Académique Documents
Professionnel Documents
Culture Documents
Volume 12
Senior Reporter
ISBN 0-85186356-6
ISSN 0300-5992
Copyright 0 1983
The Royal Society of Chemistry
All Rights Reserved
No part of this book may be reproduced or transmitted
in any form or by any means-graphic, electronic,
including photocopying, recording, taping or
information storage and retrieval systems-without
written permission from The Royal Society of Chemistry
Introduction
This is the last of the Terpenoids and Steroids Specialist Periodical
Reports. This title along with Aliphatic and Related Natural Product
Chemistry, The Alkaloids and Biosynthesis, has been subsumed into a
review journal entitled Natural Product Reports. Whilst maintaining the
thoroughness of coverage which has characterized the individual reports,
the new journal will aim to avoid overlap and, because it will appear more
frequently, the time delay between the completion of a chapter and publication which arises in the present reports from the irregular completion of
manuscripts. The title of the new journal allows for a greater flexibility in
scope and it will contain reports, particularly on techniques, which cut
across the traditional boundaries between the individual groups of natural
product. I should like to thank all those contributors who have made the
present series a success and I wish the chairman of the Editorial Board,
Professor Pattenden, good luck in this new venture.
J. R. HANSON
Contents
Part / Terpenoids
Chapter 1 Monoterpenoids
4
4
7
8
14
14
15
19
23
25
29
32
32
33
35
39
44
44
45
45
47
48
48
48
50
51
52
vii
22
41
viii
10 The Fenchane Class
53
53
53
54
55
55
56
56
57
57
60
61
62
62
Occurrence
Syntheses and Reactions
15 Cannabinoids and Other Phenolic Monoterpenoids
Cannabinoids
Thymol Derivatives
Occurrence
Reactions
16 Biogenesis, Chemotaxonomy, Biological Applications
Labelling Patterns; Cell-free Extracts
Tissue Cultures, Microbial Transformations
Chemotaxonomy
Metabolism, Biological Activity, Miscellaneous
Chapter 2 Sesquiterpenoids
65
65
66
66
67
67
68
72
73
73
75
By J. S. Roberts
1 Farnesane
75
78
3 Bisabolane
88
4 Sesquicamphane, Sesquipinane
89
92
6 Chamigrane, Widdrane
99
100
106
114
115
11 Germacrane
140
ix
Contents
12 Elemane
155
13 Eudesmane
156
163
15 Eremophilane, Ishwarane
169
172
181
18 Pinguisane
183
19 Miscellaneous
184
Chapter 3 Diterpenoids
186
By J. R. Hanson
1 Introduction
186
186
3 Bicyclic Diterpenoids
Labdanes
Clerodanes
187
187
189
4 Tricyclic Diterpenoids
Naturally Occurring Substances
Chemistry of the Tricyclic Diterpenoids
192
192
193
5 Tetracyclic Diterpenoids
Kaurenoid Diterpenoids
Gibberellins
Grayanotoxins
At iserenes
195
195
197
199
199
6 Macrocyclic Diterpenoids
199
7 Miscellaneous Diterpenoids
201
203
Chapter 4 Triterpenoids
207
By R. 8.Boar
1 Introduction
207
207
3 Fusidane-Lanostane Group
210
4 Dammaran+Euphane Group
Tetranortriterpenoids
Pentanortriterpenoids
Quassinoids
21 5
21 7
222
222
5 Lupane Group
225
6 Oleanane Group
226
7 UrsaneGroup
230
8 Hopane Group
23 1
9 Miscellaneous
232
10 Triterpenoid Saponins
234
235
G.Britton
1 Carotenoids
Introduction
Reviews
New Structures and Stereochemistry
Carotenoids
New Natural Products, Related to Carotenoids
Carotenoid-Protein Complexes
Synthesis and Reactions
Carotenoids
Retinoids
Carotenoid-like Compounds
Physical Methods
Separation and Assay
N.M .R. Spectroscopy
Circular Dichroism
Raman and Infrared Spectroscopy
Electronic Absorption Spectroscopy
Photoacoustic Spectroscopy
Miscellaneous Physical Chemistry
Photoreceptor Pigments
Biosynthesis and Metabolism
Biosynthesis
Metabolism
235
235
235
236
236
238
238
239
239
246
25 1
255
255
256
256
257
258
259
259
259
259
260
262
264
264
265
265
266
266
xi
Contents
Part I! Steroids
269
By D. N. Kirk
1 Structure and Conformation
269
2 N.M.R. Spectroscopy
lH Spectra
13CSpectra
lSFand 2HSpectra
273
273
274
277
3 Chiroptical Phenomena
277
4 Infrared Spectroscopy
278
278
280
280
281
7 Immunoassays
283
8 Miscellaneous
285
288
By 6. A. Marples
Section A: Steroid Reactions
1 General
288
288
288
290
29 1
3 Unsaturated Compounds
Electrophilic Addition
Other Addition Reactions
Other Reactions of Unsaturated Steroids
Aromatic Compounds
292
292
294
294
295
4 Carbonyl Compounds
Reduction
0t her Reactions
Reactions Involving Enols or Enolic Derivatives
Oximes
296
296
297
299
300
xii
300
6 Molecular Rearrangements
303
308
8 Photochemical Reactions
309
31 1
318
11 Pregnaiies
321
324
13 Cardenolides
325
14 Heterocyclic Steroids
327
15 Microbiological Reactions
328
Author Index
330
Part I
TERPENOIDS
1
Monoterpenoids
BY D. V. BANTHORPE AND S. A. BRANCH
1 Introduction
Owing to a chain of misfortunes, this subject has not been reviewed since Volume 9.
Consequently the present survey has to cover the literature from autumn 1978 to
that dated 3 1.12.81 (as recorded in Chemical Abstracts and Current Contents up to
1.6.82). Dr A. F. Thomas of Firmenich SA, Geneva, kindly gave access to his card
index covering the period and we are extremely grateful to him: we also thank
the Royal Society of Chemistry for providing selected abstracts.
The present half-litre pot has to contain the distillate of some 6000 monoterpenoidrelated papers: although most are trivial for the present, or indeed any, purpose,
there has obviously had to be a change of presentation from that usual in these
Reports. We have had to abandon all pretence of comprehensive coverage, and in
particular have had to be highly selective in the following categories: (a) the vast
patent literature which, although no doubt of industrial importance, often seems to
cynical eyes to be vague, trivial, and repetitive; (b) the seemingly endless reports on
occurrence and distribution of monoterpenes in plants; (c) studies on analogues of
monoterpenes (e.g. homologues of pyrethrinoids and cannabinoids) ; and ( d )
reports in journals unavailable in the U.K., and inadequately abstracted. Iridoids
are discussed but terpene alkaloids are excluded.
Even with the above restrictions, rigorous selection had to be made on the
remaining bulk of the literature. Lack of space has precluded much criticism, crossreference, and magisterial comment that are such a feature of previous Reports.
We have made an attempt to select salient papers-often those giving leading
references to earlier work within the period-but we would urge any authors who
feel that their contributions have been ignored or maltreated to send in reprints
for transmission to future Reporters.
In the following sections, the plant species that are sources of monoterpenes are
not recorded unless of some special significance, and similarly for points of stereochemistry, absolute configuration, reagents, and reaction conditions.
Excellent reviews have appeared on the synthesis of monoterpenoids,l of
cannabinoids,2 and of the use of isoprene in terpenoid ~ynthesis,~
and also on
terpenoids from marine sponge^,^ the base-catalysed isomerization of mono-
*
*
t e r p e n e ~ ,and
~ iridoids.6-s Books on secondary metabolism in plants contain
chapters on mon~terpenes,~-ll
and detailed but overlapping reviews deal with the
biosynthesis of mono and other terpenoid~?~-l~
and others cover the stereochemistry of chain-lengthening and c y c l i z a t i ~ n , ~
the
~ Jimportance
~
of membrane
systems in monoterpene biosynthesis,20the metabolism of monoterpene epoxides,21
the production of monoterpenes (inter a h ) in tissue culture,22chemotaxonomy,23
and the functions of terpenoids in plants.24
2 Physical Measurements: Chirality
Spectral and Other Physical Data.-13C N.m.r. studies on hydroxy- and chloromenthanes have revealed that certain shifts are very sensitive and reliable probes
(1)
(2)
for ring onf formation,^^ and similar studies are available of menthyl enol ethers26
and of 13C--13Ccoupling in limonene and ca~vone.~
A detailed analysis of relaxation
times has been made from the 13Cspectrum for solid camphor,28and such spectra of
J. Verghese, Perfum. Flavours, 1981, 6, 23.
H. Inouye, Planta Medica, 1978, 33, 193.
L. J. El-Naggar and J. L. Beal, J. Nut. Prod., 1980, 43, 649.
* 0. P. Verma, S. Kumar, and B. C. Joshi, Herba Pol., 1980, 26, 133.
T. Robinson, Organic Constituents of Higher Plants, Corduis Press, Amherst, Mass., 4th
Edn., 1980, 352 pp.
l o R. B. Herbert, Biosynthesis of Secondary Metabolites, Chapman and Hall, London, 1981,
250 pp.
l1 M. Vickery and B. Vickery, Secondary Plant Metabolism, University Park Press, Baltimore
Md., 1981, 335 pp.
l2 H. R. Schuelte, Prog. Bot., 1976, 38, 129.
S.Nozoe and A. Kawaguchi, Methods Chim., 1978,11,223.
l4 B . V. Charlwood and D. V. Banthorpe, Prog. Phytochem., 1978, 5,65.
l6 R. Croteau, Soap, Perfum. Cosmet., 1980, 53,428.
l6 R. Croteau in Flavor and Fragrance Substances, ed. R. Croteau, D. and P. S. Verlag,
Pattensen (W. Germany), 1980, p. 13.
l7 W. D. Loomis and R. Croteau in The Biochemistry of Plants, ed. P. K. Stumpf, Academic
Press, New York, 1980, vol. 4, p. 363
l 8 0.
Cori (and nine others), Mol. Biol. Biochem. Biophys., 1980, 32, 97.
l9 D. E. Cane, Tetrahedron, 1980, 36, 1109.
2 o J. P. Corde, C. Bernard-Dagan, and M. Gleizes, Dev. PZant Biol., 1980, 6, 441.
21 S. Voight and M. Luckner, Pharmazie, 1978, 33, 632.
ea D. K. Dougall, in ref. 17, 1981, vol. 7, p. 21
*3 V. H. Heywood, J. B. Harborne, and B. L. Turner, Biology and Compositae, Academic Press,
London, 1977, two vols., 1189 pp.
e4 V. Herout, 7th International Congress on Essential Oils, 1977, vol. 7, p. 75.
25 D. Dauzonne, N. Goadsdoue, and N. Platzer, Org. Magn. Reson., 1981, 17, 18.
2s M. P. Stribel, C. G. Andrien, D. Paquer, M. Vazeux, and C. C. Pham, Nouv. J. Chim., 1980,4,
101.
27 G. Lukacs and A. Neszmelyi, Tetrahedron Lett., 1981, 22, 5053.
R. Wasylishen and M. R. Graham, Mol. Cryst. Liq. Cryst., 1979, 49, 225.
li
Monoterpenoids
P. Brun, J. Casanova, J. Hatem, J. P. Zahrar, and B. Waegell, Org. Magn. Reson., 1979, 12,
537.
2o
3a
33
34
35
30
37
38
3g
40
41
D. Harris, S. MacKinnon, and R. K. Boyd, Org. Mass Spectrom., 1979, 14, 265.
43 D. J. Harvey, Biomed. Mass Spectrom., 1980, 7, 28.
44 D. J. Harvey, Biomed. Mass Spectrom., 1981, 8, 366.
Is D. J. Harvey, Biomed. Mass Spectrom., 1980, 7 , 278.
40 D. J. Harvey, Biomed. Mass Spectrom., 1981, 8, 575.
47 R. Hiltunen, S. Raisanen, and M. von Schantz, Planta Med., 1980, Suppl., p. 112.
4a P. L. Polavarapu, M. Diem, and L. A. Nafie, J. Am. Chem. SOC.,1980, 102, 5449.
4 * L. D. Barron and B. P. Clark, J. Chem. SOC.,Perkin Trans. 2, 1979, 1164.
K O L. D. Barron and B. P. Clark, J . Chem. SOC.,
Perkin Trans. 2, 1979, 1171.
51 L. D. Barron and J. Vrbancich, J. Chem. SOC.,Chem. Commun., 1981, 771.
L.-F. Tietze, U. Niemeyer, P. Marx, K.-H. Glusenkamp, and L. Schwenen, Tetrahedron, 1980,
42
53
s4
36, 735.
N. Harada, J. Iwabuchi, Y. Yokota, and H. Uda, J. Am. Chem. SOC.,1981, 103, 5590.
A. Forni, I. Moretti, G. Tome, and E. Vignudelli, Tetrahedron Lett., 1979, 907.
D. A. Lightner and B. V. Crist, Tetrahedron, 1981, 37, 685.
6O
61
6z
63
64
66
68
67
S. G. Vulfson and V. F. Nikolaev, Izv. Akad. Nauk SSSR, Ser. Khim., 1981, 2259.
R. D. Singh and T. A. Keiderling, J. Am. Chem. SOC.,1981, 103, 2387.
J. C. Rees and D. Whittaker, Org. Magn. Reson., 1981, 15, 363.
(4) has traditionally been known as (+)-isothjone. We here adopt a more rational, if little used,
nomenclature; cf. S. P. Achorya et al. J . Org. Chem., 1969,34,3015.
Z. Kisiel and A. C. Legon, J . Am. Chem. SOC.,1978, 100, 8166.
J. Texter and E. S. Stevens, J. Org. Chem., 1979, 44, 3222.
G. Castellani, R. Scordamaglia, and C. Tosi, Gazz. Chim. Ztal. 1980, 110, 457.
L.-F. Tietze, U. Niemayer, P. Marx, and K.-H. Glusenkamp, Tetrahedron, 1980, 36, 1231.
A. J. Birch and 17 others, Tetrahedron Supplmt., NO. 1, 1981, 37, 289.
R. A. Pauptit and J. Troffer, Can. J . Chem., 1980, 58, 2805.
V. G. Andrianov, Yu. T. Struchkov, V. A. Blinova, and I. I. Kritskaya, Zzv. Akud. Nuuk
SSSR, Ser. Khim., 1979, 2021.
R. Rogues, J. Sotiropoulous,G. Feuillerat, G. Germain, and J. P. Declercq, J . Chern. Res. (S),
1980, 370.
J. T. McDonard and V. F. Valasinsky, Proc. SPIE, Int. SOC.Opt. Eng., 1981, 154.
Monoterpenoids
P
(3)
(4)
of counter-current distillation. This has been applied very successfully to the bulk
separation of iridoid g l ~ c o s i d e sA. ~method
~ ~ ~ ~has been claimed for the identification of terpene alcohols at the pg level:71this involved g.c.-m.s. after reduction
over platinum with lithium aluminium hydride. As a result, different substrates were
said to give a pattern of products with characteristic skeleta: thus borneol yielded
camphane or tetramethylcyclopentanes.
Photoelectron spectra of fenchone derivative^'^ and e.s.r. spectra of the paramagnetic adducts between organic Si-, Ge-, and Sn-centred radicals and camphor
and t h i ~ c a r n p h ohave
r ~ ~ been studied.'
Chirality.-The simultaneous presence of (8) and (9) (L= Yb"', GaIII, or Prrrl
splits the lH and lSC n.m.r. signals of chiral a-pinene, limonene, and camphene.
As a consequence the enantiomeric purities could be readily determined :74 previously, hydrocarbons were not amenable to such techniques. Compound (9)
augmented the Ag salt shift but did not interact alone.
Ally1 boronates of substituted camphor diols (10) added to acetaldehyde to
yield (1 l), which on base treatment cleaved to give 86 % optically pure pent-4-en-
K. Hostettmann, M. Hostettmann-Kaldas, and 0. Sticher, Helv. Chim. Acta, 1979, 62, 2079.
R. K. Chaudhuri, 0. Salama, and 0. Sticher, Planta Med., 1980, 40, 164.
71 B. A. Bierl-Leonhardt and E. D . Devilbiss, Anal. Chem., 1981, 53,936.
l e D. C. Frost, N. P. C. Westwood, and N. H. Werstiuk, Can. J. Chem., 1980,58, 1659.
73 A. Alberti, M. Guerra, and G. F. Pedulli, J. Am. Chem. Soc., 1981,103,6604.
74 W. Offermann and A. Mannschreck, Tetrahedron Lett., 1981,22,3227.
6@
70
,,,,*ao
Me,C=CHCH,MgBr-CuI
75
76
77
76
78
>
pcl
Mono terpenoids
The ene reaction of aldehydes with alkenes provides a potentially valuable route
to homoallylic alcohols [cf. (14a) + (14b)l. Coupling of isoprene with 3-methylbutan-1-a1 yielded ( 1 5) in excellent yield, and limonene similarly, reacted (at the
Cii
lii
6
H COMe
3
OH
Scheme 1
BB
88
10
A
-
- Li
NNHTs
NNTs
BuLi,
MeSSMe
Li
NNTs
(23)
from verbenola7 have been reported. The gem-di-(trimethylsilane) derived from
geraniol reacts with acid to yield citronellene (3,7-dimethylocta- 1,6-diene)87.
A general route has been developed to a,p-unsaturated aldehydes of homomonoterpenes,8s and various monoterpene y- and 8-lactones have been synthesized by the
Wittig-Horner reaction. 8 9 Geraniol and also pinane derivatives have been elaborated into a-substituted methylacrylates via a Claisen-o-ester rearrangement with
trimethyl p-methoxyorthopropionate using trimethylbenzoic acid as catalyst,g0
liii
OMe
Scheme 2
E4
B6
B6
87
Monoterpenoids
11
e.g. (27) -+ (28), and the epoxides of pulegone and piperitone have been prepared
by the Wittig reaction.g1 Treatment of ally1 acetates of the menthane and pinane
classes (e.g. those of carveols and myrtenol) with sodium diethylmalonate in the
presence of diphenylphosphinoethane and a Pd catalyst effected the transformation
(29) -+ (30), with obvious scope for further modification. 92 Another reaction leading
to valuable synthetic intermediates is the addition of dichlorocarbene to camphene
followed by reduction to yield (31) and (32);93 P-pinene and limonene behaved
similarly.
LoH
*
MeO(CH,),C(OMe),catalyst
(28)
&Ac
4rb
+O2EO,
R
(30)
(29)
(31)
(32)
vTNiBrl2
(33)
-OH
--+
&OH
(34)
v
OH
-&OH
(35)
O3
9'
OS
N. Bensel, J. Hohn, H. Marschall, and P. Weyerstahl, Chem. Ber., 1979, 112, 2256.
J. C. Fiand and J. L. Malleron, Tetrahedron Lett., 1980, 21,4437.
S. Watanabe, T. Fujita, K. Suga, and K. Kasahara, Aust. J . Chem., 1981, 34, 1161.
J. Muzart and J. P. Pete, J . Chem. SOC.,Chem. Commun., 1980, 256
L. S. Hegedus and S. Varaprath, Organometallics, 1982, 1, 259.
I. Ojima and M. Kumagi, J . Organomet. Chem., 1978, 157, 359.
12
bonded at 1-2, 1-3, 1-4, 2-4, 3-4, and 4-4 positions were prepared by suitable
regiocontrolled catalysis by transition metals of the coupling of 2-methylbut-2ene- 1,6diylmagnesium or 3-methylbut-2-enylmagnesium chloride with C,-alkenyl
halides.97 Various terpene amines have been obtained in excellent yields by Pdcatalysed telomerization of isoprene with NH,. 98
Conditions have been worked out for the conversion of allylic alcohols into
1,3-dienes (e.g. nerol-tmyrcene, geraniol+trans+P-ocimene)
by a sequence
involving epoxidation, trimethylsilylation, ring-opening, desilylation, formation
of diol, then of dibromides, and debromination, e.g. (34) --f (35).99 Reaction of a
variety of monoterpenes with HOCl-CH,Cl, resulted in addition of chlorine
followed by shift of the double bond: dechlorination (Zn) led to a-olefins (60-80 %),
and the chloro-derivative of citronellol could be efficiently converted into rose
oxide [2-(2-methylprop-1-enyl)-4-methyltetrahydropyran] by successive treatment
with acid and base.loO Dehydrations of allylic monoterpenols with carbodiimideslOlaand anhydrous C U S O , were
~ ~ ~effective.
~
Hydroalumination of p-pinene,
camphene, and a-thujene in the presence of 0, gave after work-up the product of
anti-Markovnikov addition (73 % trans-product, 85 % endo, and non-stereoselective,
respectively).102 In contrast, hydroboronation (TiC1,-NaBH,) gave 85 % cisproduct from p-pinene and mainly isopinocampheol from ~ c - p i n e n e . ~ ~ ~
A very useful functionalization of the isopropylidene terminus of isoprenoids led
to the formation of terminal trans-allylic alcohols (36) * (37), e.g. 10-hydroxy-
geraniol. Step (i) was highly regioselective and (ii) could be very effectively carried
out by the Evans procedure.lo4Preoccupations with the reactions of monoterpenes
(thujenes, menthenes, and carenes) and other 1-methylcyclohexenes has obscured
the fact that 1-methylcycloalkenes with four-, five-, seven-, eight-, or twelve-membered rings show predominantly syn-side addition in the ene oxidation with photochemically generated singlet oxygen (38 ; route i). 1-Methylcyclohexenes, however,
show anti-side addition (route ii): the theoretical reasons for this dichotomy have
been very convincingly
The PdCl, complex from carvone was conY. Kajihara, K. Ishikawa, H . Yasuda, and A. Namarnura, Bull. Chem. SOC.J . , 1980, 53,3035.
W. Keim and M. Roper, J . Org. Chem., 1981, 46, 3702.
Bs A. Yasuda, S. Tanaka, H. Yamamoto, and N. Nozaki, Bull. Chem. SOC.J., 1979, 52, 1752.
looS. G. Hegde and M. K. Vogel, Tetrahedron Left., 1980, 21, 441.
lo1 A. Trius, A. Trivino, and A. Virgili, Anales de Quim., 1980, 76, 58.
l 0 l b R. V. Hoffmann, R. D. Bishop, F. M. Fitch, and R. Harderstein, J . Org. Chem., 1980, 45,
917.
l o 2 A. V. Kuchin, L. I. Alkmetor, V. P. Yurev, and G . A. Tolstikov, Zh. Obshch. Khim., 1979, 49,
1567.
l o 3 S. Kano, Y. Tanaka, and S. Hibino, J . Chem. SOC.,Chem. Commun., 1980, 414.
lo*Y. Masaki, K . Hashimoto, and K. Kaji, Tetrahedron Lett., 1978, 4539.
K. H. Schulte-Elte and V. Rautenstrauch, J. Am. Chem. SOC.,1980, 102, 1738,
97
88
Monoterpenoids
13
lo6
lo7
lo8
log
1980,45,3698.
115
116
117
11*
D.Valentine, R.C. Sun, and K. Toth, J . Org. Chem., 1980, 45, 3703.
A. Fischli and P. M. Muller, Helv. Chim. Acta, 1980, 63, 1619.
A. Fischli and P. M. Muller, Hefv. Chim. Acta, 1980, 63, 4529.
V. V. Bazylchik, T. N. Overchuk, and P. I. Fedorov, Zh. Org. Khim., 1978, 14, 2085.
R. H. Mueller and J. G . Gillick, J . Org. Chem., 1978, 43, 4647.
14
Occurrence.-In this, and later sections, only novel (or so-claimed !) compounds
or known compounds in unexpected environments will be considered. A variety of
mono- and di-hydroxy-linalools [e.g. (42), (43)] substituted at C-6 and C-7 have
been found in grapes 130-132 and may be the precursors of more volatile usual
V. Rautenstrauch, B. Willhalm, W. Thommen, and U. Burger, Helv. Chim. Acta, 1981, 64,
2109.
lz1 S. Torii, K. Uneyama, T. Nakai and T. Yasuda, Tetrahedron Lett., 1981, 22, 2291.
S. Torii, K. Uneyama, M. Ono, and T. Banou, J . Am. Chem. SOC.,1981,103,4606.
I z 3 S. C. Traynor and B. J . Kane, J . Org. Chem., 1979,44, 1557.
12* T. Oritani and M. Yamashita, Agric. Biol. Chem., 1980, 44, 2407.
l Z 5 M. Iwai, S. Okumura, and Y . Tsujisaka, Agric. Biol. Chem. 1980, 44, 2731.
128 R. Couffignal and J. L. Moreau, Tetrahedron Lett., 1978, 3713.
12' S. D. Pirozhkov, N. V. Puzitski, T. N. Myshewnova, N . G. Ryabova, and S. S. Poddubnaya,
Izv. Akad. Nauk SSSR, Ser. Khim., 1979, 784.
128 A. Matawowski, Polish J . Chem., 1980, 54,469.
129 J. C. Kholi, R. Gupta, A. K. Arora, and K. Ushminder, J . Chromatogr., 1981, 210, 370.
I 3 O P. J . Williams, C. R. Straws, and B. Wilson, Phytochemistry, 1980, 19, 1137.
H. Etoh, K. Ina, and M. Iguchi, Agric. Biol. Chem., 1980, 44, 2999.
138 A. Rapp, W. Knipser, and L. Engel, Vitis, 1980, 19, 226 (Chem. Abstr., 1981, 94, 82 103).
pH PH
Mono terpenoids
15
COZH
OH
(43)
(45)
m o n o t e r p e n e ~Two
. ~ ~ 5-ketolinaloyl
~
derivatives (previously ~ynthesizedl~~)
occur in
Citrus ~ p p . , 1and
~ ~ a corresponding 4-hydroxy-compound (cornusol) has been
isolated from a Curnus spp.136The acid (44)was the monoterpenoid moiety of a
~ap0nin.l~'Geranyl-p-D-glucoside was readily formed, transported, and metabolized when apples were injected with the alcohol;13s this and the linaloyl glucoside that occur in tea shoots were cleaved on mechanical disruption.139 These
results suggest that glycosides may generally be storage and/or transportable forms
of certain monoterpenols. 3,7-Dimethylocta-(Z)3,6-dien-1-al,1407-hydroxycitronellic
acid,141geranic
geranyl dihydroquinones and the corresponding aromatics,l43
and sulphur derivatives of m y ~ c e n e[e.g.
l ~ ~ (45)] have been isolated from a variety of
plant species. Halogenated dimethyloctadienes, e.g. 8-bromo-3,7-dichloro-2,6dimethyl-octa-1, (E)S-diene, continue to be found in marine red algae.145-147
Synthesis of the C,, Skeleton.-Isoprene in the presence of Pdo catalysts1@or
telomerized with its
gave mainly citronellene (3,7-dimethylocta- 1,6diene) and geranyl chloride respectively, although an interesting minor product
(7 %) of the latter reaction was 2,7-dimethyl-3-chloro-octa-1,6-diene-anirregular
P. J. Williams, C. R. Strauss, and B. Wilson, J . Agric. Food Chem., 1980, 28, 766.
0. S. Park, Y.Grillasia, G. A. Garcia, and L. A. Maldonado, Synth. Cornrnun., 1977, 7 , 345.
lS6 T. Kitahara, Y. Takagi, and M. Matsui, Agric. Biol. Chem., 1980, 44, 897.
T. Kurihara and M. Kikuchi, Yukuguku Zasshi, 1978, 98, 969.
13' Y.Okada, K. Koyama, K. Takahashi, T. Okuyama, and S . Shibata, Plantu Med., 1980,40,185.
R. B. H. Wills and F. M. Scriven, Phytochemistry, 1979, 18, 785.
139 T. Takeo, Phytochemistry, 1981, 20, 2145.
140 J, M. Sandra and P. Cunat, Phytochemistry, 1980, 19, 89.
141 M. L. Sethi, S. C. Taneja, K. L. Dhar, and C. K. Atal, Indian Perfum., 1979,23,167.
A. Nahrstedt, U. Vetter, and F. J. Hammerschmidt, Planta Med., 1981, 42, 313.
143 R. J, Capon, E. L. Ghisalberti, and P. R. Jefferies, Phytochemistry. 1981, 20, 2598.
144 T. L. Peppard and J. A. Elvidge, Chem. Znd. (London), 1979, 552.
Ips R. W. Dunlop, P. T. Murphy, and R. J. Wells, Aust. J . Chem., 1979, 32, 2735.
146 D.B. Stierle, R. M. Wing, and J. J. Sims, Tetrahedron, 1979, 35, 2855.
P. Bates, R. W. Blunt, M. P. Hartshorn, A. J. Jones, M. H. G. Munro, W. T. Robinson, and
S . C. Yorke, Aust. J . Chem., 1979, 32,2545.
14* K. Nozaki, Eur. P., 19 960/1980.
149 A. Erm, M. Heinvali, T. Valimae, and K. Laats, Eesti, NSV. Tead. Akad. Toim.,
Keem., 1981,
133
134
30, 56.
16
nerol,
isogeraniol
(51)
Reagents: i, H+; ii, -CH,O;
iii, -H,O;
iv, Me,C=CHCH,CI-BuLi;
v, N a or electrochemical
Scheme 3
product of tail-to-tail linkage. Dimerization with PdO and MeC0,H led (on
work-up) to 2,6-dimethylocta-2,7-dien-1-01 (regu1ar)l5Oor, under activation by Mg
in the presence of B(OBU"),,~~~
to a mixture of regular (e.g.geraniol and oc-geraniol)
and tail-to-tail linked alcohols. With Zr complexes the products were exclusively
tail-to-tail linked trienes.15, Isoprene on treatment with Mg formed a series of
dimeric and polymeric complexes in equilibrium, which on addition of 2-chloromethylbutadiene gave myrcene and irregular hydrocarbons formed by 1-2 and 1-3
linking.153Coupling of the trimethylsilyl derivative (46) of isoprene with 3-methylbutyraldehyde gave ipsenol (47) .154 A very detailed mechanistically orientated
study of theaction of HC104, F3C0,H, and HC02H on the 1,l and 3,3-dimethylallyl
alcohols has secured conditions for 'biomimetic' condensations leading to 3,7dimethylocta-6-ene-l,3-diol(86 %; and thence to geraniol) and also to lavandulyl
compounds (irregular).155Use of other suitably functionalized isoprenes has led to
the sequences (48)+(49)156 and (50)+(5 I) (Scheme 3).157J58
Other interesting routes for the construction of an acyclic Clo skeleton from C,
precursors are the selective y-alkylation of Cu enolates derived from oc,p-unsaturTakagago Perfumery Co., Jap. P., 39 366/1980.
B. Ceskis, A. M. Moiseenkov, M. I. Struchkova, and A. V. Semenovski, Izv. Akud. Nuuk
SSSR, Ser. Khim., 1981, 365.
152 H. Yasuda, Y.
Kajihara, K . Nagasuna, K. Mashima, and A. Nakamura, Chem.Lett., 1981,719.
lS3 Y.Kajihara, K. Ishikawa, H. Yasuda, and A. Nakamura, Bull. Chem. SOC.
J., 1980, 53, 3035.
150 A. Hosomi, M. Saito, and H. Sakurai, Tetrahedron Lett., 1979, 429.
156 D. Babin, J.-D. Fourneron, and M. Julia, Bull. SOC.Chim. France, Part IZ, 1980, 588.
156 N. A. Romanov, E. A. Kantor, R. S. Musavirov, R. A. Karakhanov, and D. L. Rakhmankulov,
Zh. Org. Khim., 1981, 17, 1762.
lS7 A. M. Moiseenkov, E. V. Polunin, and A. V. Semenovsky, Tetrahedron Lett., 1979, 4759.
lS8 A. M. Moiseenkov, E. V. Polunin, and A. V. Semenovsky, Angew. Chem. Znt. Ed. Engl., 1981,
150
151
20, 1057.
17
Me& =CHCH,Br
c02h
(53)
A X LOSiMe,
i
P0 h
w;
OSiMe,
(54)
(55)
ated
e.g. (52)+(53) ;the use of 3-methylbuta-l,3-dienyl phenylsulphoneas a
Michael acceptor of lithiated and protected cyanohydrins, e.g. (54)455)160 (this
has led to routes to tagetones and ocimenones); and y-alkylation via metalated
unsaturated amides, e.g. (56)-+(57).l6l
+o NHMe
i: ~ ~ c = , , c ~ s ~ r
$NHMe
fHMe
(56)
(57)
An ingenious method of linking two C , units to give ultimately 10-hydroxygeraniol, a precursor for loganin and iridodial, involved photochemical coupling of
2,5-dihydro-3-methylthiophenSS-dioxide (58) with citraconic anhydride (59)
followed by thermal extrusion of SOz, Cope rearrangement of the resulting
divinyl ester, and suitable functionalization (Scheme 4).162
This work demonstrates
that (58) and its analogues offer an alternative method to the use of cyclobutenes
for the stereospecific synthesis of cis- 1,2-divinyl systems and trans,trans- 1,5-dienes.
P. M. S a w and J. A. Katzenellenbogen, J . Org. Chem., 1981,46,239.
E. Guittet and S. Julia, Synth. Cummun., 1981, 11, 709,
M. Majewski, G. B. Mpango, M. T. Thomas, A. Wu, and S. Snieckus,J . Org. Chem., 1981,46.
lSn
160
2029.
18
K-q--;::
OH
Scheme 4
A variety of routes have been explored for linkage of (rn + n) units (m + n =
10;m,n # 5.) Methylhexenone (60) could be converted into the terminal acetylene
(61) and thence into (E)-trisubstituted olefins such as g e r a n i ~ I , ~ and
~ ~ Jcould
~ * also
be protected, oxidized at a gern-dimethyl, and functionalized to give 10-hydroxyl i n a l o 0 1 ~or~ ~converted into [1,2J4C2]geranial and thence into ionones.166Hydromagnesiation of prop-Zynylic alcohols proceeds with stereo- and regio-specificity
(64)
under mild conditions in almost quantitative yields: thus nerol has been synthesized
from (62).16' Procedures involving coupling of (C, + C,) units (Me,C=CH(CH2),C1 + MeCOCHClCH2C1) to give geranyl acetate168and of (C, + C,) units
163
E. Negishi, A. 0. King, W. L. Klina, W. Patterson, and A. Silveira, J . Org. Chem., 1980, 45,
2526.
16'
16@
1*
165
1981, 718.
19
Monoterpenoids
_.,
SPh
q S i M e 3
SPh
SiMe,
SPh
J,iii
oxidation ; reduction
t
o
[(63)+(64)] have been worked out. Compound (63) has been proposed as a new
key intermediate for the synthesis of a variety of acyclic m o n ~ t e r p e n e s .PhS
~~~
groups are well known to migrate to an adjacent positive centre, and by incorporation of a Me,% group into the molecule it has been possible to encourage rearrangement from a secondary to a secondary or even a secondary to a tertiary
migration terminus. The method was illustrated by the efficient synthesis of geraniol/
nerol and l i n a l ~ ofrom
l ~ ~ (65)
~ as shown in Scheme 5 .
Trimethylsilyl-enol ethers of pentane-2,4-dione and methyl acetoacetate reacted
with linalool at room temperature without catalysts to yield the trimethylsilyl ether
(85 %), excellent for g.1.c. or m.s.171 Other interesting routes involving couplings of
(C, + C4) and (C, + C,) units to give myrcene have been r e p ~ r t e d ~and
~~J~~
elegantly conceived several-stage syntheses of (I?)-( -)-ipsdienol and the (S)-( +)isomer [a pheromone of Ips beetles (66)] were based on a previously developed
route to ipsenol (47) and utilized (I?)-( +)-glyceraldehyde and (R)-( +)-malic acid
respectively as starting rnate~ia1s.l'~
J?
HO
lo@
22,763.
170
171
178
17a
17*
17ti
20
(70)
erythro-l,2-epoxylinalool(hydroxy and epoxy cis) with vanadium catalysts gave
dihydroxymenthanes whereas the threo-isomer was decomposed; Ti(OPri), catalysed the reaction of the erythro-compound but threo was recovered unchanged.
These results were rationalized by 'OH-assisted delivery' of the metal to the oxiran
ring.17s The synthetic uses of bisulphite adducts of citrals have been explored.17B
Myrcene deuteriated at (C-8 + C-10) has been prepared,lsOandthe 3-fluoromethyl-,
3-difluoromethyl-, and 3-trifluoromethyl-geraniols have been synthesized for use
as substrates of prenyltransferase.lsl The key reaction that defined the stereochemistry of the double bond was the syn-addition of a (4-methylpent-3-en- 1-yl)
copper reagent to derivatives of ethyl but-Zynoate bearing the appropriate
functional group at C-4.
Several interesting studies have been directed towards the synthesis of insect
pheromones (see also ref. 174). (3R)-( +)-Frontalin (67), an aggregation factor of
beetle species which can be regarded, at least from the synthetic viewpoint, as a
bis-nor-monoterpene, has been obtained (25 % ;five steps) from (3R)-(-)-linal~ol:~*~
the key step was (68)+(69) using the reagent Me,SiCMe(Li)Cl; this, as a source of
carbanion in carbonyl addition followed by intramolecular displacement of
chlorine, would seem an important general route to a,P-epoxysilanes. The diol
(70), a butterfly pheromone, has resulted from geraniol by site-specific olefin
functionalization and the subsequent anionic (2,3)-sigmatropic rearrangement of
the methoxycarbonylethylallylic sulphide.lS3 Other insect pheromones of diverse
size (C&-C29)
have been synthesized using citronellol, citronellal, or citronellic
R
0 NMe,
0 NMe,
xy
(71)
176
177
178
1'9
180
181
----+
a,
(72)
(73) X
C0,H or C0,Et
Monoterpenoids
21
focHo
(74)
-;"'
PhaPCHPh
-Ph
(75)
(76)
and the reaction of isolinalool (77) to give (78).lS9Citronellyl acetate (79) coupled
with acetylenic esters in the presence of AlC13 to give (80), and the use of ethylaluminium dichloride as a catalyst allowed the isolation of pure products from
acid-sensitive alkenes.lgoMe,Cu,Li, (prepared from CuI and MeLi-LiC1)converted
a,P-unsaturated aldehydes such as geranial efficiently into @-methylaldehydes and,
unlike Me,CuLi, it usually gave a negligible amount of the 1,2-adduct (l-methylgeraniol) even when a quaternary carbon was generated in the reaction.lgl Other
studies have recorded the coupling of myrcene with organic acids in the presence of
sodium naphthalenidelg2and with vinyl cyanide and vinyl phenylsulphone to give
l-(4-methyl-pent-3-enyl)cyclohexenes1g3~1g4
and reaction of citral with substituted
acetophenones to give, e.g. (81),lg5with allyl iodide (SnF, catalyst) to give chain
extension at C-1,1g6with bis-anions derived from furoic acid to give (82),197 with
U. Jensen and H.-J. Schafer, Chem. Ber., 1981, 114, 292.
T. Sumki, Agric. Biol. Chem., 1980, 44, 2519.
IB6 K. Mori, S. Masuda, and T. Suguro, Tetrehedron, 1981, 37, 1329.
T. Mimura, Y. Kimura, and T. Nakai, Chem. Lett., 1979, 1361.
lS8 M. Suda, Chem. Lett., 1981, 967.
F. Naf, Ger. P., 2 849 332/1979.
1 9 0 B. B. Snider, D. J. Rodini, R. S. E. Conn, and S. Sealfon, J. Am. Chem. SOC.,1979, 101, 5283.
191 D. L. J. Clive, V. Farina, and P. Beaulieu, J . Chem. SOC.,Chem. Commun., 1981, 643.
192 T. Fujita, S. Watanabe, K. Suga, and H. Nakagama, Synthesis, 1979, 310.
198 R. V. C. Carr and L. Paquette, J. Am. Chem. Soc., 1980,102,853.
194 0. P. Vig, I. R. Trehan, G. L. Kad, and A. L. Bedi, IndianJ. Chem., Sect. A , 1979,17,555.
S. Y.Dike and J. R. Merchant, Indian J . Chem., Sect. B., 1978, 16, 1111.
T. Mukaiyama, T. Harada, and S. Shoda, Chem. Lett., 1980, 1507.
D. W. Knight, Tetrahedron Lett., 1979, 469.
184
22
p-
OAc
HC = CC0,Me
(79)
(80)
(83)
lS8
lSs
(84)
(85) X
S0,Ph or C0,Me
2oo
202
*03
(86)
Monoterpenoids
23
(93)
(94)
(90) : this was cyclized to two products which were separately dehydrated to nerol
oxide (91) and its enantiomer, each in 95 % optical purity.20sNerol oxide from rose
oil is racemic and it was suggested that this was produced by the direct photoxidation of nerol [natural (-)-rose oxide is believed to be similarly produced from
( -)-citronellol]. The rose oxide was also converted into sesqui-rose oxides.208a
Epoxidations, carbene additions, etc. of 2,3-epoxycitral have been
A very detailed investigation of the dye-sensitized photoxidation of a-nerol (92)
showed the formation of the diols (93) and (94) with no cyclized products.210
Allo-ocimene and myrcene on autoxidation in DMF or DMSO give an odd variety
*04
*05
*06
*07
ao8
G. Ohloff, W. Giersch, R. Decorzant, and G. Biichi, Helv. Chim. Actu, 1980,63, 1589.
L. P. Glushko, V. N . Samsonova, M. S. Malinovskii, and L. A. Yanovskaya, Zsv. A k d . Nauk
SSSR, Ser. Khim., 1980, 1048.
*lo K. H. Schulte-Elte, B. L. Mulier, and H. Pamingle, Helv. Chim. Actu, 1979, 62, 816.
*Ow
*09
24
OH
(95)
R'
R'
(97)
R'
(98)
(99)
of products,211and geranic acid was formed in 92% yield from citral by sodium
chlorite in the presence of 2-methyl-but-2-ene (a C1. scavenger).212Benzyl ethers of
nerol were oxidized at the 6,7-bond to give poor yields of products required as
intermediates for the synthesis of the antibiotic moenocinol, but epoxidation and
conversion into the sulphone (95) allowed epoxidation to (96) in good (60%)
yields.213
Electrochemical oxidations have been previously mentioned.122A novel application is the regioselective epoxidation (80 % conversion ; 90 % selectivity) at the 6,7bond of geranyl and neryl esters and phenyl ~ u l p h o n e sAnother
. ~ ~ ~ is the one-step
conversion of olefins into allylic alcohols via electrooxidative-oxyselenylationdeselenylation, e.g. (97)+(99). This method has been applied to the synthesis of
(100) which can be converted (70%) into marmelolactone [(101) from quince], and
h0-r+
0
MeSO&l-Et.N
ho0
(100)
213
214
216
?16
Monoterpenoids
25
(W
Reagents: i, Ni(OAc),NaBH,;
scheme 6
with no 1,6addition by EtCH(OMgBr)2217or to citronellol over metallic catalysts.218-220Geraniol and nerol were reductively deoxygenated with preservation of
the E- or 2-geometry by LiAlH, and [Cp2TiC12]as catalyst.221Dehydrolinalool was
effectively reduced over Pd to l i n a l o 0 1 , ~as~was
~ ~ geranic
~ ~ ~ acid to dihydrogeranic
acid over K-gra~hite.~~*
The trimethylsilyl group continues to be used as a protecting or directing group in synthesis, viz. the sequences (104)+( 105)225and ( 1 0 6 ) j
(107) (Scheme 6).226Also, a variety of A2-butenolides may be synthesized via
oxidation of the 0-trimethylsilylcyanohydrinsof ct,p-unsaturated aldehydes with
pyridinium dichromate in DMF, cf. (108)-+(109).227
Cyclizations, Isomerizations, etc.-(See also rose oxidezo8).Citral on irradiation at
relatively elevated temperatures ( > 80 "C) gave two new products (1 10a and b)
(5-10%) and a biradical route was proposed. It was demonstrated that these
products did not arise from cleavage of (1 1l), a previously known product of the
reaction: the latter gave (1 12) and (1 13) under these conditions.228A more detailed
*17
lao
*28
2Z4
a25
aa7
26
po
j
?
o
(110a)
+CHO
E C H O
(1lab)
&\
CHO
study showed that on 'n,x* excitation (A > 347 nm) the products were (1 11) and
(1 14), whereas on %,x* excitation (A = 254 nm) (1 14) and (1 1 9 , but not (1 1l),
were formed. An intramolecular [2 + 21 photocycloaddition that was shown to be a
triplet process was found on h,x* or lx,x* excitation of (1 16) to give (1 17) only,
whereas broad-spectrum irradiation (A > 280 nm) of (1 17) gave isomers of (1 18)
which photoisomerized to the oxetans (1 19).229Irradiation of citronellyl iodide
gave citronellene and various m e n t h e n e ~ . ~ ~ ~
Lao
M. Yoshioka, K. Ishii, and H. R. Wolf, Helv. Chim. Acta, 1980, 63, 571.
K. M. Saplay, R. Sahui, N. P. Damodaran, and S. Dev, Tetrahedron, 1980,36, 1455.
Mono terpenoids
I
27
Hp$-JH
HO
(123)
( 124)
Several new, or adaptations of old, cyclizations to furan and pyran derivatives
have appeared. Geranyl acetate with RuOl gave the isomers of (120)and also (121)
(51 % and 12 %),231 A more stereocontrolled synthesis yielded the bis-tetrahydrofurans (122)and (123)containing four chiral centres (each in 90% isomeric purity)
in a four-step route from geranyl or neryl chlorides that involved two stereoselective
cyclizations. The epoxide ring of (123) could be opened by an allylic Grignard
reagent and the resulting product dimerized to give (124).232
Two new routes to rose
oxide have been claimed; one from citronellyl acetate233and the other from cyclization of 3,7-dimethylocta-(Z)2,5,7-triene,which can be easily obtained from iso~rene.~~~
236
z36
437
28
tion (NaBH,) led to bicyclic ethers [e.g. (127)l. The unexpected formation of the
C-C bond is presumably due to the proximity of the Hg and the vinyl group in the
organomercurial intermediate.23s In contrast, treatment of linalool with Hg2+
salts under different conditions was claimed to lead to mainly (128).239
pq3f
I
OH
(128)
0
(131)
(132)
(129)
$q
OHC
OH
(1 30)
P (134)
O H
241
242
243
244
246
246
241
Mono terpenoids
(136)
29
(137)
(138)
(139)
(140)
24t3
35O
251
z62
263
854
30
(144) with ethyl chloroformate gave (145), whereas conversion of the exo-isomer
into the amine oxide and Cope elimination formed (146).255-256 Two elegant
(150)
Reagents: i, Me,C=CHCH,Br; ii, SnCI,; iii, NaH; iv, ClPO(OEt),;
v, LiMe2Cu; (iii, iv: conversion to enol phosphate); vi, HC0,Et-NaH
Scheme 7
/,iii-v
(151)
Reagents: i, H,-Pd; ii, HN0,-AcCH; iii, KOH; iv, H+; v, LiAlH,; vi, BunLi;
vii, TiC1,-LiAlH, ; viii, 1-methyl-2-fluoropyridinium salts
Scheme 8
25b
eaa
Monoterpenoids
31
m0
e61
26z
263
864
266
26e
269
32
General.-Reviews,
some unfortunately badly out-of-date, have appeared on
p-menth- 1-ene,271~ - m e n t h - 3 - e n em-menthane
,~~~
derivatives,273dihydrocar~one,~74
P - t e r p i n e ~ land
, ~ ~on
~ aspects of the chemistry of a ~ c a r i d o l eThe
. ~ ~enantiomers
~
of
(155), together with products of cleavage of the dioxide bond (but no a~caridole),~~
1-hydroxy- and 1,4-dihydroxy-derivativesof ~ - m e n t h - 2 - e n e other
, ~ ~ ~ oxygenated
p - m e n t h e n e ~ ,and
~ ~ ~various 2-nitro-p-rnenthadiene~~~O
have been isolated from
assorted plants.( -)-Mint lactone (156) and its epimer at C-3 occur in Mentha spp.
and have been prepared by oxidation of menthofuran.281More extensively functionalized p-menthanes, e.g. (1 57),282(1 58) (R= Et or Pri),283and 1-vinyl-p-menth-4(8)ene284also occur naturally. Two new glucosides [schizonepetosides (1 59 ; isomers)]
occur in Schizonepeta s p ~ .and
, ~ menthyl-p-D-glucosides
~ ~
were found in Mentha
spp. :z8s the latter have been prepared and the isomers separated by g.c. of acetyl
derivatives.287Pyrolysis of an incense derived from Boswelliu spp. gave (160) and
fiH
(159)
QPh 0
II
271
279
275
270
277
478
279
280
281
283
284
28s
280
Monoterpenoids
33
related corn pound^.^^^^^^^ The optical properties (c.d. etc.) of conjugated cisoid
dienss, and enones including pulegone and cx-phellandrene, have been studied.O
A menthofuran derivative was a main constituent of an Anethum species:291menthofuran itself has been efficiently synthesized from a - p ~ l e g o l p
, ~u~l e~ g 0 n e , ~ ~or~ ~ ~ ~ 4
2-carboxyethyl-5-methylcyclohexanone.295A synthesis of the related (R)-(-)evodone (161) from (R)-(+)-citronellic acid confirmed the natural isomer to the (R)c o m p o ~ n d96. ~
A mixture of o-menthanes resulted from reduction of o-cymene with Ca(NH3),,2S7
and a neat route to the o-menthane skeleton involved photochemical addition of
allene to 3-methylcyclohex-2-en-1-one and opening of the cyclobutyl ring with
BF3.2980-Menthadi- and tri-enes resulted from pyrolysis of ~ e r b e n e n e . Acid~~Q
and base-promoted isomerizations of o-menthadienes300 and dehydration of
cis- and trans- o-menthan-8-01s with a variety of reagents have been re~orded.3~1
Optically active 2-methyl-4-isopropenylcyclohexanone(which is a useful precursor
for rn-menthane derivatives) has been prepared by pyrolysis of chiral2,2,5-trimethylbicyclo[3.1.l]heptan-2-0ne.~~~
Formation of the Menthane Skeleton.-Isoprene cyclodimerized in the presence of
Ni303 or Fe304$305
catalysts to mixtures of m- and p-menthadienes, 1,4-dimethyl-4vinyl- and 1,3-dimethyl-3-vinyl-cyclohexenes,and
dimethylcyclooctadienes. An improved synthesis of piperitone from mesityl oxide and methyl
vinyl ketone has been devised,306and the latter condensed (NaH) with methyl
2-methyl-1-carboxymethylpropyl ketone to yield (162), which could be cyclized
under appropriate conditions to give excellent ( > 80 %) yields of either 0- or p men then one^.^^' Myrcene yielded p-cymene on heating with metal
( +)-citronella1 was selectively cyclized to (-)-isopulegol by Zn halides,309and the
288
289
280
293
ZQ4
17, 320.
300
301
302
303
304
305
306
307
308
30s
34
bisulphite compound of citra1310or the PhSeOH adduct (at C-6 to C-7) of linaloyl
acetate311 (cf. ref. 242) readily cyclized to p-menthane derivatives. Long-term (8
months) treatment of citral with HCl gave a variety of oxygenated derivatives of
p-cymene and of piperitone that were responsible for the odour of deteriorated
lemon oil?, The benzylimine derived from citronellal was cyclized by SnCl, to give
(after reduction and debenzylation) menthylamine together with its neo- and
neo-iso-isomers (75 % total; 7: 1: 2):312athis shows that an imido function can
initiate acid-catalysed cyclization of polyenes, and an additional advantage of the
method is that chirality may be introduced by reason of a chiral group linked to N
(e.g. 36 % chiral induction when chiral citronella1 was used).
More defined rou+te_shave been developed to specific compounds. Use of five
equivalents of Me,PCH, under 'salt free' conditions (necessary) converted 4carboxyalkylcyclohexanones into p-menth- 1(10),7-diene.,13 An example of a
general ketone to enone homologation is the reactign of 4-methylcyclohexanone
with the anion from alkylchlorosulphoxides [R(Cl)CSOPh] to yield (after intramolecular displacement of C1) the epoxide (163), which on pyrolysis gave (164) that
could be easily converted into p-menth-3-en-8-01.~~~
A highly stereoselective route
to both diastereoisomers of p-menth-1 -en-Pol was developed using kinetically
controlled alkylations and epimerization of the lactone (165) to control the stereochemistry :315 the intermediate was synthesized from 6-methylcyclohex-2-en-1-01.
Silyl-Li reagents mixed with Cu' salts reacted with enones to give @-silylketones
in good yield. These could be used in synthesis without risk to the silyl groups and
the enone grouping could be restored by bromination-desilylbromination with
CuBr,. The method is illustrated by an efficient synthesis of carvone (166) (Scheme
9).3l6
Jiii, iv
y&L
PhMe,Si*
(166)
Reagents: i, (PhMe,Si),CuLi; ii, MeI; iii, MeLi; iv, H,O+;
V,
Scheme 9
alo
sll
312
alea
313
314
s16
Monoterpenoids
35
Another impressive use of silyl reagents came in the sequence leading to 8terpineol (167).,17 Homologation of 5-methylcyclohex-2-en-1-onecatalysed by
FeO complexes led (after appropriate functionalization) to menthone and isom e n t h ~ n ewhereas
, ~ ~ ~ Pd'I-catalysed coupling of 2-bromopropene with l-methylcyclohexa-1,3-diene gave p-mentha- 1,3,8-triene
Treatment of a-pinene
with Bz,02 and Cu' salts gave the benzyl derivative of trans-carveol, which could
be converted into carvone in 46% overall yield:320the phenylurethane of pinol
formed (1 68) on pyrolysis.321
II
C0,Me
II
C0,Me
OH
(168)
(167)
318
31g
320
321
322
323
324
386
386
327
D. H. R. Barton, J. P. Kitchin, D. J. Lester, W. B. Motherwell, and M. T. B. Papoula, Tetrahedron, Suppl. 9, 1981, 37, 73.
A. Horinaka, E. Yo, 0. Mori, and K. Naya, Bull. Chem. SOC.J., 1979, 52, 2372.
36
?G
CHO
Monoterpenoids
37
A plethora of papers records the epoxidation (both mono- and di-) ofp-menthenes
and p-menthadienes and their derivatives, and the products (usually very predictable) formed on ring-opening of the epoxides with a variety of reagents. A selection
comprises reactions of p-menth- l-ene,341p342
p-menth-7-ene (en route to p-menthenp-menth-8-en-7-01,~~
limonene,3429346-349
puleolides), 8-~hloro-p-menth-l-ene,~*~
gone,350g351
piperit~ne,~~~
carveol, 355-357 and 2,8-cineolederivatives.358
The most interesting paper of this
reports the radical-induced ringopening of the epoxide and provides a convenient alternative to the Wharton
rearrangement. As generalized from the example studied, Bun3Sn reduction
of an a,P-epoxy-o-thiolcarbonylimidazolide derivative of an alcohol led, via
(1 8 5 )
341
342
343
344
345
346
347
348
340
350
351
352
a53
s54
355
358
3J7
358
Takasago Perfumery, Co. Ltd., Jap. P., 154 929/1980 (Chem. Abstr., 1981, 94, 157 112).
K. Arata and K. Tanabe, Bull. Chem. SOC.J., 1980, 53, 299.
T. J. Brocksom and J. T. B. Ferreira, Synth. Commun., 1981, 11, 105.
R. Mestres, M. C. Polo, and M. J. Valero, An. Quim., 1979, 75,970.
T.J. Brocksom, J. T. B. Ferreira, and A. L. Braga, J. Chem. Res. ( S ) , 1981, 334.
F. Delay and G. Ohloff, Helv. Chim. Acta, 1979, 62, 2168.
R. W. Rickards and W. P. Watson, Aust. J. Chem., 1980, 33,451.
0.P. Vig, S. D. Sharma, S. S. Bori, and M. Lal, Indian J. Chem., Sect. B, 1978, 16, 739.
L. A. Mukhamedova, F. G. Nasybullina, and M. I. Kudryavtseva, Izv. Akad. Nauk SSSR, Ser.
Khim., 1979, 847.
J. Sepulveda, M. C. Polo, and R. Mestres, An. Quim., 1979, 75, 398.
A. Horunka and K. Naya, Bull. Chem. SOC.J . , 1979, 52, 1964.
A. Baragliu, G. Grandolini, C. Rossi, and C. G. Casinovi, Tetrahedron, 1980, 36, 645.
H. Orszanska, K. Witkiewicz, and Z. Chabudzinski, Pol. J. Chem., 1980, 54,45.
L. Friedman and J. G. Miller, Science, 1971, 272, 1044.
A.Yasuda, H. Yamamoto, and H. Nozaki, Bull. Chem. SOC.J., 1979, 52, 1757.
D.H. R. Barton, R. S. H. Motherwell, and W. B. Motherwell, J. Chem. SOC.,Perkin Trans.
I, 1981, 2363.
A. Itoh, K. Oshima, S. Sasaki, H. Yamamoto, T. Hiyama, and H. Nozaki, Tetrahedron
Lett., 1979, 4751.
