Total Synthesis OfNatural Products, Volume2 Edited by John Apsimon Copyright © 1973, by John Wiley & Sons, Inc.
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Total Synthesis OfNatural Products, Volume2 Edited by John Apsimon Copyright © 1973, by John Wiley & Sons, Inc.
THE TOTAL SYNTHESIS OF NATURAL PRODUCTS
Total Synthesis OfNatural Products, Volume2 Edited by John Apsimon Copyright © 1973, by John Wiley & Sons, Inc.
The Total Synthesis of Natural Products VOLUME 2
Edited by
John ApSimon
Department of Chemistry Carferon University, Ottawa
A WILEY-INTERSCIENCE PUBLICATION
JOHN WILEY & SONS
New York Chichester Brisbane Toronto Singapore
~
~~~
A NOTE TO TI IE READER This book has been electronicall>,reproduced from
digital intbnnation stored at John Wile? XL Sotis, lric We are pleased that the use of this iie\v technology \\..ill enable 11sto keep uorks of enduring scholarly value in print as long as there IS a reasonable demand for than. The content ol'this book IS identical to previous printings.
Copyright @ 1973, by John Wiley & Sons, Inc. All rights reserved. Published simultaneously in Canada. Reproduction or translation of any part of this work beyond that permitled by Sections 107 or 108 of the 1976 United States Copyright Act without the permission of the copyright owner is unlawful Requests for permission or further information should be addressed to the Permissions Department, John Wiley 8 Sons, Inc
Library of Congress Cataloging in Publication Data: ApSimon, John. The total synthesis of natural products. Includes bibliographical references. I.
Chemistry, Organic-Synthesis.
QD262.A68 547'.2 ISBN 0-471-03252-2 (V.2)
72-4075
Printed in the United States of America 10 9 8
I . Title.
Contributors to Volume 2 J. W. ApSimon, Carleton University, Ottawa, Canada C. H. Heathcock, University of California at Berkeley, Berkeley, California J. W. Hooper, Bristol Laboratories of Canada, Candiac, P.Q.,Canada D. Taub, Merck, Sharp and Dohme, Rahway, New Jersey A. F. Thomas, Firmenich SA, Geneva, Switzerland
Preface Throughout the history of organic chemistry we find that the study of natural products frequently has often provided the impetus for great advances. This is certainly true in total synthesis, where the desire to construct intricate and complex molecules has led to the demonstration of the organic chemist’s utmost ingenuity in the design of routes using established reactions or in the production of new methods in order to achieve a specific transformation. These volumes draw together the reported total syntheses of various groups of natural products and commentary on the strategy involved with particular emphasis on any stereochemical control. No such compilation exists at present and we hope that these books will act as a definitive source book of the successful synthetic approaches reported to date. As such it will find use not only with the synthetic organic chemist but also perhaps with the organic chemist in general and the biochemist in his specific area of interest. One of the most promising areas for the future development of organic chemistry is synthesis. The lessons learned from the synthetic challenges presented by various natural products can serve as a basis for this everdeveloping area. It is hoped that these books will act as an inspiration for future challenges and outline the development of thought and concept in the area of organic synthesis. The project started modestly with an experiment in literature searching by a group of graduate students about six years ago. Each student prepared a summary in equation form of the reported total syntheses of various groups of natural products. It was my intention to collate this material and possibly publish it. During a sabbatical leave in Strasbourg in the year 1968-1969, I attempted to prepare a manuscript, but it soon became vii
...
Vlll
PREFACE
apparent that if I was to also enjoy other benefits of a sabbatical leave, the task would take many years. Several colleagues suggested that the value of such a collection would be enhanced by commentary. The only way to encompass the amount of data collected and the inclusion of some words was to persuade experts in the various areas to contribute. Volume 1 presented six chapters describing the total syntheses of a wide variety of natural products. The subject matter of Volume 2 is somewhat more related, being a description of some terpenoid and steroid syntheses. These areas appear to have been the most studied from a synthetic viewpoint and as such have added more to our overall knowledge of the synthetic process. A third volume in this series will consider diterpenes and various alkaloids, and suggestions for other areas of coverage are welcome. I am grateful to all the authors for their efforts in producing stimulating and definitive accounts of the total syntheses described to date in their particular areas. 1 would like to thank those students who enthusiastically accepted my suggestion several years ago and produced valuable collections of reported syntheses. They are Dr. Bill Court, Dr. Ferial Haque, Dr. Norman Hunter, Dr. Russ King, Dr. Jack Rosenfeld, Dr. Bill Wilson, Mr. D. Heggart, Mr. G. W. Holland, Mr.D. Lake, and Mr. Don Todd. I also thank Professor G. Ourisson for his hospitality during the seminal phases of this venture. I particularly thank Dr. S. F. Hall, Dr. R. Pike, and Dr. V. Srinivasan, who prepared the indexes of Volumes 1 and 2. JOHN APSIMON Orrawa, Canada May 1973
Contents The Synthesis of Monoterpenes
1
A. F. THOMAS
The Total Synthesis of Sesquiterpenes
197
C. H. HEATHCOCK The Synthesis of Triterpenes
559
J. W. APSIMON AND J. W. HOOPER
Naturally Occurring Aromatic Steroids
641
D. TAUB Compound Index
727
Reaction Index
733
ix
THE TOTAL SYNTHESIS OF NATURAL PRODUCTS
Total Synthesis OfNatural Products, Volume2 Edited by John Apsimon Copyright © 1973, by John Wiley & Sons, Inc.
THE SYNTHESIS OF MONOTERPENES
A. F. Thomas
Firmenich SA, Geneva, Switzerland 1. 2. 3.
4.
5.
6. 7.
8.
9. 10.
Introduction The Telomerization of Isoprene 6-Methylhept-5-en-2-one 2,6-Dimethyloctane Derivatives A. Hydrocarbons B. Alcohols C. Aldehydes and Ketones Substances Derived from Chrysanthemic Acid A. The Santolinyl Skeleton B. The Artemisyl Skeleton C. The Lavandulyl Skeleton D. Chrysanthemic Acids Cyclobutane Monoterpenes Cyclopentane Monoterpenes A. Plinol B. Cyclopentanopyrans C. 1-Acetyl-4-isopropenyl-1-cyclopentene D. Campholenic Aldehyde The p-Menthanes A. Hydrocarbons B. Oxygenated Derivatives of p-Menthane The m-Menthanes 1,1,2,3-Tetramethylcyclohexanes
A.
2 3 4
8 8
14 26 34 36
40 43 49 58 59
61 62 87 88 88 88 93 137 138 138 139 139 140
Safranal Karahana Ether 11. The o-Menthanes 12. Cycloheptanes A. Thujic Acid, Shonanic Acid, Eucarvone, and Kara140 hanaenone 143 B. Nezukone and the Thujaplicins 8.
1
2
The S y n t h e s i s of Monoterpenes
13.
B i c y c l o [ 3 , 2 , 0 ] Heptanes A. Filifolone 14. B i c y c l o [ 3.1.01 Hexanes 15. B i c y c l o (2.2.11 Heptanes 16. B i c y c l o [3.3.1] Heptanes B i c y c l o [ 4 . 1 . 0 ] Heptanes 17. 18. Furan Monoterpenes A. 3 - M e t h y l - 2 - S u b s t i t u t e d I and 3 - S u b s t i t u t e d F u r a n s B. 2,5,5-Substituted Tetrahydrofurans 1 9 . Oxe t o n e s 20. Te t r a h y d r o p y r a n s Hexahydrobenzofuran-2-ones 21. 1.
144 144 145 149 154 157 159 159 165 166 167 169
INTRODUCTION
The t o t a l s y n t h e s i s of monoterpenes i s n o t a s u b j e c t t h a t h a s a t t r a c t e d a g r e a t d e a l o f a t t e n t i o n . To b e s u r e , e a c h t i m e some t e r p e n o i d c u r i o s i t y i s i s o l a t e d , t h e r e i s a c e r t a i n amount of e f f o r t expended t o s y n t h e s i z e i t , g e n e r a l l y as p a r t o f a s t r u c t u r a l " p r o o f , " b u t few c h e m i s t s have s p e n t much t i m e on a t t e m p t i n g t o s y n t h e s i z e , s a y , p i n e n e . One of t h e r e a s o n s f o r t h i s l a c k of i n t e r e s t i s c e r t a i n l y t h e v a s t n a t u r a l r e s o u r c e s of t h e more complex r i n g s y s t e m s ( e s p e c i a l l y t h e p i n a n e , b o r nane, and c a r a n e s y s t e m s ) , s o t h a t i n d u s t r y h a s had l i t t l e need of t o t a l s y n t h e s i s of t h e s e s t r u c t u r e s and h a s c o n f i n e d i t s e l f t o p a r t i a l s y n t h e s e s w i t h i n t h e s y s t e m s . These p a r t i a l s y n t h e s e s , moreover, are t h e m s e l v e s p a r t i c u l a r l y i n t e r e s t i n g i n view of t h e l a b i l i t y of many of t h e s y s t e m s , and h a v e , i n d e e d , o f t e n p r o v i d e d t h e examples f o r r e a c t i o n mechanism and s t e r e o c h e m i c a l s t u d i e s . S u p p l i e s o f raw m a t e r i a l s , however, a r e n o t always as e a s i l y a c c e s s i b l e as t h e y once were and t o t a l s y n t h e s i s from c h e a p e r materials c a n n o t a f f o r d t o be completely ignored. On the whole, t h e r e a r e t h r e e r e a s o n s f o r s y n t h e s i s . The f i r s t o f t h e s e h a s j u s t been mentioned--the p r e p a r a t i o n of " u n u s u a l " monoterpenes t h a t are n o t r e a d i l y a v a i l a b l e from n a t u r a l s o u r c e s , w i t h a view t o c h e c k i n g t h e c o r r e c t n e s s of t h e i r s t r u c t u r e s , examining t h e i r p r o p e r t i e s , and so on. The second t y p e of s y n t h e s i s i s t h e s o - c a l l e d b i o g e n e t i c t y p e . These p u r p o r t t o i m i t a t e a r o u t e t h a t a p p r o x i m a t e s t o what i s b e l i e v e d t o happen i n t h e p l a n t . There are n o t too many o f them, b u t a l t h o u g h t h e y a r e d e s i g n e d from s t r i c t l y t h e o r e t i c a l v i e w p o i n t s , t h e y c o u l d be e x t r e m e l y i m p o r t a n t , e s p e c i a l l y s i n c e t h e r e i s , so f a r , no good s y n t h e t i c r o u t e t o e v e n q u i t e s i m p l e monoterpenes t h a t a r e i n l a r g e s u p p l y i n n a t u r e . F i n a l l y , t h e r e are t h e " i n d u s t r i a l " s y n t h e s e s , a b o u t which a f u r t h e r p o i n t must be made. The l e g i s l a t i o n i n some c o u n t r i e s
Introduction
3
i s becoming i n c r e a s i n g l y concerned w i t h whether a compound i s known t o be n a t u r a l l y o c c u r r i n g o r n o t . Many of t h e u s e s o f monoterpenes by i n d u s t r y a r e i n perfumes, cosmetics, f l a v o r s , and s o on, and t h e i d e a o f t h e l e g i s l a t o r s i n t h e s e f i e l d s i s t h a t whatever occurs n a t u r a l l y i n p l a n t o r animal products has been i n e x i s t e n c e , and p o s s i b l y i n u s e , f o r a long t i m e , and so is less l i k e l y t o be harmful than a new u n t r i e d substance. Without d i s c u s s i n g t h e merits of t h i s p o s i t i o n , it must be remembered t h a t n a t u r a l l y o c c u r r i n g m a t e r i a l s a r e , on the whole, asymmetric, so i f an i n d u s t r y wishes t o use s y n t h e t i c compounds t h a t a r e going t o be placed on o r i n human b e i n g s , it may be under some p r e s s u r e t o s y n t h e s i z e n o t only t h e racemate, b u t t h e c o r r e c t o p t i c a l a n t i p o d e , s i n c e w e do n o t know, a p r i o r i , what t h e p h y s i o l o g i c a l d i f f e r e n c e s between t h e a n t i podes may b e , This f a c t o r m i t i g a t e s , t o some e x t e n t , a g a i n s t t h e use o f p u r e l y s y n t h e t i c s t a r t i n g m a t e r i a l s , s i n c e t o t a l s y n t h e s i s of o p t i c a l l y a c t i v e substances i m p l i e s r e s o l u t i o n a t some s t a g e . L e g i s l a t i o n i s , u n f o r t u n a t e l y , n o t c o n s i s t e n t , s i n c e p a t e n t law does n o t allow ( a t l e a s t i n t h e United S t a t e s and Germany) t h e p r o t e c t i o n of n a t u r a l p r o d u c t s , no m a t t e r what e f f o r t s were made t o i s o l a t e them, a s s i g n s t r u c t u r e s t o them, and s y n t h e s i z e them. There i s a f o u r t h t y p e of s y n t h e s i s t h a t appears from t i m e t o t i m e , and which might be c a l l e d t h e " b u i l d i n g block" t y p e , where t h e d e s i r e d molecule i s p u t t o g e t h e r by j o i n i n g small p a r t s of it. Apart from i t s u s e a s an i n t e l l e c t u a l exercise (such s y n t h e s e s are r a r e l y of any i n d u s t r i a l u s e ) , t h i s approach does have an advantage where l a b e l e d molecules are r e q u i r e d , s i n c e it f r e q u e n t l y allows t h e p l a c i n g o f a p a r t i c u l a r atom i n t h e molecule i n a c l e a r - c u t way. F o r t h i s r e a s o n , such s y n t h e s e s have been included i n t h i s c h a p t e r . The l i t e r a t u r e i s l a r g e l y complete up t o 1970; more r e c e n t work w i l l be found i n t h e " S p e c i a l i s t P e r i o d i c a l Report on Terpenoids and S t e r o i d s " (published annually by t h e Chemical S o c i e t y , London)
.
2.
THE TELOMERIZATION OF ISOPRENE
The ready a v a i l a b i l i t y of i s o p r e n e makes it an a t t r a c t i v e s t a r t i n g p o i n t f o r t h e s y n t h e s i s of monoterpenes, and s e v e r a l r o u t e s i n v o l v i n g t h e a d d i t i o n of halogen a c i d s (see, f o r examp l e , t h e n e x t s e c t i o n on methylheptenone) are d e s c r i b e d elsewhere i n t h i s c h a p t e r , i n a d d i t i o n t o t h e h i s t o r i c a l dimerizat i o n t o d i p e n t e n e . I t would n a t u r a l l y be much more u s e f u l t o have methods a v a i l a b l e f o r t h e d i r e c t d i m e r i z a t i o n and simultaneous hydroxylation of i s o p r e n e , and c o n s i d e r a b l e e f f o r t has been p u t i n t o t h i s a s p e c t , p a r t i c u l a r l y i n r e c e n t t i m e s i n
4
The S y n t h e s i s of Monoterpenes
Estonia and Japan. The mixtures o b t a i n e d are of c o n s i d e r a b l e complexity, and u n f o r t u n a t e l y much of t h e work i s i n j o u r n a l s t h a t a r e d i f f i c u l t t o o b t a i n , i n c l u d i n g a review of t h e t e l o m e r i z a t i o n u s i n g hydrogen c h l o r i d e ( i . e . , v i a t h e hydrogen c h l o r i d e adduct) Under t h e s e c o n d i t i o n s , t h e C1o f r a c t i o n can c o n t a i n a s much a s 45% of g e r a n y l c h l o r i d e . * * Phosphoric a c i d t e l o m e r i z a t i o n of i s o p r e n e g i v e s a - t e r p i n e n e and a l l o ocimene a s t h e main C10 hydrocarbons, t o g e t h e r with g e r a n i o l and t e r p i n e o l . 3 ' 4 I n t h e presence of a c e t i c a c i d , t h e phosp h o r i c a c i d t e l o m e r i z a t i o n r e a c t i o n l e a d s t o t h e a c e t a t e s of g e r a n i o l , l a v a n d u l o l , and o t h e r compounds, b e s i d e s a complex mixture of monoterpene hydrocarbons. There a r e o t h e r react i o n s of i s o p r e n e t h a t l e a d t o mixtures c o n t a i n i n g t e r p e n o i d s , f o r example, t h e hydrocarbon w i l l r e a c t w i t h magnesium i n t h e presence o f L e w i s a c i d s , and t h e complex t h u s o b t a i n e d g i v e s adducts with aldehydes b u t a g a i n o n l y a s m i x t u r e s . 6 Isoprene i s a l s o dimerized by l i t h i u m naphthalene i n t e t r a h y d r o f u r a n t o l i n e a r monoterpene homologs , p a s s i n g oxygen through t h e mixt u r e g i v i n g then 30 t o 40% of C10 a l c o h o l s and 30% of C10 g l y c o l s . Although t h e a l c o h o l s i n c l u d e 10% each o f n e r o l and g e r a n i o l , most of t h e remainder a r e n o t n a t u r a l p r o d u c t s . 8
.
3.
6-METHYLHEPT-5-EN-2-ONE
Although n o t s t r i c t l y speaking a monoterpene, 6-methylhetp-5en-2-one (2) i s a common c o n s t i t u e n t o f e s s e n t i a l o i l s , p a r t i c u l a r l y of t h e Cymbopogon (lemongrass) s p e c i e s . Some important terpene s y n t h e s e s s t a r t from i t , and it i s a l s o t h e c h i e f produ c t from t h e r e t r o - a l d o l r e a c t i o n and c e r t a i n o x i d a t i o n s of c i t r a l and i t s d e r i v a t i v e s . I n view o f i t s k e y p o s i t i o n , i t has been given a s e p a r a t e s e c t i o n on i t s s y n t h e s i s . Any s y n t h e s i s of methylheptenone (2) must t a k e i n t o account t h e f a c t t h a t it i s s e n s i t i v e t o a c i d , 9 r 1 0 and can undergo c y c l i z a t i o n s t o hydrogenated xylenes and t e t r a h y d r o p y r a n s , f o r example, d u r i n g t h e decomposition of i t s semicarbazone by acid. Only t h e more r e c e n t s y n t h e s e s w i l l be g i v e n , and it i s i n t e r e s t i n g t h a t t h e s e a r e a l l based on some form of e l e c t r o c y c l i c r e a c t i o n s . One of t h e e a r l i e s t of t h i s type i s t h a t of T e i s s e i r e , i n v o l v i n g t h e t r a n s e s t e r i f i c a t i o n of e t h y l aceto(2) l 1 The a l l y 1 e s t e r a c e t a t e with 2-methylbut-3-en-2-01
.
(1)
*Formulas of t h e s e s u b s t a n c e s w i l l be found i n t h e s e c t i o n s devoted t o more c l e a r l y d e f i n e d s y n t h e s e s d e s c r i b e d l a t e r . One example of t e l o m e r i z a t i o n i s a l s o d i s c u s s e d i n g r e a t e r det a i l i n t h e s e c t i o n devoted t o l i n a l o o l , n e r o l , and g e r a n i o l (P. 1 7 ) .
