. J. Kulshreshtha, D. K. Kulshreshtha, and R. P. Rastogi, ‘The Triterpenoids’, Phytochemistry, 1972, 11, 2369 (217 references). J. D. Connolly and K. H. Overton, in ‘Chemistry of Terpenes and Terpenoids’, ed. A. A. Newman, Academic Press, London, 1972, p. 207. Limonoids and Quassinoids. D. L. Dreyer, ‘Limonoid Bitter Principles’, Fortschr. Chem. org. Naturstofle, 1968, 26, 190 (127 references). J. D. Connolly, K. H. Overton, and J. Polonsky, ‘The Chemistry and Biochemistry of the Limonoids and Quassinoids’, Progr. Phytochem., 1970, 2, 385 (146 references). J. Polonsky, ‘Quassinoid Bitter Principles’, Fortschr. Chem. org. Naturstofe, 1973, 30, 101 (82 references). Cucurbitacins. D. Lavie and E. Glotter, ‘The Cucurbitanes: a Group of Tetracyclic Triterpenes’, Fortschr. Chem. org. Naturstofe, 1971, 29, 307 (136 references).
306
Terpenoids and Steroids
Holothurinogenins. E. Premuzic, ‘Chemistry of Natural Products Derived from Marine Sources,’ Fortschr. Chem. org. Nuturstofle, 1971, 29, 417 (338 references). J. S. Grossert, ‘Natural Products from Echinoderms’, Chem. SOC.Rev., 1972, 1, 1 (98 references). Triterpenoids in Mineral Sources. P. Albrecht and G. Ourisson, ‘Biogenetic Substances in Sediments and Fossils’, Angew. Chem. Znternat. Edn., 1971, 10, 209 (114 references). E. V. Whitehead, ‘Chemical Clues to Petroleum Origin’, Chem. and Ind., 1971, 1 1 16 ( I reference). J. R. Maxwell, C. T. Pillinger, and G. Eglinton, ‘Organic Geochemistry’, Quart. Rev., 1971 , 25, 57 1 (296 references).
6 Carotenoids and Polyterpenoids Caro tenoids-Gene ra 1.
J. B. Davis, ‘The Carotenoid Group’, in ‘Rodd’s Chemistry of Carbon Compounds’, Vol. IIB, ed. S. Coffey, Elsevier, Amsterdam, 1968, pp. 231-346 (ca. 900 references). C. Bodea, ‘Cyclization Reactions of Carotenoids’, Pure Appl. Chem., 1969, 20, 5 17 (16 references). B. H. Davies, ‘Structural Studies on Bacterial Carotenoids and their Biosynthetic Implications’, Pure Appl. Chem., 1969, 20, 545 ( I 8 references). S. Liaaen-Jensen, ‘Selected Examples of Structure Determination of Natural Carotenoids’, Pure Appl. Chern., 1969, 20, 421 (96 references). B. C. L. Weedon, ‘Some Recent Advances in the Synthesis of Carotenoids’, Pure Appl. Chem., 1969, 20, 531 (42 references). T. W. Goodwin and L. J. Goad, ‘Carotenoids and Triterpenoids’, in ‘Biochemistry of Fruits and their Products’, ed. A. C. Hulme, Academic Press, London, 1970, pp. 305-368 (404 references). S. Liaaen-Jensen, ‘Developments in the Carotenoid Field’, Experientia, 1970, 26, 697 (55 references). B. C. L. Weedon, ‘Allenic and Acetylenic Carotenoids’, Rev. Pure Appl. Chern. (Australia), 1970. 20, 51 (106 references). G. Britton and T. W. Goodwin, ‘Biosynthesisof Carotenoids’, Methods Enzymol., 1971, 18C. 654 (101 references). T. W. Goodwin. ‘Algal Carotenoids’, in ‘Aspects of Terpenoid Chemistry and Biochemistry’, ed. T. W. Goodwin, Academic Press, London, 1971, pp. 315-356 (175 references). ‘Carotenoids’, ed. 0. Isler, Birkhauser, Basel, 1971 ; Contents: 0. Isler, ‘Introduction’. pp. 11-27 (44 references); B. C. L. Weedon, ‘Occurrence’, pp. 29-59 (283 references); s. Liaaen-Jensen, ‘Isolation, Reactions’, pp. 61 -188 (550 references); W. Vetter, G. Englert. N. Rigassi, and U. Schwieter, ‘Spectroscopic Methods’, pp. 189--266 (65 references); B. C. L. Weedon, ‘Stereochemistry’, pp. 267-323 (184 references); H. Mayer and
Reviews on 7tJrpenoidCtlemis t rj,
307
0. Isler, ‘Total Syntheses’, pp. 325-575 (451 references); T. W. Goodwin, ‘Biosynthesis’, pp. 577-636 (350 references); H. Thommen, ‘Metabolism’, pp. 637-668 (124 references); N. I. Krinsky, ‘Function’, pp. 669-716 (266 references); G. A. J. Pitt, ‘Vitamin A’, pp. 717-742 (173 references); J. C. Bauernfeind, G. B. Brubacher, H. M. Klaui, and W. L. Marusich, ‘Use of Carotenoids’, pp. 743-770 (266 references); 0. Straub, ‘Lists of Natural Carotenoids’, pp. 771-850 (815 references); Appendix, ‘Tentative Rules for the Nomenclature of Carotenoids’, pp. 851-864. B. Ke, ‘Carotenoproteins’, Methods Enzymol., 1971, 23, 624 (39 references). S. Liaaen-Jensen, ‘Recent Progress in Carotenoid Chemistry’, in ‘Aspects of Terpenoid Chemistry and Biochemistry’, ed. T. W. Goodwin, Academic Press, London, 1971, pp. 223-254 (1 11 references). S . Liaaen-Jensen and A. G. Andrewes, ‘Microbial Carotenoids’, Ann. Reu. Microbiol., 1972, 26, 225 (156 references). S . Liaaen-Jensen, ‘Structural Elucidation of Carotenoids-A Progress Report’, Pure Appl. Chem., 1973, 35, 81 (76 references). B. C. L. Weedon, ‘Some Recent Studies on Carotenoids and Related Compounds’, Pure Appl. Chem., 1973, 35, 113 (25 references). Carotenoids-Physical Methods. L. Bartlett, W. Klyne, W. P. Mose, P. M. Scopes, G. Galasko, A. K. Mallams, B. C. L. Weedon, J. Szabolcs, and G. Toth, ‘Optical Rotatory Dispersion of Carotenoids’, J. Chem. SOC.(C), 1969, 2527 (32 references). C. R. Enzell, ‘Mass Spectrometric Studies of Carotenoids’, Pure Appl. Chem., 1969, 20, 497 (1 1 references). C. R. Enzell, G. W. Francis, and S . Liaaen-Jensen, ‘Mass Spectrometric Studies of Carotenoids’, Acta Chem. Scand., 1969, 23, 727 (8 references). U. Schwieter, G. Englert, N. Rigassi, and W. Vetter, ‘Physical Organic Methods in Carotenoid Research’, Pure Appl. Chem., 1969, 20, 365 (34 references). B. C. L. Weedon, ‘Sectroscopic Methods for Elucidating the Structures of Carotenoids’, Fortschr. Chem. org. Naturstofle, 1969, 27, 81 (82 references). H. Budzikiewicz, H. Brzezinka, and B. Johannes, ‘Mass Spectrometric Investigation of Carotenoids’, Monatsh., 1970, 101, 579 (48 references). Degraded Carotenoids. R. Hubbard, P. K. Brown, and D. Bownds, ‘Methodology of Vitamin A and Visual Pigments’, Methodr Enzymol., 1971, 18C, 615 (39 references). B. V. Milborrow, ‘Abscisic Acid’, in ‘Aspects of Terpenoid Chemistry and Biochemistry’, ed. T. W. Gbodwin, Academic Press, London, 1971, pp. 137-151 (25 references). G. A. J. Pitt, ‘Vitamin A’, in ‘Carotenoids’, ed. 0. Isler, Birkhauser, Basel, 1971, pp. 717-742 (173 references). H. F. Taylor and R. S . Burden, ‘Xanthoxin, a Recently Discovered Plant Growth Inhibitor’, Proc. Roy. Soc., 1972, B180,317 (33 references).
308
Terpenoids and Sleroids
Polyterpenoids and isoprenylutrd Quinones. F. W. Hemming, ‘Poiyprenols’, in ‘Substances Formed Biologcally from Mevalonic Acid’, ed. T, W. Goodwin, Academic Press, London, 1970, pp. 105-1 17 (29 references). 0. Wiss and U. Gloor, ‘Nature and Distribution of Terpene Quinones’, in ‘Substances Formed Biologically from Mevalonic Acid’, ed. T. W. Goodwin, Academic Press. London, 1970, pp. 79-87 (20 references). R. Barr and F. L. Crane, ‘Quinones in Algae and Higher Plants’. Methods En:~-3ketone (184) by Nocardia corallina ATCC 13259 to give the 4-hydroxylated 404
405 ‘Oh
A. I. Laskin, J. Fried, C. de L. Meyers, and P. Grabowich, Bacteriol. Proc., 1964, 25; A. I. Laskin, P. Grabowich, C. de L. Meyers, and J. Fried, J . Medicin. Chem., 1964, 7 , 406. H. H . Tai and C. J. Sih, J . Biof. Chem., 1970, 245, 5062. H. H. Tai and C. J. Sih. J . Biol. Chem., 1970,245, 5072.
Terpenoids and Steroids
502
9,10-seco-steroid (1 85)."02 Incubation of the 4-hydroxy-A4-3-ketone (I 86) with frozen cells of Nocurdia restrictus in the presence of phenazine methosulphate gave the 4-hydroxylated 9.1 O-seco-steroid (183).
(184)
0
OH
OH (185)
(186)
An alternative degradation pathway for A-ring-aromatic steroids does not involve scission of the 9,lO-bond or the intermediate (101). 3-Hydroxyoestra1,3,5(IO)-trien-17-one (77) was oxidized by Nocardia sp. (E110) to give the three metabolites (187), (188), and (189). In that 3,4-dihydroxyoestra-l,3,5(lO)-trien17-one (190) was also oxidized but 2,3-dihydroxyoestra- 1,3,5(lO)-trien-l7-one was not. it was suggested that the degradation of (77) proceeded by 4-hydroxylation Ljiu (190) to the bis-seco-steroid ( 187) with loss of the C-4 carbon 2tom. Further degradation of (187) led to (188). The third metabolite, the 4-aza-steroid (189),
(187) R = CH=CHCH,CO,H (188) R = CH,COMe
(189)
503
Microbiological React ions with Steroids
was considered to be formed in a non-enzymic side-reaction between an initially formed intermediate and ammonia.407 The 4-hydroxy-9,10-seco-steroid(183) was readily degraded by cell-free extracts of Nocardia restrictus via the 4,5 :9, 10-bis-seco-derivative408to the hexahydroindane derivative (182).2227402,409Treatment of the 4,5 :9,lO-bisseco-steroid intermediate (191) with ammonia gave ( 192),408the 9,lO-secoanalogue of the 4-aza-steroid (189) recovered from fermentation of (77) with Nocardia sp. (El
The remaining six carbon atoms of the A-ring were retained as 2-oxohex-cis-4enoic acid (193), whose hydration product (194) was further metabolized to propionic a c d (199, and pyruvic acid (196),which entered the general metabolism HO C0,H
1
yH2 Me
y 2 H
co 1
Me
of the o r g a n i ~ m . 0~t ~ her~ experiments ,~~~ with Pseudornonas testosteroni ATCC 11996 established the same points. Extracts of Pseudomonus testosteroni which oxidized [4-I4C]-(71) to CO, also accumulated [1-l4C]-DL-alanine (197) and [ 1-14C]-~-2-aminohex-cis-4-enoic acid (198) in the presence of ethylenediaminetetra-acetic acid.410 2-Oxohex-cis-4-enoic acid (193) is efficiently converted into (197) and (198) by Pseudomonas testosteroni and appears to be their common CO, H
I
THNH, I
Me (197)
H,N*CO,H (198)
40 7
R.G . Coombe, Y. Y. Tsong, P. B. Hamilton, and C. J. Sih, J . Biol. Chem., 1966, 241,
408
D. T . Gibson, K . C. Wang, C. J. Sih, and H. W. Whitlock, J . Biol. Chem., 1966, 241,
1587. 409
410
551. C. J. Sih, K. C. Wang, D. T. Gibson, and H. W. Whitlock, J . Amer. Chem. Soc., 1965, 87, 1386. D. A . Shaw, L. F. Borkenhagen, and P. Talalay, Proc. Nut. Acad. Sci. U.S.A., 1965,54, 837.
Terpenoids and Steroids
504
p r e c ~ r s o r .'~ ' Transamination of the 0x0-acid (193) and of [l-'4C]pyruvate (196)formed from (194) via an aldolase action would afford the observed products (198) and (197) respectively. It may be presumed that the pathway (71) 4(126) -+(177) +(183) *(182) is a general one for many steroids. In this formulation the C-17 side-chain and other c- or D-ring substitution remains unaltered whereas the A- and B-rings are degraded. Nocardia species degrade several sterol derivatives without degradation of the side-chain features. Cholest-5-ene-3/?,25-diol(l99)fermented with Nocardia opaca gave the degraded product (201) with the side-chain intact. Similarly, the 3P-acetate of the 27-nor-ketone (200) was degraded to (202).412
(199) R = CMe,OH (200) R = COMe
(201) R = CMe,OH (202) R = COMe
?*
I
Degradation of 3a,7a,l2a-trihydroxy-5/?-cholan-24-oic acid (203) by Streptomyces rubescens gave the hexahydroindane derivative, (204) with the side-chain i n t a ~ t .3*4 ~ 'l 4 In this instance several further degraded derivatives were formed which also incorporated nitrogen into the degraded fragments. Thus, the amide (205) and the lactams (206) and (207) retaining the C-17 side-chain were formed, together with the lactams (208), (209), and (210) degraded in the sidehai in.^'^.^'^ The 17-0x0-lactam (210) could be formed from (182) by Streptomyces rubescens. It was uncertain whether the other lactams (206)-(209) found in the fermentations were formed en~ymatically.~ l4 The dicarboxylic acid (204)
412
413
414
A. W. Coulter and P. Talalay, Biochem. Biophys. Res. Comm., 1967, 29, 413; J. Biol. Chem., 1968,243, 3238. C. J. Sih, H. H. Tai, and Y. Y. Tsong, J. Amer. Chem. Soc., 1967, 89, 1957; C. J. Sih, H. H. Tai, S. S. Lee, and R. G . Coombe, Biochemistry, 1968, 7, 808. S. Hayakawa, S. Hashimoto, T. Fujiwara, and T . Onaka, Abhandl. deutsch. Akad. Wiss. Berlin, Klasse Med., 1968, No. 2, p. 63. S. Hayakawa, S. Hasimoto, and T. Onaka, Lipids, 1969, 4, 224.
Microbiological Reactions with Steroids
I
R
H O Z C d (204) k (205) R
505
= =
OH NH,
(206) R (207) R (208) R (209) R
= CH,CHzCOzH = CH,CH,CONH, = COMe = COzH
HN
was also obtained from the C,, acid (203) fermented with Corynebacteriurn (Arthrobacter) Corynebacteriurn equi converted (204) into aminoacid conjugate^.^' Pregn-4-ene-3,20-dione (21l), 17a-hydroxypregn-4-ene-3,20-dione (212), 1 7 ~ acetoxypregn-4-ene-3,2Odione (213), and 21-hydroxypregn-4-ene-3,20-dione (214) were transformed by Nocardiu opaca SG 98 into the corresponding degraded derivatives (216)-(219) with their side-chains intact.41 1la-Hydroxypregn-4ene-3,20-dione (215 ) was transformed by Proactinomyces ruber into (220).,03
'
COCH 2R I
#--Rz
R3*J33 0
- -R2
HO,C,/
0
(211) R' = RZ = R3 = H (212) R' = R3 = H, R2 = OH (213) R' = R3 = H, R2 = OCOMe (214) R' = OH, RZ = R3 = H (215) R' = R2 = H, R3 = OH 415
COCH,R'
(216) R' = RZ = R3 = H (217) R' = R3 = H, RZ = OH (218) R' = R3 = H, RZ = OCOMe (219) R' = OH, R2 = R3 = H (220) R' = RZ = H, R3 = OH
S. Hayakawa, Y. Kanematsu, and T. Fujiwara, Nature, 1967, 214, 5 2 0 ; Biochem. J., 1969, 115, 249.
416
417
S . Hayakawa, T. Fujiwara, and H. Tsuchikawa, Nature, 1968, 219, 1160. K. Schubert, K.-H. Bohrne, F. Ritter, and C. Horhold, Biochim. Biophys. Acra, 1968, 152, 401.
506
Terpenoids and Steroids
Degradation of (211) and the epimeric pregn-5-ene-3/?,20-diols(221) and (222) by a Nocardia species to their corresponding hexahydroindane derivatives (216), (223), and (224) has been reported.418 Degradation of the 3/3,20/3-diol(222)was stimulated by calcium ions.4'
Me
Me +C-R2
R',
I
HO2C
HO (221) R' = H, R2 = O H (222) R' = OH, R2 = H
R',
oaC-R2
I
4
(223) R' (224) R'
= =
H, R2 = O H OH, R2 = H
Further degradation of the perhydroindane derivatives (182)and (216)retaining the c- and D-ring features of the parent steroids has been reported. The C1, fragment (216) was reduced by Mycobacteriurn srnegrnatis SG 98 to a variety of alcohols (225)-(230) formed by reduction of both ketone groups and of the carboxylic By contrast (182) was oxidized by Nocardia opaca to aoxoglutaric acid (231) and succinic acid (232).417 * 4 2 1 Me
R3\ 1
C-R4
M eoJ - - JJ IR R2'
(225) R' = H, R2 = O H (226) R' = OH, R2 = H
418
419
420 421
(227) R' = R3 = H, R2 = R4 = O H (228) R' = R4 = H, R2 = R3 = OH (229) R' = R3 = OH, R2 = R4 = H (230) R' = R4 = OH, R2 = R3 = H
A. Strijewski, T.-L. Tan, G. Bozler, W. Zahn, and F. Wagner, 2. physiol. Chem., 1972,353, 1440. T.-L. Tan, A. Strijewski, and F. Wagner, Arch. Mikrobiol., 1972, 87, 249. K. Schubert, K.-H. Bohme, and C. Horhold, Biochim. Biophys. Acra, 1965, 111, 529. K. Schubert, K.-H. Bohme, and C. Horhold, Acfu Biol. Med. Ger., 1967, 18, 295; Abhandl. deursch. Akad. Wiss. Berlin, Klasse Med., 1968, NO.2, p. 81.
507
Microbiological Reactions with Steroih
The 17-ketone degradation fragment (182) was metabolized by Nocardia corallina to (233) and (234) by oxidoreductases. Pseudomonas testosteroni acting on (233) gave the lactone (235).422 Studies with additional hexahydroindanepropionic acid derivatives suggested that the next step in the degradation of (182) was via P-oxidation of the propionic acid side-chain to give the hexahydroindane-4-carboxylic acid (236), which was then further degraded by scission of the six-membered ring.422
HO,C,/ (234)
Tetrahydroindane derivatives have also been obtained in certain cases from microbial degradation of (211). Mycobacterium smegmtis gave the alcohol (237),42 whereas Nocardia rhodochrous 7022 gave the acid (238).41
(237) R = C H 2 0 H (238) R = C 0 2 H
Further degradation of the hexahydroindanedione (182) by Streptomyces acid (239) reprerubescens afforded ( + )-(5R)-methyl-4-oxo-octane-1,8-dioic senting the C-9 and C - 1 1 4 - 1 7 carbon atoms of the original steroid C- and Me
422 423
S. S. Lee and C. J. Sih, Biochemistry, 1967, 6, 1395. K. Schubert, K.-H. Bohme, and C. Horhold, Acfu Biol. Med. Ger., 1967, 18, 291.
508
Terpenoids and Steroids
rings.^^^ The same C9 acid (239) was recovered in fermentations of the parent bile -acid (203) with Arthrobacter simplex, but the acid was not optically active, probably having been racemized during isolation.425 Degradation of steroids may also be initiated at points in the C-17 side-chains and C-3a positions (C-17 and C-14 by steroid D-ring numbering) to [1-14C]succinic acid (232) was obtained in Nocardia opaca fermentation^.^^^ Formation of [l-'4C]succinic acid from labelled (238) is reconciled with scission of the 1,7a- and 3a,4-bonds (13,17- and 8,14-bonds by steroid numbering). Degradation of steroids may also be initiated at points in the C-17 side-chains independently of alterations which may occur in the A-ring. Degradation of the sterol side-chain may begin by attack at the terminal isopropyl group by 26hydroxylation as has been demonstrated for several Mycobacterium species recognized as degrading s t e r ~ l s . ~ ~3~2 ' H ~ owever, ~-' Nocardia species fail to 27-norcholest-5-en-3P-01, attack the side-chains of cholest-5-ene-3P,25-diol(199), 3~-hydroxy-27-norcholest-5-en-24-one, or the 3P-acetate of the 27-nor-25ketone (200).412 Degradation reactions of the sterol side-chain appear to involve conventional fatty-acid oxidation pathways, one equivalent of propionic acid (195) being derived from the terminal*isopropyl group in the formation of C24 acids and one equivalent of acetic acid being derived from the C-23 and C-24 atoms in the formation of CZz Oxidations by Nocardia restrictus of [26,27-14C](123) gave propionic acid (195) labelled only at C-1 and C-3.41 Incubation of [4-14C]-(123) with Nocardia restrictus in the presence of 3-oxochol-4-enic acid (74) and o-phenanthroline led to recovery of 14C-labelled (74), thus suggesting that some (74) was formed from (123).412 The ultimate reaction in side-chain cleavage is transformation to the 17-ketone. Degradation of the 19-hydroxy-A4-3-ketone (240) by Nocardia species gave the four acids (242)-(245) as products, clearly demonstrating C,,-acid formation both with and without attendant A-ring a r ~ m a t i z a t i o n .The ~~~ 6j3,lPepoxy-acid (246) was degraded by Nocardia restrictus to the bisnorcholenic acid (247) and the 17-ketone (248).412 Tracer experiments suggested that the C3 side-chain of bisnorcholenic acid substrates was cleaved to propionic acid and to a 17-0x0steroid.427 The stepwise cleavage of the sterol side-chain via C24 and/or C,, acids to a 17-0x0-steroid is further exemplified by the action of Nocardia restrictus ATCC 14887 and Nocardia corallina ATCC 13259 on the seco-nor-steroid (249). The seco-nor-dicarboxylic acid (250), the 17P-alcohol (25l), and the 17-ketone (252) were also
42'
S. Hayakawa and S. Hashimoto, Biochem. J., 1969, 112, 127. S. Hayakawa and T. Fujiwara, F.E.B.S. Letters, 1969, 4, 288. K . Schubert, F. Ritter, T. Sorkina, K.-H. Bohme, and C. Horhold, J . Steroid Biochem., 1969, 1, 1 . C. J. Sih, K. C. Wang, and H. H. Tai, J . Amer. Chem. SOC.,1967,89, 1956; Biochemistry,
428
1968,7, 796. G. Lefebvre, H. Matringe, M. Maugras, and R. Gay, Compt. rend., 1968,266, D, 1196.
424
425 426
Microbiological Reactions with Steroids
509
(240) R = H (241) R = Et
&
HO,C
(249)
H
0
2
(250) C
G
H
Terpenoids and Steroids
510
Stepwise degradation of the sterol side-chain of (123) to C22intermediates of lower oxidation state by Mycobacterium sp. NRRL B-3683 and NRRL B-3805 is implied by the isolation of the C,, 22-alcohol (253) along with (71) and (126).429 Cleavage of the C-20-C-22 bond of 6p,1lcr,22-trihydroxy-23,24-bisnorchol-4en-3-one by Rhizopus arrhizus to provide 6P,1lcr-dihydroxypregn-4-ene-3,20dione has also been
Complete scission of the sterol side-chain with 17-ketone formation but without or B-ring degradation has been achieved in several ways. Selection of microorganism has received much attention, and many organisms previously mentioned in Section 3 of this Report cleave the sterol side-chain of (123) in conjunction with A-ring dehydrogenation but with no other d e g r a d a t i ~ n . ~ ' , ~"' ~Pilot-~ plant (2501) conversion of (123) into (71) and (126) has been achieved using Mycobacterium sp. NRRL B-3683.429 In other cases inhibition of nuclear degradation by the addition of specific inhibitors has permitted recovery of (126) from sterols. Screening of Mycobacterium species inhibited by 8-hydroxyquinoline resulted in selection of a Mycobacterium phlei strain for conversion of the sterol (123) into the A'74-3,17dione (126).205 Mycobacteriurn phlei inhibited by 8-hydroxyquinoline also acted on C2', C 2 8 ,and C29 steroids to give (126).204 The organism also converted 4~,5-epoxy-5~-cholestan-3-one (254) and 4P,S-epoxy-5#3-pregnane-3,20-dione (255) into (126).297 A-
(254) R = C,H1, (255) R = COMe
Nuclear degradation by species of Arthrobacter, Bacillus, Brevibacterium, Corynebacterium, Microbacterium, Mycobacterium, Nocardia, Protaminobacter, Serratia, and Streptornyces was inhibited by a,a-bipyridyl and by arsenite ion,209.2 and cleavage of the side-chain without nuclear degradation was achieved with (123) as substrate. 429
W. J. Marsheck, S. Kraychy, and R. D. Muir, Appl. Microbiol., 1972, 23,72.
Microbiological Reactions with Steroids
511
The nuclear degradation of cholest-5-en-3P-o1(123)by Mycobacterium species is inhibited by Ni2+,Co2+,Pb2+,and Se032- ions.430 A similar inhibition of a Mycococcus species by Ni2+ has been as has the inhibition of Proactinomyces asteroides 438 by Co2 ions.21 Nuclear degradations of (123) by Arthrobacter simplex IAM 1660 were inhibited by chelating agents, by a variety of heavy-metal ions, and by redox dyes, with accumulation of the A ' T ~ - ~ ketone (126).432Side-chain cleavage of 19-norcholesta-1,3,5(lO)-trien-3-01 (256) by Nocardia restrictus ATCC 14887gives in 8 % yield the 17-ketone(77)dire~tly.4~ Degradation of the side-chain only of the 3~,5a-cyclosteroids(257), (258), and (259) by a Mycococcus species has been reported. The product was the 3a75acyclosteroid 17-ketone (260).431 +
I
OH (257) R = H (258) R = Et
(259) R
=
Et, AZ2
Degradation of the sapogenin side-chain to give (126) is also reported. Mycobacterium phlei inhibited with 8-hydroxyquinoline converted (25R)-spirost-5-en3P-01(261)into (25R)-spirost-4-en-3-oneand (25R)-spirosta-1,4-dien-3-one(262) but also into the 17-ketones (71) and (126).212 Sapogenins of both the (25R)and (25S)-serieswere also degraded :(25R)-Sa-spirostan-3P-o1,(25S)-Sa-spirostan3p-01, (25R)-S/?-spirostan-3/3-01,and (25S)-SP-spirostan-3P-olwere all converted into (126) in 2.5-6.5 % yields.212 However, (25R)-spirost-4-en-3-one was degraded by Fusarium solani No. 101 in 65 % yield to androsta-1,4-diene-3,16430
431
432
433
W. F. Van der Waard, J. Doodewaard, J. de Flines, and C. Van der Weele, Abhandl. deutsch. Akad. Wiss.Berlin, Klasse Med., 1968, No. 2, p. 101. A. F. Marx, J. Doodewaard, W. F. Van der Waard, and J. de Flines, Rev. SOC.quim. MPxico, 1969, 13, 72A. M. Nagasawa, N . Watanabe, H. Hashiba, M. Murakami, M. Bae, G . Tamura, and K. Arima, Agric. and Biol. Chem. (Japan), 1970, 34, 838. A. Afonso, H. L. Herzog, C. Federbush, and W. Charney, Steroids, 1966, 7, 429.
Terpenoids and Steroids
512
dione (126) with 16a- and 16~-hydroxyandrosta-1,4-dien-3-one each formed in 5 % yield.21 These same 16-oxygenated products were also obtained from (261) but in lower yields. From fermentations using a variety of other sapogenins and 16,20-dioxygenatedpregnane derivatives the course of degradation of (261) was suggested to proceed via (262)-(267).21
0
0
(265) R = COCH,CH,CHMe, (266) R = H
Microbiological Reactions with Steroids
513
Fermentation of (25R)-spirost-4-en-3-one with Verticilliurn theobromae or (268) and with Stachylidiurn bicolor afforded 20cr-hydroxypregn-4-ene-3,16-dione 16-one (269).434 3a,ll P,20cr-trihydroxy-Sc-pregnan-
The ease of side-chain cleavage by Arthrobacter simplex IAM 1660 appeared to diminish with increasing length for Czl to C24 to C27steroids.435 The action of Arthrobacter simplex IAM 1660 on (123) gave, in addition to the expected A4-3-ketone (71) and A's4-3-ketone (126) degradation products, the additional products (16), 17P-hydroxyandrosta-1,4-dien-3-one, 17/?-hydroxy-5/?-androst-len-3-one, and 5P-androstane-3~t,l7fi-diol.~~~ Microbial degradations of bile acids include both minor alterations in the A-, B-, or c-rings and also side-chain scission. Degradation by Mycobacteriurn rnucosum 1210involvesmainly 3a-, 7a-,and 12a-hydroxy-steroiddehydrogenations coupled with A4-dehydrogenation and side-chain scissions. The A4-3-ketone acids (270) and (271) are among the degradation products of the common bile
(270) R = CH2CH2C02H (271) R = C 0 2 H
acid (203).437*4 Further alterations include 12a-hydroxy-steroid dehydrogenations to give the 12-ketones (272)-(276) and transformations to give the 434
435
436
437
E. Kondo and T. Mitsugi, Tetrahedron, 1973, 29, 823. M. Nagasawa, N. Watanabe, H. Hashiba, G. Tamura, and K. Arima, Agric. and Biol. Chem. (Japan), 1970,34, 798. M. Nagasawa, H. Hashiba, N. Watanabe, M. Bae, G. Tamura, and K. Arima, Agric. and Biol. Chem. (Japan), 1970, 34, 801. L. 0. Severina, I. V. Torgov, and G. K. Skryabin, Doklady Akad. Nauk S.S.S.R., 1968, 181,488.
438
L. 0. Severina, I. V. Torgov, G. K. Skryabin, N. S. Wulfson, V. I. Zaretskii, and I. B. Papernaja, Tetrahedron, 1969, 25, 485.
Terpenoids and Steroids
514
(272) R = CH2CH,C02H (273) R = C 0 2 H
0
I
Ly?+02H
0
0+co2H (274)
(275)
(277) R = CH2CH2C02H (278) R = C 0 2 H
B-ring-unsaturated derivatives (274)-(278).439*440 Formation of the A8derivative (275) is unprecedented, but the formation of the A6-derivatives(274), (277), and (278) may represent 7a-hydroxyl dehydrations, whereas formation of the 7-hydro~y-A~>~-3-ketone (276) probably represents 7a-hydroxy-steroid dehydrogenation with concomitant enolization. A cell-free preparation from Mycobacterium rnucosum 1210 performing these transformations has been described.441 Degradation of 3a, 12a-dihydroxy-5P-cholan-24-icacid by Mycobacteriurn rnucosurn 1210 gave the bisnorcholenic acids (279) and (280).274.275The 43q
440
44'
L. 0. Severina, I . V. Torgov, and G. K. Skryabin, Doklady Akad. Nauk S.S.S.R., 1967, 173, 1200; Izuest. Akad. Nauk S . S . S . R . , Ser. biol., 1968, 912; Doklady Akad. Nauk S.S.S.R., 1968, 181, 488. L. 0. Severina, I. V. Torgov, G. K . Skryabin, N. S. Wulfson, V. 1. Zaretskii, and 1. B. Papernaja, Tetrahedron, 1968, 24, 2145. S. M. Shust, L. 0. Severina, and E. L. Ruban, Izoest. Akad. Nauk S . S . S . R . , Ser. biol., 1973. 267.
Microbiological Reactions with Steroids
515
0
I
0' (279) R (280) R
= =
H OH
metabolism of bile salts and acids by mammalian intestinal microflora has been discussed in several monograph^.^^^.^^^ The microbial degradation of the side-chain of C,, steroids such as (211) has also received attention even through C2 steroids are not attractive raw materials for commercial syntheses. Degradation occurs by at least two distinct pathways, one giving the corresponding C l g 17-ketone directly as product, the other giving a 17P-acetoxy-steroid in an enzymic reaction analogous to the Baeyer-Villiger chemical oxidation. From the 17P-acetoxy-product esterase and 17P-hydroxysteroid dehydrogenase actions may then give the 17-ketone as product. Scission of the 17,20-bond of C2 20-ketones to give Clg 17-ketonesbut without nuclear degradation is regularly encountered. Minor nuclear alterations may co-occur, such as A'-dehydrogenation by Fusariurn solani acting on (211) to give Likewise, side-chain cleavage to the 17p(126) in yields exceeding acetoxy- or 17P-alcohol products may be accompanied by minor nuclear alterations, such as lla-hydroxylations by Beauueria bassiana strain 66358 or by Aspergillus ochraceus NRRL 405,'64 and 1% and 16a-hydroxylations by Fusarium a r g i l l a c e ~ m . ~ Chromatographic ~ methods designed specifically for monitoring the microbial degradation of the 17p-acetyl side-chain of (211) have been reported.445 The mechanism by which the 17P-acetyl side-chain is cleaved to a C19 17ketone directly does not appear to have been clarified. However, the enzymic version of the Baeyer-Villiger oxidation has received considerable attention. ,~~~ Degradation of the 3,20-diketone (211) by Aspergillus J E a ~ u s Aspergillus 64 Cladosporium h e r b ~ r u m , ~ Cladosporium ~' resiochraceus NRRL 405,' nae,448*449Cylindrocarpon radicicola, Septomyxa ~ f J i n i s , ~and ~ ' Streptomyces "9
442 443
444
445
446 447
448
449
450
'
G. A. D. Haslewood, 'Bile Salts', Methuen, London, 1967, pp. 50-58. H. Van Belle, 'Cholesterol, Bile Acids and Atherosclerosis', North-Holland Publishing Co., Amsterdam, 1965, pp. 84-89. I. Belie, E. Pertot, and H. SoeiE, Mikrobiologiya, 1968, 5, 127; Mycopathol. Mycol. Applicata, 1969, 38, 225. H. SoEiE and I. Belie, Z . analyt. Chem., 1968, 243, 291. K. Carlstrom, Acta Chem. Scand., 1967, 21, 1297. P. H. Cox and B. A. Sewell, J . SOC.Cosmetic Chemists, 1968, 19, 461. H. Nakano, H. Sato, and B.-I. Tamaoki, Biochim. Biophys. Acta, 1968, 164, 585; Steroids, 1968, 12, 291. H. Nakano, C. Takemoto, H. Sato, and B. Tamaoki, ref. 329, pp. 252 291. K. Singh and S. Rakhit, Biochim. Biophys. Acta, 1967, 144, 139.
Terpenoids and Steroids
516
grise~s~ ~’ proceeds via such a mechanism to give the 17P-acetate (281) as initial product.
16) Support for the mechanism formulated includes the report that [17B-’ 80]-( was formed in incubations of (211) with Cladosporium resinae under an I8O2 atmo~phere.~~ Furthermore, ~,~~’ the action of Septomyxa afinis ATCC 6737 spores on [17a-*H]-(211) yielded [17a-2H]-(16).450 The enzymes involved in the transformation of (211) to (16) by Cylindrocarpon radiciola ATCC 11011 have been resolved and characterized as a steroid-inducible oxygenase utilizing molecular oxygen and NADPH and an e~terase.~” The scission of the 17P-acetyl side-chain of (211) via the Baeyer-Villiger-type mechanism by Aspergillus ochraceus NRRL 405 demonstrated for vegetative cells’ 6 4 has also been demonstrated for cell-free preparations of the organism.150 The side-chain cleavage reaction was the predominant one observed in incubations of cell-free preparations. Spores of Aspergillus ochraceus NRRL 405 degrade pregna4,16-diene-3,20-dione (282) to 1la-hydroxyandrost-4-ene-3,17dione (283), which conversion is viewed as having passed through the putative Baeyer-Villiger-type intermediate enol acetate (284).” Degradation of the 16a,17a-epoxy-20-ketone (285) by Fusarium solmi spores was likewise thought
’
45’
452
K. Carlstrom, Acta Chem. Scand., 1966, 20, 2620. M. A. Rahim and C. J. Sih, J . Biol. Chem., 1966, 241, 3615.
517
Microbiological Reactions with Steroids
to pass through the 17P-acetate and 17P-alcohol intermediates (286)and (287) to the a-ketol (288).239The degradation enzymes of Fusarium solani spores appear to be bound to or imbedded in the plasma membrane.29s
(286) R = COMe (287) R = H
Whereas the degradation of 21-hydroxypregn-4-ene-3,20-dione(214) by CIadosporium herbarurn, yielding the 17P-acetate (28l), is claimed to proceed via the Baeyer-Villiger-type mechanism, the requisite initial 17P-hydroxyacetyl intermediate (289)was not observed. However, only chromatographic evidence was adduced, and several other prominent products of the degradation were not identified.447 OCOCH20H
0
Steroids of the pregnane series with more complicated structures may also be cleaved without major nuclear alterations to CI9 ketones. The 1lp,l8-epoxysteroid (290)was oxidized by Corynespora cassiicola IMI 56007 at the C-18 position to give (291)and (292)and was 9a-hydroxylated and degraded to the
(290) R = H
(291) R
=
OH
9a-hydroxy- 17-ketone (293). 118,17a,21-Trihydroxypregn-4-ene-3,20-dione (294)was transformed by Cladosporium herbarurn to 1lp-hydroxyandrost-4-ene3,17-dione (295).447
518
Terpenoids and Steroids
(293)
COCH,OH
-0
-0
(295)
('94)
Side-chain cleavage to C, 9- 17 ketones has been observed for synthetic steroids of altered nuclear shape also. 9P, 10a-Pregn-4-ene-3,20-dione (296) and its 1% hydroxylated derivative (297) were transformed by Helicosporium lumbricopsis into the corresponding 9P,lOa-17-ketones (300) and (301).124 Mastigosporiurn heterosporurn also cleaved (296) to the 17-ketone (300).12' 9-Hydroxy-9fi,lOapregn-4-ene-3,20-dione(298), on the other hand, was transformed by Gliocladium roseurn into the 17P-acetate (302) and the 9P,17/?-diol (303).84 1la-Hydroxy9P, lOa-pregn-4-ene-3,20-dione (299)was transformed by Sporomina pollaccii into the corresponding 17p-acetate (304) and 17P-alcohol (305) derivative^.'^
(296) (297) (298) (299)
R' R' R' R'
= R2 = R3 = H = R3 = H, R2 = OH = OH, R2 = R3 = H = R2 = H, R3 = OH
(302) (303) (304) (305)
(300) R = H (301) R = OH
= OH, p 2 = H, R3 = COMe R' = OH, R2 = R3 = H R' = H, R2 = OH, R3 = COMe R' = R3 = H, R2 = OH
R'
Microbiological Reactions with Steroids
519
Pregn-4-ene-3,20-dione (211) induces an enzyme for its own degradation to the 17-ketone (71) by Penicilliurn lilacinurn NRRL 895.453 The mechanism by which (211) is degraded remains obscure despite attentions paid to the fermentation. No Baeyer-Villiger-type product 17P-acetate (281) was detected even in the presence of di-isopropyl fluorophosphate to inhibit esterase action. The 17-ketone (71) was produced nonetheless.446 A pathway involving initial 1 7 ~ h y d r ~ x y l a t i o ndoes ~ ~ ~ not appear to operate.453 More recently, use of the experiments in which di-isopropyl fluorophosphate had been used as an inhibitor of the microbial esterase as an argument about the mechanism of side-chain cleavage446 has been criticized on the basis that the esterase of Penicilliurn lilacinurn was probably insensitive to the inhibitor.454 The epimeric 20-hydroxypregn-4-en-3-one derivatives (306) and (307) formed by 20-hydroxy-steroid oxidoreductases of Penicilliurn lilacinurn NRRL 895 acting on the 20-ketone (211) are both degraded by the organism. The 20P-alcohol (307) was demonstrably dehydrogenated back to the 20-ketone (211) prior to degradation to the 17-ketone (71),but the 2Oa-alcohol(306)was degraded directly to the 17-ketone (71) without prior dehydrogenation to (211).453 Different fermentation kinetics were also observed for the epimeric 20-alcohols (306) and (307), and two distinct modes of degradation were A cell-free extract of Penicilliurn lilacinurn NRRL 895 has been prepared which converts the 20-ketone (211) into the epimeric 20-alcohols (306) and (307) and into the 178-
(306) R' (307) R'
= =
H, R2 = OH OH, RZ = H
alcohol (16), 17-ketone (71), and D-ring lactone (98) degradation Treatment of D-ring lactone formation is deferred until after complete discussion of selective side-chain and A-ring degradations. An equally complicated system, which includes epimeric 20-alcohols as well as degraded CI9 derivatives, was obtained in the incubation of Fusariurn solani spores on the 16a,l7a-epoxy20-ketone (285).2 The degradation of steroids by Cladosporiurn resinae could be changed by control of aeration. Under aerated conditions (211) was transformed to the Baeyer-Villiger-type product 17P-acetate (28l), but under partially anaerobic 453
454 4s5
K. Carlstrom, Actb Chem. Scand., 1970, 24, 1759. T. L. Miller, Biochim. Biophys. Acta, 1972, 270, 167. K. Carlstrom, Actu Chem. Scand., 1972, 26, 1718.
