Total Steroid Synthesis

367 Pages·1970·10.95 MB·English

by  Afanasii A. Akhrem, Yurii A. Titov (auth.)

TOTAL
STEROID
SYNTHESIS
TOTAL
STEROID
SYNTHESIS
Afanasii A. Akhrem
and
Yurii A. Titov
Laboratory of Corticoid Chemistry
Institute of Organic Chemistry
Academy of Sciences of the USSR, Moscow
Translated from Russian by
B. J. Hazzard
g:> PLENUM PRESS· NEW YORK-LONDON· 1970
Library of Congress Catalog Card Number 69-12525
ISBN 978-1-4757-0589-8 ISBN 978-1-4757-0587-4 (eBook)
DOI 10.1007/978-1-4757-0587-4
The original Russian text, first published by Nauka Press in Moscow in 1967, has
been corrected by the authors for this edition. The present translation is published
under an agl'eement with Mezhdunarodnaya Kniga, the Soviet book export agency.
A!ti4nacl.tu AH8pee8u" AxpeM IOpuii Anopee8u" Tumo8
UOJlHblH CBBTe3 CTePO~OB
POLNYI SINTEZ STEROIDOV
© 1970 Plenum Press, New York
Softcover reprint of the hardcover 1s t edition 1970
A Division of Plenum Publishing Corporation
227 West 17th Street, New York, N.Y. 10011
United Kingdom edition published by Plenum Press, London
A Division of Plenum Publishing Corporation, Ltd.
Donington House, 30 Norfolk Street, London W.C.2, England
All rights reserved
No part of this publication may be l'eproduced in any form
without written permission from the publisher
Preface to the American Edition
Since the appearance of the Russian edition of this monograph (1967),
the main tendencies of the development of total synfuesis have not changed.
The accelerated accumulation of experimental material is continuing,
mainly in the form of the improvement of already-existing synthesis
schemes. The main new advance is the development of asymmetric syn-
theses with intermediates that have made it possible to avoid the main dis-
advantage of total synthesis - the formation of racemic final compounds.
The most important work that has appeared since the appearance of the
Russian edition is given in an Appendix to the book. Apart from this, only
a very slight rearrangement of the material and of some of the schemes
has been carried out for the American edition.
A. A. Akhrem
Yu. A. Titov
Moscow, July 1968
v
Preface to the Russian Edition
Steroids are one of the most interesting and most widely distributed
and, at the same time, one of the most structurally complex groups of
natural compounds. In spite of this, the great theoretical and practical
importance of steroids for biology and medicine has led to very intensive
scientific research work on their synthesis. The numerous methods for
obtaining steroids developed at the present time can be divided into four
main groups: isolation from natural sources, microbiological synthesis,
partial synthesis from natural raw material already containing the steroid
skeleton, and, finally, total chemical synthesis from precursors of com-
paratively simple structure. The total synthesis of steroids is the subject
of the present monograph.
Since all the most important natural steroids have already been ob-
tained by total synthesis, each reaction in the steroid series can in fact
now be regarded as a "formal total synthesis" of the products formed in it.
Such a situation requires the drawing of the clearest possible boundaries
between the partial and total synthesis of steroids. In our opinion, the
term total synthesis can be applied only to those investigations in which
the construction of the side chains distinguishing the classes of steroid
compounds was connected organically with the construction of the steroid
skeleton (as is the case in the syntheses of aldosterone and conessine).
From this point of view, it must be regarded as incorrect to describe as
total syntheses, for example, the syntheses of equilin, diosgenin, and
tomatidine; these syntheses deliberately start from natural steroids and
must be classified as partial syntheses. In view of what has been said,
in this book our main attention is devoted to the construction of the steroid
skeleton and not to the introduction of side chains. The broad develop-
ment of the chemistry of the heterocyclic steroids has made it necessary
also to consider the main methods for the total synthesis of azasteroids,
oxasteroids, and thiasteroids.