6-Methylhepg-5-en-2-one
5
obtained undergoes t h e C a r r o l r e a c t i o n , 1 2 r e s u l t i n g i n a €3k e t o a c i d through a r e a c t i o n akin t o t h e C l a i s e n r e a r r a n g e ment,13 and t h i s k e t o a c i d then l o s e s carbon d i o x i d e under t h e r e a c t i o n c o n d i t i o n s t o y i e l d t h e product (2). An e a r l i e r technique f o r t h i s type o f r e a c t i o n c o n s i s t e d i n mixing t h e a l c o h o l w i t h d i k e t e n e ; 1 3 when 2. and d i k e t e n e i s added t o h o t p a r a f f i n c o n t a i n i n g a t r a c e of p y r i d i n e , t h e methylheptenone (2) can be d i s t i l l e d from t h e mixture. l 4
+ cog
-
R02C
)-CC€H3 P
O
H
R02C
-4
-3
6OpR
-5
A f u r t h e r v a r i a n t u s e s condensation o f t h e a l l y 1 a l c o h o l (3) w i t h an acylmalonic ester (4) a t 130-200°, when a l c o h o l and carbon d i o x i d e are l o s t , g i v i n g t h i s t i m e a 8 - k e t o e s t e r (2) t h a t is c o n v e r t i b l e t o methylheptenone by ketone h y d r o l y s i s . l 5 This t y p e of procedure forms t h e b a s i s of one of t h e b e s t known commercial p r e p a r a t i o n s of methylheptenone (2), r e q u i r e d a s a v i t a l i n t e r m e d i a t e f o r s y n t h e s e s of l i n a l o o l ( g ) , t h e and vitamin A , and which i s i l l u s t r a t e d i n Scheme ionones 1. l6
(z),
Scheme 1
CHECH
Pd/BaSOb CH3 /L\
OH
6
The Synthesis of Monoterpenes
Via 6-ketoester
Linalool 6 -
- - - c Vitamin Ionones
A
Pseudoionone
The thermal rearran ement of ally1 ethers was described by Julia et al. in ~ 6 2 , ' ~and based on this idea, Saucy and Marbet synthesized methylheptenone from 2-methylbut-3-en-2-01 (2) and ethyl isopropenyl ether (8): l a
" 3 -
A0C2H5
-8
TsH, 14 hr r e f l u x in high bp ligroin; or H3P04 1 1/2 hr at 125' (autoclave)
-
6-Methylhept-5-en-2-one
7
A somewhat more c l a s s i c a l approach, namely, b u i l d i n g up t h e molecule by a s t a n d a r d ketone s y n t h e s i s from a f u n c t i o n a l i z e d i s o p r e n e is mentioned h e r e p a r t i c u l a r l y i n view of t h e importance of t h e p a r t i c u l a r C 5 m i t involved. The a d d i t i o n of halogen a c i d s t o i s o p r e n e (9) occurs i n i t i a l l y by 1 , 2 a d d i t i o n , l e a d i n g t o 2-chloro-2-methylbut- 3-ene (2) (or i t s bromo analog when hydrogen bromide i s employed). This compound can even be i s o l a t e d i n a r e l a t i v e l y pure s t a t e provided t h e a d d i t i o n i s n o t c a r r i e d through t o c 0 m p 1 e t i o n . l ~ Under t h e normal c o n d i t i o n s of a d d i t i o n , however, using an excess of For a c i d , t h e main product i s t h e primary c h l o r i d e (2). example, one mole of i s o p r e n e and two t o t h r e e moles of conc e n t r a t e d h y d r o c h l o r i c a c i d a t 0-40' f o r 1 t o 4 h r g i v e s 63% and 8% of t h e t e r t i a r y c h l o r i d e of t h e primary c h l o r i d e (2) (10) .20 Formation of t h e primary c h l o r i d e is a l s o favored by e l e v a t e d temperature and t h e presence of moisture. Treatment of t h e sodium d e r i v a t i v e of e t h y l a c e t o a c e t a t e with t h e primary c h l o r i d e t h u s l e a d s , a f t e r conventional h y d r o l y s i s and decarboxylation of t h e 6 - k e t o e s t e r t o methylheptenone (2).22 Direct condensation of acetone w i t h t h e primary chlor i d e (2) i s a l s o r e p o r t e d i n a Russian p a t e n t . 2 3
(11)
(z),
h
CH2C1
C H ~ C O C H C O ~ C 5Z H
The S y n t h e s i s of Monoterpenes
8
4.
Z16-D1METHYL0CTANE DERIVATIVES
A.
Hydrocarbons
Myrcene, Ocimene, and Alloocimene
e,
(12)and ocimene (&, cis and t r a n s ) are comnon c o n s t i t u e n t s of e s s e n t i a l o i l s . I n a d d i t i o n , myrcene i s made on t h e i n d u s t r i a l scale by p y r o l y s i s of B-pinene (14) , 2 4 ' 2 5 a r e a c t i o n t h a t also g i v e s r i s e t o a small amount of a-myrcene (g),26 n o t y e t r e p o r t e d as a n a t u r a l p r o d u c t . One of t h e problems a s s o c i a t e d w i t h cis-ocimene ( e l i s i t s ready transformation t o t h e non-naturally occurring alloocimene (16)[ t h e o n l y r e p o r t e d o c c u r r e n c e of the l a t t e r i n a p l a n t o i l h a s been a t t r i b u t e d t o r e a r r a n g e m e n t of cis-ocimene d u r i n g w ~ r k u p * ~ ] .Consequently, it i s n o t s u r p r i s i n g t h a t p y r o l y s i s of ( + ) - a - p i n e n e (2) i n l i q u i d form o v e r a nichrome w i r e a t 600' g i v e s , i n a d d i t i o n t o 48% of ocirnene, 1 6 . 5 % of a l l o o c i m e n e ( 1 6 ) , t o g e t h e r w i t h racemized a-pinene and d i p e n t e n e (18) 29 *B o t h myrcene
(s)
.
14 -
12 -
B-Pinene
Myrcene
15 -
17 -
( + I -a-Pinene I
*"Dipentene" w i l l b e used i n t h i s c h a p t e r t o d e n o t e t h e racemate, " l i m n e n e " b e i n g r e s e r v e d f o r t h e o p t i c a l l y a c t i v e iso-
mers.
2,6-Dimethyloctane Derivatives
13b -
9
18 -
trans-Ocimene
cis-Ocimene
1
Dipentene
t o ocimene can a l s o occur Isomerization of a-pinene (2) photochemically ,30 3 1 and Kropp has i n v e s t i g a t e d this and r e l a t e d r e a c t i o n s . 32 D i r e c t i r r a d i a t i o n of a-pinene i n low y i e l d was a l r e a d y known t o g i v e a product contaminated by d i pentene (18)and o t h e r products. 3 3 S e n s i t i z e d i r r a d i a t i o n of a-pinene i n xylene o r xylene-methanol was now found t o g i v e only cis-ocimene a f t e r s h o r t r e a c t i o n times, b u t w i t h longer p e r i o d s of i r r a d i a t i o n an equilibrium between cis- and trans-ocimene i s set up, although t h e product i s never seri, 3 2 a s i s t h e case with o u s l y contaminated with dipentene t h e p y r o l t i c and y-ray r a d i o l y t i c conversions of a-pinene t o ocimene. 321 This photochemical r e a c t i o n of a-pinene i s somewhat unexpected i n giving no B-pinene, u n l i k e t h e s i m i l a r r e t h a t g i v e s a 1 3 % y i e l d of p-menthaa c t i o n of dipentene (g), l ( 7 ) ,8-diene (19)on s e n s i t i z e d i r r a d i a t i o n . 3 2 I II
(a)
Q-
hv/sens
.
(13%)
A 18 -
-4 19 -
*For a d e t a i l e d d i s c u s s i o n of t h e v a r i o u s s t e r e o i s o m e r i c a l l o ocimenes , see Crowley '7
.
The S y n t h e s i s of Monoterpenes
10
T o t a l s y n t h e s i s of b o t h myrcene (2) and ocimene (2) gene r a l l y i n v o l v e s p y r o l y s i s of a s u i t a b l e a l c o h o l o r a c e t a t e . The most e a s i l y a v a i l a b l e a r e probably t h e d e r i v a t i v e s of l i n a l o o l (Scheme l), t r e a t e d i n more d e t a i l l a t e r , b u t which i s e a s i l y made by r e a c t i o n of sodium a c e t y l i d e on methylheptenone.35 L i n a l o o l i t s e l f (6) h a s been known for some y e a r s t o cjive myrcene by t r e a t m e n t with i o d i n e a t 140150', 36 b u t t h e a c e t a t e (20) can be pyrolyzed a l o n e , 3 7 while l o s s of a c e t i c a c i d o c c u r s o v e r Chromosorb P* a t t e m p e r a t u r e s a s l o w a s 140", t o g i v e t h e following amounts of t h e d i f f e r e n t hydrocarbons : 39
(12)
43%
20 -
20%
35%
2%
P y r o l y s i s of v a r i o u s o t h e r a c e t a t e s t o g i v e ocimenes and myrcene h a s a l s o been d e s c r i b e d . 2 6 38 Dehydration of g e r a n i o l (g) o r n e r o l (2) (related t o linalool allylically) i n the presence of potassium hydroxide a t 200' f o r 10 m i n u t e s t a l s o g i v e s 60% of myrcene and o t h e r p r o d u c t s , i n c l u d i n g a l l o ocimene. 1
I
I
Geraniol 21 -
12 + 16 +
Nerol 22 v
o t h e r products
* I n view of t h e i n s t a b i l i t y of l i n a l y l a c e t a t e on c e r t a i n supp o r t s , it i s always chromatographed i n t h e a u t h o r ' s l a b o r a t o r y on Chromosorb-W, on which i t i s stable up t o 200'. 'This t e c h n i q u e , developed by Ohloff4' h a s r e c e n t l y been reexamined by B h a t i b o t h f o r a l c o h o l d e h y d r a t i o n and isomerizat i o n (see below, under menthone).
2,6-Dimethyloctane Derivatives
11
A recent synthesis of myrcene on the "building block" principle (i.e., putting one unit together with another in logical sequence until the desired molecule is reached) has been described by Vig et al.42 It starts with ethyl 2carbethoxy-5-formyl butanoate (23) and follows Scheme 2.
Scheme 2 C02C2H5
1
OHC
___c
C02C2H5 23 -
I
CH20/Et2 NH
1. 2.
c : d C 0 2
H
LiAlH4 ox.
Ph3P=CH2
Hymentherene and Achillene 2,6-Dimethylocta-2,4,7-triene (26) was originally reported as a natural product, and given the name hymentherene;43 later, however, it turned out that the substance isolated was a mixThe name has been retained ture of two known m~noterpenes.~~ in this chapter for convenience, and also because it is still possible that the substance will be found in nature. The
12
The Synthesis of Monoterpenes
(e)
related cis-2,6-dimethylocta-1,4,7-triene has been isolated from A c h i l l a filipendulina by Dembitskii et a1.45r46 Early syntheses of "B-hymentherene" were unsuccessfu147~48 and the first time the substance was certainly isolated is by S ~ h u l t e - E l t e ,who ~ ~ started from the known47 (68)-(+)-2,6, the (6.5)-configuration of the dimethylocta-l,3 I 7-triene (2) positively rotating isomer of this substance having been established previously by correlation with ( - ) - t r a n s pinane. 5 0 r 5 1 Heating this triene ("trans-a-hymentherene," (25) in benzene and a catalytic amount of p-toluenesulfonic acid gave the thermodynamically more stable B-isomers (26a, The full synthesis from 2,6-dimethylocta-2,7-diene56(24) is shown in Scheme 3, which also gives the synthesis of natural
s).
ipCH3
Scheme 3
$cH3
A
Photoxidation -
/
CrOg
1
24 -
TSH
-
A
0
1
LiAlH4
PCH3 -3TGF
cis-a
benzoate
/
A
2
trans-a
5
Hymentherenes 4 3%
trans-B (UD
1
-
6.2')
Peracid
g
hv/sens
26a
(UD
cis-@ + 125.2')
i
Peracid
2,6-Dimethyloctane Derivatives
A-
OI
Ho I
Achillene 27a trans (aD - 3")
13
B (OH)3
CH3
achillene (27a) that Schulte-Elte achieved from cis-8-hymentherene ( 2 6 s 9 Although the reaction of p-toluenesulfonic acid on trans-a-hymentherene (2) leads to only 3% of the natural cis-configuration about the C-4 double bond, irradiain the presence of a sensition of the trans-compound (3) tizer leads to a mixture containing 43% of the cis compound (26a).49 Achillenol [the alcohol obtained immediately before axllene in the synthesis] has also been reported recently as a natural product,52 but the rotation does not agree with Schulte-Elte's synthetic material.4 9
(c)
Cosmene
(z),
The only natural monoterpene tetraene is cosmene, 2,6-dimethylocta-1,3,5,7-tetraene isolated from Cosmos bi innatus, Cav., and other compositae by Sarensen and SBren~en.'~ The
14
The Synthesis of Monoterpenes
hydrocarbon was synthesized by Nayler and Whiting by the route shown from 3-methylpent-1-en-4-yn-3-01 (2) 54 It is believed that the natural isomer is all-trans, (29a) and while the disubstituted ethylene is fairly well e s t m i s h e d as trans, the evidence for the trisubstituted ethylene is not so certain, in fact Nayler and Whiting state that their crude synthetic prodand =)about this double bond, uct contained two isomers (* recrystallization improving the purity. 5 4
.
1
LiA1H4
+
Cosmene
B.
x
29b -
Alcohols
Ci t r o n e l l o l
3,7-Dimethyloct-6-en-l-o1 is one monoterpene alcohols both as the acetate. It occurs naturally in most always as the 8-form (i.e.,
of the most widely distributed alcohol and the corresponding both ( + ) - and (-)-forms, alisopropylidene, e.g.,
s),
2,6-Dimethyloctane Derivatives
15
although isolated reports of the a-form (2) occurring in nature do exist. In this connection, it is worth mentioning the confusion in the literature about the terms "rhodinol" and "rhodinal." The older literature refers to a mixture, but later it has been held that citronellol and "rhodinol" are identical.5 5 56 EschinaziS7 and Naves and FreyS8 consider "rhodinol" to be (+)-a-citronellol (2) , and "rhodinal" to be the corresponding a-aldehyde. On the other hand, Chemical Abstracts refers to "rhodinol" as 3,7-dimeth loct-6-en-1-01 but "rhodinal" as 3f7-dimethyloct-7-en-l-01.~g It is the author's opinion that the name should no longer be used at all, and all references be made to citronellol, a-citronellol and citronellal.
(+) -Citronello1
(+) -a-Citronello3
Syntheses of citronellol are commercially important because supplies of the natural material are insufficient, and since geraniol is available from myrcene (see below), there are many syntheses described in the literature from geraniol or geranic acid by reduction (see Ref. 44 for a list), and these largely conventional syntheses will not be mentioned here. Somewhat more interesting is the synthesis from 2,6dimethylocta-ZI7-diene (32) using tri-isobutylaluminum then oxidizing51 (the presence of zinc isopropoxide being benethis reaction being the equivalent of a hydroboraficia16') tion.
Another synthesis is important as an illustration of the
The S y n t h e s i s of Monoterpenes
16
use of N-lithioethylenediamine t o d i s p l a c e double bonds. This r e a g e n t i s mentioned below i n s i m i l a r c o n n e c t i o n s , and, i n the s y n t h e s i s of c i t r o n e l l o l , i t was found t h a t d i h y d r o g e r a n i o l (2) , made from 6-methylheptan-2-one (2) v i a a Reformatsky r e a c t i o n 6 1 i s converted i n 70% y i e l d t o c i t r o n e l l o l . 6 2
to
C02Et
BrCH2COOEt
tCHzo I; ____c
Zn
33
-
/
LiAlH4
CH20H
~ / H ~ N C H ~ C H ~ N H Z
34 -
All t h e s y n t h e s e s of c i t r o n e l l o l from g e r a n i o l r e s u l t , of c o u r s e , i n t h e racemate, w h i l e t h e most i m p o r t a n t n a t u r a l d i a stereomer i s t h e (-)-form, and s y n t h e t i c approaches t o t h e c h i r a l form a r e r a r e . Linalool, Nerol, and Geraniol* Together w i t h c i t r o n e l l o l , t h e s e a l c o h o l s and t h e i r a c e t a t e s c o n s t i t u t e t h e most widely d i s t r i b u t e d monoterpene a l c o h o l s i n n a t u r e . Geraniol i s n o t only of some v a l u e i n i t s e l f , b u t a l s o a s an i n t e r m e d i a t e t o c i t r o n e l l o l which i s more u s e f u l t o
* A d e t a i l e d d i s c u s s i o n of t h e a l l y 1 rearrangements o c c u r r i n g between l i n a l o o l and t h e o t h e r t w o a l c o h o l s , recognized t o occur i n t h e l a s t c e n t u r y 6 3 w i l l n o t be g i v e n s i n c e i t belongs p r o p e r l y t o t h e domaine of p h y s i c a l o r g a n i c c h e m i s t r y .
2,6-Dimethyloctane Derivatives
17
the perfumery industry. The natural supplies of linalool and its acetate are insufficient to meet requirements, and these facts, together with the central position these alcohols occupy in the monoterpene field make a knowledge of their synthesis desirable. The syntheses described, particularly in the patent literature, are very numerous, and the reader is referred to Ref. 55, 64, and 65 for lists of the earlier methods. The most useful syntheses of linalool (6) have as their basis either acetone and acetylene (i.e., via methylheptenone, see Scheme 1 above15), or pinene, one of the most readily available hydrocarbons, from most types of natural turpentine. One of the latter methods involves the hydrochlorination of a f3-pinene (14)pyrolysate (i.e., myrcene (12) see above) , which, in the presence of cuprous halides gives a mixture of geranyl (37) and neryl (36) halides together with linalyl (35) and a-terpinyl (38) halides (Scheme 3) .66 These halideycan be converted under various conditions to geraniol, nerol, or linalool derivatives (see Ref. 55, p. 530), or neryl halides to a-terpineol (39), water hydrolysis at elevated temperatures favoring the formation of linalool (5) (Scheme 4).
c
CH20H
Q I
CH20H
Geraniol
Nerol
21 -
22 -
5-10%
35 -
18
k C H 2 OCOCH3
CH20COCH3
b
+p
a-Terpineol
i\
CH20COCH3
/(”
Linaloo 1
19
20
The S y n t h e s i s of Monoterpenes
A much more e l e g a n t s n t h e s i s s t a r t i n g from p i n e n e i s t h a t of Ohloff and K l e i n . 6 y T h i s r e q u i r e s t h e p i n a n o l s (+, 40b, and see b e l o w ) , t h e n , p r o v i d e d these are c h i r a l , o p t i c a l l y a c t i v e l i n a l o o l i s o b t a i n e d on p y r o l y s i s (Scheme 5 ) . The c i s - i s o m e r s r e a c t more e a s i l y and Ohloff found t h a t ( + ) c i s - p i n a n o l ( 4 0 a ) gave 86% of ( - ) - l i n a l o o l ( g )a t 600°, w h i l e ( - ) - t r a n s - p i n z l (G)o n l y gave 6 2 % of t h e same l i n a l o o l .