520
Terpenoids and Steroids
conditions the 20a-alcohol (306) was obtained instead, with no side-chain cleavage.448 Degradative metabolism of the epimeric 20-alcohols (306) and (307) by Septomyxa afinis ATCC 6737 spores was of two sorts. The 20b-alcohol (307) was A’-dehydrogenated to (308) but not degraded. However, the 20a-alcohol (306) was both A‘-dehydrogenated and degraded to the A1*4-3,17-dione(126) and to the A‘-lactone (309).4’0 It was concluded that the degradation of the 20a-alcohol (306) by spores of Septornyxa afinis proceeded by a mechanism different from that involved in the degradation of the 20-ketone (21l).450 Me
Degradation processes may take place on both the A- and wrings and on the side-chain at the same time, with formation of a variety of doubly degraded steroid derivatives. The most common pattern includes A-ring aromatization with Cz2-and Cz4-acid formation, A-ring aromatization with 17-ketone formation [a sought-after process to obtain (77) and (163)], and A-ring aromatization with 9,lO-bond scission and 17-ketone formation. Aromatization of the A-ring and C,, acid formation by Nocardia species has been mentioned already in the conversion of (240) into (243), (244), and (245).427 A-Ring aromatization and 17-ketone formation is exemplified in the transformation of 19-hydroxypregn-4ene-3,20-dione (165) by Septomyxu ufinis to (77).399 The controlled degradation of the sterol side-chain together with A-ring aromatization to give (77) in good yield has been achieved with 19-hydroxylated (240) gave substrates and Nocardia restrictus. 19-Hydroxycholest-4-en-3-one 30% yields of (77),456and the 3P-acetate of (311) gave (77) in 72% yield.457 Conversion of other 19-oxygenated derivatives, including the 6Q,19-epoxide (312) was also reported.457 Screening of numerous Mycobacterium species known to aromatize (76) for their ability to degrade the sterol side-chain and form (77) from the 19-hydroxy-steroid substrates (240), (241), (310), and (311) and from the 6fl,19-epoxy-steroids (312) and (313) has been reported. Mycobacterium phlei W-32 and Mycobacterium Jlavescens D-50 were preferred organi s m ~ . ~ ’ Screening of Proactinomyces and Mycobacterium species for the 45h
C. J . Sih and K. C. Wang, J. Amer. Chem. SOC.,1965,87, 1387.
4s8
1965,87, 2765. E. Denot, C. Casas-Campillo, and P. Crabbe, European J . Sreroids, 1967, 2, 495.
‘” C. J. Sih, S. S. Lee, Y. Y. Tsong, K. C. Wang, and F. N. Chang, J. Amer. Chem. SOC.,
521
Microbiological Reactions with Steroids
(310) R = H (311) R = Et
(312) R (313) R
=H = Et
transformation of the 3P-acetate of (310)into (77) led to Proactinomyces asteroides 438 and Mycobacterium sp. 202 as best producers.459 The A7-17-ketone(163) was likewise formed by the action of Mycobacterium sp. (RMTP) on 19-hydroxycholesta-4,7-dien-3-one (314). By contrast Nocardia sp. ATCC 19170 transformed (314) into (77) with reduction of the A'-double bonds46o
Degradation of the side-chain, A-ring aromatization, and scission of the B-ring is a commonly encountered process. Cholest-5-en-3P-01 (123) was cleaved by Mycobacterium smegmatis to the 9,lO-seco-steroid(1 77),461previously discussed in connection with the degradation of the A'-4-3,17-dione(126). Degradation of the D-ring may occur as previously reported as part of the metabolism of the hydroindanediones (182) and (238) but also as a process entirely separate from degradations involving the A-, B-, and c-rings. 178Alcohols and 17-ketones and steroids which can be degraded to 17P-alcohols and/or 17-ketones are oxidized enzymatically in a process analogous to the chemical Baeyer-Villiger reaction so as to cleave the 13,17-bond and yield the D-ring lactone (98). Examples of D-ring lactone formation include the transformation of the 17ketone (71) into the lactone (98) by Aspergillus tamarii.' 17P-Hydroxyandrost4-en-3-one (16) was transformed by Aspergillus JEavus into the D-ring lactone (98) in 40 % yield.5 4 Cylindrocarpon radicicola, Fusarium solani, and Septornyxa afJinis acting on (16) gave the A'-dehydrogenated lactone (309).'59 The 19-norA4-3-ketones (315), (316), and (317) were oxidized to the corresponding D-ring 459
460 461
Zh. D. Lebedeva, 0. B. Tikhomirova, L. M. Kogan, I. I. Zaretskii, G . K. Skryabin, and I. V. Torgov, Izuesr. Akad. Nauk S . S . S . R . , Ser. bid., 1970, 781. R. Deghenghi, S. Rakhit, K. Singh, C. Vezina, and C. J. Sih, Steroids, 1967, 10, 313. K. Schubert, H. Groh, and C. Horhold, Naturwiss., 1965, 52, 20.
522
Terpenoids and Steroids
lactones (97), (318), and (319) by Aspergillus tararnii. 1lp-Hydroxylation cooccurred with (315) or (97) as substrate to give (319).1'5,462In the case of the
SH
R '.
0 ' (315) R' = RZ = H (316) R' = Me, RZ = H (317) R' = H, R2 = OH
(318) R' = Me, R2 = H (319) R' = H, R2 = OH
17fl-hydroxy-17cc-methylderivative (91) fermentation with Arthrobacter simplex or with Mycobacteriumjavurn gave the lactol (320).298
H
Among reports of lactone formation from C, substrates are the transformations of the 20-ketone (211) into the D-ring lactone (98) by AspergillusJis~heri,'~ by Aspergillus tamarii,' ' by a Penicilliurn species,' by Penicillium chrysog e n ~ r n ,and ~ ~ by Penicilliurn lilacinurn cell-free extract^.^' Septomyxa afinis transformed (211) and the 2Oa-alcohol(306) into the A'-lactone (309),450,454and Aspergillus tarnarii converted 5a-pregnane-3,20-dione (321) into the saturated lactone (322).53 16cc,l7a-Epoxypregn-4-ene-3,20-dione (285) was oxidized by
'
'
Cylindrocarpon radicicola, Fusarium solani, or Septomyxa a@nis to the 16ahydroxy-A'-lactone (323).'59 11-Hydroxylated C, and C , steroids were not substrates for D-ring lactone formation with Aspergillus tarnarii. 3,
''
462
R. D. Garett and J. T. McCurdy, J . Medicin. Chem., 1968, 11, 194.
Microbiological Reactions with Steroids
523
The mechanism by which Septomyxa affinis degrades the C2 20-ketone (211) to the D-ring lactone (98) has been viewed as a process in which the same enzyme functions twice, first to convert (211) into the 17b-acetate (281), which is then hydrolysed to the 17/3-alcoholand dehydrogenated, and secondly by lactonization of the 17-ketone (71). Both reactions in which a carbon+arbon bond is cleaved are formally analogous to the chemical Baeyer-Villiger oxidation.454 Furthermore, the degradation of the 17-ketone (71) to the lactone (98) is inhibited by the 20-ketone (21 l), the substrate for the initial degradation reaction. Indeed, the 20-ketone (211) appeared to be the preferred substrate for the degradation to the lactone (98) rather than the 17-ketone (71).454 Ring-D lactone formation and concomitant degradation of the A- and wrings also has been observed. The A1l4-3,17-dione(126) was converted into the lactone carboxylic acid (324) by Aspergillus f l a t ~ u s The . ~ ~ same ~ lactone (324) was also obtained by the action of Nocardia restrictus on the lactone (98) as
HO,C 'J (324)
9 Miscellaneous Microbial Reactions In this section several microbial reactions of steroids will be reported which do not fall properly into one of the earlier categories but which are regularly observed. Among these miscellaneous reactions are epoxidations and epoxide transformations, dehydrations of alcohols to olefins, reductive removal of hydroxy- and carbonyl groups, epimerizations and inversions of stereochemical centres, and allylic rearrangements and methyl migrations. Epoxidation of olefinic double bonds is a well-known transformation, but relatively few have been reported recently. Epoxide formation with associated A-ring dehydrogenation of (325) by Corynebacterium simplex ATCC 6946 has been reported, the A' p4-9a,11a-Epoxide (326) being formed.464 The action of K. Schubert, K.-H. Bohme, F. Ritter, and C. Hiirhold, J . Steroid Biochem., 1971, 2, 245. C. Corelli, D. Kluepfel, and P. Sensi, Experienfia, 1964, 20, 208.
lh3
4h4
&
Terpenoids and Steroids
524
COCH,OCOMe H
& o
:'OH
Me
n 1
Me /
H
Rhizopus nigricans on the ~-nor-A'-steroid(1) gave the 5a,6a-epoxide(2b) among the A few epoxide transformations have also been reported. The 4a,5a- and 4P,5Pepoxides of several C,,, C, and C , , 3-ketones were transformed by Mycobacterium phlei into the corresponding A4- and A '*4-3-ketones.297The B-nor5a76a-epoxide(2b)obtained from the ~-hor-d'-steroid(1)by the action of Rhizopus nigricans was also hydrated to give the 5&6a-diol (2a).42 Both the 5a,6a-epoxide (24) and its 5fi,6P-epimer were transformed into the 6a- and 6P-hydroxy-A4-3ketones (25) and (86) respectively.' 9 7 The 5a,6a : 16a,17a-bisepoxide(327) was transformed by Curuularia lunata in prolonged fermentations into the 5a-6-ketones (328)and (329). The 5a,6a-epoxide
11,20-dione was opened and ring of 5,6a-epoxy-3P,14a-dihydroxy-5a-pregnaneconverted into the 6P-methoxyacetate ester of 3P75,6P,14a-tetrahydroxy-5apregnane-11,2O-dione. The 5a,6~-epoxidering of 5,6a-epoxy-3B-hydroxy-5apregnan-20-one was completely reductively removed by Curuularia lunata, giving 7a,14a-dihydroxy-5a-pregnane-3,20-dione, 11P, 14a-dihydroxy-5a-pregnane-3,20dione, and 14a-hydroxy-5a-pregnane-3,11,20-trione.
'
525
Microbiological Reactions with Steroids
Dehydration of alcohols to olefins has been reported in several cases. Dehydration of the epimeric 3-alcohols (330)and (331)to the A3,5-derivative(4)by Rhizopus arrhizus Fischer or by Rhizopus nigricans Ehrenberg occurred when the culture medium became acid (pH < 4.5).66 Similarly, the 7P-hydroxy-group of (332)
(330) R' = OH, R2 = H (331) R' = H, R2 = OH
(332)
was dehydrated to the A4v6-3-ketone(5) in acid medium conditions by the same Rhizopus species.66 By contrast dehydration of the 7P-hydroxy-A4-3-ketone(87) by Mycobacterium flavum occurred at neutral pH to give the A476-3-ketone(88). A'-Dehydrogenation occurred also to give the A'34-3-ketone(333)from substrate (87). The A4,6-3-ketone(88) could be further A'-dehydrogenated to the A1*4,6derivative (334).296 Notably, the 7P,lla-diacetate of (87) was not attacked by
(333)
.
(334)
Mycobacteriurn flavurn even on prolonged fermentation.296 A cell-free extract of Saccharornyces cerevisiae dehydrated the A7-3P,5a-diol(335) to the A597-3/3alcohol (336).465
465
R. W. Tophan and J. L. Gaylor, Biochem. Biophys. Res.
Comm., 1972,47, 180.
526
Terpenoids and Steroids
Dehydration of the 9a-hydroxy-phenol (31) by Arthrobacter simplex acetonedried cells gave the A9(' ')-product 3-hydroxyoestra-l,3,5(10),9(1l)-tetraen-17-one. Although spontaneous dehydration also occurred, it was concluded that an enzyme catalysed the dehydration in incubations of dried cells.85 Dehydration of the 16a-hydroxy-group of (337) to a AI6-derivative by mammalian intestinal microflora is suggested to account for loss of the hydroxy-group and subsequent formation of 17a-pregnane derivatives.323
(337)
The reductive removal of the 7a-hydroxy-group from the common bile acid (203) is accomplished by strictly anaerobic mammalian intestinal and faecal microflora. The 7-deoxy-steroid (338) is formed. 7a-Dehydroxylation does not occur with the bile acid conjugates (138) or (140). Several screening operations seeking intestinal micro-organisms which 7a-dehydroxylate (203) have been reported.365,466,467 The reductive removal of the 7a-hydroxy-group has been reported for Bacteroides (Zuberella) strain 28s from human faeces,468for a mixed culture of human faecal m i c r o - o r g a n i ~ m s for , ~ ~an ~ obligate anaerobe ,~~ isolated from rabbit faeces,47ofor members of the tribe L a c t ~ b a c i l l e a e1474 for the type cultures Clostridium bifermentans ATCC 9714, Clostridium biferrnentus NCIB 506, and Clostridium sordeEZii NCIB 6929,475and, for the first time, for cell-free preparations of Clostridium welchii, Eschereschia coli, and Streptococcus faecalis.220 7cc-Dehydroxylation of [24-l4C]-(2O3) was demonstrated in germ-free rats whose intestinal tract had been contaminated with a member of the tribe Lactobacilleae which 7a-dehydroxylated (203) in in uitro incubations.474 Neomycin administration reduced the amount of 7a-dehydroxylation which occurred in uiuo.470,476 Strictly anaerobic intestinal micro-organisms also 7a4hh
4h7
468 4h9
470 471
472
473 474
475 4i6
M . J. Hill and B. S. Drasar, Gut, 1968, 9, 22. T. Midtvedt and A. Norman, Acta Pathol. Microbiol. Scand., 1968, 72, 337. T. Hattori and S. Hayakawa, Microbios, 1969, 3, 287. L. Canonica, A. Ferrari, B. Rindone, G . RUSSO,and C. Scolastico, Ann. Chim. (Italy), 1971, 61, 695. V. Bokkenheuser, T. Hoshita, and E. H. Mosbach, J. Lipid Res., 1969, 10, 421. T. Midtvedt, Acta Pathol. Microbiol. Scand., 1967, 71, 147. T. Midtvedt and A. Norman, Acta Pathol. Microbiol. Scand., 1967, 71, 629. T. Midtvedt and A. Norman, Acta Pathol. Microbiol. Scand., 1968, 7 2 , 313. B. E. Gustafsson, T. Midtvedt, and A. Norman, Acta Pathol. Microbiol. Scand., 1968, 72, 433. S. Hayakawa and T. Hattori, F.E.B.S. Letters, 1970, 6 , 131. E. H . Mosbach, V. Bokkenheuser, A. F. Hofmann, T. Hoshita, and S. Frost, Circulation, 1967, 35/36, Suppl. 11, 29.
527
Microbiological Reactions with Steroids
dehydroxylate 3a,7a-dihydroxy-5~-cholan-24-oic acid (339) to (340)4719473*477 and 3a,7a,l2a-trihydroxy-5a-cholan-24-oic acid (341) to (342).470 Likwise 78acid (343) to (338) by dehydroxylation of 3a,7~,12cr-trihydroxy-5~-cholan-24-oic a mixed culture of human faecal micro-organisms has been reported.469 Much of the earlier work dealing with the microbial conversion of (203) into the 7deoxy-derivative(338) has been r e ~ i e w e d . ~ ’ ~ * ~ ’ * The enzymes which are responsible for 7a-dehydroxylation of (203) appear to be inducible.220 7a-Dehydroxylation has been viewed as involving sequential dehydration to the A6-steroid (344) and A6-reduction. However, no recent evidence for this mechanism has been reported. The requisite A6-steroid (344) could not be detected when sought in incubations of (203) with Bacteroides (Zuberella) strain 28S.468
uo2H
HO’*
HO” @02H
H
(338) R’ = H, R2 = OH (339) R’ = OH, R2 = H (340) R’ = R2 = H
HO**=02H H
’R
(341)R (342)
H (343)
ri
2
HO** 0 :
R
= =
OH H
H (344)
Reductive removal of the 12a-hydroxy-group by strict anaerobes has also been reported.365 Formation of the degradation fragment (204) from the bile Conversion of the 3flY16a-diol(337) acid (203) implies a 12~t-dehydroxylation.~~~ by rat caecal microflora to a variety of 16-deoxy-steroidsestablished the reductive removal of the 16a-hydroxy-group also. In this case, the formation of an intermediate A’ 6-derivative was suggested, with subsequent reduction giving both 17a- and 17gpregnane derivatives as products.32 Reductive removal of the 477
478
B. E. Gustafsson, T. Midtvedt, and A. Norman, J . Exp. Med., 1966, 123,413. H. Danielsson and T. T. Tchen, in ‘Metabolic Pathways’, ed. D. M. Greenberg, 3rd E X . , Academic Press, New York, Vol. 2, 1968, p. 11 7.
Terpenoids and Steroids
528
21-hydroxy-group of 3P,21-dihydroxy-Sa-pregnan-20-one by rat caecal microflora, yielding 3P-hydroxy-Sa-pregnan-20-one and Sa-pregnane-3P,20,21-triols, has also been Reductive removal of the 7-ketone function of 3P-hydroxyandrost-S-ene-7,17dione (345)by Mycobacteriurn srnegrnatis has been reported. Among the products are the A4-3,17-dione (71), the A',4-3,17-dione (126), and 5a-androst-l-ene-3,17which may be an artifact, however.480 dione, as well as androsta-3,5-dien-7-one,
Epimerization of 3-alcohols by micro-organisms has been reported. The A4-3a-alcohol (331) was reversibly epimerized to (330) by Rhizopus arrhizus Fischer or by Rhizopus nigricans Ehrenberg when fermentation conditions became acid (pH < 5.0).66Mammalian intestinal microflora epimerize the 38hydroxy-group of 3P,16a-dihydroxy-5a-pregnan-20-one(337) to give the 3aalcohols (346) and (347), among other products.32 The epimerization involves a mixed culture of micro-organisms and probably occurs by dehydrogenation and subsequent 3a-reduction. Likewise, formation of the 3a-hydroxy-6-ketone (329) from the 5a,6a-epoxy-3P-alcohol (327) by Curvularia Iunata probably proceeds via the 3,6-diketone (328)which was also a product ofthe fermentation.' l9 Epimerization of the 17P-acetyl side-chain of (337) occurs, and the 16a-hydroxygroup is also removed. The reaction sequence probably involves 16a-hydroxy dehydration to a putative AI6-intermediate which is then reduced to give the 17a-pregnane derivatives (346) and (348) as well as the epimeric 17P-steroids (347) and (349).323
(346) R' (347) R'
= =
H, RZ = COMe COMe, R2 = H
(348) R' = H, RZ = COMe (349) &' = COMe, R2 = H
Inversion of the stereochemistry at C-5 has been demonstrated for the metaacid (338) by intestinal microflora bolism of 3a,l2a-dihydroxy-SP-cholan-24-i~ of the rat. The SP-cholanic acid (338) was converted into the Sa-isomer during 479 480
H. Eriksson, J.-A. Gustafsson, and J. Sjovall, European J . Biochem., 1969, 9, 550. K. Schubert and K . Wehrberger, Narurwiss., 1965, 52, 431.
529
Microbiological Reactions with Steroids
entero-hepatic circulation in the rat, most probably by intestinal m i ~ r o f l o r a . ~ ~ The reverse isomerization of the Sa-acid (342) to the 5P-acid (338) was demonstated following intracaecal administration of the steroid to the rat.482 A few rearrangements of steroids have been reported for microbial fermentations. Both the 3a- and 3P-alcohols (331) and (330) respectively were rearranged to the A3-5/?-alcohol(350) in fermentations involving Rhizopus species in which acidic conditions prevailed.66 Fermentation of the 5a-bromo-6P-fluoro-steroid (160) with Curuularia lunata gave the A4-118-alcohol (161) which underwent Westphalen-LettrC rearrangement in acidified culture medium to give the A'(' I ) - 10P-alcohol (351). Fermentation of (160) with Aspergillus ochraceus, presumably via the A4-l la-alcohol intermediate (352), gave the A9-l la-alcohol (353).90
3. COCH,OH
HO
+*
Me
F
COCH,OH
'Me
HO
COCH,OH
Me
HO*-*
F
(352)
F
(353)
A few microbial reactions of steroid hydroperoxides and peroxides have been reported. Peroxidase action of Aspergillus ochraceus N R R L 405 on the 17ahydroperoxide (354) gave the corresponding 17a-alcohol which was then 1lahydroxylated to the 1la,l7a-diol (355).l o 3 The 5ct,8a-peroxide (356) was
(354) R' = OH,R2 = H (355) R' = H,R2 = OH 4B1 482
A. Kallner, Acta Chem. Scand., 1967, 21, 87. A. Kallner, Acra Chem. Scand., 1967, 21, 315.
5 30
Terpenoids and Steroids
isomerized by Mycobacterium crystallophagurn to the isomeric epoxy-diols 5,6aepoxy-5a-ergosta-8,22-diene-3P,7a-diol(357) and 5,6a-epoxy-5a-ergosta-8(14),22diene-3B77a-diol(358). The A8-derivative (357) is also a major thermal decomposition product of the 5a,8a-peroxide (356).48 The 5a,8a-peroxides (356)and (360). (359) were transformed by Penicilfium rubrum into the A4*6*8('4)-3-ketone The same product was obtained using ergosta-5,7,22-trien-3fi-01(336) and 5a,8aergosta-6,22-diene-3P,5,8-trioI (361) as substrates.484 A cell-free extract of
HO
j ,% '\
0/
(356)
(358)
HO
0 -'
'OH
(357)
(359)
Succharornyces cereuisiae transformed the 5a78a-peroxide (356) into the AsV73P-alcohol (336).465
483 484
K. Petzoldt and K. Kieslich, Annufen, 1969, 724,194. J. D. White and S. I. Taylor, J . Amer. Chem. Soc., 1970, 92, 581 I .
3 Steroid Conformations from X - Ray Analysis Data ~
BY C. ROMERS, C. ALTONA, H. J. C. JACOBS, AND R. A. G. DE GRAAFF
1 Introduction
A'-Ray diffraction analysis of steroids started in the early thirties with the work of Bernal,' who examined six steroids, including cholesterol, ergosterol, and calciferol. From unit-cell dimensions and space-group considerations he arrived at the conclusion that these molecules are elongated and have dimensions of about 4, 7, and 20 A. This view led to the proposal of the perhydro-l,2-~yclopentanophenanthrene ring system associated with the names of Rosenheim and King2 and Wieland and Dane.3 An extended survey of unit-cell dimensions of some eighty steroids by Bernal, Crowfoot, and Fankuchen4 confirmed this conclusion in 1940. In this survey the identified' exceptions were precalciferol and calciferol, which had different structures and dimensions. These early diffraction studies and later investigations around 1950 into the crystal structures of cholesteryl iodide6 and the 4-iodo-3-nitrobenzoyl esters of calciferol' and lumisterol* by Crowfoot et al. provided highly important information on the overall molecular structure and the position of functional groups. They did not, however, offer a detailed quantitative description in terms of bond lengths and valency angles-not to mention torsion angles, a concept that was not introduced into the crystallographic literature until 19649710and which received wider attention only some years later.' Generally, the introduction of heavy atoms to overcome the phase problem and a lack of computing facilities for the acquisition of accurate data meant that the geometrical information could not be other than crude. The use of digital computers and evaluation of complete three-dimensional photographic data by '7"
J. D. Bernal, Nature, 1932, 129, 277. 0. Rosenheim and H. King, Chem. and Ind., 1932, 51, 464. H. Wieland and E. Dane, 2. physiol. Chem., 1932, 210, 268. J . D. Bernal, D . Crowfoot, and I. Fankuchen, Phil. Trans., 1940, A239, 135. D. Crowfoot and J . D . Bernal, Chem. Weekbl., 1937, 34, 19. ' C. H. Carlisle and D . Crowfoot, Proc. Roy. SOC.,1944, A184,64. ' D. C. Hodgkin, B, M . Rimmer, J . D . Dunitz, and K. N. Trueblood, J . Chem. Sac., 1963,977,4945. * D . C. Hodgkin and D . Sayre, J . Chem. SOC.,1952,4561. ' H . J . Geise, Thesis, Leiden, 1964. l o C. Altona, Thesis, Leiden, 1964. I H. J. Geise, C. Altona, and C. Romers, Tetrahedron, 1967, 23, 439. ' * C. Altona, H. J . Geise, and C. Romers, Tetrahedron, 1968, 24, 13.
53 1
532
Terpenoids and Steroids
Romers and co-workers' 3-'5 substantially added to accuracy, resulting in standard deviations of 0.02 8, for carbon-carbon bond distances. However, the first truly accurate structure determinations of steroids without heavy atoms were accomplished in 1965 by Huber and HoppeI6 and in 1966 by High and Kraut, who claimed standard deviations of ca. 0.006A for bond distances in androsterone.' Simultaneously the first successful attempts, by Bucourt and Hainaut,' 8 * 1 to predict conformational features of steroids by simple force-field calculations of cyclohexanes became available and induced Altona, Geise, and Romers' to carry out a comparative study of eleven steroids. The results of these considerations concerning the overall shape, i.e. the convex bending of the carbon skeleton towards the r-side, the mean staggering (ca.56") of the A, B, and c rings, and the conformational decription of ring D in terms of a phase angle of pseudorotation, A, and maximum torsion angle, @ ,, were promising, but no quantitative treatment of the bond distances could be given. A very large number of X-ray structure determinations of steroids (ca. 150) comprising oestranes, androstanes, cholestanes, ergostanes, pregnanes, and compounds on the borderline with alkaloids and triterpenoids have been published since. The use of automatic diffractometers permitting accurate diffraction intensities (accuracy ca. 2 %) to be obtained within a rather short period of time ( 2-3 weeks) and the application of digital computers for direct methods2'Y2' or vector coincidence program^,"^'^ as well as the increased interest in the biochemical understanding of steroid hormones, greatly enhanced the output of published work. It is tempting to reconsider the available data for a more detailed analysis and survey of the conformational features of steroids than was possiblel1>" six years ago. Applying computer programs, the Reporters have calculated weighted mean values and population variances for bond distances and valency and torsion angles, taking into account the configurations at carbon atoms 5, 9, 10, and 13, functional groups at C-3 and C-17, and the presence of double bonds in the carbon skeleton. In addition the presence of carbonyl groups at other places in the skeleton has been accounted for. However, the effect of substituents such as hydroxy-groups or halogen atoms at positions other than C-3 and C-17 has been ignored. It is hoped that their influence on the calculated mean values will be balanced, i.e. that neglect of such groups does not introduce a bias. A careful
'
" 3 '
-
lJ
l4 l 5 l6
I*
2o 2 L
22
C. Romers, B. Hesper, E. van Heykoop, and H. J. Geise, Acta Crysr., 1966, 20, 363. H. J. Geise and C. Romers, Acta Crysr., 1966, 20, 257. H. J. Geise, C. Romers, and E. W. M. Rutten, Acta Cryst., 1966, 20, 249. R. Huber and W. Hoppe, Chem. Ber., 1965,98,2403. D. F. High and J . Kraut, Acta Crysr., 1966, 21, 88. R. Bucourt and D. Hainaut, Bull. SOC.chim. France, 1965, 1366. R . Bucourt, Bull. SOC.chim. France, 1964,2080. I . L. Karle and J . Karle, A c f a Crysr., 1964, 17, 8 3 5 . G. Germain, P. Main, and M. M. Woolfson, Acta Crysr., 1971, A27, 368. P. B. Braun, J. Hornstra, and J . I . Leenhouts, Philips Res. Report, 1969, 24, 85. R. A. Jacobsen, 'Crystallographic Computing', Proceedings of the 1969 International Summer School on Crystallographic Computing, Munksgaard, Copenhagen, p. 83.
533
Steroid Conformationsfrom X-Ray Analysis Data
comparison of the individual steroid geometry with the mean values seems to confirm this thesis. Special attention is paid to the conformation of ring A in 3-0x0-A4-steroids, since several sex hormones, drugs, and hormones of the corticoid group have this structural feature in common. Where our data are at variance with those originally published, the difference is the result of a recalculation of the geometricalentities from the published crystallographic co-ordinates. Simultaneously,we have carried out valence force (VF)calculations (‘molecular mechanics’)of equilibrium geometries and corresponding energiesfor a number of key steroid structures, adopting the ‘full relaxation’ approach. The first exploration into this area was reported in 1970,24and apparently VF calculations are rapidly reaching the stage where they can compete with diffraction techniques in accurately describing the molecular architecture of steroids. An up-to-date review of the VF approach has recently a~peared.’~ Our VF calculations serve several purposes : (i) As an aid in understanding unusual geometrical features observed, such as ‘long’ carbon-carbon bonds, abnormal bond angles, etc., i.e. the distribution of ‘strain’ over the steroid nucleus. (ii) The high accuracy of the weighted mean geometries provides an ideal testing ground for comparison of the relative merits of various force fields employed in the literature ;in some cases ‘better’VF parameters can be extracted from this work. (iii) VF calculations, by making it possible to constrain a selected geometrical feature, for instance by forcing a given torsion angle to adopt a non-optimal value, make it possible to study the ‘flexibility’ of a molecule or part of a molecule. We propose to show that ‘flexibility’, loosely defined as being inversely proportional to the price in kcal mol- a molecule has to pay for certain deformations, may well turn out to have great biological significance. Some comments have been made in this Report on the relationship between chiroptical properties (0.r.d. and c.d.) and the spatial structures of steroidal molecules. The terms for conformations such as chair, half-chair, and their abbreviations are given in the Appendix, which also contains the mathematical formulae and force-field parameters. Five-membered (D) and six-membered rings with boat conformations were analysed in terms of the rotation phase angle and the maximum torsion angle. Some remarks have been ventured on the overall shape of steroid molecules in relation to their biological activity. With the exception of functional groups at positions 3 and 17 and the 17P-alkyl side-chain occurring in cholestanes, ergostanes, and lanostanes, no attention is paid to the configurations of substituents in steroids. We are aware that some contributions to structure determinations have not been mentioned and others may have been overlooked. The literature has been
’
24 25
C. Altonaand H . Hirschmann, Tetrahedron, 1970, 26, 2173. C. Altona and D. H. Faber, Fortschr. chem. Forschung, 1974,45,1.
534
Terpenoids and Steroids
covered up to May 1st 1973. For a more exhaustive survey the reader is referred to the ‘Atlas of Steroid Structure’ by Duax and Norton.26 2 Presentation of Results The steroids under consideration are listed in Table 1 ;the abbreviations used for substituents are explained in Section (vi) of Table 1. A number of more intricate steroids such as aldosterone [see structure (70)] are reproduced separately in Section (v) of Table 1. For crystallographic details such as space groups and unitcell dimensions the reader is referred to the original literature or to the ‘Atlas of Steroid Structure’.26 The presence of solvent molecules, H,O, MeOH, etc., in some crystal structures is ignored in Table 1,since their possible influence on the structure (e.g. by hydrogen bonds) has not been taken into account in this Report. Each steroid has been allotted a number which has been used as a code for computational purposes. A steroid carrying two or more numbers indicates that two or more symmetry-independent molecules are present in one unit cell, resulting in two or more geometrical structures for such molecules. The space groups, unit-cell constants, and positional parameters of each steroid have been processed by a computational program, which computes bond distances, bond angles, and torsion angles as well as least-squares planes. As stated before the program also calculates the weighted mean value (usually called the standard value), the standard error, and the estimator of the standard deviation of the mean of these entities. This estimator gives some information on the scatter of individual points and informs us whether or not the calculated mean values are associated with one population. It also indicates that in most cases the experimental standard deviations of the mean values are greatly underestimated and should be multiplied by a factor of 3 or 4. Details of the expressions used to calculate these values are given in the Appendix, Sections (i)-(iv).
3 The Perhydro-l,2-~yclopentanophenanthreneSkeleton About eight years ago it was generally held that sp3-sp3-hybridized carboncarbon bond distances in steroid-like molecules should be equal and this assumption was used by crystallographers to estimate standard deviations of bond lengths between ‘chemically equivalent’ sp3-hybridized carbon atoms. This in turn supported the assumption, since the outcome of such estimations agreed rather well with machine-computed standard errors resulting from the least-squares refinement of crystal structures. However, standard deviations determined by least-squares methods always were somewhat lower (ca. 50 %), which should have served as a warning against the assumed equality of C-C single bond lengths. Recently obtained values of highly increased accuracy usually yield standard errors of only 0.003--0.006 8, in heavy-atom-free steroid molecules, however, the scatter of values in the range 1.51-1.57 A is about the same as was found in earlier structure determinations with standard deviations of 0.02-4.03A. This 26
D . A. Norton and W. L. Duax, ‘Atlas of Steroid Structure’, 1973.
Steroid Conformationsfrom X-Ray Analysis Data
535
Table 1 List of steroids referred to in the discussion
R' R' a
RZa
- H Designation
(i) Saturated steroids (excluding oxo-steraids) a-OH OH a-OH OH OH a-CH(0H)Me (OMe), OTs 19-nor a-OH a-Me 2a-Br C8H 1 7 2a-Br Br Cl C8H 1 7 2a-C1 a-C1 C8H17 2P-Cl ?-OH a-OH OH
H OH
C,H8CO,H C,H8COAnBrd Card Br C8H 1
,ON
OBzBr
CHClMe
H H
C8H17
C8H1,
l2a-OH 12a-OH 14P-OH 16P-Br 16a-OH 16P-OBzBr 3a,5a-cyclo, 6P-OAcCl 3a,5a-cyclo, 6P-OAcBr
Conjiguration
No.c
R ej'.
5a
5P 5a 5a 5a,14P 5a 5a 5a 5P
5P 58,148 5a 5a 5a 5a 5a
Unless stated otherwise the orientation of R ' and/or R 2 is 8. 'The configurations at carbon atoms 8,9,10,13, 14, and 17 are denoted only if different from the natural configuration (i.e.88,91, log, 138, 14a, 178). Two or more code numbers for one compound indicate For symbols used for functional groups two or more independent molecules per unit cell. see Part (vi) of this Table.
21
28
29
G. Precigoux, B. Busetta, C. Courseille, and M. Hospital, Cryst. Structure Comm., 1965, 1, 265. C. M. Weeks, A. Cooper, D. A. Norton, H. Hauptman, and J. Fisher, Acta Crysr., 1971, B27, 1562. R. A. G. de Graaff, C. A. M. van der Ende, and C. Romers, to be published in Acra Crysr.
30
31
32
33 34
35
36
37
A. Chiaroni and C. Pascard-Billy, Acra Crysr., 1972, B28, 1085. S. Candeloro de Sanctis, E. Giglio, V. Pavel, and C. Quagliata, Acra Crysr., 1972, B28,3656. J. P. Schaefer and L. L. Reed, Acfa Crysr., 1972, B28, 1743. I . L. Karle and J. Karle, Acra Cryst., 1969, B25,434. N. Mandel and J. Donohue, Acra Crysr., 1972, B28,308. E. Hoehne, I. Seidel, G. Adam, D. Voigt, and K. Schreiber, J. prakt. Chem., 1971, 313, 51. H. H. Worch, E. Hoehne, G. Adam, and K . Schreiber, J. prakt. Chem., 1970, 312, 1043. H. R. Harrison, D. C. Hodgkin, E. M. Maslen, and W. D. S. Motherwell, J. Chem. SOC.(0,1971, 1275.