D. Mrozinska and K. Piatkowski, Pol. J. Chem., 1980, 54, 693.
38
380
381
Monoterpenoids
39
3B0
381
383
40
308
380
400
Ool
Oo2
403
Oo4
Oo5
406
Oo7
408
408
410
41i
412
013
414
(16
Taiyo Perfumery Co. Ltd., Jap. P., 162 712/1980 (Chem. Abstr., 1981, 94, 127 159).
J. A. Findlay, D. N. Desai, and J. B. Macaulay, Can. J . Chem., 1981, 59, 3303.
I. Casinos, R. Mestres, and M. Valero, An. Quim., 1980, 76, 70.
D. Hoppe, R. Hanko, A. Bronneke, and F. Lichtenberg, Ang. Chem. tnt. Ed. Engl, 1981, 20,
1024.
S. D. Pirozhkov, K. V. Puzitskii, T. N. Myshenkova, K. C. Ryabora, and S. S . Poddubnaya,
tzv. Akad. Nauk SSSR, Ser. Khim., 1979, 841.
E. Pother, Bull. SOC.Chim. Fr., Part I t 1981, 335.
R. H. Frazier and R. L. Harlow, J . Org. Chem., 1980, 45, 5408.
K. Nagai and M. Nakayama, Bull. Chem. SOC.J., 1981,54, 3607.
Monoterpenoids
41
(192)
(193)
Products of addition of IF424and of N-chlorosulphonamides425
to p-menth-1-ene,
of Br, to y - t e ~ i n e n e of
, ~ ~NOCl
~
to ~-menth-3-ene,~~'
and of hydration of at e r p i n e 0 1 have
~ ~ ~ been characterized. An interesting example of remote and selective
GH GBUn3
i, NaH-CS,-Me1
m-CIC,H,CO,H
ii, Bun,SnH
(194)
(195)
42
p31
433
433
434
435
436
p37
438
438
440
441
442
443
p44
445
Monoterpenoids
43
(1 96)
(1 97)
dihydrocarvonehas been reported.44sPhotochemicallyinduced addition of allene to
piperitone gave (198), which underwent acid-catalysed rearrangement to (199).447
Irradiation of terpinen-4-01 in the presence of HgO-Iz gave 2-iodo-l,4-cineole
which could be reduced to 1,4-cineole (79 %).448 Iodometric assay of ascaridole gave
15 products, some iodinated, some derivatives of 1 , 4 - t e r ~ i nLimonene
.~~~
reacted
OMe
(203)
P. Bakuzis and M. L. F. Bakuzis, J . Org. Chem., 1981, 46, 235.
D. K. M. Duc, M. Fetizon, I. Hanna, A. Olesker, C. Pascard, and T. Prange, J . Chem. SOC.,
Chem. Commun., 1980, 1209.
u* H. Takahashi and M. Ito, Chem. Lett., 1979, 373.
E. Rucker and U. Molls, Arch. Pharm. (Weinheim, Cer.), 1980, 31, 237.
~0 R. M. Scarborough, A. B. Smith, W. E. Barnette, and K. C. Nicolaou, J . Org. Chem., 1979,44,
44a
1742.
461
46a
458
464
44
457
458
45
Mono t erpenoids
& fi
&i
OLi
(207)
471
Li
(208)
(209)
47z
478
474
476
476
477
478
479
480
481
482
,1133
484
46
486
Mono terpenoids
47
(212)
(213)
camphor on deamination gave isotricyclen-Zone(13 %) :509 opening of the C, ring
of the latter gave bicyclo[2.2.1lheptane d e r i v a t i ~ e s .Fenchocamphorone
~~~*~~~
(210)
was oxidized (Se0,) to the quinone and functionalized (CH2N2; Pd-H,) to
(21 l).512Carvonecamphor (212) gave (hv, MeOH; Br,; A) the isomers of (213). The
epimer of the initial product (exo-Me) resulted from cleavage of the C4 ring to a
biradical which r e c y c l i ~ e d . ~ ~ ~
8 The Isocamphane Class
(214)
(2 15)
(2 16)
into 5-iodocamphene and 5,6-dihydrocamphene, and so provides a route to otherwise inaccessible homoallylic functionalizations of c a m ~ h e n e . (-)-Camphene
~l~
resulted from syn-elimination of derivatives of ( +)-isocamphenilanic a~id.51~~5~0
The absolute configuration of the acid was established by X-ray analysis.52o
This confirms the previously deduced stereochemistry of (-)-camphene as (1S,4R)
but is in conflict with an earlier report of the conversion of (-)-camphene into the
(-)-acid.
An efficient route to 7-oxocamphene involved as its key step the solvolytic
rearrangement of 3,3-ethylenedioxyisobornyl tosylate (derived from camphorq ~ i n o n e )Brief
. ~ ~ (3
~ min; 0 "C) treatment (PCl,-CaCO,) of borneol gave excellent
yields of camphene hydrochloride: longer reaction times gave bornyl
0.E. Edwards, J. Dixon, J. W. Elder, J. R. Kolt, and M. Lesage, Can.J. Chem., 198 1,59,2096.
A. Garcia-Martinez and A. Garcia-Fraile, An. Quim., 1980, 76, 127.
m A. Garcia-Martinezand A. Garcia-Fraile, An. Quim., 1980, 76, 327.
612 R.F. Childs and C. V. Rogerson, J . Am. Chem. SOC.,1980, 102,4159.
T. Gibson, J. Org. Chem., 1981, 46, 1073.
614 E. Dworan and G. Buchbauer, Chem. Ber., 1981, 114, 2357.
2.M. Ismail and H. M. R. Hoffmann, J. Org. Chem., 1981,46, 3549.
616 J. Bachner, U. Huber, and G. Buchbauer, Monatsh. Chem., 1981,112,3517.
617 G. Buchbauer, W. Pernold, D. Rassl, and B. Black, Monatsh. Chem., 1981, 112, 517.
618 S. N. Sunyawanshi and U. R.Nayak, Tetrahedron Lett., 1979, 269.
a8 G. W. Hana and H. Koch, Chem. Ber., 1978,111,2527.
I B 0J. M. Midgley and six others, J. Chem. Soc., Perkin Trans. I , 1978, 1312.
621 D. G. Patil, H. P. S. Chawla, and S . Dev, Tetrahedron, 1979, 35, 527.
OZ8 R. W. Carman and I. M. Shaw, Aust. J. Chem., 1980, 33, 1631.
510
48
Monoterpenoids
49
,*.
CD,
b b
\
641
643
b43
644
645
640
647
648
64a
660
661
66*
663
50
667
668
66B
680
Oel
662
683
664
565
667
66s
c70
671
Mono terpenoids
51
(222)
(223)
(224)
(225)
and 2-methyland a l l o - o ~ i m e n e . ~
Pyrolysis
~~
of 3-methylnorpinan-2-0ne~~~
~ e r b a n o n egave
~ ~ ~the expected o-menth-3-ones but trans-verbenol was cleaved
differently to give 4-0x0-1,3,3-trimethylcyclohex-1-ene.576a-Pinene oxide was
but over salts
converted into carvacrol over Group 8 transition metals at 200 0C,577
of other metals campholenaldehyde and its 4-methyl isomer were mainly (ca. 90 %)
formed.578 P-Pinene oxide yielded p-menth-1-ene-7,8-diol on treatment with
Hg2+.57 9
Homologation, More Complicated Functiona1ization.-As an example of a genera1
synthesis of methylenecycloalkanesfrom cycloalkenes, a-pinene was coupled with
B-(cycloalkylmethyl)-9-BBN. The product was treated with CO, reduced, and
10-Trimethylfinally decomposed with PhCHO to yield 3-methylene-ci~-pinane.~~~
silyl-a-pinene on acylation (RCOC1-A1Cl3, -90 "C) gave (223) (R = Me or
CH=CMe,). The reaction also proceeded for the 7-silyl derivative of p-menth-lene, formed from P-pinene under slightly different
5-( 1,2-Diethylhepty1)resorcinol was coupled at C-4 of myrtenyl trimethylacetate to yield an
analgesic compound;582the 4-SnMe3,5834-PhS02, 4-CH20H, and 4 - m e t h ~ l e n e ~ ~ ~
derivatives have also been prepared. The lactone (224) resulted from (10-piny1)acetic acid + A c C ~and
, ~ the
~ ~corresponding saturated and unsaturated lactones
derived from the (3-0x0- lO-pinyl)-a~id~~~
and also from (225)587have been reported.
Addition of dichlorocarbeneto a- or P-pinene followed by treatment with Me3SiC1Li yielded (for the a-isomer) products (226) and (227).588Diels-Alder adducts of
10-methylene-a-pinene589
and products of annelation (with extrusion of SO2) of
@-pinenewith tetrachlorothiophen 1,l-dioxide have been
M. Nomura, Y. Fujihara, and Y . Matsubara, Yukuguku, 1979,28,919.
A. Yoshikoshi, K. Takagi, T. Nishimura, M. Iwamoto, and K. Kojo, Jap. P., 132 541/1978
(Chem. Abstr., 1979, 90, 187 171).
676 J. P. Konopelski, P. Sunderaraman, G. Barth, and C. Djerassi, J . Am. Chem. Soc., 1980,102,
2737.
6 7 6 S. Escher, W. Giersch, and G. Ohloff, Helv. Chim. Actu, 1981, 64, 934.
6 7 7 T. Kurata, Yukuguku, 1981, 30, 562.
578 K. Arata and K. Tanabe, Chem. Lett., 1979, 1017.
678 S. L. Ecoto, Eur. P., 21 952/1979.
6 B 0 H. C. Brown and T. M. Ford, J. Org. Chem., 1981, 46, 647.
681 J. P. Pillot, G. Deleris, J. Dinogues, and R. Calas, J . Org. Chem., 1979,44,3397.
6*2 R. Mechoulam, N. Lander, and S. Dikstein, U.K. P., 2 027 021/1980 (Chem. Abstr., 1981,95,
80 289).
A. N. Kashin, V. N. Bakunin, Y . K. Grishin, I. P. Beletskaya, and 0. A. Reutov, Izv. Akud.
Nauk SSSR, Ser. Khim., 1980, 1950.
684 H. Takayanage and C. Nishino, Agric. Biol. Chem., 1980,44,2877.
686 J. J. Becker, Ger. P., 3 016 111/1981 (Chem. Abstr., 1981, 94, 65 471).
686 J. J. Becker and G. Ohloff, Ger. P., 3 025 449/1981.
6a7 Z. Rykowski and Z. Chabudzinski, Pol. J . Chem., 1980, 54,741.
M. Laguerre, M. Grignon-Dubois, and J. Dunogues, Tetrahedron, 1981, 37, 1161.
68Y S. W. Markowicz and B. Bouchwic, Pol. J . Chem., 1979, 53, 221.
690 M. S. Raasch, J. Org. Chem., 1980, 45, 856.
673
674
52
(226)
(227)
(228)
Myrtanyl derivatives (i.e. a-pinene substituted at C- 10)with NHNH2,591SC(CN)NR2,592OCH,SMe, and OCH,CN593 and trans-pinane substituted at C-10 with
CH,CH,NO, (from reaction of p-pinene with nitroethylene-a possibly useful
~ y n t h o n and
) ~ ~alkylated
~
at C-10 and formylated at C-3 (as intermediates en route
to prostaglandin analogues in which ether links were replaced by carbon groupi n g ~ have
) ~ ~
been
~ reported. N-Alkylmyrtenylamines are useful for optical resolution of
The use of chiral pinane derivatives-in asymmetric syntheses has
been expanded: ( +)-(3,2,1O-q-pinene)-PdI1 acetate in the presence of Cu" and
0, catalysed the asymmetric cyclization of 2-allylphenols to benzo[b]furan
derivatives,597and chiral aminyl oxides [e.g. (228)] effected enantiomeric oxidation
(7 % e.e.) of benzoin to b e n ~ i l This
. ~ ~is~a rare example of asymmetric induction
in atom transfer from carbon. The adduct of monoisopinocamphenylborane with
NNN'N'-tetramethylethylenediamine is stable and readily prepared : treatment
with BF, liberated the free b ~ r a n e . ~ ~ ~
Norpinane Derivatives.-Apopinene (6,6-dimethylnorpin-2-ene)underwent ring
cleavage on treatment with PdC1,-AcOH to give 1,2,3-trimethylbenzene by a
concerted path involving a Pd complex; this is believed to be the first reported
opening of the C4 ring of the pinane skeleton by C-1-C-7 cleavage.600Nopinone
(6,6-dimethylnorpin-2-one)
was easily synthesized from ethyl 4-oxocyclohexane-lcarboxylate,601and was readily alkylated at C-3 by organosilicon reagents802and in
the presence of ,H,O-NaOH rapidly took up one atom of tracer at C-3 via base
attack from the cis-face (steric hindrance).544The ketone has also been ring-opened
and converted into 2,2-dimethyl-4-t-butylcyclohexan-l-one603
and converted into
apoverbenone and its ring-opened
The 6,6-dimethylnorpinane
skeleton and also that of camphane were coupled via C-3 and C-4 to the N-phenyl2,4-disulphotetrahydropyrimidinering
J . N. Shah, Indian J. Chem., Sect. B., 1979, 18, 488.
K . Friedrich and M. Zamkanei, Chenz. Ber., 1979, 112, 1916.
593 J. A. Schwindeman and P. D. Magnus, Tetrahedron Lett., 1981, 22,4925.
5 84
D. Ranganathan, C. B. Rao, S. Ranganathan, A. K. Mehrotra, and R. Iyengar, J. Org. Chem.,
1980,45, 1185.
5 95 M. F. Ansell, M. P. L. Caton, M. N. Palfreymer, and K. A. J. Stuttle, Tetrahedron Lett., 1979,
4497.
5 96 S . W. Markowicz, Pol. J. Chem., 1979, 53, 157.
5 9 7 H . Hosakawa, T. Uno, S. Inui, and S. I. Murahashi, J. Am. Chem. SOC.,1981, 103, 2318.
6 9 8 C. Berti and M. J. Perkins, Angew. Chem. Int. Ed. Engl., 1979, 18, 864.
5 9 9 H. C. Brown, J . R. Schwier, and B. Singaram, J. Org. Chem., 1978, 43,4395.
6 0 0 R. M. Giddings and D. Whittaker, Tetrahedron Lett., 1978, 4077.
801 G . S. S.Murthi and A. Mazumder, Indian J. Chem., Sect. B, 198L 20, 339.
602 T. Yanami, M. Miyashita, and A. Yoshikoshi, J. Org. Chem., 1980, 45, 607.
803 J. P. Konopelski and C. Djerassi, J. Org. Chem., 1980, 45, 2297.
604
M. T. Edgar, G. Barth, and C. Djerassi, J. Org. Chem., 1980, 45, 2680.
605
A. M. Lamazouene and J. Sotiropoulos, Teirahedron, 1981, 37,2451.
5 91
5 92
Monoterpenoids
53
Diels-Alder reaction of methylcyclopentadiene and CH,= CCl(CN) gave 1-methylnorborn-5-en-2-one (57 %), which was hydrogenated and methylated to fenchone
(30 %).606 endo-Fenchol on dehydration (KHS04) gave a mixture of fenchenes and
c y c l o f e n ~ h e n e s .Fenchone,
~~~
on treatment with Ph,PCH(Li)OMe-a
reagent
allegedly good for homologation of sterically hindered, enolizable ketones-gave the
endo-formylated derivative : menthone under similar conditions gave a 79 % yield
of expected products, but camphor only 10 %.608 Fenchone preferentially complexed
with P - c y c l o d e ~ t r i nand
~ ~ ~underwent Wittig addition followed by functionalization;610and the addition of the 2-lithio-derivative of anisole.6112-Diphenylmethylenefenchane (from Wittig reaction of fenchone) underwent photochemical WagnerMeerwein rearrangement, forming (229) ?, this singlet-state reaction, which in
the ground state is characteristic of species with electron-deficient carbon atoms at
the rearrangement terminus, suggests the intermediacy of a twisted excited state of
the substrate.
4i$&@
(230)
(231)
(229)
The chloride of fenchane-2-carboxylic acid decomposed (Et,N, hv) to tricyclof e n ~ h a n e . ~Thiofenchone
~
on irradiation gave (230) and the corresponding disulphide ; thiocamphor behaved similarly.614 Selenofenchone could easily be
converted into syn-2,2-bifenchylidene (231) : this is an excellent model system for
the study of hindered 01efins.~~~
11 The Thujane Class
607
608
608
610
Ell
612
613
614
615
54
Monoterpenoids
55
acids (232) and their ring-opened products, which were starting materials for
efficient syntheses of pyrethrin a n a l o g ~ e s . ~ ~ ~ . ~ ~ ~
1980, 1052.
56
648
648
Mono terpenoids
57
Occurrence.-A review covers the I3C and lH n.m.r. of iridoid glucosides and
includes data on new
These compounds have been produced by
cultured cells of a Gardenia sp.673The insect antifeedant properties of the glucoside
ipolamide have been
The iridoid glycosides (and to a much lesser
extent the irregular monoterpenes, Section 14) are the only naturally occurring
monoterpenes that are still being discovered in large numbers. Many new iridane
derivatives with a bewildering variety of exotic names have been reported from a
range of plant genera, not all of which produce terpene alkaloids. They are
e0
OR2
664
665
667
10
..q0
CO,Me
0-,3-G
B. M. Mane, K. G. Gore, and G. H. Kulkarni, Indian J. Chem., Sect. B, 1980, 19, 711.
M. Kozlowska and W. Sobotka, Pol. J. Chem., 1980, 54,957.
R. B. Mitra, A. S. Khanra, and A. R. A. S . Deshmukh, Indian J. Chem., Sect. B, 1981,20,436.
672 S. Damtoft, S. R. Jensen, and B. J. Nielsen, Phytochemistry, 1981, 20, 2717.
6 7 3 S. Ueda, K. Kobayashi, T. Muramatsu, and H. Inouye, Planta Med., 1981, 41, 186.
w4 E. Bernays and C . Deluca, Experientia, 1981, 37, 1289.
670
58
Mono terpenoids
59
F. U. Afifi-Yazar, 0. Sticher, S. Uesato, K. Nagajima, and H. Inouye, Helv. Chim. Acta, 1981,
64,16.
?02
7 oa
704
706
7 06
707
708
70s
710
711
712
713
714
60
pounds, 735-737 and documenting rare occurrences and unexpected sources. 738-745
Of especial interest is a revision of the structure of xylomollin: synthetic and
spectroscopic studies and X-ray analysis of the 1-0-acetyl derivative show it to be
the first characterized example of a naturally occurring trans-fused iridoid. 746
736
737
738
73n
740
742
743
744
745
7079.
F. Murai and M. Tagawa, Chem. Pharm. Bull., 1980,28, 1730.
'748 B. M. Trost and D. M. T. Chan, J . Am. Chem. SOC.,
1981,103, 5972.
748 T. H . Jones, M. S . Blum, and H. M. Fales, Tetrahedron Lett., 1980,21, 1701.
750 M. S. Blum, J. B. Wallace, R. M. Duffield, J. M. Brand, H. M. Fales, and E. A . Sokoloski,
J . Chem. Ecol., 1978, 4,47.
751 T. H. Jones and M. S . Blum, Tetrahedron Lett., 1981, 22,4373.
7 5 2 K. Kon and S . Isae, Tetrahedron Lett., 1980, 21, 3399.
753 Y. Yamada, H . Sanjoh, and K. Iguchi, Chem. Lett., 1978, 1405.
754 T. Sakai, K. Morita, C. Matsumura, A. Sudo, S. Tsuboi, and A. Takeda, J . Org. Chem., 1981,
46,4774.
755 T. Imagawa, T. Sonobe, H. Ishiwari, T. Akiyama, and M. Kawanisi, J . Org. Chem., 1980,45,
2005.
756 C. Beaupin, J. C. Rossi, J. P. Vidal, J. P. Girard, and J. Passet, Phytochemistry, 1980,19, 1541.
7 5 7 J. D. White, J. F. Ruppert, M. A. Avery, S . Torii, and J. Nokami, J . Am. Chem. SOC.,1981,103,
1813.
768 S . W. Baldwin and M. T. Crimmins, J . Am. Chem. SOC.,1980, 102, 1198.
747
Monoterpenoids
61
Dolichodiol was converted into iridoid lactones by the N-halogenosuccinimide-Me,S complex. 759 A new synthesis of loganin and related compounds
started with the regioselective sulphenylation of P-keto-esters (such as ethyl
2-oxocyclopentane- l-carboxylate) followed by conversion into the p-thioalcohols,
oxidative cleavage, and c y c l i ~ a t i o nA. ~most
~ ~ impressive route to the skeleton (237)
involved a rare type of intramolecular ene reaction of (246).761Cyclization of (247).
prepared by Wittig reaction of diethyl oxomalonate, gave elenolic acid. 762
Eight- to sixteen-step syntheses of isoiridomyrmecin and verbenalol, 763 iridomyrrne~in'~*
allodolicholactone (first synthesis), iridomyrmecin and its i ~ o - e p i m e r ~ ~ ~
and ~ a r r a c e n i nhave
~ ~ ~been reported.
The aglycones of a s p e r ~ l o s i d o and
l ~ ~ ~its derivatives76s rearranged in acid to
tetracyclic acetals : under similar conditions other iridoid glucosides (harpagide,
antirrhide) opened to cyclopentane derivatives,768 and lamiigenin was similarly
cleaved by NaBH, in a Knoevenagel-type process. 769 C a t a l p 0 1 ~and
~ ~ other
lactones771 have been reduced and functionalized, geniposide has been converted
by a biogenetic-type transformation into p l ~ m i e r i d e , ~
aucubin
~,
has been used as a
starting material for prostaglandin
and attempts have been made to
convert the aglucone of kingiside into xylomollen. 774
Secologanin on enzymic cleavage, acid treatment, and oxidation gave elenolide
(248), and the sequence established the chirality as shown at the point of attachment
of the side-chain. 7 7 5 [10-13C]Secologaninwas synthesized in a seven-step process
from ethylene a ~ e t a lHop
. ~ ~ether
~ (249), the irioid most simply related to geraniol,
was synthesized in six steps from the protected lactol form of 3-formyl-2-methoxycarbonylcyclopentanol. 7 7 7
750
760
103,3468.
767
768
76*
'70
771
772
773
775
776
777
778
K. Inoue, Y. Takeda, H. Nishimura, and H. Inouye, Chem. Pharm. Bull., 1979, 27, 3115.
M. Naruto, K. Ohno, and N. Naruse, Chem. Lett., 1978, 1419.
S. B. Hassam and C. R. Hutchinson, Tetrahedron Lett., 1980, 21, 1209.
L. F. Tietze and H. C. Uzar, Angew. Chem. Znt. Ed. Engl., 1979, 18, 539.
L. F. Tietze and S. Henke, Angew. Chem. Znt. Ed. Engl., 1981, 20,970.
T. Imagawa, N. Murai, T. Akiyama, and M. Kawanisi, Tetrahedron Lett., 1979, 1691.
D. Arlt, M. Jautelat, and R. Lantzsch, Angew. Chem. Znt. Ed. Engl., 1981, 20, 703.
62
(253)
(254)
781
782
783
784
785
786
787
788
789
7g0
7g1
7g2
7e3
784
'g6
Monoterpeno ids
63
64
acids have been developed.815-822Perhaps the two most intere$ng used 2,5dimethylhex-3-yne-2,5-diol
(commercially available) as starting materia1,"l or involved addition to 3,3-dimethylacrylate esters of the thiovinylcarbene formed on
photolysis of gern-dimethyl-5-ethylthiopyra-a~olenine.~~~
Ethyl 2-bromo-3,3-dimethylacrylate is a new synthon for p y r e t h r o i d ~ and
, ~ ~ ~useful intermediates for
these compounds could be prepared from ~ a r - 3 - e n eThe
. ~ ~ difference
~
of the 13C
n.m.r of the gem-dimethyls shows whether chrysanthemate derivatives are cis or
trans;825homogenous Pd complexes are excellent catalysts for the cis+trans isomerizations.826 Photosensitized oxidation of trans-chrysanthemic acid gave the
expected
the epoxides of both cis- and trans-acids and of pyrethrins
were decarboxylated readily ( e . g . o n t.l.c.).82R
A variety of chrysanthemic ester analogues with ~ h l o r i n e ~ or
~ ~other
-*~~
substituents (e.g. Br, SMe, or CN)833-836
on the double bond or on the ring,837and of
substituted cyclobutanones that are precursors of pyrethroids, have been obtained
by more or less standard routes. 838-840 The absolute configurations of synthetic
pyrethroids containing the a-ethylvinyl alcohol moiety have been determined84L
and p h o t ~ c h e r n i c a l ~
and
~ ~enzymic
- ~ ~ ~ (esterases from worm larvae)846degradations
of pyrethroids have been elucidated.
el5
Monoterpenoids
65
'i
QH
?!
OH
(259)
. ,
(260)
to be the first synthesis of a metabolite functionalized in both the terpenoid moiety
and in the ~ i d e - c h a i nCoupling
.~~~
of pulegone with 3-X-resorcinols (X= C5HII or
Me), protection of the phenolic group with SiMe,Bu', bromination and aromatization (NBS,hv) of the C, ring, and deprotection gave improved routes, claimed the
best available, to cannabinol and cannabiorcol respectively.853The bis-tetrahydropyranyl homocuprate of olivetol reacted with dehydrolinalool (in a reaction general
for propargylic halides and acetates) to give a versatile synthesis of cis-6a,lOa-AsTHC. 854 A modification of a previously described synthesis of this by condensation
of olivetol with citral opened a convenient route to the t r a n s - i ~ o m e r AS-THC
.~~~
with a modified side-chain at C-3 resulted from reaction of the appropriate resorcIn yet another
inol derivative with trans-verbenol in the presence of a Lewis
variant of the general method, substituted resorcinols reacted with the enolate of
( +)-citronella1 to give an intermediate which underwent a stereocontrolled
[4 + 21 heterodiene cycloaddition to give (261). The structure and conformation of
847
848
849
850
851
863
854
E55
66
this were elucidated by 13Cn.m.r. and X-ray analysis.856Less general syntheses have
been carried through for hydroxylated and oxidized derivatives of AS-THC
functionalized in the ~ i d e - c h a i or
n ~at~ ~C-1 1,868-859
for derivatives of As-THC with
the side-chain completely modified (262) (R = Ar or CR=CR2),s60and for sidechain analogues of AsaJoa-THC.8s1Most of the compounds were required for
testing as potential therapeutic agents. A8-THC glucoronide has been synthesized
and its metabolism in rats investigated.s62 [ 1 1-2H,]-cis-6a,10a-A9(11)-THC and its
trans-isomer were easily prepared from [ 1-2H, ] g e r a n i ~ and
l ~ ~14C~ and 1251-labelled
cannabinoids have also been ~ynthesized.~~~9
865 Citronella1 condensed with barbituric acid and related compounds to form enantiomeric tricyclic dihydropyrans
that are cannabinoid analogues. 866
Bucourts method for estimation of torsional strain can be successfully applied
to the THC ring system to give a surprisingly good quantitative estimate of the
relative stability of the various double-bond isomers, in particular of the position of
equilibrium for As +A9 for the parent and model compounds demethylated at C-6. 667
The long-range 1,5-substituent effect of an ester group at C-1 was held to be
responsible for the base-catalysed conversion of a methoxycarbonyl group at C-9
from an equatorial to an axial position. The axial isomer was unchanged in the
reaction conditions. A similar effect, presumably due to flexing of the carbocyclic
skeleton, was found in elimination : dehydrochlorination of the 9-chloro- l-hydroxycompound and of the 9-chloro- 1-methoxy-compound gave the isomeric As- and
119-compoundsrespectively.s68The degradation of As- and AS-THC via the epoxy
and hydroxylated derivatives has been reported. s69
Monoterpenoids
67
f OCOBut
(OCOPr
QAc
876
876
877
879
880
882
884
68
887
Mono terpenoids
69
(272)
(271)
-6
O H
eOs
70
i p s i n 0 1 , ~and
~ ~ further studies have confirmed that ipsdienol is an obligatory
precursor of the
Geniposide may easily be chemically converted into
lO-hydro~yloganin,~~~
but neither the latter nor 7-epi- 10-hydroxyloganin (unlike
deoxyloganic acid or loganin) was a precursor of secologanin in Loniceru spp.SOO
In the course of studies on indole alkaloids it was demonstrated that the 10-0x0derivatives of geraniol and nerol were converted into secologanin in a Cuthmunthus
sp. 901 8-epi-Deoxyloganin was efficiently incorporated into lamiide and ipolamiide
in a Hebenstreitiu sp.9022H N.m.r. studies (one of few such applications to biosynthesis) showed that label at C-8 of deoxyloganin was retained during its
conversion into cornin (the 6-0x0-derivative) in a Verbena sp. This shows that
oxidation occurred at an unactivated position, i.e. there was no double bond at
C-7-C-8 in the immediate precursor of cornin. 903 Semburin (273) and isosemburin
(epimeric at the point of vinyl attachment) from a Swertiu sp. were the first 2,8dioxabicyclo[3.3.1Inonane derivatives encountered naturally : they were presumed
formed from sweroside (272).904 Biogenetic speculations have also been formulated
for details of the routes to A9- and A8-THCand cannabin01.~~~
The establishment of cell-free extracts that can sustain monoterpene synthesis has
always been difficult, but recently such systems have been developed, and this has
resulted in impressive conclusions concerning mechanistic and enzymatic details.
The main improvement in methodology, which, however, has not proved successful
in other hands, seems to be the use of very young plant material. This probably
eliminates many of the problems associated with tough cell walls and the presence of
phenolics that bedevil work with older tissue. However, extensive cultivation
schemes may be necessary to develop sufficient biomass for such studies. A preliminary characterization of bornyl pyrophosphate synthetase (MW cu. 95 000 dalton)
from a Sulviu sp. has been reported, and geranyl pyrophosphate (rather than the
neryl ester) was the preferred substrate. 906 A detailed proposed mechanism that
accommodates this choice of substrate and the formation of a pyrophosphate ester
(rather than an alcohol) involved formation (perhaps via linaloyl pyrophosphate)
and collapse (with bicyclization) of an intimate ion-pair comprising pyrophosphate
as the anionic component.
Extracts from the same plant contained separable
terpinyl phosphatases and pyrophosphatases : the latter type included a system
highly specific for bornyl pyrophosphate (the cleavage of which is essential for
camphor formation) together with one which preferentially accepted geranyl
pyrophosphate. The latter enzymic system has undoubtedly proved a source of
potential interference in studies on Cl0 cyclization processes.908 Another fraction
9069907
goo
Oo2
Oo3
Oa4
Oo5
Oo8
Monoterpenoids
71
from Salvia was worked up to a partially pure (MW ca. 91 000) dehydrogenase
that oxidized (+)-borne01 to (+)-camphor. It is possibly the same as a thujol
dehydrogenase extracted from a Tunucetum sp. 909 Another soluble enzyme from the
same source catalysed the conversion of geranyl pyrophosphate into a- and
p-pinenes, limonene, and camphene. Two cyclase preparations (MW 95 000 and
57 OOO) formed a-pinene, and both a-and p-pinenes respectively,910 It was shown that
the different preparations from SaZvia produced products of different structural
classes (a-pinene, camphene, borneol, limonene, 1,8-cineole) from [ 1 3H2,
U-14C]geranyl pyrophosphate without loss of 3H,and thus eliminated a mechanism
involving redox interconversion of geraniol and nerol in favour of a scheme
whereby the E-precursor was cyclized directly by way of a bonded linaloyl intermediate.g11The key enzymes for the conversion of geranyl pyrophosphate into
camphor in Salvia were at their highest levels of activity during the period of
maximum leaf expansion. This was held to indicate that immature leaves synthesized and accumulated camphor most rapidly,912but it may also reflect the ease
of extraction of the enzymes from these sources rather than from more mature
tissue. A soluble preparation from a Foeniculum sp. converted geranyl and neryl
pyrophosphates into fenchol and f e n ~ h o n e Unlike
. ~ ~ ~ the situation for borneol,
fenchyl pyrophosphate was not produced as a primary product and partial purification showed that the activities for the two percursors were coincident and presumably one enzyme was implicated for both. N o evidence was found (via isotope
dilution techniques) for a- or P-pinene or pinanols or their pyrophosphates as free
intermediates although the formation of fenchone was considered to involve the
generally accepted rearrangement of some pinane derivative. 914 Further fractionation gave a preparation (NADP+-dependent) that oxidized fenchol to fenchone,
and a similar preparation (for thujan-3-ol+thujone) was obtained from a Tanacetum sp. Specificity studies indicated that only a narrow range of monoterpenols
related to the structural classes produced in vivo were oxidized by these enzyme
systems.915
Time-course studies with 14C02showed that in a Thymus sp., y-terpinene was
converted into p-cymene and thymol in sequence,916and the appropriate y-terpinene
synthetase (MW ca. 96 000) was partially purified. Tracer studies indicated that
loss of a proton from C-5 of the a-terpinyl-like precursor to form the A*-unsaturation was accompanied, perhaps concertedly, by a 1,Zhydride shift from C-4
to C-8 to form y-terpinene. 917 Neomenthyl-p-D-glucoside was a major metabolite of
menthone in Mentha s p ~ . , and
~ l ~a cell-free extract also acetylated menthol.919
Detailed in vivo and in vitro investigations revealed that in leaf discs the bulk of the
neomenthol and menthol (produced from menthone) was converted into the glucoR. Croteau, C. L. Hooper, and M. Felton, Arch. Biochem. Biophys., 1978, 188, 182.
Gambliel and R. Croteau, Plant Physiol., 1980, 65, Suppl., 96.
Q1l R. Croteau and M. Felton, Arch. Biochem. Biophys., 1981, 207, 460.
Q12 R. Croteau, M. Felton, F. Karp, and R. Kjonaas, Plant Physiol., 1981, 67, 820.
Q13 R. Croteau, M. Felton, and R. C. Ronald, Arch. Biochem. Biophys., 1980, 200, 524.
@ l PR. Croteau, M. Felton, and R. C. Ronald, Arch. Biochem. Biophys., 1980, 200, 534.
@15 R. Croteau and N. M. Felton, Phytochemistry, 1980, 19, 1343.
Q16 A. J. Poulose and R. Croteau, Arch. Biochem. Biophys., 1978, 187, 307.
Q17 A. J. Poulose and R. Croteau, Arch. Biochem. Biophys., 1978, 191, 400.
Q18 R. Croteau and C. Martinkus, Plant Physiol., 1979, 64, 169.
Q19 R. Croteau and C. L. Hooper, Plant Physiol., 1978, 61, 737.
QOQ
@ l oH.
72
side and acetate respectively. This was not due to the specificity of the transferring
enzymes but was rather the result of the compartmentation of each stereospecific
dehydrogenase (forming menthol and neomenthol) with the appropriate unspecific
transferase. Indeed, a UDP-glucose : monoterpenol glucosyltransferase was partially
purified which accepted either ( +)-neomenthol or (-)-menthol as glucose
a c c e p t ~ rOther
. ~ ~ cell-free
~ ~ ~ ~extracts
~
from Mentha spp. reduced the Al- and A4double bonds of piperitenone, piperitone, and pulegone: at least five different
enzyme systems were implicated, specific for substrate and the stereochemistry of the
reduction. Treatment of the mint extracts with ion-exchange resins removed endogenous monoterpenes and thus made it possible to assay terpene interconversions by
quantitative g.c., without labelled substrates, and to identify the products by g.c.m.s.922 Cell-free extracts from a Chenopodiurn sp. catalysed the oxidation of
a-terpinene to ascaridole by singlet 0, and also the formation of allylic hydroperoxides from limonene. 923 Chemical studies have shown that hydrolysis of
geranyl pyrophosphate by Mn2+ seems a better model for enzymic reactions than
does acid hydrolysis.924
Tissue Cultures, Microbial Transformations.-Little success has rewarded the
search for cell cultures that effectively biosynthesize monoterpenes de now. The
most impressive studies utilize cultures from a variety of Mentha spp. : yields of oil
were some 60 (w/v) of those in the parent plants, but the monoterpene products
were generally more oxidized (i.e. ketones; extra C = C bonds predominated). In
vitro, oxidation at C-3 of the menthane skeleton was also restricted, apparently
owing to an inhibition of the enzymic reduction of the 4(8) double bond in the
intermediates formed.
Colchicine stimulated synthesis of essential oil by
Mentha cultures. 927 Iridoid glucosides have been produced by cultured cells of
Gardenia spp.673Menthone was biotransformed to neomenthol by Mentha suspension cultures,g28and Nicoriana lines oxidized linalool and its derivatives at C-10 to
aldehydes and alcohols,929and also foreign substrates such as a-terpineol (at C-6
and C-7) and trans-p-menthan-9-en- 1-01 (at C-4 and C- lo). 930
Monoterpenols were esterified by lipases from various micro-organisms
(especially Aspergillus ~pp.),~l
and (*)-caw1 acetates were hydrolysed by other
species to give chiral carveols together with (unreacted) acetates of the enanti~ m e r The
. ~ metabolic
~ ~
pathways for the conversions of (-)-carvone into (-)9259
R. Kyonaas, C. Martinkus-Taylor, and R. Croteau, Plant Physiol., 1980, 65, Suppl., 96.
C. Martinkus and R. Croteau, Plant Physiol., 1981, 68, 99.
9 2 2 A. J. Burbott and W. D. Loomis, Plant Physiol,, 1980, 65, Suppl., 96.
923 M. Johnson and R. Croteau, Plant Physiol., 1980, 65, Suppl., 96.
924 M. V. Vial and six others, Tetrahedron, 1981, 37, 2351.
s25 J. Bricout, M. J. Garcia-Rodriguez, C. Paupurdin, and R. Saussay, C . R. Hebd. Seances Acad.
Sci., Ser. D . , 1978, 287, 611.
826 C. Paupardin, Prod. Subst. Nut. Cult. In Vitro Tissue Cell. Veg., J . Etud., 1979, 119.
O Z 7 J. Bricout, M. J. Garcia-Rodriguez, and C. Paupurdin, C. R . Hebd. Seances Acad. Sci., Ser. D,
1978, 286, 1585.
928 D. Aviv, E. Krochmal, A. Dantes, and E. Galun, Planta Med., 1981, 42, 236.
T. Hirata, T. Aoki, Y. Hirano, I. Ito, and T. Suga, Bull. Chem. SOC.J., 1981, 54, 3527.
g30 T. Suga and six others, Chem. Lett., 1980, 229.
831 M. Iwai, S . Okumura, and Y. Tsujisaka, Agric. Biol. Chem., 1980, 44, 2731.
032 T. Oritani and K. Yamashita, Agric. Biol. Chem., 1980, 44, 2637.
820
Monoterpenoids
73
2187.
946
g47
s48
g4s
s50
951
OSa
s53
s54
g55
g56
74
pyrethroids in insects has been fully worked out. 957 Chemical and ultrastructural
investigation of a Pinus species implied that the monoterpenes and other resin
components were terminal products of metabolism and were not degraded during
normal growth or starvation conditions. 958 This appears to be in contradiction to
previous studies on terpenoid metabolism.
Several pairs of cannabinoid isomers were synthesized and tested for biological
activity: two requirements were elucidated: (a) in the absence of other substituents,
the equatorial stereochemistry of substituents at C-9 determined activity and
(b) pairs of compounds with groups at C-9 and C-10, or C-8 and C-9, had the same
activity if the configurations (a or p) at the appropriate carbons were the same.959
The antifungal activity of monoterpene aldehydesg60and the metabolism of monoterpenes in mammals leading to acute poisoning by pine oil have been described.961
The effects of light on pinene synthesis in Pinus s ~ p .chloroplast
, ~ ~ ~ autonomy in the
formation of acetyl coenzyme A and in terpenoid b i o s y n t h e ~ i sterpene
, ~ ~ ~ formation
by
and the influence of metachlor on growth and terpenoid synthesis
have been i r ~ v e s t i g a t e d . ~ ~ ~
We thank Dr. Margaret Banthorpe for much help with the preparation of this
report.
*57
a58
959
g60
g61
g62
g64
866
L. 0. RUZO,L. C. Gaughan, and J. E. Casida, Pestic. Biochem. Physiol., 1981, 15, 137.
J. Benayoun and R. Ikan, Ann. Bot., 1980, 45, 645.
R. Mechoulam and seven others, J . Med. Chem., 1980, 23, 1068.
N. Kurita, M. Miyaji, R. Kurane, Y. Takahara, and K. Ichimura, Agric. Biol. Chem., 1979,43,
2365.
C. Koppel, J. Tenczer, U. Tonnesmann, T. Schikop, and K. Ibe, Arch. Toxicol., 1981, 49, 73.
M. Gleizes, G. Pauly, C. Bernard-Dagan,and R. Jacques, Physiol. Plant., 1980, 50, 16.
K. Grumbach and B. Forn, 2. Nuturforsch., Teil C, 1980, 35, 645.
G. D. Prestwich, R. W. Sowes, and M. S. Collins, Insect Biochem., 1981, 11, 331.
R. E. Wilkinson, Pestic. Biochem. Physiol., 1981, 16, 63.
2
Sesquiterpenoids
BY J.
s. ROBERTS
1 Farnesane
An investigation of the nudibranch, Chromodoris marislae, has led to the identification of marislin (la) together with the minor constituents (2a,b) and (3a,b).l
Acid or heat treatment of marislin brings about its conversion into pleraplysillin-2
(1b), a sponge metabolite of Mediterranean origin. Pleraplysillin-2 (1b) has been
synthesized by coupling 4-methyl-2-furyl-lithium with the bromo-geraniol derivative
(4) followed by deprotection, oxidative esterification, hydrolysis, and final esterification with 3-f~rylmethanol.~
Further work on the constituents of Eremophila
Br
(4)
rotundijdia has led to the isolation of ( 5 ) and 4-hydroxydendrolasin (6).3 The diene
(5) can be obtained by cyclodehydration of the alcohols derived from reduction of
dihydrophymaspermone (7). Other new farnesyl/nerolidyl sesquiterpenoids include
vernopolyanthone (8) and vernopolyanthofuran (9) (from various Vernonia
species),* 3E- and 2-semistriatin methyl ether (I 0),5 and 5-hydroxynerolidol (1 1)
(together with its 5-a~etate).~
The stereoselective synthesis of P-sinensal (14) has been achieved by reaction
of the x-allylnickel(1I) complex (12) (derived from brornomyrcene) with the chloroa
a
4
75
76
cq..&&
/
/
/
OMe
OAng
(1 1)
(15)
pyrophosphate (Scheme 1). In the first paper9 evidence is presented for a geranyl
cation-pyrophosphate ion pair which is enzyme bound, i.e. ionization of geranyl
pyrophosphate and condensation with isopentenyl pyrophosphate are not concerted. In the second communication,1 ls0-labelling studies have shown that
lo
H. J. Reich, S . K. Shah, P. M. Gold, and R. E. Olson, J . Am. Chem. SOC.,1981, 103, 3112.
C. D. Poulter, P. L. Wiggins, and A. T. Le, J . Am. Chem. SOC.,1981, 103, 3926; see also M.
Ladika, I. Bregovec, and D. E. Sunko, J . Am. Chem. SOC.,1981, 103, 1285, 7797; for an
excellent review of prenyl transferases and isomerase, see C. D. Poulter and H. C. Rilling,
Biosynthesis of Isoprenoid Compounds, Vol. 1, ed. J. W. Porter and S . L. Spurgeon, John
Wiley, New York, 1981, p. 161.
E. A. Mash, G. M. Gurria, and C . D. Poulter, J . Am. Chem. Soc., 1981, 103, 3927.
Sesquiterpenoids
77
Scheme 1
the geranyl cation-pyrophosphate ion pair has a rigid structure and does not
scramble the bridging oxygen atom with the two non-bridging oxygen atoms in the
pyrophosphate counter-ion.
Four components of the trail pheromone of the red imported fire ant, Solenopsis
invicta, have been identified as 2,E-a-farnesene (16) E,E-a-farnesene (17), and
the two homofarnesenes (1 8) and (1 9).11 In a related study12all of the eight possible
diastereoisomers of do-farnesene (20) have been synthesized. In this paper it is
claimed that the E,Z,Z-isomer is identical to material isolated from the Dufours
glands of S. invicta. Faranal (21) a trail pheromone of the pharaoh ant has been
synthesized by small scale enzymatic condensation of 2-3-methylpent-3-enyl
pyrophosphate (23) with homogeranyl pyrophosphate (22) to give the 4R-triene
(24).13 Alkaline hydrolysis of the pyrophosphiite ester followed by manganese
dioxide oxidation gave the corresponding a, P-unsaturated aldehyde. Reduction of
this aldehyde with triethylsilane in the presence of (Ph3P),RhCl gave both the
3S,4R and 3R,4R diastereoisomers and it was shown by bioassay that the former (21)
corresponds to the natural pheromone. Three other syntheses14-16of faranal using
relatively straightforward synthetic procedures have been recorded ; one of these14
produces faranal in optically active form.
An interesting review of the biosynthesis and transport of juvenile hormones iri
insects has appeared.17The syntheses of the juvenile hormones JHI-JHIII (25)-
l1
l2
I4
l5
l6
R. K. Vander Meer, F. D. Williams, and C. S. Lofgren, Tetrahedron Lett., 1981, 22, 1651.
H. J. Williams, M. R. Strand, and S. B. Vinson, Tetrahedron, 1981, 37, 2763.
M. Kobayashi, T. Koyama, K. Ogura, S. Seto, F. J. Ritter, and I. E. M. Bruggemann-Rotgans,
J. Am. Chem. SOC.,1980, 102,6602.
K. Mori and H. Ueda, Tetrahedron Lett., 1981, 22,461.
D. W. Knight and B. Ojhara, Tetrahedron Lett., 1981, 22, 5101.
R. Baker, D. C. Billington, and N. Ekanayake, J . Chem. SOC.,Chem. Commun., 1981, 1234.
S. J. Kramer and J. H. Law, Acc. Chem. Res., 1980, 13, 297.
78
(27) together with a number of analogues have been achieved by the use of vinylcuprates as key intermediates.18
1"
(16) R
(18) R
H
Me
x
(25) R' = R2 = Et
(26) R1= Et, R2 = Me
(27) R1 = R2 = Me
2o
21
22
H. KIeijn, H. Westmijze, and P. Vermeer, J . Roy. Netherlands Chem. SOC.,1981, 100, 249.
B. Sullivan, P. Djura, D. E. McIntyre, and D. J . Faulkner, Tetrahedron, 1981, 37, 979.
R. J. Capon, E. L. Ghisalberti, and P. R. Jefferies, Aust. J . Chem., 1981, 34, 1775.
R. Capon, E. L. Ghisalberti, P. R. Jefferies, B. W. Skelton, and A. H. White, Tetrahedron,
1981,37, 1613.
R. B. Von Dreele and J. P. Y . Kao, Acta Cryst., 1980, B36, 2695.
79
Sesquiterpenoids
CHO
AcO
(30)
woAc
(33) R
(34) R
=
=
H
OH
26
G. Cimino, S. De Rosa, S. De Stefano, and G . Sodano, Tetrahedron Lett., 1981, 22, 1271.
G. Schulte, P. J. Scheuer, and 0. J. McConnell, Helv. Chim. Acta, 1980, 63, 2159.
T. Kato, K. Ishii, I. Ichinose, Y. Nakai, and T. Kumagai, J . Chem. SOC.,Chem. Commun.,
1980, 1106.
A. Murai, A. Abiko, K. Kato, and T. Masamune, Chem. Lett., 1981, 1125.
80
(37)
Scheme 2
Br
Br
OH
OH
(41) R
(42) R
(39)
Br
W
N
HO
Br
(46)
2'
28
29
J;);""
Br
=
=
Br
H
PhSe
HO
Br
(47)
T. Kametani, K . Fukumoto, H. Kurobe, and H . Nemoto, Tetrahedron Lett., 1981, 22, 3653.
S. Imre, S. Islimyeli, A. OztunG, and R. H . Thornson, Phytochemistry, 1981,20,833.
A. G . Gonzalez, J . D. Martin, C. Perez, M. A. Ramirez, and F. Ravelo, Tetrahedron Lett.,
1981,22, 5071.
81
Sesquiterpenoids
(51)
(50)
This compound must arise from bromonium ion cyclization of the 6,7-bromohydrin
of farnesol acetate. Hydrolysis of the acetate group in (47) and sequential treatment
with phosphorus tribromide and water gave obtusenol (46). Other syntheses of
marine sesquiterpenoids include those of pallescensin-E (48),30furoventalene (49),31
and dactyloxene-B (50) and -C(51).32 The last mentioned established the absolute
configurations of the two dactyloxenes. A second synthesis of ancistrofuran (53) and
its C-2epimer has been recorded starting from the lactone (52)which is derived
from homogeranic acid (Scheme 3).33
Ph,PQ
w
H
h i , iii
w02w0
H
(53)
Reagents: i, Bu',AIH; ii, PhSeCI; iii, Ac0,H; iv, H 4
Scheme 3
The diverse biological activity (e.g. insect antifeeding, plant growth regulation,
molluscicidal) of a number of drimane sesquiterpenoids has stimulated considerable interest in their synthesis and the year under review has seen many
new developments and improvements. Much of the synthetic work has centred
around the key bicyclic diester (54) derived from l-vinyl-2,6,6-trimethylcyclohexene
and dimethyl acetylenedicarboxylate. In contrast to earlier
Ley et ~ 2 1 . ~ ~
30
31
32
33
34
35
82
have shown that hydrogenation of (54) under isomerizing conditions (trace of HCl)
gives the trans-fused decalin derivative (55). This finding has paved the way to
short and efficient syntheses of cinnamolide (56), polygodial(57), and warburganal
(58) (Scheme 4).36Lallemand and c o - w ~ r k e r shave
~ ~ also used the diester (54) as
the starting material for the syntheses of polygodial (57) and drimenin (60).
They found that deprotonation of (54) with LDA followed by kinetic protonation
at low temperature gives the isomerized diester (59). Normal catalytic hydrogenation
of (59) gives the key compound ( 5 5 ) which was converted into polygodial (57)
C0,Me
CO,Me
C0,Me
ix, x
/;"
'
'
(jy
H
(55)
qO,Me
/,vi
OAc
(56)
OH
...
Vlll
+
& HH
@
H
Ho
(58)
Reagents: i, H,-Pd/C; ii, LiAlH,; iii, Ag,CO,-celite; iv, Me, SO-(COCl),, then NEt3; v, Ac,Opy; vi, SeO,; vii, K,CO,-MeOH; viii, Me,SO-TFAA, then NEt3; ix, Bu',AlH; x, PTSA;
xi, LDA; xii, H +
Scheme 4
36
Sesquiterpenoids
a3
(OH
pH
...
Vlll
ix
+
OH
&OACH O
liv
&*Me
xi
f-
H O
#OACH O
.1
(63)
liv
(62)
Reagents: i, BH,-THF; ii, H,O,OH-; iii, MsC1-py; iv, DBU; v, LiAlH,, vi, H,-Pd/C;
vii, Bu',AIH; viii, PCC; ix, Pb (OAc),; x, MCPBA; xi, MeOH-H+; xii, H 3 0 + ;xiii, Ac,O-pyDMAP
Scheme 5
as
40
84
iiii
(66)
Scheme 6
f--iii
(67)
Reagents: i, KMnO,; ii, h v ; iii,
hv,
(70)
02-Rose Bengal
Scheme 7
Sesquiterpenoids
85
cleavage of the ketone (69) and the unusual photo-oxygenation of the diene (70) to
give confertifolin (67) directly. Full details and further refinements of the syntheses
of isodrimenin (6 I), confertifolin (67),41and warburganal (58)42 have been published.
Norambreinolide (71) has been synthesized by stannic chloride-promoted cycliza-
Jiv, v
n
Reagents: i, MeMgI-CuI; ii, Me3SiC1; iii,
v, H 3 0 +
(73)
-TiC14-Ti(OPri)4; iv, Ph,P==CH,;
Scheme 8
42
4a
44
46
H. Akita, T. Naito, and T. Oishi, Chem. Pharm. Bull., 1980, 28, 2166.
T. Nakata, H. Akita, T. Naito, and T. Oishi, Chem. Pharm. Bull., 1980, 28, 2172.
A. Saito, H. Matsushita, Y. Tsujino, and H. Kaneko, Chem. Lett., 1981, 757.
0. Takazawa, H. Tamura, K. Kogami, and K. Hayashi, Chem. Lett., 1980, 1257.
I. I. Mahmoud, A. D. Kinghorn, G. A. Cordell, and N. R. Farnsworth, J. Nat. Products, 1980,
43, 365.
1e
47
48
86
&
H OAc
(74)
(75) R1= H, R2 = OH
(76) R = OH, R2 = H
@$
,. H
OCOPh
HO
i 2
(77)
8WNqwp
.
..._
fl
(82)
HO
OOH
(83)
(81)
(84)
48
61
b2
63
Sesguiterpenoids
87
(88)754v55and andilesin C (89).54 Incorporation of 13C-labels indicate that the biosyntheses of these compounds can be rationalized in terms of alkylation of farnesll
pyrophosphate by a bis-C-methylated tetraketide-derived phenolic precursor to
produce the key intermediate (85). Cyclization followed by a series of rearrangements and oxidative modifications leads to these interesting metabolites. The
efficient incorporation of ethyl 2,4-dihydroxy-3,5,6-trimethylbenzoate (90) and
0
C02Me
(88)
6;
C02Et
(90) R = OH
(91) R = H
(91) demonstrates that biological Cethyl 4-hydroxy-2,3,5-trimethylbenzoate
methylation by methionine precedes aromatization of the tetraketide.56 Simpson
(92) R
(93) R
54
65
56
OH
OH
(94)
88
et uL5' have also found that a mutant of the andibenin producing strain of Aspergillus vuriecolor which lacks the polyketide-derived mycelial pigments produces the
two drimane sesquiterpenoids astellolide A (92) and B (93) which are structurally
close to the pebrolides (78)-(80).
A very complete account has been published5* of the excellent labelling studies
which have been carried out to elucidate cyclonerodiol (94) biosynthesis and the
enzymatic conversion of farnesyl pyrophosphate into nerolidyl pyrophosphate
(Vol. 10, pp. 5-7).
3 Bisabolane
New bisabolane sesquiterpenoids from a variety of plant sources include (95)( 102).59-64E-y-Bisabolene-8,9-epoxide(1 03) has been isolated from the alga
Laurenciu n i p p o n i ~ aThis
. ~ ~ compound is possibly the precursor of various halogenated chamigranes which are abundant in Laurencia algae.
Q
$, . ,A
@
,n-
F Ang
pcH
(9359
(9Q5'
(97y0
P
R
(98)''
I
\
(99y2
(100)'3
(101)s4R
(102) R
CH,OAc
CHO
68
89
Sesquiterpenoids
p Hpp
R
(108)
(109) R = CHO
(1 10) R = CH20H
4 Sesquicamphane, Sesquipinane
Two additional minor components of East Indian sandalwood oil have been
identified as trans-p-santalol(ll1) (cf. Vol 11, ref. 48) and epi-cis-p-santalol(112).71
New syntheses in this area include those of cis-p-santalol (1 13) (Scheme 9),72
68
67
6s
70
72
90
(1 13)
Reagents: i, LDA; ii,
Br TOAc
Scheme 9
1 vii
p,
I
xii, v, vi
OSiMe,But
\viii,
ix
ii, xii
Aii-xv
Y*
xvii
(1 12)
(115)
(112)
Reagents: i, A ; ii, H30+; iii, Ph,P=CMe,; iv, CrO,.py; v, NaNH,; vi, MeI; vii, Zn-TiC1,CH,Br,; viii, NMO-OSO,; ix, NaIO,; x, LiAlH,; xi, C1SiMe2Bu'-imidazole; xii, PCC;
xiii, PPh,=CHMe; xiv, BuLi ; xv, CH,O ; xvi, (EtO),POC(Me)==CO,Et ; xvii, AlH,
Scheme 10
Sesquiterpenoids
CO2H
111I
& &
+
ii, iii
--L
'
91
C02H
OH
Jiv
(116)
Reagents: i, A; ii, Ra-Ni; iii, LiAlH,; iv, E u - H g ( O A c ) , , 135 "C;v, LiAlH,-AlCl,
Scheme 11
92
Scheme 12
(120)
(121)
(122)
isolated from the liverwort Herberta a d ~ n c aIn. ~view
~ o f the fact that (-)-cuparene
is a known liverwort constituent, the genesis of herbertene by a 1,2-methyl migration
of a cuparene-type precursor seems reasonable. Caraibical (123) has been isolated
from the red algal species Laurencia caraibica and it is closely related to the bicyclic
compound (124) found in the same alga.79
Intense interest in the trichothecane sesquiterpenoids has continued unabated
on two fronts. The first concerns the conflicting reportsso of the possible use of
mycotoxins of this class of sesquiterpenoid as fungal warfare agents ('yellow rain')
in Kampuchea and Laos. The second area of research centres around the total
synthesis of trichothecane sesquiterpenoids, although it should be pointed out that
phase TI clinical trials with anguidine (125) as an antitumour drug appear to be
disappointings1 thus possibly taking the edge off the synthetic impetus.