- +,
s,
Scheme 5
(+) -a-Pinene
(-)
I
(2R)
-
(+)
-cis-
-
-a-Pinene
-
( 2 s ) (+) -trans- ( 2 s ) ( - ) -cis-
I
(2R)- ( - ) - t r a n s -
LHOpCH;+ -
(3s)- (+) - L i n a l o o l CH3
-
6a -
( 3R)
- (-) -Linalool
2,6-Dimethyloctane D e r i v a t i v e s
21
I n c e r t a i n r e g i o n s , n o t a b l y I n d i a , t h e supply of c i t r a l s u f f i c i e n t (from lemongrass) t o make up t h e l a c k of l i n a l o o l from t h i s source. Thus e p o x i d a t i o n of c i t r a l w i t h a l k a l i n e hydrogen peroxide followed by t r e a t m e n t of t h e 1 , 2 epoxide (f?l) with hydrazine h y d r a t e ( t h e Wharton r e a c t i o n 6 8 ) i n methanol a t 0' g i v e s a 30 t o 35% y i e l d of l i n a l o o l (6).69,70
(41) is
Citral
41
42 -
-6
A r e l a t e d method u s e s t h e epoxide (44) of g e r a n y l i o d i d e which, on t r e a t m e n t with p-toluenesulfonylhydrazine and calcium carbonate i n d i m e t h y l s u l f o x i d e , g i v e s a q u a n t i t a t i v e y i e l d of l i n a l o o l . 7 1
r (431,
CH2 I
__c
TsNHNH2 CaC03
____c
i n DMSO
A s y n t h e s i s t h a t i s somewhat d i f f e r e n t from t h o s e so f a r d e s c r i b e d b e g i n s with a-acetyl-y-butyrolactone (45) which i s converted t o t h e chloroketone (46) with c o n c e n t r a t e d hydroc h l o r i c a c i d , then methylated w i t h a Grignard r e a c t i o n t o t h e t e r t i a r y a l c o h o l (47). Dehydration of t h e l a t t e r w i t h sodium b i s u l f a t e g i v e s mainly t h e d e s i r e d l-chloro-4-methylpent-3-ene (48), t h a t can b e converted i n t o l i n a l o o l (6) v i a t h e l i t h i u m d e r i v a t i v e with methyl v i n y l ketone. 72
22
The S y n t h e s i s o f Monoterpenes
COCH 3
c. HC1
CH3COCH2CH2CH2Cl
CH3MgI 47 -
46 -
45 -
NaHS04
1. L i
20 -
6 -
CH2C1
I
40 -
(g)
A problem a r i s e s i n t h e s y n t h e s i s o f t h e a c e t a t e from l i n a l o o l . Conventional a c e t y l a t i o n procedures, using a c e t i c a n h y d r i d e , f r e q u e n t l y g i v e r i s e t o c o n s i d e r a b l e hydrocarbon b y p r o d u c t s owing t o t h e r e a d y l o s s of a c e t i c a c i d (mentioned above i n c o n n e c t i o n w i t h t h e s y n t h e s i s o f t h e s e h y d r o c a r b o n s ) , and t o t h e f a c t t h a t l a r g e amounts o f n e r y l and g e r a n y l acet a t e s a r e formed a t t h e same t i m e by a l l y l i c r e a r r a n g e m e n t . These m i x t u r e s are t e d i o u s t o s e p a r a t e , s i n c e t h e i r b o i l i n g p o i n t s a r e f a i r l y c l o s e t o one a n o t h e r . The d i f f i c u l t y h a s been overcome by J i r d t and V 0 n 6 Z e k ~ by ~ p r e p a r i n g t h e sodium d e r i v a t i v e of l i n a l o o l w i t h sodium h y d r i d e i n an i n e r t s o l v e n t and t r e a t i n g t h i s w i t h d i e t h y l e n e g l y c o l d i a c e t a t e . Kogami e t a l . have g i v e n an a c c o u n t of t h e problem74 and s u g g e s t e d t h a t t h e b e s t method i s by u s i n k e t e n e i n t h e p r e s e n c e o f acid e s t e r i f i c a t i o n c a t a l y s t s . 7?,76 Acid r e a g e n t s c o n v e r t l i n a l o o l i n t o g e r a n i o l and n e r 0 1 ~ ~ [thionyl chloride, f o r instance, gives only geranyl chloride ( 3 7 ) 781 s o a l l t h e s y n t h e s e s mentioned f o r l i n a l o o l c o n s t i t u t e s y n t h e s e s a l s o f o r t h e s e t w o a l c o h o l s , b u t i n view of t h e e a s i e r s e p a r a t i o n o f t h e c o r r e s p o n d i n g a c i d methyl esters (49 and s y n t h e s e s r e q u i r i n g t h e p u r e g e o m e t r i c a l isomers m o s t f r e q u e n t l y p a s s t h r o u g h t h i s s t a g e . Many methods a r e a v a i l a b l e f o r t h e c o n v e r s i o n o f rnethylheptenone (2) t o a mixt u r e of methyl g e r a n a t e (%) and methyl n e r o l a t e (=), from
so),
2,6-Dimethyloctane D e r i v a t i v e s
23
t h e Refomatsky r e a c t i o n 7 ' t o t h e use of dimethoxycarbonylmethyl phosphonate ,8 o b u t a l l t h e s e a r e s t a n d a r d s y n t h e t i c t e c h n i q u e s , t h e d e t a i l of which need n o t be d e s c r i b e d h e r e . A p a r t i c u l a r l y i n t e r e s t i n g account of t h i s t y p e o f approach is t h a t o f Weedon's l a b o r a t o r y , s i n c e t h e y confirmed t h e geometry An t h a t was accepted t r a d i t i o n a l l y by NMR e a r l i e r s t e r e o s p e c i f i c s y n t h e s i s of n e r o l involved a d d i t i o n of carbon d i o x i d e and hydrogen a c r o s s a t r i p l e bond u s i n g n i c k e l carbonyl.81a
+
CH30CECH
-
HCO'
H+
3
__c
-2
50 -
49 -
A t t h e beginning of t h i s c h a p t e r , it was b r i e f l y mentioned
t h a t methods a r e a v a i l a b l e f o r c o n v e r t i n g isoprene d i r e c t l y i n t o mixtures of monoterpenoids. One such method involves t h e t e l o m e r i z a t i o n below 20' i n 85% formic a c i d i n t h e presence of 10%p e r c h l o r i c a c i d . A f t e r 5 h r , then h y d r o l y s i s , d i p e n t e n e (18), and t e r p i n o l e n e are o b t a i n e d i n a d d i t i o n t o t h e a z o h o l s l i n a l o o l (21, g e r a n i o l n e r o l (221, and at e r p i n e o l (2) a2
.
(z)
(z),
24
The S y n t h e s i s of Monoterpenes
t
39 -
51 -
18 -
alkaloid^^^-^^
G e r a n i o l o c c u p i e s a c e n t r a l o s i t i o n i n schemes f o r t h e b i o s y n t h e s i s of i n d o l e as w e l l a s i n t h e pathway suggested f o r t h e formation of monoterpenes, and Haley, Miller, and Wood have examined t h e behavior of g e r a n y l (52) and n e r y l diphenyl phosphates, as models f o r t h e b i o s y n t h e t i c p r o c e s s . 8 6 * These compounds decompose spontaneously i n i n e r t s o l v e n t s t o g i v e m n o t e r p e n e s - - g e r a n y l phosphate (52) g i v i n g less c y c l i c t e r p e n e s t h a n n e r y l phosphate. The a u t h o r s suggested t h a t an a l t e r n a t i v e mechanism t o t h e p-menthane monoterpenes was by a l l y l i c rearrangement of g e r a n y l phosphate t o l i n a l y l phost h e n c y c l i z a t i o n a s shown i n Scheme 6 , b u t t h e y phate were unable t o i d e n t i f y l i n a l y l phosphate i n t h e r e a c t i o n mixture. Scheme 6
(z)
__c
Menthadienes
*The s t e r e o s p e c i f i c c y c l i z a t i o n of l i n a l o o l t o a - t e r p i n e o l i s , of c o u r s e , a well-known r e a c t i o n . A d i s c u s s i o n h a s been given by P r e l o g and Watanabe . 0 7
2,6-Dimethyloctane Derivatives
25
Hotrienol
-
3,7-Dimethyl-1,5 ,7-octatrien-3-01 (55) occurs a s t h e 3s- (t) enantiomorph i n Ho l e a f while t h e R-enantiomorph has been i s o l a t e d from t e a , both blackE9 and green.90 Before it had been r e p o r t e d as a n a t u r a l product, Matsuura and Butsugan had prepared i t from one of t h e photooxidation products of The g l y c o l (54), on treatment with s u l f u r i c ( - ) - l i n a l o o l (&). a c i d i n acetone, y i e l d s R-hotrienol (55).91 The r o u t e f o l lowed by Nakatani e t a l . a l s o s t a r t s from R - l i n a l y l a c e t a t e r e a c t i o n of N-bromosuccinimide on which gives a mixand from which hydroture of t h r e e bromacetates gen bromide can be remved by d i e t h y l a n i l i n e , leading t o t h e a c e t a t e (57) o f t h e R-isomer, from which t h e alcohol (55) can be obtained by conventional h y d r o l y s i s . 09
(s),
=,=, =,
Og/h~/sens
____c
6a
I (5
R-
OCOCH 3
R-
f O C H 3
R-
+
+
q0c0cH3
OCOCH 3
Br
CH2Br
56a
BrCH2
56b -
56c -
26
The S y n t h e s i s of Monoterpenes
2-Methyl-6-methyleneocta-2,7-diene-4-01 methylene-oct-7-en-4-01 (63)
(62) and
2-Methyl-6-
These two aocohols were i s o l a t e d from t h e s e x a t t r a c t a n t of t h e bark b e e t l e , Ips c o n f u s ~ s ,and ~ ~ have been s y n t h e s i z e d by Reece e t a l . 9 3 The i n i t i a l r e a c t i o n followed a procedure sugg e s t e d by Corey and S e e b a ~ h and ? ~ ~ c o~n s~i s t e d i n c o u p l i n g bromomethylbutadiene w i t h t h e t h i o k e t a l anion (2, or i t s dihydro-compound) The t h i o k e t a l (60) t h e r e b y o b t a i n e d was converted t o t h e ketone (61) w i t h s i l v e r n i t r a t e , o r , i n t h e c a s e of t h e dihydro-compound, w i t h mercuric c h l o r i d e cadmium c a r b o n a t e . The k e t o n e s were t h e n reduced t o t h e c o r r e sponding a l c o h o l s w i t h sodium borohydride.
(z)96 .
58 -
59 -
60 -
HO
63 -
C.
62 -
Aldehydes and Ketones
Ci tronellal The aldehyde c i t r o n e l l a 1 (65) i s a g a i n a widely o c c u r r i n g n a t u r a l p r o d u c t , and can be made by c o n v e n t i o n a l o r g a n i c techniques from t h e corresponding a l c o h o l , c i t r o n e l l o l (see a b o v e ) , o r by r e d u c t i o n o f c i t r a l ( s e e below). H d r a t i o n of c i t r o n e l l a 1 ( u s u a l l y v i a t h e b i s u l f i t e compound)9Yf98y i e l d s t h e
2,6-Dimethyloctane
Derivatives
27
v a l u a b l e h y d r o x y c i t r o n e l l a l * (66) t h a t i s n o t , however, r e p o r t e d a s being n a t u r a l l y o c c u r r i n g . A study of t h e dehydrat i o n of h y d r o x y c i t r o n e l l a l t o a mixture of a- ( 6 7 ) and 6c i t r o n e l l a l s has been published by Eschinazi. 57-Since citron e l l a l can be made by p y r o l y s i s o f i s o p u l e g o l (64) ,q9r100 any s y n t h e s i s of t h i s substance c o n s t i t u t e s a s y n t h e s i s of citronellal.
66 -
64 -
65 -
Isopulegol
Citronella1
41b Citral b
41a
68 -
Citral a
Isocitral
_.
1
67 a-Citronella1
Ci tral
e)
Both n a t u r a l and s y n t h e t i c c i t r a l i s a mixture of t h e two poss i b l e isomeric forms, c i t r a l a ( = g e r a n i a l , and c i t r a l b (=neral, The two isomers have been w e l l c h a r a c t e r i z e d by NMR a n a l y s i s , l o ' l o 2 and i n t h e commonly encountered mixt u r e s t h e trans- form ( g e r a n i a l , +) i s g e n e r a l l y t h e predominating isomer. In a d d i t i o n , h e a t i n g t h e mixture of c i t r a l a and c i t r a l b t o over 130' causes i s o m e r i z a t i o n t o a t h i r d isomer, i s o c i t r a l (E),t o occurq9 ( i n a d d i t i o n t o c y c l i z a t i o n r e a c t i o n s t h a t occur a t h i g h e r temperatures and under t h e
z).
*The c o n d i t i o n s necessary f o r high conversion t o t h e h y d r a t e have been examined by s e v e r a l a u t h o r s ( s e e , e . g . , Ref. 9 8 ) .
28
The S y n t h e s i s of Monoterpenes
i n f l u e n c e of a c i d c a t a l y s t s * ) . C i t r a l can be made from g e r a n i o l (21) by many v a r i e t i e s of o x i d a t i o n procedure ( s e e R e f . 103, f o r a l i s t , t o g e t h e r with many o t h e r s y n t h e s e s ) , b u t p a r t i c u l a r l y potassium dichromate i n a c e t i c a c i d , which a f t e r r e f l w i n g f o r 1 h r , t h e n steam d i s t i l l i n g , i s r e p o r t e d l b 4 t o g i v e almost q u a n t i t a t i v e y i e l d s . Various c a t a l y t i c methods a r e a l s o d e s c r i b e d , 1 0 5 p 1 0 6t h e use of c i t r o n e l l a 1 as a hydrogen acceptor being advised i n some c a s e s . O 6 Oxidation of g e r a n i o l o r n e r o l w i t h manganese d i o x i d e ought, i n p r i n c i p l e , t o g i v e c i t r a l , b u t t h e r e s u l t s a r e h i g h l y dependent on t h e sample of manganese d i o x i d e used,'l and i t has been suggested t h a t n i c k e l peroxide (which i s a similar, though more powerful o x i d a n t ) i s more e f f e c t i v e . l o 7 I t i s also p o s s i b l e t o o x i d i z e g e r a n y l bromide (691, o b t a i n a b l e from l i n a l o o l (6) w i t h hydrogen bromide a t -5" ( s e e above), w i t h v a r i o u s nitro-compounds i n a l k a l i n e s o l u t i o n ,108,109 t h i s method r e p r e s e n t i n g one o f t h e ways of o b t a i n i n g c i t r a l from methylheptenone without going through t h e g e r a n i c a c i d s t a g e .
69 -
41 -
There a r e many o t h e r ways of s y n t h e s i z i n g c i t r a l from methylheptenone, and o n l y a b r i e f survey w i l l be given h e r e t o i l l u s t r a t e c e r t a i n f a c e t s of t y p i c a l t e r p e n e s y n t h e s e s . One type i n v o l v e s t h e a d d i t i o n of a two-carbon u n i t , a s a v i n y l e t h e r , t o an a c e t a l ( e . g . , of methylheptenone) i n t h e presence of a Lewis a c i d ; a review of t h i s r e a c t i o n has app e a r e d . l 1 ° Loss of two molecules of e t h a n o l from t h e a c e t a l l e a d s t o c i t r a l . l 1 l Another method of t h u s o b t a i n e d (z)t adding a two-carbon u n i t d i r e c t l y t o methylheptenone r e p r e s e n t s a branch along t h e l i n a l o o l s y n t h e s i s d e s c r i b e d p r e v i o u s l y . The product of t h e r e a c t i o n between methylheptenone and a c e t y l e n e ( d e h y d r o l i n a l o o l , 2)can be a c e t y l a t e d , and t h e *For examples of c i t r a l c y c l i z a t i o n s ( s e e , e . g . , p-isopropenylmethylbenzene, i s o p i p e r i t e n o l , e t c . ) . tMethods f o r t h i s e l i m i n a t i o n a r e mentioned i n t h e review q u o t e d , l 1 ° s e e a l s o some more r e c e n t r e s u l t s u s i n g t h i s type of s y n t h e s i s . l 1 2
2,6-Dimethyloctane Derivatives
73 -
7 1 R - H 72 R = COCH3
74 -
iL
29
fH+
75 -
resulting acetate (12)pyrolyzed. This gives the intermediate , which on hydrolysis yields citral. I l 4 allene acetate (2) By comparison, an example of a synthesis involving successive additions of one carbon, first by formation of the hydroxymethylene compound (741, then Grignard addition of the protected aldehydoketone (75) and final dehydration, is very cumbersome. If one-carbon units must be added, then it would appear better to start from a Cq compound, as in the example of the use of the Prins reaction by Suga and Watanabe, when they obtained 7-methyl-3-methyleneoct-6-enyl acetate from the reaction of formaldehyde in acetate anhydride with 2,6dimethylhepta-l,S-diene (76) l 6 Generally speaking, the Prins reaction in the case of these open chain olefins leads to complex mixtures that are not always easy to separate and
.
(z)
30
The Synthesis of Monoterpenes
purify (see, e.g., lavandulol, below). In the case of the Japanese authors, they were able to obtain 120 g of the acetate and from this, by h drolysis (77)from 200 g of the diene and chromic oxidation, arrived at the citral desired.IY 6
[z),
1. Hydrolysis
2. CrO3
-- 41
Ta ye tones
Tagetone, 3,7-di-methylocta-l,3-dien-5-one ( E ) ,occurs in T a g e t e s g l a n ~ i u l i f e r aand ~ ~ ~other Tagetes spp. (compositae), and in Japanese Ho oil as a hydroxylated derivative.88 Dia l s o occurs 11atura1ly.l~~Ta etone has hydrotagetone (2) been synthesized by Boehm, Thaller, and Whiting,’18 and by Teisseire and Corbier,l19 and the dihydroketone by Vig et a1.120,121and by the same French authors.l19
P
4
2,6-Dimethyloctane Derivatives
Mn02 81 --
31
0
The main substance i n Tagetes g l a n d u l i f e r a is cistagetone (=), although small amounts of t h e trans-isomer occur, and it i s t h e l a t t e r t h a t Boehm e t a l . synthes i z e d , a t t h e same time proving t h e s t r u c t u r e of t h e cis-isomer by i t s conversion t o t h e s y n t h e t i c m a t e r i a l with iodine i n petroleum e t h e r . Grignard r e a c t i o n of i s o b u t y l bromide with t h e trans-enynal (80) gave t h e complete carbon skeleton of tagetone, a l l t h a t was then necessary was t o reduce t h e t r i p l e bond t o a double bond by means of the Lindlar c a t a l y s t , 1 2 2 then oxidize t h e a l l y 1 alcohol (81) t o a ketone w i t h manganese d i o x i a e . The l a s t s t e p d i d n o t give very good y i e l d s , b u t was adequate f o r t h e purpose of s t r u c t u r a l proof. The s y n t h e s i s of dihydrotagetone (2) by Vig e t a l . cons i s t s i n again making t h e carbon s k e l e t o n by an organometallic r e a c t i o n on a 3-methylhexyl oxygenated compound. They prepared 3-methylpent-4-enal ( g )by a Claisen rearrangement of c r o t y l alcohol v i n y l e t h e r , and a f t e r converting t h i s aldehyde t o t h e corresponding acid c h l o r i d e (83), obtained t h e ketone (79) d i r e c t l y by r e a c t i o n of t h e organocadmium reagent from i s o b u t y l bromide. Vig' s l a t e r syntheses of dihydrotagetone121 a r e shown i n Scheme 7.
(z)
32
The S y n t h e s i s of M o n o t e r p e n e s
h
2 . SOCLZ
I
CHO
COCl
79 -
83 -
0
+
___c
I
1. W i t t i g 2. Acid
79 -
(CUI)
The F r e n c h s y n t h e s i s (Scheme 8 ) s t a r t s from m e t h y l i s o b u t y l k e t o n e (%I, which i s f i r s t c o n v e r t e d t o t h e e n o l e t h e r
(e),
Scheme 8
84 -
85a -
c -
S
-
C
H
z
Y
V
\-
85b -
/
CH20H
I \ V /
A 86a -
87 -
A
88 -
A
79 -
33
34
The S y n t h e s i s of Monoterpenes
from which t h e a c e t y l e n i c e t h e r (86)i s made ( b u t n o t isol a t e d ) by r e a c t i o n w i t h but-2-yno1, i n t h e p r e s e n c e of potassium hydrogen s u l f a t e . During t h e r e a c t i o n , a C l a i s e n rearrangement o c c u r s , and t h e a l l e n o n e (=) c a n be i s o l a t e d i n 65% y i e l d . A second a l l e n o n e (88) i s formed from t h e accompanying isomeric enol e t h e r b u t when t h e m i x t u r e o f a l l e n o n e s i s t r e a t e d w i t h b a s e , o n l y t h e d e s i r e d one (87) r e a r r a n g e s t o a m i x t u r e o f cis- and t r a n s - t a g e t o n e s (78). U n f o r t u n a t e l y , Teisseire d o e s n o t g i v e t h e p r o p o r t i o n s o f t h e t w o , b u t the y i e l d of t h e m i x t u r e i s 45% based on t h e b u t y n o l . When c r o t y l a l c o h o l was u s e d i n s t e a d o f t h e b u t y n o l , d i h y d r o t a g e t o n e (2) i s o b t a i n e d a s the major p r o d u c t ( 6 0 % ) of t h e m i x t u r e , t h e remainder c o n s i s t i n g o f t h e two stereomers o f t h e u n d e s i r e d isomer ( a s ) , t h e l a t t e r t h r e e p r o d u c t s b e i n g d i f f i c u l t t o separate79
(z),
5.
SUBSTANCES DERIVED FROM CHRYSANTHEMIC A C I D
I n 1965, Bates and P a k n i k a r l Z 3 showed how i t w a s possible t o d e r i v e t h e s k e l e t o n s o f a number o f n a t u r a l l y o c c u r r i n g monot e r p e n e s from t h a t of n a t u r a l t r a n s - c h r y s a n t h e m i c a c i d (%) by f i s s i o n of t h e v a r i o u s bonds o f t h e c y c l o p r o p a n e r i n g . The i d e a was developed by Crombie e t a l . , l Z 4 who showed how openi n g of t h e bond marked " A " i n t h e formula (=) leads t o t h e s a n t o l i n y l s k e l e t o n , e n c o u n t e r e d i n n a t u r e i n t h e form of s a n t o l i n a t r i e n e (91),125 1 r a t o l (92), 1 2 6 and 2,5-dimethyl-3(93), I x 7 w h i l e opening of bond "B" g i v e s vinylpent-4-en-2-01 t h e a r t e m i s y l s k e l e t o n of which a r t e m i s i a k e t o n e ( E l * i s a long-known member, 1 2 * t o g e t h e r w i t h t h e more r e c e n t l y establ i s h e d s t r u c t u r e , yomogi a l c o h o l 3 0 t 1 3 1 F i n a l l y , sciss i o n o f bond "C" l e a d s t o t h e l a v a n d u l 1 s k e l e t o n , a r e p r e s e n t a t i v e o f which i s l a v a n d u l o l (96).1 5 2
(z) .