Terpenoids and Steroids
536 Table l-continued R'
R'
OMe a-OMe OAc
HzBsAc C8H1,(OBzBr), Cdl,
a-OBzBr
=C(MC)C,H
Designation
Conjiguration
5P,19-cyclo, 6/?-OMe 5P 9P,19-cyclo, 4,4,14a-Me3 5a,9p 4,4,14a-Me3, 7a,1 la-Br,, 5a,8a 8a,9a-0 18-nor, 4a,8a,14/3-Me3, 5a,8a,9/?, 1 1a-OH, 16fi-OAc 13a,14fi
No. (19) (20) (21) (22)
Ref. 38 39
40 41
[For compounds (23), (24), a n d (25), see Part (v) of this Table]
(ii) Saturated 0x0-steroids 3-0xO0 xo OH OX0 OTs OX0 OAcI OX0 OAcI OX0 OHla-Me 4-0xOEOT C,H,, C8H17 H
5a
4,4-Me, 19-nor, 4,4-Me2 4-oxa, 6a-Br
4-OXO A-homo, 3-aza, 4-0x0,
5a 5a 5a 5a
42 156 43 43
44
5a 5P
45 46
5a 5P
47 47
5a 5a
28 17
5a 5a 5a
48 49 50
5a
51
4a,4a-C1
6-0x0-
H H 17-0x0OH a-OH
OBzBr
OAc
3a,5a-cyclo, 6-0x0 3fl,SP-cyclo, 6-0x0
OX0
OX0
I1,20-di0~0-
OH OAc OH
Ac/a-OH Ac/a-OH AcBr/a-OH
16/?-Br 16P-Br
(iii) Conjugated and homoconjugated 0x0-steroids 1-0x0-A2-
H 38
40 41 42
" 44
45
46 47 48 49
50 51
OX0
1-0x0-A', 4a-Br
G. A. Sim and C. Tamura, J. Chem. SOC.( B ) , 1968,8. F. H. Allen and J. Trotter, J. Chem. SOC.( B ) , 1971, 1079. J. K.Fawcett and J. Trotter, J. Chem. SOC.( B ) , 1966, 174. A. Cooper and D. C. Hodgkin, Tetrahedron, 1968,24, 909. B. Busetta, C. Courseille, J. M. Formes-Marquina, and M. Hospital, Cryst. Structure Comm., 1972, 1. 43. G . Ferguson, E. W. Macaulay, J. M. Midgley, J. M. Robertson, and W. B. Whalley, Chem. Comm., 1970, 954. J. S. McKechnie, L. Kubina, and I. C. Paul, J. Chem. SOC.( B ) , 1970, 1476. A. Cooper and D. A. Norton, J. Org. Chem., 1968,33,3535. H.Altenburg, D. Mootz, and B. Berking, Acfa Cryst., 1972,B28, 567. R. C. Pettersen, 0. Kennard, and W. G. Dauben, J.C.S. Perkin I I , 1972, 1929. J. M. Ohrt, A. Cooper, and D. A. Norton, Acra Cryst., 1969,B25,41. J. M. Ohrt, B. Haner, A. Cooper, and D. A. Norton, Acfa Cryst., 1968,B24, 312. J. M. Ohrt, A. Cooper, G. Kartha, and D. A. Norton, Acfa Cryst.,.1968,B24, 824. J. R. Hanson, T. D. Organ, G. A. Sim, and D . N . J. White, J. Chem. SOC.(0,1970, 2111.
Steroid Conformationsfrom X-Ray Analysis Data
537
Table l+ontinued R2
R’
Designation
Conjiguration
Ref.
3-oxo-A4 OX0 OX0
Ac AcOHja-OH
OX0
OX0
OX0
OH OH Acja-0Dec OSil Ac/a-OH AcOH OH a-OH CH(0H)Me OAc OBs OAc OAcCl AcO H/u-OH Ac OAc
OX0 OX0
OX0 OX0
OX0 OX0 OX0 OX0 OX0
OX0 OX0
OX0 OX0
OX0 OX0 OX0
C2H4C02
OX0 OX0 OX0
AcOAC/U-OH AcOH/a-OH AcOH/a-OH Ac Ac AcOH/a-OH
OX0
OX0 OX0
A4 A4 A4 A4 A4 A4 A4 A4 A4 A4 A4 A4 A4, 2,2,68-C13 19-nor, A4, 2P-Me A4, 2P-OAc A4, 2B-OAc A4, 4-CI,ll-oxo A4, 6P-Br A4, 6/3,7/3-CHz A4, 7a-SAC A4, 11-0x0 A4, 11P-OH A4, 11-0x0 A4, llB-OH, 12a-Br A 4 * I 5 , 14a,17a-C,Hz, 15,16-(CF,), A4, 6a-F, 11P-OH
52 53 54 55
56 57 58 59 60 61 62 163 63 64 138 138 65 66 67 68 69 70 71 72 73 70
H. Campsteyn, L. Dupont, and 0. Dideberg, Acta Cryst., 1972, B28, 3032. L. Dupont, 0.Dideberg, and H. Campsteyn, Acta Cryst., 1973, B29, 205. 5 4 B. Busetta, G. Comberton, C. Courseille, and M. Hospital, Cryst. Structure Comm., 1972, 1, 129. 5 s A. Cooper, E. M. Gopalakrishna, and D. A. Norton, Actu Cryst., 1968, B24, 935. 5 6 A. Cooper, G. Kartha, E. M. Gopalakrishna, and D. A. Norton, Acta Cryst., 1969, B25,2409. 5 7 W. H. Watson, Kuan Tee Go, and R. H. Purdy, Actu Cryst., 1973, B29, 199. C. M. Weeks, H. Hauptman, and D. A. Norton, Crysf. Structure Cumm., 1972, 1, 79. 5 9 J. P. Declercq, G. Germain, and M. van Meerssche, Cryst. Structure Comm., 1972, 1,9. 6 o 0. Dideberg, H. Campsteyn, and L. Dupont, Actu Cryst., 1973, B29, 103. 6 1 B. Busetta, C. Courseille, F. Leroy, and M. Hospital, Acra Cryst., 1972, B28, 3293. 6 2 N. W. Isaacs, W. D. S. Motherwell, J. C. Coppola, and 0. Kennard, J.C.S. Perkin 11, 1972,2335. W. L. Duax, Y. Osawa, A. Cooper, and D. A. Norton, Tetrahedron, 1971,27,331. 6 4 V. Cody and W. L. Duax, Cryst. Structure Comm., 1972, 1, 439. 6 5 W. L. Duax, A. Cooper, and D. A. Norton, Acta Cryst., 1971, B27, 1 . 6 6 E. M. Gopalakrishna, A. Cooper, and D. A. Norton, Actu Cryst., 1969, B25, 639. 6’ P. B. Braun, J. Hornstra, and J. I. Leenhouts, Actu Cryst., 1970, B26, 352. 0. Dideberg and L. Dupont, Actu Cryst., 1972, B28, 3014. 6 9 J. P. Declercq, G. Germain, and M. van Meerssche, Cryst. Structure Comm., 1972,1,59. 7 0 L. Dupont, 0. Dideberg, and H. Campsteyn, Cryst. Structure Comm., 1972, 1, 177. ’*J. P. Declercq, G. Germain, and M. van Meerssche, Cryst. Structure Cumm., 1972,1, 13. ” A. Cooper and D. A. Norton, Actu Cryst., 1968, B24, 81 1 . 7 3 G. I. Birnbaum, Acta Cryst., 1973, B29, 54. 52
”
‘’
538
Terpenoids and Steroids
Table l-continued
R'
R2
Designat ion
AcOH/a-0 H OH/a-Me
OX0 OX0
OAcBr OAc Ac OAc OAc
OX0
OX0 OX0 OX0 OX0 OX0 OX0 OX0 OX0
OX0
Ac a-OBzBr 'gH1
7Br2
A4, 9a-F, 11P-OH A,' 9a-Br, 1l-0x0 See Part (v) of this Table See Part (v) of this Table A4 19-nor, A4 A,' 6a-Me A4, 6a-Me, 6P-F A4, 6P-Me, 6a-F A4, 9P-OH A4, 1la-OH 19-nor, A4, 7,7-Me,
A4
See Part (v) of this Table
Conjiguration
90,lOa 9P,1Oa 9P,lOa 9P,lOa 9P,lOcr 9/?,10a 9P,1Oa 8u,14P 9P
Ref: 74 75 157 76 77 78 79 79 79 79 79 80 81 82
3-oxo-A5AcOAc/a-OH ~-OXO-L\~('~)OX0 OH OX0 OAcI 3-0X0-A''4OX0 OH OX0 AcOH/a-OH 3-0~0-A~~~OX0
OX0
OX0
Ac Ac 3-0xo-A~~~OX0 OH/a-CrCH 6-0x0-A~C8H 17O2 OH OH C8H1703 17-oxo-A 4OX0 OX0
c1
14
75
76
'I 78
''
'O 81
82
83 84 85
86
*'
88
OX0
A5, 4a,6,7a-C13, 1l-0x0 lg-nor, A5('O) 19-nor, A 5 [ l 0 ) ~ 1 . 4
A1,', 6a-Me, 11P-OH ~ 4 . 6
162
83 84 133 85
A4s6,4-Br
79 79 13
19-nor, A4v9,1l-0x0
86
6-oxo-A7,2P,14a-(OH), 6-0x0-A7,2P,14a-(OH),
16 87
4,5-seco, A2,8,14,5-0x0
88
~ 4 . 6
L. Dupont, 0. Dideberg, and H. Campsteyn, Acta. Cryst., 1972, B28, 3023. A.Cooper, C. T. Lu, and D. A. Norton, J. Chem. SOC.( B ) , 1968, 1228. G . W. Krakower, B. T. Keeler, and J. Z. Gougoutas, Tetrahedron Letters, 1971, 291. W. E. Oberhansli and J. M. Robertson, Helo. Chim. Acta, 1967, 50, 53. B. Busetta, C. Courseille, and M. Hospital, Cryst. Structure Comm., 1972, 1, 235. P. B. Braun, J. Hornstra, and J. I. Leenhouts, Philips Res. Report, 1969, 24,427. D. Lednicer, D. E. Emmert, C. G. Chidester, and D. J. Duchamp, J . Org. Chem., 1971, 36, 3260. B. Hesper, H. J. Geise, and C. Romers, Rec. Truo. chim., 1969, 88,871. M. 0. Chaney and N. D. Jones, Cryst. Structure Comm., 1972,1, 197. R. R. Sobti, S. G. Levine, and J. Bordner, Acta Cryst., 1972, B28,2292. R. R. Sobti, J. Bordner, and S. G. Levine, J. Amer. Chem. SOC.,1971,93, 5588. J. P. Declercq, G. Germain, and M. van Meerssche, Cryst. Structure Comm., 1972,1, 5 . G. Lepicard, M. J. Delettre, and M. J. P. Morman, to be published in Acta Cryst. B. Dammeier and W. Hoppe, Chem. Ber., 1971,104, 1660. C. S. Yoo, J. Pletcher, and M. Sax, Acta Cryst.. 1972, B28,2838.
539
Steroid Conformationsfrom X-Ray Analysis Data
Table l-continued R’ R2 17-0Xo-A8(14)OX0
Designation 10-aza
OX0
Configuration
5b9P
No.
Ref:
(96)
89
(iv) Unsaturated steroids Monoenes
A4 A’ OAc a-I A5 OBzI C10H19 A5 OBzBr 0x0 A5 OBzBr 0x0 A’ OBzI CIlH21 A’, 9,1l-seco, 9-0x0, 11-OAc H OAcI 19-nor, A5(’O) OBzBr C9H,, A6, 5a,8a-cyclo OAcI C8H17 A’, 4,4,14a-Me3 OAcI a-C8H15 A’, 4,4,14p-Me3 [For compound (109), see Part (v) of this Table] H
90 91 92 93 94 95 96
OBs OH
c1
Dienes ED0
(105) 5a,8a,9p (106) 5a (107) 5a,13a,14p (108)
(110) 9p,lOa (111) OBzIN C,Hl, A5.7 9/I,lOa (112) OBzDN C,H,, ~ 5 . 7 (113) 1Oa [For compounds (114), (115), (116), (117), and (118), see Part (v) of this Table] OH
C(ED0)Me
Oestra-1,3,5(10)-trienes OH OH OH OH
OH OH 89
90
91
92 93 94
” 96 97
A’,’
A5,7
OH OX0
A-ar. A-ar. A-ar. A-ar.
(119) (120) (121) (122)-(125)
97 98 99 100
101 149 8 102
103 104 105 106
J. G. H. de Jong, C. J. Dik-Edixhoven, and H. Schenk, Cryst. Structure Comm., 1973,2. 33. J. Bordner, S. G. Levine, Y.Mazur, and L. R. Morrow, Cryst. Structure Comm., 1973,2, 59. C . M. Weeks, A. Cooper, and D. A. Norton, Acta Cryst., 1971,B27,531. H. C. Mez and G. Rihs, Helu. Chim. Actu, 1972,55,375. I. Nan Hsu and D. van der Helm, Rec. Trau. chim., 1973,92, 1134. J. C.Portheine, C. Romers, and E. W. M. Rutten, Acta Cryst., 1972,B28, 849. J. C. Portheine and C. Romers, Acta Cryst., 1970,BM, 1791. E. L. Enwall and D. van der Helm, Rec. Trau. chim.. 1974,93,53. J. Bordner, R. L. Greene, S.G. Levine, and R. R. Sobti, Cryst. Structure Comm., 1973,2, 55.
98 99 loo
lo’
lo’
‘06
G. L. Hardgrove, R. W. Duerst, and L. D. Kispert, J. Org. Chem., 1968,33,4393. J. Fridrichsons and A. McL. Matthieson, J. Chem. SOC.,1953,2159. C. H. Carlisle and M. F. C. Ladd, Acta Cryst., 1966,21,689. P.B. Braun, J. Hornstra, C. Knobler, E. W. M. Rutten, and C. Romers, Acta Cryst., 1973,B29,463. A. J. de Kok, E. W. M. Rutten, and C. Romers, to be published in Acta Cryst. B. Busetta and M. Hospital, Compt. rend., 1969, 268, C,1300. W. L. Duax, Acta Cryst., 1972,B28, 1864. B. Busetta, C. Courseille, S. Geoffre, and M. Hospital, Acta Cryst., 1972,B28, 1349. B. Busetta, C. Courseille, and M. Hospital, Actu Cryst., 1973,B29, 298.
Terpenoidsand Steroids
540
Table 1-ontinued
R'
RZ
OH OH OH OH OMe OMe OMe OMe OMe OMe OMe OMe
OX0
OH OH
OH CH,OBs a-CH,OBs OAcBr OAcBr ED0 OAc H OX0
Other trienes OMe OBzBr C(E D 0 ) M e CgHl,
No.
Ref: 107 108 109 110 111 111 112 113 114 114 115 116
A-ar. A-ar., 4-Br A-ar., 2,4-Br2 A-ar., 16u-OH A-ar., D-nor A-ar., D-nor A-ar., A6, 8u-Me A-ar., 7a,8u-CH2 A-ar., 6,7,8-CH A-ar., 7-thia A-ar., 8-aza, 12-0x0 A-at., A", 11,13-diaza, 12-NH2 (141)
19-nor, m(l0a)-homo, ~
ED0 OBzIN
Conjiguration
Designat ion
117
1 10).2,4 (
9,10-seco, A5*7,'( 9,1O-seco, A 5 * 7 * 1'(
9, 19)
(v) Formulae Me
1
.N-CN ,H
H
BrBzO'
H (23) ref. 118
lo'
Io8 lo9 ' l o
I
*
I I I l 3
'I5 'I6 'I7 l8
H (24) ref. 119
T. D. J. Debaerdemaeker, Cryst. Structure Comm., 1972, 1, 39. D. A. Norton, G. Kartha, and C. T. Lu, Acra Cryst., 1964,17, 77. V. Cody, F. DeJarnette, W. L. Duax, and D. A. Norton, Acta Crysr., 1971, B27, 2458. A. Cooper, D. A. Norton, and H. Hauptman, Acra Cryst., 1969, B25, 814. P. Coggon, A. T. McPhail, S. G. Levine, and R. Misra, Chem. Comm., 1971, 1133. H . P.Weber and E. Galantay, Helv. Chirn. Acta, 1972, 55, 544. C. M. Weeks and D. A. Norton, J. Chem. Soc. ( B ) , 1970, 1494. C. F. W. van de Ven and H. Schenk, Cryst. Structure Comm., 1972, 1, 121. J . N. Brown, R. L. R. Towns, and L. M. Trefonas, J. Hererocyclic Chem., 1971,8, 273. A . H. Joustra and H. Schenk, Rec. Trav. chim., 1970, 89, 988. H . Hope and A. T. Christensen, Acta Cryst., 1968, B24, 375. J . S. McKechnie and I. C. Paul, J . Amer. Chem. SOC.,1968,90, 2144. J. Guilhem, Acta Cryst., 1972, B28, 291.
54 1
Steroid Conformationsfrom X-Ray Analysis Data
Table l-continued Me
.OH ‘CH,OH
(25) ref. 120
(70) ref. 157
OH
CH,Br
______
& o y e
0
/
0
/
(83) ref. 82
(71) ref. 76 Me
Me
Me
CN BrBzO
BrAcO (114) ref. 122
(109) ref. 121
Me
(115) ref. 124
Me
(116), (117) (bromide)ref. 123
(118) (iodide) ref. 123
’” ”*
R. F. Bryan, R. J . Restivo, and S. M. Kupchan, J.C.S. Perkin II, 1973, 386. E. Thorn and A. T. Christensen, Acra Crysf., 1971, B27, 794. D. R. Pollard and F. R . Ahmed, Acra Crysf., 1971, B27, 1976. R. T. Puckett, G. A. Sim, and M. G. Waite, J . Chem. SOC.( B ) , 1971, 935. I. L. Karle and J. Karle, Acra Cryst., 1969, B25,428.
542
Terpenoids and Steroids
Table l-continued
(vi) Symbols for functional groups Halogenoacetyl (COCH,X) AcX Halogenobenzoyl (COC,H,X) BzX 3,S-Dinitrobenzo y l BzDN BzIN 4-Iodo-3-nitrobenzoyl p-Bromobenzenesulphonyl (brosyl) Bs HzAcBs p-Bromobenzenesulphonyl-N-acetylhydrazono [=N-N(COMe)SO,C,H,Br] Toluene-p-sulphonyl (tosyl) Ts Methoxycarbonyl MC Ethylenedioxy (-OCH,CH ,O-) ED0 Ethyleneoxythio (-OCH ,CH , S - ) EOT Sil Trimethylsily1 AnBr p-Bromoanilino Card Cardenolide side-chain Dec COC,H ,,COCH ,C1
means that the various sp3-sp3 distances found do not belong to the same population; in other words they are chemically non-equivalent. In Table 2 we have tabulated the average bond lengths (standard values) that we have obtained for (i) sp3-sp3 single bonds, (ii) saturated compounds having the SP-configuration, and (iii) compounds having the corresponding Scc-configuration(Figure 1). If
Figure 1 The SLY- and Si?-conjigurations of saturated steroids, (a) and (b) respectively. The numbering of atoms is indicated in (a)
Steroid Conformations from X- Ray Analysis Data
543
the observed differences between the lengths of the various sp3-sp3 bonds were random, or more precisely not systematic, their mean values should be about equal, in striking contrast with the values listed in column 2 of Table 2. Note also the small standard errors (-0.001 A) and small estimator values (-0.003 A) in columns 3 and 4. The same trend is observed if we discriminate between 5a- and 5P-configurations and only consider compounds without double bonds. The particularly small C-2-C-3 and C-3-C-4 bond lengths (1.510 and 1.513A for 5a-configuration) are biased, since nearly all inspected steroids contain electrondonating substituents (halogen atoms, hydroxy-groups) at position 3. Ignoring the C-2-C-3 and C-3-C-4 bonds, the C-8-C-14 bond is smallest, while the C-5-C-10, C-9-C-10, C-13-C-17, and C-16-C-17 bonds are ‘long’.
Table 2 Standard bond lengths r, standard errors CT, and estimators S (all in for sp3-sp3 hybridization and steroids with 5a- and 5P-conjigurations
A)
sp3-sp 3-hybrid” 5B-conjigurationa 5a-conjigurat iona 103(r - 1) 1040b 104Sb 103(r - 1) 1040 104s 103(r - 1) 1 0 4 ~ 104s 22 77 542 7 20 549 45 537 17 29 535 16 530 7 23 528 45 150 74 513 17 92 527 45 513 14 69 70 511 18 180 51 14 57 527 516 49 533 20 100 535 19 92 543 51 36 549 17 543 46 110 549 16 44 523 16 40 97 55 525 16 43 531 28 528 16 536 48 52 524 7 20 43 529 16 530 7 22 531 48 140 72 35 544 16 552 48 545 7 19 553 17 91 18 564 45 560 7 22 29 544 16 97 534 45 542 7 18 26 537 16 120 537 7 19 530 45 529 17 49 98 530 45 529 7 26 544 16 95 551 45 35 54 1 7 26 519 16 26 130 523 7 25 537 48 535 16 75 534 7 19 531 45 23 44 543 130 16 536 45 545 7 26 150 44 550 18 46 8 28 546 544 120 553 19 65 46 8 31 545 553 140 537 16 43 538 45 537 7 29 110 541 17 37 539 46 545 8 21 sp3-sp3-hybrid : a variable number (20-60) of steroids were involved 5P-configuration: compounds (2), (lo), (1 l), (12), (19), (39, (93), (94) 5a-configuration: compounds ( l ) , (3), (4),(5), (61, (8), (9), (17), 18), (26), (23, (31), (3% (36), (37h (381, (1 14).
Bond 1-2 1-10 2-3 3-4 4-5 5-10 5-6 6-7 7-8 8-9 9-10 9-11 11-12 12-13 13-14 8-14 14-15 15-16 16-17 13-17 13-18 10-19
a Single bonds without sp3-sp3 hybridization were not taken into account. tions, see Appendix, Sections (ii) and (iii).
For defini-
One might argue that the increased lengths of the C-5-C-10, C-9-C-10, and C-16-(2-17 bonds are due to overcrowding effects such as intramolecular repulsion between hydrogen atoms connected to carbon atoms 1,11, and 19 and
Terpenoids and Steroids
544
the (partial) eclipsing of those attached to C-15, C-16, and C-17. Force-field calculations (see Appendix) take account of these and other interactions. Depending on the 'softness' of the parameters for the different interactions in the fields proposed by Altona (hereafter AL),12' by Warshel and Lifson (LW),'26 by Boyd et al. (B),' 2 7 and by Allinger et al. (A),' 2 8 the various types of calculation reproduce properly either bond and torsion angles or bond length^.^' Table 3 indicates that the methods AL and A give the best agreement with the observed average distances for steroids with the 5u-configuration. Curiously, method AL
Table 3 Comparison of experimentally determined standard bond lenghts r for saturated Su-steroih and theoretical values for 20-methyl-5a-pregnane computed from various force fields. The values listed are 103(r- 1) in units of A. The agreement index s is deJined in Section (iv) of the Appendix Bond
1-2 1-10 2-3 3-4 4-5 5-10 5-6 6-7 7-8 8-9 9- 10 9-11 11-12 12-13 13-14 8-14 14-15 15-16 16-17 13-17 13-18 10-19
5a-Configuration (see Table 2) 537 535 513 511 533 549 523 528 529 544 553 544 537 529 544 519 535 543 550 553 537 54 1
104s:
AL 534 549 525" 530" 538 548 528 531 532 545 571 543 544 531 54 1 532 523 546 554 558 545 549
LW 523 544 521" 523" 529 544 528 520 533 549 54 1 533 533 515 563 502 535 547 567 540 522 525
B 542 552 538" 539" 543 558 540 537 54 1 556 567 553 545 543 538 543 536 545 550 550 554 553
78
114
117
A 532 539 523" 529" -
541 528 527 527 536 548 539 534 525 5 29 528 533 544 512b 5 14b 538 538 61
Excluded from the calculation of the agreement index, since the experimentally determined structures contain substituents at C-3. Excluded since in this calculation C-17 was substituted.
'" 12'
C. Altona, unpublished work; see also Appendix. A. Warshel and S . Lifson, J. Chem. Phys., 1970,53, 582. S. Chang, D. McNally, S. S.Tehrany, M. J. Hickey, and R. H. Boy& J. Arner. Chern. SOC.,1970, 92, 3109.
12*
N. L. Allinger and F. Wu, Tetrahedron, 1971, 27, 5093.
Steroid Conformations from X-Ray Analysis Data
545
overestimates the length of the C-9-C-10 bond (calculated value 1.571 A). This A5,and A5*7bond is indeed the longest in many SB-steroids, and in 3-0xo-A~~ compounds, but not in saturated 5a-steroids. Standard bond angles for 5a- and 5P-compounds are listed in Table 4. In this case the estimator is about five times the standard deviation, implying that in steroid molecules the degree of variation of valency angles is somewhat larger than the corresponding degree of variation in bond lengths. This is in agreement
Table 4 Standard bond angles 8, standard errors 0 , and estimators S (decimal degrees) for rings A, B, and c in 5u- and 5p-steroids Angle 10-1-2 1-2-3 2-3-4 3-4-5 4-5-10 5-10-1 4-5-6 1-1&9 1-10-19 9-10-19 9-10-5 10-5-6 5-6-7 6-7-8 7-8-9 8-9-10 7-8-14 10-9-1 1 8-14-13 14-8-9 8-9-1 1 9-1 1-12 11-1 2-1 3 12-1 3-14 15-14-8 12-1 3-17 12-1 3-1 8 14-1 3-1 8
e
5a-Configuration
113.3 112.2 111.4 112.0 112.1 107.3 111.8 110.9 109.3 111.2 107.6 112.6 111.0 112.5 110.8 112.6 111.5 113.8 114.8 109.0 111.2 113.4 110.9 108.2 119.5 117.1 111.0 112.5
io20 10 10 11 11 10 10 11 13 11 11 10 10 10 10 10 10 10 11 10 10 10 10 10 10 10 13 10 13
102S 51 69 76 85 39 50 59 56 59 28 43 50 32 38 30 31 52 27 68 33 36 62 49 58 76 53 52 61
5/?-Conjiguration 102S io2a 110 113.8 27 110.6 27 120 110.8 27 93 111.7 27 140 114.4 24 110 108.1 24 80 112.3 21 93 110.9 21 89 108.2 21 88 111.4 21 68 108.7 21 71 111.8 24 69 111.8 24 65 111.7 24 39 110.9 21 88 111.5 21 51 62 111.7 21 113.8 21 82 117.4 22 140 M8.6 22 160 111.7 22 52 112.6 22 61 111.3 22 76 41 107.8 22 118.9 22 91 113.9 22 150 120 111.2 22 114.1 22 63
e
,
with the various V F calculations since a change in bond length requires considerably more energy than an equivalent change in bond angle. We note that the endocyclic bond angles about quaternary carbon atoms 10 and 13 have small values in the range 107-109", in accord with earlier predictions by B u ~ o u r t ' ~ * ' ~ and observations by Geise et al.' Table 5 lists a comparison of the standard bond angles of 5a-steroids with theoretical values resulting from the fields AL, LW, and B. With the exception of
Terpenoids and Steroids
546
Table 5 Comparison of standard bond angles (decimal degrees) of rings A, B, and c in Sa-steroids and the corresponding theoretical values calculated ,from the force$elds AL, L W , and B Angle 1&1-2 1-2-3 2-34 34-5 4-5-10 5-10-1 4--5 -6 1--10-9 1-10- 19 9-10-19 9-10-5 10-5-6 5-6-7 6-7-8 7-8-9 8-9- 10 7-8-14 10-5-6 8-14-13 14-8- 9 8-9-1 1 9-11-12 11-12-13 12-1 3-14 15-14-8 12- 13- 17 12-13-18 14-1 3-1 8
5a-Conjguration ( S P P Table 4) 113.3
AL 115.0 111.6 110 7 111.4 115.0 106.1 112.2 111.9 108.0 109.7 108.4 112.4 110.8 112.4 112.4 114.0 112.1 117.7 115.9 111.3 110.7 114.5 113.5 106.2 119.9 117.4 109.9 113.8
112.2 111.4 112.0 112.1 107.3 111.8 110.9 109.3 111.2 107.6 112.6 111.0 112.5 110.8 112.6 111.5 113.8 114.8 109.0 111.2 113.4 110.9 108.2 119.5 117.1 111.0 112.5 s:
1.38
LW 113.6 111.9 112.0 111.3 112.8 107.1 111.3 110.1 108.8 111.2 107.9 111.9 110.8 112.4 110.3 112.1 111.3 113.8 113.6 109.8 110.7 113.0 112.1 106.9 118.8 116.8 110.5 112.4
B 113.0 11 1.4 111.6 111.0 112.8 107.4 111.1 110.3 108.8 110.8 107.6 111.8 110.5 111.6 110.7 112.0 111.1 113.5 113.3 109.0 110.8 112.5 111.1 107.7 117.4 116.5 110.0 113.3
0.62
0.74
angle 9-10-5, for which B produces too large a value, the fields B and LW predict better bond angles than the field AL. Table 6 contains the standard endocyclic torsion angles of 5cr-steroids together with theoretical values predicted by the field LW. The discrepancy between CT and S is even larger, in agreement with the fact that the amount of energy required for a change of one degree in the torsion angle is smaller than for the corresponding change of valency angles (‘Pitzer’ strain is ‘softer’ than ‘Baeyer’ strain). In Table 6 are also listed the overall average endocyclic values of rings A, B, and c according to experiment and to the four quoted fields as well as those of Qav of cyclohexane,’2 9 methylcyclohexane,’Z9 1,l-dimethylcyclohexane,’30 and 1,ldicarboxycyclohexane. Ignoring 1,l-dimethylcyclohexane the experimental
’
130 13’
H . J . Geise, H . R . Buys, and F. C. Mijlhoff, J . Mol. Srrucrure, 1971, 9, 447. H. J. Geise, F. C. Mijlhoff, and C. Altona, J . Mol. Srructure, 1972, 13, 21 1 . C. Pedone, E. Benedetti, and G. Allegra, Acra Crysr., 1970, B26, 933.
547
Steroid Conformationsfrom X-Ray Analysis Data
Table 6 Comparison of average endocyclic torsion angles @ for 5a-steroids (excluding 3-oxo-compounds), their standard errors, and estimators (decimal degrees) and theoretical values of jield L W . Included are average (Dav values of experiment and fields AL, L W , A , and B Ring A 1-10 1-2 2-3 3 4 4-5 5-10 Ring
0
55.0 - 55.7 53.0 - 53.7 56.8 - 55.6
0.2 0.2 0.2 0.2 0.2 0.2
S 0.6 1.3 2.1 2.0 1.4 0.9
58.6
- 56.9
0.2 0.2 0.2 0.2 0.2 0.2
0.6 1.1 1.2 0.5 0.6 0.8
52.6 52.8 - 54.4 55.7 - 59.6 57.6
0.2 0.2 0.2 0.2 0.2 0.2
0.5 3.4 0.7 0.9 1.1 1.o
LW 55.7" - 54.7 51.7 - 52.8 56.9 - 56.6
Average value Exp. AL LW A B C6H12
@'av
55.0 f 0.1 54.2 54.7 55.0 55.5 55.9
B
5-10 5-6 6-7 7-8 8-9 9-10 Ring c 8-9 9-1 1 11-12 12-13 13-14 8-14
a
CD
- 58.2
54.2 - 52.5
55.0
-
58.6 - 57.6
54.5 - 53.4
55.8 - 57.6 - 52.9
52.1 - 55.7 56.2 - 59.7 58.6
Exp. AL LW A B C6H11Me
55.9 53.8 56.3 55.4 56.8 55.3
*
0.1
55.4 & 0.1 53.1 55.9 53.7 56.6 51.7 55.9
Standard deviation 1.4".
values for rings A, B, and c are in close agreement with those observed for the cyclohexane compounds. It can also be seen that the best agreement is obtained with the LW field. Introduction of two 1,l -methyl groups into cyclohexane induces a considerable flattening of the ring system. The axial methyl groups 18 and 19, however, do not cause a corresponding flattening of the steroid nucleus. Close inspection of Table 6 reveals that the largest staggering is encountered in the region of the quaternary atoms C-10 and C-13* while puckering is smallest about the bonds C-2-C-3, C-3-C-4, C-6-C-7, C-7-C-8, and C-9-C-11. The total effect is a bending of the skeleton (see Figure 2) toward the a-side of the steroid molecule. This phenomenon was previously observed by Geise et a2.9,11,132 and has been mentioned subsequently by several workers, in particular by the Buffalo
* This effect is, of course, related to the small inner valency angles about (2-10 and C-13, since the mean torsion angle is related" to the mean valency angle ma, by the equation cos ma, = -cos ma,/( 1 + cos a,,). 13''
13*
C. K. Johnson, Chemical Division Annual Progress Report, Oak Ridge National Laboratory, 1967, N o . 4164, p. I16 H. J. Geise, A. Tieleman, and E. Havinga, Tetrahedron, 1966, 22, 183.
548
Terpenoids and Steroids
Figure 2 ORTEP-projections' la of saturated 5a-steroids : (a) 5a,17a-pregnane-3B,20adiol as found in the crystal structure determination by Romers et al. '5 6 Hydrogen atoms are deleted; (b) 5a,17B-pregnane-3B,20B-diolas resulting from VF calculations by Altona and H i r ~ c h m a n n ~ ~
group' 3 3 , 1 3 4 in their studies of 3-oxo-A4- and -A'i4-compounds [(58), (63), (67), (87), and (88)l. The same effect is also observed for other unsaturated steroids with normal configurations. We will return to this feature in Section 10 and mention here that an analogous effect exists for vitamin A-like compounds, the conjugated doublebond chains of which are bent by the repulsive action of protruding methyl groups.'35 It seems very likely that the preference for the bent form in all these cases is somehow connected with the biological activity. 4 The Geometry of Ring A in 3-Oxo-A4-steroids
The 3-oxo-A4 moiety is the most interesting feature of the important class of corticoid steroid hormones and of many steroid sex hormones. The geometry of ring A in these compounds can be described in terms of the various possible 133
L34
135
W. L. Duax, D. A. Norton, S. Pokrywiecki, and C. Eger, Sreroids, 1971, 18, 525. P. A. Kollman, D. D. Giannini, W. L. Duax, S. Rothenberg, and M. E. Wolff, J . Amer. Chem. Soc., 1973,95, 2869. J. C . J. Bart and C. H. MacGillavry, Acta Crysf., 1968, B24, 1587 and various papers cited therein.