77
'I3
7s
8o
M. T. Reetz, J. Westermann, and R. Steinbach, J. Chem. Sac., Chem. Commun., 1981, 237.
A. Matsuo, S. Yuki, M. Nakayama, and S. Hayashi, J. Chem. SOC.,Chem. Commun., 1981,864.
R. R. Izac, J. S. Drage, and J. J. Sirns, Tetrahedron Lett., 1981, 22, 1799.
Chem. Eng. News, 1981, Sept.21, p. 7; Oct. 26, p. 15; Nov. 16, p. 10; Dec. 14, p. 21.
Chem. Eng. News, 1981, Nov. 30, p. 29.
93
Sesquiterpenoids
..-OH
(126) R
(127) R
=0
= CH2
(128) R = 0
(129) R = CH,
Full details of the neat synthesis of the ketone (126) and its methylenation to give
trichodiene (1 27) have been published.82 Unfortunately, sixteen attempts with
different reagents to carry out a similar methylenation of the diastereoisomeric
ketone (128) to give bazzanene (129) failed. A number of new and very interesting
trichothecane sesquiterpenoids have been isolated from Myrothecium verrucuriu.
These include trichodermadienediol A (130), trichoverrol A (1 3 I), and trichoverrin
A (132) together with their B counterparts which are epimeric at C-7.83 The
trichoverrins are clearly biosynthetic intermediates of the more toxic macrocyclic
>OH
(130) R
(131) R
=
=
H
OH
trichothecanes and indeed incubation of these two compounds gives rise to verrucarin A (133) and B (134) with smaller amounts of roridin A (135) and isororidin E
(1 36). In these experiments each recovered trichoverrin is uncontaminated with its
epimer, suggesting that each undergoes conversion into the macrocyclic compounds
via a common intermediate. In an elegant piece of carbohydrate chemistry Tulshian
and Fraser-Reida4 have synthesized the C-4 octadienic methyl esters derived by
methanolysis of the six metabolites isolated by Jarvis et al.83 As shown in Scheme 13
S. C. Welch, A. S. C. Prakasa Rao, C. G. Gibbs, and R. Y. Wong, J . Org. Chem., 1980, 45,
84
4077.
B. B. Jarvis, G. Pananasasivam, C. E. Lolmlund, T. DeSilva, G. P. Stahly, and E. P. Mazzola,
J. Am. Chem. SOC.,1981,103,472.
D. B. Tulshian and B. Fraser-Reid, J . Am. Chem. SOC.,1981, 103, 474.
94
HO---
Me
CH
OH
Me
CH
OH
__j
(137)
liii
OH
A c o y O j
AcO
(139)
__3
__3
C0,Me
(140)
C0,Me
O -C
(138)
Scheme 13
the syntheses start from the carbohydrate precursors (137) and (139). Whereas the
glucal (137) gives the D-erythro-ester (138) identical in all respects with the compound derived from the B series of metabolites, the galactal (139) produces the
D-threo-ester (140) which is enantiomeric with respect to the compound obtained
from the A series of metabolites. Coupling of the THP ether of verrucarol(l41) with
the acid (142) followed by deprotection and lactonization by the Corey-Mukaiyama
procedure has produced the verrucarin A derivative (143).85
E.-A. Notegen, M . Tori, and C. Tamm, Helv. Chim. Acfu 1981, 64, 316.
Sesquiterpenoids
95
~ T H P
oq
J.
vii
OMe
o%
OMe
hii-x
yy& qJ-&
XI, XI1
OMe
OMe
(14)
Reagents: i, NaBH,; ii, SOC1,-py; iii, Bu', AlH; iv, VO(acac),-Bu'OOH; v, MeI-NaH;
+ vi, Me,N--O; vii, H,O+; viii, MeLi; ix, Cr0,-py; x, POCl,-py; xi, Ph,P=CH,; xii, MCPBA
Scheme 14
96
C0,Me
(145)
Jii,
iii
IV-VI
f--
Me0,C i
(146)
(147)
Reagents: i, A ; ii, (CH,OH),-PTSA; iii, Me,CuLi; iv, LDA;
HC=CH; piii, Bu',AlH; ix, Ac,O-py; x, H,O+
Scheme 15
HO
W
v, vi
V,
+
I
Me0,C
Me0,C
bii,viii, i
(148)
(149)
Reagents: i, A ; ii, Me,CuLi; iii, Bu',AlH; iv, H,O+; v, MeOH-H+; vi, MeMgI, vii, H + ;
viii, Ac,O-py
Scheme 16
Sesquiterpenoids
97
---+
OH
Me0,C
(145)
-@ -qo
i v , vi
Qo
Ho
vii-ix
x, x i
OMe
Me0,C
HO
Me0,C
(150)
Reagents: i, A; ii, Me,CuLi; iii, LDA; iv, MoO,*py.HMPA; v, NCS-Me,S; vi, Et,N; vii,
NaH-Mel; viii, Bu,AlH; ix, Et,SiH-BF,-Et,O; x, LiAlH,; xi, H +
Scheme 17
O
+
J
+
ii, iii
2
HO
ButMe,SiO
jiv, v
f--
CHO
HO
ButMe,SiO
ButMe,SiO
(151)
Reagents: i, B(OAc),; ii, BuMe,SiCI-imidazole; iii, K,C03-MeOH; iv, NCCH,COCl-py ;
v, DBN; vi, Bu,AIH; vii, Et,SiH-BF,*Et,O; viii, NaCIO,; ix, Et,N-ClC0,Et-NaN,; x,A-OH-;
xi, Bu,NF
Scheme 18
Ho
:
R
(152) R
(154) R
=
=
Me
(153)
0
(155)
A. J. Pearson and C. W. Ong, J . Am. Chem. Soc., 1981.103,6686; Tetrahedron Lett., 1980,21,
4641.
98
*Q
-
OPP
\OPP
Scheme 19
J. D. White, T. Matsui, and J. A. Thomas, J . Org. Chem., 1981, 46, 3376.
Y . Nakahara and T. Tatsuno, Chem. Pharm. Bull., 1980, 28, 1981.
G. A. Kraus and K. Frazier, J . Org. Chem., 1980, 45,4820.
G . A. Kraus and B. Roth, J . Org. Chem., 1980, 45,4825.
91 R. E. Banks, J. A. Miller, M. J. Nunn, P. Stanley, T. J. R . Weakley, and Z. Ullah, J . Chem.
SOC.,Perkin Trans. 1, 1981, 1096.
82 D. E. Cane, S . Swanson, and P. P. N. Murthy, J . Am. Chem. SOC.,1981, 103, 2136.
n7
nn
Sesquiterpenoids
99
(159) R
(160) R
=
=
OH
H
3H/14C
atom ratio of 1.8 :2 demonstrating that practically no loss of hydrogen from
C-1 of the precursor had occurred. This result is at variance with an earlier result by
Hanson and co-workers who claimed that loss of a C-1 hydrogen did occur in this
biosynthesis. Furthermore degradation of the labelled trichodiene clearly established
the position of the two tritium atoms as shown in (157). Cane's present evidence,
together with other findings in monoterpene and sesquiterpene biosynthesis,
strongly indicates that the biosynthesis of trichodiene (127) can be viewed as shown
in Scheme 19 with the involvement of nerolidyl pyrophosphate (158).58
Full details of two of the elegant syntheses of gymnomitrol (159)93794 and
gymnomitrene (160)94have been published.
6 Chamigrane, Widdrane
Full details of an earlier synthesis of chamigrene (161) have been published.95
Further work on the components of the red alga Laurencia nipponica Yamada has
resulted in the isolation and structural elucidation (by X-ray analysis) of the
diol (162)96and spironippol (164).97The biogenesis of the latter compound can
be viewed in terms of an intramolecular cyclization of the diol(l63) derivable from
the naturally occurring epoxide of 1O-bromo-a-chamigrene.
(163)
O4
O5
(164)
O6
*'
K. Kurata, A. Furusaki, C. Katayama, H. Kikuchi, and T. Suzuki, Chem. Lett., 1981, 773.
A. Fukuzawa, C. M. Shea, T. Masamune, A. Furusaki, C. Katayama, and T. Matsumoto,
TetrahedronLett., 1981, 22, 4087.
100
b-vii
xiii, xi;
. O
\i
A
xv xvi
Lo
OSiMe,But
(165)
(166)
Lrvii, xviii, ii
(1 67)
Reagents : MeC(OEt),-EtC0,H; ii, LiAlH,; iii, MsC1-py; iv, NaI; v, NaH-CH,(CO,Me),;
vi, MeOH-OH-; vii, A-py; viii, NBS; ix, MCPBA-TBP; x, Zn-MeOH; xi, OH-; xii, TFA;
+xiii, LDA-MeI; xiv, LDA-Bu'Me,SiCl; xv, 110 "C; xvi, Bu,NF; xvii, SOCI,; xviii, MCPBA
Scheme 20
Sesquiterpenoids
101
by Oppolzer et al.loOthat photocycloaddition of (173) gives (174) which then undergoes reductive ring-opening with lithium in liquid ammonia to produce the spiroketone (175). Full details of an alternative strategy for the synthesis of acorenone B
(172) have been presented.95Another interesting approach to this class of sesquiterpenoid is that adopted by Ficini et al.lol in which the spiroannelation step is
achieved by reaction of the enol lactone (176) with the ynamine (177) to give (178).
Me
P
p
loo
lol
W. Oppolzer, L. Gorrichon, and T. G. C.Bird, Helv. Chim. Acra, 1981, 64, 186.
J. Ficini, G. Revial, and J. P. GenCt, Tetrahedron Lett., 1981, 22, 629, 633.
102
(1 87)
Reagents: i, h v ; ii, Me,CuLi, iii, NaCI-H,O-DMSO;
vi, H2-Pt; vii, Bu'OK
Scheme 21
Sesquiterpenoids
103
an entirely new route (Scheme 21).lo6A very ingenious short synthesis of cedrene
(191) has been announced, which differs totally from previous syntheses in its
conception (Scheme 22).Io7The success of this synthesis hinged upon a detailed
(191)
( 190)
t 189)
Scheme 22
lo7
104
a
H
(??-
(-fJ
H
(198)
(197)
Scheme 23
prezizaene alcohol, jinkohol, has been ascribed the structure (2O3).l1l This is the
same structure as that put forward for ( +)-allokhusiol,'12 although the Japanese
workers seemed to be unaware of this. There is a very close similarity in the spectral
data for the two compounds except for the optical rotations ([.ID of jinkohol
claim that jinkohol (203)
-6..l', [aID of allokhusiol +45'). Nakanishi et
is not identical to the enantiomer of (201) ([aID -48.3') isolated by Carrol et al.l13
some years ago. Ganguly et
also made the same claim about the non-identical
*I2
113
Sesquiterpenoids
105
Jvi, vii, v
xi
t
VIII-x
(20 1)
(202)
Scheme 24
114
115
106
AcO
c&
ii iii
+
1
Scheme 25
Sesquiterpenoids
107
H :
(215) R
(216) R
=H
= OH
(217) R
(218) R
0
= P-OH, H
=
OR1 CHO
CHO
R20q
Hod Ho
HOaC
(224)
(225) R
(226) R
=
=
(227)
H
Me
(228) R
(229) R
=
=
H
Me
(231) R
(232) R
lal
19z
CH20H
CO,H
Hod
\
=
=
108
intramolecular ene reaction to form (240) which has been chemically converted into
( +)-isocalamendiol(241). The epimeric mixture of bicyclic enones (242) which have
previously been converted into epizonarene (243) has been synthesized (Scheme
26).123A similar type of intramolecular Diels-Alder methodology has been used to
--+
Li+
l i i , iii
iv
t--
(243)
(242)
Scheme 26
convert the acyclic enone (244) into the octalone (245), which, on treatment with
N-methylanilinium trifluoroacetate and paraformaldehyde, gave (246).lZ4This is
123
12'
109
Sesquiterpenoids
0
(244)
(245)
(246)
R
R
= H2
= CH,
(247)
the structure originally assigned to chiloscyphone but since the synthetic and
natural materials are not identical, the structure of natural chiloscyphone must be
in error. Another variant of the intramolecular Diels-Alder reaction, this time using
110
a benzyne intermediate, has been devised for the synthesis of mansonone E (249).126
Thus, generation of the substituted benzyne (247) from the corresponding anthranilic
acid spontaneously cyclizes to produce (248), which could be converted into
mansonone E (249) by standard means. Gossypol(250) is a well known constituent
of cottonseed pigment, and recently considerable interest has been generated in this
compound because of the reported male contraceptive properties of its acetate and
formate. A reasonably efficient synthesis of the nor-gossypol derivative (252) from
the bromobenzene (25 1) has been recorded (Scheme 27).lZ6Attempts to synthesise
the interesting cadinane sesquiterpenoid, arteannuin B (253), have been made
but the principal route used (Scheme 28) has only produced the stereoisomers
(254)-(256) none of which is identical to the natural product.lZ7
A re-investigation of the brown alga Dictyopteris diuaricata has resulted in
the identification of the new alcohol, epicubebol (257) together with the known
ii-iii
+
0
0
~\
0
(254)
0 :
\
0
(255)
q
H i
H i
(256)
Scheme 28
lZ5
IZ6
12'
111
Sesquiterpenoids
(258) A3*4
(259) A49I5
(257)
(26 1)
(262)
(263)
compounds, ( -)-a-cubebene (258), ( -)-p-cubebene (259), epicubenol (260),
cubenol (261), and ( +)-8-cadinene (262).12*
Several new oplopanane sesquiterpenoids, exemplified by implexin (263),
have been isolated from various Senecio s p e ~ i e s . ~ ~ Another
~ J ~ O synthesis of
oplopanone (264) has been recorded (Scheme 29).131
In a continuation of his work on dendrobine synthesis, R o u s ~ Ihas
~ ~found
that the intramolecular Diels-Alder reaction of the diene-ester (265) gives predominantly the bicyclic compound (266). This was an unexpected result because
viii-x
vi, vii
f--
0
(264)
Reagents: i, Li-NH,-Bu'OH; ii, BunLi; iii, Me,C=CH(CH,),Br ; iv, HCl; v, Ac,O-HOAc+-
112
vii
t-
MesSiO
C02Me
h i i , ix, iv, x
i , xi, xii
c
xiii
OSiMe2But
OSiMe,But
'
OSiMe,But
biv-xvi,
iv
(269)
Reagents: i , LDA; i i , [ O F 1 ; iii, MeLi; iv, H,O+; v, (MeO),P(O)CHCO,Me; vi ZnC1,0
Me,SiCl-Et,N; vii, I10 "C; viii, (CH,OH),-H+; ix, LiAlH,; x, Bu'Me,SiCI; xi, Me3SiC1;
xii, Zn/Cu-CH,I,; xiii, Feel,; xiv, H,-Pd/C; xv, Me,C=PPh,; xvi, H,-PtO, ; xvii, Bu3Pa0,NArSeCN-py; xviii, H,02
Scheme 30
Sesquiterpenoids
113
S0,Ph
%l
x-xiii
(270)
Reagents: i, LiBr; ii, NaCN; iii, PhSCl; iv, Bu',AlH; v, H,O+; vi, LiBHEt,; vii, MCPBA;
viii, MsCI-Et,N; ix, MeOH-H+; x, KN(SiMe,)2; xi, LiAlH,; xii, Li-EtNH,; xiii, CrO;py,;
xiv, Ph,P=CHOMe; xv, K,CO,-MeOH; xvi, MeLi ; xvii, Ph,P=CH,; xviii, H2-(Ph,P),RhC1
Scheme 31
(274).
laa
(275)
114
C,, hydrocarbon (271)135by a similar route but this compound is not identical to a
tricyclic hydrocarbon isolated from East Indian sandalwood oil and reported to
have this structure. (+)-Copacamphor (272) and ( +)-copaborneol(273) have been
isolated from Espeltiupsis g u a c h a r a ~ aThe
. ~ ~interesting
~
sinularene derivative (274)
and the acetoxycyclosinularane (275) have been isolated from the marine source,
Clavularia i n 3 ~ a t a .These
l ~ ~ compounds, together with an aromadendrane derivative
(see p. 18 1) are the first sesquiterpenoids from Octocorallia of the order Stolonifera.
9 Himachalane, Longifolane, Longipinane
a- (278) and p-Himachalene (279) have been synthesized (Scheme 32).138 This
route is not particularly attractive in view of the low yield (12%) at the isomerization step (276)+(277). The himachalenes can be converted into ar-himachalene
(280) with 5 % palladium on carbon and various himachalenes with trans ring
fusion can be prepared by treatment of the himachalenes with hydrochloric
acid followed by base-induced dehydroch10rination.l~~
The lzlmachalanolide (281)
Me02C
Me0,C
__+
a
Jiv, v
2Et
vi
(278)
(279)
Reagents: j, SnCI,; ii, Et,SiH-(Ph,P),RhCI; iii, aq. K,CO,; iv, LiI-collidine; v, N,CHCO,EtBF,.Et,O; vi, PTSA; vii, MeLi; viii, POCI,-py
Scheme 32
135
136
13'
138
139
Sesquiterpenoids
115
(280)
(28 1)
(282)
(283)
lQo
lQ1
116
U
(290)
Hd
jgco2H
jf--J-..
H"
H'
(297) R
(298) R
(300)151
=
=
(299)
H150
OAcl5'
(301)152
has been calculated to be 16.25 kcal mol-1 based on a line shape analysis of certain
peaks in the 13C n.m.r. spectrum. This leads to the conclusion that the two conformers (286) and (287) contribute 76% to the population equilibrium while
conformers (288) and (289) contribute 24 %. The barriers to the interconversion of
(286) and (287) and to (288) and (289) will be very small and it is interesting to note
that earlier
clearly indicated that conformer (287) leads to clovene (290) and
conformer (288) to P-caryophyllene alcohol (29 1) on acid-catalysed rearrangement
of caryophyllene. Various oxygenated caryophyllene derivatives (292)--(301)148-152
have been identified as constituents in a number of plant species.
The number of sesquiterpenoids which can be formally derived from a caryophyllene-type precursor has risen quite dramatically in the last few years and
includes the following structural types :147
148
149
l50
151
152
Sesquiterpenoids
117
Neoclovane
Panasinsane
Quadrane
Koraiane
Silphiperfolane
Presilphiperfolane
Isocomane
Modhephane
Senoxydane
Silphinane
Botrydiane
Senecrassiane
(303) by epoxidation. Another new skeleton is seen in the structure of 8-hydroxypresilphiperfolene (305), isolated from Eriophyllum staechadiJ~Ziurn.~~~
This
interesting tricyclic alcohol is the missing link in the proposed biogenesis of
the silphinane and silphiperfolane sesquiterpenoids from caryophyllene (Vol. 11,
p. 50) The silphiperfolene derivative (306) has also been identified recently in
Espeletiopsis g u ~ c h a r a c a . ~ ~ ~
153
154
118
Scheme 33
conversion of (310) into (309) with 13CH2=PPh3 could provide some insight
into this mechanism since the fate of the labelled carbon is different for the two
pathways. The latest synthesis of isocomene (Scheme 34)15* involves a classical
construction of the triquinane nucleus terminating with the tricyclic ketone (3 13),
which Paquette had already converted into isocomene in three steps.
Turning now to the intriguing propellane sesquiterpene modhephene (308),
Karpf and Dreidingls9 have provided full details of their original synthesis. Hot
155
*I6
157
lS8
Sesquiterpenoids
119
C0,Me
- /$
C0,Me
v , v i M e 0 2 C @ T e .CO,Me
C0,Me
vii, vi
\co2Me
C0,Me
t
+
Me0,C
mco2
0
0
C0,Me
Ae
0
0
k i i , xiii, x
(313)
Reagents: i, LDA; ii, Br(CH,), C0,Et; iii, NBS-aq. MeCN; iv, MeOH-pH 6.8; v, H,O+-A;
vi, KF.2H20-MeI; vii, Me,C(CH,OH),-PTSA; viii, H 3 0 + ix, NH,NH2-KOH; x, PTSA;
xi, Me1 ; xii, (CH,SH),-BF,.EtO,; xviii, Ph,P=CH,; xiv, MeI-CaC0,-aq. MeCN
Scheme 34
on the heels behind this synthesis have followed another three syntheses. The
first of theselG0(Scheme 35) hinges upon the successful application of the acidcatalysed Cargill rearrangement of the strained [4,3,2]propellanes (315) and
(319) to give (3 17) uniquely. The initial photo-addition of 1,Zdichloroethene to
the enones (314) and (318) was surprisingly not stereospecific. In the case of (314)
the desired isomer (315) was the minor one [ratio (315):(316) = 1 :2], while for
(318) the required isomer was more abundant [ratio (319):(320) = 3:2]. The
next synthesis of modhephene (308) (Scheme 36)la1 owes its success largely to the
intramolecular ene reactions (321)+(322) and (323)+(324) originally developed by
Conia. Unlike Smith's synthesis, this route achieves the stereocontrolled synthesis of
160
120
Jviii, ix, v
. .
I-IV
(318)
(319)
(320)
(308)
Reagents: i, hv-ClCH=CHCl; ii, (CH,OH),-H+; iii, Na-NH,; iv, H,O+; v, PTSA; vi, MeLi;
vii, CrO,-H+; viii, Me,CuLi-BF,.EtO,; ix, CH,=PPh,
Scheme 35
~)
-._
).$p
t
vii,viii
--
@)
o
--.
-- . _ _
(324)
(323)
(325)
Reagents: i, Me,SiC = C(CH,),MgCl-CuI-BF,.Et,O ; ii, Bu,NF; iii, 360 "C; iv, Ph,P=CH,;
v, MCPBA; vi, BF,.Et20; vii, I,; viii, K,C03-NH,NH,; ix, H,C=CH(CH,), MgBr-CuIBF,*Et,O
Scheme 36
Sesquiterpenoids
Reagents: i, CH,=CH(CH,),MgBr;
121
v, MsC1-py; vi, DBN; vii, 250 "C; viii, H,-Pd/C; ix, LDA; x, PhSeBr; xi, H202;
xii, MeMgICuBr.Me,S
Scheme 37
163
4136; (b) W. K. Bornack, S . S. Bhagwat, J. Ponton, and P. Helquist, J . Am. Chem. SOC.,1981,
103, 4647.
164 A. P. W. Bradshaw, J. R. Hanson, and R. Nyfeler, J. Chem. SOC.,Perkin Trans. 1 , 1981, 1469.
le6 A. P. W. Bradshaw, J. R. Hanson, and R. Nyfeler, J . Chem. SOC.,Chem. Commun., 1981,649.
lee A. P. W. Bradshaw, J. R. Hanson, and I. H. Sadler, J . Chem. SOC.,Chem. Commun., 1981,1169.
122
pi-xi
Jxvii
f.3
C0,Me
v, xviii,
v, xix
xx
_j
HO
H02C
$OAc
OX0
Reagents: i, CH,=CHMgBr-CuBr.Me,S ; ii, Me,SiCl-Et,N iii, MeLi ; iv, BrCH,C(OEt)=
CHPO(OMe),; v, H,O+; vi, NaH; vii, PhSCHLiC0,Me; viii, CH,O; ix, aq- NH,Cl; x, NaBH,;
xi, Me,C(CH,OH),-H+; xii, Li-NH,; xiii, 9-BBN; xiv, H,O,-OH-; xv, TsC1-py; xvi, NaI;
xvii, LiN(SiMe,),; xviii, OH-; xix, Ac,O-py; xx, PCC; xxi, 200 C
Scheme 38
Sesquiterpenoids
123
ethyl acetal of (331) obtained from B. cinerea grown on a H2 l8O medium clearly
shows l80incorporation at C-9. These results are in accord with Scheme 39 which
involves inversion of configuration at C-9 as a result of the 1,3-hydride shift.
(332)
(333) R
(334) R
(335) R
NO
(336)
= ONO,
=
NO2
(337)
167
lE8
le0
1
'
0
(338)
(339)
(340)
*Recrystallization of humulene nitrosite from hot ethanol produces both humulene and isohumulene (336) (ca. 1 :1) together with the dinitro-cbmpound (334) and the nitrosite (333). I. Bryson
and J. S . Roberts, unpublished results.
?We prefer the IUPAC numbering (see Editor's note in ref. 172) although we recognise the
preference of Professor Matsumoto and others for humulene numbering based on its derivation
from farnesyl pyrophosphate.
124
accessible humulene-epoxide (340) is treated with LDA to form the allylic alcohol
(341) which is oxidized with Bu'OOH-VO(acac), to give predominantly (342).
Collins oxidation of (342) gives the corresponding epoxy-ketone which on treatment
with hydrazine hydrate and KOH undergoes a Wharton rearrangement to furnish
zerumbol (343) which can be oxidized to zerumbone (338) with MnO,.
As mentioned in previous reports the number of bicyclic and tricyclic sesquiterpenoids which can be derived from humulene (332) has continued to grow
steadily over the past 10 years. Scheme 40 outlines briefly the 17 major structural
types whose biogeneses have been proven or are thought to involve the intermediacy
of humulene. The majority of these sesquiterpenoids have been isolated from
fungal sources, particularly the Basidiomycetes and an excellent review of these
fascinating metabolites has been written by Ayer and Browne.171 In addition to
the challenging synthetic and biosynthetic problems that these metabolites have
presented, another area of considerable interest is the biomimetic conversion of
humulene and its derivatives into the novel skeletons which form the framework of
these compounds. Of particular note is the work of Shirahama and Matsumoto who
have gained considerable success in this area. A full publication from this group172
has now appeared which describes model studies which led to the successful
conversion of the protoilludane epoxide (344) into the two hirsutane derivatives
(345) and (346), the former of which was chemically transformed to hirsutene (347).
It should be noted, however, that all evidence to date indicates that the hirsutanes
are not derived from humulene via the protoilludyl cation but arise by a different
pathway (see Scheme 40 and Vol. 1 1 , p. 39). One of the key compounds used in
humulene biomimetic cyclizations is the 4,5-epoxide (348) which, under acidcatalysed conditions, is able to generate the all important humulen-4-yl cation.
Shirahama and c o - w ~ r k e r have
s~~~
subjected the epoxide (348) to two different sets
of acid conditions. In one case, using trimethylsilyl trifluoromethanesulphonate,
the products are the two africane-type alcohols (349) which had previously been
obtained by reaction of the same epoxide with boron trifluoride e t h e ~ a t e . The
'~~
tetrasubstituted isomer of (349) has been converted into africanol (350) in five
steps. On the other hand, treatment of (348) with boron trifluoride etherate
in acetic anhydride gave the bicyclohumulane derivative (35 1) which was converted
into bicyclohumulenone (352), a naturally occurring compound, in seven steps.
171
172
173
17'
Sesquiterpenoids
125
-a
cd
22
a
J.
I
126
(344)
(346)
(345)
HO
(347)
-+
(349) R
(356) R
(348)
=H
= AC
(350)
(3 54)
? ..OAc
These two results demonstrate that cyclization of the epoxide (348) has proceeded
from two different conformations of the epoxide, namely the CT conformer (353)
in the absence of a nucleophile to produce (349) while the CC conformer (354)
in the presence of the nucleophilic acetate proceeds to (351). In a subsequent
paper175 it was shown that both conformers (353) and (354) react with boron
trifluoride etherate in acetic acid to give (351) and (355)-(357), the first two
arising from the CC conformer (354) and the second pair from the CT conformer
(353).* Another significant result in this area is the biomimetic-type synthesis of
pentalenic acid (360) from humulene (Scheme 41).176The design of this synthesis
was based on earlier results (Vol. 10, p. 40) concerning the cyclization of the
5-deoxy analogue of (358) and the subsequent conversion of (358) into (359) in 20 %
yield mimics the biosynthesis of the pentalenane sesquiterpenoids (see ref. 183).
The latest result from the Japanese
is the transformation of kumulene to
sterpurene (364), one of the newest additions to the tricyclohumulane family,
vide infra. In this case the results from a previous study (Vol. 10, p. 40) paved
the way for the successful synthesis. Thus, treatment of (361), obtained from
176
177
*A similar result has been obtained when the epoxide (348) is allowed to react with boron trifluoride etherate in wet diethyl ether. In this case the diol corresponding to the diacetate (351) is
formed exclusively. This diol reverts to the starting epoxide on treatment with PTSA. R. M.
Carman, I. Bryson, and J. S. Roberts, unpublished results.
127
Sesquiterpeno ids
iii
Ho
OH
(358)
Ho
(360)
(359)
Reagents: i, aq. Hg(N03),; ii, KBr; iii, 0,-NaBH,; iv, Cr03-H+; v, NaBH,; vi, Ac,O-py;
vii, PBr,; viii, Am'ONa; ix, Li-EtNH,; x, BF3.Et20;xi, SeO,; xii, Mn0,-KCN-MeOH;
xiii, OH-; xiv, H 3 0 +
Scheme 41
humulene, with boron tribromide gave (362) and (363) both in yields of 20%.
Further reaction of (362) with silver acetate in acetic acid gave sterpurene (364) in
61 % yield The sequence of rearrangements is interpreted in terms of Scheme 42
and this probably represents the actual biosynthetic pathway to the sterpuranes.
As noted above this new class of sesquiterpenoid has emerged recently as
a result of investigations by Ayer et al. on the metabolites of the fungus Stereum
purpureum, the cause of the so-called silver leaf disease common to a number of
fruit trees. In their first paper1'* Ayer et al. established the structures of sterpuric
acid (365), the hydroxy-derivative (366), and the ethylidene acetal (367) by a
combination of chemical and X-ray studies. Further
on this fungus led to
the isolation of sterepolide (368) and dihydrosterepolide (369) both of which are
a .cily,
Br
.*
@
0
I
H '.
OMe
(361)
178
H
(362)
=*..
H :
(363)
37, 379.
lTP
W. A. Ayer and M. H. Saeedi-Ghomi, Tetrahedron Lett., 1981, 22,2071.
128
(364)
Scheme 42
examples of the rare isolactarane group of which only one other member was known
previously (Vol. 9, p. 116), although another example, merulidial (370), has been
quoted recently.lso The co-occurrence of sterpurane and isolactarane sesquiterpenoids makes the biogenetic relationship shown briefly in Scheme 40 a distinct
possibility. The neutral components of this fungus contain the trio1 (371) and very
interestingly the parent hydrocarbon, sterpurene (364).ls1
(365) R
(366) R
=H
= OH
(367)
CHO
(370)
lEo
lal
129
Sesquiterpenoids
Paquette et ~ 1 have
. accomplished
~ ~ ~ a relatively short synthesis of the methyl
ester of pentalenolactone E (372) (Scheme 43). Full details of the biosynthesis
of pentalenolactone (373) from [ U-13C,J glucose and [6,6-2H2]glucose have been
rep0rted.1~~
These substrates were used in view of the lack of incorporation of
the more conventional acetate and mevalonate isoprenoid precursors. The stereochemical picture which has emerged from this study is that the pentalenane
H
xi, v, xii
Scheme 43
skeleton is derived from the RSR-CT conformer of humulene (374) (Scheme 44)
which results from attack on the si face of the distal double bond of farnesyl
pyrophosphate. This pathway is consonant with the proven biosyntheses of
fomannosin and the illudins. Cane et al. have further speculated about a possible
enzyme receptor site for humulene formation and subsequent cyclization. In this
work and elsewhere there is the tacit assumption that humulene retains the all-trans
arrangement of the three double bonds prior to cyclization. Models indicate that
this geometric imposition means that Lond formation between C-4 and C-8 may
not be too facile and indeed there is no in vitro example of such bond formation in
humulene chemistry. Examples of C-4-C-8 bond formation are only observed after
18s
L. A. Paquette, H. Schostarez, and G. D. Annis, J . Am. Chem. Soc., 1981, 103, 6526.
D. E. Cane, T. Rossi, A. M. Tillman, and J. P. Pachlatko, J. Am. Chem. Soc., 1981, 103, 1838.
130
(374)
(373)
Scheme 44
C-1 and/or C-2 have been converted to sp3 geometry. One possible explanation for
this apparent anomaly is to invoke a
trans+cis isomerization in humulene
prior to cyclization. This permits a more favourable interaction between a developing cationic centre at C-4 and the ABlg double bond. Thus the conformer (375)
of isohumulene could serve as a precursor for the protoilludyl-derived metabolites
while its enantiomer could proceed to the hirsutane sesquiterpenoids.
A l p 2
(375)
The biosynthetic relationship between illudol (379) and fomannosin (380)
has inspired Semmelhack and c o - w o r k e r ~ ~to~ ~aJ ~beautifully
~
constructed
synthesis of the two natural products via the common intermediate (378) (Schemes
45 and 46). This tricyclic compound (378) was obtained by a Diels-Alder reaction
between (376) and the cyclobutene derivative (377). Another photochemically-based
route (Scheme 47) has been used to obtain protoillud-7-ene (381) and several
oxygenated derivatives.la6
Full reports on the syntheses of methyl isomarasmate (382) and the naturally
occurring marasmic acid (383) have appeared.lB7Ja8A second imaginative synthesis of marasmic acid (383) has also been reported (Scheme 48).189Once again
the power of the intramolecular Diels-Alder reaction has played a pivotal role in
F. Semmelhack and S. Tomoda, J . Am. Chem. SOC.,1981, 103,2427.
M. F. Semmelhack, S. Tomoda, and K. M. Hurst, J. Am. Chem. SOC.,1980,102,7567.
H. Takeshita, I. Kouno, M. Iino, H. Iwabuchi, and D. Nomura, Bull. Chem. SOC.Jpn., 1980,
la4 M.
la6
53, 3641.
la'
la8
189
131
Sesquiterpenoids
OSiMQ
OSiMe,
>o"
C0,Et
(376)
q OOEt
E t
(377)
EtO OEt
qH qH
v-viii
iii, iv
f---
EtO OEt
EtO OEt
Et0,C
E t d OEt
.MP
H ' K
EtO OEt
H EtO
- uOEt
HY
OH
(379)
Reagents: i, A ; ii, 3A molecular sieves-MeOH; i i i , LiEt,BH; iv, NaH-PhCH,Br; v, LiAIH,;
vi, BuLi-ClPO(NMe,),; vii, Li-EtNH,; viii, Cr0,-py; ix, LDA; x, CO,; xi, H + ; xii, CH,N,;
xiii, PhSeC1; xiv, H,O,; xv, NaAl(OR),H,; xvi, Me,C=O-H+; xvii, H,O+
Scheme 45
the synthetic strategy. Thus, heating the triene (384) gave two tricyclic products
(385) and (386) in the ratio of 1 : l . Compound (385) results from cyclization
via an endo transition state whereas formation of (386) must occur by the usually
disfavoured exo transition state. In the event both adducts could be converted
into marasmic acid (383), Scheme 48 showing the sequence for (385). A similar set
of transformations was effected on (386) and this gave the trans-isomer of (383)
which was converted into the corresponding enol acetate which gave :-liarasmicacid
(383) on hydrolysis.
A full report on the structural determination of the seco-illudalane sesquiterpenoids, the cybrodins, has appeared.lgO These metabolites, which include
cybrodol (387), isocybrodol (388), cybrodal (389), trisnorcybrodolide (390), and
cybrodic acid (391), have been isolated from the bird's nest fungus Cyathus bulleri.
In addition to these compounds, pterosin C (392), previously isolated from Pteridjum ferns, together with broderol (393) and nidulol (394) for which tentative
structures have been put farward, have been isolated. The five compounds (387)l a 0 W.
132
i, ii
(378) --+
b,
vii
ButMe,SiOoH
MsO"
(380)
Reagents: i, LiAlH,; ii, 3A molecular sieves-MeOH; iii, MCPBA; iv, H,O+; v, Bu'Me,SiClimidazole; vi, NaBH,; vii, DHP-PTSA; viii, LDA; ix, CH,O; x, PhSeC1; xi, H + ;xii, H,O,;
xiii, CH,=CHOEt-H+; xiv, MsCI-Et,N; xv, HF; xvi, Cr0,-py ; xvii, Bu,NF
Scheme 46
qo
ii-iv
i
M e 0 OMe
Q
H
___,
H
(38 I )
Scheme 47
---CHO
C0,Me
Sesquiterpenoids
133
Ijr
C0,Me
q;
qoAc
liv, v
J.
2-
(mOl2!7Q
Me0,C
C02Me
Vlll
Me02C
G
xi
xii, ii
t---
Me02C
Jxiii
CHO
fi
-*...;
Me0,C
OH
0
(3183)
Reagents: Ph,P=CBrCO,Et ; ii, Bu',AlH; iii, Ni(CO),-NaOMe; iv, AcC1-py ; v, H 3 0 + ;
vi, NaH; vii, 200 "C; viii, KOBu'; ix, PTSA-MeOH; x, MsC1-Et,N; xi, DBU; xii, PhSeBrMeOH; xiii, MCPBA: xiv, BBr,
Scheme 48
OH
(387) R1= Me, R2 = CH20H
(388) R1= CH,OH, R2 = Me
(391) R1= Me, R2 = C02H
(389)
(390)
134
OH
'10'
(392)
(394)
(393)
(39 1) have all been synthesized as reported earlier.lgl The seco-illudane, hypacrone
(396) has been synthesized (Scheme 49) from the intermediate (395) previously used
in illudin syntheses.lg2
I
so
+
i
0 0
+
ii
a
(395)
H
0
iii, iJiv
Scheme 49
lg1
lg2
135
Sesquiterpenoids
&
A
j i , iii
bi,
v, vii
(347)
Reagents: i, A; ii, LiAlH,; iii, Bu'Me,SiCl-imidazole; iv, BH,; V, PCC; vi, Bu,NF; vii, (Ph,P),
RhCl; viii, NaOMe-EtOCHO; ix, BuSH-PTSA; x, K0Bu'-MeI; xi, OH-; xii, Ph,P=CH2
Scheme 50
3460.
136
vii, viii
___,
1
0-7
Jix, x
f-xi
H..'
9
H:'
MeS,CO
0-7
OMe
(409)
(347)
Reagents: i, A ; ii, hv; iii, 500 "C; iv, 310 "C; v, H2-Pd/C; vi, KOBut-MeI; vii, NaBH,; viii,
MeOCH,C1-Pri2NEt; ix, LiAlH,; x, NaH-CS,-MeI; xi, Ref: 197
Scheme 51
H OH
H OH
"OH
(410)
(411)
acid (413) (Scheme 52) has been described;lg9this terminates at the keto-ester (412),
have described a photoa key intermediate to hirsutic acid.200Pattenden et
2oo
201
lee
1974, 3745.
137
Sesquiterpenoids
kv
H
(4 13)
Reagents: i, TosNHNH,; ii, NaOMe; iii, F-; iv, DHP-H+; v, aq. NBS; vi, Bu,SnH; vii, PCC;
viii, Ph,P=CH2; ix, MeOCH: ;x, H,O+; xi, HC1-MeOH; xii, CrO,H+; xiii, CH,N,; xiv,
NaH-CH,=CHCH,Br ; xv, PdC1,-0,; xvi, KOBu'; xvii, Ref. 200
Scheme 52
138
OMe
+
OCOPh
OCOPh
pi,viii
@xii, xiii
t
xi, iv
f-ix, x
0
(418)
(420)
Reagents: i, LiAlH,; ii, PCC; iii,
(419)
; iv, MeO,CN=NCO,Me;
v, KO,CN=NCO,KAcOH; vi, KOH; vii, K,Fe(CN),; viii, A ; ix, B2H,; x, H,O,-OH-, xi, PPh,=CH,
Scheme 54
Sesquiterpenoids
139
these (Scheme 54)203is another nice example of the synthetic utility of intramolecular
1,3-diyl trapping reactions developed by Little. In this particular case the stereoselectivity of the ring closure of the intermediate cyclopenta-1,3-diyl (421) is
not as great as in other examples and this may be the result of an unfavourable
interaction between the hydrogen and the methyl group in (421). This interaction
may be responsibfe for the significant formation of the cis-syn-isomer of (419).
The second synthesis of (420) involves a stereocontrolled construction of the
triquinane nucleus (Scheme 55). 204
I vi
(420)
Reagents: i , CH,=CHMgBr; ii, MnO,; iii, P20,-MeS0,H; iv, Me,CuLi; v, LiC=CH;
vi, HC0,H-H,SO,; vii, CH,=CHMgBr-Cul; viii, 0,; ix, Me,S; x, HC0,H; xi, KOH;
xii, H,-Pt; xiii, PPh,=CH2
Scheme 55
p
p...
HO-
(423)
(424)
(425)
(426)
R, R2= CH,
R = R2= H
R1= Me, R2= OH
R = CH,OH, R2= H
140
p p --p
Terpenoids and Steroids
(428)
(429)
(430)
(434)
Previously Arigoni2I0had put forward an elegant stereochemical argument for the
co-occurrence of (-)-longifolene (432) and (-)-sativene (433) from this fungus, as
summarized in Scheme 56. The detection of (431) in the mycelium adds substantial
support to this proposal since it is the very ten-membered ring intermediate en route
to (-)-sativene. The final verification of the structure of (431) was achieved by
carbanionic cyclization of the cis,trans-farnesyl sulphide (434) followed by reductive
removal of the sulphide group and dehydration of the derived tertiary alcohol.
6p-Hydroxygermacra- 1(1 0),4-diene (435) has been isolated from various
Verbesina species as the corresponding coumaroyl and feruloyl esters.s0(-)-Mint205
206
207
208
208
210
141
Sesquiterpenoids
(433)
sulphide (436), a novel sesquiterpenoid from peppermint oil, has been synthesized
by irradiation of f -)-germacrene D (437) in the presence of sulphur.211Treatment
of the methyl sulphonium salts of mintsulphide (438) and isomintsulphide (439)
with LDA gives the homologous sulphides (440) and (441) respectively by way
of a [2,3] sigmatropic rearrangement of the corresponding sulphonium ylides.212
(435)
211
z*a
(437)
K. Takahashi, S. Muraki, and T. Yoshida, Agric. Biol. Chem., 1981, 45, 129.
T. Uyehara, T. Ohnuma, T. Saito, T. Kato, T. Yoshida, and K. Takahashi, J. Chem. SOC.,
Chem. Commun., 1981, 127.
142
(445).
iiii
Reagents: i, hv-CH,=C=CH,;
Scheme 57
OH
213
214
216
G. L. Lange, S. So, M. Lautens, and K. Lohr, Tetrahedron Lett., 1981, 22, 311.
S. L. Schreiber and C. Santini, Tetrahedron Lett., 1981, 22,4651.
M. Kodama, K. Shimada, and S. It6, Tetrahedron Lett., 1981, 22, 1523.
Sesquiterpenoids
143
WH+
SPh
o.-r
PhSO
(465)
(464)
(463)
qqq
HO
&
(OH
PhSO
OH
(466)
Rlp2
OH
(467)
OH
(468)
OH
(469) X1= Me, R2= OH
(470) R1= OH, R2= Me
M. Kodama, K. Shimada, T. Takahashi, C. Kabuto, and S. It6, Tetrahedron Lett., 1981, 22,
427 1.
m7 J.
144
Me0,C
(471)
PhS
PhS
Me0,C
HO
(475)
(476)
Four products (473)-(476) resulted from this reaction, three of which are of the
eudesmane class while the fourth has the cadinane skeleton.
Treatment of the truns,truns-germacranolide, epitulipanolide (477) and two of its
derivatives with selenium dioxide and t-butyl hydroperoxide gives the melampolidetype alcohol (478).21sA mechanism for this allylic oxidation with inversion of
configuration at the AIJo double bond is proposed. It should be noted, however,
that this is not the first report of such a process (cf Vol. 1 1 , p. 55).
(477)
(478)
The isolation and identification of germacrane lactones from a host of plant
sources is an area of continuing interest particularly in the laboratories of Professors Herz and Bohlmann. The search for biologically active compounds and the
chemotaxonomic classification of plant species are the two major driving forces
for this research. The sub-division of these lactones into germacranolides (479)-
JV
0
(479)146Costunolide
Derivative
218
Po
..--0
AcO
OAc
(480)219Artemisiifolin Diacetate
Sesquiterpenoids
145
(482)220Eupatolide Derivatives
w
o
..--0
H and OAc
CH,OH
co-occurs
with
OR2
R1O
(483)221R1 =
Cc,
R2
co
=H
CH20H
(484)22
etc.
Artemisiifolin Derivatives
(485)222R
= AC
Ovatifolin (also R
H)
&-+(
QR
- .
mg;ws
0
(486)223Blainvilleolide
Derivatives
various R goups
and
0
(487)2234,5-cis-Acanthospermolide
Derivative
&
0
(488)223Acanthospermolide
146
221
222
223
225
228
228
229
231
147
Sesquiterpenoids
bAC
(489)224Marginatin
(490)225Vautheriol Derivatives
Derivative
various R groups
HR
o..;
q 9 3 O
OH
HO'.
0
(491)226Eupaserrin
(492)2261 1 PH-Dihydrochamissonin
Derivative
(OAc
' 04
0
(493)227Eupaserrin
(494)228Costunolide Derivatives
Derivative
various R groups
q
:
0
0
= H and OH
Acanthospermolide
Derivatives
(495)22sR
(496)228Ovatifolin
(497)228Grazielia Acid
Derivative
QCAC
0
'0
(498)22s8~-Angeloyloxy-grazielolide (499)229Disyfolide
(500)229 Disyhamifolide
148
R3
(501)230Costunolide
Derivatives
(various R1,R2,R3groups)
(502)231Haageanolide
Angelate
QH
A
0
0
(503)231Zinangustolide
(also 1 18, 13-dihydro derivative)
(504)232Scandenolide
AcO
HO
(505)233Costunolide
Derivative
(506)234Arbutifolin
(and 11p, 13-dihydro derivative)
(507)235
(509)236Cordifene
,,
(5
Ineupatolide
Sesquiterpenoids
149
. ..-so
R 0
0
AcO
R
(512)238R
(51
= MeBu, Ineupatorolide A
= Ang, Ineupatorolide B
qp
0
( 5 1 3)239
I;I
I;I
*fp
..-so
..--0
OAng
(5 14)240Laurenobiolide
Derivative
I:.:"'?:"
( 5 16)240
gQ
I
OAc
0
(5 17)241Ereglomerulide
H-
OH
(5 15)240Onoseriolide
Derivatives
O
'OAng
A c
HO
0
( 5 18)2412,3-truns-Ereglomerulide
OAc
0
(51 9 y 1 Ereglomerulide
Derivative
---OH
0
(520)242Vicolide B
(521)242Vicolide C
---OR
0
(522)243R
(523)243R
= COC(Me)=CH,, Molephantin
= Tig, Molephantinin
0
(524)243Phantomolin
150
a*
OTig
HO
--.-
0
(525)5 3u- and 3P-H ydroxybejaranolide
OH
,OAc
co-occurs
with
0
(526)5 Atripliciolide
Derivative
gr:c OAc
'
04
0
(527)5 4,5-trans-Bejaranolide
(R = H)
(528)j 3u-Hydroxy-4,5-transbejaranolide
(R = OH)
HO--. -
0
(529)6 1-epi-NiveusinC
Acetate
HO
eacr
0
(531)11*Trichogoniolide
0
(530)11*Atripliciolide
Derivatives
(various R1 and R2groups)
"p::lt
eacr
0
(532)11*Isotrichogoniolide
?R'
O-S
0
(533)11*Trichosalviolide
Derivatives
(various R1 and R2 groups)
0
(534)11*Zexbrevanolide
Derivative
151
Sesquiterpenoids
mo
0
OAng
pgJ
OH
R--
(535)150 Lychnopholide
0
(536)244Niveusin C
(= A n n ~ i t h r i n ~ ~ ~ )
R=OH
=H
(537)244R
(538)244R1 = R2 = OH
(539)244R1 = OH, R2 = H
AcOQ g -
(540)246
go%
-
0
(542)24*
(541)247Heliangin
3-Acetate
(543)249Budlein
Derivative
(544)249
0
(546)250Viguestenin
Derivatives
(545)249Ovatifolin
Derivative
152
Q(Tig)
eacr
...-0
(547)251Eremantholanolide
Derivative
(also 4,5-dihydro
derivatives)
(548)251Goyazensolanolide
Derivative
(549)251Zexbrevanolide
Derivative
pp
...-o
(550)252Govazensolanolide
Deiivative
....0
OH
0
(55 1)252 Eremantholanolide
Derivative
(552)253Goyazensolanolide
Derivative
'Q*
.OAng
'
OAc
HO
0
(5 53)253Zexbrevanolide
Derivative
OAng
(554)253
Piptolepolide
HO
bAng \
HO
(555)254 Tsocentratherin
(556)255R
= CO(Me)CH,,
Calaxin
= COCHMe,,
Ciliarin
(557)255 R
0
( 5 1 % ) ~R~ =
~ CO(Me)CH,,
Zexbrevin B
(559)255R = COCHMe,,
Orizabin
Sesquiterpenoids
153
0
(560)256
Atripliciolide
Derivatives
(various R1 and R2 groups)
(also I 1,13-epoxides)
(561)256 Atripliciolide
Derivatives
(various R groups)
Derivative
o:::Q&H
0
(563)257Punctatin
Derivative
Qg
(562)256Atripliciolide
_.--
OAc
0
(564)25s1 1 p, 13-Dihydromelampodin
.OAng
co-occurs
with
HO
0
(565)259Acanthospermolide
Derivative
(566)2594,5-cis-Acanthospermolide
Derivative
CHO
OTig
0
(567)240Wunderolide
(568)260R
(569)260R
=
=
H, Rolandrolide
Ac, Acetoxyrolandrolide
(570)226R = H, Isorolandrolide
(571)260R = Et, Ethoxyisorolandrolide
154
HO
0
(572)261R1= Ac, R2 = CO(Me)=CH,
(573) R1 = Ac, R2 = COCHMe,
(574) R1= Ac, R2 = COCH(Me)Et
(575) R1= COCH(Me)Et; R2= Ac
Melcanthin D
Melcanthin E
Melcanthin F
Melcanthin G
(576)262Piptocarphins A-F
(various R1,R2,R3groups)
HO.
qoA
TigO
OTig
OAc
co-occurs
with
AcO..
(577)263Hirsutinolide
Derivative
(578)263Chrestanolide
.OAc
I~
WAC
O-X,
(579)264Hirsutinolide
(580)264Isohirsutinolide
Derivative
Derivative
(582)4
(583)4
Q;
155
Sesquiterpenoids
..OAc
A c o'0 * - ~ o A c
'0
0
(584)4
0
(585)
relatively straightforward but in other cases rather arbitrary.* The vast majority of
the lactones listed are new, their structures having been deduced by spectral
analysis. In view of the complexity of the structures of these compounds a heavy
reliance on the interpretation of n.m.r. spectra may lead to erroneous conclusions
and indeed some of the compounds listed appear as a result of structural revisions
(particularly of stereochemistry) necessitated by X-ray studies and/or correlations
with proven structures. The newest additions to this group of sesquiterpenoid
lactones are the allenic germacranolides, the vernonallenolides (58 1)-(583),
isolated from several Verrtonia specie^.^^^^^ They co-occur with a number of new
compounds two of which are the glaucolide derivatives (584) and (585).
12 Elemane
Additional examples of elemanolides from a variety of plant sources include
disynaphiolide (586),229 a series of 8-epizinamultifluoride esters (587),231isoarbutifolin (588) and its I 1,13-dihydro derivative,234and (589 ; R = COC(CH,)Me
or R = Tig).266
A full report on the preparation of the photo-adduct (590) from methylcyclobutene and (-)-piperitone and its thermal conversion into the various shyobunones
(59 1) and related sesquiterpenoids has appeared.267Another synthesis of the
cytotoxic compound ( +)-deoxyvernolepin (592) Starting from a-santonin has been
recorded. 268
265
266
e67
156
(589)
13 Eudesmane
New additions to the eudesmane family of sesquiterpenoids include (593) and its
1 I, 12-dihydro deri~ative,~
2-desoxyliguhodgonal (594),59and (595)-(601).60J48*269
Herz and Kurnar2'O have reported a compound from another Verbesina species
which may well be identical to the coumarate ester (598). With good reason,
however, they suggest a reversal of stereochemistry at C-4. The costic acid derivative
(602) and its C-7 epimer co-occur with the reynosin derivative (603) in Lasiolaena
s u n t ~ s i i .Huffman
~~~
and Pinder271have expressed some reservations about the
identity of isointermedeol (604) (Vol. 10, p. 70). They have presented evidence
to suggest that the material used may just have been an impure sample of
( +)-intermedeol (605).
In an ongoing study of the constituents of the rare Guyanan tree DuZucia
guianensis, Polonsky et al.272have identified by X-ray analysis the rather unusual
H?
(596)
26B
L70
271
B7a
(597)
(598)
Sesquit erpenoids
157
p y
OAng
(602)
P....(
HO,' H
QoH
(608)
87s
274
276
(609)
158
(61
(61O)lo3Inucrithmolide
Alantolactone
Derivative
Q3$:
(Ac)HO*o
OH(AC)
(6 I 3)154 Eridanolide
Derivatives
(various R groups)
(6 14)220Balchanin
Derivative
qIg
A
(Sen01
n
0
(615j2@Arhsculin
(612)lb4Ivangustin
Derivative
0
(6 1 6)222Arturin
(617)231Ivangustin
Derivative
Derivative
276
277
278
27s
280
281
282
283
a84
X. A. Dominguez, R. Franco, G. Cano, R . Villarreal, M. Bapuji, and F. Bohlmann, Phyfochemistry, 1981, 20, 2297.
F. Bohlmann, J. Jakupovic, and A. Schuster, Phytochemistry, 1981, 20, 1891.
B. A. Nagasampagi, J. S. Sohoni, F. Bohlmann, and C . Zdero, Phytochmisfry,1981,20,2034.
F. Bohlmann, J. Ziesche, R. M. King, and H. Robinson, Phytochemistry, 1981, 20, 1335.
F. Bohlmann, A. K. Dhar, J. Jakupovic, R. M. King, and H. Robinson, Phytochemistry, 1981,
20, 838.
F. Bohlmann, J. Ziesche, R. M. King, and H. Robinson, Phytochernistry, 1981, 20, 751.
R. Takeda, Y. Ohta, and Y . Hirose, Chem. Lett., 1980, 1461.
Y. Asakawa, M. Toyota, Z. Taira, T. Takemoto, M. Kido, and Y. Ichikawa, J . Chem. SOC.,
Chem. Commun., 1980, 1232.
Sesquiterpenoids
159
c":I.-
OTig
(618)247
Reynosin Derivative
(619)247A's5 Arbusculin Derivative
(620)247
Balchanin Derivative
(621)249Ivasperin
Derivatives
A39',
..m
OH
-..o 0
H
(622)249
__..
Po.
Ho'
(624)277
(623)276Maritimin
OH
O q Z ? ?
(625)277Ixtlixochilin
Derivatives
(626)278
w
o
Ho/
(627)278Asperilin
Derivatives
q,
0-
(628)279Isoivangustin
(629)280
R1
0'
*.. H
0
(630)280
0
"
0
(631)28'R1= R2= H
Dimerostemmolide
Derivatives
(632) R1= OH, R2 = Ang
(633) R1= OH, R2 = Mebu
160
q
OR
(634)282Oxidoisotrilobolide
Derivatives
(various R groups)
(635)2s2Trilobolide
Derivatives
(various R groups)
q Eto2c20J
Eto
6H 0
....
....
....
RO
R
2
R
R
l
2no
(645)
(646)
Sesquiterpenoids
161
p..
.,<
eudesmane-type compound (650).291In an approach to the synthesis of polyhydroxyagarofurans, Huffman and Hillenbrand292have repeated the Robinson annelation
of hydroxycarvone with ethyl vinyl ketone. In contrast to an earlier result, the major
product of this reaction is the dione (651), the minor product being the C-10
epimer. Treatment of (651) with MCPBA, followed by LiAlH4reduction and Jones
oxidation of the resultant stereoisomeric 3,9,11-trials gave 9-keto-a-agarofuran
(652). A short synthesis of frullanolide (654) has been achieved, based on a newly
developed nickel-promoted cyclization/carbonylation procedure for the one-step
preparation of a-methylene-y-lactones (Scheme 58).293Both the E- and Z-isomers
Br
+ 2-isomer
(653)
(654)
Scheme 58
M. Van Audenhove, D . De Keukeleire, and M. Vandewalle, Bull. SOC.Chirn, Belg., 1981, 90,
255.