*Not t o be confused w i t h t h e more r e c e n t l y i s o l a t e d a c e t y l e n i c compound t o which t h e same name h a s u n f o r t u n a t e l y been g i v e n . 1 2 9 I t should b e n o t e d t h a t t h e c o r r e c t s t r u c t u r e of a r t e m i s i a k e t o n e i s t h e one shown h e r e , and r e f e r r e d t o i n A s a h i n a ' s papers as " i s o a r t e m i s i a k e t o n e ," see r e l e v . a n t sect i o n below.
santolinyl
Artemisyl
94
I
I I
CH20H
35
The Synthesis of Monoterpenes
36
The Santolinyl Skeleton
A.
S a n t o l i n a t r i e n e (91),I2' L ratol vinylpen t-4-en-2-01 (93)123
(92),126
2,5-Dirnethyl-3-
There are three members of this group of compounds occurring naturally, all of which have been synthesized. Sucrow made the first, santolinatriene from 5-methyl2,4-hexadien-l-ol (971, which, on heating with a 2 1/2-fold excess of 1-ethoxy-1-dimethylainoprop-1-ene (98) in xylene, underwent the Claisen reaction of the initially formed ketene0,N-acetal (99)as Eschenmoser's group has described,133 leading to the dimethylamide (=). Reduction of the carbonyl group of the amide, followed by a Cope reaction of the N-oxide of the corres onding amine (101)gave the required santolinatriene ( 2 ) 1 9. 4
(s),
C" 3 'CH=CH-CH=CH-CH20H
/
CH3
,0C2H5 + H3C-CH=C
\
97 -
98
__c
N(CH3)2
>=CH'
CH 3'
99
I
i
t
CH=CH2 CH3 I 'C=CH-CH-CH-CON I / CH3 CH3 101 -
(CH3)2
100 -
Trost and LaRochelle have described the possibility of a "biogenetic pathway" for the construction of an artemisyl skeleton by attachment of an enzyme to the sulfur atom in a sulfur ylid (102).After the rearrangements of this ylid (to 1031, a carbonium ion can be formed (104)that can give rise to either the unchanged artemisyl skeleton--the santolinyl
S u b s t a n c e s Derived from Chrysanthemic Acid
37
s k e l e t o n (by m i g r a t i o n o f t h e v i n y l group) o r t h e chrysanthemic a c i d s t r u c t u r e (by r i n g c l o s u r e ) as shown i n Scheme 9.135
Scheme 9
104 -
t
Chrysanthemic acid
The f i r s t step of t h i s " b i o g e n e s i s " a s f a r as t h e artemi s y l s k e l e t o n h a s been r e a l i z e d i n t h e l a b o r a t o r y ( s e e b e l o w ) , and i t h a s been shown t h a t t r e a t m e n t o f yomogi a l c o h o l epoxide (105,below) w i t h p - t o l u e n e s u l f o n i c a c i d y i e l d s t h e s a n t o l i n y l s k e l e t o n , e i t h e r a s c y c l i z e d s u b s t a n c e s (see Scheme 1 0 ) o r as a d i o l (106) 36 I f t h e a c i d - c a t a l y z e d rearrangement o f yomogi a l c o h o l epoxide (105)is c a r r i e d o u t i n t h e p r e s e n c e of an e x c e s s o f benzaldehyde, t h e two acetals (107a, 107b) a r e t h e main p r o d u c t s from t h e r e a c t i o n , and t r e a t m e n t o f t h e mixt u r e w i t h b u t y l l i t h i u m i n hexanel 37 l e a d s t o s a n t o l i n a t r i e n e a l t h o u g h t h e y i e l d i s v e r y low, competing r e a c t i o n s p r e dominating (Scheme 1 0 ) 3 8
.'
(z),
.
Scheme 10
OH
Y OH
HO
s+.
/
I'OH
107b -
107a -
CbHgLi
8%
38
9%
14%
Substances Derived from Chrysanthemic Acid
39
Sucrow and Richter's synthesis of the Chrgtien-Bessisre monoterpene (Z)lz7 is illustrated in Scheme 11,13' and Sucrow's Scheme 11
H3C\
/CH3 C -CH -CH =C\ H3C/ IOH CH2 I CH3
I
1. H202 ___c
2. Cope
CH2N(CH3)2
"3C,
/CH 3 C -CH-CH=C \ H3C'hH AH CH 3
1I
CHZ 93 -
(z)lz6
lyratol synthesis is in Scheme 12.140 The principal of the two syntheses is practically the same as for the same author's earlier santolinatriene synthesis (see above). Scheme 12* H3C,
C-CX!-CH=CHOCH3 H5C202C'IOH
1. LiAlH4 2. H ~ O +
c
*In Scheme 12, the alcohol (E) is acetylated (to before proceeding with the lithium t-butoxyaluminm hydride reduction.
The S y n t h e s i s of Monoterpenes
40
L i A l H (t-BuO) 3
H3C\ /
C=CH-CH=CH-CHO
-
ROCH2
108a R 108b R -
= H
= COCH3
H 3C-CH’C H 3c, ,C=CH-CH=CH-CH20H AcOCH2
‘C=CH-CH-CH=CH~
/
AcOCH2
H3C, H3C, /
CH
,N ( C H 3 ) 2 ‘OCH 3 4
H3C\
,CH2N(CH3) 2
I
C=CH-CH-CH=CH2
HOCH 2
1. H202
____c
2 . Cope
H3C\
4%
C
I
,CH-CH=CH2
/c=c\H
HOCH2
92 -
B.
The A r t e m i s y l S k e l e t o n
A r t e m i s i a K e t o n e , A l c o h o l , and A c e t a t e , and Yomogi A lc ohol
(94)
The f i r s t a u t h e n t i c s y n t h e s i s o f a r t e m i s i a k e t o n e was t h a t of Colonge and D u m n t i n 1 9 4 4 , 1 4 ‘ a l t h o u g h t h e c a r b o n s k e l e t o n i n i t s r e d u c e d form had b e e n made much earlier by Ruzicka and R e i c h s t e i n . 1 4 ’ Much of t h i s e a r l y work w a s hamp e r e d by t h e c o n f u s i o n t h e n e x i s t i n g a b o u t t h e p o s i t i o n of t h e c o n j u g a t e d d o u b l e b o n d , t h a t had b e e n t h o u g h t a t f i r s t t o be i n t h e B y - p o s i t i o n t o t h e c a r b o n y l g r o u p (+). The s i t u a t i o n was r e s o l v e d by Takemoto and N a k a j i m a i n 1957,143 who demons t r a t e d t h a t t h e e a r l i e r “ i s o a r t e m i s i a ketone” w a s a c t u a l l y t h e c o r r e c t s t r u c t u r e f o r t h e n a t u r a l p r o d u c t (94) a n d sugg e s t e d t h a t t h e u n c o n j u g a t e d isomer (%) d i d n o t e x i s t . Act u a l l y , Colonge’s s y n t h e s i s g i v e s i n i t i a l l y t h e unconjugated
Substances Derived from Chrysanthemic Acid
41
isomer* i n o n l y small amounts by r e a c t i o n of 2,2-dimethylbut3-enoyl c h l o r i d e (109) with isobutene i n t h e presence of s t a n n i c c h l o r i d e , 14' t h e i n t e r m e d i a t e carbonium i o n cyclizi n g t o g i v e t h e six-membered r i n g carbonium i o n that s t a b i l i z e s i t s e l f by r i n g c o n t r a c t i o n t o t h e undesired major 14' product
(110) (111)
(112) .
=+xl
94 -
+
y
SnC14; .
112 -
94a -
Based on t h e rearrangement o f a l l y 1 sulfonium y l i d e s , 146 Rautenstrauch, 14' and independently, Baldwin e t a l . ,149 developed a s y n t h e s i s of a r t e m i s i a a l c o h o l , from which t h e acet a t e and t h e ketone a r e a c c e s s i b l e . When d i p r e n y l e t h e r (=) i s t r e a t e d w i t h b u t y l l i t h i u m a t -25", t h e main product (67%) i s a r t e m i s i a alcohol , by a [2,3]-sigmatropic change, t o g e t h e r w i t h t h r e e byproducts (115t o
(114)
117).
*This r e a c t i o n h a s more r e c e n t l y been checked by B a t t e r s b y and Rowlands, and t h e unconjugated ketone (94a) found t o r e a r r a n g e very r e a d i l y t o a r t e m i s i a ketone (94).lr
42
The S y n t h e s i s of Monoterpenes
CqHqLi
____c
'.
Li
'
113 -
115 -
114 Artemisia Alcohol
Owing t o t h e f a c t t h a t t h e Grignard r e a c t i o n s of p r e n y l h a l i d e s artemisia alg i v e t h e a l l y l i c a l l y r e a r r a n g e d compounds r 1 cohol (114)can be madelS1 i n h i g h y i e l d by c a r r y i n g o u t a Grignard-type s y n t h e s i s between p r e n y l h a l i d e (119) and d i m e t h y l a c r o l e i n ( " s e n e c i a a l d e h y d e " ) (118) , a l t h o u g h t h e mixt u r e must be i n c o n t a c t a t t h e same t i m e w i t h magnesium i n o r d e r t o a v o i d t h e more u s u a l Wurtz r e a c t i o n w i t h p r e n y l halides.150t151
118 -
119 (E) has
114 -
Yomogi a l c o h o l also been s y n t h e s i z e d from p r e n y l c h l o r i d e ( E )t , h e f i r s t s t e p t h i s t i m e b e i n g t h e Wurz coupli n g w i t h magnesium,150 t h i s g i v i n g ready a c c e s s t o t h e d i e n e w i t h a l l t h e c a r b o n atoms i n t h e correct p o s i t i o n . P h o t o o x i d a t i o n i n t h e p r e s e n c e of a s e n s i t i z e r y i e l d s t w o p h o t o p e r o x i d e s , t h a t can b e c o n v e r t e d w i t h sodium s u l f i t e t o t h e t w o a l c o h o l s , yomogi a l c o h o l and i n the ratio of a b o u t 5: 1. 30 Although c o n v e n t i o n a l o x i d a t i o n p r o c e d u r e s
(120)
(z)(x),
Substances Derived from Chrysanthemic Acid
43
a p p l i e d t o yomogi a l c o h o l y i e l d t r a c e s of a r t e m i s i a k e t o n e , t h e main product i s always t h e a l c o h o l epoxide (105) t h a t can be induced t o r e a r r a n g e t o t h e s a n t o l i n y l s k e l e t o n , b u t which does n o t r e a d i l y g i v e a r t e m i s i a a l c o h o l o r ketone. 3 6
>=u,
+Mg-
)-7
CH2C1
119 -
-
1. hv, 02/sens
2 . NazSOg
120 -
OH
95 -
121 -
Another s y n t h e s i s of yoxnogi a l c o h o l by Sucrow from t h e known152 2,2-dimethylbut-3-enal uses a W i t t i g r e a c t i o n . 1 5 3 p 1 5 4 CH 3
I I
H2C=CH-C-CHO
+
(CzH5O) 2PO?HCOOC2Hs
__c
CH3 CH3 I H2C=CH-C-CH=CHCOOC2H5
I
CH 3 C.
CH 3 L i
CH3
I
CH3
kH3
CH 3
I
H2C=CH-C-CH=CH-C-OH I I
The Lavandulyl Skeleton
Lavandulol , B-Cyclolavandulal s c h i n z and co-workers s t a r t e d a series of s t u d i e s on t h e synt h e s i s of l a v a n d u l o l s h o r t l y a f t e r i t s d i s c o v e r y i n lavendar,13’ most of t h e e a r l y v e r s i o n s of which c o n s i s t e d i n b u i l d i n g up a s u i t a b l e hydroxylated d e r i v a t i v e (such as o r 123lS6)and t h e n dehydrating them by, f o r example, pyrol y s i s of t h e a c e t a t e s . A disadvantage of t h i s type o f synt h e s i s i s t h a t t h e dehydration g i v e s r i s e t o o t h e r double bond isomers, such as t h e n o t n a t u r a l l y o c c u r r i n g i s o l a v a n d u l o l o r tetrahydropyran t y p e s , such as 1 2 5 , a type of c y c l i z a t i o n t h a t had been recognized s i n c e 1932,’~~
(124)
44
The S y n t h e s i s o f Monoterpenes
CH20H
122 -
125 -
124 -
1 23 -
T h i s d i s a d v a n t a g e was overcome i n the s y n t h e s i s o f Brack by s t a r t i n g w i t h 4,4-dimethylhex-5-en-2-one and S c h i n z l (126).By means of e t h o x y a c e t y l e n e , t h i s c o u l d b e c o n v e r t e d into the acetylenic ether t h a t gave t h e u n s a t u r a t e d e s t e r (128)i n t h e p r e s e n c e o f a c i d . This e s t e r w a s r e a r r a n g e d t h e r m a l l y i n a Cope r e a r r a n g e m e n t t o l e a d e x c l u s i v e l y t o t h e e t h y l e s t e r (2) corresponding t o t h e alcohol lavandulol ( E ) , which c o u l d t h e n b e o b t a i n e d c o n v e n t i o n a l l y .
(x),
126 -
127 -
129 -
128 -
Another s y n t h e s i s t h a t depends p r i m a r i l y on a n electroc y c l i c r e a r r a n g e m e n t i s t h a t of Matsui and S t a l l a B o u r d i l l o n , 1 5 9 and i s b a s e d on t h e f a c t t h a t t h e e n o l a t e s o f Aca l l y 1 e s t e r s r e a r r a n g e i n a C l a i s e n - l i k e r e a c t i o n . 16' c o r d i n g l y , t h e e s t e r from 1 , l - d i m e t h y l a l l y l a l c o h o l and 3methylbut-2-enoic a c i d (i.e. , when t r e a t e d f o r 2 h r w i t h sodium h y d r i d e i n t o l u e n e a t l l O o g i v e s a 7:3 r a t i o o f lavand u l a t e (131)t o i s o l a v a n d u l a t e (132).
z),
Substances Derived from Chrysanthemic Acid
131 -
45
132 -
A s y n t h e s i s of lavandulol by Teisseire and Rinaldi'" c o n s i s t s i n adding t h e d i m e t h y l a l l y l group t o e t h y l acetoa c e t a t e t o o b t a i n t h e 8 - k e t o e s t e r (133). The carbonyl group of t h i s compound can be converted smoothly t o a methylene group by means of t h e W i t t i g r e a c t i o n , l e a d i n g t o t h e e t h y l e s t e r (129) of l a v a n d u l i c acid.
C H ~ C O C H ~ C O O C ~ H S (NaNH2)
___c
p BrCH2CH=C 'CH
CH~CO-CH-COOC~HS
3
I
CH2CH=C
/CH3
\
3
133 -
Wittig
___c
CH3
I
CH2CH=C
p
\
129 -
3
CH3
Prenyl bromide can, i n f a c t , be coupled t o g i v e t h e lavandulyl s k e l e t o n d i r e c t l y ; z i n c c h l o r i d e i n carbon t e t r a c h l o r i d e y i e l d s t h e dibromide (=) t h a t l o s e s one molecule of hydrogen bromide i n t h e presence of potassium a c e t a t e i n t h e second bromine being r e p l a c e d by acetic acid ( t o hydroxyl v i a t h e corresponding Grignard r e a g e n t . The lavand u l o l thereby obtained (96) i s accompanied by t h e coupling product from t h e competing Wurtz r e a c t i o n (136). The appare n t l y simpler route from t h e monobromide (135) l e a d s t o elimin a t i o n of hydrogen bromide r e s u l t i n g i n t h e hydrocarbon (137).1 6 2 This same hydrocarbon r e s u l t s when t h e a l l y 1
z),
46
The S y n t h e s i s o f Monoterpenes
r e a r r a n g e m e n t p r o d u c t (138) from i s o l a v a n d u l o l * hydrated thermally. l 6
-
BrCH2
i=\
CH2Br
(124)i s
-rBr 1
KOAc I
HOAc
%
Y
O
H
137 -
22:78 136 -
de-
96 -
One of t h e problems a s s o c i a t e d w i t h t h e u s e o f t h e P r i n s r e a c t i o n f o r t h e p r e p a r a t i o n o f compounds i n t h e l a v a n d u l y l s e r i e s , f o r i n s t a n c e by r e a c t i o n of formaldehyde w i t h t h e acet a t e (=) 1 1 5 6 i s t h e p r e s e n c e of a l a r g e number of b y p r o d u c t s , o n l y 33% o f l a v a n d u l y l a c e t a t e (140) b e i n g o b t a i n e d by t h i s r o u t e . 1 5 6 ' 1 6 3 Another attempt by B a b a e t a1.164 s t a r t s from t h e same a l c o h o l ( 1 4 1 ) , b u t c o n v e r t s t h i s f i r s t t o a m i x t u r e of h y d r o c a r b o n s and (3) t h a t i s s e p a r a t e d by f r a c t i o n a l d i s t i l l a t i o n . Treatment o f t h e symmetrical hydrocarbon
(76)t
*This r e a r r a n g e m e n t can o c c u r when i s o l a v a n d u l o l is d i s t i l l e d s l o w l y o v e r columns c o n t a i n i n g metal p a c k i n g . l6 tThe P r i n s r e a c t i o n of t h i s hydrocarbon l e a d i n g t o i s o g e r a n y l a c e t a t e h a s been d i s c u s s e d above. l6
Substances Derived from Chrysanthemic Acid
47
w i t h formaldehyde i n a c e t i c a c i d g i v e s 15-20% o f l a v a n d u l o l . 164
Lk
CH20/HOAc __Ic
OCOCH 3
I
CH20COCH3
139
140 -
GC1 Py r i d i n e
+
-76
ti 142 -
CH20/HOAc
1
CH2OH Lavandulol (96)h a s a l s o been o b t a i n e d by i r r a d i a t i o n of chrysanthemol [E,o b t a i n e d by t h e r e d u c t i o n of chrysanthemic a c i d (see below)] w i t h a high-pressure mercury lamp. The main product a p a r t from l a v a n d u l o l i s 3-methylbut-2-en01 (-1,
40
The Synthesis of Monoterpenes
both substances being obtained in about 20% yield:165
i;j-
hv
__c
CH20H
CH 2 OH
h
CH 2 OH
144 -
B-cyclolavandulal (145) 166 and the corresponding acid167 have been reported to occur in Seseli i n d i c u m , but this skeleton had already been synthesized by Steiner and Schinz, who made various cyclolavandulols from 3,3-dimethylcyclohexanone (146) ,I6' and by Ferrero and Schinz from the cyclization of lavandulic acid (147). 169
ao-PoP
146 -
CH20H
Pyrolysis acetate Of
Cyclolavandulols
Q+
B ~ H ~ O H
O
I
CH20H
Q+ 0
CH20H
H
CHO
145 -
y CH20H
Substances Derived from Chrysanthemic Acid
D.
49
Chrysanthemic Acids
Dalmatian pyrethrum flowers, Chrysanthemum cinerariifolium, contain the insecticidal pyrethrum* that was shown in 1924 to R = H) by be an ester of trans-chr santhemic acid Staudinger and Ruzicka. IY1 A somewhat different structure had been developed independently by Y a m a m ~ t o lbut ~ ~ was later abandoned. In view of the insecticidal properties of many chrysanthemic acid esters, the synthesis of compounds having this carbon skeleton has received more attention than most monoterpenes, and indeed the first s nthesis dates from the The doubtful purity of same time as the structural proof. 17’ the starting material used by Staudinger et al. made the purification of the products extremely difficult at the time, however, and it was not until 20 years later that Campbell and Harper were able to repeat the earlier synthesis and show that the natural ch santhemic acid is actually the (+)-trans-isomer (ElR = H). This synthesis consists in the addition of I.t ethyl diazo-acetate to 2 ,5-dimethylhe~a-2~4-diene (148) giving a mixture of the cis- (%, R = C2H5) and trans- (E, R = CzH5) racemic esters, that were hydrolyzed to the acids. The latter were separated by crystallization, and the trans acid resolved by crystallization of the quinine salt. In much the same way, Crombie et al. were able to make the dicarboxylic acid [pyrethric acid (149, R = H) also a constituent of pyrethrum] from 2,5-dimethylhexa-2,4-dienoic acid (150) 76
(z,
’
.
-
N~CHCOOC~HSR
O I
148 -
H
I
O I
C \
90a -
\
H
M R
T
&
H
I’
H
90b -
*For a review of the earlier work in this field, see the description of the chemistry of the pyrethrins by Crombie and Elliott. 170 ?A similar s nthesis using the t-butyl ester has also been described. 17x
50
The S y n t h e s i s of Monoterpenes
N2CHCOOR
Hydrolyse , e t c .