Steroid Conformationsfrom X-Ray Analysis Data
549
conformations of cyclohexane, in addition to a specification of the endocyclic torsion angles. The relevant data are collected in Table 7. The calculation of a least-squares plane through atoms 3,4,5,and 10 indicates that this system is almost invariably planar to within 0.02 A. Frequently carbon atoms 1 and 2 and the oxygen atom at C-3 are at much larger distances, I,, i,, and I,, from this plane. We use the designation half-chair ( H C ) if I, and 1, are approximately equal but opposite in sign ;identity of sign implies a boat conformation (B). For a perfect sofa conformation ( S ) either I , or I, is zero. Intermediate forms are termed S-HC or S-B. The crossing-over points are rather arbitrariIy set at ll2/II[ (or \!,/I21) equal to and 4. Table 7 reveals that in most 3-0x0-A4-steroids ring A adopts an S or S-HC conformation. When the configuration at C-10 is P, the S(1)a form (atom 1 at the a-side of the plane of atoms 2, 3,4, 5, and 10; see also the Appendix) prevails and vice uersu. However, within the same designation appreciable variations in torsion angle and ratio !,/I1 occur. In the group of compounds (42)-(53), having no substituents in rings A, B, or c, I,/], ranges from -0.18 to -0.62 and torsion angle 3-4 varies from + 3" to - 8". We further note that in these compounds the formal double bond C-4-C-5 is always twisted in the same (negative) sense. A perfect or nearly perfect H C conformation is realized in the c-ring-substitued analogues (64)and (65). In other c-ring-substituted steroids [(62),(63),and (7011, however, the geometry of ring A is very much like that in unsubstituted specimens [note that (62) differs from (64)only in the acetoxylation of the 21hydroxy-group]. Additional introduction of fluorine in the 6a-position [cJ (63) and (67)]leaves the form of ring A unaltered. In the 6P-bromo-steroid (59) the distortion of ring B, caused by the 1,3-diaxial interaction of the 10-methyl group and the bulky 6/?-substituent, is transmitted to ring A ;the overall shape may still be called S( l)a but, as a result of changes in torsion angles, the ratio lJI1 has become positive. Curiously, no such effect is found in (60),where the presence of the 6,7P-methylene bridge profoundly affects the conformation of ring B. Introduction of an axial 7or-substituent (61) apparently does not disturb the form of ring A. In contrast, rather large changes occur on 9a-substitution. The effect of 9a-halogenation on the molecular structure of corticoid steroids has recently been discussed by Weeks, Duax, and W 0 1 f f . l ~As ~ far as ring A is concerned, owing to the interaction of the axial hydrogen atom at C-1 and the 9asubstituent, C- 1 is tilted upwards, thereby decreasing torsion angles 1-10 and 5-10 and increasing the angles 2-3 and 3-4. As a result the overall shape of ring A tends to or reaches the S(2)P conformation* [compounds (68) and (69)]. Major changes in conformation may also occur on substitution in ring A itself [steroids (54)--(58)]. In (58) the interaction of the 4-chloro-substituent with the
* As judged by the bond lengths in ring A the data of compound (71) are less reliable. In addition, in view of the rather large torsion angle 4-5, ring A can hardly be treated as a substituted cyclohexene. A distorted boat form seems to be the most appropriate designation. 136
C. M . Weeks, W. L. Duax, and M . E. Wolff, J . Amer. Chem. SOC.,1973,95, 2865.
1-10
1-2
21.9 28.9 38.9 30.6 27.6
D
(iii) Substituents in rings B, c, and -50.7 52.6 -51.9 45.9 -59.4 45.6 45.6 -53.9 48.5 -53.9
(59) (60) (61) (62) (63)
29.5 33.5 -42.4 -45.7 25.4
-51.9 -58.4 58.3 60.0 -53.2
(ii) Substituents in ring (54) 49.8 (55) 51.2 (56) - 40.9 (57) -41.9 (58) 54.8
A
-53.4 -53.0 -54.4 -58.0 -56.1 -54.5 -56.3 -56.1 -52.2 -57.5 -57.6 -55.8
28.7 27.9 29.9 31.0 34.8 32.6 35.6 35.1 33.1 37.6 36.2 36.8
2- 3
47.1 45.6 47.2 49.0 46.1 45.4 45.5 44.0 42.0 45.9 44.7 43.6
(42) (43) (44) (45) (46) (47) (48) (49) (50) (51) (52) (53)
(i) N o substituents in rings A , B, and c
Compound
3.7 -1.7 -5.6 -1.0 2.7
-2.3 12.1 18.1 -0.3
- 8.3
0.5 3.0 0.3 2.0 - 4.0 - 2.4 - 4.8 - 3.4 - 6.8 -8.1 - 4.0 -8.1
34
0.7 -3.8 -8.6 -7.0 -7.1
9.0 -6.2 4.7 - 1.1 4.0
-6.0 -9.4 -6.4 -12.0 -5.8 -6.9 -6.1 -8.7 -2.9 -3.2 -9.5 -4.0
4-5
-28.7 -18.4 - 12.5 -16.1 - 18.7
-29.0 -18.8 9.7 11.8 -31.0
-18.1 -15.2 - 17.6 - 13.0 - 16.5 -15.3 - 14.4 -12.1 -14.5 - 16.2 -11.4 -14.1
5-10
-0.10 0.11 0.29 0.14 -
-
0.04 0.17 -0.38 -0.42 -0.07
0.10 0.10 0.1 1 0.15 0.19 0.17 0.22 0.23 0.21 0.24 0.26 0.26
12
-0.70 -0.51 -0.46 -0.52
-0.58 -0.56 0.32 0.27 -0.70
-0.55 -0.54 -0.55 -0.55 -0.53 - 0.48 - 0.47 - 0.46 -0.41 - 0.46 - 0.45 - 0.42
11
0.12 0.04 -0.02 -0.02 -
0.01 -0.03 0.30 0.30 0.07
0.01 0.05 0.03 0105 -0.13 0.02 - 0.03 - 0.06 -0.04 -0.08 -0.04 -0.12
13
-
0.14 -0.21 -0.62 -0.28
-0.06 -0.30 -1.19 -1.54 0.10
-0.18 -0.18 - 0.20 - 0.28 - 0.36 -0.36 - 0.47 -0.51 -0.51 -0.53 -0.58 -0.62
lJll
S(1)a S(1)a S(1)a-HC S(l)a Sub
S(1)a S(1)a HC S(2)a-HC S(1)a
Conformation
Table 7 Conformation of ring A for 3-0x0-A4-steroids. The endocyclic torsion ungles (decimal degrees) are listed in columns 2-7; I,, l,, and I, (A) w e distances of atoms C-I, C-2, and 0 - 3 from the leust-squares plane through atoms C-3, C-4, (2-5, and C-10
$
&
Q
si%
2
ul
- 59.3 - 44.0
- 58.7
52.1 51.2 49.3 54.9 57.1 56.6 58.0 51.2 54.0
(iv) 9P,lOa-steroids (72) -45.7 (73) -48.3 (74) - 53.8 (75) - 48.4 (76) -47.7 (77) -43.3 (78) -46.5 (79) -51.7 (83) - 52.9
(v) Other configurations (80) 52.3 (81) 46.3 (82) 52.0
- 52.9 - 55.6 - 55.9 - 54.8 - 53.3
- 56.7 - 53.9 - 53.9
41.2 39.6 42.9 47.4 38.5 33.3 50.4 39.9
34.1 39.4 11.0
- 38.0 -21.4 - 25.0
- 29.5 - 24.8 - 19.3 - 30.0 - 34.1 - 39.2
40.8 39.4 34.5 27.9 43.0 49.5 26.9 28.3
13.0
- 8.7
0.4
2.2 -4.1 - 3.7 0.1 5.6 12.3 10.2 - 5.2 - 3.3
- 6.3 0.3 - 14.9 - 20.9 3.4 11.4
- 11.7 - 15.2
- 2.6 - 3.0
- 6.4
5.0 6.3 - 3.8 6.7 3.3 0.4 0.2 2.6 I .5
2.0 - 4.4 -4.3 - 3.5 - 4.0 - 6.5 - 22.2
- 4.8
- 20.4 - 17.0 - 30.0
16.9 20.4 31.8 17.4 17.2 15.1 17.8 25.3 27.8
- 10.5 - 12.1 - 14.1 - 20.5 - 8.7 - 2.8 - 20.6 - 5.6 0.40 0.55 0.04 0.12
- 0.28 -0.14 -0.63 - 0.58
- 0.49 - 0.75
- 0.62
0.12 0.23 - 0.24
-0.14 - 0.02 0.16 -0.13 -0.19 - 0.29 - 0.24 0.07 0.05
-
-
0.50 0.6 1 0.72 0.55 0.49 0.39 0.45 0.67 0.70
0.35 0.32 0.23
-0.35 - 0.28 - 0.43
0.07 0.14 + 0.24
0.07 - 0.08 -0.11 - 0.06 0.10 0.21 0.14 - 0.14 - 0.05
- 0.25 - 0.03 0.09 0.02
-
-0.23 -0.11 -0.11
+0.32
- 0.48
-0.19
- 0.27 - 0.03 0.22 - 0.23 - 0.39 -0.76 - 0.54 0.11 0.07
- 1.42 - 3.84 - 0.06 -0.21
-
-0.53
- 1.01 - 1.16
HC HC S( 1)a-H C S( 1)a HC-S(2)/? S(2)P S( 1)a B(dist.)?
s
b
x $3 4
552
Terpenoids and Steroids
equatorial 6a-hydrogen leads to virtually the same shape of ring A as noted in the 6~-bromo-compound(59). The effect of the bulky 2p-acetoxy-groups in (56) and (57) is even more drastic, leading to inversion of sign of torsion angles 5-10, 1-10, 1-2, and 2-3, i.e. to an inverted H C or S(2)ct-HC conformation, in which atoms 1 and 2 are at p- and a-positions respectively. A similar inversion of ring A is observed in the 9,10-seco-compound (142) (vitamin D anal~gue).’~’The effect has been discussed extensively by Duax et in connection with the biochemical activity (see Section 10)and by Jacobs,’39 who draws attention to the unusual type of ring junction in these compounds, where the torsion angles about the common bond C-5-C-10 (junction of rings A and B) have identical signs. The 2P-methyl-19-nortestosterone derivative (55) shows the “normal” S( 1)ct conformation. The same overall shape is also found in the 2,2,6~-trichloro-compound (54); note, however, the inversion of sign of torsion angle 4-5 and the enlargement of angle 5-10. Analogous observations may be made in the less numerous family of 9p,lOasteroids [(72H79),(83)]. The shape of ring A in the 6a-methyl compound (74), in which ring B has a twist-boat conformation, is very similar to that of the 6pbromo-compound (59). In the 6P-fluoro-6a-methyl derivative (75), however, the strain in ring B is transmitted to ring c, which also adopts a boat form, and not to ring A, which is essentially an undisturbed sofa form. Introduction of a 9psubstituent does have some effect on the torsion angles of ring A [(77)and (78)],but clearly not as much as 9a-substitution in 9a,lOP-steroids [(68) and (69)]. The difference in behaviour is probably related to the difference in orientation of the 9-substituent, which is axial to both rings B and c in 9a,lO~-compoundsbut axial to B and equatorial to c in steroids with 9P,lOct-configuration. The positive l J l 1 ratio in (79)should be ascribed to the non-bonded interaction of the equatorial lla-hydroxy-group and the la-hydrogen, as a result of which C-1 is pushed upwards, accompanied by an increase of torsion angles 1-10 and 5-10 and a decrease of angles 2-3 and 3-4. The compound with 9P-configuration (82) is very remarkable in that it shows the largest 1,/11 ratio in ring A yet observed, in addition to twist-boat forms in both rings B and c. In the past decade several attempts have been made to correlate the chiroptical properties (0.r.d and c.d.) of ap-unsaturated ketones with the molecular geometry. A survey has been published by Crabbe.’40 Although useful generalizations have been found, the subject does not seem to be closed. It seems worthwhile, therefore, to compare the available information on the conformation of 3-oxo-A4steroids in the crystal with the chiroptical properties displayed in solution. The signs of the Cotton effects associated with the n-n* transition (A ca. 335 nm) and longest-wavelength n-n* transition (A ca. 240 nm) have been correlated 13’
’
38 3q
C. Knobler, C. Romers, P. B. Braun, and J . Hornstra, Acta Cryst., 1972, B28, 2097. W. L. Duax, C. Eger, S. Pokrywiecki, and Y. Osawa, J . Medicin. Chem., 1971, 14, 295. H . J. C. Jacobs, Thesis, Leiden, 1972. P. Crabbe, ‘O.R.D. and C.D. in Chemistry and Biochemistry. An Introduction’, Academic Press, New York, 1972.
553
Steroid Conformations,from X-Ray Analysis Data
with the chirality of the C=C-C=O chromophore. From the data in Table 7 on unsubstituted 3-0x0-A4-steroidsit is clear that even in the solid state the shape of ring A is rather flexible, giving rise to torsion angles 3-4 of different sign, as well as to enone chiralities of different sign (not listed in Table 7). This flexibility, therefore, precludes the possibility of confirming or disproving the enone chirality rule from X-ray crystal data. However, it is reasonable to assume that the flexibility is sufficiently restricted not to induce major differences in the orientation of (pseudo) axial or equatorial hydrogen atoms or substituents in the immediate vicinity of the enone chromophore. This being the case one may try to correlate the nature and relative disposition of substituents on carbon atoms 2,6, and 10 with the sign and intensity of the Cotton effects. This is essentially the approach advanced by Burg~tahler'~' and by H ~ d e c . According '~~ to this approach the Cotton effect in the band at ca. 215 nm, the electronic nature of which is not yet fully known, is dominated by the chirality contribution of the pseudoaxial bond at C-2, whereas the chirality of the 240 nm n-n* transition is controlled by the axial substituent at C-6; the Cotton effect of the 335 nm n-n* transition depends on the nature of the axial substituents at C-6, C-2, and C- 10.
Table 8 Correlation between geometry and chiroptical properties of 3-oxo-A4steroids Axial substituent at c-2" C-6b
H+
c1+ Me
+
H H H H H H H H H H H
+ + + + +
Cotton efSect 335nm'
Hc1 HH Br CH, H H H
H F F H
-
+ (-15
-
+
+ +
d
-
+ + - 7 - 7
+ +
+
215nm
+
-d -d
+d
+
+ + H +
240nm
+-
+ + -
+d
-
(230) -d
-
" The sign refers to the torsion angle with the C=O bond. * The sign refers to the torsion angle with the C=C bond. 'In the case of a double-humped c.d. curve the sign of the longest-wavelength lobe is given first, brackets indicating a lobe of minor intensity. Inferred from 0.r.d. curve.
For a number of compounds of Table 7 we have indicated in Table 8 the nature of the (pseudo) axial substituent at C-2 and C-6, in addition to the sign of the torsion angle with the C=O and C=C bond, respectively. With the exception of compound (55), where it is hydrogen, the substituent at C-10 is invariably a 14' 14'
A. W. Burgstahler and R. C. Barkhurst, J . Amer. Chem. SOC.,1970, 92, 7601. R. N. Totty and J. Hudec, Chem. Comm., 1971, 785.
554
Terpenoids and Steroids
methyl group and has therefore been omitted. The Cotton effect data are in part from the literat~re,'~'in part from our measurements. The Table shows a one-to-one correspondence of the 215 nm c.d. band to the orientation of the C-2 substituent. However, the examples are admittedly rather small in number and not very varied in nature. As to the 240nm band, if we assume that the chirality contributions of hydroger, dnd fluorine are opposite in sign to those of other substituents (cf. cc-axially substituted saturated ketones), then nearly all these compounds show a correlation between the sign of the 240 nm Cotton effect and the nature and orientation of the axial substituent at C-6. The 2P-substituted compounds (55), (56), and (57) are exceptions; it should be noted, however, that the sign of the Cotton effect in these compounds has been inferred from the tailing of the 0.r.d. curve at shorter wavelengths. The possibility that a weak Cotton effect in the 3'1 ,,ln region has been obscured by a strong Cotton effect of opposite sign at shorter wavelengths should not be ignored. Subject to the same assumptions concerning the contribution of fluorine and hydrogen, we find the same correspondence between the sign of the Cotton effect at ca.335 nm and the substituent at C-6. Again the 2P-substituted steroids are exceptional ; here, however, the contribution of the axial substituents at C-2 has to be taken into account. In conclusion, it is clear that many more data are required to establish beyond doubt the type of relationship discussed above. The limited evidence available seems to indicate that the approach may be promising. Table 9 contains the standard bond lengths, standard errors, and estimators of 3-0x0-A4-steroidswith normal (9a,10P) and retro (9B,10a)configurations. Bonds C-8-C-9 and C-13-C-17 excepted, the agreement between the corresponding average bond lengths of the 901,108-and 9,!I,lOa-systems is surprisingly good. We note only a slight discrepancy between the values of the standard deviations and the estimator S . Although ring A occurs in a variety of conformations there is only a slight or no effect on the bond lengths, which may be considered to belong to the same statistical population. Note that the bond C-9-(2-10 is longest. Furthermore it can be seen that the regular sp3-sp3 bonds C-6-C-7, C-7-C-8, and C-8C-14 are rather small. A first requirement of V F calculations is a reproduction of these striking features. The field AL (Table 10) applied to 20-methylpregn-4-en3-one meets this condition.* Standard bond angles, standard errors, and estimators of 9a,lOB- and 9p,10~-30x0-A4-steroids are tabulated in Table 11. With few exceptions (notably angles 9-1&19, 6-7-8, 148-9, and 9-11-12) reversal of the configurations at C-9 and C-10 has little effect on the bond angles throughout the skeleton. The agreement between calculated and standard bond angles in the case of the 9a,lOP-configuration (force field AL) (Table 12) is less satisfying than for the corresponding bond lengths. Nevertheless the overall trend for calculated and observed values is the same.
* The other force fields used in this work cannot handle the 3-0x0-A4-system without the addition of new parameters. Therefore we decided to use only field AL, despite its shortcomings as far as prediction of angles is concerned. Similar remarks pertain to Table 12.
555
Steroid Conformations from X-Ray Analysis Data
Table 9 Standard bond lengths (A), standard deviations, and estimators 9a,lOB- and 9/?, l0a-3-oxo-A4-steroids Bond 1-2 1-10 2-3 3-4 4-5 5-10 5-6 6-7 7-8 8-9 9-10 9-11 11-12 12-13 13-14 8-14 14- 15 15-16 16-17 13-17 13-18 10-19
9a, 1Op 1.541 1.531 1.493 1.457 1.339 1.523 1.497 1.523 1.529 1.542 1.563 1.538 1.539 1.528 1.541 1.526 1.534 1.545 1.541 1,554 1.534 1.543
104g 11 11 11 11 11 11 11 12 12 12 12 12 12 12 11 12 11 11 11 11 11 12
104s 36 28 59 37 36 30 32 32 38 37 39 20 43
44 21 23 41 34 46 40 42 35
9p, 1Oa 1.543 1.526 1.492 1.454 1.340 1.525 1.508 1.513 1.538 1.563 1.572 1.547 1.540 1.535 1.536 1.522 1.537 1.546 1.541 1.534 1.540 1.550
104~ 18 18 18 18 18 18 18 18 18 18 18 18 18 18 18 18 18 18 18 18 18 18
of
1045 40 48 91 74 59 32 96 92 47 51 35 45 60 27 41 59 58 89 19 99 75 52
Table 10 Comparison of standard bond lengths (A)of 3-oxo-A4-steroids (9a,lOflconfiguration) and calculated values (forcefield A L ) of 20-methylpregn4-en-3-one Bond 1-2 1-10 2-3 3-4 4-5 5-10 5-6 6-7 7-8 8-9 9- 10
Exp. 1.541 1.531 1.493 1.457 1.339 1.523 1.497 1.523 1.529 1.542 1.563
Calc. 1.531 1.552 1.498 1.458 1.332 1.530 1.506 1.525 1.531 1.544 1.569
Bond 9-11 11-12 12-13 13-14 8-14 14-15 15-16 16-17 13-17 13-18 10-19
Exp. 1.538 1.539 1.528 1.541 1.526 1.534 1.545 1.541 1.554 1.534 1.543
Calc. 1.540 1.544 1.530 1.541 1.531 1.523 1.546 1.554 1.558 1.545 1.542
Terpenoids and Steroids
556
Table 11 Standard bond angles (decimal degrees) of 9a,lOB-and 9~,lOa-3-0~0A4-steroids, their standard errors, and estimators Angle 1@-1-2 1-2-3 2-34 3-4-5 4-5-10 5-10-1 4-5-6 1-10-9 1-10-19 9-10-19 9-10-5 1&5-6 5-6-7 6-7-8 7-8-9 8-9-10 7-8- 14 10-9-1 1 8-14-13 148-9 8-9-1 1 9-1 1-12 11-1 2-1 3 12-13-14 15-14-8 12-1 3-1 7 12-1 3-1 8 14-1 3-1 8
9a, 1Op 113.2 111.4 116.4 123.3 123.2 109.8 120.2 108.6 109.9 112.1 108.4 116.7 112.4 111.7 110.1 113.7 111.4 113.2 113.5 108.8 111.8 113.2 110.5 108.6 119.3 116.9 109.9 112.4
lO20
7 7 7 7 7 7 8 9 8 8 8 8 8 8 8 8 8 8 8 8 8 8 8 8 8 9 8 9
102s 38 35 36 36 24 42 36 39 32 24 37 32 41 27 29 33 37 33 19 17 34 43 38 22 28 34 48 30
9B,lOa ii3.9 111.3 117.5 123.6 122.7 108.3 119.3 108.3 108.6 114.0 110.0 117.9 114.2 115.0 111.9 115.4 111.8 114.4 113.3 112.1 110.5 116.7 110.9 108.2 118.3 116.1 110.9 113.6
lO20 8 8 8 8 8 8 8 8 8 8 8 8 8 8 8 8 8 8 8 8 8 8 8 8 8 8 8 8
102S 31 52 41 24 33 40 38 26 24 29 45 32 200 180 34 43 86 66 43 35 46 58 34 41 30 35 35 28
Table 12 Comparison of standard bond angles (decimal degrees) of9a, lop-3-0x0A4-steroids and calculated values (force Jield AL) of 20-methylpregn4-en-3-one Angles 10-1-2 1-2-3 2-34 34-5 4-5-10 5-10-1 4-5-6 1-10-9 1-10-19 9-10-19 9-10-5 10-5-6 5-6-7 6-7-8
Exp. 113.2 111.4 116.4 123.3 123.2 109.8 120.2 108.6 109.9 112.1 108.4 116.7 112.4 111.7
Calc. 113.6 109.7 116.8 124.6 122.5 107.7 121.4 110.0 108.9 109.1 109.1 115.4 110.7 110.7
Angles 7-8-9 8-9-10 7-8-14 10-9-1 1 8-14-13 14-8-9 8-9-1 1 9-1 1-12 11-12-13 12-1 3-14 15-14-8 12-1 3-1 7 12-1 3-1 8 14-13-18
Exp. 110.1 113.7 111.4 113.2 113.5 108.8 111.8 113.2 110.5 108.6 119.3 116.9 109.9 112.4
Calc. 110.7 114.7 112.2 116.7 115.7 111.4 110.7 114.5 113.5 106.2 120.1 117.0 109.8 113.8
Exp.
44.7 -54.9 34.2 - 3.7 - 4.5 -14.8
Bond
1-10 1-2 2-3 3-4 4-5 5-10
Ring
A
1.2 0.4 1.2 1.4 1.2 1.2
S
50.4 -57.2 31.3 - 1.7 - 4.2 -19.8
Calc. 5-10 5-6 6-7 7-8 8-9 9-10
Bond 49.5 -49.5 50.3 -53.9 56.6 -52.2
Exp.
Ring B
1.1 1.8 1.8 1.3 0.7 0.7
S
57.7 -55.8 51.4 - 45.8
- 55.7
48.1
Calc. 8-9 9-11 11-12 12-13 13-14 8-14
Bond
-51.2 51.8 -54.5 56.8 -60.6 57.2
Exp.
Ring c
0.6 1.o 1.0 0.7 0.4 0.5
S
-48.2 48.4 - 53.8 54.4 -57.3 56.1
Calc.
Table 13 Comparisonof standard torsion angles (decimal degrees) of 3-oxo-A4-steroia!swith 9a,I Ob-configuration,their estimators S , and the calculated values (force field A L ) of 20-methylpregn-4-en-3-one.Compounds (57), (56), (80),and (81) were not included in the calculation. The standard deviations are 0.1"for all angles
wl wl 4
3
b
2;.
9
b
~
9
F !XI
6s
'
3s.
s
b'
n
558
Terpenoids and Steroids
Finally, standard endocyclic torsion angles of rings A, B, and c (9a,lOP-configuration) are compared with the calculated values (field AL) of 20-methylpregn4-en-3-one (Table 13). Not included in the statistical calculation are the compounds (57) and (56) (inverted A-rings) and (80) and (81) (8a,l4/3-configuration). The rather poor agreement is hardly suprising in view of the several different conformations of ring A and the variety of substituents at positions 6,7,9, 11, 12, 16, and 17. Nevertheless the VF calculations predict the correct signs of all torsion angles and the correct order of magnitude. Ring c is most staggered about bonds C-12-C-13, C-13-C-14, and C-8-C-14 and sqmewhat flattened about C-8C-9 and C-9-C-11. This effect is also reprodcced by the calculations. The agreement is less satisfying for ring B where the forcefield predicts large puckering about bonds C-5-C-6 and C-6-C-7, whereas the standard torsion angles are largest for bonds C-7-C-8 and C-8-C-9. Since the estimator values are about ten times as large as the corresponding standard deviations, the comparison with standard torsion angles is hardly justified. The calculation of torsion angles is best tested with standard values from non-substituted compounds, but even then the agreement is rather poor. 5 The A5.'-System
The number of A5-7-steroidsanalysed by X-ray diffraction methods is very limited. This conjugated double-bond system occurs in (analogues of) ergosterol, lumisterol, pyrocalciferol, and calciferol, e.g. the compounds (1 lo), (11l), (112), (113), (142), and (143). These isomers, and others such as tachysterol and precalciferol, belong to the vitamin D series. Their chemistry and stereochemistry have been discussed extensively by Sanders, Pot, and H a ~ i n g a . 'The ~ ~ first three compounds are 9,10-stereoisomers, and calciferol is a seco-steroid, having lost the bond between atoms 9 and 10. For this reason no statistical treatment of the experimental geometrical entities has been applied. The 9a,lOp-, 9P,lOa-, and 9or,10a-A5~7-systems have been inspected by V F calculations (field AL) using the molecules 17p-methylandro~ta-5~7-diene and 9p, 1Ocr- and 9c(,lOa-androsta-5,7-dien-3/3-01,respectively. The results of these calculations are listed in Tables 14,15, and 16, which also present the experimental bond distances, valency, and torsion angles of compounds (1lo), (11l), (1 13),and (142). In view of the uncertainties and the approximate nature of the force field used for this conjugated double-bond system the agreement seems quite satisfactory. A serious discrepancy, however, is bond length C-13-C-14 (see Table 14). The assumption of combined large standard errors in observation and calculation is not sufficient to explain the observed differences for this particular bond, and we cannot offer an adequate explanation for this discrepancy. It reminds us that the calculations must be considered as a first step to our goal, an accurate prediction of the geometry of this class of compound.
* 43
G . M. Sanders, J. Pot, and E. Havinga, Fortschr. Chem. org. Naturstoffe, 1969, 27, 131.
559
Steroid Conformationsfrom X-Ray Analysis Data
Table 14 Comparison of observed and calculated bond distances (A) in ergosterol (1lo), lurnisterol(l1l),pyrocaIciferol(113),and calciferol(142). Calculated and values (Jield AL) are derived from 17fl-methylandrosta-5,7-diene 98,l Oa- and 9a, 1Oa-androsta-5,7-dien-3#I-o1. Standard deviations are 0,014, 0.006,0.004, and 0.004 A, respectively Bond 1-2 1-10 2-3 3-4 4-5 5-10 5-6 6-7 7-8 8-9 9-10 9-11 11-12 12-13 13-14 8-14 14- 15 15-16 16-17 13-17 13-18 10-19
(110) Exp. Calc. 1.550 1.531 1.530 1.541 1.523 1.500 1.523 1.520 1.510 1.512 1.540 1.530 1.340 1.343 1.452 1.450 1.340 1.342 1.520 1.519 1.540 1.567 1.547 1.550 1.536 1.560 1.525 1.540 1.527 1.580 1S O 5 1.500 1.510 1.532 1.550 1.547 1.560 1.544 1.540 1.560 1.544 1.540 1.550 1.545
(111) Exp. Calc. 1.530 1.531 1.545 1.543 1.523 1.521 1.520 1.523 1.507 1.508 1.530 1.535 1.345 1.344 1.461 1.450 1.337 1.341 1.523 1.512 1.554 1.561 1.537 1.538 1.542 1.544 1.561 1.539 1.548 1.531 1.494 1.496 1.531 1.534 1.547 1.547 1.560 1.545 1.548 1.532 1.537 1.547 1.545 1.539
(113) Exp. Calc. 1.539 1.531 1.545 1.534 1.512 1.528 1.522 1.514 1.511 1.515 1.522 1.524 1.338 1.343 1.456 1.449 1.330 1.341 1.519 1.515 1.567 1.570 1.555 1.547 1.541 1.550 1.529 1.530 1.567 1.522 1.500 1.505 1.524 1.535 1.552 1.549 1.554 1.548 1.532 1.563 1.527 1.545 1.561 1.550
(142) Exp. 1.516 1.499 1.500 1.510 1.536 1.494 1.323 1.442 1.359 1.485
-
1.529 1.551 1.535 1.566 1.490 1.522 1.533 1.554 1.559 1.539 1.317
In view of the results with saturated and 3-0x0-A4-steroidsthe agreement for valency and torsion angles is surprisingly good. Considering the torsion angles (Table 16) we note that the A-rings of (1lo), (11l), and (113) are distorted chairs. The puckering about the bonds C-2-C-3 and C-1-C-2 is large. The VF calculations (Tables 14, 15, and 16) nicely reproduce this feature. In agreement with our conjecture that the moieties C-10-C-5-C-6-C-7 and C-6-C-7-C-8-C-9 should be planar, ring B is a 1,3-diplanar ring with very small (but not zero) torsion angles about the bonds C-5-C-6 and C-7-C-8. The shape of this ring type was first discussed by Bucourt.' More recent calculations by Favini et ~ 1 . have l ~ resulted ~ in the values 0, - 17.5,0, 31.2, -44.7, and 31.2" for the torsion angles of unsubstituted 1,3-cyclohexadiene. Electrondiffraction investigations of this molecule confirm the predicted conformation.145-147 Traetteberg'46 reported torsion values of 0, - 18, 0, 32, -46, and L44 14'
146 14'
G . Favini, F. Zuccarello, and G. Buemi, J . Mol. Structure, 1969, 3, 385. G. Dallinga and L. H. Toneman, J . Mol. Structure, 1967, 1, 11. M. Traetteberg, Acta Chem. Scand., 1968, 22, 2305. H . Oberhammer and S. H . Bauer, J . Amer. Chem. Soc., 1969, 91, 10.
Terpenoids and Steroids
560
Table 15 Valency angles (decimal degrees) of compounds (1 lo), (1 1l), (1 13), and (142) and corresponding calculated values (142)
Angle
Exp.
Calc.
Exp.
Calc.
Exp.
Calc.
Exp.
1&1-2 1-2-3 2-3-4 3 4 5 4-5-10 5-10-1 4-5-6 1-10-9 1-10-19 9-1&19 9-10-5 10-5-6 5-6-7 6-7-8 7-8-9 8-9-10 7-8- 14 1&9-11 8-14-13
115 111 111 114 118 112 123 110 108 112 110 119 123 121 119 113 124 113 115 116 114 116 110 106 119 116 112 109
115.8 109.9 109.7 113.0 118.1 109.8 120.7 109.5 110.4 106.9 109.1 119.3 121.6 121.4 118.9 111.5 120.5 115.2 112.2 116.6 114.2 114.2 111.1 108.4 122.4 115.4 110.1 109-6
114.0 110.9 110.5 113.6 117.9 110.8 121.1 107.8 110.6 111.3 109.2 120.4 121.5 120.8 118.7 112.6 126.5 114.5 112.6 114.8 109.7 112.1 113.4 108.5 119.8 116.0 110.4 110.4
115.8 109.8 108.8 112.2 117.5 109.8 121.4 109.5 110.6 110.2 107.8 119.8 121.3 120.4 118.6 111.1 124.8 118.3 111.1 116.3 111.2 112.9 115.3 109.9 123.3 116.0 109.6 111.2
114.2 110.9 111.4 113.3 118.2 111.3 120.4 110.9 109.3 106.8 112.4 120.7 122.1 121.4 121.1 113.0 125.8 117.3 110.2 111.5 106.2 111.9 112.9 107.6 122.1 117.1 110.9 111.4
114.9 109.6 110.0 113.4 117.0 109.2 120.8 109.8 110.6 109.0 110.5 120.1 121.5 121.3 120.0 111.4 123.0 122.7 110.2 114.6 107.7 112.2 114.0 109.2 126.3 115.7 109.7 111.5
110.9 112.3 111.5 113.9 110.7 114.0 121.8
148-9 8-9-1 1 9-1 1-12 11-12-13 12-13-14 15-14-8 12-1 3-1 7 12- 13-1 8 14-1 3-1 8
-
122.3
-
127.5 127.3 126.5 124.3 -
122.0
-
113.2 113.4 112.6 113.1 110.4 107.8 -
115.1 111.0 109.5
32”.* The cited and experimental values roughly agree for the endocyclic torsion angles of ring B in compounds (1lo), (1 1l), and (113). Apparently only small distortions are required to fit the 1,3-diplanar ring in the A5g7-steroidskeleton. The observed torsion angles about the bonds C-5-C-6 and C-7-C-8 are small (7”) but not zero, indicating that the butadiene moieties are not quite planar and that small distortions about the double bonds are possible. A recent electron-diffraction study of tetrameth~lethene’~~ seems to corroborate this conclusion. It can be seen that the force field predicts these features and reproduces the correct signs for the torsion angles about C-5-C-6 and C-7-C-8. From mechanical-model considerations (planar double bonds) two ring B conformations can be envisaged, characterized by right-handed (+) and lefthanded (-) chirality about the C-=-7 bond. The question is whether or not 148
S. W. Eisma, C. Altona, H. J. Geise, F. C. Mijlhoff, and G. H. Renes, J . Muf. Structure, 1974, 20, 25 I .
* Inversion of ail signs of the torsion angles in 1,3-cyclohexadiene of course yields the energetically equivalent enantiomer, whereas two different conformations are envisaged in ring B of A5+’-steroids.
56 1
Steroid Conformationsfrom X-Ray Analysis Data
Table 16 Endocyclic torsion angles (decimal degrees) of compounds (1 lo), (1 1l), (1 13), and (142) and corresponding calculated values Bond Ring A 1-10 1-2 2-3 3-4 4-5 5-10 Ring B 5-10 5-6 6-7 7-8 8-9 9-10 Ring c 8-9 11-12 12-13 13-14 13-14 8-14
Exp.
Calc.
(142) Exp.
40.3
-43.6 55.9 -60.7 57.9 -49.4 40.3
-44.3 54.9 - 57.6 51.8 - 43.7 39.1
- 49.7 58.4 - 57.5 52.9 - 47.6 43.9
- 55.0 55.1 - 53.3 50.8 -49.1 51.6
-33.1 -0.8 18.5 3.1 -38.3 50.6
- 24.8 2.7 9.5 3.5 - 25.7 34.5
- 31.5 3.3 12.9 3.4 -31.9 43.8
-
33.3 - 47.9
-29.9 -0.4 15.5 4.0 -35.4 45.9
-36.1 37.6 - 51.3 61.5 - 59.6 47.9
17.7 -59.9 40.1 18.3 -61.1 42.3
3.7 -49.4 41.4 11.9 -57.7 50.8
- 62.2
- 57.6 50.9 -51.8 52.8 - 55.7 61.5
- 49.4 49.6 - 54.5 56.5 - 57.8 54.8
Exp.
Calc.
40 -55 59 - 54 42 - 35
44.6 - 56.3 59.1 - 54.7 46.6 - 39.6
34 -6 -11 -2 30 -44
- 32 36 - 53 62 - 60 46
36.2 - 6.2 - 13.3 - 2.2
-46.0 56.5 -57.9 51.8 -44.5
56.6 - 55.6 53.5 - 57.5 64.9
-
two energy minima ( = stable conformers) exist side by side in solution. In order to settle this point, computer experiments were carried out on the 9a,lOP-system, forcing ring B to adopt right-handed chirality. The resulting molecular model was unfavourable by several kcal mol- compared with the left-handed system. Moreover, when all co-ordinates were allowed to ‘relax’ the model flipped over into the low-energy conformer. We conclude that probably but one stable minimum exists. Ring c of compound (110)is a quite distorted chair. The large puckering about bonds C- 12-C- 13 and C- 1 3 4 -14 and small puckering about bonds C - 8 4 - 9 and C-9-(2-11 are neatly reproduced by the VF calculation. The agreement is less satisfying for (113), where theory predicts a flatter ring than the experiment indicates. Nonetheless theory and experiment agree that ring c of (113) is most staggered about bond C-8-C-14. It can be seen that the V F calculations reproduce the correct boat conformation for ring c in lumisterol(l1l).149 The iteration converged to a relatively steep potential well for the correct conformation. From a comparison of the torsion angles in the three configurational isomers (1lo), (11l), and (113) it is clear that ring B in the syn-isomer (113) is much flatter than in the two anti-isomers (1 10)and (111)(although considerably more puckered than suggested by Dreiding models with planar ethylene moieties). This is no doubt connected with the conflicting demands imposed on ring B by the 149
A. J . de
Kok and C. Romers, to be published in Acra Crysr.
562
Terpenoids and Steroids
a-junction to ring A as well as to ring c . This situation has been discussed extensively elsewhere.' 39 Suffice it here to mention that the B/C junction in compound (1 13) is another example of the rather unusual type of ring junction [also noted in compounds (56) and (57) ;see Section 41 involving one sp3 and one sp2 bridgehead carbon atom, with torsion angles of the same sign about the common bond. In all three 5,7-dienes the sign of torsional angle 6-7, as deduced from the observed Cotton effects on the basis of the skewed-diene rule' 5 0 accords with the results obtained from the X-ray analysis. However, an attempt to correlate the intensity of the Cotton effects with the magnitude of the torsion angles meets with considerable difficulties. In a recent detailed analy~is'~'it is suggested that in addition to torsion of the single bond C-6-C-7 the twisting of the formal double bonds C-5-C-6 and C-7-C-8 might play a role. Possibly the influence of extrachromophoric groups, e.g. allylic axially disposed groups, should also be taken into account. A theoretical evaluation of the relative importance of these three factors in the determination of sign and intensity of the Cotton effect would be most welcome.
6 The Conformation of Ring B in Oestranes and A5-Compounds In Table 17 are listed the torsion angles of ring B of As('')- and A'~3~5('0)-oestranes and A'-compounds. The experimental values of gaseous cyclohexene'5 are included at the bottom of the list. Since an approximately zero torsion angle would be expected about bond C - 5 4 - 1 0 for oestranes and about C - 5 4 - 6 for A'-steroids, it is not surprising that the half-chair form is predominant among a family of distorted chairs, sofas, in-between forms, and even nearly ideal boat conformations. The diversity of forms is much smaller for A'-steroids than for oestranes, but a close inspection of Part (iii) of Table 17 reveals that even for this class of compound the shape of ring B is not constant. It seems tempting to attribute the diversity of conformations to the direct influence of substituents. It can, however, be surmised that substituents governing the gross shape of molecules are a dominant factor in the ultimate crystal structure, thereby indirectly fixing the conformation. It is uncertain whether a flexible molecule in other surroundings (e.g.in solvent or on substrate) adopts the same ultimate shape. On the other hand, crystal-structure analyses of a large variety of substituted steroids indicate which conformations are at least possible. One might even conjecture that flexibility is an essential requirement for activity of steroid hormones. Whereas flexibility of ring A seems to be vital to the biological activity of testosterone, progesterone, and corticosteroids, it is the variable shape of ring B which conditions the action of the female sex hormones oestradiol and oestrone and their derivatives.
'" 15'
H . J . C. Jacobs and E. Havinga, Rec. Trau. chim., 1965,84,932. J. F. Chiang and S. H. Bauer, J . Amer. Chem. Soc., 1969,91, 1898.
6-7 47.8 43.1 43.1 45.4 48.3 39.5 33.7 42.9 36.3 48.0 56.3 33.8 54.0 60.5 44.3 43.0 41.0 45.6 48.2 39.3 46.7 47.6 48.0
5-6
- 15.5 - 10.7
- 9.3 - 17.0 - 14.3 - 5.2 - 3.0 - 14.7 - 6.4 - 18.7 - 24.2 - 32.9 - 23.0 - 36.4 -11.9 - 14.0 - 18.0 - 14.7 - 15.3 - 8.7 - 15.0 - 15.8 55.0 -69.1 - 66.6 - 62.5 - 62.5 - 64.0 - 64.8 -60.1 -1.9 - 64.0 - 62.2 - 65.3 - 66.0 - 62.0 - 65.7 - 67.8 - 64.5 -66.1 - 67.9 - 6.0
- 65.1 - 64.2
- 62.6 - 63.7
7-8
52.0 52.5 53.5 59.7 59.5 53.7 59.9 51.1 28.3 -32.4 41.0 36.4 52.1 58.0 57.0 52.2 52.1 57.6 50.9 53.1 56.0
43.3 51.0
8-9
- 31.2 - 26.7 - 30.8 - 22.5 4.2 35.2 - 10.0 - 2.3 - 20.0 -31.0 - 34.0 - 23.2 - 19.9 - 28.5 - 20.1 - 20.3 - 58.0
- 19.4 - 25.1 - 20.7 - 26.5
- 20.1
-11.1
9-10
9P
9PJ4P
9P
Conjiguration
HC-S(8)/? HC-C (distorted) HC S(8M S(8)P HC-C (distorted) S(8)8 HC S(7)a B (flattened) HC-S(7)a S(7b HC HC-C (distorted) C (distorted) HC HC HC-S( 8)P HC HC B
HC HC-S(S)P
Conformation
Table 17 Conformation of ring B of oestranes and A5-compounds. The angles quoted in columns 2-7' are in decimal degrees
o w \
ul
b 3
E.