292
294
162
MOMO
OSiMe,But
x-xii
(655)
Jxiii-xvi
MOMOw S i M e z B u t
xvii-xx, ii,
Jxxi, xxii
AcO
AcO
a
OAc
pxV,
OAc
xxvi
HO
HO
HO
0,
But Me,SiO
>xviii,
iv, xxvii,
xix,
xxix, xix
ButMe,SiO
OSiMe,
II
Reagents: i, ClCH,OMe-PhNMe,; ii, KOH; iii, Me,&,; iv, LDA; v, MeCH=CHCO,Me;
vi, Br,; vii, NaBH,; viii, Zn-EtoH; ix, KOBu'; x, LiAlH(OBu'),; xi, Bu'Me, SiC1-imidazole;
xii, aq. NBS-Na,CO,; xiii, Bu',AlH; xiv, MsCI-Et,N; xv, NaI; xvi (CH,=CH),CuLi ;
xvii, Et3NHF; xviii, LiCH,CO,Li; xix , H + ; xx, 0,;xxi, Ac,O-py; xxii, (CH,SH)2-BF3Et20;
xxiii, PCC; xxiv, PhSeCl ;xxv, K,CO,-MeOH ;xxvi, Bu'Me,SiCI-py-then Me3SiC1; xvii, CO,;
xxviii, CH,O-Et,NH ; xxix, (CH,=CMeCO),O-py-DMAP
Scheme 59
Sesquiterpenoids
163
(657) R
(658) R
=
=
CHO
CH20H
R
Or&,
(661) R = H
(662) R = OH
(664) R = AC
(665) R = H
HO
164
(-)-Phytuberin (664) has been the synthetic target for three groups in the
year under review. The first of these (Scheme 60) started from (-)-2-carone
(668).299The second one (Scheme 61), commencing with (-)-carvone (669), is
rather inadequately described.300 For instance, it is claimed that the lithium
i, ii
PhCH,O
OQiii
I
PhCH,O
%
0
I
OCH2Ph
PhCH,?
H;q
PhCH20
&
OCHzPh
OAc
OCH,Ph
C
/
C0,Et
Reagents: i, LDA; ii, PhCH,OCH,Cl; iii, PhCH,OH-PTSA; iv, LiC rCC0,Et; v, Me,CuLi
(-24 "C); vi, H,-Pd/C; vii, Bu',AlH; viii, OH-; ix, Ac,O-Et,N-DMAP
Scheme 60
.1.;,
vii
(672)
(67 1)
Reagents: i, LDA; ii, CH,OH; iii, LiCECH; iv, Ac,O-py; v, HgS0,-aq. MeOH;
vi, EtOC=CLi; vii, (CO,H),--MeOH; viii, MCPBA; ix, LiAIH,; x, 150 "C
Scheme 61
aoo
Sesquiterpenoids
165
enolate of (-)-camone reacts with formaldehyde to give (670) plus its C-10
epimer (do the authors mean dihydrocarvone?); no conditions are given for the
conversion of (671) into (672); not a single optical rotation is recorded for any
of the optically active compounds in the synthetic sequence. The final synthesis
(Scheme 62) involves an interesting elaboration of elemol (673) to give the lactone
(674) which had previously been converted into phytuberin (664).301
\\
piv,
ii
Scheme 62
Solavetivone (661) has also been a synthetic objective with two new syntheses
having been completed. The first of these (Scheme 63) achieved syntheses of
both solavetivone (661) and the hydroxy derivative (675), whose glucoside has
been identified in
The second synthesis (Scheme 64) relied upon a
Diels-Alder reaction to construct a bicyclo[2,2,2]octyl framework which was then
cleaved by acid to release a prenyl-mesylate (679) for further acid-promoted
301
ao2
F. Kido, H. Kitahara, and A. Yoshikoshi, J. Chem. Soc., Chem. Commun., 1981, 1236.
C. Iwata, T. Fusaka, T. Fujiwara, K. Tomita, and M. Yamada, J . Chem. SOC., Chem.
Cornmun., 1981,463.
166
s CHNz
--+
i
---+
i
OH
0
/,iii
CQ,
2=xcyq)toy&
OMS
C0,Et
j,x-xiii
OH
kii
Scheme 63
c y c l i ~ a t i o nIn
. ~ ~the
~ event, conditions were found for the obtention of all four
Diels-Alder a d d u c t ~ ,the
~ ~ syn-endo,exo
~
isomers (676) being transformed to
hinesolone (680) and p-vetivone (68 l), while the anti-endo,exo isomers (677) were
converted into solavetivone (661). In a subsequent communication the same
devised an alternative method (Scheme 65) for the preparation of the
anti-endo- and antfexo-adducts (682) and (683) corresponding to (678). A full paper
on the synthesis of epihinesol (684) (ragarospirol) (see Vol. 2, p. 111) and the
further elaboration of an intermediate to hinesol (685) has been published.306An
interesting new spiro-annelation procedure has been developed which involves
regiospecific intramolecular alkylation of enolates generated by non-hydrolytic
decarboxylation of w-halo-p-keto-esters. Applying this method to the two ketoesters (686) and (687) (Scheme 66) provided a short route to p-vetivone (681) and
p-vetispirene (688) (together with minor amounts of their C-4 e p i m e r ~ ) . ~ ~ '
303
,04
305
306
307
Sesquiterpenoids
167
Scheme 64
168
i-iii
Iv-vii
Hd
H6
(682)
(683)
Scheme 65
J,iiiv,
i, ii, v
(687)
(681)
Scheme 66
Sesquiterpenoids
169
15 Eremophilane, Ishwarane
q&
qly
0
with its C-7 epimer and the eudesmane analogue (693). A variety of furanoeremophilanes, eremophilanolides, and cacalol derivatives (694)-(706)649312-314 have
been isolated from various Senecio species. Noteworthy are the structures of
the eremophilene derivative (699)312which has the same stereochemistry as capsidiol
(667) and senaequidolide (705),313an oxidized cacalol derivative. An X-ray analysis
of istanbulin-B has shown it to have structure (707).315A variety of seco-eremophi-
&
0
A
RO-*
(694)64various R groups
(695)64R
(696) R
= H,
=0
OH
(697)312
OH
HO
(698)312R
308
308
310
311
H or OH
***
(699)312
(700)313
314
315
46,1048.
P. J. Cox, F. Hall, and G. A. Sim, Tetrahedron, 1980, 36, 3437.
313
.*
170
@&AngO...(y&
OMe
R.
OH
(701)313
OR
(703)313various R groups
(702)313
OMe
HO
(705)313
Senaequidolide
(706)314Nemosenin
(704)313
mo
(707)
OAc
( J OR
Y k o
(708)
A very neat method for the synthesis of furanoeremophilanes has been devised
which incorporates a so-called bis-heteroannulation process.31sThis is achieved
by an intramolecular Diels-Alder reaction between an oxazole and an acetylenic
grouping and is nicely demonstrated by the synthesis of ligularone (711) and
petasalbine (7 12) (Scheme 67).319 A number of straightforward syntheses of
316
317
s18
81B
Sesquiterpenoids
171
(7 12)
Reagents: i, MCPBA; ii, LiCH,NC; iii, Me,SO-(COCl),; iv, LiCzCMe; v, A
Scheme 67
R2
HO
(713) R1= R2 = H
(714) R1= Ac, R2= H
(715) R1= Bu', R2= H
(716) R1= Pr; R2= OPr
J$Jq
(7 19)
172
eremophilane sesquiterpenoids include those of 6P-hydroxy-1,lO-dehydrofuranoeremophilan-9-one (7 13),320decompositin (714),320adenstylone (715),320 dihydrodecompositin (7 17),3203 ~,6~-dipropionyloxyeuryopsin-9-one
(7 16),320eremofortin
B (7 18),321 furanoeremophilan-3,6-dione (7 19),322and furanoeremophilan-6a, 14olide (720).322The unusual seco-furanoeremophilanes (72 1)323 and (722)324have also
been synthesized.
The biosynthesis of PR toxin (723), derived from Penicillium roqueforti, has
been examined by incorporation of [ 1,2-13C2]acetateinto the fungus.325 The
labelling pattern as observed from the I3C n.m.r. spectrum is completely in accord
with the original Robinson proposal involving a C-10, C-5 methyl migration from a
eudesmane-type precursor, as has been demonstrated before.
A new type of seco-ishwarane alcohol (724) has been identified in the roots
of A ristolochia i ~ d i c aThis
. ~ ~compound,
~
which co-occurs with ( +)-led01 (725),
has antifertility properties when tested on mice. Its structure was deduced on the
basis of spectral analysis together w.ith its correlation with a derivative of ishwarane
(726). A full report on the synthesis of ishwarone (727) has been presented.327
(723)
(726) R
(727) R
=
=
H2
0
321
322
323
324
325
46, 4602.
Sesquiterpenoidr
173
Name
Substituents
Ref.
2P,8P-diOH ;
9P-0COC(CH2OAc)==CHMe
Preeupatundin*
3,4;11,13;10,14
2P,9P-diOH ;
8P-OCOC(CHzOAc\-CHMe
3,4;11,13;10,14
Preeupatundin*
2P,9P-diOH ;
8P-OCOC(CHzOH+CHMe
Agriantholide*
3,4;11,13
2/3,9a-diOH;
8P-OCOC(CH2OAc+CHMe ;
1Oa,14-epoxy
4,15;9,10
1 1a-Me
Eremantholide*
4,15;11,13;10,14 3-keto; 8a-OH
Zaluzanin C*
4,15
Zaluzanin C*
3P,8a-diOH; 4a, 11a-diMe
3,4;1,10;11,13
Guaiagrazielolide*
8P-OAng; 9,14-P-lactone
Lasiolaenin*t
3,4;11,13;10,14
e.g. 8P-OTig; 9P-OH
Dehydrocostus lactone" 4,15 ;11,13 ;10,14 9a-0MeBu
Dehydrocostus lactone* 4,15;11,13;lo, 14 9a-Oval i
Dehydrocostus lactone* 4,153 1,13;lo, 14 8cr-OAng
Dehydrocostus lactone* 4,15;11,13;9,10
14-OAng
Zaluzanin C*
3P-OAng; 1la-Me
4,15 ;lo, 14
Jaquilenin*
3,4;1,10
2-keto; 15-OAc; 11P-Me
Estafiatin*
11,13
3a,4a-epoxy; 8a-OAng ; 10a-OH
Vicolide A
3,4;11,13
2-keto; 8a-OH; 9P-OAng; IOP-Me
Cumambranolide*
3,4;11,13
8a-OCOCHMe, ; 1 Ocr-OH
3,4;11,13;1,lO
KauniolideG
3,4 ;11,13 ;10,14
Rupicolin*
2u-OH
3,4;11,13
Arbiglovin*0
2-keto; 10a-OH
1,10;11,13
2-Oxoludartin
2-keto ; 3u,4a-epoxy
10,14
Solstitidin*
3-keto ; 4a-Me ; 1 1or-OAc ; 1 3-OAc
2,3;11,13
la,4a-peroxy; 9a-OAc; 1Oa-OH
Apressin
11,13;1,10
2-keto ; 3a,4a-epoxy ; %-OH ;
Guevariolide
8P-OCOCH=CMez
4,159 1,13;10,14 2,3-diOH ; 8a-OCOC(Me)==CH
Costus lactone*
11,13;10,14
3,4-diOH; 8a-OCOC(CH,0H)-CH2
Acrorepioli de
11,13;10,14
Repin*
3P,8P-diOH; 4p,15-epoxy
3,4;11,13
Spicatin*$
2P-OH ; 8P-X ; 1Oa,14-epoxy
3,4;11,I3
Spicatin*$
2P,lOa-diOH; 8P-X; 1 4 4
10,14
(no name)
3-keto; 4a,l la-diMe; 9p-OH
4,15;1 I , 13;9,10
Eremanthine*
8a-OCOCH2CHMe,
4,15; 1 1,13;10,14 8a-OCOCH,CHMe2
Costus lactone*
3,4;11,13
Cumambranolide*
8a-OCOC(Me)=CH 2 ; 1Oa-OH
3,4;11,13
Cumambranolide*
8or-OTig; 1Ou-OH
11,13;10,14
Estafiatin"
3a,4a-epoxy;8a-OCOC(Me)=CH
3,4;9,10
PorelladiolidelI
2P,14-y-lactone; 1 Icr-Me
Eregoyazidin
9,lO
3-keto; 4a,l la-diMe
Preeupatundin*
61
61
61
61
152
224
224
228
230
23 1
23 1
23 1
23 I
23 1
233
241
242
251
329
329
329
329
330
33 1
332
333
333
334
335
335
336
337
337
337
337
337
338
339
*Derivative of. ?Eight different compounds, four of which have 3a,4a-epoxide. $Also 11p,l3dihydro derivative. SX =
11 Also 3a,4a-epoxy derivative.
15
Q
3
11
13
174
(733)279
* IH
(734)337R = H, Elehirtanolide
(735) R = OCOCH,CHMe,
0
(736)340R1 = CH,OH, R2 = Ac, Lactucin Derivatives
(737) R1 = CHO, R2 = COC(Me)=CH,
343
F. Bohlmann, J. Jakupovic, W.-R. Abraham, and C. Zdero, Phytochemistry, 1981, 20, 2371.
K. Ito and T. Iida, Phytochemistry, 1981, 20, 271.
Z. Samek, T. VanEk, and M. Holub, Coll. Czech. Chem. Commun., 1981, 46, 941.
J. F. Malone, M. Parves, A. Karim, M. A. McKervey, I. Ahmad, and M. K. Bhatty, J . Chem.
344
SOC.,
Perkin Trans. I , 1980, 1683.
J. Beauhaire, J. L. Fourrey, J. Y.Lallemand, and M . Vuilhorgne, Tetrahedron Lett., 1981, 22,
340
s41
a4a
2269.
345
346
347
348
349
360
Sesquiterpenoids
175
(739)341Inuchinenolide B
(740) Inuchinenolide C
Go
and
OAc
,
I
(741) Inuchinenolide A
Q.oAc
---0Ang
q.H
0
0
(742)342Acetylisomontanolide
(743)343Grilactone
0
(744)344Isoabsinthin
(745)345R = OH Chamissonolide
(746) R = H
(747)346R1= R2 = H , R udmollin
(748) R1= Ac, R2 = H Derivatives
(749) R1 = H, R2 = AC
(750)34sRudmollitrin
(751)347Microhelenin A
176
(752)347R
(753) R
(754) R
=
=
=
H, Plenolin
COCH(Me)Et, Microhelenin B
Tig, Microhelenin C
aoQ
;.Q
(755)347Microlenin Acetate
(756)34s3-Hydroxyambrosin Damsinate
(757)349Kingiolide
(758)350Isoheleniamarin
Two stereochemically different sets of bourbonolides (759), (760),4 and (76 1)(763)224have been identified in various Vernonia species. Co-occurring with the
last three is the guaianolide (764). A further examination of Trixis species has
resulted in the isolation of the trixic acid derivative (765) and other examples of
trixikingolides (766) together with the rotundene analogue (767).225Additional
examples of xanthanolides are the tomentosin derivatives (768)-(770)27s and
2-epixanthanol (771).351It is interesting to note that it has been reported that
xanthumin (772) and 8-epixanthatin (773) are potent insect development inhibitors. 352
0
(759) R
(760) R
asl
= Tig
=
COC(Me)=CH,
Sesquiterpenoids
177
---OR
co-occurs
with
(761) R
(762) R
(763) R
= AC
= Tig
= COC(Me)=CH,
'0
(764)
(772)
(773)
3bb
178
o+
H OSiMe,
(774)
(775 )
(776)
0
(777)
&0-
(778)
(779)
the thermolysis of compounds such as (782) which gave predominantly (783) and
(784)356 before hydrolysis. A mechanistic rationale for the formation of these
compounds which includes a trimethylsilyl from one oxygen to another has been
given. A careful analysis of the thermally-induced tandem Cope-Claisen rearrangement of the vinyl ether (785) has shown that products (786) and (787) are formed
in the ratio of 7:3."' The mechanistic implications of this are that the initial Cope
rearrangement proceeds through a chairlike transition state preferentially, followed
by a Claisen rearrangement of the intermediate (788). The synthetic interest in (786)
and (787) is that they have been converted into a mixture of (789) and (790).
356
357
Sesquiterpenoids
179
i
d
ii, iii
+
'1
Y-i
CHO
0
*.
I
0 -
HO
vii, viii
0
Jix-xii
kii-xv
v, vi
c-
HO
OH
\-xviii
(793)
(792)
Reagents: i, CuI.(MeO),P-CH,=CHCH,Br; ii, 0,-Me,S; iii, H 3 0 + ; iv, OH-; v, P,05MeS0,H; vi, LiAlH,; vii, Me,NCMe(OMe),-K,C03; viii, I,; ix, Bun3 SnH; x, (Me,N),
CHOMe; xi, Bu',AIH; xii, PCC; xiii, LDA; xiv, PhSeC1; xv, [ O ] ;xvi, DBN; xvii, H,-Pt02;
xviii, Ac,O-py
Scheme 68
In the area of total synthesis, a full description of aromaticin (791) has app e a ~ e d in
, ~addition
~~
to newly announced syntheses of aromatin (792) and confertin (793) (Scheme 68),359compressanolide (794) (Scheme 69),360and carpesiolin
(795) (Scheme 70).361
A full report on the short stereocontrolled synthesis of racemic patchouli alcohol
has been
the key steps of which are the Grignard addition of the
magnesium derivative of the bromide (796) to the dienone (797) followed by an
intramolecular Diels-Alder reaction. The preparation of the two enantiomers of
368
359
360
3s1
382
P. T. Lansbury and D . G. Hangauer, Jr., Tetrahedron, 1981, 37, Suppl. No. 1, 371.
F. E. Ziegler and J.-M. Fang, J. Org. Chem., 1981, 46, 825.
A. A. Devreese, P. J . De Clercq, and M. Vandewalle, Tetrahedron Lett., 1980, 21, 4767.
K. Nagao, M. Chiba, I. Yoshimura, and S.-W. Kim, Chem. Pharm. Bull., 1981, 29,2733.
F. Naf, R. Decorzant, W. Giersch, and G. Ohloff, Helv. Chim. Acta, 1981, 64, 1387.
180
P3 &
iii-v
+
i, ii
+
60
viii-x
f---
t---
....
0
(794)
i-iv
ButO
o +v-viii
ButO
---OH
ButO
Jix, x
pii,
xix
(795)
Reagents: i, H2-Pt02; ii, MeO-; iii, LDA-CH,Br,; iv, BuLi; v, LDA; vi, PhSeBr; vii, HzOz;
viii, LiAlH,; ix, MCPBA; x, LiCH, CO,Li: xi, (CF,CO),O-py; xii, PTSA; xiii, DHP-H+;
xiv, aq. K,CO,; xv, CH,O; xvi, MsC1-py; xvii, DBU; xviii, PCC; xix, H,O+
Scheme 70
Sesquiterpenoids
181
(796) from (-)- and (+)-a-pinene has permitted syntheses of both natural (-)patchouli alcohol (798) and its antipode. The olfactory properties of these two
enantiomers are quite different, the natural isomer having the highly prized
earthy camphoraceous aroma while the unnatural ( +)-enantiomer is rather
nondescript and by no means reminiscent of patchouli oil, thus providing another
example of odour differences between enantiomers. This detailed study should settle
the long-standing claim that pure (-)-patchouli alcohol is odourless and that
norpatchoulenol (799) is responsible for the typical note of the essential oil.
It has now been shown that a very minor constituent of patchouli leaves is the diol
(800), previously obtained from mammalian hydroxylation of patchouli alcohol.3s3
This diol may be the precursor of the norsesquiterpene (799) in the plant. Patchouli
alcohol has been used as a test substance for a 13C n.m.r. technique which determines carbon connectivity by measurement and analysis of all one-bond 13C-13C
coupling constants at natural abundance
A limiting factor of this interesting
technique for natural product structural elucidation is the relatively large sample
required-3g of (798) in 0.3ml of C6D6.
An earlier synthesis of seychellene (801) has been reported in full and improvements in some-key steps have been accomplished.365(Vol. 9, p. 155, Vol 11, p. 84).
(799)
17 Aromadendrane, Nardosinane, Neolemnane, Bicyclogermacrane
In addition to the two sinularane derivatives isolated from the marine source
CZavularia injluta (see p. 114), the aromadendrane derivative (802) has also been
identified in the related species Clavularia k0e1likeri.l~Another aromadendrane
compound is the diol(803) obtained from the plant Senecio nemoren~is.~~
An X-ray
analysis of nardosinone has confirmed its structure as (804).366The soft coral
Lemnalia africana is a rich source of sesquiterpenoids and recent investigations
SO4
so5
866
182
H o W ' * * ( ) A c
How.'.b
H o W * , . IIo C ~
4OH
H+CHO
(805)
A
0
(807)
(806)
have uncovered some more examples. These include the ent-nardosinane-type
compounds (805)-(807).367 The metabolites from another sample of L. africana
collected from the Western Caroline Islands have been identified as (808)-(810),
(808) R
(809) R
=H
= AC
d
A
(819)
367
Sesquiterpenoids
183
@
0
36 8
88 9
870
371
0 0
3 7a
878
374
875
3 76
377
378
184
i, iv
t--
a5
(828)
Reagents: i, Me,CuLi; ii, Br,-AcOH; iii, CaCO,; iv, CICH,COCI; v, 9-BBN; vi, Pr'SH;
vii, NaIO,; viii, A-CaCO,
Scheme 71
19 Miscellaneous
The two epimeric sesquiterpenoids (829) have been synthesized and shown to be
identical to minor constituents of Eumorphia p r ~ s t a t a Cantharidin
.~~~
(832) has,
378
a80
381
382
383
a64
Sesquiterpenoids
185
385
3
Diterpenoids
BY J. R. HANSON
1 Introduction
This review follows the pattern of previous Reports with sections based on the
major skeletal types of diterpenoid. The literature that has been covered is that
which was available to August, 1981. The useful Kyoto series of reviews has
continued to appear.l An interesting number of new clerodanes have been obtained
from the Labiateae, particularly Teucrium species, and the absolute stereochemistries
of many of these have now been clarified. The extensive survey of the Compositae
by Bohlmann has led to the description of many new diterpenoids although some
of the structures which have been assigned purely on n.m.r. evidence require
confirmation by chemical inter-relationships. The occurrence of particular diterpenoid skeleta may have taxonomic significance. The chemistry of the gibberellin
plant hormones has attracted considerable attention during the year with a number
of total and partial syntheses being recorded. Marine organisms have continued
to yield many diverse types of diterpenoid skeleta.
2 Acyclic and Related Diterpenoids
20-Hydroxygeranylnerol has been obtained2 from Kingianthus paradoxus (Compositae). The biogenetic significance of a number of hydroxylated acyclic diterpenoids with internal cis double bonds [e.g. (l)], which were obtained from the
resin of Eremophila exilijiolia and E. glutinosa, has been discussedSin relation to
the cembrane and serrulatane diterpenoids which have been found in other
Eremophila species. Marine organisms have been the source of a number of alicyclic
diterpenoids. Some further acyclic diterpenoids [e.g. (2)] which are related to
crinitol and eleganolone have been obtained4 from the brown alga, Cystoseira
H OH
E. Fujita, K. Fuji, Y.Nagao, and M. Ochiai, Bull. Znst. Chern. Res., Kyoto Univ., 1980,58,484.
F. Bohlmann, J. Ziesche, H. Robinson, and R. M. King, Phytochemistry, 1981, 20, 1146.
E. Ghisalberti, P. R. Jefferies, and G. M. Proudfoot, Aust. J . Chem., 1981,34, 1491.
V. Amico, G. Oriente, M. Piatelli, G. Ruberto, and C. Tringali,Phytochemistry, 1981,20, 1085.
186
Diterpenoids
187
crinitu. The lactone (3), which may be derived by the internal hydrolysis of an
epoxide, was amongst the terpenoids which were obtained from A canthospermurn
uustrule.=
OH
(3)
3 Bicyclic Diterpenoids
Labdanes.-The 13C n.m.r. data for some labdanes related to andrographolide
have been reported6and 13Cn.m.r. methods have been applied to the determination
of the C-14 configuration of some 8,13-epoxylabdan-14-ols.The empirical correlation between structure and the optical rotation of the Cistus lubduniferus
diterpenoids has been questioned.6 A number of labdane 13-0-glycosides have
been obtained9 from Aster sputhulifolius (Compositae) and ent-3cr-hydroxy-13epimanool (4) has been obtained from Croton sublyrutus.1 Some labdane dialdehydes [e.g. ( 5 ) ] have been reportedll in Alpiniu species. In the course of a search
CH,OH
Br-
for compounds with insect anti-feeding activity, the grindelane diterpenoid (6)
and its succinate ester were isolated12from Crysothumnus nuuseosus (Compositae)
(rabbitbrush). Various diacetates of the grindelane diterpenoid lagochilin have been
F. Bohlmann,J. Jakupovic, A. K. Dhar, R. M. King, and H. Robinson, Phytochemistry, 1981,
20, 1081.
188
described.13 Some simple labdane acids are amongst14 the constituents of Morithamnus crassus and a number of labdanes and kolavenes were obtained15 from
Acritopappus (Compositae) species. Chemical and spectroscopic data have been
reported16for the structure of isoconcinndiol(7) which is a brominated diterpenoid
from the red alga Laurencia snyderae.
A series of andalusol derivatives (8) have been obtained1' from Sideritis foetens
(Labiatae). 7a-Acetoxytranscommunic acid (9) was reportedla from Chrornoluenu
collina. The acetate (10) and hemi-acetal (1 1) were describedlg as constituents of
(9)
(13)
Schkuhria species. Some labdane derivatives [e.g. (12)] were obtained20 from
Ageratium fastigiaturn. 7a-Hydroxylambertianic acid was isolated21from Gutierreziu
dracunculoides. Dodonaea species have been a rich source of bicarbocyclic diterpenoids. The X-ray crystal structure of the acid (1 3), obtained from D . petioluris,
has been reported.22
A further group of acetals has been prepared from m a n 0 0 1 ~for
~ structure-odour
studies. Some lY5-diepoxidesin this group underwent rearrangement based on the
intramolecular opening of 8@,9p-epo~ides.~~
(1 1)
(12)
la
I4
1141.
2o
21
a2
*a
24
D iterpenoids
189
w
**.
e7
ao
a1
a4
190
intermediate between the labdane and clerodane series. A similar feature is revealed35
by the 19-epimeric hemi-acetals, mallotucins C and D (20), which are constituents
of Mallotus repandus (Euphorbiaceae). Sonderianin (21) is a clerodane which was
from Croton sonderianus, and the diacetate (22) has been reported37 as
a constituent of C . pyramidalis. The structure (23) of croverin, which was obtained
from C . verreauxii, was determined3* by X-ray analysis.
86
s7
38
ag
40
48
Diterpenoids
191
J
\
O0
OAc
(27)
(28)
(29)
OAc
43
44
46
OAc
192
SMe
(35)
(36)
(37)
Prernna latifolia. The structure of the unusual ether (34), obtained from Acacia
Zeucophloea,was established by X-ray analysis.53Micrandrol C (35) and micrandrol
D (36) are constituents of Micrandropsis ~ c l e r o x y l o nUrbalactone
.~~
(37) is another
49
48
(H. Shimomura, Y. Sashida, K. Ogawa, and Y. Litaka, Tetrahedron Lett., 1981, 22, 1367.
O8
Lo
6a
63
64
46, 3135.
M. C. Garcia-Alvarez, B. Rodriguez, S. Valverde, B. M. Fraga, and A. G. Gonzalez, Phytochemistry, 1981, 20, 167.
N. Cagnoli, P. Ceccherelli, M. Curini, N. Spagnoli, and M. Ribaldi, J . Chem. Res. (S), 1980,
276.
A. C. Pinto, L. M. Valente, R. S. Da Silva, W. S . Garzez, and P. P. Queirez, An. Acad. Bras.
Cienc., 1981, 53, 73 (Chem. Abstr., 1981, 95, 98 071).
B. C. Rao, K. Suseela, and E. K. S. Vijayakumar, Indian. J. Chem., Sect. B, 1981, 20, 175.
A. Perales, M. Martinez-Ripoll, J. Fayos, R. K. Bansal, K. C. Joshi, R. Patni, and B. Rodriguez, Tetrahedron Lett., 1980, 21, 2843.
M. A. De Alvarenga, J. J. Da Silva, H. E. Gottlieb, and 0. R. Gottlieb, Phytochemistry, 1981,
20, 1159.
193
Diterpenoids
member of the podolactone series which have been isolated from Podocarpus
~ r b a n i iA
. ~ ~further report has appeared56 on the caesalpin from Caesalpinia
bonducella.
Diterpenoid quinones have been isolated from a number of the Labiatae. An
o-quinone, ethiopinone (38), has been described as a c o n ~ t i t u e nof
t ~ the
~ roots of
Salvia aethiopis (Labiatae) and the known quinones horminone and 7cc-acetoxyroyleanone have been isolated58from S. lanata. The dehydroabietic acid derivative
(39) was obtained59from S. tomentosa. The partial synthesis of the epimeric ring B
C0,Me
(39)
(40)
(41)
mono- and di-hydroxyroyleanones has been reported60 and coleon U has been
synthesized61from a podocarpic acid derivative.
Some unusual rearranged tricyclic diterpenoids with a cis- A/B ring fusion have
been isolated62 from Rondeletia panamensis (Rubiaceae). Panamensin has the
structure (40) whereas its dihydro-derivative, rondeletin, has the 2-keto structure
(41).
Chemistry of the Tricyclic Diterpenoids.-The addition of chlorosulphonyl isocyanate to the methyl esters of levopimaric and neoabietic acids with the formation
of C-12 carboxyamides has been described.63 The well documented aromatic
substitution reactions of dehydroabietic acid continue to be examined,64together
65
5
.'
6B
Eo
Ea
63
6*
194
with the cleavage65of the aromatic ring to form drimane sesquiterpenoids. The
preparation of shonanol from dehydroabietic acid has also been reported.66 An
improved route for the synthesis of methyl vouacapenate from podocarpic acid
has been de~cribed.~'
The photo-oxygenation of pimara-8-enes and isopimara-8-enes to afford the
As(14)-9-alcohols has been described.6s The preparation and cleavage of some
isopimarane-7,8-epoxides,with the formation of
(11 )-dienes, has been examStudies on the rearrangement of some 8a,9a-epoxypodocarpanes with boron
trifluoride etherate have been directed 70 at inducing a backbone rearrangement to
afford the rimuene skeleton. The structure of an unusual pentacyclic ether (43),
prepared by the action of boron trifluoride etherate on the epoxypimarane (42),
A799
CH202CPh
(42)
(43)
(44)
(45)
was established'l by X-ray analysis. The acid (45)was formed72by carbonylation
of dihydroabietic acid (44)in the presence of carbon monoxide. The cyclization of
methyl copalate to the tricyclic analogue of isoagathic acid has been followed75
by the conversion of the product into the enantiomer of the marine diterpenoid
spongiadien- 12-01.
The stereochemistry of the S,i cyclization in the biosynthesis of ent-sandaraco~ i m a r a d i e n eand
~ ~ virescenol B 75 has been studied using stereospecifically
as
O6
67
69
'O
71
74
7s
Diterpenoids
195
deuteriated substrates. The cyclization has been shown to proceed with the antistereochemistry .
5 Tetracyclic Diterpenoids
:*
H
CO,H
(48)
CO,H
(49)
7~
83
84
78
79
82
1981,217.
196
(50) R
(51) R
=
=
H
OH
&
'3.H
HO
R2H2C OH
(54)
(55)
(56)
(57)
R' = H, R2 = OAC
R' = OH, R2 = OAC
R1= OACR2 = H
R' = OAC,R2 = OAC
similar structure (5 1) for trichorabdal B, another diterpenoid from the same plant,
was establishedg1 by X-ray analysis. On treatment with sodium hydroxide this
compound underwent a retro-Claisen and aldol condensation to afford (52).
Excisanin A (53) and B (the 12-acetate) are hydroxylated kaurenoids which were
T. Tanaka, H. Kohda, 0.Tanaka, F. H. Chen, W. H. Chou, and J. L. Leu, Agric. Biol. Chem.,
1981,45,2165.
I. Kubo. T. Kamikawa, T. Isobe, and T. Kubota, J . Chem. SOC.,Chem. Commun., 1980, 1206
E. Fujita, K . Fuji, M. Sai, M . Node, W. H. Watson, and V. Zabel, J . Chem. Soc., Chem,
Commun., 1981,899.
Diterpenoids
197
R 3
= R3 = R4 = OH, R2 = OAC
(59) R' = R2 = OAC,R3 = R4 = OH
(60)R' = R2 = R4= OAC,R3 = OH
(61) R' = R2 = R3 = OAC,R4 = OH
(62) R1 = H, R2 = OAC, R3 = R4 = OH
(58) R'
(64) R
(65) R
= OH
=H
g9
H.-D. Sun, X.-C. Sun, Z.-W. Lin, Y.-L. Xu, Y. Minami, T. Marunaka, and T. Fujita, Chem.
Lett., 1981, 753.
T. Fujita, Y. Takeda, and T. Shingu, Heterocycles, 1981, 16, 227.
Y. Takeda, T. Fujita, and A. Ueno, Chem. Left., 1981, 1229.
T. Isobe, Y. Noda, K. Shibata, and T. Kubota, Chem. Lett., 1981, 1225.
L. Rivier, P. Gaskin, K. Y . S. Albone, and J. MacMillan, Phytochemistry, 1981, 20, 687.
J. T. Lin and E. Heftmann, J. Chromatogr., 1981, 213, 507.
T. Yokota and N. Takahashi, Agric. Biol. Chem., 1981, 45, 1251.
P. Gaskin, P. S. Kirkwood, J. R. Lenton, J. MacMillan, and M. E. Radley, Agric. Biof. Chem.,
loo
P. S. Kirkwood, J. MacMillan, and M. L. Sinnott, J . Chem. Soc., Perkin Trans. I , 1980, 2117.
O8
93
94
86
96
O7
88
1980,44, 1589.
198
(68) R = Hal
(69) R = H
Several groups have reported lo1-lo3the isomerization of h1( 2 )-3-hydroxygibberellins
to A2 ( 3 )- 1-chlorogibberellins (68) on treatment with various halogenating agents.
Hydrogenolysis of the 1-halides provides a convenient route for the preparation of
gibberellin A, (69). The hydrogenolysis of 13-chlorogibberellins by tributyltin
hydride has also been reported. The partial synthesis of gibberellins A7,104A,, and
A2t05from gibberellic acid has been described together with routes for the preparation of labelled gibberellins A29and A51.106
The unsaturated ketone (70) is a catabolite of gibberellin A29. It has been preparedlo7 from gibberellic acid. The 2-position of gibberellins is metabolically
reactive and consequently the biological activity of a number of 2-substituted
Io2
1741.
113
114
Diterpenoids
199
of gibberellin A, have been noted115and a method for introducing a 15-carboxygroup has been described.l16
Methanolysis of' a C-20' mixed anhydride of gibberellin A,, gave the unusual
19-ortho-ester, the structure (71) of which was established by X-ray a n a 1 ~ s i s .The
l~~
formation of this compound and the corresponding 19-epimeric 20-tl9-lactols by
sodium borohydride reduction of the mixed anhydrides reveals the facile participation of the 19-estersin the reactions of C-20. This feature may be of biosynthetic
significance.
A number of metabolic studies have been reported in connection with gibberellin
biosynthesis. ent-Kaur-6,16-dien-19-oic acid has been described as a key intermediate in the biosynthesis of the kaurenolides in Cucurbita maxima.l18 The
production of 16,16-difluoro- derivatives of gibberellin A, and 7-hydroxykaurenolide using 16,16-difluoro-17-norkauranoic acid as a substrate with G. fujikuroi
has been reported,l19 and ent-15p-fluorokaurenoic acid has been shown to give rise
to a group of 15-fluorinated gibberellins.lZ0Some 7-fluorogibberellins may act as
gibberellin biosynthesis inhibitors.lZ1The production of 12p-hydroxygibberellins
by incubation of the corresponding ent- 12a-hydroxykaurene with Gibberella
fujikuroi has also been described.122
Graymotoxins.-The X-ray crystal structures for grayanotoxins XVI-XIX have
been r e p ~ r t e d . ~Routes
~ ~ - ~to~1,5-secograyanotoxins
~
(grayanol) derivatives have
been d e ~ c r i b e d . ~ ~ ~ ~ ~ ~ ~
Atiserenes.-The
1 1a,16,17-trihydroxyatiserene structure has been proposedlZ8
for atisideritol, obtained from Sideritis pusilla (Labiatae), on the basis of chemical
and spectroscopic evidence.
6 Macrocyclic Diterpenoids
Marine organisms, particularly corals, have continued to be a source of novel
diterpenoids. Cembrenene (72) and mayol (73) are two new cembranoid diterpenoids from the soft coral Sinularia mayi.129The cembrene alcohol (74) has been
116
116
L.N . Mander, J. V. Turner, and B. Twitchin, Tetrahedron Lett., 1981, 22, 3017.
11'
118
119
1689.
200
(75)
(76)
131
132
B. F. Bowden, J. C. Coll, S. J. Mitchell, and R. Kazlauskas, Aust. J . Chem., 1981, 34, 1551.
Y. Kashman, S. Carmely, and A. Groweiss, J . Org. Chem., 1981, 46,3592.
S . Carmely, A. Groweiss, and Y. Kashman, J . Org. Chem., 1981, 46, 4279.
J. A. Toth, B. J. Burreson, P. J. Scheur, J. Finer-Moore, and J . Clardy, Tetrahedron, 1980, 36,
1307.
134
136
13e
la'
I38
lP0
T. Nakagawa, M. Kobayashi, K. Hayashi, and H. Mitsuhashi, Chem. Pharm. Bull., 1981, 29,
Y . Yamada, S. Suzuki, K. Iguchi, I. Kikuchi, Y. Tsukitani, H. Horiai, and F. Shibayama,
Tetrahedron Lett., 1980, 21,3911.
V. A. Paldugin, N. I. Yaroshenko, and Y . V. Gatilov, Khim. Prir. Soedin., 1981, 174.
B. A. Burke, W. R. Chan, K. 0. Pascoe, J. F. Blount, and P. S. Manchand, J . Chem. SOC.,
Perkin Trans. 1, 1981, 2666.
W. Adolf and E. Hecker, Tetrahedron Left., 1980, 21,2887.
M. I. Tyler and M. E. H. Howden, Tetrahedron Lett., 1981, 22,689.
H. J. Opferkuch, W. Adolf, B. Sorg, S. Kusumoto, and E. Hecker, 2.Naturforsch., Teil B,
1981, 36, 878.
Diterpenoids
20 1
(78) R = OAC
(79) R = H
7 Miscellaneous Diterpenoids
Taonianone (80) is an unusual furan obtained141from Taonia australasica. A full
paper has appeared142on the structures of the diterpenoids based on the dolabellane
skeleton which were obtained from Dictyota dichotoma. 18-Hydroxydollabella3,7-diene (81) is another member of this group of compounds obtained from the
same source. A number of tricyclic relatives with the dolastane ring system,
including (82), were isolated144from Dictyota divaricata. Spectral and chemical
evidence has been
for the structure (83) of linearol, obtained from
a
HO
(84)
141
148
143
lP4
145
(85)
202
Dictyota linearis. This name has been used previously for another diterpenoid.
The unusual tricyclic structure (84) has been proposed for the spatane diterpenoids,
which were
from the alga Stoechospermum marginatum (Dictyotaceae).
A diterpenoid (85) related to cladiellin has been isolated147from a Pacific soft coral,
and a further member of the asbestinin series, asbestinin epoxide, was obtained14s
from the Caribbean gorgonian, Briareum asbestinum.
Full papers have appeared on the
and absolute configuration150 of
the decipiene diterpenoids. The structure (86) was assigned151to a new member of
this series on the basis of X-ray evidence.
The defensive secretions of termites have afforded an unusual group of diterpenoids. Spectral and X-ray crystallographic evidence has been presented for the
structure (87) assigned to a secotrinervitane which was
from Nasutitermes princeps. X-Ray crystallographic studies have also led to the structures of
147
6825
156
168
157
203
Diterpenoids
Some aspects of the chemistry of lauren-1-ene, including the remote functionalization of other rings based on the I,-Pb(OAc), oxidation of laurenan-2-ols, have
been described.158 X-Ray crystallographic evidence has been presented for the
structure (92) of cinncassiol D,a pentacyclic diterpenoid from the dried bark of
Cinnamomum cassia possessing anti-complement activity.159
CHO
OAc
(93)
158
i6@
l80
(94)
(95)
204
attenti0n.1~~3-l~~
The total synthesis of dihydro-8-epiacrostalidic acid has been
reported.166
The synthesis of perhydrophenanthrenes related to tri- and tetra-cyclic diterpenoids has continued to be an active area.167Compound (94) has been synthesized
as a possible intermediate for the synthesis of cafestanone.168A synthetic approach
to diterpenoids with an abnormal trans-syn AB ring junction [e.g. (95)] has been
described.169The syntheses of 13-methoxypodocarpatrien- 19,20-dioic acid170 and
the 1l-hydroxyabieta-2,8,11, I3-tetraen- 1-one,l" isomeric with shonanol, have been
described.
AH
(97)
A
'
---CH,SiMe3
(99)
J. M. Luteijn, M. Van Doorn, and A. De Groot, Tetrahedron Lett., 1980, 21, 4127; J. M.
Luteijn and A. D e Groot, ibid., p. 4129
ltt4 J. M. Luteijn and A. D e Groot, Tetrahedron Lett., 1981, 22, 789.
le6 J. M. Luteijn and A. D e Groot, J . Org. Chem., 1981, 46, 3448.
I. H. Sanchez and J. C. Aranda, Tetrahedron Lett., 1980, 3655.
167 R. V. Venkateswaran, D. Mukherjee. and P. C. Dutta, J . Chem. Soc., Perkin Trans. I, 1981,
1603.
205
Diterpenoids
(101)
(102)
R
R
=H
= OH
gibberellic
The general strategy was based on a retrosynthetic analysis
which utilized the construction of the C-3-C-4 bond by an Aldol process (103),
the C-4-4-5 bond by a Michael process (104), and the C-I-C-10 bond by the
addition of a nucleophile to the enone (105). The latter was prepared from 1,7dimethoxynaphthalene (1 07) via (106).
173
l74
175
176
17?
206
G. Stork, W. C. Still, J. Singh, and S. Takei, Tetrahedron Lett., 1980, 21, 4051.
S. Takane, C. Kasahara, and K. Ogasawara, J . Chem. SOC.,Chem. Commun., 1981, 635.
180 M. L. Greenlee, J . Am. Chem. SOC.,1981,103,2425.
0.P.Vig. S.S. Bari, I. R. Teehan. and R. Vig, ZndianJ. Chem., Sect. B, 1980, 19, 446.
178
17*
4
Triterpenoids
BY R. B. BOAR
1 Introduction
This chapter follows the pattern of last years Report with the addition of a section
on Triterpenoid Saponins. The highlight of this years Report is undoubtedly the
total synthesis of dl-quassin by Grieco and his co-workers?
Reviews have appeared on the occurrence of triterpenoid saponins and sapogenins,2 the mass spectra of pentacyclic triterpenoids,s and the possible role of
triterpenoids as membrane component^.^ The plenary lectures from the 12th
IUPAC Symposium on the Chemistry of Natural Products have been p~blished.~
2 Squalene Group and Triterpenoid Biosynthesis
The biosynthesis of triterpenoids is discussed at some length in a new book.8 The
bacterium Acetobacter pasteurianum forms hopanoids such as diploptene (1) by
(1) R = H,
(4) R = H,
(5) R = H,a-OH
(2) R = H,a-OH
(3) R = H,B-OH
(6) R ==H,P-OH
cyclization of squalene. When a cell-free system was fed with the unnatural substrate (3RS)-squalene 2,3-epoxide, hop-22(29)-en-3a-ol (2) and -3p-01 (3) were
formed. Appropriate experiments established that the 3a-hydroxy-compound (2)
is derived from the (3R)-epoxide and the 3P-hydroxy-compound (3) from the
(3S)-epoxide. Similarly, a cell-free system from the protozoon Tetrahyrnena
pyriformis was shown to convert squalene into tetrahymanol (4) and (3R)- and
P. A. Grieco, S. Ferrino, and G. Vidari, J. Am. Chem. SOC.,1980, 102, 7586.
* R. S.Chandel and R. P. Rastogi, Phytochemistry, 1980, 19, 1889.
L. Ogunkoya, Phytochemistry, 1981, 20, 121.
W. D. Nes and E. Heftmann, J. Nat. Prod., 1981, 44, 377.
Pure Appl. Chem., 1981, 53, No. 6.
C. P. Manitto, Biosynthesis of Natural Products, Ellis Horwood Ltd., Chichester, 1981.
M. Rohmer, C. Anding, and G. Ourisson, Eur. J. Biochem., 1980, 112, 541.
207
208
and 228 methyls labelled in each case), but that (5) arises from the (3R)-epoxide
(8) with a boat-chair-chair-chair-chair folding (4p and 22p methyls labelled)
(Scheme 1).8
HO
' P. Bouvier, Y . Berger, M. Rohmer, and G. Ourisson, Eur. J . Biochem., 1980,112, 549.
Trit erpenoids
209
(9) R = H2
(10) R = H,P-OH
(11) R = H,a-OH
presence of two separate cyclases has now been obtained. A cell-free preparation
from M . capsulatus converted squalene into diploptene (1) [but not into 5a-lanosta8,24-diene (9)], (3S)-squalene 2,3-epoxide into hop-22(29)-en-3p-ol (3) and lanosterol (lo), and (3R)-squalene 2,3-epoxide into hop-22(29)-en-3a-o1 (2) and
3-epilanosterol(ll). In that it does not reject the (3R)-epoxide, the squalene epoxide
cyclase is less specific than that present in typical e~karyotes.~
Details have been published of the biosynthesis of olean-12-ene and urs- 12-ene
type triterpenoids in tissue cultures of Isodon japonicus (Labiatae).lo The results
are fully in accord with the original biogenetic postulates of Ruzicka and his
colleagues.11 By using [5-13C, 5-2H2]MVAas substrate it was shown that, as expected, both squalene 2,3-epoxides [part structures (12) and (13)] are involved in
the biosynthesis of 2a-hydroxyursolic acid (14), 3-epimaslinic acid (13, and
p-sitosterol in I. japonicus. The 13C n.m.r. spectra of (14) and (15) suggested
Jvu
Jvu
(14)
(15)
additionally that in the olean-12-ene series the double bond is formed by elimination
of the 12a-H, but that in the urs-12-ene series it is the 12p-H that is lost.12
It has been shown that the hydrogen migration from C-24 to C-25 that occurs
during the biosynthesis o f isofucosterol in Pinus pinea (Pinaceae) occurs such that
lo
l2
210
(16)
(17)
the pro-E methyl group of the precursor (16) becomes the pro-R methyl group of
isofucosterol [as (1 7)].13 24-Methyl-25-azacycloartanol (1 8) has been synthesized.
It acts as a potent inhibitor of C-24 methyltransferase in higher plant cells.14 It is
more potent than 25-azacycloartanol (1 9).15 The effects of various triterpenoids
on the growth of the fungus Phytophthora cactorum have been investigated.16.The
enzymic preparation of [14C]-labelled squalene from [2-14C]MVA has been
described.l
(18) R = Me
(19) R = H
3 Fusidane-Lanostane Group
The bark of Pinus monticolu (Pinaceae) contains many triterpenoids of the lanostane
and serratane groups. Of these, the lanost-9(1 I)-enes (20)-(27) are new natural
products (see also Section 9).lS The sea cucumber Stichopus chloronotus affords a
series of antifungal oligoglycosides which on enzymatic hydrolysis yield the genuine
sapogenins stichlorogenol(28) and 25,26-dehydrostichlorogenol(29).The structure
and stereochemistry of (28) were confirmed by X-ray analysis. Acid hydrolysis of
the saponins gave artefact sapogenins containing the 8-ene or 9( I 1)-ene system.lg
Other sea cucumbers contain oligoglycosides based on the sa?ogenins (30) and (31)
(Bohadschia bivittata)20 and (32) (Actinopyga echinites).21Two further 27-nortril3
l4
l6
l8
l7
l8
l9
21
21 1
Trit erpenoids
RO
(22) R
(23) R
(20) R = Me
(21) R = H
As (20)
Me
H
{p
= Me (24s)
= H (24Q
(28)
(29) 25,26-dehydro
terpenoids from Muscari comosum (Liliaceae) have the interesting structures (33)
and (34).22 Polyporenic acid D (35) is a new natural product from Polyporus
oficinalis (P~lyporaceae).~~
The cytotoxicity of various lanosterol derivatives
isolated from the fungus Poria cocos (Polyporaceae) has been inve~tigated.~~
5cc-Lanost-S-en-24-one [as (36)] has been converted into 5a-lanost-S-en-23-one
[as (37)J in 21 % overall yield (Scheme 2). A similar sequence was successfully
applied to 29-nor-5a-lanost-9( 1l)-en-24-0ne.~~A series of 9,ll -epoxy-7-ketolanostane derivatives with degraded side chains has been synthesised,26as has a
range of side-chain modified lanosterol analogue^.^' Details have been reported
21
M. Parrilli, R. Lanzetta, M. Adinolfi, and L. Mangoni, Tetrahedron, 1980,36, 3591. See also,
M. Parrilli, R. Lanzetta, V. Dovinola, M. Adinolfi, and L. Mangoni, Can. J . Chem., 1981, 59,
2261.
2s
2p
25
86
27
212
HO
(30) R1 = R2= H
(31) R1= OH, R2= H
(32) R' = R2= OH
(33) R = H,P-OH
(34) R = 0
<vii, viii
+ &
~
v, vi
Me0
(37)
Reagents: i, LDA; ii, Ph,S,; iii, Pb(OAc),; iv, MeOH-I,; v, LiAlH,;
vi, HCI; vii, Ac,O; viii, Ca-liq. NH,
Scheme 2
Triterpenoids
213
Further new natural products are (38) from the toxic micro-organism Fusarium
triphyllol (41) from Adenosporotrichioides 92Z,30(39) and (40) from olive
and cyclonervilol (42) and cyclohomonervilol
phora triphyh (Campan~laceae),~~
(43) from Nerviliapurpurea (Orchidaceae). The structure of (43)was supported by
its conversion into cycloeucalenol.33Two new xylosides from Cimicifuga japonica
(Ranunculaceae) are based on the genuine sapogenins (44) and (45). Treatment of
(43)
OH
(47)
(45) R = OH
(46) R = H
30
31
s2
83
214
(44) with sulphuric acid in aqueous methanol gave cimigenol (46).34 Cyclosadol
(47) from Zea mays (Gramineae) has been shown by n.m.r. spectroscopy to have
the 23E c ~ n f i g u r a t i o n3.1-Norcycloswietenol(48)
~~
has been isolated from Swietenia
mahagoni (Meliaceae) heartwood.36 The assigned structure is supported by 13C
n.m.r. spectral data.37The ketone (49), itself readily available from cycloartenol,
has been converted into the Buxus alkaloid, cyclobuxophylline-M (50).38
The seed oil of Cucumissativus (Cucurbitaceae) contains (51) and (52) in addition
Momordicosides A-E from the seeds
to other known 4a-methyl
of Mornordica charantia (Cucurbitaceae) are based on the sapogenins (53)-(56).
The structure and stereochemistry of compound (53) were established by X-ray
analysis.4oThese cucurbitacins are notable for the absence of an oxygen function
(51) R
(52) R
Me, 8,9-ene
H, 7,8-ene
OH
OH
H
=
..*
~ v n
As (53)
As (53)
(54)
34
35
36
37
38
39
I0
OH
yCHO
As (53)
(55)
(56)
N. Sakurai, 0. Kimura, T. Inoue, and M. Nagai, Chem. Pharm. Bull., 1981, 29, 955.
T. Itoh, N. Shimizu, T. Tamura, and T. Matsumoto, Phytochemistry, 1981, 20, 1353.
A. S. R. Anjaneyulu, V. Lakshminarayana, Y. L. N. Murty, and L. R. Row, Indian J . Chem.,
1979,17B, 423.
V. Lakshminarayana, Y . L. N. Murty, and L. R. Row, Org. Magn. Reson., 1981, 17, 77.
M. C . Desai, J. Singh, H. P. S . Chawla, and S . Dev, Tetrahedron, 1981, 37, 2935.
T. Itoh, Y. Kikuchi, N. Shimizu, T. Tamura, and T. Matsumoto, Phytochemistry, 1981, 20,
1929.
H. Okabe, Y. Miyahara, T. Yamauchi, K. Miyahara, and T. Kawasaki, Chem. Pharm. Bull.,
1980,28,2753; Y. Miyahara, H. Okabe, and T. Yamauchi, ibid., 1981,29, 1561.
215
Triterpenoids
at C-1 1, as is lOa-cucurbita-5,24-dien-3P-o1
which has now been isolated from
seedlings of Bryonia dioica (Cu~urbitaceae).~'
The biogenesis of the cucurbitacins
has been discussed.*l
4 Dammarane-Euphane Group
The bark of Rhus javanica (Anacardiaceae) contains rhuslactone (57), a novel
dammarane-type triterpenoid with an a-oriented side chain. The structure followed
@
p
HO
HO=*
(58)
(57)
(59) 24,25-dihydro
OH
(61)
(62) 24,25-dihydro
from X-ray analysis of the derived tri01.~~
Acid hydrolysis of the saponin of
Emmenospermum pancherianum (Rhamnaceae) affords ebelin lactone (58) together
with 24,25-dihydroebelin lactone (59) and the novel D-homo aromatic triterpenoid
(60). All three compounds are artefacts since Smith-de Mayo degradation of the
saponin affords the genuine, acid-labile, sapogenins jujubogenin (6 1) and dihydrojujubogenin (62).43The saponins of Zizyphus jujuba (Rhamnaceae) are also based
on j ~ j u b o g e n i n Other
. ~ ~ dammaranes reported this year are vellozone [(20R)-20hydroxy-24-methylenedammar-3-one]from VeZlozia stipitata (Vell~ziaceae),~~
41
42
44
45
L. Cattel, G. Balliano, 0. Caputo, and F. Viola, Planta Med., 1981, 41, 328.
C.-K. Sung, T. Akiyama, U. Sankawa, Y. Iitaka, and D.-S. Han, J. Chem. Soc., Chem.
Commun., 1980,909.
G. V. Baddeley, J. J. H. Simes, and T.-H. Ai, Aust. J. Chem., 1980, 33, 2071.
N. Okamura, T. Nohara, A. Yagi, and I. Nishioka, Chem. Pharm. Bull., 1981, 29, 676.
A. C. Pinto, P. M. Baker, B. Gilbert, R. Pinchin, F. A. M. Reis, M. S. Waineraich, and
D. H. T. Zocher, Phytochemistry, 1980, 19, 2486.
216
6
R'
(63)
(64)
(65)
(66)
(70)
46
47
48
48
50
51
52
53
(71) R
(72) R
=H
= Me
M. Nagai, K. Izawa, S. Nagumo, N. Sakurai, and T. Inoue, Chem. Pharm. Bull., 1981,29,779.
G. V. Malinovskaya, V. L. Novikov, V. A. Denisenko, and N . 1. Uvarova, Khim. Prir. Soedin.,
1980, 346; English translation, Chem. Nat. Compoundr, 1980,16, 257.
N. D. Pokhilo, G . V. Malinovskaya, V. V. Makhan'kov, V. F. Anufriev, and N. I. Uvarova,
Khim. Prir. Soedin., 1980, 513; English translation, Chem. Nat. Compounds, 1980, 16, 368.
G. V. Malinovskaya, N. D. Pokhilo, V. V. Isakov, and N. I. Uvarova, Chem. Abstr., 1980, 93,
220 945.
L. N. Atopkina and N.I. Uvarova, Khim. Prir. Soedin., 1980,205; English translation, Chem.
Nut. Compounds, 1980, 16, 159.
G. F. Spencer, J . Nat. Prod., 1981, 44, 166.
J. A. Akinniyi, J. D. Connolly, D. S. Rycroft, B. L. Sondengam, and N. P. Ifeadike, Can. J .
Chem., 1980,58, 1865.
A . Merrien, B. Meunier, C. Pascard, and J. Polonsky, Tetrahedron, 1981, 37, 2303.
217
Triterpenoids
OAc
a
OAc
(77)
21 8
was confirmed by X-ray analysis.54 Seed oil of A . indica gave three compounds
with insect antifeedant activity-3-deacetylsalannin (82), salannol (83), and the
known 1,3-diacetylvilasinin (see Vol. 10, p. 145).55The fruit of Melia azedarach
(Meliaceae) contains ohchinolides A and B (see Vol. 11, p. 117), nimbolidins A
(82) R
(83) R
(84) R = COPh
(85) R = tiglate
= tiglate
= COCH,CHMe,
~o
AcO"'
"OTig
'*,a
(86) R = AC
(87) R = H, (12R)
AcO-..