____L
H' COOH
149 -
150 -
I t was found by J u l i a e t a l . t h a t b i c y c l o [ 3 . l . 0 l h e x a n 2-ones can be r e a d i l y c o n v e r t e d i n t o chrysanthernic a c i d s . 17' Thus, t h e oxime of tetramethylbicyclo[3.1.0]hexan-2-one , undergoes t h e (151), p r e p a r e d from t h e d i a z o k e t o n e Beckmann r e a c t i o n w i t h phosphorus p e n t a c h l o r i d e i n e t h e r , y i e l d i n g m a i n l y t h e n i t r i l e s of c i s - c h r y s a n t h e m i c (153and The potassium c i s - i s o c h r y s a n t h e m i c (154)acids (Scheme 1 3 )
(152)
.
Scheme 1 3
PClg/ether
CN 154 -
30
Substances Derived from Chrysanthemic Acid
51
hydroxide i n e t h y l e n e g l y c o l r e q u i r e d t o hydrolyse t h e n i t r i l e s causes simultaneous i s o m e r i z a t i o n * t o t h e t r a n s - a c i d s ; 79 doub l e bond isomerism i s n o t , however, complete under t h e s e cond i t i o n s , b u t can be e f f e c t e d by p - t o l u e n e s u l f o n i c a c i d i n xylene. 1 8 0 A somewhat d i f f e r e n t a p p l i c a t i o n of a b i c y c l o [ 3 . 1 . 0 ] hexan-2-one i s t h e s y n t h e s i s of c i s - i s o p y r e t h r i c a c i d (155)by J u l i a and L i n s t r u m e l l e from 6,6-dimethylbicyclo[3.l.Olhexan2-one (156) , 1 8 1 t 1 8 2 a compound t h a t w a s c o r r e l a t e d with t h e knownl8-is-homocaronic a c i d (157) The b i c y c l i c ketone was made e i t h e r from t h e d i a z o k e t o n Z E ) , o r from p i n o n i c a c i d (159)o b t a i n a b l e from pinene (2)(Scheme 1 4 ) ,1 8 4 b u t t h e
.
Scheme 1 4
r= Methanesulfonate KOH/EtOH on
( E t O ) 2CO
+f=Jf 158 -
cis-Homocaronic acid
HOCH2
COOEt
EtOOC
*Actually, t h e easiest way of i s o m e r i z i n g cis-chrysanthemate esters t o t h e t r a n s compounds i s simply by p y r o l y s i s of t h e cis-ester a t 240'-260°, when t h e t r a n s - e s t e r i s obtained i n good y i e l d . 17*
The S y n t h e s i s of Monoterpenes
52
'7
160 -
M s O -CH2 EtOOC
OH
'COOH
n
y i e l d s i n t h e l a t t e r pathway were bad and t h e u s e of d i a z o methane on a l a r g e r s c a l e i s u n d e s i r a b l e . N e v e r t h e l e s s , once t h e bicyclo[3.1.O]hexanone i s a v a i l a b l e , a d d i t i o n of t h e e t h oxycarbonyl g r o u p f o l l o w e d by formaldehyde i s simple, and the m e s y l a t e of t h e a l c o h o l (160)t h e r e b y o b t a i n e d , on t r e a t m e n t w i t h a l c o h o l i c potassium h y d r o x i d e , y i e l d s c i s - i s o p y r e t h r i c a c i d (155)t o g e t h e r w i t h t h e t r a n s - i s o m e r v e r y e a s i l y . One of t h e ways J u l i a e t a l . a t t e m p t e d t o f o l l o w i n order t o a v o i d u s i n g diazomethane i s i l l u s t r a t e d i n Scheme 15,185t186 Scheme 15
x
+ "c,
c
EtOOC
NC
OEt
I
Benzyl peroxide
oc::/ 53
Substances Derived from Chrysanthemic Acid
KOH
0
'COOE
CN
CHO
COOEt
CHMgBr HO
I
CN
Ethylene glycol
Na t-amylate
10-20%
c1 dOOE t
b u t this t o o involves a r a t h e r l a r g e number of s t e p s , and a m r e r a p i d method f o r t h e s y n t h e s i s of chrysanthemic e s t e r s i s t h a t of Martel and Huynh, t h a t c o n s i s t s i n allowing an e s t e r of 3-methylbut-2-enoic a c i d t o r e a c t with d i m e t h y l a l l y l s u l fone (161),t o g e t h e r with two e q u i v a l e n t s of potassium tb u t o x i d e i n t e t r a h y d r o f u r a n , when t h e intermediate ion (162)
t
54
The S y n t h e s i s of Monoterpenes
c y c l i z e s t o g i v e only trans-chrysanthemic a c i d e t h y l e s t e r 1163). 18’
162 -
L
1 63 -
J
There are a few s y n t h e s e s of chrysanthemic a c i d t h a t start from A3-carene (=), r e a d i l y a v a i l a b l e from P o l i s h and e s p e c i a l l y I n d i a n (Pinus l o n g i f o l l a ) t u r p e n t i n e . Volkov and Khachatur’yan c o n v e r t e d c a r e n e e p o x i d e (165)i n t o the with benzyl alcohol i n s u l f u r i c monobenzylated g l y c o l a c i d , and d e h y d r a t i o n of t h i s f o l l o w e d by permanganate o x i d a t i o n l e d t o t h e same p r o d u c t a s t h a t o b t a i n e d by t h e a c i d c a t a l y z e d a d d i t i o n o f a l c o h o l s t o t h e d o u b l e bond of cischrysanthemum d i c a r b o x y l i c acid ( i . e . , =).The Russian a u t h o r s have a l s o c a r r i e d o u t a n o x i d a t i o n of t h e d e b e n z y l a t e d a l c o h o l (E), b u t t h e m i x t u r e i s . v e r y complex, and b e t t e r res u l t s are o b t a i n e d t h r o u g h t h e b e n z y l d e r i v a t i v e .
’’’
(166)
”’
A3-Carene
164
165 -
55
Substances Derived from Chrysanthemic Acid
KHSO4
H
167 -
19% I
B
A s y n t h e s i s of Yoshioka e t a1.190 a l s o s t a r t s from A 3 carene, t h e f i r s t s t e p being ozonolysis t o t h e ketoaldehyde (169).19' The l a t t e r can be converted i n t o e i t h e r (-)-transor (+)-trans-chrysanthemic a c i d s (Scheme 1 6 ) .
Scheme 16
169 -
1. CH2N2 2. CH3Mg.I
1
-
F C O C H 3
Hoa
COfcmH
03/H202
1%
oy I
CH3MgI
CH 3 OOC
1
Ho
?imH \ / -cis
1. E s t e r i f y 2. B a s e
(+)-trans
21. . B E as st e r i f y
(-1 - t r a n s
Chrysanthemic Acids
56
2 . CH3S03H
o~
H~SOL,/H~O
(-)
1. KOH
HZS04/H20
(+I -cis
Substances Derived from Chrysanthemic Acid
57
The s y n t h e s i s of p y r e t h r i c a c i d ( o r i t s esters) from chrysanthemic acid ( o r i t s e s t e r s ) has been c a r r i e d o u t i n s e v e r a l p l a c e s , always following a very s i m i l a r r o u t e (Scheme 1 7 ) .
AH
Scheme 17 CH300C
CH300C
H'
\ \
170 -
CHO
CH3
1
(C2H5O)2PCHCOOCH3
II
0
171
m 3 ° H w' b 4
'COOCH3
0
174 CHO ('1 2.. CH 300~' H
CH 3 ood
\H
B-
OAOAOH
SOC12 (epimerizes C-1)
H'
I
H'
COOCH 3
COOH
COOCH 3
58
The S y n t h e s i s o f Monoterpenes
Ueda and Matsui made a l l f o u r g e o m e t r i c a l isomers of ( ? ) p y r e t h r i c a c i d by c o n v e r t i n g t h e a p p r o p r i a t e ( c i s - or t r a n s - ) methyl e s t e r o f c h r y s a n t h e m i c a c i d t o t h e a l d e h y d e w i t h ozone (170,f o r example, r e p r e s e n t s t h e a l d e h y d e o b t a i n e d from t h e t r a n s - e s t e r ) , and p u t t i n g on t h e a p p r o p r i a t e s i d e c h a i n by means o f t h e phosphonate (171) . l g 2 T h i s method was a l s o used by Crombie e t a l . f o r m a k i n g ' 4 C - l a b e l e d methyl c h r y s a n t h e mates by r e a c t i o n o f t h e aldehyde (170) with t h e appropriately l a b e l e d W i t t i g r e a g e n t . l q 3 M a r t e l and Buenida a l s o followed a similar p a t h , b u t w i t h a somewhat d i f f e r e n t end i n view. Commercial s y n t h e s i s o f n a t u r a l c h r y s a n t h e m i c a c i d d e r i v a t i v e s e n d s w i t h o p t i c a l r e s o l u t i o n of t h e r a c e m a t e , l g 4 and t h i s l e a d s t o t h e u n n a t u r a l epimer [ w i t h t h e 1(S) , 2 ( S ) - c h i r a l i t y , 1721 a s a b y p r o d u c t . By i n v e r t i n g f i r s t one c a r b o n atom and t h e n t h e o t h e r ( a s shown i n Scheme 1 7 ) , Martel and Buenida were able t o a c h i e v e a s y n t h e s i s o f n a t u r a l p y r e t h r i c acid (173)from c h r y s a n t h e m i c a c i d of t h e o p p o s i t e c h i r a l i t y . l g 5 The same problem, t h a t of u t i l i z i n g t h e "wrong" [l(S), 2 (S)epimer] c h r y s a n t h e m i c a c i d h a s found a s l i g h t l y d i f f e r e n t s o l u t i o n w i t h Ueda and M a t s u i , who used t h e p y r o l y s i s p r o d u c t , " p y r o c i n e " ( E )o, f c h r y s a n t h e m i c a c i d , which t h e y succeeded i n racemizing t h r o u g h a f a i r l y l o n g s e r i e s o f r e a c t i o n s . l g 6
-
6.
CYCLOBUTANE MONOTERF'ENES
Although common i n b i c y c l i c s y s t e m s (see l a t e r ) , u n t i l the i s o l a t i o n o f t h e s e x a t t r a c t a n t (175)o f t h e male b o l l w e e v i l (Anthonomus g r a n d i s Boheman), monocyclic c y c l o b u t a n e monoterpenes were unknown. The i s o l a t i o n of t h i s compound, t o g e t h e r w i t h c e r t a i n other 3-ethylidene-l,l-dimethylcyclohexane d e r i v a t i v e s h a s been d e s c r i b e d i n p a p e r s r e p o r t i n g b r i e f l y t h e synt h e s i s . 1 9 7 r 1 q * Only one o f t h e s e s y n t h e s e s i s stereoselect i v e , 1 9 8 and f o l l o w s t h e r o u t e shown i n Scheme 18. Scheme 18
Li2CO3 CH 3 CONMe2
1
Cyclobutane Monoterpenes
7.
59
CYCLOPENTANE MONOTERPENES
Although the only two monoterpene cyclopentane hydrocarbons ("chamene"l99 and "osmane"zOO) to be claimed as naturally occurring were both later shown to be spurious (the former being probably a mixture of other monoterpenesZo1 and the latter arising from the solvent used in the extractionszo2), the basic hydrocarbon of the cyclopentane monoterpenes, 2,3dimethylisopropyl cyclopentane (-1 , for which the name "iridane" has been s u g g e ~ t e d is , ~of ~ some ~ ~ ~importance ~ ~ since it was su gested as the unit from which the indole alkalo i d ~ ~ ~ and ~ # the ~ !quinuclidine ~ ring of quininezo7 might arise biogenetically. All the possible stereoisomers of the structure (E to 176d) have been synthesized by Sisido et a1.202 and by C r o w l p
The S y n t h e s i s of Monoterpenes
60
176a -
176b -
176c -
176d -
G e n e r a l l y , one of t h e two methods i s used f o r a c c e s s t o t h e c y c l o p e n t a n e monoterpenes. The f i r s t of t h e s e is by c y c l i z a t i o n of a n open-chain monoterpene, examples of which a r e t h e d e h y d r a t i o n of l i n a l o o l (6) t o t h e p l i n o l s (E)208 (see n e x t s e c t i o n ) or t h e p h o t o c y c l i z a t i o n of c i t r a l (41) t o p h o t o c i t r a l s A (178)and B (179) .209 The second method cons i s t s i n b r e a k i n g a bond i n a b i y c l i c compound, s u c h as happ e n s i n t h e t r e a t m e n t of t h u j o n e 2 (=) or t h u j y l t o l u e n e s u l f o n a t e s 2 1 1 (181) w i t h a c i d , o r p i n e n e o x i d e (182)w i t h a Lewis a c i d . 2 1 2
'
-
&CHO
I
hv
__c
CHO
-P P s 41 -
178 -
P h o t o c i t r a1 A (Major p r o d u c t )
'.
180 ThGne
4
181, a l l isomers
179 -
Cyclopentane Monoterpenes
61
Many of t h e cyclopentane monoterpenes are l a c t o n e s , b u t t h e r e i s one l e s s o x i d i z e d substance o c c u r r i n g n a t u r a l l y , which i s d e a l t with f i r s t . A.
Plinol
A monoterpene a l c o h o l , p l i n o l , occurs i n t h e h i g h e r b o i l i n g
f r a c t i o n of camphor t h e t o t a l s t r u c t u r e of which, i n cludinq t h e c h i r a l i t y ( R ) a t C-3, was e s t a b l i s h e d by Sebe and Naito2 (177d). S y n t h e s i s of p l i n o l was f i r s t r e p o r t e d by Ikeda and Wakatzuki,Z13 b u t t h e p y r o l y s i s of l i n a l o o l t h e y rep o r t is a c t u a l l y more com l e x , and t h e s t r u c t u r e a t t r i b u t e d t o a n o t h e r o f t h e i r productsf15 w a s i n c o r r e c t , and t h e whole s i t u a t i o n was reviewed i n some d e t a i l by S t r i c k l e r , Ohloff, and Kovdts.208 A l l f o u r p o s s i b l e p l i n o l s to are formed i n t h e r e a c t i o n i n t h e y i e l d s shown. They can be
(3 m)
8.7%
a
28.2%
4.8%
b
C
Plinols
10.7% d
(177)
s e p a r a t e d gas chromatographically,216 and it was shown t h a t t h e n a t u r a l product corresponded t o p l i n o l - d (177d).
62
B.
The Synthesis of Monoterpenes Cyclopentanopyrans
Although t h e s e substances a r e n o t very widely d i s t r i b u t e d i n n a t u r e , t h e i r e f f e c t i n t h e surroundings where they do occur i s s o dramatic t h a t a g r e a t d e a l of work has gone i n t o an examination of t h e i r i s o l a t i o n , s t r u c t u r e and s y n t h e s i s . The compounds i s o l a t e d from v a r i o u s s p e c i e s of Iridomyrmex and o t h e r a n t s a r e used b y them a s agents of defense a g a i n s t a t o r y i n s e c t s , 2 1 7 and a r e , i n f a c t , p o t e n t i n s e c t i c i d e s , 2 G e d while many of t h e compounds i s o l a t e d from c a t n i p o i l (Nepeta c a t a r i a ) and o t h e r v e g e t a b l e sources a r e h i g h l y a t t r a c t i v e t o c a t s and o t h e r animals of t h e Felidae and Chrysopidae. Table 1 g i v e s a l i s t of some of t h e s e compounds, with t h e i r s o u r c e s , and h i s t o r i c a l d a t a necessary t o l o c a t e t h e f i r s t syntheses. The l a t t e r a r e by no means t h e only synt h e s e s and some s e l e c t i o n has been necessary i n what i s presented i n g r e a t e r d e t a i l below. There a r e some a c i d s and e s t e r s not l i s t e d , b u t which a r e c l o s e l y r e l a t e d t o t h e compounds shown. Some more r e c e n t l y i s o l a t e d i r i d o i d s a r e l i s t e d i n Ref. 2 1 9 , b u t no syntheses of t h e s e compounds a r e r e p o r t e d .
ln 4
ln
ffl
s
R tn
W
N
W N
-3 N
I
N
I
N
T?
9
N
N
N
N
N
N N
N
N
4 N
N
N
N
ffl
a
.iia 0 u
D N
v
u
&
N
' C 1
9,
2
63
m
N N
3
E m
P
N N
0
N N
m
N
N
P
0, N
N
N
a
N
N
0
m
N
v1
e
v)
k
0
..-I
k
Lr,
0
H
a a
7
c u c
.rl
0
V
:
4
E
64
u)
H
d,
Loganin (pentaacetate,
210)
D~lichodial~~ jlnisomorphal2 3 ( l a t t e r of unknown s tereochernis t r y )
S t r y c h n o s nux V ~ r n i c a ~ 237 ~ ~ and other p l a n t s
2 34
233
D o l i c h o d e r u s 232 and I r i d o r n y r m e x 233 spp
189a -
Ani somorpha buprestoides
229
Iridomyrrnex c o n i f e r Iridomyrmex d e f e c t u s 229
I ri dodi a1
-
2 31
2 31
A c t i n i d i a polygama
A cti ni d i a pol ygama 2 31
Isoneomatatabiol 200b
-
Neomatatabiol 200a
qCHo
OH
238
c f . 235
228
231
2 31
u)
.rl u)
d
a,
5c
rY
(\1
x
m
o g 8 g m
rn
X
V
8
u
0 X
COOH
COOCH 3
206 -
205 -
Monotropa h y p o p i t h y s
Monotropein
A c t i n i d i a polygdTEi
A c t i n i d i a polygama 249
247
V a l e r i a n a o f f i c i n a l is K e n t r a n t h u s r u b e r and other spp 246
244
Verbena o f f i c i n a l i s
Valtratum
Verbenalin
248
246
244
249
249
220) -
245
(aglncone,
Cyclopentane Monotelrpenes
69
Lactones The t o t a l s y n t h e s i s of nepetalactone (183)by Sakan e t a l . 2 2 3 (Scheme 19) is long and does not t a k e s t e r e o -
Nepetahctones.
Scheme 19 Base
COOC2H5
+
- CHBrCH3
0
1. Hydrate 2 . Hydrolyse
t
COOC2H5
1
Base
Hg/cat.