9
b
5-10
19.0 14.4 16.6 13.1 7.1 20.8 11.0 14.0
15.2
(iv) Cyclohexene (ref:151)
(101)
(loo)
(102) (103) (98) (99) (109) (104) (84)
(iii) A5-Compounds 12.0
Compound
Table 17-continued
0
5.0 0 1.3 0.6 3.5 6.4 - 2.6 3.0 1.o
5-6
15.2
12.0 11.0 16.1 12.3 11.5 14.6 12.8 17.0 13.0
6-7
- 44.9
- 48.0 - 42.0
- 40.8
- 46.1
-42.5
- 44.0 - 39.0 - 46.8 - 40.6
7-8
60.2
62.0 60.0 66.0 60.1 60.6 63.9 60.7 64.0 59.0
8-9
- 44.9
- 45.0 - 50.0 - 47.5 - 46.8 - 44.1 - 42.7 - 48.7 - 44.0 - 43.0
9-10
Configuration
HC (ideal)
HC HC HC HC HC S(8)P HC HC HC
Conformation
Y
Steroid Conformations from X-Ray Analysis Data
565
7 Five-membered (D) Rings It has been shown earlier' 2 , 4 5 , 1 5 2 that five-memberedD-rings can be characterized by the maximum angle of puckering amand the phase angle of 'pseudo-rotation', which are related to the endocyclic torsion angle Q j by the equations
aj = omcos where
j = 0, 1,2,3, or 4
(; +
j6)
6
and
=
144",
and
fl
The adopted numbering of torsion angles in ring D as well as in the other rings is indicated in Figure 3. 2
5 05
3
4
1
43
2
Figure 3 Convention for the numbering of endocyclic torsion angles in rings A,
B,
c, and
D
The configurations and angles A and a,,,of 129 D-moieties (and corresponding to 118 different compounds; see note c to Table 1) are tabulated in Table 18. The following conclusions can be drawn : (i) Irrespective of the configurations of atoms 5 , 8 , 9 , and 10, the phase angles of steroids with normal 13p,14a-configuration are confined to a range of values between + 38.0" and - 42.8", corresponding with D-ring conformations between C,(13)P and C,(14)a. Exceptions to this rule are compounds (70) and (83), having phase angles of - 74.6" and 60.1". They will be discussed below. (ii) The A values of 17-0x0-compounds obeying the first rule always are negative; the lower limit is -42.8" for compound (41). It has been shown earlier12 that the carbonyl group at C-17 requires small torsion angles about bonds C-13C-17 and C-16-C-17. This demand constrains the range of possible conformations to the conformation range between C,(16) and Cs(14)a. This rule also applies when there is an exocyclic double bond C=C or C=N at position 17. An examples is compound (19). (iii) The phase angle of the remaining steroids obeying the first rule is usually confined to the positive part of the quoted range of values. Exceptions to this rule are observed for the compounds (12) and (115) with unusual 5p,14Pconfigurations, the 8-aza-compound (139) with 9P-configuration, and the steroid 5a,17a-pregnane-3P,20-diol(3,4) bearing a 17a-CHOHMe group. (iv) The remaining steroids with A values outside the range + 38 to - 43" have the unusual configurations 13a,14a, 13P,14P, or 13a,14#3,i.e. compounds with cis or inverse trans couplings between rings c and D. H. J . Geise, C . Altona, and C . Romers, Tetrahedron Letters, 1967, 1383.
566
Terpenoids and Steroids
Table 18 Conformation of ring D. The angles are in decimal degrees Compound A @In Conjigurat ion (i) 17B-Hydroxy-compounds(oestranes) 45.9 (119) 20.9 49.1 (120) 22.3 49.8 (127) 21.9 (128) 19.7 46.8 49.8 (129) 22.0 48.5(130) 22.0 (131) 29.6 50.0 50.0 (132) 28.7 46.3 (137) -7.2 52.3 8a (135) 11.5 (121) 17.4 47.2 (ii) 17~-Hydroxy-cornpounds(androstanes) (2) 24.6 47.3 5a 46.5 (85) 21.3 (45) 13.1 47.0 46.3 (46) 17.5 47.1 (98) 27.2 (99) 32.8 49.3 47.7 (87) 17.5 47.3 (92) 13.8 47.0 (51) 19.2 45.9 (83) 60.1 46.6 (26) 15.7 (1) 19.7 48.5 (30) 22.0 57.5 44.5 (52: 17a) 9.2 48.5 (69) 24.1 (iii) 17-Oxo-compounds(androstane and oestranes)
(36) (37) (102) (103) (77) (78) (89) (95) (140) (41) (122) (123) (124) (125) (126) (44) (96)
153
- 11.2
-7.5 - 10.2 327.0 -32.4 -24.1 -7.5 450.0 274.2 -42.8 -19.4 -16.0 - 5.9 -37.1 -18.2 -23.8 -22.3
45.2 45.1 43.0 40.2 44.6 43.8 44.6 24.9 35.0 39.5 42.3 43.2 40.9 42.4 43.1 41.7 30.9
-
-
1301 9P,lOa 9P,lOa 9P,lOa 13a 9P914P -
5b9B
"The nomenclature has been adopted from ref. 153. For instance C,(14) means an envelope with 14 as flap, C2(16) means a half-chair with a two-fold axis running through 16; C,( 1 3)-C2(16) indicates a conformation between C,(13) and C,(16). C. Romers, C. Altona, H. R. Buys, and E. Havinga, Topics Stereochem., 1969, 4, 39.
567
Steroid Conformations from X-Ray Analysis Data
Table 18-continued Compound A @In Conjiguration (iv) 3-Oxo-A4-compounds(pregnanes and androstanes) 19.8 47.6 (60) 24.1 48.5 (69) 9P,10a 19.4 48.8 (76) 9,!?,lOu 19.7 48.0 (75) 12.0 45.5 (59) 46.5 (65) 11.4 11.7 47.8 (58) 4.2 45.6 (67) (74) 0.1 47.6 9&10a (79) 22.7 49.5 9P,lOa (68) 15.2 47.9 1.7 46.2 (42) (61) 18.5 46.3 46.8 (53) 23.1 24.1 49.7 (57) 11.7 46.0 (56) 23.8 46.9 (54) (72) 28.7 49.0 9P,lOa 31.9 47.7 (71) 9P 25.4 45.2 (82) 26.6 48.0 (63) 33.3 8a,14P 129.5 (80) 8a,14p 134.0 36.0 (81) 35.2 58.6 (66) 13.4 45.0 (50) 23.0 47.7 (47) 38.0 46.9 (43) 5.1 45.2 (49) (64) 12.6 46.7 (62) 28.4 50.2 (48) 22.4 49.3 2.7 47.5 9p, 1Oa (73) (55) 33.9 50.0 (70) -74.6 40.8 (v) Remaining compounds -23.3 47.4 (139) 15.8 47.6 (136) 21.8 48.7 (141) 24.3 50.4 (5) 24.6 47.5 (62) 15.5 42.5 (114) (19) -20.8 48.7 (90) 4.6 47.6 2.0 46.7 (91) (3) -37.1 42.1 (4) -4.6 46.1 3.7 45.6 (142) 3.7 42.2 (143) (110) 21.6 47.2 5.0 46.2 (38)
9P 8a --
5P 9P,lOa 9P,lOa -
-
Conformat ion"
Terpenoids and Steroids
568
Table l k o n t i n u e d Compound
A 4.0 21.2 9.0 16.5 8.6 16.1 351.3 11.5 - 22.9 32.2 399.5 7.8 15.1 14.0 6.4 12.0 28.0 6.1 7.5 7.2 26.6 14.4 8.5 - 30.9 27.8 9.0 - 9.2 16.6 20.8 2.3 33.7 22.9 23.8 440.1 25.9 26.5 18.1
@Ill
48.5 45.9 47.9 50.2 46.8 46.6 41.7 48.3 18.8 47.1 41.1 43.3 48.7 48.6 51.7 53.8 44.2 52.1 56.1 50.3 44.1 46.6 45.2 35.7 52.2 49.7 48.3 46.8 48.8 47.1 48.1 44.5 47.1 43.6 49.1 49.8 48.0
(v) The mean (Dmvalue of steroids belonging to the third category is ca. 48". For
17-oxo-compounds we observe the somewhat lower value of 43". Interestingly, the puckering in gaseous cyclopentane' 5 4 amounts to 42.5", whereas the value 37.2" is observed for gaseous cyclopentanone.*' 5 5 L54 55 ' 5 6
W. J. Adams, H. J. Geise, and L. S. Bartell, J . Amer. Chern. Soc., 1970, 92, 5013. H. J. Geise and F. C. Mijlhoff, Rec. Trau. chim.,1971, 90,577. R. A. G . de Graaff and C. Romers, to be published in Acta Cryst.
* This reduction of Om is a phenomenon which has also been encountered in ring A of the saturated 3-oxo-compounds (27), (28), and (29). Although steric hindrance of axial methyl groups at positions 4 and 10 can be invoked for compound (28) (mean puckering angle 49.4") such an explanation holds neither for the serious flattening156 observed in ring A of compound (27) (O,,, = 48") nor for the smaller flattening of ring A of compound (29) ( Oav = 53.6") and the flattening of ring D of 17-oxo-compounds.
Steroid Conformations from X-Ray Analysis Data
569
OH 0
2.2
3r9
26.9
A
20.6 47.0
B
E
28.1
12
-
F
35.3
T3
CH 20H
15
8
56.5
(a) 4
6
y43 12
25.0
0
A 4
27.8 2 r 9
B 6
I
.OH
26.8
(b)
Figure 4 Endocyclic torsion angles of compounds (70)(a)'and ( 8 3 )(b)
The compounds (70)and (83)(Figure 4) deserve special attention. Aldosteronet (70)is highly strained by the presence of two additional five-memberedrings E and F, which results in unusually large torsion angles about bonds C-9-C- 11, C- 11C-12, C-12-C-13, and C-13-C-14 in ring c. Instead of its usual value of ca. -40" the torsionangle@(14-13-17-16)is reduced to - 10.6",and@(17-13-14-15) is reduced from 47" to 31.7". It is difficult to surmise why, in particular, torsion angle @( 14-13-17-16) has suffered this reduction, and possibly future force-field calculations can pinpoint which interaction terms are responsible for the observed change. The total effect is, however, a rather low Om value (40.8"),a very low A value (- 74.6"), and the unusual C2(17)-C,(15) conformation. W . L. Duax and H. Hauptman, J . Amer. Chem. SOC., 1972,94, 5467. The torsion angles of ring D given in the original paper' 5 7 should be shifted clockwise by one bond. 157
570
Terpenoids and Steroids
Compound (83) contains a seven-membered ring c with @(12-13-14-8) = The sum rule' demands a value of ca. 109" for the sum of@(12-13-14-8) and (D(17-13-14-15). The corollary that q17-13-14-15) should be reduced to a lower value (observed 39.3') in order to relieve (at least partially) the strain in the junction of rings c and D is inescapable. Since in a 'strain-free' ring D amamounts to ca. 47", it can be deduced that its conformation shoots through the 'magical' barrier A = + 36" to the value A = 60.1" in which @(14-13-17-16) now acquires the largest value ( - 45.6"). Note that the molecules (3) and (4) are 17a-pregnane derivatives. They are tightly hydrogen-bonded with a water molecule in the crystal lattice.' 5 8 The V F calculations of Altona and HirschmannZ4indicate that the phase angle A of 17a-pregnane-20-diols adopts a value of ca. -36", in contrast to the positive value (&-36") found for 17P-pregnanes. In view of these calculations 17apregnane-3P,20-diol(3) has a 'normal' A value ( - 37.1'), whereas its companion molecule (4) (A = -4.6') behaves differently. The occurrence of two molecules in the asymmetric unit [the pairs (77,78), (131, 132), (3,4), (98,99), (32,33), (15, 16), (116, 117),and (80, Sl)] or polymorphy [the quadruplet (122, 123, 124, 125)] offers a good opportunity to study the flexibility of ring D of the same compound in diflerent surroundings. Taking into account a standard deviation o(A) = 1" the observed differences of A values are insignificant for the pairs (131,132),(32,33),and (15,16), small for the pairs(80,81) and (98,99),but large for the pairs (77,78), (116,117),and (3,4)and the quadruplet (122-125). For (3) and (4) the observed conformations are the envelope C,(14) and the half-chair C,( 16),respectively. The quadruplet displays the forms C,( 14), C,(16), and the in-between forms C,(14)-C2(16) and C2(16)-C,(14). Since it is well-known that packing forces (van der Waals type, hydrogen bonds) are relatively weak we can accept the observed conformational differences in these examples as experimental evidence for the concept of flexibility of steroidal D-rings. - 82.9".
8 Six-membered Boat Conformations Since boats or twist-boats are less stable than chairs (the difference amounts to 5.6 kcal mol- for cyclohexane) we can easily understand why they rarely occur in steroids and other biologically important molecules containing six-membered rings. So far only 13 boat/twist-boat conformations (Table 19) have been encountered in 11 sterojds.* It has been shown by Buys and G e i ~ e that ' ~ ~six-membered boats display the same sort of pseudorotation as five-membered rings.' 5 2 Their presence introduces a certain amount of flexibility comparable with the variable shape of ring A in 3-0x0-A4-steroids and ring B in oestranes and A5- and A5*7-compounds.Its
'
Is*
159
C. Romers, R. A. G. de Graaff, F. J. M. Hoogenboom, and E. W. M. Rutten, Acta Cryst., 1974, B30, 1063. H. R. Buys and H. J. Geise, Tetrahedron Letters, 1968, 5619,
* Another example of a boat conformation in ring A can be found in: D. S. Savage, A. F. Cameron, G. Ferguson, C. Hannaway, and 1. R. Mackay, J. Chem. SOC.( B ) , 1971, 410.
Chd
=
a0
-40.5 25 42 42.3 -27.2 - 48.7 46.6 58.6 - 19 45.9 26.8 39.7 66.9 0
@I
-11.6 30 19 17.7 -27.8 11.2 13.6 10.5 - 32.9 -28.1 -60.1 19.6 -37.7 55.0
cyclohexane-1 ,Cdione.
Compound
Chd" (82) (82) (111) (74) (75) (75) (115) t 136) (22) (139) (24) (84) (138)
52.5 - 58 - 58 - 59.9 58.7 42.5 - 58.5 - 66.6 33.8 - 30.0 29.0 -56.9 - 17.5 - 48.0
a2
27 23 18.3 - 25.5 18.7 17.8 9.2 - 32.4 - 49.1 - 63.6 33.2 - 10.7 56.0
29 35 40.1 - 31.6 - 57.7 40.9 55.2 - 1.9 67.0 30.0 29.5 ' 43.0 - 6.0
a4
- 12.4
@3
- 39.9 53.3 - 55 - 66 -61.1 54.0 31.5 - 64.4 - 66.0 35.6 - 5.4 32.0 - 68.4 -41.1 - 58.0
@,
B
A
B B C D
A
C
B
B C C B
Ring
Table 19 Boat conformations in steroids. The angles are in decimal degrees
137 - 60 - 49 - 47 122 156 - 45 - 37 93 11 61 - 59 -3 267
A 55 56 62 61 55 75 62 73 39 57 60 61 58 63
@In
Configuration Conformation TBB TB 9PJOP TBB 9PJOP 9P,lOa TBB 98,lOa TB 9p, 1Oa B (distorted) 98,lOa TBB 58,148 B 8a B (flattened) 8a,9P,13a,148 TB TB 9B TB 13a,14a T B (distorted) B 9B
E
b
9G.
3b
e2a
F
3
6'
E
$
$
K
5 2
572
Terpenoids and Steroids
pseudorotation can be described by the equations = @, cos (A
j = 0, I, 2,3,4, or 5
and
+ jS)
(3)
6 = 120",
and tan(A
+ jd) =
@j+2
- @j+l
m j f i
where Qrn and A have meanings similar to those stated before. Values A = 0" & (n x 60") indicate twist-boat forms ( T B ) with C2 (222) symmetry. Values A = 30" k ( n x 60") refer to ideal boat forms ( B ) with Czc (mm2) symmetry. Other A values reveal the in-between forms (TBB) with C 2 (2) symmetry in which only the non-intersecting dyad perpendicular to the average plane of the ring is retained. Using equations (3) and ( 5 )we have analysed the boat conformations occurring in compounds (22), (24), (74), ( 7 3 , (82), (84), ( l l l ) , (115), (136), (138), and (139). The numbering of angles $ j is indicated in Figure 3. Whereas equations (1) and (2) usually hold well within 0.5" for five-membered wrings, the application of (3) and ( 5 )to six-membered rings is questionable. Equation (4) holds nicely for cycloh e ~ a n e - 1 , 4 - d i o n e ' ~and ~ * ' to ~ ~a lesser degree also for compounds (82), (1 1 l), (24), (115), (139), and (138), but is not satisfactory for the remaining compounds. Nevertheless the analyses give information on the conformation and the degree of deformation. With the exception of (84)the occurrence of boat conformations is related to unusual configurations. In (84)the presence of two sp2-hybridized carbon atoms in ring A as well as of three chlorine atoms (see Figure 5) is responsible for the excep-
Figure 5 Torsion angles in rings A and I6O 16'
B
of (84)
A . Mossel and C . Romers, Acta Cryst., 1964, 17, 1217. P. Groth and 0. Hassel, Acta Chem. Scand., 1961, 18, 923.
Steroid Conformations from X-Ray Analysis Data
573
tional behaviour. The 4a-chlorine atom, already hindered by the presence of 6and 7a-chlorine atoms, would have too small an intramolecular contact'62 with 0 - 3 if ring A were to assume its normal chair form. This and similar conclusions are usually deduced ad hoc from Dreiding models. However, not too much credit should be given to these or other models. For example, on the basis of a model of a BP,lOa-steroid one might suppose that the short intramolecular distance between the angular 10-methylgroup and the axial hydrogen atoms at c-12 and C-14 should lead to a (twist) boat conformation of either ring B or ring c ; the steric relationship is analogous to that in the axial conformer of t-butylcyclohexane. In actual fact [see (72), (90), and (91)] the steric interactions are relieved by a considerable decrease of torsion angles 148-9-1 1 and 8-9-1 1-12, thereby turning the 10-methyl group away from the a-side of ring c and leaving ring c in a distorted chair conformation.
9 The Conformation of the Side-chain at C-17 It is obvious that 17P-side-chains play an important role in the activity of pregnanes, cholestanes, ergostanes, and cholic acids. A characterization of the conformation and the designation of the chirality of the asymmetrically substituted carbon atoms may, therefore, contribute to a better description and understanding of these functional groups. A number of dihedral angles about the bonds C- 17-C-20, C-20-C-22, C-22-C-23, C-23-C-24, and C-24-C-25 are listed in Table 20. In view of the large torsion angles (ca. 180")it can be concluded that the normal cholestane side-chain, 21
20
22
23
CH, -CH-CH2-CH2-CH2
24
25
-CH-(CH,),
is fully stretched in compounds (11l), (7), (8), (9), (32), (33), (20), and (18). This is also true for the ergostane compound (82). The ergostane derivative lumisterol (113)and the gorgosterol compounds (101)and (104)(steroids extracted from soft corals), calciferol (143), and compound (113) exhibit a folded chain with a sharp bend about bond C-20-C-22. Although the seco-compound (104) has an open ring c and (101) has an extra C-30, forming a cyclopropane ring with C-22 and C-23, their side-chain conformations are quite similar. The insect-moulting hormones (93) and (94) are also folded about bond C-20-C-22. The side-chain of cholic acid (11) is stretched, but the tail of (10) is folded, again about C-20c-22. With the exception of the lanostane compound (108) (having the 13a,14ficonfiguration) methyl group 21 invariably is oriented towards the a-side of the molecule. From the value of the dihedral angle (D(13-17-20-21) (see Table 20 and Figure 6) we note that this &-orientation is nearly perfect for the cortico= -89') but gauche for the remaining steroids (58), (67), (63)J and (88) (aav 162
R. W. Kierstead, J. Blount, K. E. Fahrenholtz, A. Faraone, R. A. LeMahieu, and P. Rosen, J . Org. Chern., 1970, 35,4141.
Terpenoids and Steroids
574
Table 20 Dihedral angles (decimal degrees) in the side-chain. The column numbers refer to the following angles: 2 : @( 13-1 7-2&2 1) 3: @(16--17-2&21) 4 @( 13-1 7-2&22) 5 : @( 17-2&22-23) Compound 2 (8) -59 (9) -57 (7) -55 (17) -55 (18) -50 (20) -58 (32) -51 (33) -60 (111) -54 (82) -55 (113) -57 (143) -49 (104) -53 (101) -54 (93) -56 (94) -53 (108) 194 (10) -59 (11) -63 (53) -57 (90) -70 (74) -76 (79) -82 (58) -88 (88) -89 (67) -89 (63) -89
3 182 182 184 183 192 183 189 181 184 182 182 186 185 183 187 181 -45 185 177
4 5 181 204 180 195 183 206 177 181 183 187 181 197 183 200 180 185 182 179 172 184 181 236 190 -119 189 -104 185 -91 180 74 184 71 57 70 185 62 176 188
6 q20-22-23-24) 7 @(22-23-24-25) 8 : q23-24-25-26) 9 @(23-24-25-27) 6 7 8 9 181 179 173 -62 176 184 164 -73 63 13 181 179 130 174 177 -67 184 163 191 -73 183 176 175 -60 196 194 176 -57 61 177 175 185 72 195 176 184 175 177 184 -57 184 111 60 -65 175 111 -55 65 188 145 149 -42 65 191 148 147 -54 181 189 -100 194 -88 -39 192 173 -38 181 174
Type Cholestane Cholestane Cholestane Cholestane Cholestane Cholestane Cholestane Cholestane Cholestane Ergostane Ergostane Ergostane Ergostane Ergostane Ergostane Ergostane Lanostane Cholic acid Cholic acid 20-OH-Pregnane 20-0x0-Pregnane Pregnane Pregnane Corticosteroid Corticosteroid Corticosteroid Corticosteroid
H
I
21,
Ha
(a)
I Ha
(b)
(Cl
Figure6 Newman projections along the bond C- 17-C-20 for normal pregnanes, cholestanes, ergostanes,.and cholic acids (a), corticosterozds (b) and retro-steroids (c)
Steroid Conformations from X-Ray Analysis Data
575
= - 56"). The retrosteroids, including 20-hydroxyprogesterone (53) (aav (74), and (79) are an intermediate group between the cholestanes and steroids (W), corticosteroids, with 0 values between - 70" and - 82". The chirality of the side-chain is given in Table 21. First turning our attention to 20-hydroxyprogesterone (53), we note that the chirality of centre 20 is
Table 21 Chirality of the side-chin according to the Cahn-lngold-Prelog rules'64 c-20 R R R R R R R R R R R R R R R R R R S R
This molecule is the 2Oa-epimer. VF calculation^^^ indicate that this epimer in the gauche conformation is, indeed, most stable, but that in the liquid state the anticonformation with CD ca. 190" may play a role for some derivatives, such as c-18 ~ x i m e s Nonetheless .~~ the C-21 methyl group is always oriented towards the aside of the molecule, even in the case of the 2 0 P - e ~ i m e r having ' ~ ~ R chirality. Although ( 108) deviates completely from the regular dihedral-angle pattern, it has the usual R chirality at centre 20. Table 21 may be useful rather for establishing relationships between possible epimers than for reading the conformation. The conformation of corticosteroids about bond C - 1 7 4 - 2 0 has been discussed extensively by Duax and collaborator^.^^^^^^^+^^^ All these studies indicate that the constant C - 1 7 4 - 2 0 conformation in the solid (crystalline) state may also be dominant when acting on biological receptors. 16'
N. W. Isaacs, W. D. S . Motherwell, J. C. Coppola, and 0. Kennard, J.C.S. Perkin ZZ, 1972, 2331.
16'
166
R. S . Cahn, C. Ingold, and V. Prelog, Angew. Chem., 1966,78,413. H. Lee, V. S. Bhaca, and M. E. Wolff, J. Org. Chem., 1966, 31, 2692. A. Cooper and W. L. Duax, J. Pharm. Sci., 1969, 58, 1159.
Terpenoids and Steroids
576
10 Biological Activity at the Molecular Level It is with reserve that we comment on the physiological properties of hormonal steroids in correlation with molecular geometry, because their biological activity is one of the most important reasons for crystallographic research into this class of compound. Unfortunately, most steroid hormones have more than one function and some play an intermediary role between two or more organs. Whereas enzymes have a straightforward function in the living cell or in the digestive tract, hormones usually work on special organs (glands) or membranes. The diversity of their functions is also reflected in synthetic drugs, which have the disadvantage of sometimes showing unwanted side effects. The arguments in favour of their non-specificity are : (i) Their diverse functions. For example, adrenocorticosteroids are important as (a)regulators of electrolyte excretion (membranes in kidneys),(hj participants of glucometabolism (liver), and ( c ) agents for anti-inflamatory action (mucous membranes). (ii) The introduction of substituents such as methyl groups or fluorine-atoms (usually at positions 6, 9, 11, or 16) gradually changes their properties. (iii) Takeover of some of the functions by chemically quite different drugs. For example, the molecule diethylstilbestrol' 67-169 is a potent agent for uterus oestrogen receptors, competing in activity with natural oestradiol. '
(ivj Experimental evidence for quantitatively different effects at different concentrations, say at moll- (inhibitory) and at 10- moll- or lower (stimula t ing). The most favoured view'70 of the mechanism of action is embodied in the receptor theory involving a combination of steroid (substrate) with protein (receptor). The interaction may be direct, but, more likely, is indirect via a third substance, such as a pyridine nucleotide, or via lipids in membranes. The globular protein surface (usually an enzyme) largely consists of a fl-pleated structure,17' although the hydrophobic a-helix sometimes occurs at the outside of the molecule. The 0-3-0-17 separation in oestranes and testostereone' l 2 and the 0-3-0-20 16'
16' '69
''I
M. Hospital, B. Busetta, and C. Courseille, Communication on the Stockholm Symposium on the Structure of Biological Molecules, July 9-12, 1973. E. C. Dodds, L. Goldberg, W. Lawson, and R. Robinson, Nature, 1938, 141, 247. C. M. Weeks, A. Cooper, and D. A. Norton, Actu Cryst., 1970, B26,429. ( a ) H. G. Williams-Ashman and A. H. Reddi, Ann. Rev. Physiol., 1971, 33, 3 1 ; ( h ) E.-E. Baulieu, A. Alberga, I . Jung, M.-C. Lebeau, C. Mercier-Bodard, E. Milgrom, J.-P. Reynaud, C . Raynaud-Jammet, H . Rochefort, H. Truong, and P. Robel, Rec. Progr. Hormone Res., 1971, 27, 3 5 1 ; ( c ) E. V. Jensen and E. R. DeSombre, Ann. Rev. Biochem., 1972, 41, 203. R. E. Marsh, R . B. Corey, and L. Pauling, Actu Cryst., 1955, 8, 710.
Steroid Conformations from X-Ray Analysis Data
577
separation in corticosteroids and progesterone"* are in the range 1l . G l 1 . 8 A. These distances roughly correspond both with two turns of the protein a-helix (10.76 A) and with a few interchain 0-.-N distances occurring in antiparallel chain-pleated protein sheets. It is difficult, however, to envisage a close approach of the steroid molecule to the innate hydrogen bonds which support the backbone of the protein structure. The bulky side-groups would prevent such an attack. It is more likely that hydrophilic side-groups of the enzyme become hydrogenbonded to the substrate molecule, e.g. to hydroxy- or 0x0-groups at C-3, C-17, and C-20. In this view the steroid probably does not act on the active side (cleft) of the enzyme but on its surface. The disruption of the tertiary protein structure might enhance or block the biological activity. The flexibility of ring A (progesterone, testosterone, and corticosteroids) and/or ring B (oestranes and A5*7-steroidsof the vitamin D group), together with the -flexibility of ring D, also fits into this picture. This flexibility is a prerequisite for arranging the steroid functional groups in the proper directions for the formation of hydrogen bonds with the receptor groups. It had been thought earlier' that the bend of the steroid molecules towards the a-side might be correlated with activity. The hydrophobic P-side with protruding methyl groups 18 and 19 might be complementary to the receptor surface. The optimum oestrogenic activity of oestradiol with a 13P-Me group relative to the 13P-H and 13P-Et analogues' supports this idea. The P-side hydrogenation of 17/3-hydroxy-l,4-androstadien-3-one by heterogeneous catalysis,' 3 3 as well as the optimum anti-inflammatory activity of 9a-fluorocortisol with maximally bent surface in comparison with also seems to agree with this view. Serious objections against the complementarity theory can be put forward. It does not give an account of the role of the hydrophilic functions of 0 - 3 and the 17P-side-group. It is necessary to presuppose either (a) a ternary complex of a steroid attached with its P-side to the receptor and hydrogen-bonded to a third body by means of its hydrophilic side groups ( b )consecutive action by means of its P-side with a complementary receptor and of its hydrophilic side-groups with a third body, or (c) oice versa. Such operations seem to be quite artificial and unnecessarily complicated. Moreover, the presence of a hydrophilic 11-0x0- or 11-hydroxy-group in corticosteroids contradicts the complementary theory, since surface interactions cannot be both hydrophobic and hydrophilic within short distances of, say, 3.5 A. It is more probable that the presence of the 10-Me group contributes to the overall bent shape, thereby arranging the C-3-0-3 and C-20-0-20 vectors in the appropriate directions. These directions' 7 2 are 138" for cortisol, 145" for progesterone, and 160" for cortisone. It is clear that rather than further diffraction analyses of steroid crystal structures, future crystallographic work should be focused on investigations into steroid-receptor complexes.
'
172
0. Dideberg, L. Dupont, and H. Campsteyn, Communication on the Stockholm Symposium on the Structure of Biological Molecules, July 9-12, 1973.
578
Terpenoids and Steroids 11 Summary
Some 140 steroid crystal structures have been subjected to statistical and conformational analysis, in which weighted average experimental values for bond distances and valency and torsion angles are compared with values obtained by valence force calculations. The analysis takes into account the configuration, the hybridization, and the character of substituents bonded to carbon atoms 3 and 17. Special attention is drawn to 3-0x0-A4-steroids for which the conformation and the Cotton effect are discussed at some length. The data, compiled in several tables, underline the flexibility of biologically active steroids. With rare exceptions nearly all steroids have flexible five-membered D-rings. The flexibility at the other end of the molecule can be assessed in terms of the sofa and/or halfchair conformation (and in-between forms) of ring A in 3-0x0-A4-steroids,and of the same conformations of ring B in oestranes and A5-steroids. Six-membered boat. forms sometimes occurring in steroids with abnormal configurations also display a large degree of flexibility. It is speculated that flexibility at both ends of the steroid nucleus is a necessary condition for the formation of hydrogen bonds with receptor molecules. The authors wish to thank Miss S. Amadio and Mrs. H. Bavelaar for respectively their linguistic and typewriting help in preparing this Report. They are indebted to Messrs. D. van Ingen Schenau, H. de Sitter, H. van der Lee, and J. M. G. Bonfrer for computational aid in producing some of the data used in this Report. 12 Appendix
(i) Weighted Average Value or Standard Value qav. q,, =
E
i:
qi.;'/
i= 1
a;2
i= 1
qi is the individual observation, bi its standard deviation, and n the number of observations. (ii) Standard Error (Deviation) 0.
. [i =
.;2]-"'
i= 1
(iii) Estimator of the Standard Deviation S.
ij is the unweighted average of entity qi (assuming weights 1).
(iv) Agreement Zndex s. s = [(n-l)-'
i
(qyb
- qf"'")2
i= 1
q'b and q;alc are observed and calculated values of q i .
1
lI2
579
Steroid Conformationsfrom X-Ray Analysis Data
chair,
C
4,
boat,
B
c,,,
twist-boat,
TB
D,
sofa,
S(5b
c,
sofa,
S(5W
c,
half-chair,
HC
C,
1,3-diplanar,
C,
half-chair,
C,!4)
c,
envelope,
CS(4b
c,
1
4
2
5
5 5
3
5 3
5 4
Figure 7 Five- and six-membered ring conformations
580
Terpenoids and Steroids
(v) Geometrical Forms qj' Rings used in the Discussion. The observed geometrical forms are depicted in Figure 7. The first column shows the ring in a projection perpendicular to the bond C-1-C-2. The plane of projection is perpendicular to a dyad (two-fold rotational axis) for the six-membered chair, twist-boat, halfchair, 1,3-diplanar chair, and the five-membered half-chair. The projection is perpendicular to the plane of atoms 1,2,4, and 5 (boat), 1,2,3,4, and 6 (sofa),and 1,2,3, and 5 (five-memberedenvelope). The second column presents the ring with signs of endocyclic torsion angles, the third the name, the fourth the abbreviation, and finally the fifth the symmetry in Schoenflies notation. (vi) Valence Force Culculutions und Parameters. The basic ideas and principles of the V F method have been reviewed r e ~ e n t l y . ~ ~In" 'all ~ V F calculations the total strain energy is written as the sum of several types of energy contribution, as follows :
V,,,
=
V(r)+ V ( 0 ) + V ( 4 ) + V ( 6 ) + V(1,3) + V(nb) + V(cou1) + cross terms
where V(r),V ( @ ,V($),and V ( S )represent the total energies of bond length, bond angle, torsional, and out-of plane deformations, respectively, and V (1,3), V(nb), and V(coul) stand for Urey-Bradley, non-bonded, and coulomb interaction energy contributions. The computer program package used in the present work has recently been ~ u t l i n e d . ' The ~ central routine UTAH is a modification of the program devised by Boyd.' 74 In addition to a set of interactions describing the structural parameters and the constants for the chosen potential expressions the input consists of the Cartesian co-ordinates of the trial model. The program collects the appropriate interactions for the participating kinds of atoms and the first and second derivatives of the energy with respect to the deformations, i.e. the potential energy surface is expanded in a truncated Taylor series around the trial structural parameters. The resulting set of simultaneous equations is solved directly. Because of thc approximations involved in the various transformations' 7 4 the calculated shifts of the atomic co-ordinates will not minimize the potential energy in a single calculation. Therefore, the new model is automatically used as input for another cycle of computations until the co-ordinate shifts are smaller than a prespecified value (a convergence limit of 0.001 8, was used). The output consists of a list of energies, geometrical properties, and Cartesian co-ordinates of the refined model. The program user may choose between the force fields ,41,,'".'7"77 B,'27 and LW.'26 We wish to stress that the calculated geometry in no way depends on the input co-ordinates (except by being biased toward a particular conformer because during the iteration process the structure J. E. Williams, P. Stang, and P. von R. Schleyer, Ann. Rev. Phys. Chern., 1968, 19,
'" l i b
''-
531. R. H. Boyd, J . Chem. Phys., 1968, 49, 2574. C. Altona and M. Sundaralingam, J . Amer. Chem. Soc., 1970, 92, 1995. C . Altona and M. Sundaralingam, Tetrahedron, 1970, 26, 925. N. L. Allinger, J. A. Hirsch, M . A. Miller, I. J. Tyminski, and F. A. Van-Catledge, J . Amer. Chem. Soc., 1968, 90, 1199; N. L. Allinger, J. A. Hirsch, M . A. Miller, and I. J. Tyminski, ibid.. 1968, 90, 5773; ibid., 1969, 91, 337.
58 1
Steroid Conformations from X-Ray Analysis Data
cannot 'jump' over an energy barrier separating two conformers) but only on the force-field equations and parameters ~ h o s e n . ~A more detailed discussion concerning the a priori calculation of steroid molecules is given elsewhere.24 In the calculations with force field AL the same parameters were used as reported earlier ; l 75,1 7 6 since the original set did not contain constants appropriate for the calculation of structures containing one or more double bonds these are shown in Table 22. In our earlier report24 the non-bonded interaction list had to be cut
Table 22 Additional force-field parameters used in the valence .field A L for the calculation of steroids containing one or more carbon-carbon double bonds (i) Bond stretch: V
=
ik,(r, - r J 2
-
Bond" C-=-C --= =-H =-C
kk(ri - ro)
ki
kr
9.7 1.56 5.3 1.56
ro 1.336 1.370 1.087 1.424
0 - 0.077 0 - 0.045
(ii) Angle bend: see ref. 177; the k, values shown were multiplied by 1.15 throughout the calculations. Angle H
4
k,
0.66
80
119.1"
122.6"
=q"
0.66
I 17.8"
0.55
122.4"
1.1
122.6"
1.1
I 16.9"
2.1
121.6"
H
c
4'
C
582
Terpenoids and Steroids
Table 22 (continued) (iii) Torsions:’
V
=
+K{ I
Torsion angle
R
R
R
R
h=&
‘/
f cos ( n $ ) }
V,
n
Sign
R
40.0
1
-
H or C
1.5
3
-
3
+
3
-
0.49
(iv) Out-of’-plane bending: V
=
3
+
-
-
C H
3
+
HorC
3
+
H or C
0.5k,h2
R
=3 R
k,
R
0.4
H or C
(v) Non-bonded interacfions: the Hill exponential equation’
Atoms C(sp2).. C(sp2) C(sp2).-C(sp3) C(sp2)** .H C(spZ)-..o (vi) 1,3-lnteractions: the Hill 6/12 equation‘” Atoms C(sp2).. C ( s p 2 ) C(sp2).. C(sp3) C ( s p 2 ) -.H .
i
1.85 1.75 1.65 1.70
77
was used. E j
0.0200 0.0283 0.0447 0.0374
was used. r* 1.39 1.39
1.215
E
0.22 0.22 0.09
” C stands for C ( s p 3 ) unless indicated otherwise. ‘ I n m d y n k ’ . In mdyn. “n A. In mdyn A rad - *. The torsional functions and parameters are chosen to reproduce the curvature at the bottom of the potential well and arc not intended to reproduce the entire torsion potential. In kcal mol-’. In mdynA r a d - *. ‘ In A. ’In kcal mol-’.
short at a given distance for practical reasons. In the present work all nonbonded interactions were included in the calculations. All calculations were carried out on an IBM 360/65 computer of the University of Leiden.
Steroid Conformations from X-Ray Analysis Data
583
Note added in proof. Recently it was found that certain slight modifications of field B'27 led to significant improvements of calculated bond lengths, bond angles, and torsion angles of the saturated steroid skeleton (C. Altona et al., unpublished work).
ERRATA Vol. 3, 1973 Page 72, line 5 up. Delete the name ‘orthodene’ as applied for formula (344). ‘Orthodene’ is the trivial name for 3,7,7-trimethylnorpin-2-ene. Page 82, line 5 up. For ‘p-caran-4-01’ read ‘p-caran-3-01’. Page 86. Formula (425) lacks a methyl group at C-2 of the chromene ring.