As (88)
"OH
0
(88) R
(89) R
(91) R
64
56
58
=
=
=
H,P-OH
H,a-OH
H2
Triterpenoids
219
AcO"'
OAc
0
I
(94)
220
(99) R = tiglate
(100) R = A c
fi0
H
*cO
b: OH
0
"OH
7
p
"=/p
HO
Triterpenoids
22 1
0
H
C0,Me
h1
?H
As (111)
(113)
(111) R
(112) R
C(OH)Me,
=H
62
83
84
85
86
68
222
0
' 0
OH
(116) R = A c
(117) R = H
(118) R
(119) R = A c
0
H
.
H
(120) R = H
(121) R = AC
6B
'O
Triterpen oids
223
dehydroexcelsin (124) from Ailanthus excelsa (Simaroubaceae),72 and dehydrobruceine A (125) and dihydrobruceine A (I 26) from Brucea javanica (Simaroubaceae).73
Grieco and his co-workers have completed a most notable total synthesis of
dl-quassin (130) (Scheme 3).l The synthesis of the hydroxy-lactone (127) was
outlined last year (see Vol. 1 1 , p. 121). The conditions developed for the conversion
of the bis-(cc-hydroxy-ketone) (1 28) into the bis-(O-methyldiosphenol)(1 29) also
achieved the crucial inversion of configuration at C-9.74The close proximity of
the C-7 oxygen atom to the C-11 carbon atom in the 9-epiquassin skeleton is
evident from a series of reactions in which intramolecular participation occurs.
Thus, for example, treatment of the epoxide (131) with lithium aluminium hydride
gave the ether (132) whose structure and stereochemistry were established by X-ray
analysis.75Synthesis of the tetracyclic (133), a possible intermediate for quassinoid
synthesis, involved the intramolecular cycloaddition of a quinonedimethane as the
key step.76
Various workers have attempted the chemical 77-80 or microbiologica181 modification of quassinoids in the search for compounds with potent antileukaemic
activity.
73
74
75
7e
77
78
78
224
viii, ix
&
OMe
Me0
! H
OMe
x,xi
MeO&o
OMe
j H
Scheme 3
Me0
OMe
OMe
Me
225
Triterpenoids
5 Lupane Group
-OH
HY,
8
J.
Me0,C
Me0,C
(136) R = H,P-OH
(137) R = H,p-OAc
(138) R = 0
19, 2210.
H. Ageta, K. Shiojima, K. Masuda, and T. Lin, Tetrahedron Lett., 1981, 22, 2289.
226
(14)
(141)
Details have appeared of the synthesiss1 and rearrangements2 of 3a,4a- and
3P,4p-epoxy-~:A-friedo-l8P,19cr-H-lupanes (see Vol. 1 1, p. 123). Wagner-Meenvein
type rearrangements of some lupane derivatives have been
The I3C
n.m.r. spectra of some lupanes have been reported. s4
6 Oleanane Group
The confusingly named periandric acid I1 (142) and periandric acid IV (143) are
the aglycones of periandrins 11 and IV respectively, sweet glycosides from Periundra
dulcis (Leguminosae).s5 Other new olean- 12-ene natural products are 16p-hydroxy3-0x0-olean-12-en-28-oicacid and 16~-hydroxy-3-oxo-oleana1,12-dien-28-0icacid
from grape peel, 96 canthic acid (3p,7p-dihydroxyolean-12-en-28-oic acid) from
Canthiurn dicoccum (Rubia~eae),~'
and bartogenic acid (2a,3p, 19a-trihydroxyolean12-ene-24,28-dioic acid) from Burringtoniu speciosa (Lecythadaceae).D8 Napoleogenol (see Vol. 11, p. 126) is now considered to be identical to aescigenin
(16cc,2l0c-epoxyolean-12-ene-3~,24,28-tri01).~~
The unusual structure (144) has been
proposed for salviolide from Sulviu rnexicunu (Labiatae).lo0 X-Ray analysis of
methyl morolate acetate (145) has been reported.lof
The friedelanes (146)-( 148) have been isolated from Cutha cussinoides (Celastraceae). The structure and stereochemistry of (147) were proved unambiguously
by X-ray analysis of the corresponding acetate.lo2Structure (147) had previously
been assigned to octandronal (see Vol. 4, p. 214), a compound with different
91
O2
O3
O4
227
Triterpenoids
HO
(142) R
(143) R
(147) R
(148) R
= CHO
= CH,OH
CH20H
= CO,H
(149) R = H,
(150) R = 0
physical and spectral properties. It follows that the structures of octandronal and
the related octandronic acid require revision. Other new friedelanes include kokzeylanol (149) and kokzeylanonol (150) from Kokoona zeylanica (Celastraceae),lo3
lp-hydroxyfriedel-6-en-3-onefrom Momordica foetida (Cucurbitaceae),lo4and
3 p-hydroxyfriedelan-7-onefrom Pergularia extensa (As~lepiadaceae).~~~
Following
the X-ray analysis of compound T, the structures of triterpenoids Q, T, and U
from Sulacia prinoides (Hippocrateaceae) have been revised to (151)-( 153)
respective1y.lo6The X-ray analysis of salaspermic acid has been p~b1ished.l~~
Io3
Io5
lo6
lo'
lo*
249
1980, 1048.
1980, 1049.
228
(151) R
(152) R
(153) R
= CHO
= CH,OH
= COzH
loQ
110
ll1
112
113
11*
115
ll6
11'
118
Triterpenoids
229
09
(165) 13,18-ene
(166) 12,13-ene, 18a-H
The selective oxidation of oleanane triterpenoids by a Cr0,-py-BunOH-H,Oderived reagent has been studied.llgSome reactions of glycyrrhetic acid have been
llQ
230
des~ribed.l~O-l~~
Reaction of 16-oxofriedel-3-ene with zinc chloride in acetic acid
affords the rearranged products (164) and (165) in addition to the previously
described (1 66).124The enol acetylation of friedel-3-en-2-one has been
Rearrangements of friedelaneslZsand of the epoxide (1 67) have been studied.12'
The lH 128 and 13ClZ9 n.m.r. spectra of some friedelanes have been assigned,
olean-18-enes,131 hederas have the 13C n.m.r. spectra of some 0lean-l2-enes,1~~
agenin g l y c o ~ i d e sand
, ~ ~taraxeranes.
~
94 The mass spectra of some bryonolic acid
derivatives133and some f r i e d e l a n e ~have
l ~ ~ been discussed.
7 Ursane Group
New natural products include ursonic aldehyde (3-oxours- 12-en-28-al) from
Dragon's Blood, a resin from Daemonorops draco (Palmae),135dulcioic acid (168)
from Scoparia dulcis (Scr~phulariaceae),~~~
rubifolic acid (169) from Rubia cordifolia (Rubiaceae),13' esculentic acid (2a,3a,23-trihydroxyurs-12-en-28-oic
acid)
121
lZ3
124
lZ5
126
lZ7
128
lZ9
130
131
132
133
13*
135
136
137
H.-0. Kim, M. P. Irismetov, R. Kh. Garyanov, M. I. Goryaev, and Kh. A. Alibaeva, Zzv. &ad.
Nauk Kaz. SSR, Ser. Khim., 1980, 61.
H.-8. Kim, R. Kh. Garyanov, M . P. Irismetov, and M. I. Goryaev, Izv. Akad. Nauk Kaz.
SSR, Ser. Khim., 1980, 85.
M. Kanaoka, S. Yano, H. Kato, and N. Nakano, Chem. Pharm. Bull., 1981, 29, 1533.
K. Takahashi, S. Shibata, S. Yano, M. Harada, H. Saito, Y. Tamura, and A. Kumagai, Chern.
Pharm. Bull., 1980, 28, 3449.
T. Kikuchi, M. Niwa, M. Takayama, T. Yokoi, and T. Shingu, Chern. Pharm. Bull., 1980, 28,
1999.
Y. P. Gupta and J. L. Courtney, Indian J . Chem , Sect. B, 1981, 20, 65.
A. S. R. Anjaneyulu and M. N. Rao, Indian J . Chern., Sect. B, 1980, 19, 634,
P. Sengupta, M. Sen, and S. N. Maiti, J . Indian Chem. SOC.,1980, 57, 1181.
T. Kikuchi, T. Yokoi, M. Niwa, and T. Shingu, Chem. Pharm. Bull., 1980, 28, 2014.
A. A. L. Gunatilaka, N. P. D. Nanayakkara, M. U. S. Sultanbawa, and M. I. M . Wazeer,
Org. Magn. Reson., 1980, 14, 415.
A. Patra, A. K. Mitra, S. Ghosh, A. Ghosh, and A. K. Barua, Org. Magn. Reson., 1981, 15,
399.
A. G. Gonzalez, B. M. Fraga, P. Gonzalez, M. G. Hernandez, and A. G. Ravelo, Phytochemistry, 1981, 20, 1919.
A. I. Kalinovskii and N . 1. Chetyrina, Khirn. Prir. Soedin., 1980, 359; English translation,
Chem. Nut. Compounds, 1980, 16, 269.
A. G . Panosyan, G . M. Avetisyan, V . A. Mnatsakanyan, and B. V. Rozynov, Bioorg. Khim.,
1980, 6 , 1094.
J. Schmidt, S. Huneck, and W. Ihn, J . Prakt. Chem., 1980, 322, 695.
G . Nasini and F. Piozzi, Phytochemistry, 1981, 20, 514.
S. B. Mahato, M . C . Das, and N. P. Sahu, Phytochemistry, 1981, 20, 171.
S. K. Talapatra, A. C. Sarkar, and B. Talapatra, Phytochemistry, 1981, 20, 1923.
Triterpenoids
23 1
Fe @
C0,Me
AcO
AcO
( 174)
(175)
The 13C n.m.r. spectra of some urs-12-enes130 and the mass spectra of 18x,19pH-ursane ring E lactoneslQ4have been reported.
8 Hopane Group
140
141
142
143
144
145
R. Tandon, G. K. Jain, R. Pal, and N. M. Khanna, Indian J . Chem., Sect. B, 1980, 19, 819.
R. Tandon, G. K. Jain, R. Pal, and N. M. Khanna, Indian J . Chem., Sect. B. 1981. 20. 46
M. Katai, T. Terai, and H. Meguri, Chem. Pharm. Bull., 1981, 29,261.
C. M. Ojinnaka, J. I. Okogun, and D. A. Okorie, Phytochemistry, 1980, 19, 2482.
S. Escher, W. Giersch, and G. Ohloff, Helv. Chim. A d a , 1981, 64, 943.
A. K. Sil, J. K. Ganguly, K. P. Dhara, C. P. Dutta, and D. N. Roy, IndianJ. Chem., Sect. B,
1981, 20, 201.
J. Protiva, E. Klinotova, H. Skorkovska, and A. Vystrcil, Collect. Czech. Chem. Commun.,
1981, 46, 1023.
D. L. Howard and D. J. Chapman, J . Chem. Soc., Chem. Commun., 1981, 468.
232
( 180)
such as diploptene (1) together with many modified hopanoids typical of sedimentary rocks. This supports the hypothesis that the former are precursors of the
latter.146 The trisnormoretane (1 78) is the major saturated hydrocarbon of a
The structure of thysanolactone (179), a novel ring A seco moreJurassic
tane from Thysanospermum dzflusum (Rubiaceae) was established by X-ray
analysis.148The X-ray crystal and molecular structure of 9(11)-fernene (180) has
been r e ~ 0 r t e d . l ~ ~
9 Miscellaneous
The stereochemistries of the three isomeric onoceranediol diacetates have been
assigned.150Wightianol-A ( 1 8 I ) and -B (1 82) from Lycapodium wightianum (Lycopodiaceae)151 and 3a-hydroxy- 14-serraten-21-one (1 83)152 and the novel norserratene (1 84)153from Pinus monticola (Pinaceae) are new natural products. The
lA6
M . Rohmer, M . Dastillung, and G. Ourisson, Naturwissenschaften, 1980, 67, 456; see also.
149
IS0
151
lS2
153
233
Triterpenoids
OH
(181) 14,15-dihydro,14P-OH
(1 82)
fl-(cH2
0 .
(185)
(186)
(187)
R
R
=0
= H,P-OAc
234
L. Cattel, L. Delprino, and A. Dietsch, Gazz. Chim. Ital., 1979, 109, 705.
B. N. Ravi, R. J. Wells, and K. D. Croft, J . Urg. Chem., 1981, 46, 1998.
156 U. Shmueli, S . Carmely, A. Groweiss, and Y. Kashman, Tetrahedron Lett., 1981, 22, 709.
15' C. R. McIntyre and T. J. Simpson, J . Chem. Soc., Chem. Commun., 1981, 1043.
15* Y. Kimura, Y. Kobayashi, T. Takeda, and Y . Ogihara, J . Chem. Soc., Perkin Trans. I , 1981,
1923; M. Ikram, Y. Ogihara, and K. Yamasaki, J . Nar. Prod., 1981,44,91; M. Okano, K.-H.
Lee, I. H . Hall, and F. E. Boettner, ibid., p. 470; S . E. Chen, E. J . Staba, S. Taniyasu, R. Kasai,
and 0. Tanaka, Planta Med., 1981, 42, 406.
15B P. K. Minocha and K. P. Tiwari, Phytochernistry, 1981, 20, 135; D. Mandloi and P. G. Sant,
ibid., p. 1687.
H. Ishii, M. Nakamura, S.,Seo, K. Tori, T. Tozyo, and Y. Yoshimura, Chem. Pharm. Bull.,
1980, 28, 2367; H. Kizu and T. Tomimori, ibid., pp. 2827, 3555; T. Konoshima, H. Inui, K.
Sato, M. Yonezawa, and T. Sawada, ibid., p. 3473; S. Takabe, T. Takeda, Y. Ogihara, and
K. Yamasaki, J . Chem. Res. ( S ) , 1981, 16; H. Ishii, K. Tori, T. Tozyo, and Y. Yoshimura, J .
Chem. Soc., Perkin Trans. I , 1981, 1928; P. N . Singh and S . B. Singh, Phyrochemistry, 1980,
19, 2056; R. D. Tripathi and K. P. Tiwari, ibid., p. 2163; T. Konoshima, H. Fukushima, H.
Inui, K. Sato, and T. Sawada, ibid., 1981, 20, 139; M. Moreno and V. M. Rodriguez, ibid.,
p. 1446; M. Masood, P. K. Minocha, K. P. Tiwari, and K. C. Srivastava, ibid., p. 1675; T.
Aoki, K. Shido, Y . Takahashi, and T. Suga, ibid., p. 1681; P. Forgacs and J. Provost, ibid.,
p. 1689; R. Encarnacion, L. Kenne, G . Samuelsson, and F. Sandberg, ibid.. p. 1939; Y. Okada,
K. Koyama, K. Takahashi, T. Okuyama, and S. Shibata, Planta Med., 1980,40,185; S . Ghosal,
A. K. Srivastava, R. S . Srivastava, S. Chattopadhyay, and M. Maitra, ibid., 1981, 42, 279;
H. Ishii, I. Kitagawa, K. Matsushita, K. Shirakawa, K. Tori, T. Tozyo, M. Yoshikawa, and
Y. Yoshimura, Tetrahedron Lett., 1981, 22, 1529.
P. K. Minocha and R. N. Tandon, Phytochemistry, 1980, 19, 2053.
162 K. Hostettmann, J. Doumas, and M. Hardy, Helv. Chim. Acta, 1981, 64, 297.
163 I. Kitagawa, T. Kamigauchi, H. Ohmori, and M. Yoshikawa, Chem. Pharm. Bull., 1980, 28,
3078.
164 A. A. Akimaliev, N. Sh. Pal'yants, P. K. Alimbaeva, and N. K. Abubakirov, Khim. Prir.
Soedin., 1979, 668; W. Janiszowska, B. Wilkomirski, and Z. Kasprzyk, Pol. J . Chem., 1980,
54, 2147; see also ref. 50.
l5*
155
5
Carotenoids and Polyterpenoids
BY G.BRITTON
1 Carotenoids
Introduction.-This Report covers the literature published up to approximately the
end of September, 1981. Few new carotenoid structures have been reported. The
main advances in carotenoid chemistry have been in the stereospecific synthesis of
carotenoids with chiral end-groups. Current interest in the possible use of retinoids
in cancer chemotherapy has prompted the preparation of a considerable number of
retinoic acid analogues. There has been no major new development in the use of
physical methods but h.p.1.c. becomes more and more the method of choice for
carotenoid separation, purification, and assay, and the increasing number of
papers on resonance Raman spectroscopy emphasizes the potential value of this
technique in the carotenoid field.
Reviews.-The major new publication is Volume 1 of the completely rewritten
second edition of Goodwin's book1 'The Biochemistry of the Carotenoids'. This
volume gives an introduction to carotenoid chemistry and a comprehensive survey
of the distribution, biosynthesis, and functions of carotenoids in plants and microorganisms. The biochemistry of plant carotenoids is also dealt with in an extensive
review by Spurgeon and Porter.2 The second edition of Czygan's book3 'Pigments
in Plants' includes chapters on carotenoid bio~ynthesis,~"
xanthophyll interconversion^,^^ photoregulation of carotenoid bio~ynthesis,~"
and carotenoids in
algal c h e r n o t a ~ o n o m yElsewhere,
.~~
reviews have been published on the use of
carotenoids as food c o l o u r ~ , the
* ~ ~metabolic and nutritional significance of carotenoids,6 carotenoids in green and purple photosynthetic bacteria, and carotenoid
biosynthesis in plants, especially enzymic aspects.a The retinoid field is surveyed in
T. W. Goodwin, 'The Biochemistry of the Carotenoids', Vol. 1, 2nd Edn., Chapman and Hall,
London, 1980,432 pp.
S. L. Spurgeon and J. W. Porter, in 'Biochemistry of Plants,' ed. P. K. Stumpf, Academic Press,
New York, 1980, Vol. 4, p. 419.
'Pigments in Plants', 2nd Edn., ed. F.-C. Czygan, Gustav Fischer, Stuttgart and New York,
1980; (a) B. H. Davies, p. 31; (b) A. Hager, p. 57; (c) W. Rau, p. 80; (d) A. Weber and M.
Wettern, p. 104.
J. N. Counsell, Dev. Food Colours, 1980, 1, 151.
H. Klaui, in 'Natural Colours in Food and other Uses, International Symposium 1979', ed.
J. N. Counsell, Applied Science Publishers, London, 1981, p. 91.
K. L. Simpson and C. 0. Chichester, Ann. Rev. Nutrition, 1981, 1, 351.
T. W. Goodwin, J. Sci. lad. Res., 1980, 39, 682.
J. W. Porter, S. L. Spurgeon, and D. Pan, Dev. Plant Biol., 1980, 6, 321.
235
236
two extensive b o o k ~ , ~
and
J ~two collections of Symposium proceedings deal with
light-energy transduction mechanisms in visual cellsll and HaIohacterium halobium12
respectively.
New Structures and Stere0chemistry.-Carotenoids. Of the few new carotenoid
structures that have been reported, all but one are from marine animals. Lactucaxanthin, a major xanthophyll in chloroplasts of lettuce (Lactuca saliva) and
OH
&--,
-=.
(1) R1 = R2 = a
(2) R1 = b, R2 = c
(3) R1= d, R2 = c
(4) R1= e, R2 = f
( 5 ) R1 = g, R2 = h
(6) R1 = c, R2 = i
(7) R1 = R2 = j
(8) R1 = R2 = d
(9) R1 = d, R2 = k
(10) R1 = R2 = k
(11) R1 = k, Ra = i
237
related species, has been identified13by n.m.r. and c.d. correlation as (3R,6R,3R,
hR)-~,~-carotene-3,3-diol
(I), the sixth of the ten possible chiral isomers of this
diol to be found in Nature. 78-Didehydro-p,p-carotene-3,4,3-triol
(2) has been
obtained from a number of she1lfish.l4-l6The structure was confirmed by NaBH,
reduction of pectenolone (3,3-dihydroxy-7,8-didehydro-p,p-caroten-4-one
(3).
The 3,4-cis-vic-diol thus formed was identical to the new carotenoid. Three new
pigments from the sponge Microciona prolifera have been characterized by their
spectroscopic properties1 as 3,4(or 2,3)-didehydro-y,~-carotene
(4),3-hydroxy-x,~carotene-6,8-dione [trikentriophidin (5)], and 7,8-didehydro-p,p-caroten-3-01
[allobetaxanthin (6)]. The occurrence of free actinioerythrol [3,3-dihydroxy-2,
2-dinor-p,p-carotene-4,4-dione
(7)] and its monoester in the sea anemones
Actinia equina and A . tenebrosa has been reported for the first time.18 The fatty
acid composition of the (7) diester, actinioerythrin, the main pigment of these
animals, has been describedlg along with those of astaxanthin [3,3-dihydroxy-p,
p-carotene-4,4-dione (S)] esters from Haematococcus pluvialis and Panadalus
borealis. The preparation of ( -)-camphanate diesters followed by h.p.1.c. separation is a good method for determining the isomeric composition of samples of (8)
and adonirubin [3-hydroxy-p,p-carotene-4,4-dione (9)].20The astaxanthin of the
shrimp Pandalus borealis21and of salmon22contained the (3R,3R)-, (3R,3S)-, and
(3S,3S)-isomers. The absolute configuration of mimulaxanthin [6,7,6,7-tetradehydro-5,6,5,6-tetrahydro-p,p-carotene-3,5,35-tetrol
(12)] from Lamium montanum has been determined23 as (3S,SR,sR,3S,SR,6R) by degradation and
R2
(12) R1 = R2 = a (X = H)
(13) R1 = a (X = H), R2 = b (Y = CH=CH)
(14) R1= a (X = H), R2= c
(15) R1= a (X = Ac), R2= b (Y = CH2CO)
D. Siefermann-Harms, S. Hertzberg, G. Borch, and S . Liaaen-Jensen, Phytochemistry, 1981,
20, 85.
l4 T. Matsuno, T. Maoka, and K. Hiraoka, Bull. Jpn. SOC.
Sci. Fisheries, 1981,47, 143.
16 T.Matsuno and T. Maoka, Bull. Jpn. SOC.Sci. Fisheries, 1981,47, 377, 495.
l8 T. Matsuno, K. Hiraoka, and T. Maoka, Bull. Jpn. SOC.Sci. Fisheries, 1981,47, 385, 501.
C. Litchfield and S . Liaaen-Jensen, Comp. Biochem. Physiol., 1980,6 W ,359.
J. D. Tauber, A. Fiksdahl, and S. Liaaen-Jensen, Biochem. Syst. Ecol., 1980,8,437.
l 8 B. Renstrcam and S. Liaaen-Jensen, Comp. Biochem. Physiol., 1981,69B,625.
8o R. K. Muller, K. Bernhard, H. Mayer, A. Ruttimann, and M. Vecchi, Helv. Chim. Acta, 1980,
63,1654.
*l B. Renstrram, G. Borch, and S. Liaaen-Jensen, Comp. Biochem. Physiol., 1981,69B,621.
88 K.Schiedt, F. J. Leuenberger, and M. Vecchi, Helv. Chim. Acta, 1981,64, 449.
R. Buchecker and C. H. Eugster, Helv. Chim. Acta, 1980,63,2531.
la
238
OH
New NaturalProducts Related to Carotenoids. New compounds which have norcarotenoid-like structures include ambliol A (19), dehydroambliol A (20), and ambliolide
(21), diterpenoids from the sponge Dysidea a m b l i ~ deoxyabscisic
,~~
acid (22), a
precursor to abscisic acid (23) in Cercospora rosicolaYz6and two tobacco products,
3-hydroxy-5,6-epoxy-p-ionyl-~-~-glucopyranoside
(24)27 and 8,9-dihydroxy-8,9dihydromegastigmatrienone (25).28 The absolute configuration of (-)-(S)-2hydroxy-p-ionone (26) has been determined by correlation with ursolic acid and
( -)-trans-verbenol. 29
Carotenoid-Protein Complexes. Three new purple-blue carotenoprotein complexes
from invertebrate animals have been described. That from the carapace of
Orconectes Iimosus (Amax 335, 460, 675 nm) has astaxanthin (8) and canthaxanthin
and that from the fly Rhyn[p,p-carotene-4,4-dione(lo)] as prosthetic
chosciara americana (Amax 465,545 nm) has one canthaxanthin and one echinenone
[p,p-caroten-4-one (1 l)] per mole of protein.31 The sponge Suberites domuncula
H. Ranneberg, P. FOSS,
T. Ramdahl, G. Borch, 0. M. Skulberg, and S. Liaaen-Jensen, Phyrochemistry, 1980, 19, 2167.
25 R. P. Walker and D. J. Faulkner, J . Urg. Chem., 1981, 46, 1098.
28 S. J. Neill, R. Horgan, T. S. Lee, and D. C. Walton, FEBS Lett., 1981, 128, 30.
2 7 H. Kodama, T. Fujimori, and K. Kato, Agric. Biol. Chem., 1981, 45, 941.
2 8 Y . Takagi, T, Fujimori, H. Kaneko, and K. Kato, Agric. Biol. Chem., 1981,45, 787.
2 g S . Escher, W. Giersch, and G. Ohloff, Helv. Chim. Acta, 1981, 64, 943.
30 B. Czeczuga and S. Krywuta, Comp. Biochem. Physiol., 1981, 68B, 339.
31 W. R. Terra, C. Ferreira, A. G. De Bianchi, and K. Zinner, Comp. Biochem. Physiol., 1981,
68B, 89.
Z4
239
6.X
b*
Me
OH
OMe
(21)
-Glucose
0W
(22) X
(23) X
HO
=H
= OH
(24)
yielded a blue carotenoprotein (31 000 dalton) in which the carotenoid was not
identified but described as similar to a monohydroxymonoepoxycarotene.32A new
fucoxanthin [5,6-epoxy-3,3,5-trihydroxy-6,7-didehydro-5,6,7,8,5,6-hexahydroP,P-caroten-8-one 3-acetate (1 5)]-chlorophyll a-protein complex from brown algae
and diatoms has been described.33
HO
w c M e 2 O M e x&H20H
Y
(28)
(31) X
(32) X
= OH,
3 Br-
(29) X =OH, Y = H
(30) X = H, Y = OH
= H,
Y =H
Y = OH
36
240
(33)
(34)
&
HO
p
i
c1-+
HO
Wittig salt (37) for reaction with (34) to give lutein. The synthesis of all-trans(3S,3S)-7,8,7,8-tetradehydroastaxanthin [3,3-dihydroxy-7,8,7,8-tetradehydrop, p-carotene-4,4-dione (3S)] and all-trans-(3S,3S)-7,8-didehydroastaxanthn[3,3dihydroxy-7,8-didehydro-P,p-carotene-4,4-dione
(39)], the two components of
asterinic acid, and of their 9-cis- and 9,9-di-cis-isomers from (4S)-(2E)-5-(4hydroxy-2,6,6-trimethy1-3-oxocyclohex1-eny1)-3-methylpent-2-en-4-ynal(40)
as
starting material in a CI5 + C,, + C15Wittig scheme.38The (3R,3R)-, (3S,3S)-,
and (3R,3S)-isomers of astaxanthin (8) can be obtained from a synthetic racemate
by separation of the diastereomeric di-( -)-~amphanates.~~
The preparation of
(3R)+-citraurin [3-hydroxy-8-apo-P-caroten-8-al
(41)], (3R)-P-citraurol [8-apoP-carotene-3,8-diol (42)], and (3R)-p-citraurinene [8-apo-P-caroten-3-01 (43)]
from the C,, Wittig salt (31) has been reported.40
36
37
38
38
24 1
(38) X = Y = C E C
(39) X = C E C , Y = CH=CH
HO
(41) R = CHO
(42) R = CH20H
(43) R = Me
0
(4.0)
0
a
(44) R1= a, R2 = b
(45) R1= C, R2= b
Further syntheses of zeaxanthin (27) and rhodoxanthin [4,5-didehydro-4,5retro-p,p-carotene-3,3dione(48)] have been described.42In a simplification of a
previous procedure, the acetylenic trio1 (49) was reduced (LiAlH,) to the allenic
diol (50), which with PPh,Br underwent rearrangement to the 3-hydroxy-p-ring
41
P. R. Ellis, A. E. Faruk, G . P. Moss, and B. C. L. Weedon, Helv. Chim. Acta, 1981, 64, 1092.
242
Wittig salt (51). Wittig reaction with the C,, dialdehyde (52) gave racemic (27).
The 3-hydroxy-p-ring system was also obtained from a-ionone (53). Oxidation
with t-butyl chromate gave the ketone (54), which with ethanediol underwent
double-bond migration to give (55), which was hydrolysed in the presence of
(53)
(54)
(57)
243
(61)
(62)
(63)
(64)
(65)
R1= a, R2= b
R1= R2= a
R1= c, R2= a
R1 = d, R2= a
R1= e, R2= b
(66)
(67)
(68)
(69)
(70)
R1= R2= e
R3= f, R2= b
R1= R2= f
R1= R2= g
R1= R2= h
(71)
(72)
(73)
(74)
(75)
R1= R2= i
R1= R2= j
R = R2= k
R1= R2= 1
R1= R2= c
and 1,2-epoxy-l,2-dihydro-~,$-carotene
(64)].44The acetonides (65) and (66) of
the 1,2-diol(67) and 1,2,1,2-tetrol (68) were also prepared.43Synthetic carotenoid
analogues with 2- and 3-pyridyl, 2- and 3-furyl, and 2- and 3-thienyl end-groups,
(69)-(74), have been made from the corresponding Wittig salts and the C,,
crocetindial (76).45 A novel carotenoporphyrin ester (77) has been prepared and
used as a model in light-energy transfer s t ~ d i e s . ~An
~ - ~unusual
*
1,6-methano[lO]annulene homologue (78) of P-carotene [P,P-carotene (75)]has been synthesized
by a Wittig reaction between the retinol derivative (79) and the cyclic dialdehyde
Treatment of zeaxanthin (27) with chlorsulphonic acid followed by base
gave the disulphate salt (8 l).50 Lycoxanthin ($,$-caroten- 16-01) monosulphate (82)
43
44
45
H. Pfander, M. Kamber, and Y . Battegay-Nussbaumer, Helv. Chim. Acta, 1980, 63, 1367.
46
47
48
4s
6o
G . Dirks, A. L. Moore, T. A. Moore, and D. Gust, Photochem. Photobiol., 1980, 32, 277.
A. L. Moore, G . Dirks, D. Gust, and T. A. Moore, Photochem. Photobiol., 1980, 32, 691.
R. V. Bensasson, E. J. Land, A. L. Moore, R. L. Crouch, G . Dirks, T. A. Moore, and D. Gust,
Nature, 1981, 290, 329.
R. Neidlein and H. Zeiner, Arch. Pharm. (Weinheim, Ger.), 1980, 313, 970.
T.Ramdahl and S. Liaaen-Jensen, Acta Chem. Scand., Ser. B, 1980, 34,773.
244
HO
0
d
(81) R1= R2 = a
(83) R1= R2 = d
245
(84)
HO
0
0
OH
HO
was prepared similarly. Epoxidation of astacene [3,3'-dihydrox~-2,3,2',3'-tetradehydro-@,@-carotene-4,4'-dione(83)] with perbenzoic acid gave the 9,lO-, 11,12and 9,12-epoxides (84)-(86).51 Astacene has been
to form complexes with
Al, Cr"', Cd*,
Fe'I', and Hg" salts, including a stable 1 : 1 complex with Fe(NO,),.
Cleavage of 8'-apo-p-carotenylidene oxazolone (87) with aqueous or methanolic
NaOH, piperidine, or morpholine gave the 7'-benzoylamino-@-apo-6'-carotenoic
acid derivatives (88) (R = OH, OMe, piperidinyl, or m o r p h ~ l i n o ) Mono.~~
and
di-anions of p-carotene have been formed by reaction with a Na mirror in THF.54
The oxidation of @-carotenewith nitroxyl radical compounds has been
The pyrolysis of p-carotene under various conditions afforded a range of methylbenzenes, methylnaphthalenes and p h e n a n t h r e n e ~ Kinetic
. ~ ~ ~ ~ studies
~
have been
reported of reactions of @-caroteneand retinyl acetate (89) with various radicals58
and with peroxide oxygen and dicyclohexyl peroxydicarb~nate.~~
61
6s
64
bb
66
b7
O8
D. Osianu, E. Nicoara, and C. Bodea, Rev. Roum. Chim., 1980, 25, 261.
J. Zsako and T. Laszlo, Rev. Roum. Chim., 1981, 26, 237.
V. Ciurdaru, V. Tamas, and K. L. Simpson, Rev. Roum. Chim., 1980, 25, 571.
G. N. Sinyakov, Zh. Prikl. Spektrosk., 1981, 35, 487.
0. T. Kasaikina, T. V. Lobanova, A. B. Gagarina, and N. M. Emanuel, Dokl. Akad. Nauk
SSSR, 1980, 255, 1407.
M. Ishiwatari, J. Anal. Appl. Pyrolysis, 1980, 2, 153.
M. Ishiwatari, J . Anal. Appl. Pyrolysis, 1981, 2, 339.
0. T. Kasaikina, Z. S. Kartasheva, and A. B. Gagarina, Zzv. Akad. N a u ~SSSR,Ser. Khim.,
1981, 536.
Z. S. Kartasheva, 0. T. Kasaikina, and A. B. Gagarina, Izv. Akad. Nauk SSSR, Ser. Khim.,
1981, 541.
246
NHCOPh
(87) X
NY
Ph
(88) X
'.*?
COR
(89) R = CH20Ac
(90) R = CHO
(91) R = CH20H
(92) R = C02H
Retinoids. The 9,ll-di-cis-isomer of retinaldehyde (90) has been prepared in six
steps from the C15 aldehyde (93) and used to form a 9,ll-di-cis-rhodopsin with
cattle opsin.60The 9,ll-di-cis-isomer was also one of four di-cis forms obtained
by irradiation of all-trans-retinaldehyde in acetonitrile.61The sterically hindered
7-cis- and 7,13-di-cis-isomers of vitamin A [retinol (91)] have been prepared via
the 7-cis photoisomerization product of the sulphone (94).62Several isotopically
labelled species of retinaldehyde and derivatives have been synthesized, including
11-cis-[18-2H3]retinaldehyde(95) and 11-cis-[19-2H,]retinaldehyde,63(96), the alltrans-, 9-cis-, 1 1-cis-, and 13-cis-isomers of [ 10-2Hl]-, [ 1l-2Hl]-, [ 12-2Hl]-, and
[l 1, 12-2H,]-retinaldehyde,64 all-trans-[ 13,14-14C2]- and [ 1 l-3H,]-retinoic acid
(92),65-67 trans-[11-3H,]-5,6-epoxyretinoic acid (97),66 and trans-[1 1-3Hl]retinyl
acetate (89).67
(93)
R'
6O
62
63
64
6B
13'
(94)
(97)
247
Many retinaldehyde, retinol, and retinoic acid derivatives and analogues have
been synthesized. The (3R)-3-hydroxy-derivatives (98), (99), and (100) were
prepared from the optically active C,, Wittig salt (3 1).689-Bromoretinaldehyde
(101 ; trans and 9-cis), 13-bromoretinaldehyde (102; trans and 11-cis), phenylretinaldehyde (103; trans and 9-cis), and p-dimethylarninophenylretinaldehyde
(104; trans) have been prepared and used to make bacteriorhodopsin analogue^.^^
5,6-Dihydroretinaldehyde(105) and its desmethyl analogue (106) also formed
(98) R = CH,OH
(99) R = CHO
(100) R = COzH
10
(103) R = H
(104) R=NMe,
(1 05)
(106)
**
OS
70
71
72
73
74
76
70
248
R3+R5
iP
(109)
(110)
(111)
(112)
(113)
249
(123) X = 0
(124) X = H,OH
(125)
(128) R
(129) R
(132) R
77
78
CHO
CHO
250
(129), (132), and (134). The synthesis of D-glucuronic acid conjugates of N(4hydroxypheny1)- and N-(2-hydroxyethyl)-retinamide (135) (X = p-C,H, or CH,
NH
/
0
(133) R
HO
(134) R
OH
CHO
(135)
CH2) from trans-retinoyl chloride has been reported.8o Retinyl phosphate (136)
has been prepareda1in 40-60 % yield from retinol and POCI,. Thermal sigmatropic
rearrangement of the allenic retinoids (138) (R = H or SiMe,CMe,) gave the
12,14-retroretinol compounds (139) as a mixture of geometrical isomers.82 The
preparation of a water-soluble retinaldehyde-dextran complex has been described.
Two-electron electrochemical reduction of N-retinylidene-n-butylamine(I 37) gave
the 5,6-dihydro-derivative.84
(136) R
(137) R
= CH20POgH2
=
CH=NBu"
(141)
(142)
83
84
86
25 1
+J-
S0,Ph
+M,,,
R
(143)
(1.44)
(1 46)
(145)
(147)
(148)
(149) R = CH,SPh
(150) R = CHO
Ph*f%zAc
&Ho
\
88
O1
93
252
t 157)
(158) R = H
(160)
(159) R = OH
preparation of safranal(154). 94 Cyclization of 2-geranylthiophen and its 5-carboxyderivative (155) (R = H or C02H)gave products including (156) and (157).95New
syntheses have been reported for p-damascone (158) from P-cyclocitral( 150)9sand
3-hydroxy-P-damascone (159) in four steps from the keto-ester (160).9 7 a-Ionone
(161) was the starting material in new syntheses of dihydroedulans (163) and
theaspiranes, e.g. (1 64),98 and of the theaspirones (165). gg (&)-(166) has been
.o
Me
(161) R = 0
(162) R = H,OH
m
(165) R = 0
(166) R = H,
(171)
84
95
O7
WH
(172)
T. Kametani, K. Suzuki, H. Kurobe, and H. Nemoto, Chem. Pharm. Bull., 1981, 29, 105.
A. V. Semenovskii and M. M. Emelyanov, Izv. Akad. Nauk SSSR, Ser. Khim., 1980, 2578.
R. Pellicciari, E. Sisani, and R. Fringuelli, Tetrahedran Lett., 1980, 21, 4039.
Y . Tsujino, M. Shibagaki, H. Matsushita, K. Kato, and H. Kaneko, Agric. Biol. Chem., 1981,
45, 1731.
253
pN
(173)
(174) R
(175) R
= CH=CH
(176)
= CHO
OH
(180)
acetaldehyde (140) from p-ionone (142) via the nitrile (173) has been described.lo3
Mild acid dehydration of a-ionol (162) gave products including megastigma-4,
7(E),Ptriene (1 74), which was oxidized to the aldehyde (175).lo4Other natural
products with carotenoid-like rings for which syntheses have been reported
include Latiu luciferin ( 176)lo5and mokupalide (177)?05J06( +)-farnesiferol C
(178),107 trans-y-monocyclofarnesol (179),lo8and the glucoside picrocrocin (18O).lo9
S. Torii, K. Uneyama, T. Nakai, and T. Yasuda, Tetrahedron Lett., 1981, 22, 2291.
T.Kato and H. Kondo, Bull. Chem. Soc. Jpn., 1981, 54, 1573.
lo2 S. Shibata, H. Matsushita, K. Kato, H. Kaneko, M. Noguchi, M. Saburi, and S. Yoshikawa,
Agric. Biol. Chem., 1981, 45, 315.
lo3
R.W.Dugger and C. H. Heathcock, Synth. Commun., 1980,10, 509.
lo4
B.-H. Song, D.L. Davis, and C. M. Song, J . Agric. Food Chem., 1980, 28, 997.
lo6
F.W. Sum and L. Weiter, Tetrahedron,Suppl. 1981, 303.
lo6 M. Kobayashi and E. Negishi, J . Org. Chem., 1980, 45, 5223.
lo' T. Mukaiyama and N . Iwasawa, Chem. Lett., 1981, 29.
lo*
0. P.Vig, M. L. Sharma, N. Trehan, and N. K. Verma, IndianJ . Chern., Sect. B, 1980,19,450.
loo H. Mayer and J. M. Santer, Helv. Chim. A d a , 1980, 63, 1463.
loo
lol
254
The I , 1-didesmethyl analogue (1 8 1) of abscisic acid (23) has been prepared.l1 The
cis-trans photoisomerization of (23) has been studied.l1 A convenient procedure
has been developed for the catalytic hydrogenation of p-ionone (142) to the cis-5,6dihydroionone (182).l12 On treatment with Me2S+CH;, P-ionone gave the epoxide
(183), which with MgBr, afforded the aldehyde ( 1 84) without halohydrin formatio n .l13
The photochemical reactions of ionones and related compounds have been
studied extensively and in most cases large numbers of products have been characterized. Compounds whose behaviour on irradiation have been investigated include
@R
(188) R
(189) R
111
02Me
p
\
@d
OR
= H,
= CH,
(190) R = 0
(191) R = CH,
(192)
E. Nagano, T. Oritani, and K. Yamashita, Agric. Biol. Chem., 1980, 44, 2095.
D. E. Brabham and R. H. Biggs, Photochem. Photobiol., 1981, 34, 3 3 .
C. N. Filer, J. C. Pugliese, J. C. Morrison, and D. G . Ahern, Org. Prep. Proced, Znt., 1981,
13, 140.
113
M. Rosenberger, W. Jackson, and G . Saucy, Helv. Chim. Acta, 1980, 63, 1665.
255
(E)- and (2)-p-ionone and the bicyclic compound (185)>14(E)- and (Z)-a-i~none,~
(E)-p-ionone oxime ethyl ether (186)>16 the cyclopropane derivative (187);17 the
epoxy-esters(188)llSand (189),119and the epoxides (19Oy2O (192) (R = H or Ac),121
(191), and (193).122The catalytic hydrogenation of compounds including p-ionone
with K,[Co(CN),H] in aqueous solution with phase-transfer reagents has been
described.12, The mechanisms of hydrogenation of 13-ionong~~
and pseudoionone
(1 94)125have been studied.
Physical Methods.-Separation and Assay. A range of isomers of astaxanthin (8)
diacetate (9-cis, I3-cis, 15-cis, 9,9-di-cis, 9,13-di-cis, 9,13-di-cis, 13,13-di-cis,
13,15-di-cis), prepared by thermal and iodine-catalysed isomerization of rrans-(8)
have been separated by h.p.l.c.126A procedure has been developed for separation
of bean leaf etioplast pigments, including c a r ~ t e n o i d s ,by
~ ~h.p.1.c.
~
H.p.1.c.
separations of esters of all-trans-, 9-cis-, 11-cis-, and 1 3 - ~ i ~ - r e t i n o l , l ~and
*-~~~
determinations of retinol in
retinol and 13-cis-retinoic
and the
aromatic retinoid (195)13,in plasma have been described. A reversed-phaseion-pair
h.p.1.c. method has been used for analysis of plant hormones including abscisic
acid.ls4T.1.c. methods have been described for the separation of green plant135and
phyt~planktonl~~
carotenoids, and paper chromatography of chloroplast pigments
114
116
116
117
118
lZo
lal
K. Murato, H. R. Wolf, and 0. Jeger, Helv. Chim. Acta, 1980, 63, 2212.
N. Nakamura, W. B. Schweitzer, B. Frei, H. R. Wolf, and 0. Jeger, Helv. Chim. Acta, 1980,
63,2230.
12z
lZ3
lZ4
lZ5
126
lZ8
lZ0
132
133
la4
lS5
136
A. P. Alder, H. R. Wolf, and 0. Jeger, Helv. Chim. Acta, 1981, 64, 198.
256
13
138
139
140
141
142
143
144
145
146
14
148
149
lS0
161
257
Raman and Infrared Spectroscopy. Two reviews deal with resonance Raman
spectroscopy of carotenoid-containing biomolecules and rnicro-organism~~~~
and
of carotenoids and chlorophylls in photosynthetic bacteria.153 The resonance
Raman excitation profile of lycopene in acetone has been determined.154Calculations previously used for p-carotene do not explain the lycopene data. Several
papers report detailed studies of the time-resolved resonance Raman spectra of
lba
lS3
lS4
ls5
lS6
lS0
160
16a
16s
164
R. Wilbrandt and N.-H. Jensen, Eer. Bunsenges. Phys. Chem., 1981, 85, 508.
R. Wilbrandt and N.-H. Jensen, J . Am. Chem. SOC.,1981,103, 1036.
G. H. Atkinson, J. B. Pallix, T. B. Freedman, D. A. Gilmore, and R. Wilbrandt, J . Am.
Chem. SOC.,1981, 103, 5069.
P. K. Dutta, R. Dallinger, and T. G . Spiro, J . Chem. Phys., 1980, 73, 3580.
R. F. Dallinger, W. H. Woodruff, and M. A. J. Rodgers, Photochem. Photobid., 1981,33, 275.
A. V. Lukashin and M. D. Frank-Kamenetsky, Chem. Phys. Lett., 1981, 80, 119.
K. Kodama and A. D. Bandrauk, Chem. Phys. Lett., 1981, 80, 248.
A. E. Allan and A. Cooper, FEBS Lett., 1980, 119, 238.
4
258
~ c 0 p y .A
l ~detailed
~
resonance Raman study of invertebrate astaxanthin-proteins
has been published.166
Many papers report resonance Raman studies of the retinaldehyde-protein
visual pigments and bacteriorhodopsin. A Symposium proceedings
contains several, including review article^.^^^-^^* Papers published elsewhere deal with
resonance Raman spectroscopic studies of rhodopsin and intermediates in the
visual
including deuterium-labelled ana10gues.l~~
Resonance Raman
studies on bacteriorhodopsinare covered in a review174and a number of p a p e r ~ . l ~ ~ - l ~ l
Hydrogen-bonding between the trans-N-retinylidene-butylamine Schiff base
and phenols has been studied by i.r. spectroscopy.ls2
Electronic Absorption Spectroscopy. The pressure dependence of the absorption
spectrum of p-carotene in pentane-isopentane, up to 60 kbar, has been studied.ls3
A large red shift and broadening of vibronic peaks was observed. The absorption
spectra of charge-transfer complexes of trans-p-carotene, 8-apo-p-caroten-8-al
(1 99), astacene (83), and methylbixin(200) have been determined.ls4The orientation
of P-carotene and retinaldehyde in lipid bilayers has been investigated.ls5Agreement was found between the theory of elastic light scattering accompanying light
absorption and the blue part (but not the red part) of the absorption bands of three
carotenoids.ls6
U.V.spectra have been reported for the 9 4 s - and all-trans-G, and -C1,, and the
all-trans-C,, and -CZ4homologues of retin01.l~~
Several retinaldehyde isomers in
iso-octane solution with [Eu(fod),] gave a new characteristic absorption band.les
lB6
259
IDO
217
260
224
225
226
227
22 8
229
230
231
232
a33
26 1
235
238
237
238
230
240
241
262
R2
X
2
HO
A- &.
HO
HO
0
C
(212)
(213)
(214)
(215)
(216)
842
243
844
245
246
241
*48
248
a60
851
a62
263
864
W. Rau, in Blue Light Syndrome, ed. H. Senger, Springer, Berlin, 1980, p. 283.
W. Rau, in Pigments in Plants, 2nd Edn., ed. F.-C. Czygan, Gustav Fischer, Stuttgart and
New York, 1980, 1981, p. 80.
E. L. Schrott, in Blue Light Syndrome, ed. H. Senger, Springer, Berlin, 1980, p. 309.
E. L. Schrott, Planta, 1980, 150, 174.
E. L. Schrott, Planta, 1981, 151, 371.
M. S. Kritsky and E. K. Chernysheva, Dokl. Akad. Nauk SSSR, 1980,255,228.
M. S. Kritsky, V. Y. Sokolovsky, T. A. Belozerskaya, and E. K. Chernysheva, Dokl. Akad.
Nauk SSSR, 1981, 258, 759.
R. W. Harding and R. V. Turner, Plant Physiol., 1981,68, 745.
B. D. Whitaker and W. Shropshire, jun., Exp. Mycol., 1981, 5, 243.
I. Lopez-Diaz and E. Cerda-Olmedo, Planta, 1980, 150, 134.
Y. Koyama, Y. Yazawa, K. Kato, and S . Yamagishi, Chem. Pharm. Bull., 1981, 29, 176.
F. Kato, Y. Koyama, S. Muto, and S. Yamagishi, Chem. Pharm. Bull., 1981, 29, 1674.
S. Torres-Martinez, F. J. Murillo, and E. Cerda-Olmedo, Genet. Res., 1980, 36, 299.
F. J. Murillo, S. Torres-Martinez, C. M. G. Aragon, and E. Cerda-Olmedo, Eur. J. Biochem.,
1981,119, 511.
*66
263
(217)
(218)
(219) R
(-!5J*
x
(222) R
6. &*
(223) R
(224) R
@
0
T. Matsuno and S. Nagata, Bull. Jpn. SOC.Sci. Fisheries, 1980, 46, 1363.
T. Matsuno, H. Matsutaka, and S. Nagata, Bull. Jpn. SOC.Sci. Fisheries, 1981, 47, 605.
m0 R. Castillo, Comp. Biochem. Physiol., 1980, MA, 695.
261 U. C. Goswami and A. B. Barua, Zndian J. Biochem. Biophys., 1981,18, 88.
C. A. Frolik, L. L. Dart, and M. B. Sporn, Biochim. Biophys. Acta, 1981, 663, 329.
s63 H. F. DeLuca, M. Zile, and W. K. Sietsema, Ann. N . Y. Acad. Sci., 1981, 359, 25.
s64 C. A. Frolik, B. N. Swanson, L. L. Dart, and M. B. Sporn, Arch. Biochem. Biophys. 1981,208,
s68
a59
344.
s65
Y . Mikami, Y . Fukunaga, T. Hieda, Y . Obi, and T. Kisaki, Agric. Biol. Chem., 1981, 45, 331.
264
(232) n = 3-6
(236) X
(237) X
266
267
268
269
270
272
= OMe,
= Me,
=
=9
1-10
or 10
Y . Mikami, Y . Fukunaga, M. Arita, and T. Kisaki, Appl. Environ. Microbiol., 1981, 41, 610.
Y. Mikami, Y. Fukunaga, M. Arita, Y. Obi, and T. Kisaki, Agric. Biol. Chem., 1981,45, 791.
T. Suga and T. Shishibori, J . Chem. SOC.,Perkin Trans. 1, 1980, 2098.
T. Suga, T. Shishibori, and K. Nakaya, Phytochemistry, 1980, 19,2327.
L. L. Danilov, D. Maltsev, V. N. Shibaev, and N. K. Kochetkov, Caubohydr. Res., 1981, 88,
203.
A. Okubo, H. Kawai, T. Matsunaga, T. Chuman, S. Yamazaki, and S . Toda, Tetrahedron
Lett., 1980, 21, 4095.
K. Sato, S. Inoue, A. Onishi, N. Uchida, and N. Minowa. J . Cfiem.SOC.,Perkin Trans. I , 1981,
761.
265
OMe
S0,Ph
OMe
(238) X = Me0
(239) X = Me
OMe
OMe
OMe
(241) X = Me0
(242) X = Me
OMe
(243)
274
276
277
266
Physical Methods. H.p.1.c. procedures for the separation and assay of ubiquinone
and h o m o l o g ~ e s ~and
~ ~of- ~menaquinone
~~
cis- and trans-isomers, 2,3-epoxides,
and chain-length homo10guesZ81~282
have been described. A lH n.m.r. study has
been reported2B3of the location and motion of ubiquinones in perdeuteriated phosphatidylcholine bilayers. Other aspects of the interaction of ubiquinone with
phospholipid monolayers have been
Biosynthesis. An alternative pathway has been proposed for the early stages of the
biosynthesis of the isoprenoid side-chain of ubiquinone in bacteria, via acetolactate
acid (248)286and
rather than a c e t o a ~ e t a t e 3,4-Dihydroxy-5-hexaprenylbenzoic
.~~~
(248) R = H
(249) R = Me
3-methoxy-4-hydroxy-5-hexaprenylbenzoic
acid (249)287have been identified as
intermediates in the biosynthesis of ubiquinone-6 in Saccharomyces cerevisiae. In
Escherichia coli, an enzyme-complex-bound pool of 2-octaprenylphenol (250)
accumulated under anaerobic conditions, and was rapidly converted into ubiquinone-8 in air.288The enzymic synthesis of o-succinylbenzoate,z89the conversion
of this into its coenzyme A thioester, and the cyclization of this to 1,4-dihydroxy2-naphthoic acid (25 1)290 have been demonstrated with bacterial cell-free preparations. Micrococcus luteus membrane fractions catalysed the prenylation of (251)
by C15-C4, prenyl pyrophosphates en route to m e n a q u i n ~ n e The
. ~ ~ chloroplast
~
envelope has been reported as the site of (25 1) prenylation by phytyl pyrophosphate
in phylloquinone b i o s y n t h e s i ~Several
. ~ ~ ~ genetic studies of bacterial menaquinone
biosynthesis have been d e ~ c r i b e d . ~Two
~ ~ -papers
~ ~ ~ report the formation of
plastoquinone (237) in spinachzg6and lettucesg7chloroplasts,
G. Katsui, Bitamin, 1981, 55, 305.
M. D. Collins and D. Jones, J . Appl. Bacteriol., 1981, 51, 129.
2no S. Ikenoya, M. Takada, T. Yuzuriha, K. Abe, and K. Katayama, Chem. Pharm. Bull., 1981,
29, 158.
281 Y . Haroon, M. J. Shearer, and P. Barkhan, J . Chromatogr., 1980, 200, 293.
282 Y . Haroon, M. J. Shearer, and P. Barkhan, J . Chromatogr., 1981, 206, 333.
283 P. B. Kingsley and G . W. Feigenson, Biochim. Biophys. Acra, 1981, 635, 602.
284 P. J. Quinn, Biochem. hr., 1980, 1, 77.
2n5 S. Pandian, S. Saengchjan, and T. S . Raman, Biochem. J . , 1981, 196, 675.
z86 R. R. Goewert, C . J. Sippel, and R. E. Olson, Biochemistry, 1981, 20, 4217.
287 R. R. GoewFrt, C . J. Sippel, M. F. Grimm, and R. E. Olson, Biochemistry, 1981, 20, 5611.
H. E. Knoll, FEMS Microbial. Lett., 1981, 10, 59, 63.
28B R. Meganathan, J . Biol. Chem., 1981, 256, 9386.
L. Heide and E. Leistner, FEBS Lett., 1981, 128, 201.
*B1 Y . Saito and K. Ogura, J . Biochem. Tokyo, 1981, 89, 1445.
2s2 G. Schultz, B. H. Ellerbrock, and J. Soll, Eur. J . Biochem., 1981, 117, 329.
J. R. Guest and D. J. Shaw, Mol. Gen. Genet., 1981, 181, 379.
zB4 R. Meganathan, R. Bentley, and H. Taber, J . Bacteriol., 1981, 145, 328.
28s H. W. Taber, E. A. Dellers, and L. R. Lombardo, J . Bacteriol., 1981, 145, 321.
8B6 J. Soll, M. Kemmerling, and G . Schultz, Arch. Biochem. Biophys., 1980, 204, 544.
2B7 K. G . Hutson and D. R. Threlfall, Biochim. Biophys. Acta, 1980, 632, 630.
278
278
Part II
STEROIDS
1
Physical Methods
BY D. N. KIRK
The Table beginning on p. 271 lists steroids whch have been the subject of X-ray
crystallographic studies during the year. Comment on the conclusions is limited
to only a few of the compounds.
X-Ray crystallographic study of synthetic (23S)-cholest-5-ene-3p,23,25-triol,
and comparison of the derived 23,25-dihydroxycholecalciferol(1) with a new
natural metabolite of vitamin D has established the configuration of the latter
compound.l Syntheses of the (25s)- and (25R)-isomers of 25,26-dihydroxycholecalciferol, using C 5precursors of known configuration to elaborate the sidechain, have established the configuration of the natural compound as (25s). The
configuration was confirmed by X-ray crystallographic analysis of the intermediate
compound (2).2
OAc
1
(4)
(3)
N. Ikekawa, T. Eguchi, Y.Hirano, Y.Tanaka, H. F. DeLuca, A. Itai, and Y.Iitaka, J . Chern.
SOC.,Chem. Commun., 1981, 1157.
R. Barner, J. Hubscher, J. J. Daly, and P. Schonholzer, Helv. Chim. A d a , 1981, 84, 915.
269
270
5a-~holestane-3,4-dione.~
The C- 17 configurations of the epimeric 17-ethynyl-14p-androstane- 14,17-diols
( 5 ) and (6) have been established by X-ray crystallographic s t ~ d y They
. ~ were
formed stereospecificallyby use of either LiC = CH or BrMgC = CMgBr (Scheme 1).
OH
/
CH
111
Scheme 1
(&)-17p-Hydroxy-8a-androst-4-en-3-0ne
crystallizes with molecules in two conformationally distinct forms.6 Ring A has the la-sofa conformation, but rings B
exist in two conformations, each deviating somewhat from the ideal twist and
characterized by small negative and positive torsion angles, respectively, about the
C-9-C-10 bond. Two polymorphic forms of 17~-acetoxy-6p-bromoandrost-4-en3-one exhibit markedly different crystal packings and solid-state i.r. spectra
although the conformations of individual molecules show only slight variation.