In the majority of existing reviews on total synthesis [1-16] the ma-
terial is arranged in accordance with the classes of the steroid com-
vii
viii AUTHORS' PREFACE
pounds synthesized and, within these classes, according to the methods de-
veloped by the individual research groups. In contrast to this, we have
based our classification of total syntheses on the type of syntheses,
which is connected with a definite sequence of the construction of the rings
forming the steroid skeleton. The division of the book into chapters and
sections has been carried out on this basis; in the first chapter we con-
sider general questions -of total synthesis, and the remaining three chap-
ters are devoted to an account and analysis of experimental results. The
primary elements of organization in these chapters are the s c hem e s
of sy nth e sis, which include all the experimental material; they are
numbered successively throughout the book.
The authors consider it their pleasant duty to thank N. N. Pivnitskaya
and I. G. Reshetova and the workers of, the library of the N. D. Z elinskii
Institute of Organic Chemistry of the Academy of Scienc'es of the USSR for
great assistance in the selection of the literature material, and also E. M.
Terletskaya, L. R. Samu s 'ko, and L. E. Kulikova for help in the prepara-
tion of the manuscript for the press.
This book is a first attempt at a monograph on total steroid synthesis;
the authors will be grateful for all critical observations.
A. A. Akhrem
Yu. A. Titov
Contents
Abbreviations . . . . . . . . . . . . . . . . . . . . . . . . . . . l1li • l1li • • • • • 1
Chapter I. General Questions of Total Synthesis .• 0 • • • • • • • • • 3
1. Statement of the problem of total synthesis • • • • • • • • • • 4
Classes of steroid compounds. • . • • • • • • • • • • • • • • • • 4
History of total steroid synthesis. • • • • • . • . • • . • . • • • 6
Prospects for total synthesis •••• 0 0 •••••• 0 • • • • • • • 10
2. Building up of the steroid skeleton •••••••• 0 • • • • • • • 15
Methods of introducing side chains . • • 0 • • • • • • • • • • • • 16
Methods of forming and transforming the rings •••••• 0 • 32
Diene synthesis ........ l1li 0 • l1li ••••••••••••••• l1li 41
3. F ormation of centers of asymmetry . • • • • • • • • • • • • • • 43
Sterochemistry of polycyclic systems. • . • • • • • • . • • • • 45
Reactions for the formation of centers of asymmetry. • • • 50
Electrophilic reactions with ketones •••••••••• 0 • 0 • • 53
Reduction with alkali metals •••• ••••• 0 ••••• 0 • • • 60
Catalytic hydrogenation •••• 0 •••••••••• 0 • • • • • • • 64
Isomerization of double bonds •••••••••.•• 0 • • • • • • 72
Stereochemistry of cyclization. • • • • • • . • • • • • • • • • • • 73
Methods of resolving racemates. • • • • • • • • • • • • • • • • • 74
4. Nomenclature of synthetic steroids. • • • • • • • • • • • • • • • 78
Chapter II. Total Syntheses from AB, AC, and AD Fragments. • • 83
1. Synthe se s of the type AB - C - D. • • • • . • • • • • • • • • • • 84
Synthesis via C14 ketones with aromatic rings A and B. • • 84
Syntheses via C M ketones with an aromatic ring A. • • • • • 97
Syntheses from bicyclic ketones. • • • • • • • • • . • • • • • • • 105
Syntheses via diacids. • • . . • • • • • . • • • . . • • • • • • • • • 109
ix
x CONTENTS
2. Syntheses of the type AB -CD. • • • • • • • • • • • • • • • • • • 111