584
Author Index
Aasen, A. J., 238 Abdel-Fattah, A. F., 286, 405 Abd-Elsamie, M. E., 420 Aberhart, D. J., 285 Abon-Chaar, C. I., 293 Abou-Donia, S., 20 Abraham, N. A., 481 Abubakirov, N. K., 408 Abul-Hajj, Y. J. 285,474, 475 Achaya, K. T., 17 Achilladelis, B. A., 90, 305 Achini, R., 90 Ackman, R. G., 271 Adam, G.,3 15,535 Adams, D. L., 45 Adams, J. A., 456 Adams, P. M., 90, 92 Adams, W. J., 568 Afonso, A., 5 11 Agre, N. S., 405 Agurell, S., 73 Ahlgren, G., 188 Ahmad, M. S., 364 Ahmad, S. A., 160 Ahmed, F. R., 541 Aida, M., 22 Aizawa, M., 155 Akaki, K., 41 1 Akhmedov, A. I., 9 Akhrem, A. A., 3 13,394, 395,458,460,478,490 Akhtar, M., 275 Akimoto, A., 338 Akiyama, K., 379 Akiyama, T., 2 14 Alberga, A., 576 Albrecht, K., 471, 477 Albrecht, P., 306 Alburn, H. E., 424, 459, 463 Alexander, C. W., 37 Alexandre, C., 42 Alfsen, A., 286,487,488, 489 Allcock, C., 256 Allegra, G., 546 Allen, C. M., 293 Allen, F. H., 536
Allen, J., 183, 210 Allinger, N. L., 312, 544, 580 Allred, J. B., 252 Almqvist, S. O., 238 Altenburg, H., 536 Altman, L. J., 226 Altona, C., 531,533,544, 546,560,565,566,580 Alvarez, F. S., 360, 365 Amano, T., 22 Ambrus, G., 404, 460, 47 1 Amelina, A. S., 479 Amiard, G., 472 Amos, B. A., 314 Ananchenko, S. N., 312 Andersen, N. H., 25, 95, 102, 139 Anderson, A. B., 160 Anderson, C. G., 277 Anderson, G. D., 135, 136,266,303 Anderson, R. A., 393 Anderson, R. J., 183 Anderson, W. K., 6 Anding, C., 274 Andrewes, A. G., 221, 233,307 Andrews, A. L., 338 Andrews, G. C., 16 Anetai, M., 142, 240 Anjyo, T., 474, 475 Annen, K., 338 Ansari, H. R., 13 Anthonsen, T., 148, 151 Anthony, G. M., 131 Anthony-Mote, A., 457 Aoki, K., 107 Aoyagi, R.. 215, 216 Appleton, R. A., 302 Aragon, M. C., 253 Araujo, J., 9 Arbuzov, B. A., 61,63,64 Archer, B. L., 300 Arditti, J., 277, 392 Aries, V. C., 461, 473, 493 Arigoni, D., 107, 174, 186,288 Arima, K., 460, 51 1, 513
585
Arita, M., 149 Armsen, R., 233 Arnold, R. A., 86 Arnold, R. T., 60 Arnold, Z., 10 Arnould, D., 15, 237 Arpesella, 0. A., 53 Arpin, N., 229 Arpino, P., 172, 246 Asai, A., 24 Asako, T., 464 Ash, L., 226 Astakhova, A. S., 17 Atal, C. K., 213 Atherton, L., 277 Atkin, S. D., 272 Audley, B. G., 300 Aul’chenko, I. S., 44 Auret, B. J., 404 Aversa, M. C., 123 Avery, M. D., 283 Avotins, F., 62 Axelrod, L. R., 283 Ayer, W. A., 23, 170 Ayyar, K. S., 241 Azizullah, 46 Azzaro, M., 3, 40 Bachelor, F. W., 57, 61 Baddiley, J., 295 Badger, R. A., 103 Bae, M., 460, 511, 513 Baggaley, K. H., 272 Bagli, J. F.. 498 Baisted, D. J., 259, 261 Bakhanova, E. N., 17 Bakkei, J., 422 Bakker, S. A., 386 Balanson, R. D., 94 Balasubramaniam, S., 283 Balavione, G., 455 Baldwin, D., 332 Baldwin, J. E., 65 Balko, T. W., 17 Ballio, A., 179, 180 Balmain, A., 147 Bancher, E., 232 Bang. L., 139 Bannon, C. D., 212
Author Index
5 86 Banthorpe. D. V., 8, 14, 19, 110, 112, 113, 254, 260, 261, 263, 298, 300,301, 302 Baranowska, E., 218 Barbier, M., 366, 373, 383 Barkhurst, R. C., 553 Barlow, S. A., 267, 268 Barnes, F. J., 227, 228, 290 Barnes, R. K., 363 Baron, D. N., 455, 457 Barr, R., 308 Barrett, T. M., 353 Barron, L. D., 4 Barrow, K. D., 166, 179, 27 1 Barry, G. T., 70 Barry, J., 35 Bart, J. C. J., 548 Bartell, L. S., 568 Bartels, A. P., 110 Barth, C. A., 251 Bartlett, L., 307 Bartley, J. P., 193, 358 Barton, D. H. R., 43, 47, 166, 179, 193, 210, 271, 344, 355, 356, 363,369,384,392,400 Barton, R. E., 313 Bartz, J. K., 294 Barua, A. B., 235 Barua, A. K., 213, 218 Bascoul, J., 187, 296 Baskevitch, Z., 150 Bassett, R. A., 293, 299 Basu, K., 2 18 Bateson, J. H., 162 Batey, I. L., 189 Batra, P. P., 290 Batta, A. K., 208 Battersby, A. R., 262 Bauer, B., 469 Bauer, S. H., 559, 562 Bauernfeind, J. C., 307 Raulieu, E.-E.: 456, 470, 488,489, 576 Baumann, P., 386 Rautista, M., 404 Baxendale, D., 263 Baxter, C., 263 Bean, N. E., 301 Bearder, J. R., 269 Beastall, G. H., 258 Beaton, J. M., 363 Beaudoin, G. J., 384 Beck, H. C., 408, 413 Beckett, A. H., 49 Beckett, B. A., 132 Beckmann, H., 455,487
Beckwith, A. L. J., 384 Bedi, K. L., 213 Beecham, A. F., 226,313 Beedle, A. S., 253 Beg, Z. H., 252 Begley, M. J., 20 Behbud, A., 102 Beilby, J. P., 160, 269 Beiner, J. M., 53 BeliC, I., 293, 425, 441, 459, 515 Bell, A. M., 398, 403 Bell, J. J., 300 Bell, R. A., 167 Bellamy, A. J., 65 Bellas, T., 455 Bellet, P., 465 Bellino, A., 158 Bello, O., 234 Bena, B., 286,482 Ben-Aziz, A., 289, 299 Benedetti, E., 546 Benesova, V., 135 Benezra, C., 326 Benfield, E. F., 143 Benisek, W. F., 286, 489 Benjamin, B. D., 288 Benjamin, B. M., 47 Benn, M. H., 5,164,364 Bennet, R. D., 203 Benson, A. M., 299,487 Benveniste, P.. 258, 273, 278 Ben-Zvi, Z., 71, 72, 74 Berezin, G. H., 324 Berg, W., 263 Bergland, G., 151 Bergmann, E. D., 218 Berking, B., 536 Berkoff, C. E., 299 Bernal, J. D., 531 Berndt, H.-D., 405 Berndt, J., 253 Bernhard, R., 222 Berrier, C., 373 BerthCICmy, P., 472 Berthet, D., 9 Berti, G., 208 Bertrand, C., 36, 50 Bessiere-ChrCtien, Y., 56, 60, 61, 97 Bestmann, H. J., 233 Betz, G., 469 Beugelmans, R., 195 Beukers, R., 394 Beverwijk, C. D. M., 3 Beytia, E. D., 259 Beziat, Y., 457 Bezzubov, V. M., 56 Bhaca, V. S., 575 Bhacca, N. S., 204
Bhadane, N. R., 115,123, 133,266 Bhalla, V. K., 70 Bhatia, M. S., 13 Bhatt, R. S., 68 Bhattacharya, S., 207 Bhattacharyya, S. C., 101, 129,303 Biellmann, J. F., 154 Bigham, E., 342 Bikbulatova, G. Sh., 64 Billett, E. H., 51 Billing, B. H., 457 Billups, W. E., 23 Bimpson, T., 278 Birch, A. J., 31, 164, 297 Birnbaum, G. I., 329,537 Bisarya, S. C., 88 Bittler, D., 337 Bittner, M., 152, 196 Bjorkhem, I., 282, 285, 286,460,484,486 Blachkre, H., 479 Blackburne, I. D., 83,143 Blackwell, D. S. L., 52 Blair, I. A., 344 Blanchard, M., 44 Blank, R. H., 397,495 Blickenstaff, R. T., 326 Bliss, C. A., 24 Block, J. H., 214 Blossey, E. C., 342 Blount, J., 573 Blum, S., 4 Blunt, J. W., 418, 446 Boar, R. B., 183, 191, 192, 193, 199, 210, 273,332,341,369 Bobbitt, J. M., 301 Bochwic, B., 53, 58 Bodea, C., 306 Boeckx, R. L., 297 Bohme, K.-H., 483, 497, 505,506,507,508,523 Boettger, H., 221 Bogard, T. D., 47 BogdanoviC, B., 5 , 20 Boguslavsky, V. A., 342 Bohlmann, F., 12, 23, 127,149,150,157 Boiteau, P., 163 Bokkenheuser, V., 526 Boll, M., 253 Bollinger, P., 98 Bolt, C. C., 398 Bolton, M., 43 Bolton, R., 330 Bolton, S., 169 Bombardelli, E., 159 Bonnafous, J.-C., 222 Booth, W. D., 284
Author Index Boots, M. R., 253 Boots, S. G., 253 Borchere, G., 174 Bordner, J., 538, 539 Borgna, J.-L., 457 Boris, A., 354 Borkenhagen, L. F., 503 Bornati, A., 159 Borovskaya, A. G., 61 Bose, A. K., 3, 315 Boswell, G. A., 324 Bosworth, N., 23, 56 Boul, A. D., 446 Boulerice, M., 419 Bouquant, J., 313 Bourgeois, G., 29 Boutigue, M.-H., 350 Bowen, D. H., 159 Bowlus, S. B., 84 Bownds, D., 307 Boyd, G. S., 283 Boyd, R. H., 544, 580 Boyd, W. A., 56 Boyer, J., 455, 487 Boyle, P. H., 302 Bozler, G., 506 Bozzi, E. G., 33 Brambilla, R. J., 3 Branch, G. B., 207 Brandange, S., 5 Brandenburg, C. F., 61 Brandt, K., 286 Brandt, R. D., 273 Branlant, G., 154 Brannigan, L. H., 62 Brannon, D . R., 404, 427 Braselton, W. E., 286, 297 Braun, P. B., 532, 537, 538,539,552 Bravet, J.-L., 326 Breitmaier, E., 7 Breslow, R., 386 Bretschneider, H., 9 Brewer, H., 284 Bricker, L. A., 274 Bridgeman, J. E., 398, 446 Briedis, A. V., 252, 290 Brieger, G., 18 Brieskorn, C.H., 29 Briggs, D. E., 161, 269 Briggs, L. H., 193, 358 Brikenshtein, Kh. A., 17 Brine, D. R., 71 Britton, G., 228, 289, 290,299,306 Britton, R. W., 115, 206 Broaddus, C. D., 87 Brocard, J., 28
587 Brock, F. X., 172 Brocksom, T. J., 86 Brodie, H.. J., 284, 338, 398, 409, 469, 470, 474,475 Brooks, C. J. W., 4, 131, 312,393,468 Brown, C. A., 29 Brown, F. S., 496 Brown, H. C., 56, 348 Brown, J. N., 540 Brown, M. S., 252 Brown, P. K., 307 Brown, R. L., 401,460 Brown, S. A., 297, 298 Brown, W. E., 448, 451, 476 Brown, W. V., 164 Browne, J. W., 398, 403, 446,447 Browne, L. E., 12 Browne, L. M., 23 Brubacher, G. B., 307 Bruce, S. E., 320 Brufani, M., 179 Brundret, K. M., 166 Bryan, R. F., 116, 152, 541 Bryant, R., 303 Brzezinka, H., 307 Buchecker, C., 367 Buchecker, R., 38, 225, 226 Buckingham, A. D., 4 Bucourt, R., 532 BudCSiriskjr, M., 209,332, 352 Budzikiewicz, H., 307, 445 Buchi, G., 26, 31, 39, 136 Buki, K. G., 460,488 Buemi, G., 559 Bukeo, M., 261 Bukhar, M. I., 405, 470 Bull, J. R., 328, 377 Bu’Lock, J . D., 219, 288, 299 Bunton, C. A., 17, 254 Burbott, A. J., 256, 260, 261,263 Burden, R. S., 139, 307 Burger, B. V., 234 Burgess, D. V., 207 Burgstahler, A. W., 20, 553 Burlingame, A. L., 188 Burnett, R. D., 358 Burrow, D. F., 4 Burrows, E. P., 18, 313 Burstein, S., 300, 358
Busetta, B., 535, 536, 537,538,539,576 Bush, P. B., 273 Butcher, D. N., 293 Butler, G. B., 56 Butt, Y., 13, 244 Butterworth, J. H., 205 Buys, H. R., 546, 566, 570 Buzan, G. A., 298 Byrd, B. G., 393 Caccia, G., 339 Cafieri, F., 173 Caglioti, L., 368, 369 Cagnoli-Bellavita, N., 150 Cahn, R. S., 139, 575 Caine, D., 139 Cainelli, G., 237 Calas, B., 35 Calas, M., 35 Calimbras, T., 274 Caln, V., 357 Cama, H. R., 222, 231, 235 Cambie, R. C., 145, 152, 155,305,330 Cameron, A. F., 570 Cameron, E. H. D., 284, 300 Campion, T. H., 322 Campsteyn, H., 537, 538, 577 Candeloro de Sanctis, S., 535 Cane, D. E., 97 Cannon, J . W., 281 Canonica, L., 176, 179, 279,291,295,305,526 b p e k , A., 394,405,500 Caple, R., 45 Caputo, R., 145, 200 Cardemil, E., 296 Cardillo, B., 75 Cardillo, G., 237 Cardon, P. V., 71 Carini, S., 484 Caristi, C., 123 Carlisle, C. H., 210, 531, 539 Carlon, F. E., 425 Carlson, J. A., 26 Carlson, J. P., 274 Carlson, R. C., 63 Carlson, R. M, 353 Carlstrom, K., 515, 516, 5 19 Carman, R. M., 31, 33, 146 Carpio, H., 345
Author Index
588 Carstensen, H., 457 Cary, L. W., 214 Casas-Campillo, C., 404, 520 Case, J., 481 Casinovi, C. G., 179, 180 Caspi, E., 276, 282, 285, 348,396,433 Castagnoli, N., jun., 74 Castelli, P. P., 339 Castro, E. A., 225 Catalano, S., 376 Catroux, G., 479 Catsoulacos, P., 156, 382 Cave, A., 377 Cavill, G. W. K., 301 Cazaux, M., 58 Ceccherelli, P., 150 Cerfontain, H., 245 cerny, V., 320, 347, 352 Cerrini, S., 179 Chaabouni, R., 50 Chabudzinski, Z., 4, 31, 41 Chachaty, C., 314 Chadha, N. K., 26 Chaigneau, M., 70 Chain, E. B., 166, 179, 271,293 Chaineaux, J., 14 Chakkaborti, P. C., 168 Chakrabarti, P., 218 Chakravarti, K. K., 101, 129 Chambers, R. J., 388 Chambers,'V. E. M., 447 Chan, N. G., 466 Chan, W. R., 203 Chan, W.-S., 190 Chander, J., 15 Chandra, P., 456,469 Chaney, M. O., 538 Chang, C.-F., 9 Chang, F. N.. 446, 520 Chang, G. C., 200 Chang, P. K., 487 Chang, S., 544 Chansang, H., 291 Charles, G., 193, 367 Charlwood, B. V., 19, 112,113,261,300,302 Charney, W., 394,5 11 Chaudhuri, R. K., 200 Chavis, C., 457 Chayet, L., 82, 256 Chen, J. W., 449,476 Chen, Y.-C., 423 Cheriyan, U. O., 57, 61 Chernyavskava, M. A., 286
Cherry, P. C., 398, 400, 446 Chetty, G. L., 181 Cheung, H. T., 191,213 Chiang, C., 200 Chiang, J. F., 562 Chiaroni, A., 535 Chichester, C. O., 221, 228,290 Chidester, C. G., 396, 538 Chigaleichik, A. G., 479 Chihara, C., 460 Chin, C.-C., 393 Chin, K., 231 Chin, W. J., 219 Chlebicki, J., 6 Choay, P., 383 Chogovadze, Sh. K., 9 Christensen, A. T., 540, 54 1 Christensen, H. D., 71 Christensen, P., 5 Christensen, R. L., 225 Chu, J. W., 286 Chuang, V. T., 391 Chuche, J., 313 Chugh, 0. P., 13 Chung, S. K., 186 Chwastek, H., 346 Cimino, G., 142, 173, 248,295 Cizinska, A., 453 Clandinin, D. R., 222 Clapp, L. B., 33 Claquin, M. J., 488 Clardy, J., 12, 214 Clark, A., 455 Clark, I. M., 363, 398, 418,449 Clarke, D. G., 75 Clarke, R. L., 450 Clegg, A. S., 399, 446 Cleve, G., 428 Clifford, K., 255 Clinkenbeard, K. D., 252 Coates, R. M., 186, 258 Cocker, W., 301 Cocucci, M. C., 484 Cody, V., 537,540 Coggins, C. W., 290 Coggon, P., 540 Cohen, A., 42 Cohen, C. F., 275,484 Collins, C. J., 47, 49 Collman, .I. P., 316 Colunga, F., 180 Colvin, M., 487 Combe, M. G., 398 Comberton, G., 537 Compernolle, F. C., 286
Conia, J.-M., 28, 361 Conlay, C., 179 Connolly, J. D., 92, 123, 147, 158, 160, 201, 204,220,300,305 Constantine, G. H., jun., 214 Contento, M., 237 Cook, I. F., 282 Cook, R. J., 4 Cookson, R. C., 241 Coolbaugh, R. C., 267, 268 Coombe, R. G., 503,504 Cooper, A., 535, 536, 537, 538, 539, 540, 575,576 Cooper, D. Y., 287 Cooper, M. A., 42 Coppola, J. C., 537,575 Corbett, K., 293 Corbett, R. E., 217, 219 Corelli, C., 523 Corey, E. J., 94, 97, 98, 103, 119, 120,353 Corey, R. B., 576 Cori, O., 82, 254, 256, 296 Cornforth, J. W., 69, 77, 222,255,298,299,300 Corrie, J. E. T., 164 Coscia, C. J., 24,263,264 Costes, C., 233 Cotton, W. D., 46 Coulter, A. W., 504 Courseille, C., 535, 536, 537: 538, 539, 576 Court, W. A., 152 Covey, D. F., 49 Cowley, P. S., 273 Cox, M. R., 36, 116 Cox, P. H., 515 Cox, P. J., 117 Cox, R. E., 188,271 Coxon, J. M.. 61 Crabbe, P., 3 18,345,366, 382,520,552 Craig,'W. J:, 146 Crane, F. L., 300, 308 Crastes de Paulet, A., 187, 296,456 Crawford, R. J., 29, 87 Crilly, W., 65 Crombie, L., 20, 75, 228, 258 Cross, B. E., 162, 163, 300,304 Cross, J . H., 23 Croteau, R., 112, 256, 259,260,261,264 Crout, D. H. G., 77
Author Index Crowe, D. F., 354 Crowell, J. D., 119 Crowfoot, D., 531 Crown, J., 302 Crowther, J. S., 493 Crozier, A., 161 Csernay, L., 297 Culvenor, C. C. J., 154 Cumming, S. D., 217 Cunningham, A., 147 Cupas, C. A., 53 Curry, S. H., 302 Curtis, A. J., 110 Curtis, P. J., 466 Cushman, M., 74 Cuvigny, T., 6 Cynkowski, T., 338 Czerniawski, E., 421 Czygan, P., 287 Dagonneau, M., 52 Dailey, R. G., 152 Dakshinamurti, K., 297 d’albuquerque, I. L., 217 d’Alcontres, G. S., 123 Dallinga, G., 559 Dalzell, H. C., 73 Dalziel, W., 166 Dames, M. E., 70 Damiano, J., 40 Darnmeier, B., 538 Damodaran, N. P., 29 Damps, K., 199, 273 Dana, S. E., 252 Dane, E., 531 Danheiser, R. L., 126 Daniel, A., 49 Daniel, D. S., 103, 120, 265 Danielli, B., 159 Daniels, P. J. L., 391 Danieison, T. J., 24 Danielsson, H., 253, 286, 527 Danishefsky, S., 304 Danishefsky, S. E., 304 Dann. M., 397 Darias, J., 96, 147 Dastur, K. P., 31 Dauben, W. G., 188,312, 324,386,387,536 Daum, S. J., 450 Dauphin, G., 5 David, C. W., 44 Davidson, S. J., 472, 473 Davies, B. H., 299, 306 Davies, V. H., 116 Davies, H. Ff. S., 8 Davies, K. H., 71 Davis, J. B., 306 Davydova, L. P., 243
589 Dean, P. D. G., 187, 287 Debaerdemaeker, T. D. J., 540 de Boer, Th. J., 57 de Botton, M., 8 de Broissia, H., 89 Decker, K. F. A., 251 Declercq, J. P., 537, 538 de Flines, J., 394, 398, 401, 408, 413, 417, 441,442,446,452,5 11 Deghenghi, R., 419,521 Degny, E., 44 de Graaf, R. A. G., 535, 568,570 de Groote, R., 133 Dehennin, L., 359 De Iglesias, D. I. A., 53 De Jarnette, F., 540 de Jong, J. G. H. 539 de Kok, A. J., 539, 561 de la Mare, P. B. D., 330, 361 De Leo, P., 179 Delettre, M. J., 538 Delle Monache, F., 2 17 de L. Meyers, C., 501 Delpech, B., 334 De Luca, H. F., 287, 383 De Luca, L., 234 Delwiche, C. V., 299 de Mayo, P., 52 Dembitskii, A. D., 9 de Mello, J. F., 2 17 Demole, E., 9, 44 Dempsey, M. E., 274,283 Demuth, M., 74 de Nijs, H., 377 Denning, R. G., 48 Denny, R. W., 391 Denny, W. A., 363, 398, 403,447,449 Denot, E., 520 De Pascual, T. J., 63 De Pauw, G., 286 de Reinach-Hirtzbach, F., 196 De Roos, J. B., 120 De Rosa, M., 219, 288 Deshmane, S. S. 372 Deshpande, P. D., 170 Desiderio, D. M., 327 De Sombre, E. R., 576 De Stefano, S., 142, 173, 248,295 Detre, G., 329 Dev, C., 314 Dev, S., 6, 29, 70, 88, 89, 164, 181,194 Devon, T. K., 301, 303, 304,305
Dhindsa, A. S., 13 Diamlarneh, G. H., 248 Diassi, P. A., 439 Diaz, E., 133 Diaz-Parra, M. A., 139 Dickson, L. G., 275 Dideberg, O., 537, 538, 577 Diem, M., 4 Dietschy, J. M., 252 Di Giorgio, J. B., 391 Dik-Edixhoven, C. J., 539 Dimmel, D. R., 47 Dini, M., 274 Di Pietro, D. L., 3 13 Djerassi, C., 36, 193,330 340, 349 Dmochowska, J., 461 462 Dodds, E. C., 576 Dodson, R. M., 446 Doellgast, G. J., 442 Doherty, C. F., 20 Donohue, J., 535 Doodewaard, J., 51 1 Dorfman, R. I., 394, 469 Dorn, F., 107 Dorokhov, V. G., 17 Doskotch, R. W., 115 Downing, M., 24, 253, 263 Doyle, P. J., 282 Draber, W., 222 Drabkina, A. A., 26, 303 Drakenberg, T., 113 Drasar, B. S., 492, 493, 526 Drews, J., 455, 456 Dreyer, D. L., 305 Drozdz, D., 115 Duax, W. L., 311, 534, 537, 540, 548, 549, 552,569,575 Duch, M. W., 223 Ducharnp, D. J., 396,538 Durr, F. H., 407 Duerst, R. W., 539 Dugan, R. E., 252, 253, 258 Dumas, P., 6 Duncan, J. M., 277 Dunitz, J. D., 531 Dunphy, P. J., 256 Dunstan, P. J., 207 Duphorn, I., 172 Dupont, L., 537,‘538,577 Duprey, R. J. H., 14 Durham, N. N., 427 Durley, R. C., 161, 269 Durst, F., 273 Dutky, S. R., 275
590 Dutla, N. L., 207 Dutta, S. P., 213 Dvonch, W., 459 D'yakonova. R. R., 64 Dzhaiani, G., 260 Dzhemilev, U. M., 57, 328,332 Dziewanowska, K., 2 18 Eade, R. A., 207, 212 Eber, J., 101 Ebersole, R. C., 285 Ebrey, T. E., 226 Eck, C. R., 100 Ecklund, P. R., 267 Edery, H., 71, 72 Edmond, J., 19, 187,227, 228, 258 Edward, J. T., 3 5 3 . Edwards, B. E., 474 Efimochkina, E . F., 460, 497,498 Eger, C., 548, 552 Eger, C. H., 357 Eglinton. G., 188, 306 Egorova, V. V., 3 12 Eguchi, S., 8 Eigendorf, G., 190 Einarssonn, K., 286 Einhorn, J., 366 Eisenbraun, E . J., 36 Eisma, S. W., 560 Eisner, T., 84 Ekundayo, O., 344 Elahi, M., 290 El-Feraly, F. S., 115 El Gaied, M. M., 60 El-Gorab, M . , 223 Elin, E. A., 448,467,468 El-Kady, I. A., 405, 419, 448,449 Ellestad, G. A., 150, 157, 270 Elliott, M., 22 Ellis, J., 207 El-Olemy, M. M., 284, 470 El-Refai, A.-M. H., 286, 404,405,419,448,449 Els, H., 41 1, 446 El-Tayeb, 0. M., 466 Emerman, S. L., 454 Emmert, D. E., 538 Eng, S., 365 Engel, Ch. R., 384 Engel, L. L., 286, 297, 456,489 Englert, G., 223, 306, 307,411 Ensley, H. E., 333 Entwistle, N., 192, 3 18
Author Index Enwall, E . L., 539 Enzell, C. R., 9,238,302, 307 Epps, R., 442 Epstein, W. W., 19, 226, 227,263,302 Epsztein, R., 346 Erickson, R. C., 476 Eriksson, H., 485, 486, 528 Erlanger, B. F., 179 Erm, A., 10 Erman, W. F., 87, 97 Ernst, R., 392 Eschinasi, E . H., 110 Esders, T. W., 493 Eugster, C. H., 38, 152, 225,226 Eustace, E. J., 25, 55 Evans, B. B., 153 Evans, D. A., 16, 298 Evans, F. J., 273 Evans, J. M., 398, 417, 418,446,447 Evans, R., 90, 256, 267, 268 Evans, R. H., 397,495 Everling, B. W., 44 Evrard, M., 44 Eyssen, H. J., 286 Faass, U., 23 Faber, D. H., 533 Fahrenholtz, K. E., 573 Faini, F., 82, 254 FajkoS, J., 319, 324, 332, 336, 337, 350, 365, 371,401,418 Falardeau, P., 421, 448 Falcone, M. S., 95 Falcoz-Kelly, F.. 488 Fall, R. R., 267 Fallis, A. G., 61 Fankuchen, I., 531 Faraone, A., 573 Fare, L. R., 401 Farnham, A. W., 22 Fattorusso, E., 173, 182 Faulkner, D. J., 12, 86, 173 Fauve, A., 356 Favini, G., 559 Favre-Bonvin, J., 301 Fawcett, J. K., 536 Fayez, M . B. E., 420 Fayos, J., 12, 214 Fazli, F. R. Y., 273 Fedeli, W., 179 Federbush, C., 51 1 Feigenbaum, A., 389 Feiner, S., 328
Feldman, L. I., 397 Feller, H., 469 Fenemore, P. G., 152 Fenical, W., 96, 146, 166, 270 Fenton, T. W., 222 Fentrill, R. J., 9 3 Feofilova, E. P., 299 Ferguson, G., 201, 536, 570 Fermin, C. M., 157 Ferrari, A., 484, 526 Fetizon, M., 328, 369 Fiecchi, A., 176, 179, 276,305 Fieser, L. F., 379 Fieser, M., 379 Findlay, J. W. A., 347 Findley, D. A. R., 20, 228,258 Finkelhor, R. S., 8 8 Fisch, M. H., 392 Fish, R. E . M. H., 277 Fisher, J., 535 Fisher, N., 5 3 Fisher, R. D., 47 Fleischer, E. B., 481 Fleming, I., 51 Flick, B. H., 277, 392 Flood, T. C., 329 Floss, H. G., 293, 297 Foell, T., 398, 463, 494 Fonina, N. A., 497 Fonken, G. S., 394 Fonquernie, M., 461 Font Cistero, J. M., 36 Foo, L. Y., 207 Fordham, W. D., 14, 110 Formes-Marquina, J. M., 536 Forrester, J. M., 9 0 Fort, R. C., 338 Fosset, M., 456 Foster, E. L., 326 Fournier, J.-C., 479 Fracheboud, M., 1 31 Fraga, B. M., 147, 158 Framon-dino, M., 180 Francis, G. W., 223, 307 Francis, M. J. O., 19, 112, 254,264,300,302 Franck-Neumann, M., 367 Frank, S. G., 393 Frankowski, A., 366 Frantz, I. D., 300 Frappier, F., 376 Freeman, C. W., 275 Frey, M. J., 407 Freyberg, M., 277 Fridrichsons, J., 539
Author Index Fried, J., 481, 501 Fried, J. H., 345 Friedell, G. H., 282 Friedrich-Fiechtli, J., 154 Frohlich, H. H., 29 Frohlich, A., 124 Frost, R. G., 268 Frost, S., 526 Fry, J. L., 4 Frye, N. L., 327 Fu, W., 47 Fiirst, A., 41 1, 446 Fujikura, T., 149 Fujimori, K., 47 Fujimoto, T. T., 16 Fujino, A., 386 Fujino, M., 10 Fujita, E., 159, 160, 167, 269,304 Fujita, K., 18 Fujita, S., 9 Fujita, T., 8, 10, 11, 115, 116,160,167,269 Fujita, Y., 9 Fujiwara, T., 504, 505, 508 Fukuda, T., 10 Fukui, K., 155 Fukushima, D. K., 397 Fukushima, K., 171 Fulke, J. W. B., 201 hllerton, T. J., 155 Furfine, C. S., 466 Furst, G. T., 55 Furth, B., 45 Fuhkawa, H., 116 133 , Furuta, T., 26 Furuya, T., 200,284,483 GaB1, I., 363 Gabelta, R., 299 Gabetta, B., 159 Gabinskaya, K. N., 425 Gadsby, B., 444 Gaede, K., 234 Gagnon, R. E., 287 Gain, R. E., 433 Galantay, E., 540 Galpnter, 1. M., 71 Galasko, G., 307 Galbraith, M. N., 239, 2 84 Gall, R. E., 320 Gallay, J., 286 Gallegos, E. J., 393 Galli, G., 276 Galli Kienle, M., 176, 179,396 Gambacorta, A., 219,288 Gandhi, R. P., 390 Ganem, B., 126
59 1 Ganguly, S. N., 161 Ganguly, T., 161 Gaoni, Y., 41, 42 Garabedian, D., 383 Garbers, C. F., 234 Garcia-Peregrin, E., 253 Gardi, R., 327, 339, 345 Gardner, D., 92 Gardner, J. N., 425 Garey, K. L., 274 Garland, R. P., 61 Garmston, M., 240, 266 Garrett, R. D., 426, 479, 522 Garsky, V., 60 Garst, M. E., 68, 84 Gary, W., 35 Gasa, S., 164 Gaskin, P., 142, 161, 240 Gasparrini, F., 368 Gatford, C., 8 Gattuso, M., 123 Gaudry, R., 498 Gaurnert, R., 253 Gavrilova, T. F., 44 Gay, R., 286,482,508 Gaylor, J. L., 297, 299, 300,525 Gefter, M. L., 294 Geiger, R., 10 Geise, H. J., 531, 532, 538, 546, 547, 560, 565,568,570 Geissman, T. A., 77, 116, 123,133,266, 303 Geith, H., 449 Gelbke, H. P., 343 Gensler, W. J., 66 Geoffre, S., 539 George-Nascimento, C., 82,256 Georghiou, P. E., 338, 360 Geraghty, M. B., 103,129 Gerhards, E., 469 Geribaldi, S., 40 Gerlach, H., 4 Germain, G., 532, 537, 538 Germain, P., 286, 482 Gero-Robert, M., 154 Gesson, J. P., 381 Geuns, J. M. C., 273 Geynet, P.,286 Ghatak, U. R., 168 Ghazarian, J. C., 287 Ghera, E., 425 Ghirlanda, C., 70 Ghisalberti, E. L., 160, 165,207,269,288 Gholson, R. K., 297
Ghosal, S., 200 Ghosh, M. C., 235 Ghraf, R., 286 Giannini, D. D., 311, 548 Gibaja, S., 303 Gibb, W., 285, 468 Gibbons, G. F., 276, 283 Gibbs, J. A., 203 Gibian, H., 449, 464 Gibson, D. M., 252 Gibson, D. T., 503 Gibson, F., 294, 299 Gibson, T. W., 47,97 Giessner-Prettre, C., 223 Giglio, E., 535 Gijzeman, 0. L. J., 225 Gilbert, J. D., 4, 312 Gilbert, M. T., 4 Gill, D., 225 Gillen, D. G., 35 Gilmore, C. J., 152 Gingras, G., 231 Giral, L., 35 Girard, C., 361 Girotra, N. N., 94 Giry, L., 70 Gitany, R., 135, 266 Giumanini, A. G., 50 Gladiali, S., 345 Glasenapp, A., 286 Gleason, R. M., 290 Glen, A. T., 92 Gloor, U., 308 Glotter, E., 305, 323 Gnoj, O., 457 Goad, L. J., 277, 278, 279,280,285,299,306 Gochnauer, M. B., 290 Goddard, P., 473, 498 Godtfredsen, W. O., 285 Godunova, L. F., 32 Gorlich, B., 407 Goldberg, L., 576 Goldfarb, S., 252 Goldman, A. S., 286,456 Goldrnan, J. M., 136 Goldman, R., 296 Golfier, M., 328, 369 Goll, P. H., 394 Gollnick, K., 6 Gomez, F., 180 Goncalves de Lima, O., 217 Gonzalez, A. G., 96, 147, 158 Goodfellow, R., 285 Goodfellow, R. G., 186, 258 Goodman, J. J., 494
A uthot Index
592 Goodwin, T. W., 228, 258, 277, 278. 279. 280, 282,' 284, 289, 290,298,299,306,307 Goosen, A., 384 Gopalakrishna, E. M., 537 Gora, J., 16 Gorbach, S., 493 Gordon, K. D., 286, 328, 489 Gordon, M., 127, 493 Gorovits, M. B., 408 Goryaev, M. I., 9 Gosztonyi, T., 7 3 Gotovtseva, V. A., 479 Gough, L. J., 147 Gougoutas, J. Z., 538 Gould, R. G., 252 Goutarel, R., 376, 385 Govindachari, T. R., 197, 217 Gower, D. B., 284 Grabowich, P., 501 Grabowski, G. A., 283 Graebe, J. E., 267 Grande Benito, M., 6 3 Grandi, R., 119 Grandolini, G., 180 Granger, P., 223 Granger, R., 8 Grant, D. M., 223 Grant, P. K., 146 Grasselli, P., 237 Grassmayr, K., 9 Gravel, D., 353 Graves, J. M. H., 455,470 Gravestock, M. B., 167 Gray, J. C., 253, 254 Green, A. E., 124 Green, C. L., 298 Green, G. H., 207 Green, J., 272 Green, M. J., 481 Green, T. R., 259 Greene, R. L., 539 Greenspan, G., 398, 424, 444,459,463 Gregonis, D. E., 226 Greim, H., 287 Greiner, M., 357 Grenz, M., 149 Grieco, P. A., 8 8 Grieder, A., 131 Grierson, D. S., 194 Griffith, G . R., 24, 263 Griffiths, E., 300 Grimshaw, J., 46, 6 0 Grimwade, A. M., 283 Grinenko, G. S., 425 Grison, C . , 56, 61, 97
Groh, H., 399, 404, 492, 497,521 Gros, E. G., 410 Gross, D., 221, 243, 263, 298 Grossert, J. S., 306 Groth, P., 572 Grove, M. J., 492 Grunfeld, Y., 71, 72 Grunwald, C., 273 Grutzner, J. B., 223, 297 Gsell, L., 399, 410 Guarnaccia, R., 24, 263, 264 Gubkina, N. I., 61 Gueldner, R. C., 8 Guenther, H. F., 293 Guerrero, H. C., 221 Guest, I. G., 93, 375 Guida, A., 325 Guilhem, J., 540 Guillaumon, J.-C., 5 0 Gulaya, V. E., 465 Gullo, V. P., 2 17 Gumulka, M., 338 Gunasekera, S. P., 214, 215 Gunn, P. A., 201 Gunville, R., 283 Gupta, A. S., 181 Gupta, R. N., 297 Gurny, O., 71 Gusakova, E. G., 479 Gustafsson, B., 73 Gustafsson, B. E., 526, 527 Gustafsson, J.-A., 282, 285, 286, 458, 460, 484,485,486,528 Gut, M., 300, 474 Guthrie, J. P., 367 Guthrie, R. W., 354 Guyer, K. E., 253 Guzman, A., 318 Habermehl, G., 383 Hach, V., 7, 42, 317 Hachey, D. L., 17 Hackenschmidt, J., 25 1 Hackett, P., 347 Hackler, R. E., 17 Hafez-Zedan, H., 450, 466,476 Hagef, L. P., 496 Hainaut, D., 532 Hall, J. B., 6 1 Haller, F., 222 Haller, R., 5 Halsall, T. G., 200