One polymorph comprises two conformers in I : 1 ratio, whereas the other contains
only a single conformer. It is concluded that in this case crystal packing has little
effect on molecular conformation, while causing changes in carbonyl stretching
frequencies. Crystalline cholesterol, with a bilayer structure, has hydrophilic
regions with parallel chains of hydrogen bonds. Side-chains exist in two distinct
conformations.8 The crystal habit of anhydrous cholesterol varies with solvent
27 1
Physical Methods
Ref.
Oestranes
17P-Acetoxyoestr-4-en-3-one
2a-Fluoro-17 p-hydroxyoestr-4-en-3-one
17p-Hydroxy- 17a-methyloestra-4,9,1 l-trien-3-one
17~-Hydroxy-8a,l0a-oestr-4-en-3-one
dl-3-Methoxy-8a,l4p-oestra-l,3,5(
10),9(ll)-tetraene-l4,17a-diolmonohydrate
17a-Ethynyl-l7~-hydroxyoestranes
: see pregn-20-ynes, below
13
14
15
16
17
Androstanes
17p-Acetoxy-6 P-bromoandrost-4-en-3-one
17p-Hydroxy-7 a-methylandrost-5-en-3-one
dZ-17/3-Hydroxy-8a-androst-4-en-3-one
(8-isotestosterone)
17-Methoxy-16,17-seco-8a,13a-androsta-4,9(1
l)-diene-3,15,17-trione
17@-(5-Methyltetrazol-1-yl)-7a-aza-~-homoandrost-5-eno[7a,7-d]tetrazol-3
p-yl
acetate
6
18
6, 16
19
20
17a-Ethynyl-l7~-hydroxyandrostanes:
see pregn-20-ynes, below
Pregnanes
16a,l7a-Cyclopropanopregn-4-ene-3,20-dione
16a,l7a-Cyclobutanopregn-4-ene-3,20-dione
lo
I1
21
22
N. Garti, L. Karpuj, and S. Sarig, Cryst. Res. Techno[., 1981, 16, 1111.
M. C. Attwell, T. F. Massiah, R. A. Vergottini, and P. Ziegler, Belg. Pat. 879 844 1980,
P. F. Lindley, M. M. Mahmoud, F. E. Watson, and W. A. Jones, Acta Crystullogr. Ser. B,
1980,36, 1893.
272
Compound
Ref
6a-Methyl-16
u , 17a-cyclohexanopregn-4-ene-3,20-dione
23
1 1 p,17a,21-Trihydroxypregn-4-ene-3,20-dione
(Cortisol)
24
1 1 ~,17a-Dihydroxy-21-iodopregn-4-ene-3,20-dione
24
21-Chloro-9a-fluoro-ll~-hydroxy-l6u,l7u-isopropylidenedioxypregn-4-ene3,20-dione
25
5a,14P-Pregn-20-yne-14,17a-diol
5
5a,14p,17P(H)-Pregn-20-yne-l4,17P-diol
5
18-Methyl-1l-methylene-19-nor-l7~(H)-pregn-4-en-20-yn-l7~-ol
26
17P-Hydroxy-l l ~-methoxy-l8-methyl-19-nor-17~(H)-pregna-4,9-dien-20-yn-3-one
27
17~-Hydroxy-l2-methyl-l7(3(H)-pregna-4,9,1
l-trien-20-yn-3-one
28
21-Bromo-9a-fluoro-1 1 p, 17aa-dihydroxy16P-methoxy-~-homo17-oxapregna39
1,4-diene-3,20-dione
Cholesterol
Cholesteryl hexanoate
Cholesteryl p-bromobenzoate
Cholest-5-ene-3
p,23(S),25-triol
2,4,6-Tribromocholest-4-en-3-one
(Z)-3~-Hydroxy-5(10)-secocholest-l(
lO)-en-5-one 3-p-bromobenzoate
3 ~,22(S),25(S),26-Tetrahydroxycholest-5-en-7-one
3,22,26-triacetate(2)
Brassinolide (3)
Spiro-lactone(4)(see text)
3a,7a-Dihydroxy-5
P-cholan-24-oicacid (chenodeoxycholic acid; high m.p.)
Deoxycholic acid-norbornadiene (2: 1) complex
Choleicacidinclusion complexes (see text)
8, 9
30
31
1
32
33
2
3
4
11
34
12
Cardenolides
24
e6
26
27
28
30
s1
32
33
34
36
36
35
36
37
38
39
40
41
Physical Methods
273
2 N.M.R. Spectroscopy
lH Spectra.-The total analysis of the IH n.m.r. spectrum of 11p-hydroxyprogesterone, reported briefly last year,42has now been described in full.43This is a
further illustration of the value of computer-controlled use of a 400 MHz spectrometer to obtain two-dimensional J spectra, and n.0.e. difference and decoupling
difference spectra, which provided all the lH chemical shifts and virtually all
geminal and vicinal coupling constants. Comparisons with the previously reported
findingP for 1-dehydrotestosterone acetate represent the first step in a correlation
of detailed n.m.r. and structural parameters which promises to have widespread
application in future studies on steroidal and terpenoid compounds. 220 MHz
spectra permit quantitative estimation of C-24 epimeric mixtures of 24-alkyl
A combination of procedures using IH n.m.r. allowed assignment of configurations to a series of 15,16,17-trisubstituted oestra- 1,3,5(lO)-triene~.~~
Coupling
constants between ring D protons were not alone sufficient, but were augmented
by chemical shift data, including the downfield shifts of methine proton signals on
reaction of hydroxy-groups with trichloroacetyl isocyanate. Spectra of protonated
forms of androst-4-en-3-ones, androsta-4,6-dien-3-one, and 17,17-dimethy1-18norandrosta-4,6,8(14)-trien-3-one in 80 % H2S04 indicate the presence of the
0-protonated species. The trienone was the only one of the compounds to undergo
vinyl proton exchange in 80% D2S04.46The presence of a 5-hydroxy or particularly a 5-acetoxy substituent in either 5a- or 5p-steroids causes deshielding
effects on neighbouring protons (at C-4 and 6a) which can be useful in structural
assignments.4
Although aldosterone exists in the crystalline state in the 1 1p, 18: 18,2O-diepoxy20-hydroxy form (7), and in solution as a mixture containing both the diepoxy
form (7) and the 11p, 18-hemiacetal-20-0x0 form (8) in substantial proportions,
n.m.r. and i.r. data show that 21-deoxy-3a,5p-tetrahydroaldosteroneexists in
solution essentially in the 11p, 18-hemiacetal-20-0x0form (9), with two epimers at
C-18 in the ratio 5 : 1.48 3a,5P-Tetrahydroaldosterone itself, however, is similar to
aldosterone in solution, where the n.m.r. spectrum indicates the presence of forms
(10) and (1 1) in ca. 1 : 1 ratio.49
s7
s8
38
A. Messerschmidt, E. Hoehne, and R. Megges, Cryst. Struct. Commun., 1981, 10, 157.
A. Messerschmidt, E. Hoehne, and R. Megges, Cryst. Struct. Commun., 1981, 10, 399.
E. Hoehne, A. Messerschmidt, B. Streckenbach, and I. Seidel, Cryst. Struct. Commun., 1981,
10,415.
40
41
4s
44
47
48
G. Reck, A. Messerschmidt, and R. Megges, Cryst. Struct. Commun., 1981, 10, 637.
E. Hoehne, A. Messerschmidt, R. Megges, and I. Seidel, Cryst. Struct. Commun., 1981,10,407.
Terpenoids and Steroids, ed. J. R. Hanson (Specialist Periodical Reports), Royal Society of
Chemistry, London, 1981, Vol. 11, p. 173.
L. D. Hall and J. K. M. Sanders, J. Org. Chem., 1981,46, 1132.
P. L. Chiu and G. W. Patterson, Lipids, 1981, 16, 203.
B. Schonecker, D. Tresselt, G. Schubert, and K. Ponsold, J . Prakt. Chem., 1981, 323, 207.
H. Takagi, M. Kokuryo, T. Miura, and M. Kimura, Bunseki Kugaku, 1981,30, 191.
M. Lj. MihailoviC, L. Lorenc,V. PavloviC, and H. Fuhrer, Helv. Chim. Actu, 1981, 64, 1032.
D. R. Crump, D. N. Kirk, and B. W. Miller, J. Chem. Soc., Perkin Trans. 1, 1980, 2597.
D. N. Kirk and B. W. Miller, J. Chem. SOC.,Perkin Trans. 1. 1980. 2818.
274
OH
P
(9) R
(10) R
=H
= OH
(11)
OH
The effect of the lanthanoid shift reagent [Ho(fod),] on spectra of sterol 3acetates is unusual. Induced shifts with this reagent are normally upfield, and the
C-19 and C-18 proton signals conform, although only weakly in the latter case.
The peculiarities lie in downfield shifts of the signals of side-chain methyl protons.
Moreover the C-26 and C-27 methyls are rendered non-equivalent by [Ho(fod)J,
and (24R)- and (24S)-24-methyl sterols are easily distinguished by the methyl
shifts.5oLanthanoid-induced shifts of methyl signals are reported for a series of
sterols with various ring and side-chain structures and substituents.61Jj2
13C Spectra.-An
n.m.r. technique53 for studying 13C-13C spin-spin coupling at
natural abundance offers a remarkable way of establishing the carbon-carbon
connectivities within an organic framework. Based upon the principle of doublequantum coherence, it suppresses the strong signals from isolated 13C nuclei and
reveals the weak 13C satellite spectrum. A complex pulse sequence (at 50 MHz)
and a two-dimensional Fourier transformation affords a spectrum with the 13C
satellite lines in the F, dimension and the corresponding double-quantum frequencies in the Fl dimension. Directly coupled 13C resonances generate the same
double-quantum frequency, and so can be recognized. Application of the technique
to 5a-androstane shows that it is capable of detecting even the complex connectivities within this four-ring system.63
Pulse sequences used to induce lH-13C polarization transfer (PT), with suitably
chosen delays (A) before data acquisition, provide a simple and reliable way of
separating 13C resonances according to the number of attached
In an
illustration for cholesterol, the seven CH carbons are displayed with A = (U)-l
bo
61
6s
6a
b4
Physical Methods
275
= 3.8 ms. When A = 3(4J)-l = 5.7 ms, CH and CH3 signals appear in-phase and
CH2 signals 180" out-of-phase (inverted). Spin-echo Fourier transform (SEFT)
experiments which simplify 13C n.m.r. spectra to singlets offer another method for
distinguishing methyl, methylene, methine, and quaternary carbons which is
superior to off-resonance decoupling for complex molecules, illustrated by application to cholester01.~~
Cholesteryl acetate has been used as a model to demonstrate
the indirect measurement of proton relaxation rates by 'INEPT' polarization
transfer to directly bonded 13C nuclei;56direct measurement of proton Tl values is
impractical except for those few signals which are well separated from the crowded
methylene envelope.
Steroidal and other rigid alcohols have been used to derive a four-parameter
equation for the calculation of 13C chemical shifts due to substitution by the OH
Calculated 13C chemical shifts for all the likely saturated sterol sidechains with from seven to eleven carbon atoms have been tabulated and compared,
where possible, with published data.58 Good agreement is found in most cases,
with standard deviations of ca. 1 p.p.m. Only C-20, attached to the steroid nucleus,
showed serious deviations (ca. + 5 p.p.m.) from calculated values. The results
will be useful in future structural assignments of new sterols.
The aromatic ring of oestradiol or oestrone methyl ether readily forms a tricarbonyl chromium (0) complex in which the 13C signals from the aromatic ring
are shifted strongly upfield (by ca. 14-34 p.p.m.). Smaller upfield shifts for other
carbon atoms close to the aromatic ring (e.g. 2 p.p.m. for C-6) have been used to
settle uncertainties in the earlier literature concerning the assignments of individual
13C resonance^.^^ 13CN.m.r. spectra discriminate between A4- and A5-isomers of
spiro-3-steroidal ketone derivatives; thiazolidine formation results only in the
(3R)-isomer (12), whereas hemithioacetals are mixtures of the (3R)- and (3s)forms.60
(12) R = H or C0,Et
lSCN.m.r. data for a series of A5- and saturated 4,4-dimethyl-3-oxo-steroids and
related compounds reveal the distorting effect of A5-unsaturation on rings A and
B, and the effects of compression between the 4p- and C-19 methyl groups.61Longstanding uncertaintiess2 about the regioselectivity of the Beckmann, Schmidt, and
Baeyer-Villiger reactions of 3-keto-steroids and their derivatives have at last been
resolved by a 13C n.m.r. study of the reaction products and of the pure lactams or
sK
s7
68
IJO
276
(13)
Assignments are proposed for the 13C n.m.r. spectra of some natural and
synthetic hormonal steroids, including the acetates of cortisone, cortisol, prednisone, prednisolone and some of its derivatives [6a-Me; 9a-F, 16a-Me (dexamethasone) ; 9a-F, 16p-Me (betamethasone) ; 6a-F, 16a-Me (paramethasone)], and
a few miscellaneous compounds.6613C N.m.r. assignments have been revised for
p-sitosterol and its 3 - g l u ~ u r o n i d eand
~ ~ ~a reassignment of signals from ring F is
reported for (25S)-spiro~tans.~~
H and 13Cn.m.r., with n.0.e. experiments, have
established the structures (1 5 ) and (1 6) for gomphoside and afroside;69 other related cardenolide glycosides have also been studied. 70
(15) R
(16) R
H
OH
1980, 2169.
Physical Methods
277
phytosterols 24-methylenecholesterol,
lSCN.m.r. data are reported for the A24(2s)
fucosterol, isofucosterol, and cycloeucalenol acetate, 71 for hecogenin acetate,
11-oxotigogenin, 6-methyldiosgenin acetate, botogenin, and other s a p o g e n i n ~ , ~ ~
for a series of 6,23-dihydroxylated sapogenins [e.g.solaspigenin (17), as triacetate],75
and for 29 withanolides and other polar c z s steroids.74
19F and 2H Spectra.-Substituent effects are reported on the lSF n.m.r. of sterol
trifluoroacetates.75 2HN.m.r. has been used to study the state of labelled cholesterol
in multibilayers of egg yolk lecithin containing digitonin. 78
3 Chiroptical Phenomena
3
%OF-
pa
Positive
+Yo
H
O
(+)c.d. at ca. 230 nm
C.d. curves for the imines (Schiff bases) formed from some keto-steroids and
2-phenylethylamine, tyramine, or hexanamine show n+x* bands generally of the
same sign as those of the corresponding ketones, but near 235 nm.80Additional
A. G. McInnes, J. A. Walter, and J. L. C. Wright, Org. Mugn. Reson., 1980, 13, 302.
M. H. A. Elgamal, M. S. Bedour, and H. Duddeck, Indian J. Chem., Sect. B, 1980,19, 549.
A. K. Chakravarty, S. C. Pakrashi, and J. Uzawa, Cun. J. Chem., 1981,59, 1328.
'* H. E. Gottlieb and I. Kirson, Org. Mugn. Reson., 1981, 16, 20.
76 T. Iida, T. Tamura, and T. Matsumoto, Nihon Duiguku Kogukuba Kiyo Bunrui A , 1980,21,223.
T . Akiyama, S. Takagi, U. Sankawa, S. Inari, and H. Saito, Biochemistry, 1980, 19, 1904.
'I7 A. F. Beecham and D. C. Collins, Aust. J. Chem., 1980,33, 2189.
7 8 C.-Y. Byon, M. Gut, and V. Toome, J. Org. Chem., 1981, 46, 3901.
N. Haroda, J. Iwabuchi, Y. Yokota, and H. Uda, J . Am. Chem. SOC.,1981,103, 5590.
H. C. Price, D. G. Sawutz, T. E. Wagner, and C. Shewmaker, Tetrahedron, 1981, 37, 1679.
71
10
278
bands at 218-219 nm are attributed to the aromatic lLa transition for derivatives
of imines containing an aromatic group. Imines derived from testosterone or
oestrone showed additional c.d. features associated with the ap-unsaturation and
the aromatic ring A, respectively.
3 p-Acetoxyeti-5-enic esters have been used to resolve enantiomers of perhydroanthracenol (1 8)s1 and perhydrophenanthren-4-01( 19y2 as tricyclic systems for
study of the c.d. characteristics of the corresponding ketones.
(18)
(19)
C.d. and u.v.-visible spectra are reported for solutions of the antitumour triterpenoid tingenone in aqueous sodium deoxy~holate,~~
and c.d. curves have been
recorded for morphine and related alkaloids in cholesteric liquid crystals.84
4 Infrared Spectroscopy
Rather little attention is normally paid to the intensities of i.r. absorption bands
of steroids, but two papers now detail interesting variations in v(C=O) for primary,
secondary, and tertiary acetoxy-gro~ps,~~
and in v(C=O) and v(C=C) for variously
substituted progesterone derivatives.s5p861.r. absorption intensities of progesterone
derivatives have been studied with a Fourier-transform ~pectrometer.~~
-2H
8a
8a
84
87
Physical Methods
279
by the other cleavages illustrated. Hydrogen transfers during such processes have
been determined by specificdeuterium labelling. The very unusual loss of 44 mass
units from the 4,6-dienone involves expulsion of C2H40instead of the usual keten,
through a complex rearrangement which transfers the hydrogen atoms from C-4
and C-9 to the eliminated fragment.
5a-Androstane-7,17-dionesundergo a major and very strange mass spectral
fragmentation to give an ion with m/z = M - 47, irrespective of substitution in
~ ~
measurements indicate loss of CH302,and preliminary
ring A . High-resolution
experiments with deuteriated material (at 6, 6, 8P, 16, 16) indicate loss of CHD,02.
The nature of the fragmentation is as yet unknown. Trienes of the vitamin D
series show competition between two fragmentations with very similar energy
requirements. 5,7,10(19)-Trienes (20), irrespective of configuration, favour rupture
of the 7,8-bond, whereas 5(10),6,8-trienes(21) break preferentially across ring c.
(20)
(21)
In each case the resulting ions may fragment further. This very detailed study includes measurements of appearance energies of ions and ionization energies of
derivatives and isomers of vitamin D.90
Cleavage of side-chain trimethylsilyl ethers in the pregnane series is complicated
by Me,& exchange between oxygen atoms at C-17 and C-20.91Mass spectral data
are reportedg2for derivatives of 5?-pregnane-3a,17a,20a-trioI silylated selectively
at the 3- and 20-positions with either t-butyldimethylchlorosilane or t-butyltetramethylenechlorosilane and fully silylated by vigorous treatment with trimethylsilylimidazole. The mass spectral fragmentations of 3-methoxyoestra-l,3,
5(10)-trienes with hydroxy substitution at C-14, -15, -16, or -17 show distinctive
patterns, although the configuration of the hydroxy-group matters only at C-14 or
C-15,O3 Ions resulting from loss of water in the mass spectra of spirostan-3-01s
isomeric at C-3 and C-5 show characteristic relative intensities which can be
helpful in assigning configurations.94 The mass spectral fragmentation of 3a,5srcyclo-6-0x0-steroidsand other cyclopropyl ketones is a complex process.95 Selective
deuterium IabeIIing has shown that the [M - H20]+ ion from 3a,5-cyclo-5acholestan-6-one is derived from hydrogen atoms located at the 2P- and 9a-positions;
Bo
OS
oI
g6
280
the detailed mechanism is not yet clear. Characteristic fragmentations are reported
for other 3,5-cyclocholestanyl derivatives (@-OH, -OMe, -OEt, -OBU'),~~
for the
corresponding cholesteryl
and for the ring B-hydroxylated 3P-acetoxy~-homo-5a-cholestanes.97 An interactive system of computer programs for the
elucidation of structures from mass spectral data is illustrated with reference to
some marine sterols. 98 The program generates all structural isomers compatible
with the data, and evaluates them in terms of biological plausibility.
Chemical Ionization Mass Spectrometry (CIMS).-Monohydroxylated cholesterols
are differentiated by h.p.1.c. and CIMS, with ammonia as reagent gas. Trimethylsilyl ethers of side-chain hydroxylated cholesterols fragment in CI mass spectra
with methane to give [C,H,,OSiMe,]+ ions characteristic of the site of hydroxyl a t i ~ nCIMS
. ~ ~ with ammonia as the reagent gas proved highly efficient for producing [ M + NH,]+ ions as base peaks from a series of methyl ester-acetate
derivatives of bile acids. Minor peaks permitted selective detection of 3-keto or
unsaturated bile acids.looAnother paper lol describes the application of CIMS to
the identification of side-chain hydroxylated cholesterols, sterol esters, bile acids,
and even underivatized steroid glycosides, and a CIMS study of (20s)-protopanaxadiol (22) and (20s)-protopanaxatriol (23) is reported.lo2
(22) R = H
(23) R = a-OH
Further
of the application of negative ion CIMS to steroids have
shown that use of Freon 12 (CF,Cl,) as reagent gas provides very satisfactory
[A4 + Cl]- ions, even from polyfunctional compounds like prednisolone which are
prone to fragmentation. Bile acid chlorides, with CH, as reagent gas, gave
[ M + OH]- peaks (doublets, containing chlorine).lo4Negative ion CI (with OH-)
provides mass spectra of underivatized steroid glucuronides (RO-gluc), showing
abundant [ M - HI- and [ROI- ions. lo5
Gas Chromatography-Mass Spectrometry (g.c.-m.s.).-Syntheses
of twenty
different steroids (oestrogens, androgens, progesterone, and corticosteroids and
their metabolites) with from two to four deuterium atoms per molecule have
F. J. Brown, I. J. Massey, and C. Djerassi, Can. J. Chem., 1980, 58, 2592.
F. Turecek and L. Kohout, Collect. Czech. Chem. Commun., 1980, 45, 2433.
N. A. B. Gray, A. Buchs, D. H. Smith, and C. Djerassi, Helv.Chim. Acta, 1981, 64, 458.
Y.Y.Lin, C.-E. Low, and L. L. Smith, J . Steroid Biochem., 1981, 14, 563.
loo B. R. DeMark and P. D. Klein, J . Lipid Res., 1981, 22, 166.
lol Y . Y . Lin, Lipids, 1980, 15, 756.
Ioa M. Desage, M. Becchi, M. Trouilloud, and J. Raymaud, Planta Med., 1980, 39, 189.
Io3 H. Fujiwara and A. K. Bose, Pract. Spectrosc., 1980, 3, 329.
lo4 H. Fujiwara and A. K. Bose, Pract. Spectrosc., 1980, 3, 373.
Io6 A. P. Bruins, Biomed. Mass Spectrom., 1981, 8, 31.
O7
Physical Methods
28 1
A review of h.p.1.c. of steroid hormones traces the history of the subject, and
describes methods for h.p.1.c. analyses of the main classes of steroids in biological
fluids and pharmaceuticals.112
H.p.1.c. of adrenal 18-hydroxy-steroids (e.g. 18-hydroxycorticosterone, which
exists as the 18+20-hemiacetal) is complicated by their labile nature. Normal
handling, without special precautions, may result in the formation of 20-alkoxyderivatives, dehydration products, or dimers. Procedures are now described113for
the extraction and reversed-phase h.p.1.c. of these compounds from biological
sources without the appearance of artefacts. H.p.1.c. separations of aldosterone
and its metabolites from biological sources have distinguished between known
derivatives and some unidentified reduced and polar metabolites, which may have
physiological significance.l14 H.p.1.c. separations and retention data are reported
for all the isomeric reduced metabolites of progesterone, where combinations of
normal and reversed-phase columns can resolve complex mixtures of biological
origix~,l~~*ll~
and for the steroid hormones in adrenal and testicular
An extensive review (155 references) of the separation and determination of D
vitamins by h.p.1.c. includes discussion of the problem of instability, and a detailed
lo6
282
NMe,
(25) R = O-steroid
(24)
(26) R = CN
Practical problems of chemical reaction detection following elution from
h.p.1.c. columns have been examined with particular reference to the formation of
fluorescent derivatives of corticosteroids. Steroidal 4-en-3-ones are allowed to
react, for example, with isonicotinoylhydrazide, in an air-segmented tubular flow
system to minimize eluate mixing or band-broadening. Following de-aeration, the
solution then passes through a fluxescence detector, giving a system sensitive to
ca. 100 ng samples.122Dansyl derivatives have been used for h.p.1.c. of equine
oestrogens, with fluorescence detection ; the 17-keto-oestrogens were separated
after reduction with bor01iydride.l~~
4-Dimethylaminonaphthalene-1-carboxylates
(25), prepared from steroidal alcohols by reaction with the acyl cyanide (26), may
be used for h.p.1.c. with absorbance and fluorescence detectors.lZ4
H.p.1.c. procedures are described for the separation of cardiac glycosides,125
metabolites of ecdysone,126and solanum and veratrum alka10ids.l~~
Sterol intermediates in cholesterol biosynthesis have been resolved by a threestep chromatographic procedure.128A detailed study of reversed-phase thin-layer
chromatography of a wide variety of steroids (on silanized silica gel) includes a
correlation of ARM values of substituents with hydrophobicity
R.Vanhaelen-Fastre and M. Vanhaelen, Chromatogr. Sci., 1981, 16, 173.
D.A. Seamark, D. J. H. Trafford, P. G. Hiscocks, and H. L. J. Makin, J . Chromatogr., 1980,
Ile
llB
197,271.
G.Jones, J . Chromatogr., 1980, 221, 27.
121 G. J.-L. Lee, R. M. K. Carlson, and S. Kushinsky, J . Chromatogr., 1981, 212, 108.
12% E. Reh and G. Schwedt, Fresenius' 2. Anal. Chem., 1980,303, 117; G. Schwedt and E. Reh,
120
Physical Methods
283
7 Immunoassays
Those immunoassays which depend upon a tracer attached by a bridge to the
steroid have a potentially serious disadvantage compared with the use of the
tritium-labelled steroid as tracer. Antibodies produced in response to a steroidprotein complex (antigen) may recognize not only the steroid but also the bridge
by which the steroid-protein linkage is achieved. If the same bridging group links
the steroid to the moiety which ultimately acts as tracer, competition between the
natural steroid and the steroid-tracer complex for antibody binding may excessively favour the tracer if the antibody recognizes the bridge as well as the steroid.
The resulting preferential binding of the tracer complex by the antibody reduces the
sensitivity of the immunoassay.
Bridge recognition has proved to be a problem when the tracer is the y-emitting
p251]iodotyrosinelinked to the steroid via a succinoyl bridge. For a [lZ5I]-based
assay of androstenedione, using an antibody to the ester-linked 19-succinoyl-BSA
complex (27), bridge recognition has been reduced to produce a sensitive assay by
employing an ether-linked bridge from C-19 to tyramine as the iodinated label
(28)?%
NH-BSA
(27)
(28)
The principle of bridge heterology has been applied also to cortisol enzymeimmunoassay, by linking !3-galactosidase through a variety of bridges to C-4
(29).134A shorter bridge than that used for the antigen gave improved sensitivity,
but a longer bridge gave no advantage.
Antibodies with high specificity for 4-hydroxy-oestrogens have been obtained
by use of a 17-(O-carboxymethyl)oxime-BSA conjugate as antigen; the same hapten
combined with [1251]iodohistaminewas employed as radioactive tracer.135Antisera
K. Hostettmann, K. M. Hostettmann, and 0. Sticher, J. Chromatogr., 1980, 202, 154.
R. R. Heath, J. R. Jordan, and P. E. Sonnet, J . High Resolut. Chromatogr. Chromatogr.
Commun., 1981, 4, 328.
13a A. B. Benko and V. Mann, Anal. Lett., 1980, 13, 735.
G. D. Nordblom, R. Webb, R. E. Counsell, and B. G. England, Steroids, 1981,38, 161.
13* H. Hosoda, N. Kawamura, and T. Nambara, Chem. Pharm. Bull., 1981, 29, 1969.
lab D. Berg and E. Kuss, 2. Physiol. Chem., 1980, 361, 1743.
13*
284
---OH
(29)
R = SCH,CO,H, or SCH,CH,CO,H, or SCH,CH,0COCH,CH,C02H,
or OCOCH,CH,CO,H
for testosterone and 17P-hydroxy-5a-androstan-3-one(DHT) having low crossreactivities have been obtained by pretreatment of mice with the cross-reacting
steroid coupled via a 15~-carboxymethylmercapto
bridge to a copolymer of Dglutamic acid and D-lysine, before immunization with testosterone-protein or
DHT-protein complex in the usual
Radioimmunoassay of solasodine and
related plant alkaloids is rep0~ted.l~
New enzyme-immunoassays include use of the P-galactosidase conjugate of
1 1a-hemisuccinoyloxyprogesteroneas tracer for a sensitive assay of progesterone
in bovine milk,13*one for the synthetic anti-inflammatory steroid betamethasone,
using the 3-(O-carboxymethyl)oxime-~-~-galactosidase
conjugate as labelled
antigen and 4-methylumbelliferyl-~-D-galactoside
as a fluorescent tracer,139 and
a method for the quantification of d i g o ~ i n . l ~ ~
A fluorescence-quenching immunoassay for cortisol, based upon the use of a
tracer comprising fluorescein linked to the steroid via a 21-amino-group, claims a
good correlation with radioimmunoassay results. Separation of free and bound
fractions is unnecessary with this
Chemiluminescence-labelling has been applied to the immunoassay of oestriol
16a-glucuronide by synthesis of the N-aminobutyl-N-ethylisoluminolderivative
(30), which emits light when oxidized with H,O,-microperoxidase. Binding of the
conjugate (30) to an antibody for the steroid enhances light emission. Competitive
13
Physical Methods
285
binding of oestriol 16a-glucuronide itself by the antibody inhibits the enhancement of emission, providing the basis of a very sensitive assay.142
A direct chemiluminescence assay for urinary pregnanediol 3-glucuronide
employs the isoluminol conjugate (3 1) as tracer, with monoclonal antibodies.
Specificity is excellent, the assay being sensitive to 30 pg.lP3A solid-phase chemiluminescence assay for plasma progesterone uses as tracer the isoluminol conjugate
(32) derived from 1 1a-hydroxyproge~terone.~~~
\)...OH
(32)
Hydroxy-steroid dehydrogenases co-immobilized on Sepharose 4B with
NADH : FMN oxidoreductase and luciferase provide light-emission assays for
picomole levels of androsterone or testo~terone.'~~
8 Miscellaneous
The nitroxide (33) closely resembles cholesterol in its physical and biological
properties, and has been used as a spin-labelled analogue of cholesterol to investigate cholesterol-protein interactions in human high-density 1ip0protein.l~~
The
fluorescent cholesterol analogue N-(7-nitrobenz-2-oxa-1,3-diazole)-22-amino-23,
24-dinorchol-5-en-3p-01(34) has been used as a substrate for lecithin : cholesterol
F. Kohen, J. B. Kim, G. Barnard, and H. R. Lindner, Steroids, 1980, 36, 405.
Z. Eshhar, J. B. Kim, G. Barnard, W. P. Collins, S. Gilad, H. R. Lindner, and F. Kohen,
Steroids, 1981, 38, 89.
14* F. Kohen, J. B. Kim, H. R. Lindner, and W. P. Collins, Steroids, 1981, 38, 73.
J. Ford and M. DeLuca, Anal. Biochem., 1981, 110, 43.
u6 J. F. W. Keana, T. Tamura, D. A. McMillen, and P. C. Jost, J . Am. Chem. SOC.,1981, 103,
lQB
4904.
286
(33)
(34)
acyltransferase, and as its linoleate ester was incorporated into low-density lipop r o t e i n ~ .A
~ ~fluorimetric
'
assay for ecdysteroids is sensitive to 10-l' rn01e.l~~
Esters of oestradiol and other steroids with ferrocenecarboxylic acid149have
been converted into [103R~]ruthenocenecarboxylatesby exchange with [lo3Ru]RuC13,150 for use as y-emitting tracers in organ-affinity s t ~ d i e s . l ~ ~
Improved
J~l
yields were subsequently obtained by esterifying the steroid with [103R~]ruthenocenecarboxylic acid chloride obtained via metal exchange in o-chlorobenzoylferr0~ene.I~~
lo3Ruprovides a useful alternative to 1251as a y-radioactive tracer.
The use of tetrazolium salts in the analysis of corticosteroids and other pharmaceuticals has been reviewed.153Polarographic study of cholesterol, 7-dehydrocholesterol, Vitamin D3,and related compounds has revealed differences in oxidation potentials which were correlated with molecular shape.154The measured
dipole moment of cholesterol in toluene (1.55 D at 40 "C) increases at lower
temperatures owing to molecular aggregati~n.'~~
Equilibration of the diastereoisomers of cholestane (Pt-C at 600 "C) has shown the most stable to be (20R)and (20S)-5a,14p, 17P-ch01estanes.l~~
A review of the use of torsion angle notation
to describe stereochemical processes in cyclic molecules includes some steroid
exam~1es.l~~
An interactive computer programme (SCRIPT) which can provide
conformers and their relative energies has been applied to steroid molecules by
drawing their formulae on a cathode ray tube.15*
The relationship between crystal packing and liquid crystalline ordering has been
discussed for cholesteryl n-alkanoates with between two and eighteen carbon
atoms in the acyl group.159The mesomorphic transition temperatures of cholesteryl
oleate, linoleate, and linolenate are pressure-dependent.160The thermal stabilities
147
14*
lSo
151
15a
153
150
168
lS7
ld0 M.
Nakahara, K. Maeda, and J. Osugi, Bull. Chem. Sac. Jpn., 1980, 53, 2499.
Physical Methods
287
of the cholesteric mesophase of esters of cholesterol with a series of m- and p substituted benzoic acids (PhXC6H,C02H) depend upon the nature of the linkage
(X), and decrease in the order CO > 0 > S > CH2.161A further study has been
reported16aon the blue phases163of cholesteryl nonanoate and myristate.
A bibliography, Fifty years of oestrogen analysis, is available in rni~rofiche.16~
la
m2
le3
Ref. 42, 1980, Vol. 10, p. 211; 1981, Vol. 11, p. 185.
R. W. A. Oliver, C. T. Brooks, and J. E. Sugden, Biological Materials Analysis Unit, University of Salford M5 4WT, U.K., 1980.
le4
2
Steroid Reactions and Partial Syntheses
BY 6. A. MARPLES
1 General
Reviews on the use of DMSO in synthesis,l functionalized polymers as heterogeneous reagents,2 methods of fl~orination,~
and the application of the torsion
angle notation in 5-, 6 ,and 7-membered rings4 all contain steroidal examples.
2 Alcohols and Carboxylic Acids and their Derivatives, Halides, and
Epoxides
Solvolysis, Substitution, Elimination, and Reduction.-Studies on the solvolysis of
3~-tosyloxy-5,10-secocholest-l(
lO)-en-5-ones have been reported5 and are complementary to those reported earlier6 on similar compounds. Considerable double bond
participation was observed for the 2-3a-compound (I), the E-3a-compound (2),
&
TsO
288
289
and the E-3p-compound (3) but not for the 2-3p-compound (4). A study' of the
conformations of esters of 2-3E-hydroxy-5,lO-secocholest1(lO)-en5-ones and the
related 3,5-diketone is also relevant to this work.
Diethylazodicarboxylate-Ph,P mediated reactions have been reviewed and
steroid substitution reactions were included.* Reactions of 3-O-acetyldigitoxigenin
with SF4-KF gave the 14~-fluoro-derivative. Sa-Cholestan-3p-01 was converted
into 3a-cyano-cholestanol by treatment with NaCN-Me3SiCI (2 equivalents) and
NaI (catalyst) in DMF-MeCN.1 Acetolyses of 4-, 6a-, and 6p-bromocholest-4-en3-ones catalysed by AgOAc gave the 6-acetoxy-compounds in contrast to similar
reactions with KOAc where 2- and 4-acetoxy-compounds may result.ll In those
cases where the S,l mechanism operated the attack on the mesomeric cation at C-6
was largely stereoelectronically controlled 6p. Controlled alkaline hydrolysis of
16a-bromo- 17-keto-steroids with NaOH in aqueous pyridine gave the 16a-hydroxy17-keto-compounds and no rearranged ketols.12J3 Studies with l8O-1abelled base
suggested that epimerization of the 16~-bromineis followed by its direct displacement,12 21-Mesyloxy-20-keto-17-hydroxy-compounds were reported to react
smoothly with thiolate anions [e.g. thiolacetate and O-ethylxanthate] in contrast
with other nitrogen and oxygen nu~leophiles.~~
The 17-hydroxy-group appeared to
catalyse the reactions.
Calculations suggested that the preferred elimination of 3-substituted androstanes to give A2- rather than A3-compounds could not be explained alone by
differences in calculated heats of formation. Differences in the energies of the
respective transition states appeared to be irn~0rtant.l~
Dehydration of the cyclobutanol (5) gave largely the exo-alkene (7) but the tetradeuterio-compound (6)
(9)
H. Fuhrer, L. Lorenc, V. PavloviC, G . Rihs, G. Rist, J. Kalvoda, and M. Lj. MihailoviC,
Helv. Chim. Acta, 1981, 64, 703.
0. Mitsunobo, Synthesis, 1981, 1.
A. Haas and D. Kortmann, Chem. Ber., 1981,114,1176.
l o R. Davis and K. G. Untch, J. Org. Chem., 1981, 46, 2985.
l1 T. Koga and Y . Nogami, Tetrahedron Lett., 1981, 22, 3075.
l2 M. Numazawa and Y . Osawa, J. Am. Chem. SOC.,1980,102, 5403.
l3 M. Numazawa and Y . Osawa, Steroidr, 1981,38, 149.
l4 S. S. Simons, M. Pons, and D. F. Johnson, J . Org. Chem., 1980, 45, 3084.
l5 W. Gschwendtner, V. Hoppen, and H. J. Schneider, J. Chem. Res. (S), 1981, 96.
290
gavel6 a greater proportion of the endo-alkene (8) which was used to prepare 18oxoprogesterone (9). Hydrogenolysis of 3- and 24-fluoro-compounds was effected
with potassium and dicyclohexyl-18-crown-6 in toluene or dig1yme.l'
Epoxide Ring 0pening.-A detailed study has been reported for the Li-NH3
reductions of la,2a-epo~y-h~~~-3-keto-steroids.~~
Reproducible and optimum
yields of the 1a,3~-dihydroxy-A5-compounds
were obtained by using an initial
reduction with a stoicheiometric quantity of Li-NH, followed by protonation with
NH4Cl and repeated alternating treatment with NH4C1 and Li. Diaxial chlorohydrins were formed from the reactions of 5,6-epoxy-cholestaneswith trimethylsilyl
ch10ride.l~The participation of 19-substituents in the HBr- and HC104- catalysed
cleavages of 5a,6a-epoxycholestanes was compared20with similar reactions of the
3 P-acetoxy-derivati~es,~~
The absence of the 3P-acetoxy-group was significant in
that in the reaction of the 19-acetoxy-5a,6a-epoxide(10) with HBr, the participation
(10) R
AC
(11) R = Me
of the 19-acetoxy-group was only partially rather than fully suppressed. In the
reaction of the 19-methoxy-5a,6a-epoxide(1 1) with HBr, no participation of the
methoxy-group was observed and only the normal bromohydrin was formed. A
study of similar reactions of 3cc,4a- and 4a,5a-epoxycholestanes was reported.22
The effects of a-acetoxy- and cc-hydroxy-groups on the aqueous HCIO,-catalysed
ring opening were reported for the l-oxo-4,5-epoxycholest-2-enes(12) and the
(12) R'=
R'
R'
R'
R'
=
=
=
=
R2= H
OH, R2= H
H, R2= OH
OAC, R2= H
(13) R
H, Me, or Ac
H, R2= OAC
3p,6p-disubstituted-4,5-epoxycholestanes(1 3).23 In the former, it was suggested
that the polar group repulsions in the transition state were important and it was
M. Mujano, J. Org. Chem., 1981, 46, 1854.
T. Ohsawa, T. Takagaki, A. Haneda, and T. Oishi, Tetrahedron Lett., 1981, 22, 2583.
A. Fiirst, L. Labler, and W. Meier, Helv. Chim. Actu, 1981, 64, 1870.
l o M. Husain and N. H. Khan, Synth. Commun., 1981, 11, 185.
2o P. KoEovsky and V. Cerny, Collect. Czech. Chem. Commun., 1980, 45, 3190.
21 See 'Terpenoids and Steroids' ed. J. R. Hanson (Specialist Periodical Reports), The Royal
Society of Chemistry, London, 1981, Vol. 10, p. 216.
22 P. KoEovsky and V. terny, Collect. Czech. Chem. Commun., 1980, 45, 3199.
M. Ishiguro, H. Saito, Y. Hirano, and N. Ikekawa, f. Chem. Soc., Perkin Trans. I , 1980,2503.
l6
l7
29 1
observed that the 6p-acetoxy-group prevented cleavage of the 4a,5a- and 4p,5pepoxides, while in the latter, the participation of the 3p- or 6p-acetoxy-groups
in the ring opening process was of particular importance and it was noted that the
4p,5@-epoxideswere unreactive.
Esters, Carboxylic Acids, and Ethers.-The rates of hydrolysis of 38- and 68acetoxy-4E,5E-epoxides and la-acetoxy-2p,3P-epoxides were observed to be
accelerated relative to those acetates not containing a neighbouring epoxide
Bile acid methyl esters were readily prepared from the carboxylic acids by
reaction with methanol in the presence of toluene-p-sulphonic
Bile acids were
readily converted into the amino-amides (14) by successive reaction with BulN-
25
292
OR
{gH
OR
---0COH
(18) n
1 or 3
3 Unsaturated Compounds
52
a3
34
35
293
alkenes and 3-oxostigmasta-4,22-diene gave the aldehyde (22) in high yield using
solvent Red 23.36 Ozonolysis of hl6-20-oxopregnanes in CH2C12-lower alkanol
followed by reductive work-up with Me,S gave the novel 16P-alkoxy-17aahydroxy-D-homo-17-oxapregnanes (23).37
dcHo
o&OR /
(22)
(23) X = AcO, C1 or Br
Addition of HOBr to the 3p-acetoxy-oestr-4-ene (24) gave the 4p-acetoxy-5~bromo-3 p-hydroxy-compound (25) resulting from participation of the neighbouring
acetoxy-group.38 Equilibration of the major product (25) or its 3p-acetoxy-4phydroxy-isomer (26) led to a mixture containing largely the latter (ca. 85%).
Participation of 19-substituents in the additions of HOBr to A5-cholesteneswas
compared39 with that in the similar reactions of the 3p-a~etoxy-analogues~~
and the
AAJ
AcO
(25) R1= H, R2 = AC
(26) R1= Ac, R2 = H
(24)
AcO
&
HO
ir
(28)
@
Ho OR
(29) R
(30) R
36
s8
39
*O
=H
= AC
OH
(31)
(32)
294
CN
(33)
(34)
(35) R = a-OH, H
R = a-OAc, H
R=0
R=
H
2
R = @-OH,H
at C-3 (for the 3-0x0-derivative) was noted particularly in those reactions in which
significant saturation of the double bond was a~hieved.~'
Other Reactions of Unsaturated Steroids.-Allylic alkylations catalysed by palladium have been reviewed and steroid examples are i n c o r p ~ r a t e d .The
~ ~ full
41
42
43
44
45
46
47
4B
295
(39)
61
52
5s
54
296
diphenyl derivative and the minor product (18 %) was the 4-phenyl derivative.55
Oestradiol reacted in a similar manner but oxidation of the 17-hydroxy-group also
occurred.
4 Carbonyl Compounds
Reduction.-Further
were reported on the use of poly(N-isopropyliminoalane) as a selective reducing agent for steroidal dicarbonyl compounds and
selective reduction of the 6-0x0-group was reported for 3a,5-cyclo-5a-androstane6,17-dione and 3cr,5-cyc10-5a-pregnane-6,20-dione.~~
A reinvestigation of the
Clemmensen reduction of tigogenin established that the major products were
tetrahydrotigogenin (43) and furostan (44) both of which were relatively
Reductive cyclizations of the acetylenic-5-ox0-5,6-secocholestanes(45) and the
(43)
R
= H or Me, n
R=H.n=2
(45) R
olefinic analogue (46) (inter a h ) using Na-NH,THF and Na-THF were compared
with those reported earlier for C,oH,Na-THF.59 The presence of ammonia in the
reducing medium allowed reduction to the secondary alcohol to compete with the
reductive cyclization and from a study60 of these competing reactions it was concluded that alkali metal-ammonia reductions of enolizable or a,&unsaturated
ketones proceeds through the vicinal dianion. Reduction of A4-3-0x0-steroidsto the
3-0x0-compounds was achieved by treatment of the pyrrolidinium salts with
1,4-dihydropyridine derivatives.61
D. H. R. Barton, J.-C. Blazejewski, B. Charpiot, D. J. Lester, W. B. Motherwell, and M. T.
Barros Papoula, J . Chem. SOC.,Chem. Commun., 1980, 827.
56 See Terpenoids and Steroids ed. J. R. Hanson (Specialist Periodical Reports), The Chemical
Society, London, 1978, Vol. 8, p. 240.
5 7 M. P. Paradisi and G . P. Zecchini, Tetrahedron, 1981, 37, 971.
5 8 M. Zachis and J. A. Rabi, Tetrahedron Lett., 1980, 21, 3135.
5 9 S. K. Pradhan, S . R. Kadam, J . N. Kolhe, T. V. Radhakrishnan, S. V. Sohani, and V. B.
Thacker, J . Org. Chem., 1981, 46, 2622.
6D S . K. Pradhan, S . R. Kadam, and J. N. Kolhe, J . Org. Chem., 1981,46, 2633.
R. A. Gase and U. K. Pandit, Red. Trav. Chim. Pay-Bas, 1980, 99, 334.
55
297
&
H
{I3
OH
"(48)
(49)
(47)
R'
R'
=
=
Me,Si
&
'
H
CECH, R2 = OH
OH, R2 = C E C H
(50)
w
\
( 5 5 ) 12a and 12p
(54)
OAc
(57)
(56)
epimer (49) was obtained from the reaction with the equivalent acetylenic Grignard
reagent.64Scr-Cholestanewas converted into 3,3-dimethyl-5cr-cholestane
by sequential treatment with MeMgX, ZnC1,-HCI, and ZnMe2-TiC1,.65 A new method for
1,2-transposition of ketones was appliedaa to 5cc-cholestan-3-one. The initially
formed vinyl silane (50)67was oxidized with MCPBA to the epoxide (51) which on
62
63
64
65
66
298
reduction with LiAlH, gave the hydroxy-silanes (52) and (53). Final oxidation with
chromic acid gave a mixture of the 2- and 3-ketones. The Prins reaction of lumihecogenin acetate (54) was reported to give the 14-hydroxy-compounds (55).68 A
novel base-catalysed cleavage of steroids containing the 17-dihydroxyacetone group
was reported to yield 1 7 - 0 x o - ~ t e r o i dAttempted
~.~~
acetylation of the novel marine
sterol (56) was reported7* to give the retro-aldol product (57).
of hydrocyanation of 3-oxo-Al-steroids and analogues were
The full
reported, 73 and a full account was available for the acid- and base-catalysed
additions of thiols to 3-OXO-A'- and related s t e r o i d ~and
, ~ thiourea
~ ~ ~ ~ was observed
to react with androst-l-en-3-ones to give the adduct (58). Reaction of 2-bromo-Al729
(59) R
(60) R
(61) R = C02Et
= C0,Et
= CN
(62) R
CN
and - A 1 ~ 4 ~ 6 - ~ t with
e r ~ i malonic
d~
ester and tetramethylguanidine gave the cyclopropanes (59) and (61) respectively as expected. 76 However, the cyano-derivatives
Me,N
(Me,N),C=O
(60)
f-
Scheme 1
68
Be
70
71
72
73
14
76
76
299
(60) and (62) were also isolated and the suggested mechanism from the initial
Michael adduct from the 2-bromo-Al-compound is outlined in Scheme 1.
Reactions Involving Enols or Enolic Derivatives.-The full account was reported
for the dehydrogenation of ketones using benzene seleninic anhydride. 77 Further
studies were reported on catalysts specific for the isomerization of A5-cholestenone
to A4-cholestenone.78
8a-Methylation of the 7-OXO-1
3,17-seco-steroid (63) was reported79with MeIAmtOK and efficient2 1-methylation of 20-oxo-pregnanes was achieved with MeILDA and led to the synthesis of 16a,17cc,21-trimethylpregnanes.
8o a-Thiocyanation
THPO&OTHP
(63)
of ketones was reported using copper(I1) thiocyanatesl and 21-hydroxylation of
pregnenolone exemplified a general procedure of a-hydroxylation of ketones
involving oxidation of the silyl enol ethers with OsO,-N-methyl morpho1ine-Noxide.82 6a-Methylation of the 3-oxo-androst-4-ene(64) was achieved by allowing
the silyl dienol ether (65) to react with dithienium fluoroborate and treatment of the
resultant substituted enone (66) with Raney nickel.83 The enol triflate (67) was
(66)
D. H. R. Barton, D. J. Lester, and S. V. Ley, J. Chem. SOC.,Perkin Trans. 1, 1980, 2209.
7 8 A. Fauve and A. Kergomard, Tetrahedron, 1981,37, 1697.
79 H.-R. Schlatter and W. Graf, Helv. Chim. Acta, 1980, 63, 1554.
80 J. Cairns, R. T. Logan, G. McGarry, R. G. Roy, D. F. M. Stephenson, and G. F. Woods,
J. Chem. SOC.,Perkin Trans. 1, 1981, 2306.
S. M. Ali, D. Clarke, G. R. Cliff, and G. A. Morrison, J. Chem. Res. ( S ) , 1981, 234.
J. P. McCormick, W. Tomasik, and M. W. Johnson, Tetrahedron Lett., 1981, 22, 607.
8a I. Paterson and L. G. Price, Tetrahedron Lett., 1981, 22, 2833.
77
300
coupled with lithium dimethyl cuprate and with lithium diphenyl cuprate to give
3-methylcholest-2-ene and 3-phenylcholest-2-ene respectively.s4 Ketones or their
derived enol acetates were converted into the cc-iodo-ketones with iodine and
copper(r1) acetate. 85
0ximes.-Treatment of ketoximes with acetyl chloride-acetic anhydride-tertiary
amine followed by hydrolysis gave the a-acetoxy-ketones and was exemplified by
the conversion of 5cc-cholestan-3-one oxime to the 2a-acetoxy-3-oxo-derivative.~6
An investigation of the mechanism of the Moffatt fragmentation of oximes suggested that the bond which breaks is antiperiplanar to the h y d r o x y - g r ~ u pAccor.~~
dingly, the Z-isomers (68) gave the 13,17-seco-nitrile (70) through the intermediate
(69) where as the E-isomers (71) gave the 16,17-seco-nitrile (73) through the
intermediate (72). Reaction of 6-oximino-steroids with trimethylsilyl chloride was
reported to give the cc-chloro-derivatives.19
+O
(73)
85
B6
87
88
301
&--OH
(77)
Steroidal alcohols were reported to be deoxygenated by conversion into the
selenocarbonates and reduction with Bu,SnH-AIBN. Carboxylic acids were
similarly converted into the selenoesters which on treatment with Bu,SnH-AIBN
gave mainly the aldehyde or the nor-alkane depending whether xylene or benzene
was used as solvent. 92 Deoxygenation was reportedg3in full for N,N-dialkylaminothiocarbonyloxyalkanes by treatment with potassium in t-butylamine containing
18-crown-6.
(79)
x =0
(80) X
So
S1
92
s3
H2
302
Treatment of 3~-t-butyltellurocarbonyloxy-5a-cholestane
with benzene seleninic
anhydride gave the cholestanyl ester (79) whereas with sodium hydrogen telluride
the ethers (80) and (81) were ~ b t a i n e d . ~
Reaction
*
of the vic-iodothiocyanate (82)
and the iodoisothiocyanates (83) and (84) with BuLi at room temperature gave
a n d r o ~ t - 2 - e n eit; ~was
~ observed that the diaxial nature of the substituents was
responsible for the elimination. It was reported that the reaction of the aminomesylate (85) with basic reagents gave Wagner-Meenvein rearrangement products
OMS
(85) R = H
(86) R
MS
(87) R
(88) R
H
MS
(89) 16P917P
(90) 16a,17a
SCH2CH,N3
H
(94)
. ,
(95)
gg
303
The previously observed backbone rearrangement of cholest-5-ene to cholest13(17)-ene in acetic acid-toluene-p-sulphonicacid and the subsequent slow epimerization at C-20 were shown by a deuterium incorporation study to involve a
series of carbo-cation-olefin equilibria.lo1The full account was reported for the
BC1,-catalysed backbone rearrangement of 4,4-dimethyl-6,20-epoxy-5a-androstane.lo2The oxetane (96) was reportedlo, to react with RCN-HBF, to give the
~@HI3F4
{j$F
(99)
AcO
(96) 16P917P
(97) 16a,17a
(98)
lol
327.
304
(102). Further rearrangement of the 11P, 17p-epoxide (102) with SnC1, in acetic anhydride gave cyclobutene (103). A convenient method for the introduction of the
isopropenyl group into a$-unsaturated ketones involved the BF,*Et,O-catalysed
cleavage of the allene-enone photo-adducts.lo5 Thus, for example photo-adduct
(104) gave the 4-isopropenyl-A4-3-oxo-compound
(105). The BF,-Et,O-catalysed
(104)
(105)
rearrangement of the 3,19-epoxy-androstane (106) to the 10-formyl-compound
(108) was shown106 to involve a reversible 1,5-hydride ion shift which was highly
stereoselective for the H, and involved the intermediate (107). Whereas-the
19-hydroxy-5p76p-epoxides
(109) underwent cleavage of the 10,19-bond with BF,
(109) R
(110) R
AC
BF3
(1 12)
gas in benzene to give the dienes (1 1 I), the equivalent 19-acetoxy-compounds (1 10)
(1 12):lo7A study of the acid-catalysed
rearranged to the 5-formy~-~-n0r-~0mpounds
reactions of 3p-acetoxy-5-hydroxy-5ct-cholestan-6-one
and the 3p-tosylate was
lo5
lo6
'07
305
(1 17)
(1 18)
reported.lo8Aromatic ~-ring-6-oxo-compounds
were the major products from the
former with CC1,CO2H, ClCH2C02H,or CBr,C02H whereas the latter gave mainly
the dienone (113) and the diketone (114) with KHS04 and HBr respectively.
Reaction of the 1cc,2cc-rnethyleneandrost-4-en-3-one
(1 15) and the 2a73a-methyleneandrost-6-en-4-one (1 17) with HBr gave the simple bromomethyl derivatives (1 16)
and (1 18) respectively and no dienone-phenol rearrangement was reported.lo9
*p;
BzO-
(124) lop
(125) 10a
lo*
(126) R = Bz, R2 = AC
(127) R = Ac, R2= BZ
RIO
loB
0r2
306
The full account was reported for the study of the intramolecular ene reactions
of the enols of 5-vinyl-3-oxo-steroidsand an examination of the photolysis of the
bridged bicyclic ketone (1 19) was incorporated.110A by-product of the reaction of
3p-tosyloxy-5,6p-dihydroxy-5~-cholestane
(120) with ButOK-Bu'OH was reportedlll
to be the A-nor-compound (123) which arose from an ene reaction of the enol(l22)
of the fragmentation product (121). Buffered acetolysis of the tosylate (124) gave
the A-homo-compounds (125) and (126) while the tosylate (127) gave the related
A-homo-compounds (128) and (129).lI2 Thermally and photochemically induced
fragmentations of the hypoiodites of 3-methylcholest-5-en-3-01,1~~
4,4-dimethylcholest-5-en-3p-01,~~~
cholesterol, epicholesterol, and 3a,4,4-trimethyl-cholest-5-en3p-o1115which were generated in situ from the parent alcohols were reported to give
a variety of products all derived from the oxyl radicals (130).
(130)
Oxidation of cholestane-2,3-dione with thallium(m) acetate gave the A-nor-pketo-ester (131) whereas a low yield of the keto-lactones (132) was obtained from
3,4-diketo-steroids.l16
(131)
(1 32)
OOH
(135) R = 0
(136) R = p-Cl, H
P.Yates and F. M. Winnik, Can. J. Chem., 1981, 59, 1641.
D.S.Brown, R . W. G. Foster, B. A. Marples, and K. G. Mason, Tetrahedron Lett., 1980, 21,
(133)
l10
ll1
5057.
115
116
112
113
114
307
(138)
from the acidic fraction of the product after methyl ester formation and acetylation.lS0 Oxidation of cholest-4-ene-3,6-dione with excess perbenzoic acid in the
presence of toluene-p-sulphonic acid gave the oxetalactones (142) and (143).121
The a-azido-sulphide (145), which was generated in situ from the thioacetal (144),
was reported122to undergo SnC1,-catalysed rearrangement to the cyclic iminothiomethyl ethers (146) and (1 47).