Condensations of aromatic dienes. . • • • • • • • • . • • • • • • 111
Condensations of nonaromatic dienes • • • • • • • • • • • • • • 132
Syntheses of thiasteroids • • • • • • • • • • • • • • • • • • • • • • 136
3. Syntheses of the type AB -D -C. • • • • • • • • • • • • • • • • 137
Syntheses with the initial formation of the C8-C 14 bond. • 137
Syntheses with the initial formation of the C 12 -C 13 bond. • 149
Syntheses of azasteroids, ox asteroids , and thiasteroids • • 169
4. Syntheses of the type AC - B - D. • • • • • • • • • • • • • • • • 175
Syntheses via biphenyl derivatives • • • • • • • • • • • • • • • • 175
Syntheses via diphenylethane derivatives. • • • • • • • • • • • 179
5. Syntheses of the type AD - BC. • • . • . • • • • • • • • • • • • • 184
Syntheses via diacids • • • . • • . • • • • • • . • • • • • • • • • • • 184
Syntheses via diketones . • • • • • • • • • • • • • • . • • • • • • • 185
Syntheses via dienynes • • . • • • • • • • • • • • • • • • • • • • • • 191
Chapter III. Total Syntheses from BC and BD Fragments. • • • • • 193
1. Syntheses of the type BC - A-D. • . • • . • • . . . • . • • . • 193
Syntheses of 11-deoxysteroids • • • • . • • • • • • • . . • • • • • 194
Syntheses of ll-hydroxy steroids. • • • . • • • • . • . • . • • • 201
2. Syntheses of the type BC - D - A. . • • . • • . . . • . . . • . • 220
Syntheses via BCD intermediates with a five-membered
ring D 0 0 0 ••••••••• 0 0 • 0 •• 0 •• 0 ••••••••• 0 0 • 220
Syntheses via BCD intermediates with a six-membered
ring D . 0 •• 0 0 0 •••••••••••• Q • 0 0 0 0 •••• 0 0 • • • 232
3. Syntheses of the type BD - C - A. • • • • . • • . . • • . . • • . 235
Chapter IV. Total Syntheses from CD Fragments. • • • • • • • • • . 243
1. Syntheses of the type CD - A - B. • . • • • . . • . . . • • • • . 243
Syntheses of estrogens and 19-norsteroids. . . . . • • • . • . 244
Syntheses of vitamin D derivatives. • • . • . . . . . . . • . • • 254
Syntheses of azasteroids. • • . . • . . • . . • • • • . . . • • • . • 258
2. Syntheses of the type CD - B - A • • . • . . . • . • • . . . • . . 260
Syntheses from 5-methoxy-2-tetralone • • • • • • . • . . . • • 260
Syntheses from 6-methoxy-2-tetralone • • . • . . • . . . . . . 282
Syntheses from nonaromatic CD fragments • • • • • • • • . . 287
CONTENTS xi
3. Syntheses of the type CD -BA. • • • • • • • • • • • • • • • • • • 306
Appendix • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • 309
Bibliography. • • • • • • . • • . • • • • • • • • • • • • • • • • • • • • • • • • • 315
Index. .. ......................•.............. 353
Abbreviations
Ac -COCH3, acetyl
Am -CsHu, amyl (pentyl)
Bu -C4HS' butyl
i-Bu =: -CH2CH(CH3h, isobutyl
t-Bu -C (CH3h, tert-butyl
Bz =: -COCsHs , benzoyl
D5 five-membered ring D
Ds six-membered ring D (D-homo-)
Et -C2H5' ethyl
LAH LiA1H4' lithium aluminum hydride (lithium tetrahydro-
aluminate)
Me -CH3, methyl
Ms =: -02SCH3, mesyl (methane sulfonyl)
NBS C4H40 2BrN, N - bromosuccinimide
Ph -C5HS' phenyl
Pr -C3H7' propyl
i-Pr -CH(CH3h, isopropyl
Py C5H5 ' pyridine
THF C4H80, tetrahydrofuran
TP =: -CsHsO, tetrahydropyranyl
TS =: -02SC7H7' tosyl (p-toluenesulfonyl)
The abbreviations given are used both in the text and in writing the
formulas. The hydrogen atoms in cyclic structures are not shown; only
their configuration is indicated.
1