Hamanaka, N., 164 Hamasaki, T., 230 Hamilton, M. A., 283 Hamilton, P. B., 503 Hamilton, W. D., 8 3 Hammer, C. F., 466 Hanayama, N., 96 Hank, O., 394, 405, 453, 5 00 Haner, B., 536 Hanna, R., 316 Hannan, B. N. B., 361 Hannaway, C., 570 Hanni, R., 205 Hanover, J. W., 9 Hansbury, E., 274 Hansen, H.-J., 344 Hanson, F. R., 449 Hanson, J. R., 77, 90,92, 113, 145, 162, 256, 267, 268, 296, 298, 300, 303, 304, 305, 332,377,536 Hanson, R. F., 283 Hanson, S. W., 51 Happ, G . M., 9 Harada, N., 139,142,226 Harano, K., 322 Hardgrove, G. L., 539 Harding, A. E., 92, 160 Harding, B. W., 286, 300 Harding, K. E., 266, 298' Hardman, R., 273 Hargie, M. P., 447 Harita, K., 381 Harkness, A. L., 223 Harper, P., 207 Harrison, H. R., 535 Harrison, I. T., 180 Harrison, S., 180 Harry, D. S., 274 Hartman, R. E., 495 Hartmann, M. A., 273 Hartshorn, M. P., 6 1 , 3 1 1 Harvey, D. J., 315, 326 Hasegawa, S., 203 Hashiba, H., 511, 513 Hashimoto, S., 504, 508 Haslewood, G . A. D., 515 Hassel, O., 572 Hassner, A., 382 Hasunuma, M., 410,434 Hata, G., 11 Hatanaka, H., 259 Hatem, J., 59 Hattori, T., 526 Haupt, O., 343 Hauptman, H., 535, 537, 540,569 Hausen, B. M., 69, 295 Hauser, F., 73
Author Index Haussler, M. R., 287 Havinga, E., 386, 547, 558, 562, 566 Hawes, E. M., 24 Hawker, J., 162,268,296 Hawkes, G. E., 3, 313 Hawkins, D. W., 193,369 Hawks, R. L., 73 Hawksworth, G., 493 Hay, C . E., 338,398,409 Hayakawa, S., 504, 505, 508, 526 Hayakawa, T., 5 Hayakawa, Y., 107 Hayano, M., 469,470 Hayashi, A., 22 Hayashi, J., 388 Hayashi, M., 133 Hayashi, S., 56 Hayashi, Y., 265 Hayward, L. D., 313 Hayward, R. C., 155, 330 Heathcock, C. H., 77, 103, 303 Hedin, P. A., 8 Hedman, K., 73 Hefendehl, F. W., 9, 35, 262 Heftmann, E., 293 Hegnauer, R., 301 Heidel, P., 282 Heidenpriem, H., 464 Heimberger, S. I., 297 Heinrich, G., 250 Heinrichs, W. L., 284 Heintz, E., 278 Heintz, R., 258, 274 Heller, J., 226 Heller, R. A., 252 Helting, T., 234 Hemesley, P., 20 Hemingway, J. C., 115 Hemingway, R. J., 115 Heniming, F. W., 294, 308 HCmo, J. H., 367 Henc, B., 5 Henderson, M. S., 148, 20 1 Henderson, R., 204 Hendrickson, J. B., 77 Heng, C. K., 219 Hengartner, U., 188 Hentchoya, J., 193 Herber, R., 223, 290 Hermann, I., 486 Hernandez, M. G., 147, 158 Herout, V., 102, 115, 133,135 Herz, J. E., 329
593 Herz, W., 115, 116, 117, 135,136,208,266,303 Herzog, H. L., 318, 394, 457, 511 Hesp, B., 166 Hesper, B., 532, 538 Hesse, R. H., 355, 356 Hessler, E. J., 483 Heyde, M. E., 225 Hickey, M. J., 544 Higashi, Y . , 295, 296 Higgins, M. J. P., 251 Higk, D. F., 532 Higo, A., 22 kiigson, H. G., 42 Hikino, H., 163 Hikino, Y., 163 Kill, F., 408, 491 Hill, F. L., 342 Hill, J., 389 Hill, M. J., 461,473,492, 493,498,526 Hillman, J. R., 266 Hills, F. J., 476 Hiltunen, R., 12, 264 Hino, K., 2 13 Hiraga, K., 464 Hirai, H., 22 Hirai, K., 176 Hiraka, Y., 165 Hirakata, A., 3 Hirao, N., 6 Hirata, T., 60, 63 Hirata, Y., 93, 107, 125, 188,292 Hirayama, K., 41 1 Hirose, Y., 88, 95, 122 Hirotani, M., 284, 483 Hirsch, J. A., 580 Hirschfeld, D. R., 166, 270 Hirschmann, F. B., 371 Hirschmann, H., 37 1, 372,533 Hirsjarvi, P., 44 Hobbs, P. D., 23 Hobe, G., 483 Hochstetler, A. R., 97 Hodgkin, D. C., 531,535, 536 Hodgkinson, A. J., 377 Hodgson, G. L., 87, 99 Hofle, G., 7 Hoehne. E., 535 Horhold, C., 399, 404, 415, 445, 453, 460, 483, 490, 497, 505, 506,507,508,521,523 Hoffman, E., 469 Hoffman, W. A., 315 Hoffmann, R., 386
Hoffmann, W., 11,28 Hofmann, A. F., 526 Hofmeister, H., 355 Hogg, J. W., 102 Hohenlohe-Oehringen, K., 9 Holden, C. M., 42 Holden, K. G., 401 Holick, M. F., 383 Holland, H. L., 404 Hollaway, P. W., 298 Hollister, L. E., 71 Holmberg, I., 286 Holmlund, C. E., 397, 495 Holtom, A. M., 90, 256 Holton, R. A., 183 Holub, M., 115, 123, 133 Honig, B., 226 Honwad, V. K., 37 Hood, L. V. S., 70 Hoogenboom, F. J. M., 570 Hooper, S. N., 271 Hope, H., 540 Hopla. R. E., 183 Hoppe, W., 532, 538 Horan, H., 186 Horan, M., 288 Horibe, I., 115 Horie, M., 491 Horie, Y., 282 Horn, D. H. S., 230, 284 Hornstra, J., 532, 537, 538,539,552 Horster, H., 262 Hortmann, A. G., 103, 120,265 Horwitz, J., 226 Hosada, H., 474,475 Hoshita, T., 526 Hospital, M., 535, 536, 537,538,539,576 House, H. O., 168 Hovorkova, N., 208 Hoyer, G.-A., 337, 351, 428 Hsia, S. L. 286 Hsiao, J. C. Y., 283 Hsu, A. C., 203 Hsu, W. J., 290 Huang, H.-C., 116 Huang, M., 423 Hubbard, R., 307 Huber, H., 169 Huber, R., 532 Hudec, J., 553 Huckel, W., 47 Huffman, J. W., 123,265 Hufford, C. D., 115
Author Index
5 94 Hughes, C. R., 9 3 Hugl, H., 334, 335 Hui, W.-H., 190 Hulcher, F. H., 252 Hunt, J. D., 342 Hunter, D. H., 49 Huntrakul, C., 146 Hursthouse, H. B., 36 Husson, H.-P., 163, 377 Hutchins, M. G., 318 Hutchins, R. O., 34, 318, 3 64 Hutterer, F., 287 Hutto, F. Y., 8 Hrycay, E., 286 Iaccarino, R., 145 Ibekawa, N., 282 Ibuka, T., 107 Ichino, T., 338 Ida, Y., 149 Iguchi, M., 119, 139 Iida, M., 459, 470 Iida, T., 144 Iitaka, Y., 176, 180, 182, 27 1 Iizuka, H., 394, 459 Ikada, I., 57 Ikai, K., 163 Ikawa, M., 222 Ikegawa, S., 475 Ikekawa, N., 197, 333, 381 Ikeshima, H., 340 Ila, L., 477 Imai, K., 199 Imai, S., 155 Imaizumi, K., 125 Imakura, Y., 218 Imanishi, M., 467 Imshchenetskii, A. A., 460,497,498 Inamura, K., 120 Inayama, S., 135, 266 Ingold, C. K., 139, 575 Ingwalson, P. F., 139 Innocenti, S., 352, 384 Inoue, S., 249 Inouye, H., 23, 24, 301 Inubushi, Y., 107 Iocco, D., 336 Ireland, R. E., 188 Iriate, J., 366 hie, T., 9 3 Irwin, M. A., 116, 123, 133,266, 303 Isaacs, N. W , 537, 575 Isaeva, Z. G., 63, 64 Ishibashi, K., 176 Ishidate. M., 408
Ishii, H., 314 Ishii, T., 200 Ishikawa, K., 124 Ishikawa, M., 336 Isidor, J. L., 353 Isler, O., 233, 306, 307, 308 Isobe, T., 160 Isoe, S., 242, 291 h e r , S. J., 108 Istomina, Z. I., 3 13 Itai, A., 176 Itaya, N., 22 Ito, A., 460 Ito, M., 474 Ivanova, L. S., 56, 61 Ivaseva, T. N., 66 Ivashkiv, E., 446, 482 Iwamnra, J., 6 Iwasaki, S., 370 Jackson, R. W., 394 Jackson, W. R., 37 Jacob, G., 82, 254 Jacobs, H. J. C., 552,562 Jacobsen, R. A., 532 Jacobson, H., 451 Jacobson, H. I., 456 Jacobus, J., 1 8 Jacquesy, J. C., 373, 381 Jacquesy, R., 350, 373, 381 Jaeger, G., 10 Jain, T. C., 118 Jaitly, K. D., 421 James, N. F., 22 James, P., 212 Jamison, V. W., 497 Janes, J. F., 14 Janoski, A. H., 442 Janot, M.-M., 4 4 8 , 4 6 1 Jarabak, R., 487 Jarreau, F. X., 376 Jarvis, J. A. J., 166 Jautelat, M., 223 Jaworski, A., 421 Jeanloz, R. W., 247 Jedlicki, E., 82, 254 Jedziniak, E. J., 385 Jefferies, P. R., 150, 160, 165,207,269,288 Jeffery, J., 284, 285, 468, Jefford, C. W., 4 5 Jeger, O., 387 Jenkins, E., 442 Jensen, E. V., 576 Jeremic, D., 102 Jerussi, R., 474 Jewers, K., 203 Jirku, H., 407 Joblin, K. N., 145
Johannes, B., 307 John, J., 222, 231, 235 Johns, S. R., 3 Johnson, A. L., 4 9 Johnson, C. K., 49,547 Johnson, R. A., 394 Johnson, R. C., 274 Johnson, W. S., 86, 107 Johnston, J. P., 156, 270 Jokic, A., 102 Joly, G., 373 Jommi, G., 298 Jones, A. J., 164 Jones, C. A., 260 Jones, E. R. H., 90, 363, 398, 399, 400, 403, 417,418,446,447,449 Jones, J. B., 286, 328, 370,472,488,489 Jones, J. G. Li., 384 Jones, N. D., 538 Jones, W. R., 381 Josephson, S., 5 Joshi, B. S., 214 Joska, J., 324, 332, 337, 350,401 Joulain, D., 58, 59 Joustra, A. H., 540 Jowett, W. F. A., 406 Joyce, C. R. B., 302 Joye, N. M., jun., 9 Julia, M., 15, 237 Julia, S . . 318, 330 Juneja, H. R.,6 0 Jung, I., 576 Junta, B., 412, 439 Jurd, L., 6 9 , 2 9 5 Just, G., 338, 360 Kaal, T., 10, 11 Kabuto, C., 127 Kagan, H., 455 Kagi, D. A., 241 Kahn, P., 226 Kahovcova, J., 10 Kalja, I., 10 Kalkman, M. L., 284 Kallner, A., 529 Kalsi, P. S., 102 Kamat, V. N., 214 Kamikawa, T., 160 Kaminaga, M., 349 Kamogawa, H., 234 Kan, G., 286,342 Kan, K. W., 283 Kanayama, K., 2 13 Kaneda, M., 182,271 Kaneko, C., 336 Kaneko, K., 411 Kanematsu, A., 190 Kanematsu, Y ., 505
Author Index Kaplan, N. O., 455 Kapoor, S. K., 110, 156 Kapteyn, H., 12 Kapur, J. C., 68 Karasiewicz, R., 338 Karim, A., 406 Karle, I. L., 532,535,541 Karle, J., 532, 535, 541 Karlsson, B., 93 Karlsson, K., 9, 238 Kartha, G., 536, 537,540 Kasal, A., 320, 398, 403, 417,446,447 Kasprzyk, Z., 218 Kasumov, L. I., 243 Katagiri, T., 1 0 , 1 1 , 13 Katayama, C., 149 Katayama, H., 160 Kates, M., 290 Katkov, T., 284 Kato, N., 149 Kato, T., 5 , 144 Katsui, N., 125, 142, 240 Katsuki, H., 259 Katsumi, M., 161 Katsumura, S., 242, 291 Katz, J. J., 223 Katzenellenbogen, J. A., 15,84 Kaufman, M., 353 Kaufmann, G., 445,490 Kaur, J., 68 Kawaguchi, A., 187, 271, 272 Kawaguchi, K., 284,483 Kawahara, M., 155 Kawamata, T., 135, 266 Kawamatsu, Y., 249 Kawasaki, T., 149 Kawashima, K., 233 Kawata, M., 386 Kayahara, H., 32 Kazakova, E. Kh., 64 Ke, B., 307 Keates, R. A. B., 131 Keeler, B. T., 538 Keely, S. L., jun., 115 Keene, €3. R. T., 354 Kekwick, R. G. O., 251, 253,254 Kellogg, T. F., 493 Kelly, R. B., 101, 132 Kelly, T. R., 112, 125 Kelly, W. G., 442 Kelsey, R. G., 115 Kempe, T., 53 Kennard, O., 312, 536, 537,575 Kennedy, R. M., 347 Kerb, U., 405,491 Kergomard, A., 5, 356
595 Kern, H.-J., 47 Khan, G., 393 Khan, H., 181 Khatoon, N., 223 Khattak, I., 372 Kheifits, L., 44 Khidekel', M. L., 17 Khuong-Huu, Q., 334, 366,367,383,385 Kido, F., 96, 103 Kienle, M. G., 276 Kie'nzle, F., 233,235, 342 Kierkegaard, P., 93 Kierstead, R. W., 71,354, 573 Kieslich, K., 394, 403, 405, 408, 413, 415, 425, 427, 428, 449, 452, 458, 464, 491, 493,530 Kiruchi, T., 107, 212, 215,216 Kilian, R. J., 44 Kim, I., 276,398 Kim, Y.-H., 379 Kimball, H. L., 358 Kimland, B., 238 Kimura. K., 286 Kimura, M., 332, 343, 379,381, 386 Kinawy, M. H. K., 404 King, H., 531 King, J. C., 362 King, J. F., 6 King, T. J., 144 Kirk, D. N., 311, 313, 358,372 Kirtany, J. K., 97 Kis, Z., 287 Kispert, L. D., 539 Kitagawa, H., 155 Kitagawa, I., 199, 213, 218 Kitahara, Y., 127, 144 Kitchens, G. C., 97 Kitigawa, I., 128 Kitihara, Y., 5 Kjersgaard, D., 5 KjBsen, H., 229, 233 Klabunovskii, E. I., 32 Klaui, H. M., 307 Kleigman, J. M., 363 Klein, E., 8 Kleinig, H., 22 1,23 1,290 Klemm, D., 315 Kleo, J.. 225 Klimontovich, N. N., 479 Klinot. J., 208, 218 Klinotovoa, E., 208 Kloti, R., 9 Klubnichkina, G. A., 479
Kluender, H. C.. 115 Kluepfel, D., 498, 523 Kluepfel. K., 394 Klyne, W., 307, 313 Knapp, F. F., 278, 280 Knight, S. A., 193, 314 Knights, B. A., 282, 393 Knobler, C., 539, 552 Knowles, G. D., 190, 194 Knuppen, R., 343 Kobayashi, A., 20, 22 Kobayashi, H., 187, 272 Kobayashi, M., 133, 363 Koch, H.-J., 403, 405, 449,464,493 Koch, H. P., 36 Koch, W., 413,425 Kocor, M., 194, 338 Koepsell, H. J., 476 Kogan, G. A., 313 Kogan, L. M., 394, 405, 444, 448, 460, 465, 467,468,490,521 Kogure, T., 7, 243 Kohler, B. E., 225 Kohler, D. F., 274 Kohli. J. C., 102 Kohout, L., 319, 336, 365,371 Kohoutova, J.. 127 Kojima, H.. 200 Kokke, W. C. M. C., 50 Kokkinas, C., 156 Kokor, M., 2 13 Kollman, P. A., 311, 548 Komori, T., 149 Komoto, R. G., 316 Kondo, E., 401,413,446, 460,513 Kondo, K., 86 Kong, Y. C., 284 Konstantinovii, S., 20 Kontonassios, D., 352 Konz, W. E., 183 Kooreman, H. J., 421 Koreeda, M., 139, 222, 226 Koriyama, S., 163 Korn, E. D., 499 Korovkina, A. S., 479 Korpi, J., 318 Korvola, J., 43 Koshcheenko, K. A., 491 Kosmol, H., 413, 425, 464,491 Koss, F. W., 286 Kossanyi, J., 45 Koster, D., 60 Kotake, M., 68 Kovacic, P., 47
Author Index
596 Koveshnikov, A. D., 408 Kovnazkaja, I. S., 313 Kovylkina, N. F., 468 Kowerski, R. C., 226 Koyama, T., 86, 257 Kozhin, S. A., 30, 34 Kozlava, V. Kh., 497 Kozuka, M., 116 Kozuka, S., 47 Krakower, G. W., 538 Krasnova, L. A., 466 Kratzer, O., 233 Kraut, J., 532 Kraychy, S., 510 Kreiser, W., 193, 355 Kremen, A., 293 Krinsky, N. I., 230, 307 Krishnamurthy, S., 348 Krishnamurti, M., 468 Krishnappa, S., 88 Kroeger, H. W., 20 Krojidlo, M., 127 Kroszczynski, W., 29 1 Krueger, S . M . , 65 Kruger, C., 329 Krugyel, W. C., 284 Krumer, M. Z., 39, 245 Ksandopula, G. B., 479, 49 1 Kuan Tee Go, 537 Kubina, L., 536 Kubo, I., 160 Kuboe, K., 70 Kubota, T., 160 Kucherov, V. F., 39, 245 Kucinski, P., 342 Kuczynski, H., 3 7 , 4 1 , 5 1 , 66 Kudryavtsev, I. B., 10 Kuehl, D. W., 4 5 Kuehne, M. E., 362 Kukharenko, N. V., 342 Kulesza, J., 16 Kulig, M. J., 342, 393 Kulikova, L. E., 458,460, 478 Kulshreshtha, D. K., 198, 206,305 Kulshreshtha, M. J., 305 Kumai, S., 18 Kumar, V., 417, 446 Kumazawa, S., 5 Kumazawa, Z., 132 Kumta, U. S., 290 Kunde, R., 37 Kunstmann, M. P., 150, 157,270 Kupchan, S. M., 115,116, 152, 195, 196, 206, 303,347,541 Kupletskaya, M. B,, 468
Kurbanov, M., 245 Kurek, A., 365, 371 Kurosawa, E., 93 Kurosawa, Y., 463, 493 Kushner, D. J., 290 Kushwaha, S. C., 290 Kusner, E. J., 479 Kutney, J. P., 190, 194 Laats, K.. 10, 11 Labriola, R., 199 Labruykre, F., 50 Lachman, H. H., 328 Lacko, A. G., 297 Ladd, M. F. C., 539 Laing, D. E., 262 Laing, M., 161 Laing, S. B., 360 Lakshmanan, M. R., 253, 29 1 Lal, B., 315 Lalancette, J.-M., 6 Lalande, R., 29, 58 Lamazoukre, A.-M., 52 Lambert, J. L., 49 Lan, N. T., 49 Land, E. J., 225 Lane. H. D., 252 Lang, A., 304 Langbein, G., 446 Lange, W., 497 Langenheim, J. H., 147 Langlet, J., 223 Langlois, R., 393 Larcheveque, M., 6 Larsen, B. R.,226 Larsson, P.-O., 450 Laskin, A. I., 501 Lassak, E. V., 35, 192, 341 Lauer, R. F., 14, 17, 332 Laurence, R. H., 292 Laurent, H., 351, 355, 455 Lavergne, J.-P., 4 2 Lavie, D., 151, 201, 305, 323 Law, A., 249 Lawrence, B. M., 102 Lawrence, K. H., 305 Lawrence, R. V., 9 Lawson, M. E., 283 Lawsan, W., 576 Leander, K., 7 3 Lebeau, M.-C., 576 Lebedeva, Zh. D., 460, 521 Leblanc, A., 42 Lecadet, D., 5 3 Lederer, E., 300 Lednicer, D., 538
Lee, B. K., 448,451 Lee, H., 575 Lee, H. J., 284 Lee, K.-H., 116, 133 Lee, R. A., 36, 354 Lee, S. S., 462, 500, 504, 507,520 Lee, T. H., 290 Leeming, M. R. G., 444 Leenhouts, J. I., 532,537, 538 Leete, E., 299, 300, 410 Lefebvre, G., 286, 482, 508 Le Goff, N., 346 Lehmann, H., 243 Leibfritz, D., 3, 313 Leinert, J., 286 Leistner, E., 297 Leitereg, T . J., 188 Leman, J. D., 472 LeMathieu, R. A., 573 LeMatre, J., 286, 426 Lemberger, L., 71 Lenox, R. S., 1 5 Lenskaya, G. S., 497 Lenton, J. R., 277, 280 Leonard, R., 212 Le Patourel, G. N. J., 254 Lepicard, G., 538 Le Quesne, P. W., 338 Leresche, J.-P., 17 Leroy, F., 537 Lestrovaya, N. N.,. 470, 491 Leuenberger, F. J., 228, 290 Levey, G. S., 274 Levine, S. D., 496 Levine, S. G., 538, 539, 540 Levinson, H. Z., 298 Levisalles, J., 89, 360 Levitz, M., 407, 454 Levy, E. C., 201 Levy, H. R., 456 Lew, F., 304 Lewbart, M. L., 325, 326 Lewis, D. A., 191, 192, 332,341 Lewis, N. F., 290 Lewis, R., 493 Li, T., 86 Liaaen-Jensen, S., 22 1, 229,233,299,306,307 Libit, L., 97 Lifson, S., 544 Light, R. J., 493 Ligon, R. C., 266 Lin, G. H. Y., 146, 166, 270
597
Author Index Lin, Y. Y., 403,407,448, 454 Lincoln, D. E., 262 Link, S., 126 Lipton, M. A., 71 Lisboa, B. P., 284 Liu, I. S., 228 Liu, K.-T., 3 Liu, R. S. H., 13, 244 Lloyd-Jones, J. G., 282, 284,285 Loder, J. W., 154 Loeber, D. E., 223 Loew, P., 86 Lowell, M., 253 Loftus, P., 42 Long, L., 404 Loomis, W. D., 112, 256, 259,260,261,263,264 Lopez, L., 357 Lopez, M. I., 362 Lopotko, N. V., 342 Loriaux, I., 163 Lorne, R., 330 Louda, J. W., 290 Louis, J.-M., 369 Louloudes, S. J., 484 Loutfy, R. O., 389 Lowe, G., 90 Lu, C. T., 538, 540 Lugtenburg, J., 386 Luhan, P. A., 116 Luis, J. G., 147;158 Lukacs, G., 314 Lusuardi, W. G., 74 Lutsenko, G. N., 290 Lyall, J., 300 Maalouf, G., 316 Maassen, J. A., 57 McAndrews, C., 36, 354 Macaulay, E. W.,536 McCarty, R. N., 48 McClelland, M., 230 McCloskey, J. A., 230 McCloskey, J. E., 118 MacConnell, J. G., 238, 298 McCormick, J. P., 186, 288 McCoy, K. E., 274 McCrindle, R., 148, 160, 201,204,304 McCune, R. W., 283 McCurdy, J. T., 426, 522 McCurry, P. M., 126 McDermott, J. C. B., 289, 299 MacDonald, C. G., 294
MacDonald, I. A., 286, 46 1 McDonough, G. R.,49 McEwen, R. S., 135,266 McFarland, J. W., 324 McGhie, J. F., 191, 192, 193,210,332,341,369 MacGillavry, C. H., 548 McGregor, W. C., 442 Macharia, B. W., 53 Machida, Y.,90 McIntyre, N., 274 Mack, J. P. G., 207 Mackay, I. R., 570 McKechnie, J. S., 536, 540 McKelvey, R. D., 387 McKenzie, G. P., 212 McKenzie, R. M., 297 McKillop, A., 342 McLaughlin, G. E., 161 McMaster, D., 148 MacMillan, J., 142, 159, 161, 240, 269, 287, 304,305 McMurry, J. E., 108 McMurry, T. B. H., 124 McNally, D., 544 McNamara, D. J., 252 McPhail, A. T., 116, 133, 540 MacSweedey, D. F., 87, 99 McWha, J. A., 266 Maddox, M. L., 382 Madjid, A. H., 222 Madyastha, K. M., 24, 263,264 Maeda, S., 127 Maekawa, E., 233 Malkonen, P. J., 43 Maestri, .M., 234 Maghane, D. T., 283 Magno, S., 182 Magnus, P. D., 23,43,47, 56,344,392 Magnusson, G., 39, 113 Mahajan, J. R., 154 Mahato, S. B., 207 Maheswari, M. L., 129 Mahler, W., 393 Mahony, D. E., 286,461 Maier, D. P., 69 Maier, V. P., 203 Maikowski, M., 351 Maillard, B., 58 Main, P., 532 Maiti, B. C., 207 Major, F.,253 Malhotra, H. C., 273 Malhotra, S. K., 488
Mallaby, R., 255 Mallams, A. K., 307 Malya, P. A. G., 281 Manchanda, A. H., 203 Manchard, P. S., 149 Mandel, L., 457 Mandel, N., 535 Mandelbaum, A., 208, 3 14 Mangoni, L., 145,200 Manhas, M. S., 315 Mani, J.-C., 222 Mann, J., 260 Manners, G., 69,295 Manuel, M. F., 293 Manville, J. F., 88 Manson, A. J., 454 Marathe, K. G., 43 Marchesini, A., 119 Margulis, T. N., 379 Marhenke, R. L., 55 Marik, M., 363 Marini-Bettolo, G. B., 217 Marino, M. L., 158, 159 Markova, E. V., 479 Markowicz, S., 53 Markwell, R. E., 163 Marples, B. A., 375, 384, 388 Marsh, R. E., 576 Marsh, W. C., 201 Marshall, D. J., 419, 499 Marsheck, W. J., 394, 406,510 Marsili, A., 208 Marten, T., 113 Marti, F., 387 Martin, A., 148 Martin, J., 427 Martin, J. D., 96, 147 Martin, S. S., 147 Martinelli, J. E., 120,265 Martinkova, J., 406, 409, 477 Martyr, R.J., 286,489 Marumo, S., 82, 256 Marusich, W. L., 307 Maruyama, M., 115 Marvel, C. S., 62 Marx, A. F., 394, 408, 413,421,511 Marx, M., 494 Maryanoff, B. F., 364 Marzin, C., 3 Masaki, N., 215 Masamune, S., 86 Masamune, T., 93, 125, 142,240 Masi, P., 368, 369 Maslen, E. M., 535
Author Index
598 Maslova, L. K., 32 Massiot, G., 377 Masuda, S., 206 Mathew, C. T., 94 Mathieu, J., 465 Mathis, P., 225 Mathur, S. B., 157 Matkovics, B., 363 Matringe, H., 508 Matsuda, A., 213 Matsui, K., 8 6 Matsui, M., 22, 167 Matsui. T., 61 Matsumoto, H., 9 0 Matsumoto, T., 155, 164 Matsunaga, A., 125 Matsunaga. T., 24 1 Matsuo, A., 56 Matthieson, A. McL., 539 Mattox, V. R., 327 Maturova, M., 355, 487 Maudinas, B., 223, 290 Maugras, M., 286, 426, 508 Maurer, B., 131 Mauri, M., 179 Mavrina, L. A., 460, 497 Maxon, W. D., 449,476 Maxwell, J . R., 188, 271, 306 Mayama, M., 41 1 Mayer, D., 286 Mayer, H., 233, 306, 308 Mayer, M., 448 Mayle, W. R., 284 Maynard, D. E., 71 Maynard, P. V., 284 Mayo, D. W., 136 Mazaleyrat, J.-P., 367 Mazur, Y., 314. 386, 539 Meakins, G. D., 363,398, 399, 400, 403, 417, 418,446,447,449 Mechoulam, R., 71, 72, 74,302 Meck, R., 133 Meehan, T. D., 263 Mehrotra, A. K., 58 Mehta, G., 59, 70, 110, 156 Meinwald, J., 84, 238 Meister, B., 5 Mejer, S., 462 Mekhtiev, S. D., 243 Melillo, D. G., 168 Mel’nikova, V. I., 468 Mendelsohn, H., 494 Meney, J., 379 Mennona, F. A., 354 Menzies, I. D., 392 Mercier-Bodard, C., 576
Meremkulovq, K. N., 49 1 Merep, D. J., 5 3 Merichini, F., 180 Merits, I., 447 Merlini, L., 75 Merrill, E. J., 359 Mktayer, A., 366, 383 Metge, C., 36, 50 Metzner, H., 299 Metzner, P., 6 0 Meyer, A., 359 Mez, H. C., 539 Michatek, E., 65 Michel-Briand, Y., 455 Middleditch, B. S., 468 Middleton, E. J., 284 Midgley, I., 330, 340,349 Midgley, J. M., 536 Midtvedt, T., 526, 527 Mielczarek, I., 41 Mihashi, S., 145 Mijlhoff, F. C., 546, 560, 568 Mijs, W. J., 398 Miki, T., 464 Miks, E., 10 Miksch, F., 446 Milborrow, B. V., 222, 240, 266, 307 Milewich, L., 283 Milewski, C. A., 3 18, 364 Milgrom, E., 456, 576 Miller, C. H., 84 Miller, I. R., 225 Miller, M. A., 580 Miller, T. L., 483, 5 19 Mills, J. S., 147 Mills, R. W., 22, 99, 100 Minale, L., 142, 173,219, 248, 288, 295 Mincione, E., 336 Minemura, Y., 459 Mirando, P., 150 Mirgasanova, M. I., 243 Mirrington, R. N., 93, 139 Mischenko, V. V., 243 Mislow, K., 4 Misra, R., 314, 540 Mitani, S., 5 Mitchell, E. D., 24, 253, 263 Mitra, A. K., 167 Mitropoulos, K. A., 276, 283 Mitsugi, T., 401, 413, 460, 5 13 Mitsuhashi, H., 363, 41 1 Mitsui, S., 349 Miura, I., 217 Miura, T., 379, 381 Miyake, A., 11
Miyashita, M., 108 Mizuta, K., 151 Moinet, G., 28 Moir, M., 69, 295 Molin, P., 4 1 Monaco, P., 200 Monder, C., 284,286 Money, T., 8, 87, 90, 99, 100 Monneret, C., 366, 383 Montagnac, A., 376 Montalvo, S. C., 329 Monteiro, M. B., 154 Montero, J. L., 75 Moody, J. A., 448 Mookherjee, B. D., 12 Moolgavkar, S. H., 487 Moore, B. P., 164 Moore, T. A., 221, 225 Moore, T. C., 267, 268 Mootz, D., 536 Morand, P., 300, 314 Morand, P. F., 498 Moreau, C., 58 Morelli, I., 208, 376 Morgan, B., 272 Morgan, E. D., 205 Mori, K., 40, 139, 162, 167,240, 366 Moriconi, E. J., 5 5 Morimoto, H., 249 Morisaki, M., 90, 171, 176,179,282,333,381 Morisawa, Y., 398, 446, 447 Moriyama, Y., 130, 206, 215 Morizur, J. P., 45, 238 Morman, M. J. P., 538 Morozova, G. R., 479 Morozova, L. S., 425 Morris, M. S., 115 Morrison, G. A., 322 Morrow, L. B.,539 Morton, G. O., 150, 157, 270 Mosbach, E. H., 526 Mosbach, K., 450 Mose, W. P., 307 Moss, G. P., 303, 400 Moss, J., 252 Mossel, A., 572 Motherwell, W. D. S., 535,537,575 Mourgues, P., 328 Mousseron-Canet, M., 222,325,457 Mrozinska, D., 34 Muckensturm, B., 316 Muller, B. L., 242 Muller, F. J., 11
5 99
Author Index Muller, R., 394 Muir, R. D., 446, 510 Mukai, T., 324 Mukaiyama, T., 353 Mukam, L., 193 Mukawa, F., 401 Mukherjee, D., 384 Mukherji, S. M., 390 Mulchandani, N. B., 288 Mulheirn, L. J., 268, 276, 297, 299, 314,396 Muller, B., 9 0 Muller, J.-C., 124 Muller, W. E., 398 Mullin, J. G., 354 Munakata, K., 149 Munday, K. A., 253 Murae, T., 206 Murakami, M., 5 11 Murakami, Y., 5 Murayama, K., 22 Murofushi, N., 158, 161 Murphy, G. J. P., 161,269 Murphy, G. M., 457 Murphy, P., 304 Murray, M. J., 262 Murray, R. D . H., 22,148 Musaev, M. R., 243 Muschaweck, R., 10 Muscio, F., 226 Muscio, 0. J., 186, 258 Musser, J. H., 119 Mustafaeva, M. T., 39, 245 Muzart, J., 359 Myant, N. B., 283 MySlinski, E., 65 Nada, S., 286, 405 Nadeau, R., 269 Naemura, K., 108 Nag, K., 218 Nagai, J., 259 Nagai, Y., 6, 7, 243, 493 Nagasampagi, B. A., 89, 190 Nagasawa, M., 460, 511, 513 Nagase, H., 107 Nagell, A., 35 Nair, G. V., 481 Nair, P. P., 493 Naito, A., 394 Nakachi, O., 11, 13 Nakada, Y., 22 Nakadaira, Y., 388 Nakamoto, T., 56 Nakamura, H., 107 Nakamura, S., 133, 167 Nakanishi, K., 139, 217, 222,226,388
Nakano, H., 515 Nakasone, S., 282 Nakata, T., 155, 168 Nakayama, M., 56 Nakayama, Y., 176 Namara, D. J., 251 Nambara, T., 474, 475 Nan Hsu, I., 539 Narang, S. C., 5 9 Narasaka, K., 353 Narula, A. S., 194 Nasipuri, D., 167 Nath, A., 200 Nathansohn, G. G., 457 Natori, S., 190 Naumov, V. A., 56 Naves, Y.-R., 35, 302 Naya, K., 133 Nayak, U. R., 70, 164 Nazaki, Y., 41 1 Nazarova, T. S., 460,498 Nazaruk, M. I., 470 Nearn, R. H., 154 Needham, P. H., 22 Neeman, M., 324 Neff, S. E., 143 Negishi, A., 86 Neidle, S., 166 Neidleman, S. L., 439, 496 Nelson, J. D., 45 Nelson, S. J., 329 Nemorin, J., 315 Nepokroeff, C. M., 253 Nes, W. R., 273, 281 Nespiak, A., 461 Ness, G. C., 253,259 Neumaier, H., 8 4 Neville, A. M., 456 Ngan, H. L., 253 Nguyen-Dang, T., 448, 46 1 Nicholls, R. J., 9 3 Nickon, A., 49, 391 Nieh, M. T., 329 Nielsen, B. E., 495 Nigam, S. S., 9 Nihonyanagi, M., 6 Niizato, N., 284 Nikaido, T., 145 Nikitin, L. E., 460, 497, 498 Nikolaidis, D., 187, 296 Nishida, R., 132 Nishimura, K., 115 Nishimura, O., 10 Nishimura, S., 338 Nishino, T., 257, 258 Nishio, M., 200 Nishioka, I., 7 0 Nishiyama, A., 119
Nishizawa, M., 265 Nitsche, H., 230 Niwa, H., 188,292 Niwa, M., 119, 139, 212, 215,216 Njimi, Th., 193 Noble, C. M., 253 Noguchi, S., 397, 467 Nomink, G., 465,472 Norden, B., 3 13 Norin,T., 36,53,93,220, 305 Norman, A., 526,527 Norris, R. K., 344 Norton, D . A., 357, 534, 535, 536, 537, 538, 539,540,548,576 Novotny, L., 127 Nowicki, H. G., 248 Nozoe, S., 90, 171, 176, 179,266,271 Ntokos, G., 156 Oae, S., 47 Obayashi, M., 467 Ober, R. E., 406 Oberc, M. A., 496 Oberhansli, W. E., 538 Oberhammer, H., 559 O’Brien, P. J., 286 Ochiai, K., 284 Oda, O., 28 Odom, H. C., jun., 129 Oehlschlager, A. C., 277, 427 Ogata, Y., 235 Ogilvie, A. G., 377 Ogino, T., 115 Ogura, K., 86, 257, 258, 259 Oh, S. K., 143 Ohara, S., 168 Ohkawa, M., 176 Ohloff, G., 131,242,291, 302 Ohnsorge, U. F. W., 166, 179,271 Ohrt, J. M., 536 Ohsawa,T., 155,170,199 Ohsuka, A., 68 Ohta, A., 197 Ohta, T., 163 Ohta, Y., 9 5 Ohtaka, H., 282, 381 Ohtsuka, Y., 155, 156 Oie, T., 26 Ojima, I., 6, 7, 243 Okada, M., 348,408,410, 434 Okada, Y., 167 Okaniwa, K., 370
Author Index
600 Okazaki, T., 68 Okubayashi, M., 282 Okuda, S., 171, 176, 179, 187, 188, 271, 272, 292,370 Okukado, N., 230,231 Okuno, T., 164 Olejniczak, B., 58 Oleson, W. H., 252 Olivk, J.-L., 222 Oliveto, E. P., 425, 457 Olson, J. A., 291 Olson, R. E., 248 Omi, J., 164 Onaka, T., 504 Oosterhoff, L. J., 50 Opheim, K. E., 84, 266 Opitz, G., 53 O'Rangers, J. J., 286 Organ, T. D., 536 Oritani, T., 241 Orr, J. C., 286, 297 Ortar, G., 357 Ortega, A., 133 Ortiz de Montellano, P., 3 18 Osawa, Y., 324,463,537, 552 Osband, J . A., 172, 239 Oshima, H., 284 Osiecki, J., 36 Osman, H. G., 420 Oster, M., 304 Otsuka, H., 467 Ouannes, C., 195 Ourisson, G., 124, 139, 179, 193, 196, 199, 246,264,274,306 Overton, K. H., 57, 82, 144, 156, 204, 220, 256,270,300,304,305 Owen. P., 57 Ozainne, M., 23 Ozaki, K., 340 Paasivirta, J., 44 Pacheco, P., 198 Packter, N. M., 299 Padhy, S. N., 207 Pagnoni, U. M., 119 Pais, M., 376 Pajkowska, H., 421 Paknikar, S. K., 97, 101 Pal, S. K., 213 Palmer, R. H., 457 Palmere, R. M., 439 Palumbo, G., 200 Pan, S. C., 412, 439 Panar, M., 393 Panctazi, A., 385
Pandey, R. C., 89 Pankova, M., 10 Pantulu, A, J., 17 Paoletti, E. G., 276, 298 Paoletti, R., 276 Paolucci, G., 368 Papastephanou, C., 290 Papernaja, I. B., 471,5 13, 514 Pappo, R., 107 Paquet, D., 52, 53 Paradisi, M. P., 329 Paris, M. R., 70 Paris, R. R., 70 Park, R. J., 83 Parker, W., 77, 300 Parkhurst, R. M., 214 Parmentier, G. G., 286 Parrish, F. W., 404 Pars, H. G., 302 Partridge, J . J., 26 Pascard-Billy, C., 535 Pascual, C., 147 Passet, J., 8 Pasteels, J. M., 9 Patashnik, S. L., 358 Patel, K. M., 36, 354 Patil, V. D., 164 Paton, W. D. M., 302 Pattenden, G., 20 Patterson, G. W., 275 Patterson, J. W., 103 Pattnaik, N., 156 Pankstelis, J. V., 53 Paul, I. C., 151, 536, 540 Pauling, H., 5, 49 Pauling, L., 576 Paulose, M. M., 17 Pavel, V., 535 Pavia, A. A., 49 Payne, 'T. G., 165 Peach, C. M., 372 Pechet, M. M., 355, 356 Pedone, C., 546 Pegel, K. H., 161 Peila, E., 179 Pelletier, S. W., 305 Pellicciari, R., 179 Penasse, L., 470, 472 Pendlebury, A., 363,447, 449 Perey, G. R., 205 Perez, C. S., 171 Perez-Reyes, M., 71 Perkins, D. W., 277 Peron, F. G., 428 Perry, G. J., 83 Pertot, E., 425, 441, 515 Pesce, G., 357 Petcher, T. J., 287