MeS
&
MeS
Mes@NS
(145)
(144)
(144)
11'
11*
lln
121
122
(147)
308
7 Functionalization of Non-activated Positions
(150)
(151) R
H or OAc
(152)
H or OAc
(153)
lZ3
lz4
lZ5
126
309
nitroamine (153) after the photolysis and reaction with AgOAc gave the similar
18-functionalized derivative (154). Jervine was reportedla' to be transformed into
the 18-functionalized c/D-trans-D-homo-c-nor-compound
(153, the 1l-oxofunction of which was readily removed by Wolff-Kishner reduction.
8 Photochemical Reactions
Aspects of photosensitization in organic synthesis were reviewed12* and stereospecific and regiospecific photoreactions inside the channels of choleic acids were
r e ~ 0 r t e d . lIrradiation
~~
of saturated acids or esters was reportedlsO to lead to
Norrish type I1 reaction or a 1,Zelimination and was exemplified by conversion of
cholanic acid or its ethyl ester into the A20(22)-compound
(156). Photolysis of the
PAC
(157)
enol ester (157) gave131the P-diketone (158) through a photo-Fries type rearrangein methanol saturated with
ment. Irradiation of 3a,5-cyclo-5a-cholestan-7-one
oxygen was reported132to give the 7-oxa-compound (159) along with the 7,S-seco-
(159)
(160)
H. Suginome, H. Ono, and T . Masamune, Bull. Chem. SOC.Jpn., 1981, 54, 852.
l Z 8A. Albini, Synthesis, 1981, 249.
12@ R. Popovitz-Biro, H. C. Chang, C. P. Tang, N. R. Shochet, M. Lahav, and L. Leiserowitz,
Pure. Appl. Chem., 1980,52,2693.
l3O G.Wolff and G. Ourisson, Tetrahedron Lett., 1981, 22, 1441.
131 D.Veierov, Y.Mazur, and E. Fischer, J. Chem. SOC.,Perkin Trans. 2, 1980, 1659.
lS2 H. Suginome and C.-M. Shea, Bull. Chem. SOC.
Jpn., 1980, 53, 3387.
lZ7
3 10
ester (160). The a,@-unsaturated8-lactone (161) was converted into the aldehydeSimilar photolyses in methanol of the
ester (162) by irradiation in rnethan01.l~~
(161)
(162)
analogous %lactones (163) gave the 5,l O-seco-derivatives (164) whereas the isomeric
&lactones (165) led to the 1,lo-seco-derivatives (166).13* A further study was
reported135 of the photochemical reactivity of 3-oxo-h5(lo)-steroids. Photolysis of
(163)
, a aR
M = H or Me
(164) R
=H
&
or Me
R-N
0
(166) R
9 &
=H
0'
or Me
(167)
C8H1,
AcO
(168)
(1 69)
the related A-homo-enone (167) in benzene was shown to give the spiro-ketone
(168), probably via a singlet or short-lived triplet excited
A triplet-sensitized
photo-equilibrium may be established between vitamin D, and trans-vitamin D,
in which the equilibrium position depends on the energy of the triplet sensitizer.
In the presence of oxygen selective photo-oxygenation of the trans-isomer was
re~0rted.l~'
As would be predicted from steric considerations, the photo-adduct
(169) derived from allene and 3 ~-acetoxycholest-8-en-7-one
has the 8a,9a-configuration. However, since the isomeric As-1 l-oxo-compound did not react, it is
133
l3*
A. Canovas and J.-J. Bonet, Helv. Chim. Acta, 1980, 63, 2390.
A. CCmovas, J. Fonrodona, J.-J. Bonet, M. C. Brianso, and J. L. Brians6, Helv. Chim. Actu,
1980, 63,2381.
la6
31 1
confirmed that not only steric considerations operate and that the configuration of
the adducts may be predicted assuming an intermediate species which is trigonal in
the a-position and pyramidal in the p-position.13* Photo-Beckmann rearrangement
of 4,4-dimethylcholest-5-en-3-oneoxime and 4,4,6-trimethylcholest-5-en-3-one
oxime gave essentially the predicted lactams and little or no nitrile in contrast to the
SOC1,-induced Beckmann rea~rangernent.~~~
It is inferred that ionic or radical
species derived by cleavage of the 3,4-bond are not involved in the photo-Beckmann
rearrangements. The photo-Beckmann rearrangement of ~-nor-Sa-androstan-l6one oxime gave140,inter alia, a 13a-lactam. A similar inversion had previously been
reported for a 17-ketoximeand in both cases some form of open-chain intermediate
is implied. The photo-Beckmann rearrangement of 3a,5-cyclo-5a-cholestan-7-one
oxime was u n e ~ c e p t i o n a l .The
~ ~ ~photolysis of ~-nor-Sa-androstan16-one acetyl
hydrazone in the presence of oxygen gave the expected142lactams and some
inversion at C-13
SECTION B: Partial Syntheses
9 Cbolestane Derivatives and Analogues
Recent studies in marine sterols were reviewed144and related to this is a review of
sterol biosynthesis and metabolism in marine invertebrate^.^^^ Mutasterol (171), a
ii, iii
(171)
Reagents: i, LDA-MeCOCMe,Et; ii, H,-Pd/C; iii, BuLi-Ph,P+MeBr-; iv, H30+
Scheme 2
J. F. Blount, G. D. Gray, K. S. Atwal, T. Y. R. Tsai, and K. Wiesner, Tetrahedron Lett., 1980,
21,4413.
139 H. Suginome, N. Maeda, Y.Takahashi, and N. Miyata, Bull. Chem. SOC.
Jpn., 1981,54,846.
loo
H. Suginome and T. Uchida, Bull. Chem. SOC.Jpn., 1980, 53, 2292.
1 4 1 H. Suginome and C.-M. Shea, J. Chem. SOC.
Perkin Trans. 1, 1980, 2268.
14e See Reference 6, p. 209.
143 H. Suginome, T. Uchida, K. Kizuka, and T. Masamune, Bull. Chem. SOC.
Jpn., 1980,53,2285.
144 C. Djerassi, Pure Appl. Chem., 1981,53,873.
14s L. J. Goad, Pure Appl, Chem., 1981, 53, 837.
138
3 12
novel sponge sterol alkylated at C-25, was synthesized from the stigmasterolderived 3,5-cyclo-aldehyde (170) as indicated in Scheme 2.14sA synthesis was
reported for 22-methylenecholestero1147
which along with (22S), (23S)methylene~ h o I e ~ t e r o 1 , 1observed
~ ~ ~ a ~to be a novel marine sterol. The key step in the synthesis
of stellasterol (173) involved the reaction of the allylic alcohol (172) with triethyl-
(172)
(173)
o r t h o a ~ e t a t e The
l ~ ~ ene reaction product (174) of ergosteryl acetate and diethyl
azodicarboxylate was reduced with Li-EtNH, to afford lichasterol (175).150
ca17
AcO&02Et
HN, C0,Et
J&
(175)
( 1 74)
14
313
I
OMe
--\
b i , iii
v,
v1
(176) 252
(177) 25E
Reagents: i, LDA-Me,CHCO,Me; ii, EtMgBr; iii, SOC1,-pyridine; iv, H,O+; v, MCPBA;
vi, Me,Si-SiMe3-KOMe-HMPA
Scheme 3
(178)
with diethylaluminium chloride and methyl p r ~ p i o l a t e or
l ~ with
~
ethylaluminium
dichloride and methyl p r ~ p i o l a t gave
e ~ ~ the
~ A15p22-dieneesters (180) which had the
natural configuration at C-20 and which could be hydrogenated to give the 17pconfiguration. Hydroboration of 2-1 7(20)-pregnenes (179)with9-borabicyclo[3.3.1Jnonane and subsequent reaction with chloroacetonitrile and base led to the
21-cyano-compounds (181).158 Reaction of the x-ally1 palladium complex (182)
with isohexenyl zirconium gave the diene (1 83) with the natural configuration at
C-20.159 The 15p,16p-epoxy-Z- 17(20)-pregnene (184) was allowed to react with
lithium isohexylcyanocuprate to give the 15~-hydroxy-A16-compound
(185) which
could be modified to give cholesterol.lG0
314
(186)
0 "C. A key step in the stereoselective synthesis of 24,25- and 25,26-dihydroxycholesterol is the asymmetric reduction of the A25-24-oxo-compound(188) using a
complex of LiAlH, and optically active 2,2'-dihydroxy-1,l'-binaphthyl. Thus, the
reduction of (188) with the R-( +)-dihydroxybinaphthyl gave largely the alcohol
(1 89) which was converted into the diols (190) and (19 1) as indicated in Scheme 4.1s3
A Claisen rearrangement, effected by treatment of the deuteriated substrate (192)
with ethyl orthopropionate led to the 24-deuterio-ester (1 93) which was converted
A novel synthetic approach to the
into [24R-2H]-25-hydroxyprovitamin
ecdysone side chain was demonstratedls5 with pregnenolone acetate, which was
reported to react with 2-lithio-5-methylfuran to give, after reacetylation, the AZ0-
162
laa
164
165
V. Pouzar and M. Havel, Collect. Czech. Chem. Commun., 1980, 45, 2443.
R. P. Manley, K. W. Curry, N. C. Dens, and M. D. Meyer, J. Org. Chem., 1980,45,4385.
M . Ishiguro, N. Koizurni, M. Yasuda, and N. Ikekawa, J. Chem. Soc., Chem. Commun., 1981,
115.
J. D. Meadows and D. H. Williams, Tetrahedron Lett., 1980, 21, 4373.
T. Kametani, M. Tsubuki, and H. Nemoto, Tetrahedron Lett., 1981, 22, 2373.
315
ji
iiii
?H
(191)
(190)
Reagents : i, VO(acac),-Bu'OOH ; ii, K,CO,-PrOH ; iii, LiAIHo
Scheme 4
(192)
188
316
( I 94)
Scheme 5
iii, iv
v, vi
Reagents: i, Me,CH-C = CLi ; ii, Lindlar catalyst-H2; iii, Bu'OOH-VO(acac),; iv, Ac,Opyridine; v, HCN-Et3A1; vi, KOH
Scheme 6
16'
168
317
Schemes 5 and 6 respectively.Reformatsky reaction of 3@,21-diacetoxy-pregn-5-en20-one (199) was reported169to give the 20-acetoxy- and 20-hydroxy-lactones(200)
which were converted into 3@,23-diacetoxy-24-norchol-5-ene
via hydrogenation of
the A20-compound(201) allowing incorporation of isotopic label at C-20 and C-21.
OAc
&
AcO
(200) R
=H
or Ac
@-' &
iii, iv
0
R
(203)
Reagents: i, R-C
Scheme 7
169
318
172
173
174
176
176
177
178
178
180
181
319
which was believed to have the 25s-configuration. A key step in the synthesis of
(24R)-24,25-dihydroxycholecalciferolwas the reaction of the epoxide (208) with the
(210)
sulphone (209), which led to the diol sulphone (210). The epoxide(208) was obtained
from the tosylate (207) which was synthesizedfrom D-glyCeriC acid.ls3A synthesis of
calcitroic acid (21 1) involved184the previously reported direct hydroxylation procedure of vitamin D and related compounds which was also reported in full.lS5JS6
HO'
(213) R = SiMe,But
(214) R = MeOCH,
Three syntheses were r e p ~ r t e d l ~
for~ -25-hydroxycholecalciferol-26,23-lactone
~~~
(216) which was assigned1E8~1Eg
the 23R,25S-configuration. The most stereoselective of these syntheseslsginvolves the LDA-catalysed reaction of the sulphone
(212) with the aldehyde (213) to give the hydroxy-sulphone (215) which was
modified as in Scheme 8 to give the required side chain. The sulphone (212) was
derived from S-citramalic acid. Reaction of the trideuterio-Grignard reagent (217),
which was derived from S-lactic acid, with the aldehyde (214) led to 25R-[26-2H,]las
18*
320
b,
(215)
iii, iv
Reagents: i, Na-Hg ;ii, TsOH-H,O; iii, Ac,O-pyridine; iv, EtOH-PPTS; v, DMSO-pyridineSO3-Et3N; vi, 1,KOH; vii, 1,MeCN; viii, Bu,SnH
Scheme 8
321
cholecalciferol and the study was extendedlg4to include the synthesis of 3-deoxy3,3-dimethyl- l-hydroxycholecalciferolsfrom the thermolysis of the vinyl allenes
(222) and (223).
Act
(218) R = AC
(219) R = Me
(223) R'
H, R2= OH
11 Pregnanes
Three new approaches to the construction of the dihydroxyacetone side chain were
rep~rted.~
Pregenolone
~ ~ J ~ ~ was oxidized with PhIO-KOH-MeOH to the hydroxyacetal(224) which, after acetylation and heating in xylene with toluene-p-sulphonic
acid, gave the acetoxy-enol ether (225). Oxidation (MCPBA) and hydrolysis gave
the required compound (266).lg5The other two routes which started with 17-oxosteroids are outlined, in part, in Schemes 9lQ6and
Tetrazolium salts were
(224)
(225)
(226)
reported to be oxidizing agents suitable for the conversion of 21-hydroxy-20-0~0steroids into the 20-hydroxy- or 20-oxo-21-oic a ~ i d s . 1
~
A~synthesis
was reportedlg9
(Scheme 11) of 1l-deoxyaldosterone from the exo-epoxide mixture (227) which was
ls4
196
322
Scheme 9
{go
OAc
___,
ii, iii
d
iv
Scheme 10
&
($
CH20H ii,iii
i
+
?OH2.-
p,
(227)
1 1-deoxyaldosterone
Reagents: i, LiNEt2-THF; ii, , Ac,O-pyridine ; iii, N-methylmorpholine N-oxide-Os0,Bu'OH-THF-H,O; iv, NaIO,; v, K,CO,
Scheme 11
obtained from the methylene cyclobutane (7).16 The hypoiodite reaction of 20hydroxy-pregnaneswas a key step in the synthesesof 1 8-hydroxycorticosterone200~201
and in the syntheses of 21-deoxy-3a,5~-tetrahydroaldosterone
(228)202and 3a,5p-
2*1
202
323
& &[g
Meo
\ OSiMe,
5 (231)
RO-=
(228)
(229)
(230)
(231)
Scheme 12
The hydroxy-lactone (233) was obtainedzo4by treatment of the 16,17-epoxy-200x0-21-acetate (232) with KOBut. The trifluoroacetoxypregnan-20-ones(234) were
converted into the spirofuranones (235) with DBU in benzene.205The conversion
(232)
of 15a-hydroxy-l l-oxo-progesterone to 3p, 1 1a, 15p-trihydroxypregn-5-en-20-one
has been reported.20s The synthesis of (20R)-5ct-pregn-9(11)-ene-3p,6a,20-triol, a
minor starfish sterol, was reported from ll-oxoprogesterone.zo7A key step in the
synthesis of 10P-ethenyl-hydrocortisoneacetate is the addition of LiC 3 CH to the
5,lO-epoxide (236).208Syntheses of 10-norprogesterone and 19-nordeoxycortiA series
costerone have been reported from 19-norandrost-4-ene-3,17-dione.z09
of hormonally active D-homopregnanes has been synthesized210 and c-homo20a
204
206
20*
1867.
324
(236)
compounds were obtained from hecogenin, the ring expansion being achieved by a
Demjanov reaction on the 12-aminomethyl-12-hydro~y-derivative.~~~
e o
hP
213
211
3221.
1924.
214
216
325
synthesis of 16a-hydroxy-~-nor-5a-oestran-2-one
involved regioselective hydroboration of a AIG-derivativewith di-isoamylborane.216
The synthesesof 1l-hydroxy9a- and -9p-oestrones were reported217and an investigation into stereoselective
routes to 14,15,17-trisubstituted oestra-l,3,5(10)-trienes from the A14-compounds
demonstrated that both the 17@-acetoxy-14a,l5a-epoxideand its 14@,15@-epimer
gave largely the 14p-15-oxo-compound.218
Oestriol 16-glucuronidewas synthesized
through reaction of 2,4-dibromo-16a-hydroxyoestrone with methyl l-bromo-ldeoxy-2,3,~-tri-~-acety~-a-~-pyranosuronate.~~~
13 Cardenolides
+
vi
vii, viii
Scheme 13
genin was
from the A5~14-diene-20-oxo-compound
(244) which was
obtained from the enone (243). An improved synthesis225of 14p-hydroxy-cardenolides from the A 1 4 - ~ ~ m pinvolved
~~nd~
sequential reaction with NBA and Bu3SnH.
Syntheses of the saturated lactones (245)226and their a,@-unsaturatedanalogues227
21@
21*
$lQ
220
221
222
233
224
aa6
12
326
6'.
{
(247)
(248)
(249)
(250)
OH
(251)
(252)
(253)
(254)
R' = R2 = H, 20p-H
R1 = R2 = H, 20a-H
R1 = Me, R2 = H
R1 = H, R2 = Me, 203-H
olides (25 1)-(254) were reported.229The p-steroidyl crotonate methyl esters (255)
and (256) were synthesized from the 14~-hydroxy-20-oxo-compound.230
kCHC02Me
3-OAc
220
230
\ ,.CHCO,
327
U k S
NH
-.
(257)
(258)
(259)
(260)
16a-bromo-oestrone methyl ether and 3-mercapto-1,2,4-triazole and its 5-methyl
derivative, but with 2-mercaptoimidazole simple displacement of the bromine was
observed. In NaHC0,-DMSO, 16a-aminomethyl- and 16a-benzyIarninomethy13-methoxy-17~-tosyloxyoestra-l,3,5(10)-trieneunderwent cyclization to the
tetrahydro-oxazin-2-ones(26 1) and (262) respectively.234Tomatidine was converted
into the (22S,25S)-N-methyl-derivative
stereospecifically,whereas solasodine led to
and the (22S,25R)-N-methyl-deriva mixture of the (22RY25R)-N-methyl-derivative
a t i ~ e .Treatment
~~~
of 17p-acetoxy-17a-ethynyl-steroids with NOF-NOBF,
gave236the diacylfuroxans (263) which on thermolysis gave the acylnitrile oxides
(264) which could be trapped with suitable d i p o l a r o p h l e ~ A
, ~ ~synthesis
~
of
26-(3-methylindol-l-yl)cholesterolwas
Hexachlorotriphosphazene was
to react with a variety of steroidal alcohol sodium salts to give the
substituted derivatives (265). Organopalladium complex-catalysed coupling of
acetylenic organozincs with 5-iodo-3,5-0-bis(trimethylsilyl)deoxyuridinegave
5-alkynyl-2-deoxyuridinesand was exemplified by the preparation of the steroidal
example (266).240
R. C. Cambie, G. D. Mayer, P. S. Rutledge, and P. D. Woodgate, J. Chem. SOC.,Perkin
Trans. 1, 1981, 52.
232 J. S.Bajwa and P. J. Sykes, J. Chem. SOC.,
Perkin Trans. 1, 1980, 1859.
2S3 J. S. Bajwa and P. J. Sykes, J . Chem. SOC.,Perkin Trans. 1, 1980, 2146.
234 G. Schneider, L. Hackler, and G. Dombi, J. Chem. SOC.,Chem. Commun., 1980, 891.
235 H. E. Gottleib, I. Belic, R. Komel, and M. Mervic, J. Chem. SOC.,
Perkin Trans. I , 1981, 1888.
236 D.R.Britteli and G. A. Boswell Jr., J. Org. Chem., 1981, 46, 312.
237 D.R.Britteli and G. A. Boswell Jr., J . Org. Chem., 1981, 46, 316.
2s8 T. Arunachalam, P. J. MacKouI, N. M. Green, and E. Caspi, J. Org. Chem., 1981, 46,2966.
239 H.R.Allcock, T. J. Fuller, and K. Matsumura, J. Org. Chem., 1981,46, 13.
240 P. Vincent, J.-P. Beaucourt, and L. Pichet, Tetrahedron Lett., 1981, 22,945.
231
328
(261) R
(262) R
CH,Ph
C1 O-Steroid
deoxyribose
I
CI-P,
/ N
c1
P-Cl
Me0
15 Microbiological Reactions
?44
245
246
329
24i
248
240
250
251
2j2
Author Index
Abdel-Magid, A., 310
Abdel Salam, N. A,, 102
Abe, F., 59
Abe, H., 312
Abe, K., 266
Abiko, A., 29, 79
Abraham, W.-R., 75, 174
Abryutina, N. N., 286
Abubakirov, N. K., 234
Accrombessi, G., 39
Achari, B., 172
Acharya, S. P., 6
Achenbach, H., 58
Acklin, G., 304
Acton, N., 249
Adam, G., 198
Adam, W., 38
Adams, R. P., 73
Addae-Mensah, I., 58
Adesogan, E. K., 59, 60
Adesogan, K. A., 189
Adinolfi, M., 21 1
Adlercreutz, H., 281
Adolf, W., 200
Adriani, C., 59
Afifi-Yazar, F. U., 5, 59
Agami, C., 298
Agarwal, P. K., 115
Agarwal, S. G., 211
Ager, D. J., 34
Ageta, H., 225
Aggarwal, R. C., 39
Agosta, W. C., 25
Agurell, S., 66
Ahem, D. G., 254
Ahmad, I., 174
Ahmad, M. S., 307
Ahmad, V. U., 225
Ahmed, M., 88, 111, 115,
146,156,169,188,189,196
Ahmeij, M., 66
Ahn, B. Z., 59
Ai, T.-H., 215
Aimi, N., 232
Akelah, A., 288
Akhila, A., 39, 68
Akhmetov, L. I., 12, 48
Akimaliev, A. A., 234
Akimoto, K., 135
Akinniyi, J . A., 146, 216
Akita, H., 85, 193, 194, 259
Akiyama, T., 60, 61, 215,
277
Akporiaye, D. E., 303
Akutogawa, S., 42
w.,
252
Appeldoorn,
ApSimon, J. W., 228, 323
Aragon, C. M. G., 262
Aranda, J. C., 204
Arata, K., 37,42, 51
Aratani, T., 40, 89
Arbuzov, B. A., 43, 5 5 , 56,
57
Argade, P. V., 258
Argyriadou, N., 44
Arigoni, D., 140, 209
Arita, M., 31, 264
Ariwa, M., 176
Arlt, D., 61
Amaboldi, M., 247, 260
Arnold, E. V., 196
Arnoux, B., 219
Arora, A. K., 14
Aruldhas, G., 278
Arunachalam, T., 327
Arvidson, G., 258
Asakawa, Y., 73, 8 5 , 158,
172, 183, 184
Asano, S.,62
Ashref, M., 31
Aslanov, K. A., 188
Atal, C. K., 15, 33, 211
Atimoshone, M. V., 195
Atkinson, G. H., 257
Atopkina, L. N., 216
Atsumi, K., 183
Attwell, M. C., 271
Atwal, K. S., 3 11
Audenaert, F., 178
Aulchenko, I. S., 20, 34
Avery, M. A., 60, 99
Avetisyan, G. M., 230
Aviv, D., 72
Ayafor, J. F., 221
Ayengar, K. N. N., 228
Ayer, W. A., 124, 127, 128,
131, 134, 202
Baas, P., 255
Babin, D., 16, 39, 64, 89
Babler, J. H., 25, 64
Bachner, J., 47
Back, T. G., 302
Baddeley, G. V., 21 5
Badripersaud, S., 323
Badruddoza, S., 193
Bagan, E., 291
Baggiolini, E. G., 318
Bailey, T. R., 42, 297
33 1
Author Index
Bailleul, F., 58, 59
Baines, D. A., 55
Bajwa, J. S., 327
Baker, P. M., 215
Baker, R., 23, 77, 81
Bakunin, V. N., 49, 51
Bakuzis, M. L. F., 43
Bakuzis, P., 43
Bal, B. S., 24, 36, 38
Balashov, S. P., 259, 260
Balasubramanian, V., 308
Balci, M., 32
Baldwin, J. E., 91
Baldwin, S. W., 60
Balliano, G., 215
Balogh-Nair, V., 247, 259,
260
Balsevich, J., 54, 160
Bambagiotti, A. M., 5
Band, P. R., 255
Bandrauk, A. D., 257
Banerjee, A. K., 204
Banerjee, D. K., 270, 271
Bang, L., 21 1
Banks, R. E., 98
Bano, S., 225
Banou, T., 14
Bansal, R. K., 192
Banthorpe, D. V., 4, 13, 39,
63,68
Bapuji, M., 158
Baragliu, A., 37
Barany, F., 25
Baranyai, M., 256
Barba, R., 45
Barbara, P. F., 259
Barden, T. C., 91
Bardyshev, I. I., 45, 5 5
Barer, D. G., 42
Bari, S. S., 18, 206
Barker, A. J., 105
Barkhan, P., 266
Barnard, G., 285
Barner, R., 269, 318
Barnett, R., 255
Barnette, W. E., 43
Barrero, A. F., 48, 118
Barrett, A. G. M., 292, 301,
302
Barrick, R. C., 232
Barron, L. D., 5
Barros Papoula, M. T., 296
Barrow, S. E., 13
Barth, G., 51, 52
Bartlett, A. J., 87
Bartlett, P. A., 27, 34
Barton, D. H. R., 35,37,213,
292, 296, 299, 301, 302,
321
Barua, A. B., 263
Barua, A. K., 187,226, 230
Baruah, R. N., 146
Basak, A., 187, 227
Bateho, A. D., 312
Bates, P., 15
Bates, R. B., 219
Battaglia, R., 135
Battalova, S., 49
Battegay-Nussbaumer, Y .,
243
Battersby, A. R., 70
Bax, A., 274
Baxter, R. L., 86
Bayley, H., 260
Bazylchik, V. V., 13, 33
Beal, J. L., 4
Beale, M. H., 198, 228
Bearder, J. R., 198
Beaucourt, J.-P., 327
BeauLaire, J., 174
Beaulieu, P., 21
Beaupin, C., 60
Becchi, M., 280
Beck, J.-P., 211
Becker, J. J., 51
Becker, R. S., 258
Bedi, A. L., 21, 39
Bedour, M. S., 277
Beecham, A. F., 277
Begley, M. J., 146
Begue: J. P., 9
Beier, R. C., 106
Bekhtereva, M. N., 261
Bekker, A. R., 247
Belanger, A., 324
Belanova, E. P., 33
Beletskaya, I. P., 49, 51
Belic, I., 327
Bell, A. A., 106
Bell, K. H., 46
Bellesia, F., 61
Bellido, I. S., 32
Bellus, D., 64
Beloeil, J.-C., 270, 297
Belousova, L. I., 46
Below, P., 33
Belozerskaya, T. A., 262
Belyaeva, M. E., 55
Ben-Ari, C., 276
Benayoun, J., 74
Bendall, M. R., 58, 60
Benezva, C., 318
Benko, A. B., 283
Bennett, N., 259
Bennett, R. D., 221
Bensasson, R. V., 243
Bensel, N., 11
Bentley, R., 266
Benveniste, P., 210
Ben-Zvi, Z., 66
Berbalk, H., 318
Berg, D., 283
Berger, D. E., 312
Berger, Y., 208
Bermejo, J., 146
Bernard-Dagan, C., 4, 74
Bernardini, A., 114
Bernasconi, S., 184, 194
Bernays, E., 57
Bernhard, K., 237, 240
Berry, R. A., 261
Berti, C., 52
Bertran, J. F., 5
Bertrand, C., 42
Bertranne, M., 270, 297
Besai, D. N., 39
Besner, J. G., 255
Bessiere, Y., 3
Best, W. M., 110
Bestmann, H. J., 249
Betancor, C., 226
Bettolo, R. M., 61
Bevelle, C. A., 146
Beydon, P., 282
Beyer, P., 261
Bezzubov, A. A., 256
Bhadbhade, M. M., 193,271
Bhagwat, S. S., 121
Bhardwaj, T. R., 271
Bhat, N. E., 55
Bhat, N. G., 57, 64
Bhat, U. G., 146
Bhatt, M. V., 300
Bhatta, A. K., 312
Bhattacharyya, S. C., 65, 66
102, 104
Bhatty, M. K., 31, 174
Bialer, M., 307
Bianco, A., 5, 58, 59, 60, 61
Biedrzycki, H., 10
Bierl-Leonhardt, B. A., 7,63
Biggs, R. H., 254
Biguet, J., 172
Bikbulatova, G. S., 56, 57
Billington, D. C., 77
Bilton, R. F., 328
Binder, M., 65, 73
Biran, C., 10
Birch, A. J., 6, 44
Birch, A. M., 138
Bird, T. G. C., 101
Birge, R. R., 259
Bishop, R. D., 12
Biswas, S., 187
Bjoroy, M., 232
Black, B., 47
Blackwell, D. S. L., 53
Blais, C., 282
Blanc, P. A., 312
Blanco, L., 63, 88
Blazejewski, J.-C., 292, 296
Bledsoe, J. O., 38
Blinova, V. A., 6
Blosczyk, G., 226
Blount, J. F., 143, 146, 174,
200, 202,311, 318
Blum, M. S., 60
Blunden, G., 279
Blunt, J. W., 194
Blunt, R. W., 15
Bluthe, N., 50
Bobrowski, K., 251, 259
Author Index
332
Boccalotte, A., 69
Bocelli, G., 61
Bodea, C., 245
Bodor, N., 275
Boeckman, R. K., jun., 130
Boger, P., 210, 260
Boelens, H., 252
Boeren, E. E., 65
Boettner, F. E., 234
Bohlmann, F., 32,62,66,73,
75, 88, 102, 106, 107, 111,
114, 115, 116, 117, 146,
155, 156, 158, 160, 169,
170, 172, 174, 176, 184,
186, 187, 188, 189, 190,
195,196,225
Bohlmann, R., 67, 116
Bokel, M., 218
Bolard, J., 256
Bolli, D., 58, 59
Bond, F. T., 46
Bondavalli, F., 43, 46
Bonet, J.-J., 310
Bonnet-Delpon, D., 9
Bonini, C., 5 , 59
Borch, G., 237, 238
Borden, W. T., 50
Bordner, J., 205
Borg-Karlson, A.-K., 106
Bori, S. S., 37
Bornack, W. K., 121
Borowiecki, L., 46
Borschberg, H. J., 45
Borthakur, N., 146
Bose, A. K., 60, 280
Bosshardt, M., 35
Boswell, G. A., jun., 327
Botten, J. A., 28
Boucher, F., 259
Bouchier, I. A. D., 291
Bouchisic, B., 51
Boulton, K., 199
Bourgeay-Causse, M., 255
Boussac, G., 31, 82
Bouvier, P., 208, 209
Bowden, B. F., 172,182,200
Bowen, J. M., 278
Boya, M. T., 193
Boyd, J. D., 38
Boyd, R. K., 5
Boyer, J., 40
Brabham, D. E., 254
Bradshaw, A. P. W., 140
Braekman, J. C., 114, 202
Brahmana, H. R., 243
Braiman, M., 258
Bramley, P. M., 261
Branca, S. J., 63
Brand, J. M., 60
Brand, M., 41
Brandange, S., 8
Brangeon, J., 260
Braz Filho, R., 190
Bregovec, I., 76
Caballero, E., 48
Cagnoli-Bellavita, N., 192,
194
Cahiez, G., 29
Caine, D., 164
Cainelli, G., 3, 239
Cairns, J., 297
Calas, R., 10, 25, 51
Cole, W. J., 281
Callahan, J. F., 107,143, 155
Callant, P., 61
Callender, R. H., 258, 259
Calzadilla, C. H., 85, 86
Camara, B., 260
Cambie, R. C., 292,302,327
Campanelli, A. R., 278
Campbell, I. M.,85
Campbell, M. M., 298
Camps, F., 192
Canceill, J., 325
Cane, D. E., 70, 88, 98, 129,
194
Cane, O., 4
Cano, G., 158
Cannistraro, S., 259
Cannon, J. R., 226
Canoras, A., 310
Cantineau, R., 328
Capdevielle, P., 49
Capomacchia, A. C., 256
Capon, R. J., 15, 17
Caporusso, A. M., 13
Capp, M., 281
Caputo, O., 215
Cardenas, C. G., 38, 45
Cardillo, G., 3, 239
Cariello, L., 239
Cargill, R. L., 205
Carlsen, P. H. J., 27
Carlsen, W., 258
Carlson, R. M. K., 282
Carman, R. M., 38, 41, 46,
47,195,213
Carmely, S., 200,234
Carpenter, R. C., 226
Carr, D., 28
Carr, R. V. C., 21, 36
Carroll, G. L., 139
Carrol, P. J., 104
Caruso, A. J., 81
Casanova, J., 5
Casellato, M., 210
Casida, J. E., 64, 74
Casinos, I., 40
Casinovi, C. G., 37, 223
Caspi, E., 327
Cassady, J. M., 146
Castanet, Y.,48
Castellani, G., 6
Castellano, E. E., 272
Castillo, R., 263
Castognino, E., 31
Castro, A., 284
Castro, V. A., 225
Author Index
Caton, M. P. L., 52
Cattel, L., 215, 234
Cazes, B., 64
Cave, A., 85
Ceccherelli, P., 192, 194,324
Ceolin, R., 272
Cerda-Olmedo, E., 262
Cerfontain, H., 255
Cerny, N. H., 290
Cerny, V., 293, 294, 325
Cerrini, S., 270, 306
Ceskis, B., 16
Chabudzinski, Z., 10,37,40,
49, 50,51
Chadha, N. K., 318
Chakrabarti, P., 270, 271
Chakrabarty, S., 172
Chakravarty, A. K., 277
Chalmers, A. A., 172
Chalmers, W. T., 228
Chambers, D., 302
Chan, D. M. T., 60
Chan, K.-K., 247
Chan, R. L. S., 247
Chan, W. H., 46
Chan, W. R., 200, 202
Chandel, R. S., 207
Chandrasekharan, V., 65,66
Chang, C.-J., 146
Chang, F. C., 312
Chang, H. C., 271, 309
Chang, I.-M., 276
Chang, T. C. T., 35
Chao, P. D. L., 59
Chao, W.-R., 247
Chapman, A. C., 123
Chapman, D. J., 231,261
Charlwood, B. V., 4
Charpentier-Morize, M., 9
Charpiot, B., 292,296
Chastrette, F., 27
Chastrette, M., 27
Chatterjee, S., 23
Chatterjee, T. K., 226
Chattopadhyay, K., 256
Chattopadhyay, S., 234
Chaudhuri, R. K., 5, 7, 58,
59, 60
Chawla, H. P. S., 47, 214
Chayabunjonglercl, S., 99
Chekhlov, A. N., 271
Chekulaeva, L. N., 260
Chen, C. C., 49
Chen, E. Y., 157
Chen, F. H., 196
Chen, S. E., 234
Cheng, Y. S., 35
Chernysheva, E. K., 262
Cheron, M., 256
Chetyrina, N. I., 230
Cheung, H. T. A., 276
Chew, E. 246
Chhabra, B. R., 123
Chiaroni, A., 85
333
Chiba, M., 179
Chichester, C. O., 235, 256
Chien, M. M., 223
Chien, P.-L., 246
Chihiro, M., 223
Childers, W. E., 24, 36
Childs, R. F., 47
Chiu, P. L., 273
Chou, W. H., 196
Choudhury, M. K., 55
Chowdhury, P. K., 146
Chriki, G., 54
Christenson, P. A., 48, 89
Christi, N. H., 31
Christie, J. J., 177
Christou, P. N., 63
Chuiko, V. A., 62
Chuman, T., 264
Chun, M., 246
Chung, S. G., 59
Chytil, F., 250
Cimarusti, C. M., 272, 293
Cimino, G., 79, 298
Ciurdaru, V., 245
Clardy, J., 60, 127, 183, 196,
200, 201, 202
Clark, B. C., 36, 57
Clark, B. P., 5
Clark, R. D., 63
Clark, R. J. H., 258
Clarke, D., 299
Clarke, F. H., jun., 102
Clegg, W., 66
Cliff, G. R., 299
Clive, D. L. J., 21, 38
Clover, M. G., jun., 102
Coates, R. M., 103, 194
Cocker, W., 41, 55
Cohen, N. C., 286
Cohen, T., 39
Coisne, J. M., 228
Cole, J. R., 60, 219
Coleman, J. B., 45
Colin, H., 100
Colin, P., 286
Coll, J. C., 172,182, 192,200
Collera, O., 226
Collins, D. C., 277
Collins, D. J., 295, 318
Collins, M. D., 266
Collins, M. S., 74
Collins, W. P., 285
Comins, D. L., 67
Condran, P., jun., 320
Confalone, P. N., 3 18
Conia, J. M., 63, 89
Conn, R. S. E., 21,48
Conner, A. H., 73, 210, 232
Connolly, J. D., 146, 216,
221
Cooke, R. S., 54
Cookson, A. D., 284
Cookson, R. C., 29, 62
Cooney, J. J., 261
Author Index
334
Dalton, J. R., 205
Daly, J. J., 269, 318
Dalzell, H. C., 65, 66
Damtoft, S., 5, 57, 70
Damodaran, N. P., 26
D'Andrea, A., 272
Daniel, T., 265
Danilov, L. L., 264
Danishefsky, S., 100, 121,
135
Dantes, A., 72
Darby, N., 45, 48
Dart, L. L., 263
Darwish, F. A., 223
Das, J., 204
Das, M. C., 230
Das, P. K., 251, 258, 259
Dasgupta, EL, 193
DaSilva, R. S., 19%
DaSilva, J. J., 192
Dastidar, P. P. G., 172
Dastillung, M., 232
Dauben, W. G., 118, 185,
312
Daunis, J., 114
Dauzonne, D., 4
Davydov, V. Y., 282
Dave, V., 276, 307
David, S., 5
Davini, E., 58
Davis, D. L., 253
Davis, R., 289
Dawson, M. I., 247, 250
Dawson, P. J., 329
Day, R. O., 53
Dayal, B., 291, 312
Daza, L. R., 146
De Alvarenga, M. A., 192
De Bernardi, M., 135
De Bianchi, A. G., 238
Declercq, J. P., 6, 114, 202,
228
De Clercq, P. J., 179
De Graeve, J., 328
Degraw, J. I., 246
De Groot, A., 204
Dehennin, L., 281
Deja, I., 110
de Jesus, A. E., 172
Decorzant, R., 23, 179
De Keukeleire, D., 39, 161
Delaris, G., 62
Delaude, C., 226
Delaveau, P., 58, 59
Delay, F., 37
Deleris, G., 10, 51
Delettre, J., 272, 303
Dellers, E. A., 266
Delpech, B., 42
Delprino, L., 234
del Rio, R. E., 115
Deluca, C., 57
DeLuca, H. F., 263,269,319
DeLuca, M., 285
Demailly, G., 34
De Mark, 3. R., 280
Demath, M., 61
de Mayo, P., 53
Dernbitski, A. D., 48, 62
De Miranda, D. S., 194
Demole, E., 23
Denisenko, V. A., 216
Denny, M., 246,250
Dens, N. C., 314
De Pascual Teresa, J., 32,48,
118
Depezay, J.-C., 89
De Rosa, M., 329
De Rosa, S., 79, 298
Derwish, G. A. W., 198
Desage, M., 280
Desai, D. N., 40, 164
Desai, M. C., 214
Descesare, J.-M., 55
Deshchits, G. V., 55
Deshmukh, A. R. A. S., 57,
67
DeSilva, T., 93
De Simone, F., 318
Deslongchamps, P., 45, 166
De Stefano, S., 79, 298
Destro, R., 184
Detty, M. R., 292
Dev, S., 26, 41, 47, 115, 214
Devilbiss, E. D., 7
De Vos, M. J., 64
Devreese, A. A., 179
Dewey, W. L., 66
Dhar, A. K., 88, 116, 146,
158, 172, 187, 188, 189
Dhar, D. N., 193
Dhar, K. L., 15, 33,211
Dhara, K. P., 231
Dhekne, V. V., 67
Diaz, E., 190
Diem, M., 5
Dieter, R. K., 63, 300
Dietsch, A., 234
Diez-Masa, J.-C., 100
Dike, S. Y., 21
Dikstein, S., 51
Dime, D. S., 297
Dimitriadis, E., 75
Din, Z. U., 33, 64
Dinge, A. S., 67
Dini, A., 318
Dinogues, J., 5 1
Dipietro, R. A,, 46
Dirks, G., 243, 256
Ditzel, E. J., 194
Dixon, J., 47
Djerassi, C., 51,52,278,280,
311, 312
Djura, P., 78
Dmitrovskii, A. A., 250
Doddrell, D. M., 274
Doehner, R. F., 41
Doi, E., 34
Dolhyj, S. R., 35
Dombi, G., 327
Dominguez, X. A., 146, 158
Donnelly, D. M. X., 73
Donskova, A. I., 56
Doolittle, R. E., 38
Do Prado, S. K., 196
Dorn, F., 140
Doskotch, R. W., 58
Dougall, D. K., 4
Doukas, A. G., 258,259
Doumas, J., 234
Dovinola, V., 21 1
Draffehn, J., 282
Drage, J. S., 92
Drawert, F., 33
Drebyschak, T. D., 73
Dreiding, A. S., 110, 118
Drengler, K. A., 194
Drief, A., 64
Driessen, R. A., 66
Du, P. C., 321
Duax, W. L., 270, 271
Dubois, G., 85
Dubovenko, Z. V., 73
DUC,D. K. M., 33, 43, 304
Duddeck, H., 277, 298
Duffield, R. M., 60
Duffley, R. P., 65
Dugger, R. W., 253
Duncia, J. V., 61
Dung, J. S., 40
Dunlop, R. W., 15
Dunogues, J., 10, 25, 51
Dupont, A., 114,202
Du Preez, H. E., 62
Durocher, C. K., 281
Duri, Z. J., 198
D'Urso, N. R., 258
Dutta, C. P., 231
Dutta, P. C., 204
Dutta, P. K., 257
Dworan, E., 47
Dyakonova, R. R., 56
Dyer, R. D., 205
Eade, R. A., 225
Ebrey, T. G., 247, 259, 260
Ecoto, J., 50, 100
Ecoto, S. L., 51
Edamura, F. Y., 116
Edenharder, R., 281
Edeny, H., 66
Eder, U., 324
Edgar, M. T., 52
Edwards, 0. E., 47
Eenkhoorn, J., 323
Egger, J. C., 32
Eguchi, T., 269
Eguren, L., 191
Egyed, O., 278
Ehrenberg, B., 258
Eichinger, K., 318
335
Author Index
3gendorf, G., 210
Zilerman, R. G., 166
Zkanayake, N., 77
Zlder, J. W., 47
3lgama1, M. H. A., 277
Zliel, E. L., 44
Zlizalde Gonzalez, M., 282
Zllerbrock, B. H., 266
Zlliott, W. H., 281
Zllis, A. B., 258
Sllis, J., 225
Zllis, P. R., 241
Zllison, B. O., 73
Zl-Naggar, L. J., 4
Slnaggar, S. R., 58
3-Sayed, M. A., 258
Zl-Sebakhv. N. A.. 195
Elsohly, M: A., 65, 66, 70,
174
Elvidge, J. A., 15
Emanuel, N. M., 245
Emanuelson, I., 73
Emelyanov, M. M., 33, 252
Emmer, G., 221
Encarnacion, R., 234
Endo, T., 32, 59
Engel, C. R., 325
Engel, L., 14
Enggist, P., 23
England, B. G., 283
Englert, G., 255
Enriquez, R., 103
Ensley, H. E., 36
Epstein, W. W., 62
Erasmuson, A., 195, 199
Erickson, E. W., 44
Eridente, A., 69
Erm, A., 15
Erman, M. B., 20, 34
Ernst, L., 48
Eschenmoser, A., 209
Escher, S., 32, 51, 231, 238
Escoffier, A., 260
Eshhar, Z., 285
Eskins, K., 255
Esposito, P., 58
Esvelt, R. P., 319
Etheredge, S. J., 135
Etoh, H., 14, 252
Eugster, C. H., 193, 237
Eyring, G., 258
Ezaki, Y., 241
Author Index
336
Fujita, E., 186, 190, 196
Fujita, T., 11, 21, 60, 197
Fujita, Y., 265
Fujiwara, H., 60, 280
Fujiwara, T., 165
Fukamija, N., 40, 89
Fukumoto, K., 27, 80, 223
Fukunaga, Y., 31, 263, 264
Fukungaga, T., 41
Fukushima, H., 234
Fukuzawa, A., 99
Fuller, T. J., 327
Fung, S., 316
Fung, V. A., 247
Furukawa, H., 146, 174
Furusaki, A., 99, 124, 157,
199,306
Fusaka, T., 165
Fusitani, M., 33
Gabbard, R. B., 325
Gabke, S. Y., 45
Gadwood, R., 121
Gaertner, W., 259, 260
Gagarina, A. B,, 245
Gage, D., 174
Gal, C., 42
Galdecki, Z., 55
Galindo, A,, 158
Galum, E., 72
Gambacorta, A., 329
Gambliel, H., 71
Ganguly, J. K., 231
Ganguly, R. N., 104
Cannon, M., 50
Garbers, C. F., 62
Garcia, C., 225
Garcia, G. A., 15
Garcia-Alvarez, M. C., 187,
188, 190, 192, 225
Garcia-Fraile, A., 47
Garcia-Granados, A., 199
Garcia-Martinez, A., 47
Garcia-Rodriguez, M. J., 72
Gardlik, J. M., 46
Gariboldi, P., 184, 194
Garnero, J., 31
Garti, N., 271
Garyanov, R. Kh., 230
Garzez, W. S., 192
Gasa, S., 199
Gase, R. A., 296
Gasic, M. J., 288
Gaskin, P., 197, 198
Gatilov, Y. V., 200
Gatuma, A. K., 146
Gaudioso, L. A., 62
Gaughan, L. C., 64, 74
Gaughan, R. G., 63
Gautier, B., 256
Geenevasen, J. A. J., 255
Gelbaum, L,. T., 102
Gemal, A. L., 13
Gendin, D. V., 46
Geneste, P., 39
Gen&t,J. P., 64, 101
Geoffre, S., 271, 272
Gerder, J. M., 306
Germain, G., 6, 114, 202,
228
Geroghty, N. W. A., 55
Gerr, R. G., 272
Gerstenberger, M. R. C., 288
Gerval, J., 10
Gerwick, W. H., 202
Ghaffiari, M. A., 307
Ghisalberti, E. L., 15, 78,
104, 186, 189, 202
Ghosal, S., 234
Ghosh, A,, 230
Ghosh, P. K., 193
Ghosh, S., 40, 230
Giacomelli, G., 13
Giannellini, V., 5
Gibbs, C. G., 93
Gibson, T., 47
Gibson, T. W., 312
Giddings, R. M., 52
Giebfried, J., 28
Gielen, J. E., 328
Gielen, J. W. J., 310
Giersch, W., 23, 38, 51, 179,
231, 238
Giglio, E., 272, 278
Giguere, R. J., 40
Gilad, S., 285
Gilbert, B., 215
Cilgan, M. W., 323
Gillick, S. G., 13
Gillis, H. R., 111
Gilrnore, C. J., 193
Gilmore, D. A., 257
Ginsburg, G. S., 49
Ginzburg, M. A,, 25
Girard, J. P., 60
Giumanini, A. G., 45
Gleizes, M., 4, 74
Glowka, M. L., 55
Glusenkamp, K.-H., 5, 6, 70
Glushko, L. P., 23
Goad, L. J., 311
Goadscloue, N., 4
Godfrey, J. D., 205
Goewert, R. R., 266
Goh, S. H., 202
Gold, P. M., 76
Goldberg, O., 110
Gollob, L., 73
Gomora, E., 226
Gonzalez, A. G., 80, 146,
158, 192, 195, 199, 225,
226, 230,
Gonzalez, D., 40
Gonzalez, P., 230
Gonzalez Sierra, M., 194
Goodman, M., 188
Goodwin, T. W., 235
Gopalkrishnan, B., 39
Gora, J., 55
Gordon, A. G., 41
Gordon, M. H., 102
Gore, K. G., 55, 56, 57, 64
Gorrichon, L., 101
Gorst-Allman, C. P., 172
Goryaev, M. I., 48, 62, 230
Goswami, A., 32,228
Goswami, S., 227
Goswami, U. C., 263
Got, R., 256
Goto, J., 282, 284
Goto, N., 282
Goto, T., 45
Gott, A. M., jun., 286
Gottlieb, H. E., 192, 276,
277, 292, 327
Gottlieb, 0. R., 192
Gougoutas, J. Z., 293
Gould, R. O., 88
Govind, N. S., 262
Govindan, S. V., 146, 155
Govindjee, R., 247, 260
Grabowich, P. G., 272, 293
Gradmann, W., 146
Graebe, J. E., 199
Graf, W., 221,299,300,301,
304
Graham, M. R., 4
Granat, M., 73
Grande, M., 32
Grandi, R., 61
Grandolini, G., 37, 223
Grant, H. G., 59
Grant, P. K., 188
Gras, J.-L., 108
Gray, G. D., 31 1
Gray, N. A. B., 280
Grayson, D. A., 55
Greaves, A. M., 228
Green, M. B., 64
Green, N. M., 327
Green, S., 8
Greenblatt, G. A., 106
Greenhouse, R., 291
Greenlee, M. L., 206
Greenlee, W. J., 130
Grenz, M., 88, 146,188,189,
196
Greuter, H., 64
Grice, P., 54, 160
Grieco, P. A., 61, 207, 223
Grignon-Dubois, M., 51
Grillasia, Y., 15
Grimm, M. F., 266
Grimminger, W., 219
Grishin, Y. K., 51
Groenendijk, G. W. T., 246
Gros, E. G., 195, 317
Groweiss, A., 200, 234
Grumbach, K., 74
Gschwendtner, W., 289
Guchi, S. E., 187
337
Author Index
Gudova, V. N., 55
Guelz, P. G., 44
Guerra, M., 7
Guest, J. R., 266
Guillerm, D., 82
Guirado, A., 45
Guiso, M., 5, 58, 59, 61
Guittet, E., 17
Gujval, V. K., 58
Gullerm, D., 31
Gumulka, J., 305
Gumulka, M., 325
Gunaherath, G. M. K. B.,
228
Gunatilaka, A. A. L., 227,
228, 230
Gunn, B. P., 34
Gupta, B. D., 259
Gupta, C. D., 187
Gupta, R., 14
Gupta, R. K., 75, 88, 106,
111, 115, 146, 155, 170,
172, 188, 189
Gupta, S. R., 58
Gupta, Y. P., 230
Gurria, G. M., 76
Gurst, J. E., 279
Gurudutt, K. N., 42
Gust, D., 243, 256
Gustafson, D. L., 239
Gut, M., 277
Gutierrez, A., 158
Gutman, A., 46
Gutwillinger, H., 33
Guziec, F. S., 53
Haas, A,, 288, 289
Habib, H. A. A., 195
Habib, M. M., 38, 255
Haces, A., 194
Hachey, D., 28
Hackler, L., 303, 327
Hadorn, M., 240
Haffer, G., 324
Haf-Muller, R., 62
Haginiwa, J., 232
Hahn, W. E., 46
Halim, A. F., 172
Hall, F., 169
Hall, I. H., 146, 174, 234
Hall, L. D., 273
Hall, T.-W., 172
Halls, T. D. J., 192
Halsall, T. G., 140
Hamada, Y., 19
Hamanaka, N., 199
Hamaoka, T., 284
Hamelin, J., 44
Hamer, L. F., 325
Hammerschimdt, F. J., 15
Hammond, M. L., 320
Han, D.-S., 215
Han, Y.-K., 99, 118
Hana, G. W., 47
Handley, J. R., 36
Handrick, G. R., 65, 66
Handy, G. A., 146
Haneda, A., 290
Hangauer, D. G., 179
Hanko, R., 40
Hanna, I., 33, 43, 304
Hansbury, E., 282
Hansen, K. B., 257
Hanson, J. R., 121,140,190,
195, 198, 199,292, 305
Hanson, R. C., 258
Harada, M., 230
Harada, N., 5
Harada, T., 21
Harborne, J. B., 4
Harderstein, R., 12
Harding, R. W., 262
Hardy, M., 234, 321
Harlow, R. L., 40
Harms, K., 66
Haroda, N., 277
Haromy, T. P., 232
Haroon, Y., 266
Harref, A. B., 114
Harris, D., 5
Harris, L., 255
Hart, R. J., 318
Hartley, G. S., 64
Hartshorn, M. P., 15, 194
Haruna, M., 144
Harvey, D. J., 5 , 279
Harwood, L. M., 49, 64
Hasa, T., 199
Hasegawa, I., 189
Hasegawa, S., 54, 221
Hashiba, N., 124
Hashimoto, H., 136
Hashimoto, K., 12, 33, 63
Hashimoto, T., 59
Hashimoto, Y., 226
Haslanger, M. F., 45
Hasler, H., 194
Hassam, S. B., 61
Hatem, J., 5
Hattori, H., 49
Hattori, S., 73, 183
Hausen, B. M., 232
Hauser, A., 81
Havel, M., 314, 325
Havinga, E., 310
Hayano, K., 49, 124, 126
Hayashi, C., 284
Hayashi, K., 8 5 , 200
Hayashi, S., 92,183,187,199
Hay Motherwell, R. S., 301
Hayward, G., 258, 259
Heath, R. R., 38,283
Heathcock, C. H., 177, 253
Heck, R. F., 35
Hecker, E., 200
Hedden, P., 199
Hedges, J. I., 232
Hefendehl, F. W., 73
Heftmann, E., 197, 207, 281,
282
Hegde, S. G., 12, 27, 31, 42
Hegedus, L. S., 11
Heide, L., 266
Heikes, J., 45
Heima, K., 86
Heindze, I., 33
Heinvali, M., 15
Heissler, D., 113, 114
Helbling, S. M., 61
Helquist, P., 121
Hendry, L. B., 70
Henke, S., 61
Hensens, 0.D., 228
Herak, R. M.; 272
Herbert, R. B., 4
Herlihy, W. C., 258
Hermann, A. O., 278
Hernandez, J. D., 115
Hernandez, M. G., 195,199,
230
Hernandez, R., 225, 308
Herold, T., 8
Herout, V., 4
Herz, W., 146, 155, 156, 172,
174
Herzfeld, J., 258
Hertzberg, S., 237
Hesse, M., 58
Hethelyi, E., 54
Heuberger, C., 301
Heywood, V. H., 4
Hibino, S., 12
Hickey, J. P., 275, 276
Hieda, T., 263
Hielsen, B. J., 60
Higo, M., 54
Hikino, H., 213
Hilgenberg, W., 210,261