%
OAc
1. Hydrolyse 2 . Oxidize
70
The Synthesis of Monoterpenes
1. Hydrolyse 2. Oxidize -
184 -
Nepetalic acid
chemistry into account, but it does illustrate t h e need for an efficient preparation of nepetalic acid (184)(which also occurs in catnip in order to make the lactones by the action of heat--a reaction that was recognized from the days of the earliest isolation of the lactones.220 This particular facet of the synthesis is, indeed, rather more complicated than at first realized, and has been examined in some detail by Trave et al. , 2 5 1 who prepared all the optically active stereoisomers of the nepetalactones (Scheme 20). In order to Scheme 20 (Ref. 251)
Ref. 2 5 2
P
185 Furopelargone
[ a ] , -56.1'
(chl.) 186a trans, cis-Nepetonic Acid
-
Cyclopentane Monoterpenes
2. ClCH20C2Hs Mg CH3
1. KOH
2. HCOOH
183b Nepetalac tone COOH CHO
[ a ] -7.9' ~
186b -
(chl.)
cis, trans-Nepetonic acid
184b -
71
72
The S y n t h e s i s of Monoterpenes
be c e r t a i n of t h e c h i r a l i t y o f t h e i r s t a r t i n g m a t e r i a l s , t h e nepetonic a c i d s and B), t h e s e were made by degrada'5' t i o n of n a t u r a l l y o c c u r r i n g m a t e r i a l s , f u r o p e l a r g o n e i n t h e c a s e of t h e t r a n s l e i s - a c i d (E) and n a t u r a l nepetal a c t o n e (183)i n t h e c a s e of t h e e i s , t r a n s - a c i d ( E l . The nepetonic a c i d s are r e a d i l y converted t o t h e n e p e t a l i c a c i d s (= and b u t t h e l a c t o n i z a t i o n of t h e l a t t e r i s n o t e n t i r e l y s t r a i g h t f o r w a r d , s i n c e i n t h e c a s e of t r a n s l e i s (the h e a t i n g f o r 1 1/2 h r a t 270'-280' nepetalic acid c o n d i t i o n s used t o c o n v e r t t h e a c i d s t o n e p e t a l a c t o n e s ) i n volves e p i m e r i z a t i o n of t h e c a r b o x y l group, and a s i n g l e l a c is o b t a i n e d . I n o r d e r t o t o n e , t h e c i s , t r a n s isomer (=) Trave e t a l . found prepare t h e trans,cis-nepetalactone t h a t it was n e c e s s a r y t o make t h e c h l o r o l a c t o n e first, using a c e t y l c h l o r i d e , then by thermal dehydrohalogenation i n t h e g a s chromatograph, t h e y a r r i v e d a t a m i x t u r e c o n t a i n i n g and 40% of t h e re60% of t h e d e s i r e d t r a n s , c i s - l a c t o n e arranged c i s t r a n s - n e p e t a l a c t o n e (=). Inexplicably, the o p t i c a l r o t a t i o n of t h e I t a l i a n s y n t h e t i c t r a n s , e i s - l a c t o n e (E), although t h e same i n a b s o l u t e v a l u e , was of o p p o s i t e s i g n t o t h a t of t h e n a t u r a l l a c t o n e i s o l a t e d by Bates and Sigel.222 The conversion o f i s o n e p e t a l a c t o n e ( t r a n s , e i s , into appears t o be b a s e c a t a l y z e d , s i n c e h e a t n e p e t a l a c t o n e (-) i n g t h e former i n xylene w i t h potassium c a r b o n a t e e f f e c t s t h e i s o m e r i z a t i o n . 224 The I t a i i a n work does n o t , of c o u r s e , r e p r e s e n t a t o t a l s y n t h e s i s i n t h e same s e n s e a s t h e e a r l i e r Japanese work d o e s , and n e i t h e r does t h e s y n t h e s i s c a r r i e d o u t by Achmad and ( e x c e p t i n so f a r a s c a v i 1 1 2 5 3 from n a t u r a l (+)-pulegone (E) t h e l a t t e r h a s a l s o been s y n t h e s i z e d ) ; b u t t h e l a t t e r synt h e s i s i s a l s o i n t e r e s t i n g a s b e i n g a s y n t h e s i s of i r i d o d i a l (189). The method employed by t h e A u s t r a l i a n a u t h o r s i s shown i n Scheme 21, b u t l e a d s t o t h e enantiomers o f t h e natur a l p r o d u c t s . For f u r t h e r d e t a i l s , t h e r e a d e r i s r e f e r r e d t o Achmad and C a v i l l ' s f u l l p a p e r . 2 5 4
(m
(185)
s), (w),
(m),
(187)
(e)
e)
Scheme 2 1
(+) -Pulegone
188 -
Pulegenic Acid
I
Cyclopentane Monoterpenes
73
I
t
in
A
189 -
I
Neonepetalactone (190). This w a s s y n t h e s i z e d by t h e groups of Sakan and W o l i n s k y y s t a r t i n g from limonene epoxide (191). Ring opening followed by g l y c o l f i s s i o n l e a d s t o t h e i n t e r e s t i n g keto-aldehyde (=) t h a t can be converted w i t h p i p e r i d i n e i n a c e t i c a c i d t o t h e c o r r e c t carbon s k e l e t o n (Scheme 2 2 ) f o r p r e p a r a t i o n of neonepetalactone. 2 5 7 (The same keto-aldehyde (192) has been used by Wolinsky i n t h e s y n t h e s i s of o t h e r cyclopentanes, u s i n g d i f f e r e n t reagents--aqueous a l k a l i , f o r example--to e f f e c t d i f f e r e n t r i n g c l o s u r e s . ) The remainder of t h e s y n t h e s i s c o n s i s t s i n o x i d i z i n g t h e aldehyde f u n c t i o n and p l a c i n g an oxygen atom i n t h e isopropenyl s i d e c h a i n , and f i n a l l y r i n g c l o s u r e by h e a t i n g .
Q
The S y n t h e s i s of Monoterpenes
74
Scheme 22
I
1. H ~ O / H + 2. ~a104
piperidine/HOAc
____c
191 -
190
I
I
NeonGtalactone T h e Iridomyrrnecins and B o s c h n i a l a c t o n e .
The s y n t h e s i s of isoiridomyrmecin by Robinson's group (which i n c l u d e d a synt h e s i s of n a t u r a l i r i d o d i a l , a t t h e same t i m e ) was i n t e r e s t i n g from two p o i n t s of view. F i r s t , i t was a very simple s y n t h e s i s of t h e n a t u r a l product having t h e c o r r e c t c h i r a l i t y , and it was a l s o claimed as a p o s s i b l e b i o g e n e t i c r o u t e from L - c i t r o n e l l a l . (Other p o s s i b i l i t i e s of b i o g e n e t i c r o u t e s have been g i v e n by Wolinsky e t a l . 2 5 8 ) I n t h e i r p a p e r , Clark e t a l . p r o t e c t e d t h e aldehyde group of c i t r o n e l l a 1 f i r s t , then o x i d i z e d w i t h selenium d i o x i d e , c y c l i z e d and l a c t o n i z e d a s shown i n Scheme 23,228 and i t was a l s o claimed t h a t oxidat i o n of t h e d i o l (193)w i t h chromium t r i o x i d e i n p y r i d i n e gave a dialdehyde t h a t could be c y c l i z e d with sodium methoxide i n c a t a l y t i c amounts t o i s o i r i d o m y n e c i n 259--0ne f e e l s , however, t h a t t h e y i e l d s i n t h e o x i d a t i o n s t e p cannot have been very high.
e,
(194)
Scheme 2 3
TCH0
Cyclopentane Monoterpenes
f
75
50% HOAc
CHO
189a -
11. OH-
r 1. Cr03/pyridine
2 . NaOCH3
(+)
- Isoiridomyrmecin 194 -
193 -
Another synthesis of (+)-isoiridomyrmecin (the enantiomer of the natural product) from citronella1 has been described by Cavil1 and Whitfield.260 Korte' s first iridomyrmecin synthesis227 involves a Prins reaction, which, as we have seen in earlier cases (notably lavandulol), is not generally a very good reaction for the synthesis of monoterpenes, but Korte developed a second synthesis which not only avoids this, but also has the virtue of simplicity,261 and is shown in Scheme 24. Scheme 24
The S y n t h e s i s of Monoterpenes
76
Another s y n t h e s i s s t a r t i n w i t h a preformed c y c l o p e n t a n e r i n g i s t h a t o f S i s i d o e t a l . , q 6 2 who, u s i n g a s u i t a b l e bromoe s t e r w i t h t h e B - k e t o e s t e r (195)were able t o make a cyclopentanone w i t h t h e n e c e s s a r y s i d e c h a i n (196).The s u b s e q u e n t s t e p s of t h e i r s y n t h e s i s are shown i n Scheme 2 5 , b u t t h e
c1-"
COOE t
195 !
197 -
9 Scheme 25
COOEt
196 -
194 -
s y n t h e s i s i s somewhat l o n g . Like many of t h e s y n t h e t i c i r i d o myrmecins, t h i s p r o d u c t w a s shown t o have t h e s t e r e o c h e m i s t r y d e s i r e d by permanganate o x i d a t i o n t o t h e c o r r e s p o n d i n g ( & ) n e p e t a l i n i c a c i d s (197); S i s i d o e t a l . have, i n f a c t , publ i s h e d a d e t a i l e d d i s c u s s i o n of t h e s t e r e o c h e m i s t r y and conformation of t h e various i r i d o l a c t o n e s (including boschnialactone). 263 Wolinsky, b e l i e v i n g t h a t many of t h e s e e a r l i e r s y n t h e s e s had g i v e n t h e c o r r e c t r i n g j u n c t i o n more o r l e s s "by c h a n c e , " s e t o u t t o a c h i e v e a p l a n n e d c i s - r i n g j u n c t i o n w i t h a transs i t u a t e d m e t h y l group i n t h e c y c l o p e n t a n e r i n g . 2 5 7 The f i r s t s t a g e s a r e similar t o t h o s e of C a v i l l ' s n e p e t a l a c t o n e synh a s been t h e s i s from p u l e g o n e , b u t once t h e y - l a c t o n e (198) made, t h e r o u t e i s as shown i n Scheme 26.
h-Qp
77
Cyclopentane Monoterpenes
Scheme 26
Pulegone 188 -
1. LiAlH4 2. A c ~ O
198 -
h CH20Ac
1. R2BH 2. Cr03
.CH20Ac
+
"THCOOH
I
CH3
1. NaOH 2 . H+
NaOCH 3
- H
H
The noriridomyrmecin, boschnia lactone (199)has been synthesized by Sakan et al. ;230 they made the cis- and transfused lactones, that were not, of course, optically active, but racemates (Scheme 27). Scheme 27
+
CHOCH 3
Ph3P=CHOCH3
COOEt
+
Starting material H2/Ni CH20CH 3
(t)-Boschnia Lactone 199
-
COOEt
70
The Synthesis of Monoterpenes
Neomatatabiols (= and =). These compounds, isolated from A c t i n i d i a polygama are chrysope attractants, and are related to the nepetalactones. They were also made231 by reduction of dihydronepetalactones with lithium aluminum hydride.
The
OH
I
200a -
200b -
A 1 d ehydes
In addition to the original synthesis of iridodial (%) by Robinson's group2*' mentioned above, Cavil1 and Whitfield have synthesized a number of doliThey chodials, and correlated them with the irid~dials.'~' started with (+)-citronellal, presumably on account of the difficulty of obtaining large amounts of pure (-)-citronella1 referred to by Robinson's group,228 and therefore arrived at enantiomers of natural dolichodial. The route followed is shown in Scheme 28, and the key intermediate (201) was shown
I r i d o d i a l and Dolichodial.
Scheme 28
(+)-Citronella1
+
r
CH2OH
i
OH
CH20H
qi-
Cyclopentane Monoterpenes
+
\
202b -
202a -
1. L i A l H 4 2 . Mn02 3 . HOAc
203a -
203b -
qCH
bCHO FCH0 .+
204b -
204a -
c
79
Enantiomers of n a t u r a l d o l i c h o d i a l Iridodial
t o be p r e s e n t a s two isomers, t h e two s t r u c t u r e s shown being a s c r i b e d t o them. A t t h e s t a g e of t h e methylation from t h e a c i d (202)t o t h e corresponding methyl e s t e r it was
(E),
The S y n t h e s i s of Monoterpenes
80
found t h a t i f methanolic hydrogen c h l o r i d e was used a s t h e methylating a g e n t , o n l y one methyl ester was o b t a i n e d , w h i l e two were o b t a i n e d and i f diazomethane w a s used. O f t h e s e two s u b s t a n c e s , a f t e r c a r r y i n g o u t t h e remaining s t e p s of t h e s y n t h e s i s , one peak i n t h e gas chromatogram corresponded t o n a t u r a l d o l i c h o d i a l , and when t h i s peak was rechromatographed a t a lower temperature, two peaks were observed, a s i s t h e c a s e with n a t u r a l d o l i c h o d i a l and i r i d o d i a l b u t n o t with t h e i r i d o d i a l prepared by t h e Robinson method s e e a b o v e ) . T h i s s p l i t t i n g of t h e peaks i s a s c r i b e d t o t h e presence of t h e two p o s s i b l e isomers of t h e formyl group i n t h e n a t u r a l product ( i , e . , and 204b f o r d o l i c h o d i a l , and t h e corresponding reduced s u b s t a n c e s f o r i r i dodial) . 2 3 5
(z g)
(m,
204a
Ethers
There a r e a number of e t h e r s p r e s e n t i n A c t i n i d i d polygama ( e . g . , 2 0 5 - 2 0 8 ) , and s e v e r a l of t h e s e have been s y n t h e s i z e d by Wolinsky and Nelson.249 T h e i r r o u t e s are shown i n Scheme 2 9 . The s y n t h e s i s of m a t a t a b i e t h e r (207) f o l l o w s t h e same r o u t e a s t h a t of I s o e e t a 1 . , 2 5 0 and i n a l l t h e s e p a p e r s , a s w e l l a s t h e e a r l i e r one from b o t h g r o u p s , 2 2 4 t h e conversion of matatais d e s c r i b e d [ r i n g b i e t h e r (207)i n t o neonepetalactone t h e n manganese d i opening with formic a c i d t o t h e d i o l oxide o x i d a t i o n , s e e Scheme 291.
(190)
(z),
Scheme 2 9
I
I
1. L i A l H 4 2 . Ac20 3 . R2BH e t c
Y H 2 O H
Cyclopentane Monoterpenes
81
OH-
2 09 -
.
H COOH
Matatabiether 207 -
Neonepetalactone 190
-
Esters, Glucosides, etc. Loganin. Loganin h a s a p o s i t i o n of s p e c i a l importance, s i n c e it has been shown t o be a key i n t e r m e d i a t e i n t h e biosynt h e t i c pathway t o t h e Corynanthe, A s p i d o s p e r m , Iboga,264-266 and I p e ~ a c u a n h a ~i n~d o l e a l k a l o i d s . Although discovered i n t h e l a s t century i n Strychnos nux v o n ~ i c a , *c~e ~ r t a i n t y of
82
The S y n t h e s i s of Monoterpenes
s t r u c t u r e i s o f much more r e c e n t d a t e (see Refs. 237, 238, and l i t e r a t u r e q u o t e d t h e r e i n ) , t h e x-ray a n a l y s i s of l o g a n i n d a t i n g from 1 9 6 9 . 2 6 8 The t o t a l s y n t h e s i s o f l o g a n i n acetate (210) w a s o n l y d e s c r i b e d i n 1970 by BUchi e t a l . 2 3 8 (Scheme 30) and depends on t h e c o n s t r u c t i o n o f t h e m e t h y l t e t r a h y d r o coumalate p a r t o f t h e i r i d o i d s i n a s i n g l e p h o t o c h e m i c a l Scheme 30
COOCH
212 -
211 -
1. HCOOME 2 . CqHgSH
58%
t
214 -
kQCH 3
213 -
215 -
4
Na0CH3
Cyclopentane Monoterpenes
COOCH 3
COWH 3
1. HClOq/aq. HOAc 2 . Glucose t e t r a a c e t a t e (low y i e l d )
83
1
216 -
OAc
#oj /
Loganin P e n t210 aacetate
-
COOCH 3
o p e r a t i o n , an e x t e n s i o n of de Mayo's method f o r t h e s y n t h e s i s of &-diketones by photochemical c y c l o a d d i t i o n of e n o l i z e d B-diketones t o o l e f i n s . 2 6 9 2-Formylmalonaldehydic a c i d methyl e s t e r (211) i s prepared i n two s t e p s from t r i m e t h y l o r t h o formate and ketene followed by condensation o f t h e a c e t a l t h u s o b t a i n e d w i t h methyl formate, then u l t r a v i o l e t i r r a d i a t i o n of t h i s t r i c a r b o n y l compound (211) i n 3-cyclo-pentenyl t e t r a hydropyranyl e t h e r (=) followed by t r e a t m e n t of a methanol s o l u t i o n of t h e crude photoproducts with Amberlite IR-120 c a t i o n exchange r e s i n , gave a mixture of t h e l i q u i d hydroxya c e t a l s (213) t h a t were o x i d i z e d t o t h e corresponding k e t o n e s , t h e major ( d e s i r e d ) isomer being i s o l a t e d from t h e mixture by c r y s t a l l i z a t i o n , and whose c o n f i g u r a t i o n r e p r e s e n t s t h e most stable isomer w i t h c i s - f u s e d r i n g s and an a x i a l l y o r i e n t e d methoxy group (214). This ketone is converted t o a mixture of hydroxymethylene d e r i v a t i v e s and then without p u r i f i c a t i o n , t o t h e butylthiomethylene d e r i v a t i v e s . I t i s f o r t u n a t e t h a t t h e main r e a c t i o n i s on t h e s i d e of t h e carbonyl where i t i s des i r e d t o i n t r o d u c e t h e methyl group, t h e small amounts of t h e
The S y n t h e s i s of Monoterpenes
84
o t h e r isomers on t h e o t h e r s i d e of t h e carbonyl group b e i n g removed by chromatography. From h e r e on, t h e s y n t h e s i s i s more conventional (Scheme 30) , although i t should be noted t h a t t h e mixture o b t a i n e d on d e s u l f u r i z a t i o n of t h e b u t y l t h i o methylene d e r i v a t i v e s with Raney n i c k e l c o n s i s t s mainly of t h e wrong methyl epimer (215) t h a t i s isomerized t o t h e c o r r e c t one (216) by t r e a t m e n t w i t h sodium methoxide. N e v e r t h e l e s s , t h e r e a l elegance of t h i s s y n t h e s i s c e r t a i n l y l i e s i n t h e i n i t i a l s t e p s where t h e n a t u r a l i r i d a n e s k e l e t o n i s produced i n a v e r y d i r e c t way. The e a r l i e s t o f t h e more complex i r i d a n e s y n t h e s e s is probably t h a t of genepin by BUchi e t a l . i n 1967.241 Genepin (217)has a long h i s t o r y , s i n c e it i s r e s p o n s i b l e f o r t h e dark b l u e p e r s i s t e n t c o l o r s t h a t t h e p l a n t (Genipa arnericana) forms with aminoacids, t h a t were observed some c e n t u r i e s ago on t h e s k i n of t h o s e coming i n t o c o n t a c t with t h e e x t r a c t . 2 3 9 BUchi's s y n t h e s i s (Scheme 31) s t a r t s w i t h a s u b s t a n c e (218) Scheme 3 1 H
H
q
2 18 -
H
Li/NH3
q
MeOH
p-Toluene Sulphonic a c i d
COOH
Os04/HCON ( C H 3 ) 2 ;
-
HO
H
HO
H2S
H
C02CH3
Pb ( O W ) 4 HOAc
.._----
H
OH $
nu--
?* ..T\..J 1 J, 219 -
C02CH3
-
Piperidine acetate
Cyclopentane Monoterpenes
o+
85
L i (t-Bu0)AlH-j
ether
-.L
C02CH-j
2 17 ( 2 )-Genipin having t h e c o r r e c t c i s - r i n g j u n c t i o n , and while t h e r o u t e p a s s e s through many i n t e r m e d i a t e s t h a t a r e isomeric m i x t u r e s , o r , a t any r a t e i s o m e r i c a l l y undefined, t h e f i n a l product h a s only one more asymmetric c e n t e r t h a n t h e s t a r t i n g m a t e r i a l , so t h a t it w a s n o t necessary t o e l u c i d a t e t h e s t e r e o c h e m i s t r y o f t h e i n t e r m e d i a t e s . The v i t a l s t e p t h a t a s s u r e d t h e success of t h i s synthesis w a s t h e lead t e t r a a c e t a t e glycol f i s s i o n ( t o _ 2191, . where use was made of t h e f a c t t h a t c y c l o p e n t a n e d i o l s cleave more r a p i d l y t h a n cyclohexane d i o l s , e n a b l i n g t h e former t o be cleaved i n t h e presence of t h e l a t t e r . Other i r i d a n e d e r i v a t i v e s from Genipa americana (genipini c a c i d (220) and a n o r t e r p e n e , g e n i p i c a c i d , 2 4 2 remain t o be synthesized.
The aglucone verbena101 (221) from t h e Verbena g l y c o s i d e , v e r b e n a l i n , h a s been synthesized by Sakan and Abe by t h e r o u t e shown i n Scheme 32.245
S c h e m e 32
CH3MgBr/CuBr
"H
&J3 0
0
1. R e d u c e (reagent?) 2 . AcZO/pyr.
I 86
Ref.
271
87
Cyclopentane Monoterpenes
CH2N2 20% HOAc
;111:1 =
Pb(OAc)k
4
H
Benzene
) "%,,,
C'OOCH 3
/
0
COOCH3
221 -
(?)-Verbena101 C.
1-Acetyl-4-isopropenyl-1-cyclopentene
I n 1947, H. Schmidt i s o l a t e d a compound from E u c a l y p t u s g 1 0 b u l u s ~t~o ~which an i n c o r r e c t s t r u c t u r e was a t f i r s t a t t r i b u t e d , b u t which t u r n e d o u t t o be t h e t i t l e compound, a s
Wolinsky and Barker found a c c i d e n t a l l y . 2 7 3 I n t h e course of work on limonene epoxide (191)they t r e a t e d t h e g l y c o l obt a i n e d from it by a c i d - c a t a l y z e d opening of t h e epoxide r i n g with sodium p e r i o d a t e , when t h e keto-aldehyde was obt a i n e d , which h a s a l r e a d y been r e f e r r e d t o i n another connect i o n . A s s t a t e d above, t h i s ketoaldehyde undergoes r i n g c l o s u r e w i t h p i p e r i d i n e a c e t a t e t o g i v e a cyclopentenealdehyde used i n t h e neonepetalactone s y n t h e s i s , b u t potassium hydroxi d e c a t a l y z e s a d i f f e r e n t r i n g c l o s u r e , t o 1-acetyl-4-isoprot h a t t u r n e d o u t t o be i d e n t i c a l penyl-1-cyclopentene with Schmidt's n a t u r a l p r o d u c t .