Pete, J. P., 359, 389 Petersen, M. R., 86 Peterson, G. E., 401 Peterson, P. A., 234 Petit, F., 44 Petit, G. R., 381 Petrow, V., 394 Petrzilka, T., 74, 302 Pettersen, R. C., 312,536 Petzoldt, K., 408, 413, 425,451,455,464,530 Peyre, M., 470 Pfander, H., 222 Pfau, M., 58,302 Pharis, R. P., 161, 269 Phelps, D. J., 328 Phillips, G. T., 255 Phillips, L., 161, 332 Piacenza, L. P. L., 161 Piatak, D. M., 200, 344 Piatkowski, K., 30, 34 Pichat, L., 187, 296 Pickenhagen, W., 39 Pierce, J. K., 63 Pieroni. J., 55 Piers, E., 103, 129 Piessens-Denef, M., 286 Pillai, N. K., 364 Pillinger, C. T., 306 Pilotti, A.-M., 93 Pincus, M., 225 Pinder, A. R., 129, 301 Pinevich, V. V., 221 Pinhey, J. T., 35, 189, 192, 341, 363, 399, 418,446,449 Piotrowska, G., 41 Piozzi, F., 158, 159 Piriou, F., 314 Pisano, M. A., 406 Pisareva, T. N., 61 Pitcher, R. G., 71 Pitt, C. G., 71, 73 Pitt, G. A. J., 307 Plantadosi, C., 133 Plasse, J. C., 284 Pletcher, J., 538 Plourde, R., 450, 466, 476 Plouvier, V., 301 Pocklin ton, T.. 468,469 Pohlancf A., 4 Poiret, M., 154 Pokrywiecki, S., 548, 552 Pollard, D. R., 541 Pollock, J . F., 13 Polonsky, J., 150, 174, 183,300,305 Poltavchenko, Yu. A., 9, 297 Polyachenko, L. N., 243
Author Index Ponsold, K., 315 Pont-Lezica, R., 82, 256 Poole, N. J., 406 Poon, Y.-C., 115 Popjik; G., 19, 187, 227, 228,253,258 Popper, H., 287 Porath, G., 71 Porter, J. W., 227, 228, 252,253,258,259,290 Porthheine, J. C., 539 Possanza, G., 474 Pot, J., 558 Potier, P., 377 Poulter, C. D., 19, 186, 258,263,302 Poulton, G. A., 43 Povodyreva, I. P., 66 Powell, J. E., jun., 26 Poyser, J. P., 196 Poyser, K. A., 196 Pragnell, J., 447 Pratt, A. D., 192, 318 Pratt, W. B., 455, 456 Precigoux, G., 535 Prelog, V., 139, 575 Premuzic, E., 306 Preston, A. F., 145 Previtera, L., 145 Price, P., 370 Prince, A., 360 Principe, P. A., 412 ProchBzka, 400, 401, 419,447,466 Protiva, J., 406,409,423, 458,477 Protti, D. J., 297 Proveaux, A. T., 9 Pryce, R. J., 161, 162 Puckett, R. T., 541 Pulman, D. A., 22 Punja, N., 22 Purdy, R. H., 537 Pyrek, J. St., 194, 209, 213, 218,
z.,
Quackenbush, F. W., 230 Quagliata, C., 535 Quayle, J. R., 297 Quijano, L., 180 Quinn, H., 497 Qureshi, A. A., 227, 228, 259 Qureshi, N., 259 Raab, K., 474 Raab, W., 491 Radlick, P., 96, 166, 270 Raghavan, K. V., 17 Rahal, S., 353
601 Rahim, M. A., 492,516 Rahimtula, A. D., 275 Raible, M., 286 Railton, I. D., 161, 269 Rakhit, S., 515, 521 Ralph, B. J., 35, 189 Ram, B., 15 Ramachandran, J., 284 Ramage, R., 77, 93, 262, 300 Ramaiah, M., 9 Ramamurthy, V., 13,244 Raman, H., 48 Raman, P. B., 428 Ramasarma, T., 274 Ramm, P. J., 299,433 Ramsey, R. B., 299 Ramseyer, J., 286 Randall, P. J., 280, 282 Randazzo, G., 180 Rane, D. F., 124 Ranganathan, D., 58 Ranganathan, S., 48, 58, 274 Rangaswami, S., 208 Ranu, B. C., 168 Ranzi, B. M., 179, 291, 295 Rao, A. A., 101 Rao, A. S. C. P., 70 Rao, M. S. S., 235 Rao, N., 127, 157 Rao, P. N., 474 Raphael, R. A., 22 Rapoport, H., 66 Rappaport, L., 269 Raska, K., 487 Rasmussen, R. A., 260 RaspC, G., 452, 469 Rastogi, R. P., 198, 206, 305 Ratajczak, T., 150 Rathore, B. S., 56 Ratner, V. V., 63 Raulais, D., 136, 303 Rautenstrauch, V., 17, 20,242,291 Raymond, R. L., 497 Raynaud-Jammet, C., 576 Razdan, R. K., 70, 73, 302 Reback, J., 493 Reddi, A. H., 576 Reed, L. L., 535 Reed., W. D., 252 Rees, H. H., 258, 280, 282,284,298 Rees, R., 398,424, 463 Regan, T. H., 69 Rehacek, Z., 293
Reich, R., 225 Reichenbach, H., 221, 231, 290 Reif, W., 28 Reimann, H., 457 Reimann, K. A., 200 Renard, M. F., 356 Renes, G. H., 560 Repke, K., 486 Restivo, R. J., 116, 201, 54 1 Retamar, J. A., 53, 61 Rendi, P., 152 Reusch, W., 36, 354 Reusser, P., 41 1 Reynaud, J.-P., 576 Rhoads, S. J., 61 Riano, M. M., 450,454 Rice, G., 13 Rich, D. H., 86 Richards, E. E., 446 Richards, J. B., 294 Richards, J. H., 77 Riederer, P., 232 Riemann, J., 449 Rienacker, R., .14 Riess, J., 326 Rigassi, N., 223,306,307 Rihs, G., 539 Rilling, H. C., 226, 227, 274 Rimai, L., 225 Rimmer, B. M., 531 Rindole, B., 295 Rindone, B., 291,526 Ringold, H. J., 455, 474, 488 Rios, T., 171, 180 Ritchie, E., 207 Ritter, F., 497, 505, 508, 523 Ritter, M. C., 274 Rizzardo, E., 356 Roach, W. S., 53 Robbers, J. E., 293 Robel, P., 576 Roberts, D. W., 3, 313 Roberts, F. M., 82, 256 Roberts, J. C., 144 Roberts, J. D., 3,45,223, 313 Roberts, J. L., 155, 330 Roberts, J. S., 77, 117, 300,303 Roberts, S., 283 Robertson, J. M., 536, 538 Robeson, C. D., 69 Robins, R. K., 487 Robinson, C. H., 425,488 Robinson, D., 304
Author Index
602 Robinson, J.. 283 Robinson, R., 576 Robinsr>i~,W . H . , 186,
25s Rcxhcfort, [I.? 576 Rochefort, J . G., 419 Roddick, J. G., 293 Rode, L.. 266 Rodig, 0. R., 49 Rodin, J . O., 12 Rodriguez, P., 234 Rodwell. V. W., 251,252 Roe. C. R., 455 Ropke, H., 44'9 Rogers, D., 36 Rogers, I. H., 88, 194 Rohmer. M., 273 Rojahn, W., 8 Rokos, J. A . S., 247 Rollin, G., 6 Romeo, A., 329. 357 Romers, C., 531, 532, 535, 538. 539, 552. 561, 565, 566, 568, 5 7 0 , 572 Rorno, J . , 303 Ronchetti, F., 279 Ronchi, A. U., 237 Roscher, N . M.. 385 Rose. E., 360 Rose. G., 404, 41 5, 460 Rosen, P., 338, 573 Rosenbaum, N., 294 Rosenheim. O., 531 Rosenthal, O . , 287 Rosini. G., 368, 369 Rossi, C., 180 Rosso, G., 234 Rossotti, F. J. C . , 48 Rothberg, I.. 193 Rothenberg, S., 3 11, 548 Rotman, A , , 314. 386 Kottink, R . A., 9 Rouessac, F., 42. 59 Rowan, M. G . , 187, 287 Rowe, J . W.. 190, 304 Roy, N. K.. 56 Rozen, S.. 218 Ruban. E. L., 514 Rubio-Lightbourn, J., 333 Ruhottom. G. M., 362 Kudakov, G . A.,9,56.61, 297 Ruden, R . A . . 353 Rudler, H., 89 Rufer. C., 464 Kulko. F.. 4 Ruscoe, C . N. E., 22 Kussell, G. B., 152, 154 Russo, G., 279, 526
Rutenberg, H. L., 297 Rutledge, P. S., 155, 193, 330,358 Rutten, E. W. M., 532, 539, 570 Ruzicka, L., 77, 298 Ryan, R. J., 318 Ryback, G., 139,222 Rykowski, Z., 6 1 Ryu, D. Y., 448,451 Ryzhkova, V. M., 466, 479,491 Saakov, V. S., 290 Sachdeva, Y. P., 390 Sadykova. I. M.. 6 1 Sate, S., 277 Saito, H., 349 Saito, Y., 348, 408, 434 Sajdl, P., 293 Saji, I., 107 Sakaguchi, M., 3 Sakai, K., 28 Sakai, T., 88 Sakakibara, J.. 163 Sakan, T., 242, 265, 291 Sakashita, T., 353 Sakimoto. €I., 22 Saleemuddin, M., 252 Sallam, L. A. R., 286, 404, 405, 419, 420, 448,449 Salmon, M., 133 Salvatori, T., 179 Sam, T. W., 118 Samek, Z.. 115, 123, 127, 133 Sammes, P. G., 148, 152. 196, 198, 302 Samokhvalov, G. I., 243 Samuelov, Y., 74 Sanadze, G. A , , 260 zanchez Bellido, I., 63 Sanda, V., 418 Sandermann, H., 295, 296 Sanders, G. M., 558 Sandris, C., 352 Sangare, M., 314 Santacroce, C., 173, 182 Santaniello, E., 291 Santhanam, P. S., 208 Santurbano, B., 179 Sanyal, B., 168 Sanyal, P. K., 218 Sapleva, V. T., 491 Saraswathi. G. N., 33 Sardinas, J. L., 406 Sarel, S., 4 Sarre, 0. 2..457
Sartorelli, A. C., 487 Sasaki, M., 249 Sasaki, T., 8 SaSek, V., 400 Sassa, T., 180 Sassu, 0. G., 290 Sastry, S. D., 129 Sathe, S., 73 Sato, H., 388, 515 Sato, K., 249 Sato, Y., 425 Satoh, D., 41 1, 491 Sattar, A., 93 Saucy, G., 446 Sauter, F. J., 168 Savage, D. S., 570 Savchenko, V. I., 17 Savigny, P., 286, 426 Savko, L. M., 491 Savochkina, I. E., 62 Savona, G., 159 Sawai, M., 493 Sawaya, T., 386 Sax, K. J., 397, 495 Sax, M., 538 Sayre, D., 531 Scala, A., 176, 179, 276, 295 Scallen, T. J., 274 Scanlon, J . T., 35 Scarset, A., 5 Scartazzini, R., 174 Schade, G., 6 Schaefer, J. P., 535 Schattner, F., 287 Schenck, J. R., 447 Schenk, H., 539, 540 Scherrer-Gervai, M., 399 Schildknecht, H., 84 Schiller, H., 3 15 Schimmer, B. P., 230 Schlegel, J., 404, 483 Schleyer, P. von R., 580 Schmalzl, K. J., 139 Schmid, H., 344 Schmidt, S., 225 Schneider, G., 162 Schneider, H. J., 5 Schneider, J. J., 3 13 Schnoes, H. K., 287 Schocher, A. J., 228,290, 41 1 Schoening, C. E., 376 Scholler, R., 359 Schrader, H., 33 Schreiber, J., 359 Schreiber, K., 315, 535 Schriefers, H., 286 Schriider, E., 464 Schroepfer, G . J., 300 Schubert, A., 421, 446
603
Author Index Schubert, K., 399, 404, 415, 445, 453, 460, 483, 490, 492, 497, 499, 505, 506, 507, 508, 521,523, 528 Schuette, H. R., 243, 263 Schulte-Elte, K. H., 242, 29 1 Schultz, J. S., 397 Schulz, G., 4 0 3 , 4 0 5 , 4 1 5 Schumann, W., 453,497 Schuytema, E. C., 447 Schwartz, M. A., 119 Schwarz, H., 149 . Schwarz, S., 421 Schwarz, V., 372, 406, 409,423,458,477 Schwarzel, W. C., 188, 284 Schwenker, U., 231 Schwieter, U., 223, 306, 307 Schwimmer, S., 293 Scolastico, C., 291, 295, 526 Scopes, P. M., 307, 313 Scott, A. I., 297,300,301, 303,304, 305 Scott, L. T., 46 Sedlaczek, L., 421 Sedmera, P., 135 Sedzik-Hibner, D., 31 Seeto, J. C. F., 191 Sefton, M. A., 160, 207, 269,288 Segal, G. M., 286 Segal, R., 209 Segebarth. K.-P., 301 Sehgal, S. N., 394, 407, 416,419,476,498 Seidel, I., 535 Seifert, W. K., 393 Seiler, M. P., 183 Seki, M., 197 Sekine, K., 149 Sellars, P. J., 4 8 Semakhina, N. I., 6 4 Semar, J., 41 2 Semenovskii, A. V., 39, 245 Semmelhack, M. F., 98 Semmler, E. J., 227, 228 Senda, Y., 349 Sensi, P., 523 Seto, N., 474 Seto, S., 86,257,258,259 Settim, G., 174 Severina, L. O., 471,497, 513, 514 Sewell, B. A., 515 Shaffer, G. W., 110
Shafizadeh, F., 115, 123, 133,266 Shagidullin, R. R., 66 Shah, S. N., 274 Shahak, I., 218 Shaikhutdinov, V. A., 6 4 Shani, A.,,71 Shankaranarayanan, R., 88 Shapiro, D. J., 252 Shapiro, E . L., 3 18 Shaposhnikov, V. N., 460 Sharma, B. R., 213 Sharma, R. P., 166, 179, 271 Sharma, T. D., 390 Sharpless, K. B., 14, 17, 322,329 Shaw, D. A., 503 Shaw, G., 291 Shaw, 1. M., 146 Shaw, J., 19 Shaw, P. E., 2 9 , 4 5 0 Shaw, R., 364 Shay, A. J., 397 Shechter, I., 256 Sheldon, T., 35 Sheppard, P. N., 160, 269 Sherma, J., 221 Sheth, K., 286 Shibahara, M., 403, 448 Shibasaki, M., 38, 245, 246 Shibata, S., 145,182,199, 214, 271 Shibayarna, M., 149 Shibuya, M., 160, 167 Shibuya, S., 115 Shikita, M., 487 Shilova, S. V., 491 . Shimada, T., 10 Shimagaki, M., 168 Shimizu, I., 259 Shimoiima. H.. 463 Shinaiaawa; S.,’10 Shine, H . J., 376 Shine, W. E., 256 Shiner, M., 493 Shingu, T., 133, 2 6 Shinka, T., 259 Shiozaki, M., 167 Ship, S., 488 Shirasaka, M., 17( Shishibori, T., 120, 261 Shiue. C., 33 Shizuri, Y., 125 Shmelev, L. V., 245 Shono, T., 18, 57 Shoppee, C. W., 3 15 Shoyama, Y., 70
Shulman, S., 107 Shust, S. M., 514 Sica, D., 182 Sidall, J. B., 8 5 Siddiqi, M., 252 Sidhaye, A. R., 197 Siebert, R., 446 Siefert, J. H., 3 12 Siehr, D. J., 447 Siemieniuk, A., 30, 34 Siewinski, S., 461, 462 Sigel, C. W., 195, 206 Sigg, H.-P., 9 8 Sih, C. J., 300, 446, 462, 485, 492, 500, 501, 503, 504, 507, 508, 516, 520,521 Silva, M., 148, 152, 196, 198 Silverstein, R. M., 12, 238,298 Sim, G. A., 117,133,536, 54 1 Sirn, S. K., 6 Simatupang, M. H., 69, 295 Simes, J. J. H., 35, 189, 192, 207,212, 341 Simmonds, D. J., 20 Simpson, K. L., 228, 290 Simpson, R. L., 221 Simpson, T. J., 287 Sims, J. J., 37, 96, 146, 166,270 Singh, B., 365 Singh, H., 222, 231 Singh, K., 394, 407, 416, 419, 476, 498, 499, 515, 521 Singh, M., 390 Singh, P., 152 Singh, R. K., 126, 289, 299 Siperstein, M. D., 252 Sircar, S. M., 161 Sis, J. D., 444, 490, 497 Sivaramakrishnan, K. P., 62 Sjovall, J., 458, 485, 528 Sjogren, R. E., 454 Skinner, W. A., 2 14 Skralant, H. B., 274 Skryabin. 6.K., 394,405, 444, 460, 468, 470, 471, 478, 479, 490, 491, 513, 514, 521 Skwarek, M., 41, 61 Slakey, L. L., 252, 259 Sliwowski, 3 . . 218 Slusarchyk, W. A., 172, 239
604 Smale, T. C., 179 Smallidge, R. L., 230 Smiley, K. L., 492 Smit, A., 401,422 Smit, V. A., 39, 245 Smith, A. G., 285 Smith, A. R. H., 279 qmith, C. V., 23 Smith, D. S. H., 406 Smith, H., 444 Smith, H. E., 313, 333 Smith, L. L., 342, 393, 398, 403, 407, 420, 424, 446, 448, 451, 454,463,494 Smith, M. S., 447 Smith, R. G., 333 Smith, S. E., 95 Smith, W. K., 470 Sobti, R. R., 538, 539 Sotif, H., 293, 425, 441, 459,515 Sodano, G., 173 SON, D., 294 Sokolova, I., 470 Sokolova, L. V., 466,468, 479,491 Solo, A. J., 365 Soloff, L. A., 297 Solomon, P. H., 66 Solomon, S., 442 Somell, A., 286 Sondengam, B. L., 367 Sondheimer, E., 142, 240 Song, P.-S., 221, 225 Sorarrain, 0. M., 225 Sorkina, T., 508 Sorm, F., 10, 102, 127, 133, 135, 303, 324, 350, 352, 365, 371, 401,418,419 Sorochinskaya, E. I., 30 Sota, K., 22 Sotiropoulos, J., 52 Soucy, M., 103 Spalding, B. P., 153 Speckamp, W. N., 377 Spencer, T. A., 68, 84 Spenser, I. D., 297 Spillner, C. J., 186, 258 Spiteller, G., 154 Sprague, J. T., 3 12 Spycherelle, C., 172, 246 Srikantaiah, M. V., 274 Sriraman, M. C., 89 Staba, E. J., 300 Stackhouse, J . . 4 Stahl, E., 37 Stallard, M. O., 12 Stang, P., 580
Author Index Stanton, D. W., 154 Stark, E., 7 Steel, R., 449 Steelink, C., 38 Stefano, S., 75 Stefanovic, M., 102 Steglich, W., 7 Steinfelder, K., 3 15 Sterkin, V. E., 479 Stern, M. H., 69 Stevens, K. L., 69, 295 Stevenson, P. M., 283 Stevenson, R., 379 Stodola, F. H., 394 Stoessl, A., 127 Stohs, S. J., 284, 470 Stolp, C. T., 269 Stone, K. J., 246,295,296 Storer, R., 20 Stork, G., 126 Stothers, J. B., 44,49,127 Strain, H. H., 221, 223 Straka, R., 218 Strandberg, G. W., 492 Straub, O., 307 Streith, J., 366 Strijewski, A., 506 Strobel, R. G., 497 Strominger, J. L., 246, 295,296 Stroobant, P., 294 Stutz, A., 59 Suarez, M. D., 253 Suga, K., 8, 10, 11 Suga, T., 63, 120,261 Sugawara, T., 199 Sugie, A., 206 Sugihara, H., 249 Sugimoto, A., 336 Suginome, H., 390 Sugiura, K., 125 Sugiyama, T., 20,22,252 Suhadolic, T., 441 Sukh Dev, 6, 29, 70, 88, 89, 164, 181, 194 Suleimanova, E. T., 243 Sultanbawa, M. U. S., 214,215 Sun, M., 221 Sundaralingam, M., 580 Sundin, S., 93 Surve, K. L., 101 Susuki, M., 107 Sutherland, J. K., 118 Sutherland, M. D., 83, 143 Suvorov, N. N., 466,468, 479,491 Suzuki, K., 188 Suzuki, K. T., 266, 292 Suzuki, M., 93
Suzuki, T., 11, 22, 144 Suzuki, Y., 82, 256 Svec, W. A., 223 Svoboda, M., 10 Swidersky, K. P., 383 Swingle, R. B., 190 Syhora, K., 409,423 Sykes, A., 225 Sykes, P. J., 360 Syono, H., 200 Syrdal, D. D., 95, 102 Sys, D., 497 Sys, Zh. D., 444, 490 Sysko, R. J., 49 Szabo, A., 471 Szabolcs, J., 307 Szewczuk, A., 197 Szpilfogel, S. A., 398 Szymanski, E. S., 466 Tabei, T,, 284 Tada, M., 130 Tadenkin, B., 442 Tadra, M., 394, 405, 5 00 Taguchi, T., 322 Taguchi, V. Y., 167 Tahara, A., 155, 156, 168, 170 Tai, H. H., 501, 504 SO8 Tait, A. D., 333 Takabe, K., 10, 11, 13 Takada, N., 127 Takagi, I., 133 Takagi, K., 235 Takahashi, A., 197 Takahashi, K., 11, 213 Takahashi, N., 158, 161, 176 Takahashi, R., 182, 271 Takahashi, T., 130, 206 215,216,467 Takani, M., 213 Takao, S., 269 Takasugi, M., 142, 240 Takayama, M., 216 Takeda, K., 115,303 Takeda, R., 128 Takeda, Y., 24,299 Takemoto, C., 5 15 Takemoto, T., 163 Takimoto, S., 23 1 Talalay, P., 299,455,456, 472,487,488,503,504 Talapatra, B., 207 Talapatra, S. K., 207 Tali, M., 10 Tamaki, A., 284 Tamaoki, B.-I., 515
Author Index Tamm, C., 90, 205, 399, 410,446 Tamura, C., 536 Tamura, G., 460, 511, 5 13 Tamura, M., 343 Tamura, S., 9, 176 Tamura, T., 176 Tan, L., 420, 421, 448, 451 Tan, T.-L., 506 Tanabe, K., 425 Tanabe, M., 329,354 Tanabe, Y., 213 Tanahashi, Y., 130, 206 Tanaka, A., 102 Tanaka, H., 26 Tanaka, I., 22 Tanaka, J., 10, 11, 13 Tanaka, K.,107 Tanaka, N., 199 Tanaka, O., 145,199,214 Tanaka, R., 96, 102 Tang, C. S. F., 66 Tanielian, C., 1 4 Taoka, M., 160 Tarasov, 0. S., 467 Taska, M., 159 Taube, A., 209 Tauscher, B., 8 4 Taylor, D. A. H., 201, 203, 204 Taylor, D. R., 203 Taylor, E. C., 342 Taylor, H. F., 139, 307 Taylor, P., 469 Taylor, R. F., 222 Taylor, S. I., 277, 530 Taylor, W. C., 207 Tchapla, A., 367 Tchen, T. T., 527 Teeter, R. M., 393 Tegtmeyer, E., 24, 264 Tehrany, S. S., 544 Templeton, W., 324 Teng, J. I., 342, 393 Teng, S., 10 Terashima, S., 38, 245, 246 Terhune, S. J., 102 Teshima, S., 459 Teuscher, G., 298 Teutsch, G., 318 Thampi, N. S., 281 Theodoropoulos, D., 156 Thierry, J., 376 Thies, P. W., 23, 24, 302 Thijssen, J. H. H., 457 Thom, E., 541 Thoma, R. W., 448, 451, 476
605 Thomas, A. F., 6, 23, 29, 40,57,264,301 Thomas, D. W., 214 Thomas, G., 249,294 Thomas, R., 166, 179, 299 Thomas, V. E. M., 446 Thommen, H., 222,307 Thompson, A. C., 8 Thompson, D. J., 144 Thompson, M. J., 484 Thompson, R. M., 327 Thompson, W. E., 4 Thomson, J. A., 284 Thomson, J. B., 212 Thomson, R. H., 6 9 , 2 9 5 ThorCn, S., 39, 113 Thornton, I. M. S., 92, 123, 158 Thornton, M. D., 205 Threlfall, D. R., 249,294, 300,308 Thuillier, A., 53 Thweatt, J. G., 69 Tichy, M., 10 Tieleman, A., 547 Tietze, L.-F., 26 Tikhomirova, 0. B., 444, 460,490,521 Timmons, M. C., 71 Tinelli, E. T., 142, 240 Tirodkar, S. V., 101 Titov, Yu. A., 394, 395, 478 Tkatchenko, I., 360 Toda, M., 9 3 , 1 8 8 , 2 9 2 Todesco, P. E., 357 Tokes, L., 314, 382 Tomorkeny, E., 460,477 Tohma, M., 332,386 Tokane, K., 107 Tolstikov, G. A., 57,328, 332 Tomita, B., 95, 122 Tomita, T., 332 Tomiyama, K., 125 Tomizawa, K., 235 Toneman, L. H., 559 Tonolo, A., 179 Tophan, R. W., 525 Torelli, V., 472 Torgov, I. V., 286, 405, 444, 460, 465, 467, 468, 470, 490, 513, 514,521 Tori, K., 115, 314, 413, 446 Torii, S., 26 Torrado, M. T., 222 Torrance, S., 3 8 Torri, G., 4 0
Torri, J., 3 Tbth, G., 307 Totty, R. N., 553 Toube, T. P., 223 Townend, J., 389 Towns, R. L. R., 540 Townsley, J. D., 398,469, 470,474 Tracey, B. M., 313 Trager, L., 4 5 5 , 4 6 9 Traetteberg, M., 559 Trave, R., 119 Treadgold, C., 22 Trefonas, L. M., 540 Trenkle, R. W., 12 Trivellone, E., 142, 173, 295 Trost, B. M., 8 5 , 3 0 3 Trotter, J., 536 Trueblood, K.N., 531 Trulzsch, D., 287 Trumbull, E. R., 45 Truong, H., 576 Truscott, T. G., 225 Tsai, T. Y. R., 169 Tsatsas, G., 352 Tschesche, R., 172, 286, 299,338 Tsfasman, I. M., 491 Tsizin, Yu. S., 26, 303 Tsong, Y. Y.,462, 485, 500,503,504, 520 Tsou, G., 195, 196 Tsuchikawa, H., 505 Tsuda, K., 176, 179 Tsuneda, K., 338 Tsunetsugu, J., 391 Tsurkova, V. I., 405 Tsuyuki,T.,206,215,216 Tucker, G., 287 Tummler, R., 315 Tbma, J., 405 Tunemoto, D., 86 Turnberg, L. A., 457 Turnbull, J. K., 160 Turner, A. B., 378 Turner, W. B., 77, 92 Tursch, B. M., 193 Turuta, A. M., 313 Tykva, R., 297 Tyler, T. W., 198 Tyminski, I. J., 580 Uata, K., 10 Uchida, T., 390 Uchida, Y., 47 Uchio, Y., 56 Uda, H., 9 6 , 1 0 2 Ueda, S., 24 Uemura, D., 165
Author Index
606 Uh. H.-S., 25, 139 Ulehlova, E.. 218 Uliss, D. B., 73 Ulrich, W., 193, 355 Ulsamer, A. G., 499 Umbreit, J. N.. 246, 296 Umbreit, M. A , , 329 Underwood, B. A., 223 Underwood, R. H., 327 Ungar, F., 283, 394 Unrau, A . M., 277 Uotani, K., 200 Uskokovic, M. R., 26 Uzarewicz, A . , 58 Uzarewicz, I., 58 Vaala, A. R., 222 Vaciago, A.. 179 Vahnier, J. E., 286 Valcavi, U., 352,384,437 Valenta, J. R., 401 VallCn, S., 5 Vanasek, F., 102 Van Belle, H., 5 15 Van Cantfort, J., 286 Van-Catledge, F. A., 580 van der Ende, C. A. M., 535 Van der Gen, A., 136 van dcr Helm, D., 539 Van der Hoeven, T. A., 284 Van der Linde, L. M., 136 Van der Molen, H. J., 284 Van der Sijde, D., 401, 417,421,441,442 Van der Vusse, G. J., 284 Van der Waard, W. F., 398, 401, 408, 413, 417, 441, 442, 446, 452, 511 Van der Weele, C., 5 11 van de Ven, C. F. W., 540 van Dongen, J . P. C. M., 3 Vangedal, S., 285 van Heykoop, E.. 532 van Lier, J. E., 342, 393 van Meerssche, M., 537, 538 van Tamelen, E. E., 183, 300 Van Tongerloo, A., 314 van Wageninger, A.. 245 Varcnn;, H., 72, 74 Varma, K. R., 396 Varma, K. K.. 276 Varner, E. L., 447 Vasileva, V. E., 221 Vaughan, W. R., 44, 45 Vazin, C , 353 Vederas, J. C., 3 1
Velarde, E., 345, 382 Velgova, H., 320 Velluz, L., 472 Vemcera, D., 9 3 Vendt, V. P., 342 Venturella, P., 158 Venzke, B. N., 3 1 , 3 3 Vereshchagin, A. N., 61 Verghese, J., 33, 301 Vernice, G. G., 359 Vestling, C. S., 406, 446 Vetter, W., 223,306,307 Veysoglu, T., 6 VCzina, C., 394,407,416, 419,476,498,499,521 Vialle, J., 52, 53, 60 Viallefont, Ph., 42 Vig, 0. P., 13, 15, 68 Vigevani, A., 369, 457 Vigneron, J.-P., 455 Vilhuber, H. G., 391 Villoutreix, J., 223, 290 Vincent, F., 487 Viswanathan, N., 197, 214, 217 Vitali, R., 327, 339, 345 Vitek, A., 209 Vlasinich, V., 472 Vossing, R., 464 Vogtmann, H., 222 Voigt, D., 315, 535 Voigt, W., 286 Voishvillo, N. E., 458, 460,478,490 Volkova, I. M., 405, 460 von Ardenne, M., 315 von Bahr, C., 286 von Fraunberg, K., 11 von Rudloff, E., 120 von Schantz, M., 12, 264 Vouros, P., 315,326 Vrieze, W. D., 327 Vul’fson, S. G., 61 Vystrcil, A., 208, 209, 218 Wachsman, M. A., 5 5 Wacker, A., 455, 456, 469,487 Wada, H., 125 Wadia, M. S., 102 Waegell, B., 59 Wagner, F., 506 Wahlberg, I., 9, 115, 116, 208,238,302 Waight, E. S., 161, 179 Waisser, K., 209 Waite, M. G., 541 Wall, M. E., 71, 7 3 Wallach, O., 33 Wallen, L. L., 3 9 4
Waller, G. R., 292 Wallwork, J. C., 300 Walters, R. L., 112 Walton, D. C., 142, 240 Wang, A. H. J., 151 Wang, K. C., 462, 485, 500,503,508,520 Wang, P. A., 475 Wang, P. T., 286 Ward, M. G., 489 Warren, C. D., 247 Warren, J. C., 393, 469 Warshel, A., 544 Washuettl, J., 232 Watanabe, A. M., 71 Watanabe, I., 180 Watanabe, M., 164 Watanabe, N., 511, 513 Watanabe, S., 8, 10, 11, 37 Watanatada, C., 5 Watson, J. A., 252, 274 Watson, T. R., 191 Watson, W. H., 537 Watt, A. N., 365 Watt, D. S., 103, 119 Wawrzenczyk, C., 37, 51, 66 Weavers, R. T., 146 Weber, H.-P., 98, 287, 540 Weber, L., 3 18 Weedon, B. C. L., 221, 223,306,307 Weeks, C. M., 535, 537, 539,540,549,576 Weeks, 0. B., 221 Weete, J. D., 299 Wehrberger, K., 528 Wehrli, F. W., 204 Wehrli, H., 387 Weickgenannt, G., 150 Weihing, R. R., 499 Weinert-Orlik, H., 31 Weintraub, H., 487, 488, 489 Weis, E. E., 251 Weisenborn, F. L., 172, 239 Weiss, G., 139, 222, 226 Weiss, J. L., 71 Weiss-Berg, E., 446 Weissenberg, M., 323 Welch, A. D., 487 Welch, S. C., 112 Weldt, E., 196 Wells, D., 16 Welzel, P., 338 Wenkert, E., 108 Wermuth, C.-G., 359 Werstiuk, E. R., 391
607
Author Index
'
Werthermann, L., 86 Wesolowski, M. F., 304 West, C. A., 267, 298, 304 West, P. J., 43 Westcott, N. D., 194 Weston, R. J., 200, 305 Wetter, L. R. 297 Wetzel, M. G., 499 Whalley, W. B., 36, 536 Wharton, P. S., 115 Wheeler, D . M. S., 353 Wheeler, J. W., 9, 143 Whistance, G. R., 308 White, A. F., 268 White, D. N. J., 536 White, I. H., 284, 469 White, J. D.,26, 149,214, 277,530 White, J. G., 55 Whitehead, E. V., 217, 3 06 Whiting, D. A., 20, 75, 228,258 Whitlock, H. W., 300,503 Whittaker, D., 42, 298, 301 Whysner, J. A., 300 W'icha, J., 348, 417 Wickramasinghe, J. A. F., 396 Widin, K.-G., 12, 264 Wiechert, R., 337, 351, 355,405,469,497 Wieglepp, H., 408, 427, 428 Wiehager, A.-C., 93 Wieland, H., 531 Wierenga, W., 183 Wiesner, K., 169, 498 Wigfield, D. C., 328.488, 489 Wikvall, K., 286 Wiley, B. J., 404 Wilke, G., 5 Wilkins, A. L., 219 Wilkomirski, B., 218 Williams, C. N., 286, 461 Williams, J. E., 580 Williams, K. I. H., 314 Williams, R. E. D., 493 Williams, R. G., 387 Williams, S. R., 8 Williams, V. P., 227 Williarns-Ashman, H. G., 576 Williamson, K. L,107 Willoughby, E., 295, 296 Wilson, C. W., tert., 29 Wilson, D. M., 188 Wilson, J. E., 406, 446
Wilson, L. D., 300 Wilson, M. A., 372 Wilton, D. C., 253, 275 Wiltshire, C., 355 Windisch, J., 491 Windreich, S., 225 Winell, B., 220 Wing, R. M., 96, 146, 166, 270 Winter, M., 9 Winter, S. R., 316 Winternitz, F., 75 Wiss, O., 308 Witkiewicz, K., 4 Witschi, E., 284 Witteveen, J. G., 136 Wittstruck, T. A., 314, 338,409 Wix, G., 404, 460, 471 Wojnarowski, W., 45 Wojtowski, R. K., 353 Wolf, G., 234 Wolf, G, C., 326 Wolf, H. R.. 7, 243 Wolff, G., 174 Wolff, M. E., 311, 548, 549,575 Wolinsky, J., 25, 34, 47, 55 Wolkowski, 2. W., 314 Wolter, J., 407 Wong, S., 258 Wong, S.-M., 19, 187, 227,228 Wood, D. L., 12 Wood, R. C., 460 Woodgate, P. D., 398, 446 Woodward, R. B., 51,386 Woolfson, M. M., 532 Wootton, M., 189 Worch, H. H., 535 Worth, G , K., 165 Wrange, O., 285, 484 Wray, V., 332 Wright, P. L., 499 Wu, F., 544 Wu, T., 266 Wuest, H., 39 Wulff, G., 299 Wulfson, N. S., 444,471, 513, 514 Wunderli, A., 344 Wuu, T., 261 Wyatt, R. J., 71 Yagen, B.. 276, 282, 396 Yakhimovich, R. I., 342 Yarnada, A., 408 Yamada, H., 3 , 8 Yamada, K., 9 3 , 1 0 7 , 1 2 5
Yamada, S., 38,206,216, 245, 246, 336 Yamada, Y., 22 Yamaguchi, I., 161 Yamaguchi, M., 230,231 Yamaguchi, R., 249 Yamakazi, K., 386 Yarnamoto, H., 5 Yamamoto, W., 299 Yamamura, S., 119, 139, 188,292 Yarnane, H., 161 Yamanishi, T., 233 Yamashita, K., 20, 22, 24 1 Yamashita, Y., 349 Yamauchi, T., 70 128 Yamazoe, Yan, T. C., 213 Yanagisawa, I., 145 Yanagita, M., 135, 266 Yang, C., 13,244 Yang, P., 13, 244 Yarborough, C., 357 Yaroshenko, Y. F., 342 Yasue, M., 163 Yazawa, H., 93 Yeboah, S. K., 287 Yobiko, Y., 5 Yokoi, T., 212, 216 Yokota, T., 158, 161 Yokoyama, H., 221. 290 Yoo, C. S., 538 Yoshii, E., 340 Yoshikawa, M., 218 Yoshikoshi, A., 96, 102,108 Yoshioka, H., 22 Yoshioko, M., 188 Yosioka, I., 128, 199, 213,218 Yoshizawa, I., 343 Young,T. G., 294 Young, M. R., 1 4 , 1 1 3 Young, R.N., 47 Younglai. E., 442 Yura, Y., 22 Yur'ev, V. P., 57, 328. 332 &'.,
Zabza. A., 37, 41, 51, 66 Zagalak, B., 4 Zahn, W., 506 Zaikin, V G",444 Zaitsev, V. V., 34 Zakharycheva, A. V., 312 Zakrzewski, Z., 476 Zala, A. P.. 371
Author Index
608 Zalkaw, L. H., 123,427 Zaman, A., 160, 181 Zamecnik, J., 132 Zander, J., 457 Zane, A., 164 Zanin, V. A., 460,497, 498 Zank, L. C., 304 Zaretskaya, I. I., 444, 460,490 Zaretskii, V. I., 444, 471, 513, 514, 521
Zbiral, E., 59,334,335 Zdero, C . , 23,127,150 Zedeck, M. S., 487 Zeelen, F. J., 398 Zeevart, J. D., 161 Zelkova, N. T., 468 Zelnik, R., 151, 201 Zhukova, A. I., 497 Ziegler, M. F., 206 Zink, M. P., 7, 243 Zinkel, D . F., 153, 304 Zinsou, C . , 233
Zsindely, J., 344 Zuccarello, F., 559 Zuidweg, M. H. J., 394, 446 zur Nedden, K., 9 Zvyagintseva, D. G., 479 Zvyagintseva, I. S., 405,470,478,479 Zweifel, G., 56 Zyakin, A. M., 479 Zych, L., 421