Hill, A., 291
Hillenbrand, G. F., 161
Hilscher, J.-C., 29 1
Hiltunen, R., 5
Hirano, H., 66
Hirano, Y.,72, 269, 290
Hiraoka, K., 237
Hirata, T., 69, 72
Hiroi, K., 61
Hirose, Y., 54, 105, 158, 184
Hirotsu, K., 201
Hirschy, L. M., 41
Hirsl-Starcevic, S., 42
Hiscocks, P. G., 282
Hitchcock, P. B., 199
Hiyama, T., 10, 37, 42
Hixson, S. S., 53
Ho, T. L., 33, 64, 89
Ho, Z. Z., 258
Hoad, G. V., 198
Hoard, L. G., 270
Hobbs, P. D., 247,250
Hochlowski, J. E., 75, 202
Author Index
338
Hocquemiller, R., 85
Hoehne, E., 198, 272, 273
Hoeneisen, M., 146
Hoffmann, H. M. R., 40,47
Hoffmann, J. J., 60, 219
Hoffmann, K., 286
Hoffmann, R. V., 12
Hoffmann, R. W., 8
Hofmeister, H., 323
Hogge, L., 73
Hohn, J., 11
Holker, J. S. E., 87
Holland, D., 64
Holland, H. L., 329
Holly, S., 278
Holub, M., 174
Honda, K., 89
Honda, T., 223
Honig, B., 258,259,260
Honkan, V. A., 202
Hooper, C. L., 71
Hopf, H., 260
Hoppe, D., 40
Hoppen, V., 289
Horgan, R., 238
Hori, M., 210
Hori, T., 50
Horiai, H., 200
Horibe, I., 170
Horinaka, A., 35
Horiuchi, C. A.,295,360,318
Horn, P., 213
Horsewood, P., 294
Horunka, A., 37
Horvath, G., 328
Hosakawa, H., 52
Hoshino, Y . , 13
Hoskins, L. C., 257
Hosoda, H., 283
Hosomi, A., 16
Hostettmann, K., 7,234,283
Hostettmann-Kaldas, M., 7
Howard, B. M., 188
Howard, D. L., 231
Howbert, J. J., 103
Howden, M. E. H., 200, 318
Howell, S. C., 81
Hoye, T. R., 81
Hsieh, C.-L., 258
Huang, H.-C., 146
Huang, J. T., 58
Huang, K.-S., 260
Hubbard, L. M., 259
Nuber, C . P., 228
Huber, U., 47
Hubscher, J., 269, 318
Huchette, D., 33
Hudlicky, T., 63, 135
Huffman, J. C., 39, 223
Huffman, J. W., 156, 161
Hull, W. E., 276
Huls, R., 226
Huneck, S., 230
Hung, H. K., 31
Hunt, J. M., 73
Hunter, G . L. K., 57
Hunter, I. R., 281, 282
Hurst, K. M., 130
Hurtado, H. E., 204
Husain, J., 271
Husain, M., 290
Hutchinson, C. R., 60, 61
Hutchinson, S. A., 85
Hutson, K. G., 266
Hwang, K.-J., 38
Hylands, P. J., 228
Iacobucci, L. A., 36
Iavarone, C., 5, 58, 59, 61
Ibe, K., 74
Ibragimova, N. D., 55, 56
Ibuka, T., 146
Ichikawa, Y . , 158
Ichimoto, I., 33
Ichimura, K., 74
Ichinohe, Y . , 232
Ichinose, I., 20, 79, 203
Ida, T., 312
Ifeodike, N. P., 216
Ignatov, V. N., 271
Iguchi, K., 29, 60, 200
Iguchi, M., 14, 252
Ihm, H., 54
Ihn, W., 230, 279
Iida, H., 195
Iida, T., 174, 274, 277
Iijima, S., 44
Iino, M., 130
Iitaka, Y., 32, 59, 195, 215,
226, 232, 269,
Ikan, R., 74
Ikawa, I., 22
Ikeda, R., 199
Ikegami, A., 256, 260
Ikegami, S., 136
Ikegawa, S., 284
Ikekawa, N., 269, 290, 291,
314, 316
Ishihara, M., 59
Ishihara, S., 284
Ishii, H., 234
Ishii, K., 26, 79, 255
Ishikawa, H., 18, 25
Ishikawa, K., 12, 16, 259
Ishikawa, T., 274
Ishiwatari, M., 245
Ishiwari, H., 60
Ishizone, H., 226
Islamov, R., 188
Islimyeli, S., 80
Ismail, J., 47
Isobe, T., 196, 197
Itai, A., 226, 269
Ito, I., 46, 72
Ito, K., 144, 174
Ito, M., 43, 189
Ito, S., 13, 28, 142, 143, 146,
190
339
Author Index
Jackson, W. K., 295, 318
Jacobi, P. A., 170
Jacobs, H., 5 5
Jacobs, H. J. C., 310
Jacoli, G. G., 228
Jacquemin, H., 59, 156
Jacques, J., 325
Jacques, R., 74
Jacquier, R., 114
Jadhav, P. K., 115
Jaffer, J. A., 279
Jagodzinski, J. J., 305
Jahodar, L., 58
Jain, G. K., 231
Jain, K. M., 258
Jakobsen, P., 46
Jakupovic, J., 66, 75, 111,
116, 117, 146, 155, 158,
169, 170, 174, 187, 188,
189, 196
Jallali-Naini, M., 82
Jalsovszky, G., 278
James, J. C., 219
Janero, D. R., 255
Janiszo wska , W., 234
Janitschke, L., 48
Jansen, P. A. A., 246
Janssen, B., 298
Janus, J., 50
Jarchow, 0. H., 232
Jarvis, B. B., 93
Jasiczak, J., 321
Jautelat, M., 61
Jefferies, P. R., 15, 78, 186,
188, 189, 202
Jeffery, C., 111
Jeffrey, S. W., 255
Jeger, O., 209, 255
Jelenkovic, B., 272
Jennings, B. H., 308
Jensen, N.-H., 257, 259
Jensen, S. R., 57, 58, 59, 60,
70
Jensen, U., 21
Jerebzoff, S., 261
Jerebzoff-Quintin, S., 261
Jerris, P. J., 119
Jewers, K., 279
Jigajinni, V. B., 298
Jimenez, F. G., 226
Jizba, J., 169
Joffe, A. Z., 213
Johansson, L. B. A., 258
John, L. S., 321
Johne, S., 58
Johnson, D. F., 289, 298
Johnson, K. K., 13
Johnson, M., 72
Johnson, M. A., 5,205
Johnson, M. W., 299
Johnston, J. O., 324
Jolad, S. D., 60, 219
Jommi, G., 184, 194
Jones, A. J., 15
Jones, B. B., 36
Jones, D., 266
Jones, G., 282
Jones, T. H., 60
Jones, W. A., 271
Jonkers, F. L., 34
Jordan, J. R., 283
Joseph, J. M., 312
Joseph-Nathan, P., 103, 115
Joshi, B. C., 4
Joshi, B. S., 227
Joshi, G. D., 5 5 , 56, 64
Joshi, K. C., 192
Joshi, R. S., 56
Jost, P. C., 285
Joucla, M., 44
Joulain, D., 31
Julia, M., 16, 39, 49, 62, 64,
89, 239
Julia, S., 17, 64
Julien, R., 272
Jung, M. E., 181
Jungk, S., 69
Junior, P., 59
Juranic I., 288
Kabore, I., 42
Kabuto, C., 81, 143, 213
Kad, G. L., 21
Kadam, S. R., 296
Kadota, S., 213
Kaegi, H., 246
Kagan, H. B., 4
Kahn, M., 135
Kaiya, T., 199
Kaji, K., 12, 20, 33, 63
Kajihara, Y., 12, 16
Kajtar-Peredy, M., 256
Kakitani, H., 251, 259
Kakitani, T., 251, 259
Kalikhman, I. D., 46
Kalinovskii, A. I., 230
Kalisky, O., 260
Kalkoff, H., 50
Kalvoda, J., 272, 289
Kalyani, K., 193
Kamber, M., 243
Kameoka, H., 70
Kametani, T., 27, 28, 29, 34,
80,223, 252, 314
Kamernitskii, A. V., 271,272
Kamga, C. S., 221
Kamigauchi, T., 189,234
Kamikawa, T., 196
Kamogawa, H., 259
Kanaiwa, T., 115
Kanakura, A., 10
Kanaoka, M., 230
Kane, B. J., 14, 41, 45, 50
Kaneko, H., 85, 238, 252,
253
Kanemoto, Y., 124
Kano, S., 12
340
Kawashima, T., 190
Kawazu, K., 176
Kayukova, G. P., 286
Kazi, M. A., 58
Kazlauskas, R., 200
Keana, J. F. W., 285
Keiderling, T. A., 6
Keim, W., 12
Kelecom, A., 275
Keller, P., 323
Keller, U., 32
Kemertelidze, E. P., 73
Kemmerling, M., 266
Kempe, U. J., 172
Kenne, L., 234
Kepner, R. E., 73
Kerb, U., 308, 323
Kergomard, A., 299, 329
Kern, M., 48
Kerr, K., 66
Kessel, C. R., 185
Khan, I. A., 307
Khan, N. H., 290
Khan, S. A., 223
Khan, V. A., 73
Khanna, N. M., 46, 231
Khanna, R. N., 67
Khanra, A. S., 57
Khatri, L. M., 58
Khastgir, H. N., 228
Khoi, N., 223
Kholi, J. C., 14
Khorana, H. G., 260
Khuong-Huu, Q., 42
Khrostik, G. M., 48
Kido, F., 81, 165
Kido, M., 158, 203, 210
Kienzle, F., 240
Kikuchi, H., 88, 99, 157, 200
Kikuchi, M., 15
Kikuchi, T., 213, 230
Kikuchi, Y . , 214
Killinger, T. A., 61
Kim, H.-O., 230
Kim, J. B., 285
Kim, S.-W., 179
Kimbu, S. F., 221
Kimmel, Y., 66
Kimura, K., 34
Kimura, M., 273
Kimura, O., 214
Kirnura, Y., 21, 234, 260
King, A. O., 18
King, R. M., 62, 66, 73, 75,
88, 106, 114, 115, 116, 117,
146, 155, 156, 158, 169,
170, 172, 174, 186, 187,
188, 189, 195, 196, 225
Kinghorn, A. D., 85
Kingsley, P. B., 266
Kini, A,, 246
Kinoshita, M., 135
Kinosita, K., 260
Kinting, A., 42
Author Index
Kirby, G. W., 294
Kircher, H. W., 225
Kirfel, A., 181
Kirk, D. N., 140, 273, 303,
322, 323
Kirkwood, P. S., 197, 198
Kirmse, W., 53
Kirson, I., 277, 292
Kirtany, J. K., 67, 103
Kisaki, T., 31, 263, 264
Kise, N., 64
Kiselev, A. V., 282
Kisiel, Z., 6
Kitagawa, I., 31, 46, 48, 189,
210,234
Kitahara, H., 165
Kitahara, T., 15
Kitazawa, E., 187
Kitchin, J. P., 35
Kitson, D. H., 85
Kim, H., 234
Kizuka, K., 3 11
Kjonaas, R., 71
Klaui, H., 235
Kleijn, H., 19, 78
Klein, E., 33
Klein, P. D., 280
Kleinig, H., 260
Klemmenson, P. D., 64
Klimash, J. W., 146
Klimetzet, D., 28
Klina, W. L., 18
Klinotova, E., 231
Klyner, Y. P., 41
Kneen, G., 64
Knight, D. W., 21, 75, 76
Knight, J. C., 328
Knights, S. G., 305
Knipser, W., 14
Knoblauch, K., 54
Knoll, H. E., 266
Knoll, F. M., 22
KO, S. S., 130
Kobayashi, K., 57
Kobayashi, M., 77,200,210,
229, 253
Kobayashi, S., 58
Kobayashi, Y., 234, 284
Koch, H., 47
Koch, M., 58, 59
Kochetkov, N. K., 264
Kochhar, K. S., 36
Kocienski, P. J., 24
Koco'r, M., 298
Koc'orsky', P., 290, 293, 294,
325
Kodama, H., 238
Kodama, K., 257
Kodama, M., 28, 142, 143,
146
Koden, M., 287
Koedam, A., 44
Koenst, W. M. B., 252
KGster, F.-H., 111
Author Index
Kroszczynski, W., 298
Krow, G. R., 46
Krueger, H., 284
Kruglaya, 0.A,, 46
Kruppa, G., 46
Krgukov, P. G., 260
Krywuta, S., 238
Ksander, G. M., 205
Kubo, I., 196
Kubo, S., 163
Kubota, N., 183
Kubota, T., 196, 197
Kucaba, W., 59
Kuchin, A. V., 12, 48
Kuczynski, H., 43
Kudryavtseva, M. I., 37
Kueh, J. S. H., 136
Kula, J., 38
Kulesha, I. D., 318
Kulikova, K. E., 272
Kulishov, V. I., 272
Kulkarni, G. H., 55, 56, 57,
64
Kulshreshtha, M. J., 46
Kumagai, A., 230
Kumagai, T., 20, 79, 203
Kumagi, M., 11
Kumar, N., 146, 156, 172,
174
Kumar, S., 4
Kumar, V. P. S., 226
Kumobayashi, H., 42
Kunesch, N., 85
Kurane, R., 74
Kurata, K., 99
Kurata, T., 51, 67
Kurek, A,, 325
Kurihara, T., 15
Kurita, N., 74
Kuriyama, K., 170
Kurobe, H., 28, 29, 34, 80,
252
Kurosawa, E., 88, 111, 157
Kurusu, Y., 13
Kusabayashi, S., 287
Kushinsky, S., 282
KUSS,E., 283
Kusumoto, S., 200
Kutchan, T. M., 63, 135
Kutney, J. P., 54, 55, 160,
210,228
Kutnik, J., 259
Kutschabsky, L., 198
Kuwajima, I., 46
Kuwata, M., 41
Kuzmichkin, P. V., 62
Kuznetsova, R. E., 25
Kwon, Y. C., 312
Kyogoku, Y., 210
Kyonaas, R., 72
Laats, K., 15
Lablache-Combier, A., 172
341
Labler, L., 290
Lachenmeier, A,, 240
Ladika, M., 76
Ladner, W., 8
Ladwa, P. H., 55
Lafont, R., 282
Lafontaine, J., 166
Laguerre, M., 51
Lahav, M., 271, 309
Lakshminarayana, V., 214
Lal, M., 37
Lalande, J., 31
Lallemand, J.-Y., 31,82, 174
Lamatkin, A. I., 41
Lamazouene, A. M., 52
Lamb, N., 48
Lambert, G., 65
Lamberton J. A,, 190
Lambotte, R., 328
Lammel, G., 60
Lamparsky, D., 32
Land, E. J., 243
Lander, N., 51, 66
Lang, C., 303
Lange, G. L., 42, 142
Lansbury, P. T., 179
Lanteri, S., 43
Lantzsch, R., 61
Lanzetta, R., 211
Lapalme, R., 45
Larcheveque, M., 82
Lardicci, L., 13
Laszlo, P., 328
Laszlo, T., 245
Laudova, V., 169
Lauer, M., 44
Lauher, J. W., 202
Laurent, H., 323
Lautens, M., 142
Law, J. H., 77
Lawrence, R. F., 10
Laycock, D. E., 302
Lazare, S., 33, 50, 304
Lazarev, Y. A., 260
Le, A. T., 76
Leander, K., 66
Leblanc, R. M., 259
Leboeuf, M., 85
Leclaire, R., 255
Leclercq, J. M., 259
Leclercq, M., 255
Lee, E., 315
Lee, G. J.-L., 282
Lee, J. G., 50
Lee,K. H., 53, 146, 174, 223,
234
Lee, T. S., 238
Lee, Y.-W., 315
Legon, A. C., 6
Lehmann, D., 59
Leiserowitz, L., 271, 309
Leistner, E., 266
Lemaitre, P., 3 1, 82
Le Merrer, Y., 89
342
Logan, R. T., 297, 299
Lohmann, J. J., 64
Lohr, K., 142
Lojewska, Z., 259
Lok Ho, T., 39
Lolmlund, C. E., 93
Lombardo, L., 199, 205
Lombardo, L. R., 266
Lonergan, G. C., 164
Lonergan, G. T., 39
Loomis, W. D., 4, 72
Lopez-Diaz, I., 262
Lopez, H., 114
Lorenc, L., 272,273,288,289
Lotan, D., 250
Lotan, R., 250
LOW,C.-E., 280
Lu, P. Y., 259
Luche, J. L., 13
Luckner, M., 4
Luft, R., 41
Lugaro, G., 210
Lugtenburg, J., 246,258,259
Lukacs, G., 4, 181, 276
Lukashin, A. V., 257
Lusinchi, X., 303
Luteijn. J. M., 65, 204
Lutz, W., 36
Lyman, H., 239
Lynch, J. E., 44
Lyon, G. D., 54
Lyse-Petersen, S. E., 59
Lythgoe, B., 318
Lyuts, A. E., 48, 62
Mabry, T. J., 193
MacAlpine, D. K., 123
Macaulay, J. B., 40
McCaskill, R. H., 131, 134
McCombs, C. A., 181
McConnell, 0. J., 31, 79,201
McCorkindale, N. J., 85, 86
McCormick, J. P., 299
Macdonald, J. E., 10
McDonard, J. T., 6
McElhinney, R. S., 50
McGarry, G., 299
McGrath, M. J., 55
McGuire, F. J., 116
McInnes, A. G., 277
McIntyre, C. R., 86, 234
McIntyre, D. E., 78
McIntyre, H. B., 281
Mackae, I. C., 38
McKervey, M. A., 174
MacKinnon, S., 5
MacKoul, P. J., 327
MacMillan, J., 197, 198
McMillen, D. A., 285
McMorris, T. C., 323
McMurry, J. E., 205, 300
McMurry, T. B. H., 160
McPhail, A. T., 190
Author Index
Maddocks., P. J., 10
Madruzza, G. F., 194
Maeda, K, 286
Maeda, N., 306, 3 11
Maemoto, K., 36
Maentele, W., 260
Magasuna, K., 16
Magno, S., 201
Magnus, P., 20
Magnus, P. D., 52
Mahato, S. B., 189, 230
Mahmoud, I. I., 85
Mahmoud, M. M., 271
Mahmoud, Z. F., 102
Mahon, M., 81, 82, 83
Mailahn, W., 107
Maillo, M. A., 83
Main, P., 272
Maione, A. M., 270, 306
Maiti, S. N., 230
Maitra, M., 234
Majerski, Z., 42
Majewski, M., 17, 63
Maji, K. S., 204
Makhankov, V. V., 216
Makin, H. L. J., 282
Makino, M., 259
Makowski, B., 46
Malakov, P., 190
Maldonado, L. A., 15
Malingre, T. M., 60
Malinovskaya, G. V., 216
Malinovskii, M. S., 23
Mallavarapu, G. R., 226
Malleron, J. L., 11, 43
Mallik, B., 258
Mallinson, P. R., 271
Malone, J. F., 174
Maltsev, D., 264
Manchand, P. S., 200, 202
Mancuso, A. J., 288
Mandai, T., 19, 251
Mander, L. N. 195, 199, 205
Mandloi, D., 234
Mane, B. M., 56, 57
Mangoni, L., 211
Manh, D. D. K., 100
Manitto, P., 207
Manley, R. P., 314
Mann, V., 283
Mannschreck, A., 7
Mansilla, H., 158
Mansour, E . 4 . S., 228
Mantulin, W. W., 286
Manukov, E. M., 62
Mao, B., 247,259, 260
Maoka, T., 237
Maradufu, A., 146
Marazza, F., 121
Marcelin, G., 50
Marcelle, G. B., 221
March, G., 201
Marchand, B., 46
Marekov, N. L., 312
343
Author Index
Matsuo, A., 92, 183, 187
Matsuo, K., 116
Matsuo, N., 64
Matsuo, T., 19
Matsushita, H., 23, 85, 253
Matsushita, K., 234
Matsuura, Y., 199
Matsuzaki, T., 199
Matteson, D. S., 50
Matveets, Y. A., 260
Matz, J. R., 39
Maumy, M., 49
Maurer, B., 81
May, E. L., 66
Mayer, G. D., 327
Mayer, H., 237, 240, 247,
253
Maynard, J. K. L., 41
Mayol, L., 201
Mazumdar, P. C., 189
Mazumder, A., 52
Mazur, Y., 276, 309
Mazza, F., 270, 272, 306
Mazzola, E. P., 93
Meadows, J. D., 314
Mechoulam, R., 51, 66, 74,
318
Medarde, M., 48, 118
Mednikova, N. A., 251
Medwick, T., 282
Meganathan, R., 266
Megges, R., 272,273
Meguri, H., 199,231
Mehrotra, A. K., 52
Mehta, G., 39, 135, 193
Meiboom, S., 287
Meier, B., 59
Meier, H., 193
Meier, W., 290
Meijer, E. W., 53
Meijer, J., 19
Mekeev, E. M., 255
Mellerio, G., 135
Mellor, M., 136
Meltzer, P. C., 65, 66
Menarchy, M. D., 196
Merchant, J. R., 21
Merchlinsky, M. J., 298
Merienne, C., 222
Merrien, A., 216
Mervic, M., 327
Meskens, F. A. J., 297
Messerschmidt, A., 272, 273
Mesta, C. K., 102
Mestres, R., 37, 40
Metcalf, B. W., 226, 324
Metge, C., 42
Meunier, B., 48, 216
Meyer, M. D., 314
Meyers, A. I., 44
Mhehe, G. L., 31
Michon, J., 53
Micovic, I., 272
Midgley, J. M., 47
Author Index
344
Mukherjee, D., 204, 325
Mukherjee, K., 226
Mukherjee, K. S., 193
Mukhopadhyaya, S. K., 204
Mukitanova, T. R., 49
Mulholland, D. A., 219
Muller, B. L., 23
Muller, G. W., 135
Muller, P. M., 13
Muneyuki, R., 50
Munro, M. H. G., 15, 194
Murae, T., 21 1, 223
Murahashi, S. I., 28, 52
Murai, A., 29, 79, 163, 166
Murai, F., 58, 59, 60
Murai, N., 61
Murakami, T., 195
Muraki, S., 32, 141
Muramatsu, T., 57
Murata, S., 124
Murata, Y., 126
Murato, K., 255
Murgia, S. M., 259
Murillo, F. J., 262
Muro-Oka, Y., 22
Murphy, C. J., 53
Murphy, P. T., 15, 201
Murphy, R., 29
Murray, M. J., 73
Murray-Rust, J., 124
Murray-Rust, P., 124
Murthi, G. S. S., 52
Murthy, P. P. N., 98
Murty, V. S., 226
Murty, Y. L. N., 214
Musavirov, R. S., 16
Musiani, M. M., 45
Musser, J. H., 205
Muto, S., 262
Mutsushita, S., 38
Muzart, J., 11, 13
Myers, A. B., 259
Myshenkova, T. N., 40
Myskewnora, T. N., 14
Nabeya, H., 199
Nadaya, K., 183
Naf, F., 21, 179
Nafie, L. A., 5
Nagai, K., 40
Nagai, M., 214, 216
Nagai, S., 46
Nagai, Y., 13
Nagajima, K., 59
Nagakura, A., 54
Nagano, E., 254
Nagao, K., 179
Nagao, Y., 186
Nagaoka, M., 325
Nagar, P. K., 256
Nagasaki, M., 187
Nagasampagi, B. A., 146,
158, 210,232
Nagata, S., 262, 263
345
Author Index
Noyori, R., 24, 44, 124
Nozaki, H., 25, 29, 37, 42,
63, 183
Nozaki, K., 15
Nozaki, N., 12
Nozari, H., 10
Nozoe, S., 4
Numazawa, M., 270, 289
325
Nunn, M. J., 98
Nyfeler, R., 121
Obermann, H., 33
Oberti, J. C., 195
Obi, Y.,31, 263, 264
OBrien, E., 87
Ochi, M., 201
Ochiai, M., 186
Oda, N., 46
Odeh, I. M. A., 170
ODowd, M. L., 45
Oesterhelt, D., 259, 260
Offermann, W., 7
Ogasawara, K., 38, 206
Ogawa, K., 192
Ogawa, M., 229
Ogihara, Y., 229, 234
Ogiso, A., 187
Ognyanov, I., 172
Ogunkoya, L., 207
Ogura, H., 160
Ogura, K., 77
Ogura, M., 226
Oguri, K., 66,266
OHare, M. J., 281
Ohashu, K., 39
Ohbao, S., 189
Ohfune, Y., 124
Ohloff,G.,23,37,38,51,81,
91,179,231,238
Ohlsson, A., 66, 73
Ohmizu, H., 64
Ohmori, H., 234
Ohmori, M., 319
Ohnishi, R., 49
Ohno, A., 45
Ohno, K., 61
Ohnuma, T., 141
Ohsawa, T., 290
Ohta, Y., 158
Ohtsuka, T., 124, 126
Oikawa, T., 25
Oishi, T., 8 5 , 193, 194,290
Ojhara, B., 77
Ojima, I., 11
Ojinnaka, C. M., 231
Oka, S., 45
Okabe, H., 214
Okada, S., 210
Okada, Y., 15,234
Okamoto, K. A., 73
Okamura, N., 215
Okamura, S., 14
346
Paul, D., 271
Paul, V. J., 31
Pauly, G., 74
Pauptit, R. A., 6
Paupurdin, C., 72
Pavanasasivam, G., 93
Pavel, N. V., 272
Pavia, A. A., 39
Pavlin, M. S., 49
Pavlovic, V., 272, 273, 289
Pawson, B. A., 247
Payan, C., 260
Payne, T. G., 188
Pearce, A., 19
Pearson, A. J., 97
Pecher, J., 228
Pedulli, G. F., 7
Pegg, D. T., 274
Pelister, Y.,39
Pelizzoni, F., 68, 204
Pelliciari, R., 31, 192, 194,
252, 324
Pena, A., 199
Pentegova, V. A., 73
Peppard, T. L., 15
Perales, A., 191, 192
Pereira, V. A., 42
Perez, C., 62, 80
Peries, R., 31
Perkins, M. J., 52
Pernold, W., 47
Perz, R., 40
Pete, J. O., 11, 13
Peters, J. A. M., 307
Petiaud, R., 33
Petit, F., 33, 48
Petrasiunas, G. L. P., 53
Petrov, A. A., 286
Petzdolt, K., 323
Pfander, H., 240, 243
Pfenninger, J., 300, 301
Pham, C. C., 4
Philibert, D., 324
Phillips, F. L., 227
Phillips, L. R., 35, 39
Phillipson, J. D., 223
Phinney, B. O., 198
Piatkowski, K., 35, 37, 43
Piattelli, M., 186, 201
Piau, F., 64
Picard, J. P., 10
Pichet, L., 327
Pickard, J., 106
Pickenhagen, W., 62
Pierce, T. E., 36
Piers, E., 172
Pietrzak, J., 298
Pillai, N. K., 307
Pillot, J.-P., 10, 25, 51, 62
Pinchin, R., 196, 215
Pinder, A. R., 156
Pinnick, H. W., 24, 36, 38
Pinto, A. C., 192, 196, 215
Piozzi, F., 190, 191, 230
Author Index
Pirozhkov, S. D., 14, 40
Pirrung, M. C., 118
Pitha, J., 250
Pitt, C. G., 65, 66
Piwinski, J. J., 178
Pizza, C., 318
Pizzi, P., 328
Pizzo, C. F., 34
Platzer, N., 4
Plimmer, J. R., 63
Plummer, T. L., 180
Poddubnaya, S. S., 14, 40
Podlejski, J., 38
Pokhilo, N. D., 216
Pol, A. V., 50, 56
Polavarapu, P. L., 5
Poldidon, G., 59
Poletti, A., 259
Polishchuk, A. P., 272
Polo, M. C., 37
Polonsky, J., 156, 194, 216,
222,223
Polunin, E. V., 16
Pomilio, A. B., 195
Pons, M., 289
Ponsold, K., 273, 282, 302
Ponton, J., 121
Poots, I., 68
Popa, D. P., 195
Popli, S. P., 228
Popov, A. A., 49
Popov, 0. S., 255
Popov, S., 312
Popovitz-Biro, R., 271, 309
Popp, A., 73
Popplestone, R. J., 23
Porath, G., 66
Porte, A. L., 123
Porter, J. W., 235
Postlewhite, A., 50
Potlier, E., 40
Poulose, A. J., 35, 71
Poulter, C. D., 20, 63, 76
Pouskouleli, G., 275, 276
Pouzar, V., 314, 325
Povelikina, L. N., 46
Povodyreva, I. P., 5 5 , 56
Powell, L. A., 250, 251
Pownall, H. J., 286
Poznyakov, S. P., 250
Pradhan, S. K., 296
Prager, R. H., 29
Prakasa Rao, A. S. C., 93,99
Prange, T., 43,156,226,270,
297
Prasad, R. S., 205
Prasanna, S., 226
Precigoux, G., 271, 272
Prelesnik, B. V., 272
Prestwich, G. D., 74, 202
Pretzsch, G., 174
Pribytkova, I. M., 20, 34
Price, H. C., 277
Price, J. C., 256
347
Author Index
Ratner, V. V., 43, 55
Rau, W., 261, 262
Raucher, S., 10, 38
Rautenstrauch, V., 12, 14
Ravelo, A. G., 230
Ravelo, F., 80
Raverty, W. D., 44
Ravi, B. N., 234
Ravichandran, R., 302
Ravindranath, B., 42, 67
Ray, R., 50
Rayer, R. C., 62
Raymaud, J., 280
Razdan, R. K., 65, 66
Read, C. M., 292
Read, R. W., 292, 302
Reck, G., 198, 273
Recti, M. T., 8
Reddy, A. V., 39, 135
Reddy, G. C. S., 228
Reddy, G. S., 300
Reddy, N. S., 106
Redshaw, S. D., 22
Rees, J. C., 6, 54
Reetz, M. T., 92, 297
Reger, D. L., 255
Reh, E., 282
Reich, H. J., 76
Reichert, U., 177
Reiffsteck, A., 281
Reinbold, A. M., 195
Reis, F. A. M., 215
Renstrom, B., 237
Rentzepis, P. M., 259
Repke, K., 326
Rettig, M. F., 64
Reutov, 0. A., 49, 51
Reverdy, G., 53
Revial, G., 101
Rey, M., 110
Reye, C., 40
Ribaldi, M., 192
Riccio, R., 318
Richard, C., 323
Riche, C., 85
Rickards, R. W., 37
Riddell, F. G., 124
Riechst, R. A. K., 38
Rieger, D. L., 38
Riehl, J.-J., 113, 114
Riesselmann, B., 286
Rihs, G., 272, 289
Rilling, H. C., 76
Rimpler, H., 59, 60
Risinger, G. E., 69
Rist, G., 272, 289
Ritter, F. J., 77
Rivera, A., 308
Rivier, L., 197
Rizvi, S. H., 228
Rizvi, S. Q. A., 275
Roberts, J. S., 116, 124
Roberts, M. R., 161
Robinson, C. H., 308
Rubin, M. B., 46
Rubinova, N. R., 5 5
Rucker, E., 43
Rudnick, M. S., 239
Rucker, G., 38, 181
Rueedi, P., 193
Ruel, O., 64
Ruest, L., 166
Riittimann, A., 237, 240
Ruhdorfer, J., 59
Rulko, F., 63
Rullkotter, J., 232
Ruppert, J. F., 60, 99
RUSSO,
G., 210, 328
Rustaiyan, A., 88, 146, 172
Rustidge, D. C., 75
Rutledge, P. S., 292,302,327
Ruveda, E. A., 194
Ruzicka, L., 209
RUZO,L. O., 64,74
Ryabora, K. C., 40
Ryabushkina, N. M., 33
Rybakov, V. B., 271,272
Rychlewska, U., 146
Rychnovsky, S. D., 27
Rycroft, D. S., 146, 216, 221
Rykowski, Z., 41, 49, 50, 51
Ryoshentseva, M. A., 33
Saburi, M., 253
Sadasivan, V., 41
Sadler, I. H., 121, 140
Sadowska, H., 55
Saeedi-Ghomi, M. H., 127,
128
Saengchjan, S., 266
Saenz de Buruaga, A., 199
Saga, H., 54
Sahu, N. P., 230
Sahui, R., 26
Sai, H., 190, 196
Sainton, J., 48
Sainty, D., 59
Saito, A., 85
Saito, H., 230,277,290,291
Saito, M., 16
Saito, T., 29, 141, 213
Saito, Y., 189, 266
Sakai, K., 126
Sakai, S., 232
Sakai, T., 59, 60, 70, 172
Sakakibara, J., 199
Sakan, F., 134, 136
Sakan, T., 59
Sakata, I., 32
Sakata, J., 73
Sakdarat, S., 29
Sakina, K., 59
Sakuma, K., 20, 33, 63
Sakurai, H., 16
Sakurai, N., 214,216
Salama, O., 7,, 58, 60
Salazar, J. A., 226, 308
348
Salemink, C. A., 67
Salen, G., 291, 312
Salisbury, P., 45, 48
Salisbury, P. J., 228
Salomon, R. G., 40
Sam, F. W., 31
Samaddar, A. K., 203
Samek, Z., 169, 174
Sammon, M., 287
Samokhvalov, G. I., 247,
255,261
Samsonova, V. N., 23
Samuel, O., 44
Samuelsson, G., 234
Sanchez, I. H., 103, 204
Sandberg, F., 234
Sanders, J. K. M., 273
Sandmann, G., 210, 261
Sandorfy, C., 259
Sandra, J. M., 15
San Feliciano, A., 118
Sangaiah, R., 67
Sanghui, Y. S., 67
Sanjoh, H., 29, 60
Sankaram, A. V. B., 106
Sankawa, U., 215, 277
Sannikov, 0. B., 255
Sano, H., 19,42
Sano, T., 232
Sansoulet, J., 9
Sant, P. G., 234
Santaniella, E., 295
Santelli, M., 40, 42
Santer, J. M., 247, 253
Santiago, M. L., 307
Santini, C., 142
Saplay, K. M., 26
Sarel, S., 54
Sarg, T. M., 102
Sarig, S., 271
Sarkar, A. C., 230
Sarkisian, G. M., 310
Sarma, M. R., 41
Sasaki, H., 32, 59
Sasaki, M., 63
Sasaki, S., 37, 42
Sashida, Y., 192
Sastre, B. A., 32
Sato, F., 18, 25, 44
Sato, K., 76, 89, 234, 264
Sato, M., 18, 25, 44
Sato, S., 61, 166
Sato, T., 9,30,33,36,39, 170
Sato, Y., 211
Satoh, J. Y., 295, 300, 318
Satoh, T., 172
Sattar, A., 31, 124
Saucedo, R.,190
Saucy, G., 13, 254
Sauer, G., 324
Sauer, M. J., 284
Saul, J. A., 329
Saussay, R., 72
Saussine, L., 62
Author Index
Savard, S., 193
Saverwein, P., 28
Savoia, D., 25
Savona, G., 190, 191, 225
Savu, P. M., 17
Sawada, T., 234
Sawitzki, G., 218
Sawutz, D. G., 277
Sawzik, P., 286
Sayama, S., 157
Sayed, Y., 65
Scallen, T. J., 282
Scarborough, R. M., 43
Schade, W., 279
Schafer, H.-J., 21
Schaffner, K., 61
Scharf, H. D., 50
Scheffer, J. J. C., 44, 73
Scheidl, O., 33
Schene, A. L., 42
Schenk, H. P., 32
Schenone, P., 43, 46
Scheuer, P. J., 79, 200
Schiedt, K., 237
Schikop, T., 74
Schlatter, H.-R., 299
Schlessinger, R. H,, 161
Schlewer, G., 318
Schlosser, M., 35
Schmalle, H. W., 232
Schmidt, G., 25
Schmidt, J., 230
Schmitt, K., 286
Schmitt, P., 210
Schmuff, N. R., 43
Schneider, G., 198,303,327
Schneider, H. J., 50, 289
Schnelle, G., 8
Schnoes, H. K., 319
Schonecker, B., 273, 279,
282, 302
Schonholzer, P., 269, 318
Scholler, R., 281
Schostarez, H., 119, 129
Schouwey, M., 32
Schram, K. H., 219
Schreiber, K., 198
Schreiber, S. L., 38, 142
Schreier, P., 33
Schreiner, R., 258
Schrock, A. K., 279
Schroepfer, G. J., jun., 318
Schrott, E. L., 262
Schrott, U., 8
Schuber, F., 210
Schubert, G., 273,279
Schuelte, H. R., 4
Schulte, G., 79
Schulte-Elte, K. H., 12, 23,
28
Schulze, P.-E., 308
Schultz, A. G., 302
Schultz, G., 266
Schurig. V.,8
Author Index
Sharma, S. P., 37, 39
Sharpless, K. B., 20, 23, 27,
50
Shaw, D. J., 266
Shaw, I. M., 38,47
Shchirina-Eingoru, I. V., 48
Shea, C. M., 99, 309, 311
Shearer, M. J., 266
Shefer, S., 312
Sheldrick, G., 66
Sheldrick, W. S., 48
Sheppard, P. N., 202
Sheth, J. P., 135
Sheves, M., 247
Shewmaker, C., 277
Shiao, M. S., 70, 88
Shibaev, V. N., 264
Shibagaki, M., 252
Shibasaki, M., 136
Shibata, K., 197
Shibata, S., 15,230,234,253
Shibayama, F., 200
Shichida, Y., 259
Shido, K., 234
Shieh, H.-S., 270
Shiga, M., 59
Shimada, A., 241
Shimada, K., 142, 143
Shimizu, M., 46, 48
Shimizu, N., 63, 214
Shimokawa, T., 115
Shimomura, H., 192
Shimozuma, K., 33
Shimpo, T., 54
Shingu, T., 58, 197, 230
Shioiri, T., 19
Shiojima, K., 225
Shiota, H., 59
Shirahama, H., 49, 115, 123,
124, 126, 134, 136
Shirai, N., 199
Shirakawa, K., 234
Shiroishi, M., 256
Shishibori, T., 68, 264
Shiuey, S.-J., 318
Shkrob, A. M., 247
Shmelev, L. V., 20, 34
Shmitz, R., 66
Shmueli, U., 234
Shochet, N. R., 271, 309
Shoda, S., 21
Shoeb, A., 228
Shono, T., 64
Shoolery, J. N., 63, 106
Shoppee, C. W., 318
Shoyama, Y., 66
Shropshire, W., jun., 262
Shukla, Y. N., 60
Sicva, M., 146
Siddall, J. B., 316
Siebert, F., 260
Siefermann-Harms, D., 237
Siegman, A., 258
Siemienink, A., 43
349
Sieng, L. H., 194
Sietsema, W. K., 263
Sigurdson, E. P., 45
Sil, A. K., 231
Sillesen, A. H., 257
Silveira, A., 18
Silveira, E. R., 190
Silverman, R. B., 265
Silverstein, R. M., 36
Sim, G. A., 123, 146, 169,
193
Simes, J. J. H., 215, 225
Simmross, F. M., 44, 91
Simonov, V. I., 271, 272
Simons, S. S., 289, 298
Simpson, I. C., 198
Simpson, J. B., 69
Simpson, K. L., 235, 245,
256
Simpson, T. J., 86, 87, 88,
234
Sims, D., 174
Sims, J. J., 15, 92
Sims, R. J., 81
Singaram, B., 52
Singh, A. K., 5 , 55
Singh, H., 271
Singh, J., 206, 214
Singh, P., 146
Singh, P. N., 234
Singh, R. D., 6
Singh, S. B., 32,234
Sinnott, M. L., 197
Sinyakov, G. N., 245
Sippel, C. J., 266
Sircar, P. K., 256
Sircar, S. M., 256
Sisani, E., 194, 252
Sisti, M., 184, 194
Sivaramakrishnan, R., 295
Sjostrand, U., 312
Skattebol, L., 20
Skatovski, E. D., 33
Skeiton, B. W., 78, 182
Skorkovska, H., 231
Skorobogatova, E. V., 46
Skripiuk, 0. B., 56
Skulberg, 0. M., 238
Slack, D. A,, 22
Slade, C. J., 322, 323
Slemt, J., 281
Sloan, K. B., 275
Slougui, N., 63, 89
Smit, E. N., 73
Smith, A. B., 43,63,119,300
Smith, A. G., 281
Smith, D. H., 280
Smith, E., 256
Smith, I. H., 64
Smith, L. C., 286
Smith, L. L., 280
Smith, T. L., 164
Smoczkiewicz, M. A., 321
Smolik, R., 303
Snajbark, K., 73
Sneden, A. T., 228
Snider, B. B., 9, 21, 28, 40,
48, 61, 63, 312
Snieckus, S., 17
Snieckus, V., 63
Snowden, R. L., 91, 113
So, S., 142
Soai, K., 44
Sobotka, W., 57
Sodano, G., 79, 298, 329
Soderlund, D. M., 64
Sohani, S. V., 296
Sohar, P., 303
Sohoni, J. S., 158
Sokoloski, E. A., 60
Sokolovsky, V. Y., 262
Sokolov, V. N., 48
Sokolskii, D. V., 25, 255
Soler, A., 45
Soll, J., 266
Solladie, G., 34
Soman, R., 41
Someya, T., 32
SommC-Martin, G., 282
Sonawane, H. R., 50, 56
Sondengam, B. L., 216,221
Song, B.-H., 253
Song, C. M., 253
Sonnay, P., 91
Sonnet, P. E., 38, 283
Sonobe, T , 6 0
Sonoda, Y., 211
Sood, G. R., 58
Sorg, B., 200
Sotheeswaran, S., 226
Soti, M., 328
Sotiropoulos, J., 6, 52
Soucy, P., 45
Soulen, R. L., 39
Southwick, E. W., 63
Sowes, R. W., 74
Sozzi, G., 303
Spagnoli, N., 192
Spaleck, N., 53
Spanton, S. G., 202
Specian, A. C., 247
Speek, J., 291
Spencer, G. F.. 213, 216
Spindell, D., 40
Spiridonova, M. E., 46
Spiro, T. G., 257
Sponsel, V. M., 198
Sporn, M. B., 263
Spring, O., 146
Spronck, H. J. W., 65
Spurgeon, S. L., 235
Sree, A., 226
Srinivas, P., 67
Srinivasan, C. V., 61
Srinivasan, R., 38
Srivastava, A. K., 234
Srivastava, K. C., 234
Srivastava, R. S., 234
Author Index
350
Staba, E. J., 234
Stahle, M., 35
Stahly, G. P., 93
Stahnke, M., 308
Stampf, J.-L., 318
Stanley, P., 98
Starzemska, H., 35
Steenkamp, J. A., 62
Steglich, W., 128
Steinbach, R., 8, 92, 297
Steinberg, 1. Z., 258
Steinbuch, K., 8
Steiner, E., 64
Stenstrou, Y., 20
Stenzel, D. J., 86
Stepanova, T. P., 286
Stephenson, D. F. M., 299
Stephenson, G. R., 44
Sterligova, G. I., 46
Stevens, E. S., 6
Stevens, K. E., 103, 139
Steyn, P. S., 172
Sticher, O., 5, 7, 58, 59, 60,
283
Stierle, D. B., 15
Still, W. C., 206
Stillman, M. J., 163
Stipanovic, R. D., 106
Stockburger, M., 258
Stockis, A,, 28
Stoeckenius, W., 259, 26)
Stoessl, A., 163
Stork, G., 102, 206
Stothers, J. B., 163, 276, 307
Strand, M. R., 77
Straws, C. R., 14, 15, 27
Streckenbach, B., 272,273
Stribel, M. P., 4
Strong, P. D., 270, 271
Struchkov, Yu. T., 6, 272
Struchkova, M. I., 16
Stryer, L., 258
Stuart, A. D., 202
Stuart, K. L., 193, 228
Stuerle, H., 255
Stuttle, K. A. J., 52
Stutts, K. J., 250
Suarez, E., 225, 308
Subbarao, G. S. R., 39, 226
Subramanian, K., 193
Suda, M., 21
Suding, H., 114, 146, 196
Sudo, A., 60
Suehara, H., 21 3
Sueiras, J., 250
Suemitsu, R., 38
Suga, K., 11,21
Suga, T., 68,69,72,234,264
Sugden, J. E., 287
Suggs, J. W., 39, 294
Sugie, Y., 91
Sugimoto, Y., 172
Suginome, H., 306, 309, 3 11
Suguro, T., 21
Suhr, H., 46
Suire, C., 183, 184
Sullivan, B., 78
Sullman, E. M., 255
Sultanbawa, M. U. S., 202,
226, 227, 228, 230
Sum, F. W., 253
Sun, H.-D., 197
Sun, H. H., 201
Sun, R. C., 13
Sun, X.-C., 197
Sundar, N. S., 39
Sundaralingam, M., 232
Sunderaraman, P., 51
Sung, C.-K., 215
Sunko, D. E., 42, 76
Sunyawanshi, S. N., 47
Surburg, H., 183
Surcouf, E., 272
Suri, S. C., 193
Suseela, K., 192
Suterjadi, A., 60
Sutherland, M. D., 59
Suwita, A., 67, 88, 146
Suyunbaev, U., 255
Suzukamo, G., 46
Suzuki, H., 22, 259
Suzuki, K., 29, 54, 252
Suzuki, M., 111
Suzuki, S., 200
Suzuki, T., 21, 88, 99, 157,
258,259, 320
Svendsen, A. B., 44, 64, 73
Svovoda, G. H., 59
Swanson, B. N., 263
Swanson, S., 98
Swayze, J. K., 293
Sweeney, J. G., 294
Swenson, D. C., 271
Swern, D., 288
Swiatek, L., 59
Swiger, A. A., 36
Swindells, D. C. N., 271
Sykes, P. J., 327
Szabolcs, J., 256
Szalontai, B., 258
Szczepanski, A., 46
Szczepek, W. J., 305
Szeleczky, Z., 328
Taarit, Y. B., 33
Tabata, T., 232
Taber, D. F., 34
Taber, H. W., 266
Tada, M., 33, 170, 172
Tagawa, M., 58, 59, 60
Tagle, B., 127, 183, 202
Taguchi, H., 32, 59
Taira, Z., 158, 172
Takabe, K., 30,251
Takabe, S., 234
Takada, M., 266
Takagaki, T., 290
Author Index
Tandon, R., 231
Tandon, R. N., 234
Taneja, S. C., 15, 33
Tang, C. P., 271, 309
Tange, K., 69
Tani, T., 48
Tanida, K., 38
Tanis, S. P., 81
Taniyasu, S., 234
Tasumi, M., 257
Tateishi, K., 284
Tatsuno, T., 98
Tauber, J. D., 237
Tavecchia, P., 194
Taylor, D. A. H., 219
Taylor, G. J., 329
Taylor, W. G., 64
Tazawa, H., 24
Teehan, I. R., 206
Tellado, F. G., 199
Tempesta, M. S., 219
Temple, J. S., 312
Tenczer, J., 74
Tenneson, M. E., 328
Terai, T., 199, 231
Ternai, B., 226
Terpugov, E. L., 260
Terra, W. R., 238
Terui, Y., 276
Teutsch, G., 303, 323, 324
Texter, J., 6
Thacker, V. B., 296
Thaisrivongs, S., 205
Thakur, R. S., 32
Thaller, V., 140
Thappa, R. K., 211
Theil, F., 326
Thies, P. W., 5 , 59
Tho, N.-D., 228
Tho, Y. P., 202
Thomas, A. F., 3, 32
Thomas, D. M., 60
Thomas, H., 59, 62
Thomas, J. A., 98
Thomas, M. T., 17, 63
Thommen, W., 14
Thompson, M., 70
Thomson, R. H., 80
Threlfall, D. R., 266
Thyagarajan, G., 146
Tice, C. H., 177
Tietze, L.-F., 5,6,61,66,70,
177
Tilchourova, L. A., 46
Tillman, A. M., 129
Timms, R. N., 295, 318
Timoney, R. T., 73
Timoshina, T. N., 56
Tingoli, M., 324
Tint, G. S., 291, 312
Tishchenko, V. G., 272
Tius, M. A,, 53, 204
Tiwari, K. P., 234
Toda, H., 52
351
Toda, S., 264
Toder, B. H., 63
Toeplitz, B. K., 272, 293
Toia, R. F., 189
Tokoroyama, T., 201
Tokubuchi, N., 203
Tokunaga, F., 260
Toledo, F., 146
Tolstikov, G. A., 12, 48
Toma, L., 328
Tomasik, W., 299
Tomb, F., 118
Tome, G., 5
Tomimatsu, T., 203
Tomimori, T., 234
Tomita, B., 105
Tomita, K., 165
Tomita, M., 36
Tomita, Y., 209
Tomoda, S., 130
Tomosue, K., 48
Tomuro, Y., 25
Tonnesmann, U., 74
Toome, V., 277
Torelli, V., 321
Tori, K., 50, 170, 209, 234,
276
Tori, M., 94
Torii, S., 14, 24, 60, 99, 160,
253
Toromanoff, E., 286,288
Torres, C., 32
Torres-Martinez, S., 262
Tosi, C., 6
Toth, J. A., 200
Toth, K., 13
Towner, P., 259, 260
Townsley, P. M., 228
Toyota, M., 73,85, 158, 172,
183, 184
Tozyo, T., 234
Trabucco, A., 329
Trafford, D. J. H., 282
Traldi, P., 5
Tramell, M., 246
Tramontano, A., 8
Tran-Viet, D., 61
Trave, R., 61
Traynor, S. G., 14, 20, 33,
41, 44, 45, 50
Trehan, I. R., 18, 21
Trehan, N., 253
Treppendahl, S., 46
Tresselt, D., 273
Trifilieff, E., 181
Tringali, C., 186, 201
Tripathi, R. D., 234
Trius, A., 12
Trivedi, G. K., 102, 104
Trivino, A., 12
Trka, A., 279
Troffer, J., 6
Trogolo, C., 5 , 58, 59, 61
Trombini, C., 25
Author Index
352
Untch, K. G., 289
Uobe, K., 59
Urata, M., 41
Urbanovich, T. R., 55
Ushminder, K., 14
Uskokovic, M. R., 312, 318
Utaka, M., 38
Uto, S., 183
Uvarova, N. I., 216
Uyehara, I., 20
Uyehara, T., 141, 203
Uzar, H. C., 61
Uzarewicz, A., 49
Uzarewicz, I., 35, 49
Uzawa, J., 277
Vakhrameeva, A. A., 55
Vakulova, L. A., 247, 261
Valasinsky, V. F., 6
Valencia, A., 190
Valenta, Z., 271
Valente, L. M., 192
Valentine, D., 13
Valero, M. J., 37, 40
Valimae, T., 15
Valisolalao, J., 21 1
Vallen, S., 8
Valverde, S., 191, 192, 193,
199
van Audenhove, M., 39, 161
van der Gen, A., 34
Vander Meer, R. K., 77
Van de Ven, M., 258
Vandewalle, M., 39, 61, 161,
178, 179
Van Doorn, M., 204
Vanek, T., 174
van Engen, D., 60, 127
Vanhaelen, M., 282
Vanhaelen-Fastre, R., 282
van Leeuwen, P. W. N. M.,
33
van Leusen, A. M., 44
van Leusen, D., 44
Van Meerssche, M., 114,
202, 228
Van Noort, P. C. M., 255
van Os, F. H. L., 60
van Straten, J., 63
Van Tri, M,, 222
van Vliet, N. P., 307
Varaprath, S., 11
Varenne, J., 156
Varkey, T. E., 177
Varma, R. K., 272, 293
Vasanth, S., 146
Vasilyuk, S. M., 62
Vathke-Ernst, H., 40
Vaughan, K., 121
Vaultier, M., 307
Vazeux, M., 4, 5
Vecchi, M., 237, 240, 255
Veeman, G. E., 286
Veeravalli, J., 62
Veierov, D., 309
Velenyi, L. J., 35
Venkatesan, K., 193, 270,
27 1
Venkateswaran, R. V., 204
Venuti, M. C., 110
Venzke, B. N., 213
Vereshchagin, A. N., 56
Verghese, J., 4, 32, 41, 55
Vergottini, R. A., 271
Verhoeven, T. R., 23
Verma, K., 58
Verma, N. K., 253
Verma, 0. P., 4
Verma, S. M., 5
Vermeer, P., 19, 78
Vettel, P. R., 103
Vetter, U., 15
Veysoglu, T., 19, 293
Via, D. P., 286
Vial, M. V., 72
Viallefont, P., 114
Vickery, B., 4
Vickery, M., 4
Vidal, J. P., 60
Vidari, G., 135, 207, 223
Vig, 0. P., 18,21,37,39,206,
253
Vig, R., 18,206
Vignudelli, E., 5
Vijayakumar, E. K. S., 60,
192
Vijayalakshmi, K. U., 60
Vile, J. P., 28
Vilkas, E., 48
Vilkas, M., 48
Villarreal, R., 146, 158
Vincent, P., 327
Vincien, F. F., 5
Vinogradov, L. I., 33
Vinson, S. B., 77
Viola, F., 215
Virgili, A., 12
Visser, C . P., 255
Viswanathan, N., 227
Vita-Finsi, P., 135
Voelter, W., 225
Vogel, M. K., 12
Voight, S., 4
Voigt, B., 198
Vokoun, J., 279
von der Eltz, H., 61
Von Dreele, R. B., 78
von Kiedrowski, G., 66
von Rudloff, E., 73
von Schantz, M., 5
Von Zastrow, M., 258
Voss, W., 48
Vostrowsky, O., 54
Vouros, P., 279
Vrbancich, J., 5
Vrkoc, J., 202
Vuilhorgne, M., 174
Vulfson, S. G., 6, 56
Vyazankin, N. S., 46
Vyaznikovtseva, 0. V., 25,
255
Vyrdov, V. A., 49
Vystrcil, A., 231
Wada, K., 199
Waegell, B., 5
Wagner, J., 256
Wagner, T. E., 277
Waibel, R., 58
Waineraich, M. S., 215
Waki, T., 48.
Walckhoff, B., 259, 260
Walde, A,, 35
Walden, M. K., 282
Walker, D. G., 170
Walker, D. M., 118
Walker, G. J., 292
Walker, R. P., 238
Walkinshaw, M. D., 87, 88
Walkowicz, C., 56
Walkowicz, M., 56
Wallace, J. B., 60
Walter, J. A., 277
Walton, D. C., 238
Warin, R., 226
Warkentin, J., 46
Warnhog, E. W., 276,307
Warshel, A., 258
Wasiowich, C. A., 18
Wasserman, H. H., 294
Wasylishen, R., 4
Watanabe, A., 50
Watanabe, F., 284
Watanabe, H., 18
Watanabe, K., 66, 76
Watanabe, M., 155
Watanabe, S . , 11, 21
Watson, F. E., 271
Watson, S. W., 42
Watson, T. R., 276
Watson, W. H., 115, 196
Watson, W. P., 37
Wazeer, M. I. M., 228, 230
Weakley, T. J. R., 98
Weavers, R. T., 203
Webb, R., 283
Webster, M., 290
Weedle, M., 42
Weedon, B. C. L., 241
Weeks, C. M., 270
Wege, D., 110
Wegerstahl, P., 44
Weigand, E. F., 50
Weihe, G. R., 323
Weiler, E. W., 284
Weiler, L., 31
Weinberg, M. L. D., 31
Weinges, K., 61
Weiss, R. M., 258
Weissberger, E., 28
Author Index
Weiter, L., 253
Welch, S. C., 93, 99
Wells, R. J., 15, 201, 234
Welmak, M., 46
Welniak, M., 46
Wender, P. A., 103
Wenderoth, B., 8
Wendisch, D., 174
Wenkert, E., 192
Wenzel, M., 286
Werbin, H., 265
Werstiuk, N. H., 7, 45
West, J. W., 53
West, T. F., 64
Westbrook, E., 272
Westermann, J., 8, 92, 297
Westfall, S. S., 256
Westmijze, H., 19, 78
Westmore, J. B., 279
Westwood, N. P. C., 7
Weyerstahl, P., 11, 91
Whelan, J. K., 73
Whitaker, B. D., 262
White, A. H., 78, 182, 188,
189,202,226
White, J. D., 60, 83,98,99
White, L. S., 38
White, P. S., 39, 164, 271
Whitesell, J. K., 61
Whiting, D. A,, 22
Whittaker, D., 6, 52, 54
Whittle, J. A., 177
Whybrow, D., 64, 183
Wicha, J., 325
Wichmann, J. K., 319
Wiechert, R., 308, 323, 324
Wieslander, A., 258
Wiesner, K., 311, 325
Wiggins, P. L., 20, 76
Wightman, R. M., 250, 251,
298
Wilbrandt, R., 257, 259
Wilk, M., 286
Wilkinson, R. E., 74
Wilkomirski, B., 234
Will, G., 181
Willhalm, B., 14, 32, 62
Williams, D. H., 314, 319,
320
Williams, D. L., 65, 66
Williams, E., 223
Williams, F. D., 77
Williams, H. J., 77
Williams, J. L., 64
Williams, J. R., 17, 107, 143,
155, 275, 310
Williams, P. J., 14, 15, 27
Williams, R. O., 329
Willis, B. J., 48, 89, 166
Wills, R. B. H., 15
Willuhn, G., 174
Wilson, B., 14, 15, 27
Wilson, R. S., 66
Wilson, S. R., 35, 39, 108
353
Wing, R. M., 15
Winkler, T., 5 , 58, 64
Winnik, F. M., 306
Winter, R. E. K., 140
Wirtz, G. H., 256
Witkiewicz, K., 10, 37, 40
Wodzki, W., 46
Wolf, H., 111
Wold, H. R., 26, 63, 255
Wolff, G., 309
Wolff, S., 25
Wolinsky, J., 31, 42
Wollenberg, R. H., 31
Wong, R. Y., 93
Wood, D. L., 70
Woode, K. A., 227
Woodgate, P. D., 292, 302,
327
Woodruff, W. H., 257, 259
Woods, G. F., 299
Woodward, R. B., 130
Worth, B. R., 55, 210,228
Worthington, P. A., 81
Wovcha, M. G., 328
Wray, V., 275
Wright, C. L., 324
Wright, J. L. C., 277
Wrzesien, J., 41, 49, 50
Wu, A., 17, 63
WU, R.-W., 174
WU, R.-Y., 146
WU, S.-C., 256
Wuest, H., 39, 46
Wydra, R., 211
Wynberg, H., 53
XU, Y.-L., 197
Yagen, B., 213
Yagi, A., 215
Yagihashi, F., 163
Yakovleva, I. M., 247, 261
Yamada, M., 165
Yamada, T., 30, 251
Yamada, S., 319, 320
Yamada, Y., 13,29, 60, 200
Yamahara, Y., 58
Yamagata, E., 104
Yamagishi, S., 262
Yamagiwa, S., 63
Yamaguchi, A., 256
Yamaguchi, H., 19, 251
Yamaguchi, K., 232
Yamaguchi, M., 241, 243
Yamakawa, K., 172
Yamakawa, T., 22
Yamaki, M., 59
Yamamoto, I., 64
Yamamoto, H., 10, 12, 22,
25, 37, 42, 63
Yamamura, A., 48
Yamamura, S., 91, 189
Author Index
354
Yurev, V. P., 12, 48
Yurina, R. A., 48, 62
Yuzuriha, T., 266
Zabel, V., 115, 196
Zachis, M., 296
Zagalsky, P. F., 258
Zaghloul, A. M., 172
Zahra, J.-P., 40
Zahrar, J. P., 5
Zainutdinov, U. N., 188
Zalkow, L. H., 102
Zamarlik, H., 31