(192)
(z),
191 -
192 -
222 -
The Synthesis of Monoterpenes
88
D.
Campholenic Aldehyde
Campholenic aldehyde (2,2,3-trimethylcyclopent-3-ene acetaldehyde, 223) has only recently been found in nature in the oil of Juniperus c o ~ n m u n i s ,but ~ ~ ~has been known for more than 60 years as a product from the photolysis of camphor (3) .275 It is most conveniently synthesized by the action of Lewis acids (boron t r i f l ~ o r i d e ,zinc ~ ~ ~bromide,277 etc.) on apinene epoxide (=).
223 -
182 -
Campholenic Aldehyde
224 -
Camphor
8. THE p-MENTHANES (EXCLUDING BICYCLIC SYSTEMS) A.
Hydrocarbons
Limonene, Terpinolene, a-terpinene, y-terpinene, and the Phellandrenes
225 (+) -Lhonene
51 Terpinolene
It is customary to reserve this name for the optically active forms, the racemate being called dipentene
226 a-Terpinene
227 y-Terpinene
The p-Menthanes
228 -
89
229 f? -Phellandrene
a-Phellandrene
The p-menthadienes, p a r t i c u l a r l y t h o s e i l l u s t r a t e d above are very common i n n a t u r a l o i l s , and v e r y l a r g e amounts of limonene, f o r example, a r e a v a i l a b l e from c i t r u s o i l s . In a d d i t i o n , t h e racemate can be o b t a i n e d (as every o r g a n i c chemistry t e x t book informs u s ) by t h e d i m e r i z a t i o n of i s o p r e n e i n a D i e l s Alder s y n t h e s i s . This i s n o t t h e o n l y Diels-Alder s y n t h e s i s t h a t has been used t o g i v e limonene, a 5-carbon t o 4-carbon coupling having been used by Vig e t a l . ,278 followed by addit i o n of t h e methylene group by a W i t t i g r e a c t i o n t o t h e ketone
(230):
I
I
2 30 -
Since t h e a c t i o n of a c i d o r b a s e on limonene produces a mixture of some of t h e o t h e r menthadienes [notably t e r p i n o l ene (51), t h e t e r p i n e n e s , and i s o t e r p i n o l e n e (231), s e e Ref. 279 and l i t e r a t u r e quoted t h e r e i n ] t h a t i s s e p a r a b l e by d i s t i l l a t i o n , t h e s e hydrocarbons are r e a d i l y a v a i l a b l e f o r f u r t h e r s y n t h e s e s . Acid t r e a t m e n t of t h u j e n e s 2 8 0 and B-pinenePB1 ( i n t h e s e p a p e r s a c a t i o n i c exchange r e s i n i s employed) a l s o l e a d s t o menthadienes. Although t h e p h e l l a n d r e n e s are n o t r e a d i l y a v a i l a b l e by methods of t h i s n a t u r e , B-phellandrene (229) and B-terpinene (232)are t h e main p r o d u c t s of t h e high temperature (600' ) p y r o l y s i s of sabinene (233),2 8 2 which , s i n c e sabinene h a s i t s e l f been s y n t h e s i z e d (see below), cons t i t u t e d a s y n t h e s i s of B-phellandrene. Since 8-phellandrene i s converted i n t o a-phellandrene (228)by a c i d (abietic a c i d f o r 2 h r a t 180' being r e p o r t e d t o g i v e a v e r y pure
The Synthesis of Monoterpenes
90
-3 ;? 231 -
232 -
Isoterpinolene
8-Terpinene
233 Sabinene
product283) any synthesis of 8-phellandrene is a synthesis of a-phellandrene. A synthesis of the phellandrenes that should be mentioned is that of Kuczyfiski and Zabia.2e4 They made l-hydroxymenth2-ene (234)by a rather long method (it is itself a natural product, and is described below), and then pyrolyzed its phenylurethane, when a 3:l mixture of ( + ) -8-phellandrene (-1 and (+) -a-phellandrene was obtained.
(a)
234 -
( + I -8 229a -
(+)-a 3:1
228a -
(+)-8-Phellandrene has also been synthesized by means of a Wittig reaction on (+)-4-isopro ylcyclohex-2-en-1-one (+)-cryptone, described below]. 2
€If
[E,
The pMenthanes
1,3,8-Menthatriene
91
(236)
Garner0 e t a l . have i s o l a t e d t h i s compound from p a r s l e y (Petroselenium sativum) i n which it i s reported t o be responsible f o r t h e t y p i c a l odor of t h e p l a n t , 2 8 6 and a s y n t h e s i s has been described by Birch and Subba Rao, although t h e product they obtained was n o t completely c h a r a c t e r i z e d , and was r e p o r t e d t o be t o o unstable t o allow f u r t h e r p u r i f i c a t i o n . 2 8 7 Neverthel e s s , t h e u l t r a v i o l e t and n u c l e a r magnetic resonance s p e c t r a r e p o r t e d by them a r e i n agreement with t h e n a t u r a l product. Their s y n t h e s i s involves making t h e acetylcyclohexadienes by t h e r o u t e shown (Scheme 3 3 ) , and c a r r y i n g o u t a Wittig react i o n . The main problem is i n t h e gas chromatographic separat i o n of t h e products. The author has a l s o achieved a synt h e s i s of t h i s menthatriene (and i t s isomer 237, a l s o described by Birch and Subba Rao287) by t h e r o u t e shown i n t h e lower p a r t of Scheme 33.288 Although t h e r e was some p-cymene (238) formed, t h e impurity found t o hinder p u r i f i c a t i o n was r a t h e r and it was necessary t o chromatop,a-dimethylstyrene graph t h e products on both p o l a r (Carbowax) and nonpolar ( s i l i c o n e o i l ) c o l m s i n t h e gas chromatograph i n order t o o b t a i n t h e menthatrienes completely pure. This was, however, achieved, and they were both s u f f i c i e n t l y s t a b l e f o r a l l spect r a l and combustion analyses t o be made. I n s o l u t i o n they a r e s t a b l e a t room temperatures € o r s e v e r a l weeks, a t any r a t e . 2 8 8
(z),
Scheme 3 3
CHOHCH 3
CHOHCH 3
CH2CH3
0
4+ 0-.4 COCH3
COCH 3
1
Wittiq
The S y n t h e s i s of Monoterpenes
92
2 37 -
2 36 -
d 9
+
-
V
2 38 -
2 39 -
Pb (OAc)4
/
CH20COCH3
241 -
h
h
0
F i n a l l y , t h e a l c o h o l (240) d e s c r i b e d by Birch and Subba Rao287 ( s e e below) is t h e main product of t h e o x i d a t i o n of limonene with selenium d i o x i d e , t o g e t h e r with some of t h e a l c o h o l corresponding t o t h e l e a d t e t r a a c e t a t e p r o d u c t (241) , and t h e a c e t a t e of t h i s a l c o h o l t o o l e a d s t o t h e same mixture of menthatrienes and d i m e t h y l s t y r e n e on p y r o l y s i s . 2 8 8
Aroma t i c Hydrocarbons p-Cymene (238) and dimethylstyrene (239) a r e v e r y widely occ u r r i n g i n e s s e n t i a l o i l s ( t h e a u t h o r has never examined a s i n g l e n a t u r a l o i l so far t h a t d i d n o t c o n t a i n a t l e a s t a t r a c e of p-cymene) and i t i s h a r d l y n e c e s s a r y t o d e s c r i b e synt h e s e s of t h e s e compounds. One might j u s t draw a t t e n t i o n t o t h e f a c t t h a t under a c i d c o n d i t i o n s , c i t r a l i s converted by
The p-Menthanes
93
steam d i s t i l l a t i o n i n t o dimethylstyrene (239) and o t h e r hydrocarbons-indeed, t h e presence of n a t u r a l c i t r i c a c i d i n an o i l i s enough t o e f f e c t some conversion,289 making one wonder what percentage of t h e t o t a l dimethylstyrene r e p o r t e d i n v a r i o u s o i l s is i n r e a l i t y an a r t e f a c t 1
2 39 -
B.
Oxygenated D e r i v a t i v e s of p-Menthane
Of t h e v a s t l i t e r a t u r e about t h e many d i f f e r e n t p-menthane a l c o h o l s , aldehydes, k e t o n e s , and a c i d s , a c e r t a i n s e l e c t i o n has been made. Very l i t t l e of t h e o l d e r work has been i n cluded, s i n c e t h i s can be found i n t h e work t h a t i s quoted. Many more of t h e syntheses concern products t h a t a r e n o t n a t u r a l l y o c c u r r i n g and t h a t f a l l o u t s i d e t h e scope of t h i s book. F i n a l l y , t h e r e is much work, p a r t i c u l a r l y i n t h e p a t e n t l i t e r a t u r e , t h a t i s merely of a r e p e t e t i v e n a t u r e , and only work of a wider i n t e r e s t has been included. A d e p a r t u r e from t h e e a r l i e r c l a s s i f i c a t i o n i n t o a l c o h o l s , then ketones, then o t h e r f u n c t i o n a l groups has been made, s i n c e it i s more conv e n i e n t t o t r e a t t h e oxygenated p-menthanes according t o t h e p o s i t i o n of t h e oxygen atom o r atoms, and r e l a t e t h e a l c o h o l s t o corresponding oxidized compounds.
The T e r t i a r y Alcohols Menthan-8-01. The only s a t u r a t e d menthanol having an oxygen a t C-1, C-4, o r C-8 t o be r e p o r t e d n a t u r a l l y with any degree of c e r t a i n t y i s menthan-6-01 ( t r a n s ) (242)t h a t was i s o l a t e d
from American p i n e o i l r e s i d u e s by Z e i t s c h e l and Schmidt,290 and r e p o r t e d i n f l o t a t i o n o i l from Pinus s i l v e s t r i s by Bardyshev and L i ~ s h i t s . ~ 'Even ~ i n t h e s e c a s e s , however, one is tempted t o consider it a s an a r t i f a c t , s i n c e t h e German work was c a r r i e d o u t on o i l t h a t had p r e v i o u s l y been p u r i f i e d by t h e " t e r p i n hydrate" method, t h a t i s , it had been i n cont a c t with a c i d , and t h e antecedents of t h e Russian o i l ,
94
The S y n t h e s i s of Monoterpenes
although n o t known w i t h any p r e c i s i o n , were c e r t a i n l y n o t such a s would remove a l l doubt of a d i s p r o p o r t i o n a t i o n r e a c t i o n t h a t could be r e s p o n s i b l e i n both cases f o r t h e p r e s e n c e of t h e substance ( a r i s i n g , of c o u r s e , a s a minor by-product from a - t e r p i n e o l ) . The geometry of trans-menthan-8-01 (242) was e s t a b l i s h e d by t h e d i s c o v e r e r s , 2 9 0 confirmed by K e a s 2 and by t h e s y n t h e s i s from trans-4-methylcyclohexanecarboxylic a c i d (243) u s i n g a Grignard r e a c t i o n by van Bekkum e t a l . 2 9 3 The Dutch a u t h o r s a l s o made t h e c i s - a l c o h o l (of h i g h e r m e l t i n g from t h e ~ i s - a c i d . ~ ~ ~ p o i n t , 46.5'-47.5')
CH3MgI
COOH
24 3 -
-
9
mp 35'-36'
OH
242 -
1-Oxygenated p-Menthanes. Menth-2-en-1-01 (G),B-Terpineol ( 2 4 4 1 , Menth-3-en-1-01 (245), and y-Terpineol Transmzh-2-en-1-01 (=) h a s been i s o l a t e d from t h e o i l of Chamaecyparis o b t u s a (Hinoki)'01 and r a s p b e r r i e s ,294 and t r a n s - 6 - t e r p i n e o l (244) h a s long been known a s a c o n s t i t u e n t of t ~ r p e n t i n e . T~h e~i r~ s ,y n~t h~e s i s is mst e a s i l y accomplished by :he d y e - s e n s i t i z e d p h o t o o x i d a t i o n of menth-1-ene (247) i n t h e f i r s t c a s e , and limonene (225)i n t h e second, from which t h e t r a n s - a l c o h o l s are t h e main p r o d u c t s . (A thorough review of t h e e a r l i e r l i t e r a t u r e h a s been given by S ~ h r o e t e r * ~and ' Schenck e t a l . 2 9 8 ) . For B - t e r p i n e o l , t h e d i e n o l (248) must t h e n be p a r t i a l l y reduced. The photochemical a d d i t i o n of h y d r o x y l i c compounds h a s been examined e x t e n s i v e l y by Kropp, and i r r a d i a t i o n of limonene i n aqueous s o l u t i o n with a t r a c e of xylene a s s e n s i t i z e r l e a d s t o a 1 . 2 : l mixture of cis- and t r a n s - f i - t e r p i n e ~ l s . ~Other ~~ chemical methods ( e . g . , t h e mercuric a c e t a t e o x i d a t i o n of t h e s e hydrocarbons296) may a l s o g i v e p r i m a r i l y t h e t r a n s p r o d u c t , b u t t h e Grignard react i o n o f cryptone (235, see below) y i e l d s a mixture of b o t h isomers. The a b s o l u t e c o n f i g u r a t i o n o f n a t u r a l menth-2-en-l01 i s n o t r e p o r t e d , b u t t h a t of t h e m a t e r i a l o b t a i n e d by r i n g opening of o p t i c a l l y a c t i v e p i p e r i t o n e epoxide* (=) h a s been
(246).
*This s u b s t a n c e i s a l s o n a t u r a l l y o c c u r r i n g ; see Ref. 300 f o r sources.
The p-Menthanes
95
firmly e s t a b l i s h e d . 300
hv /O 2 /sen s
or Hg (OAc) 2
-
+
(+ 1
247 -
Other p r o d u c t s
2 34 -
hv/H20/xylene
-
___c
244 -
248 -
225 -
8-Terpineol
t
N2H4 ‘ H 2 0
I
$lo 249
I
-
250 P i p e r i t o n e -
96
The S y n t h e s i s of Monoterpenes
6-Terpineol may a l s o be made from limonene by r i n g opening of t h e epoxides; f o r a review of t h e r e l e v a n t l i t e r a t u r e see Ref. 301. I n t h i s connection, however, it might be thought t h a t a very quick method f o r t h e p r e p a r a t i o n of menth-2-en-l01 (234)would be by p y r o l y s i s of t h e a c e t a t e o b t a i n e d by r h g opening of menth-1-ene (247) epoxide. T h i s r e a c t i o n h a s been found by Leffingwell and Shackelford t o l e a d t o a ring-cont r a c t e d ketone (Scheme 3 4 ) , although some of t h e d e s i r e d alcoh o l (234) i s produced a t t h e same t i m e . 3 0 2 Scheme 34
(245)
2 34 -
Menth-3-en-1-01 ma be a n a t u r a l p r o d u c t ( i n Origanum v u l g a r e , f o r examplero3) and w a s made by Wallach and Heyer b a Grignard r e a c t i o n on 4-isopropylcyclohex-3-enone (251)13’4 a compound d i s c u s s e d below i n t h e s e c t i o n on cryptone.
251 -
245 -
y-Terpineol (246) is always p r e s e n t i n commercial t e r p i n e o l , b u t i t s s e p a r a t i o n from a - t e r p i n e o l i s v e r y t e d i o u s . Gas chromatographic s e p a r a t i o n of t h e a c e t a t e s h a s been employed, b u t even s o , t h e r e t e n t i o n t i m e of y - t e r p i n y l a c e t a t e v e r y s l i g h t l y l o n g e r than t h a t of a - t e r p i n y l acetate. is S y n t h e s i s of y - t e r p i n e o l h a s been achieved u s i n g a 306 Grignard r e a c t i o n on 4-isopropylidenecyclohexanone (3)
.
The p-Menthanes
97
The l a t t e r can be made by t h e r o u t e shown i n Scheme 35 from y-acetyl-y-isopropenylpimelic a c i d (253), O6 b u t t h i s is somewhat t e d i o u s , and i f y - t e r p i n e o l i s r e q u i r e d i n t h e l a b o r a t o r y , it i s $ r e f e r a b l e t o p r e p a r e it by t h e o r i g i n a l method of is dihydrobrominated w i t h hydroBayer. O 7 I 308 Limonene gen bromide, O 9 t h e n t h e dibromide i s f u r t h e r brominated t o t h e t r i b r o m i d e (254) w i t h bromine i n t h e presence of l i g h t . on t r e a t m e n t w i t h z i n c i n acetic a c i d This tribromide g i v e s y - t e r p i n y l acetate (255) i n f a i r l y good y i e l d . 3 0 8
(225)
(g),
Scheme 35
‘
KCOCH3 O o COOH H
2 2 2 1 NaOCl
‘
K
O
o
252
I
HBr
I
t
a 225 -
H
CWH BaC03
246 -
= 255 R = Ac
-
a-Terpineol
254 -
Cryptone (235). 4-Isopropylcyclohex-2-enone (cryptone) o c c u r s n a t u r a l l y i n b o t h ( + I - and (-)-forms i n s e v e r a l p l a n t s , p a r t i c u l a r l y i n t h e Eucalyptus s p e c i e s , and i s , as we have a l r e a d y seen, a u s e f u l i n t e r m e d i a t e [ t o g e t h e r with i t s isomer, 4isopropylcyclohex-3-enone (25111 i n t h e p r e p a r a t i o n of o t h e r substances. I t can be s y n t h e s i z e d , by analogy of t h e sodium i n l i q u i d annnonia r e d u c t i o n of s u b s t i t u t e d a n i s o l e s ,3 1 0 by t h e r e d u c t i o n of 4-isopropylanisole (256)with l i t h i u m i n l i q u i d annnonia, when t h e e n o l e t h e r (257) t h u s o b t a i n e d , i s converted d i r e c t l y t o ( 2 )-cryptone semicarbazone w i t h s e m i -
98
The Synthesis of Monoterpenes
carbazide hydrochloride3” 1 312 (Soffer showed that lithium was distinctly better than sodium for this reduction.311) The problem that is here encountered, is that there is an equilibrium set up between cryptone (235) and its isomer, 4-isopropylcyclohex-3-enone (251) in acid conditions, so that recovery of c ptone from the semicarbazone must be done very carefully.3f7; This equilibrium interferes even in the dehydrobromination of 4-isopropyl-2-bromocyclohexanone (258) from the reduction of 4-isopropylphenol (259) and subsequent bromination) , 3 1 1 but the t w o compounds can be separated by careful distillation, s o from a preparative point of view, this is not too serious.
2 56 -
AI II
259 -
257 -
Hs/Cat
1
\Collidine
4
231
A I
I
258 -
There are at least two syntheses that involve ringclosure reactions, one of Mukherji et a1.314 that starts by addition of acrylonitrile to the substituted ethyl acetoacetate (260). Hydrolysis with hydrochloric acid and ring closure of the ester of the resulting ketoacid (261) gives 4-isopropylcyclohexae-l,3-dioen (262) the monoisobutyl enol ether of which (263)was reduced with lithium aluminum hydride to cryptone. Perhaps more simple is the synthesis of Stork et a1.315 involving addition of but-1-en-3-one to the piperidine enamine (=) of isovaleraldehyde. Without isolating the resulting dicarbonyl compound, it is cyclized with hydrochloric acid to yield (according to Stork et al.) 74% of
The p-Menthanes
99
cryptone. A c t u a l l y , t h i s s y n t h e s i s t o o l e a d s t o a mixture of t h e two isomers and 3); indeed, it is an e x c e l l e n t method f o r making e i t h e r of them, s i n c e t h e undesired one can always be e q u i l i b r a t e d a f t e r w a r d s and r e d i s t i l l e d . We have found t h a t cryptone is always t h e major product from t h e S t o r k s y n t h e s i s , although one might have expected t h e e q u i l i b r i u m mixture ( r e p o r t e d l y only 40% of t h e conjugated ketone i n t h i s c a s e 3 1 6 ) t o be o b t a i n e d . 317
(235
FIH
COCH3
rck
COOEt
COCH 3 >-SCH2CH2CN
OH-
COOH
HCl/AcOH
-
COCH3
261 -
1. E s t e r i f y 2 . NaH
A
26 3 -
262 -
2 64 -
235 -
CHCH2CH2COOH
I
260 -
2 35 -
>I
251 -
100
The S y n t h e s i s of Monoterpenes
S i n c e c r y p t o n e h a s been r e s o l v e d by S o f f e r and G h a y a s t h e p-carboxyphenylhydrazone q u i n i n e s a l t I 3 1 8 t h e s e s y n t h e s e s a l l c o n s t i t u t e t o t a l s y n t h e s e s of t h e n a t u r a l p r o d u c t .
.
Menth-1-en-4-01, M e n t h - l ( 7 ) -en-4-01 (265and 266) The f i r s t of t h e s e t e r p e n e a l c o h o l s (265) i s v e r y w i d e l y d i s t r i b u t e d i n n a t u r e and was s y n t h e s i z e d i n v a r i o u s ways by Wallach i n t h e l a s t c e n t u r y , for example, by t h e a c t i o n of oxalic acid on 1,4t e r p i n (267). 3 1 9 I t i s also a v a i l a b l e from mentha-1,e-dienI a compound r e c e n t l y found t o be n a t u r a l l y o c c u r r i n g 4-01 (24q) ( i n J a p a n e s e pepper3" and C i t r u s j u n e s and which h a s been s y n t h e s i z e d i n v a r i o u s ways. K l e i n and Rojahn showed t h a t p h o t o o x i d a t i o n o f t e r p i n o l e n e (5.1) i n t h e p r e s e n c e of a s e n s i t i z e r l e a d s t o t h e d i e n o l (240)i n 56% y i e l d . 3 2 2 L e f f i n g w e l l opened t h e r i n g o f t e r p i n o l e n e e p o x i d e (268) w i t h 40% dimethylamine a t 130" t o 140' f o r 2 1 / 2 d a y s , t r e a t i n g t h e r e s u l t i n g m i n o a l c o h o l w i t h 50% hydrogen p e r o x i d e i n methanol and h e a t i n g t h e amine o x i d e (Scheme 3 6 ) . Raney n i c k e l reduc(265).323 On t i o n o f the d i e n o l (240) gave menth-1-en-4-01 t h e o t h e r hand, d i r e c t r e d u c t i o n of the e p o x i d e (268) from t e r p i n o l e n e * w i t h l i t h i u m aluminum h y d r i d e a l s o l e a d s t o Scheme 36
267 -
x"
240
18 -
* T e r p i n o l e n e e p o x i d e i t s e l f i s r e p o r t e d t o be a n a t u r a l produ c t , o c c u r r i n g i n t h e o i l of J u n i p e r u s conununis.324
The p-Menthanes
.
101
menth-1-en-4-01 (265) 325 Mentha-1.8-dien-4-01 (240) is also available from dipentene with selenium dioxide. 327
28v26 1
\
255 -
+
/\
-
\
H
l LiA
269 -
terpinolene 271
!
z
H$
-
6
CH20
___c
17
-
aCH 2CH20H
fH2CH20H
1. A 2. H ~ O +
270
The corresponding alcohol with the exocyclic double bond
(266) has only been reported to occur in commercial terpineo T z 8 and it was synthesized by lithium aluminum hydride ring 6-terpineol (270) opening of the appropriate epoxide
(E),
being also obtained during this reaction (see below) .32T
102
The S y n t h e s i s of Monoterpenes
Mentha-l(7) , 4 ( 8 ) - d i e n e (2711, r e q u i r e d t o prepare t h e epoxide was made by t h e p y r o l y s i s of y - t e r p e n y l a c e t a t e
(F), (255). 305
6-Terpineol
(270,)a - T e r p i n e o l (2) , Mentha-2-en-8-01
8-Xydroxy-p-cymene ( 2 7 4 )
.
(270)i s
6-Terpineol
(273),
present i n commercial terpineo1,"n a n d , i n a d d i t i o n t o b e i n g formed i n t h e r e a c t i o n j u s t m e n t i o n e d , 3 2 8 can a l s o be made from a-pinene by a P r i n s r e a c t i o n ( a d d i t i o n of f ~ r m a l d e h y d e ~ ~ , 't)h e n a c i d c a t a l y z e d h y d r a t i o n o f t h e p r o d u c t formed by p y r o l t i c c l e a v a g e ( g i v i n g 272) and f i n a l p y r o l y s i s o f t h i s d i o l . $29
(z)
a - t e r p i n e o l (9) i s t h e major compound p r e s e n t i n comerc i a 1 t e r p i n e o l , t h e s y n t h e s i s o f which by h y d r a t i o n of t u r p e n t i n e ( i . e . , a - p i n e n e , 17) h a s been known f o r many y e a r s . * I n a d d i t i o n , b o t h i t and i t s esters are v e r y w i d e l y d i s t r i b u t e d i n p l a n t s . A more r e c e n t s t u d y 3 3 2 h a s d e s c r i b e d good condit i o n s f o r h y d r a t i o n w i t h 70% p h o s p h o r i c a c i d , 70% f o r m i c a c i d , and a-pinene i n p r o p o r t i o n s 1 : 3 : 5 a t 35' f o r 6-8 h r , when 616 3 % c o n v e r s i o n i s a c h i e v e d w i t h t h e y i e l d s shown i n Scheme 37. Scheme 37
+
68.5%
!2+ 3.1%
t
11.5%
+
10.7%
6- T e r p i n e o l
y-Terpineol Terpin-1-en-4-01
*For a l i s t of the v a r i o u s t e c h n i q u e s t h a t have b e e n u s e d , see R e f . 331.
The p-Menthanes
103
OH 2.0% a-Fenchol
0.2%
4%
Bornylene
Camphene
The conventional syntheses o f t h i s compound by v a r i o u s Grignard r e a c t i o n s on 4 - s u b s t i t u t e d methylcyclopentenes belong more t o t h e realm of chemical h i s t o r y than t o a summary of t h i s n a t u r e , and a r e given i n a l l t h e s t a n d a r d textbooks of t e r p e n e chemistry [ s e e , e . g . , Ref. 3311. Menth-2-en-8-01 (trans 273) h a s been made by Chabudziikky and K ~ d i k b, u~t has ~ ~ n o t y e t been p o s i t i v e l y i d e n t i f i e d a s a (274)a l s o occurs n a t u r a l n a t u r a l p r o d u c t . 8-hydroxy-p-cymene l y and can be made by a v a r i e t y of o x i d a t i v e methods from pcymene (238) c f . , e . g . , t h e photo-oxidation3 3 4 )
.
27 3 -
2 38 -
274 -
The 2-Oxygenated Menthanes Phenols and Their Ethers. The most o x i d i z e d 2-oxymenthane d e r i v a t i v e found so f a r i n n a t u r e i s 2-methyl-5-isopropenylo c c u r r i n g i n t h e o i l o f Chamaecyparis oba n i s o l e (G), tusa.201 This h a s been s y n t h e s i z e d 3 3 5 from t h e known methyl 3-nitro-4-methylbenzoate (276)36 by t h e r o u t e shown (Scheme 3 8 ) , d i r e c t o x i d a t i o n of t h e methyl ether of c a r v a c r o l (277) w i t h a v a r i e t o f r e a g e n t s having l e d t o o x i d a t i o n of t h e 1methyl group. 7 3 5
The S y n t h e s i s o f Monoterpenes
104
Scheme 38 CH 3
I
1. Pd/C, 2. HN02/A
H2
-
3. CHzN2/CH30H
e3 I
COOCH 3
COOCH 3
2 76 -
1. CH~SOCH; 2. Al/Hg
Both c a r v a c r o l (278)and i t s methyl e t h e r (277) are found n a t u r a l l y , and w h i l e i t is n o t such an i m p o r t a n t p r o d u c t comm e r c i a l l y a s thymol ( s e e b e l o w ) , it can be made from c mene (238, above) by s u l f o n a t i o n and t r e a t m e n t w i t h base. 3 3 y Most methods of t h i s n a t u r e t h a t s t a r t from p-cymene (238) l e a d , however, t o a p r o d u c t t h a t i s u s u a l l y c o n t a m i n a t e d b y thymol, and a method l e a d i n g t o c a r v a c r o l o f h i g h p u r i t y i n 39% overa l l y i e l d h a s been described by T a y l o r e t a l . T h i s i n v o l v e s t r e a t m e n t o f p-cymene (238) w i t h t h a l l i u m t r i f l u o r o a c e t a t e i n t r i f l u o r o a c e t i c a c i d . The r e s u l t i n g t h a l l i u m o r g a n i c compound (279) is s u b s t i t u t e d i n o n l y t h e 2 p o s i t i o n , and is c o n v e r t e d t o c a r v a c r y l t r i f l u o r o a c e t a t e (280) by t r e a t m e n t f i r s t , w i t h l e a d tetraacetate i n t r i f l u o r o a c e t i c a c i d , then t r i p h e n y l phosphine
.
’
The p-Menthanes
-
T 1 (OCOCF3 )
238
-
_
f
1. Pb(0Ac)b
105
OCOCF 3
NaOH
270 -
O f course t h e carvone-derived compounds ( s e e below) can a l l be converted i n t o t h e aromatic c a r v a c r o l by s u i t a b l e oxid a t i o n t e c h n i q u e s , b u t only carvone i t s e l f (281) i s a l r e a d y of t h e c o r r e c t o x i d a t i o n s t a g e , and t r e a t m e n t of i t s oxime w i t h 5N h y d r o c h l o r i c a c i d r e s u l t s i n a f a i r l y h i g h y i e l d (74-77%) of c a r v a c r o l . 3 3 9 The rearrangement can a l s o be c a r r i e d o u t w i t h l i t h i u m i n ethylenediamine. 340
1. HzSO4
____c
226
P 0
2 . KOH
2 78
Carvacrol
Carvone and I t s R e d u c t i o n P r o d u c t s .
281 -
Carvone
A l i s t of t h e s e compounds i s given (Scheme 3 9 ) ; many, indeed most of them occur n a t u r a l l y , and t h e y can g e n e r a l l y be prepared by s e l e c t i v e reduct i o n of carvone, choosing s u i t a b l e r e a g e n t s . A f u l l d i s c u s s i o n of t h e e a r l i e r work, t o g e t h e r with t h e s t e r e o c h e m i s t r y of t h e isomeric compounds o b t a i n e d , h a s been g i v e n by S c h r o e t e r and E l i e l . 34
Scheme 39
The S y n t h e s i s of Monoterpenes
106
p
o
H @OH
A
P3?%
Carvacrol
P
O
C
H
Carvotanacetols
3 Carvotanacetone
Carvomenthones
Carvomenthols
OH
(-I-Carvone
Dihydrocarvones
Dihydrocarveols
"?%_:Iii; (p Carveols
:+I -Mentha-
l(7)
Carvenone
Menth-4 (8)-en-2-01
,8-dien-2-01
*The p r o p i o n a t e of t h i s compound i s l i s t e d i n t h e Chemical Abstracts Index for V o l . 66 as a n a t u r a l p r o d u c t , b u t the o r i g i n a l p u b l i c a t i o n makes no mention of i t . 3 4 2
The p-Menthanes
107
Arrows r e p r e s e n t r o u t e s t h a t can be followed w i t h s u i t a b l e reducing agents (see Schroeter and E l i e 1 3 4 1 ) .
Carvomenthols: (The a p p r o p r i a t e p r e f i x e s a r e used a l s o with o t h e r compounds of t h e s e r i e s t o i n d i c a t e s t e r e o c h e m i s t r y . ) O f a l l t h e s e compounds, carvone (281)i s probably t h e most widely d i s t r i b u t e d , and conunercially the most important, i n view of i t s "spearmint" odor. I t occurs i n both o p t i c a l l y a c t i v e isomers, and t h e s e have been i n t e r ~ o n v e r t e d ~ ~ following Scheme 40.
Scheme 40
Hp Op/NaOH
NpH4/HOAc c___f
(-1-281 HO
-c
ox
(+)
-281
Carvone i t s e l f i s a v a i l a b l e , u s u a l l y i n poor y i e l d and by v a r i o u s mixed with o t h e r substances, from limonene oxidation techniques, t h e b e s t of which i s probably chromium t r i o x i d e - p y r i d i n e complex i n methylene c h l o r i d e , which l e a d s t o a mixture of 36% carvone (281) and 33% piperitenone
(225)
108
The S y n t h e s i s of Monoterpenes
(282). 344 I n t h e s e a l l y l i c o x i d a t i o n r e a c t i o n s , it i s f r e q u e n t l y found t h a t menth-1-ene g i v e s a c l e a n e r r e a c t i o n t h a n limonene, owing t o competing r e a c t i o n s i n v o l v i n g t h e o t h e r double bond, and a l s o because of t h e l a b i l i t y o f t h e i s o p r o penyl group i n t h e a c i d c o n d i t i o n s f r e q u e n t l y r e q u i r e d ( s e e , e.g. , T r e i b ~ ~ ~ ~ ) . Limonene epoxide (191)( t h e two d i a s t e r e o i s o m e r s of which a r e o b t a i n a b l e by p e r a c i d o x i d a t i o n of limonene, see review, Ref. 300) c a n , of c o u r s e , be i s m e r i z e d t o dihydrocarvone (283) w i t h v a r i o u s r e a g e n t s of t h e L e w i s a c i d t y p e , n o t a b l y boron t r i f l u o r i d e e t h e r a t e ,3 4 6 b u t can a l s o be converted i n t o mixtures c o n t a i n i n g carvone (up t o 20%) by h e a t i n g f o r prolonged p e r i o d s ( 3 d a y s ) with aluminum o x i d e . 3 4 7 The y i e l d s of t h e v a r i o u s 2-oxygenated menthane d e r i v a t i v e s u s i n g t h i s method a r e shown i n Scheme 4 1 , which a l s o shows t h e y i e l d s of
p
Scheme 4 1
+
Pyridine/Cr03complex i n CHC12 b Q 0
6%
225 -
-
-
;1'
0
+
P 4 6 % 281
282
f
CH20H
23%
24%
CH2OH
191 -
+
33%
28%
The p-Menthanes
109
t h e p r o d u c t s o b t a i n e d by simple chromatography on b a s i c alumina,348 a method known t o c a t a l y z e r i n g opening of epoxi d e s . 349 P r e p a r a t i o n s of carvone from limonene do n o t i n v o l v e t h e assymetry a t C-4, provided a symmetrical ion over p o s i t i o n s 1, 2 , and 6 i s n o t formed. Thus, t h e sequence of s t e p s from ( + ) - limonene epoxide (191) r i n g opening t o t h e 1 , 2 - d i o l , p y r o l y s i s of t h e d i a c e t a t e hydro1 s i s t o c a r v e o l t h e n o x i d a t i o n g i v e s (-)-carvone 3 54;
(E),
[(-)-a]. 1. H ~ O + 2. A c 2 0
___c
A (+)
-191 OAc
1. A 2. OH-
3 . Oxidize
Oxidation with selenium d i o x i d e i s somewhat l e s s s p e c i f i c and depends on t h e s o l v e n t . (+)-Menth-1-ene can be o x i d i z e d t o t r a n s - c a r v o t a n a c e t o l (285) i n e t h a n o l with 44-55% r e t e n t i o n of s t e r e o c h e m i s t r y , 3 5 and t h e mechanism h a s been d i s c u s s e d by Schaefer e t al.352 The r e a c t i o n h a s a l s o been e f f e c t e d on (+)-limonene.288r 326 1 327 Attack of selenium d i o x i d e on a double bond i n a cyclohexane system o c c u r s so t h a t oxygen is i n s e r t e d i n i t i a l l y i n t o t h e a x i a l p o s i t i o n , and the a x i a l a l l y l p r o t o n is a b s t r a c t e d ( l e a d i n g t o 286). Bimolecular d i s placement by t h e water p r e s e n t i n t h e mixture now occurs through an S N ~ 'p a t h l e a d i n g mainly t o t h e a x i a l t r a n s - c a r v e o l (287) having 80% r e t e n t i o n of c o n f i g u r a t i o n i n t h e case of (+)-limonene, although h e r e t h i s i s n o t t h e main p r o d u c t , (288).288,326 r 3 2 7 which i s racemic mentha-lI8-dien-4-ol
110
The S y n t h e s i s of Monoterpenes
285
’
I
(+) i n x h a n o l
( 2 ) i n CH3COOH
z:t’52
These o x i d a t i o n s t a k e a d i f f e r e n t c o u r s e i n a c e t i c a n h y d r i d e t o t h e f o r m a t i o n o f i o n p a i r s by t h e a c e t i c a c i d p r e s and i n t h i s t y p e of s o l v e n t , b o t h (+)-menth-1-ene (290) 3 5 1 and (+)-limonene (225)288 g i v e racemic c a r v e y l ace(Scheme 4 2 ) , b u t o p t i c a l l y a c t i v e ( + ) -trans-mentha-1( 7 ) ,8-dien-2-yl a c e t a t e (289),288 t h e a c e t a t e of an a l c o h o l
tate
Scheme 4 2
Q CH20SeOH
Q /
Hose?.Q
Hoseo\\.Q
CH20SeOH
2 86 -
a”
Q
QOH
\ 288 -
ROCH2
Q
The p-Menthanes
\
CH20SeOH
\
\
287 -
R = H I ( + ) - in EtOH R = Act ( ? ) - in Ac20 AcO,
111
‘Q I
discovered by Naves and Grampoloff in gingergrass oil (Cymbopogon d e n s i f l o r u s ) and to which they erroniously attributed the cis-structure.353 The correct structure of this alcohol (289) was given by Schroeter, who also synthesized it as one of the products resulting from the sensitized photochemical oxidation of (+) -1imonene.297 2 9 8 An example of a (+)-menth-1-ene (290) oxidation during which chirality is lost is the tristriphenylphosphinechlororhodium catalyzed oxidation that leads to racemic carvotanacetone (291)and piperitone (250) presumably via the symmetrical intermediate (292). 35rSimilar intermediates have been proposed by Schenck et al. to account for racemic products in the autoxidation of limonene (as opposed to the sensitized photoxidation) .355
A 292
112
The Synthesis of Monoterpenes
Finally, of the "building block" type syntheses of carvone, that by Vig et a1.356 is probably the most interesting, and is shown in Scheme 43. Scheme 4 3
A O E t HgOAc
190° 30 min
The p-Menthanes
113
Dihydrocarveols a r e g e n e r a l l y made by reduction of carvone ( 2 8 1 ) ; sodium i n e t h a n o l reduction gives a l l f o u r of them, with t F a l l e q u a t o r i a l one i n l a r g e s t amount357 ( t h e names under t h e formulas a r e taken by analogy with t h e carvomenthol names-see a l s o , Ref. 341).
Y
Y
O
Dihydrocarveol Na/EtOH
74.2%
___c
H
Neo3.4%
P OH
281 -
Iso-
9.3%
Neoiso8.7%
Dihydrocarvone can be made from t h e s e a l c o h o l s , of course, b u t has a l s o been synthesized i n s e v e r a l ways, t h e most s t r a i g h t f o r w a r d being again by Vig e t a l . ,358 who t r e a t e d 2-methylcyclohex-5-enone (293)with isopropenyl magnesium bromide i n t h e presence of cuprous i o d i d e t o o b t a i n a 60% y i e l d of t h e d e s i r e d product (294).
114
The S y n t h e s i s of Monoterpenes
-
0
cuI
2 94 -
293 -
Dihydrocarvone Carvenone (295) i s e a s i l y s y n t h e s i z e d from the compound o b t a i n e d by r e a c t i o n o f t h e Mannich b a s e m e t h i o d i d e (297) der i v e d from b u t a n o n e , and t h e €5-ketoester (298). T h i s compound (296) can b e c c l i z e d t o carvenone w i t h s u l f u r i c acid i n a c e t i c a c i d . 3 5 3 t 3 6 0 I t i s g e n e r a l l y n o t even n e c e s s a r y t o go t o t h e s e l e n g t h s , s i n c e carvenone i s one of t h e p r o d u c t s o r more e s p e c i a l l y formed by t h e r e a c t i o n o f fenchone camphor ( 2 2 4 ) w i t h s u l f u r i c a c i d (see r e f e r e n c e q u o t e d by Lutz and Roberts,361 who g i v e a d e t a i l e d d i s c u s s i o n o f t h e react i o n s i n v o l v e d ) . Carvenone i s a l s o t h e main p r o d u c t o f t h e m i x t u r e o b t a i n e d on s o l v o l y s i s of m e n t h a - 1 ( 7 ) , 8 - d i e n - 2 - ~ 1 e t h y l e t h e r (300) [ a c c e s s i b l e from limonene e p o x i d e (191) I w i t h a c e t i c a c i d c o n t a i n i n g a trace o f p e r c h l o r i c a c i d , t h e r e a c t i o n t a k i n g a d i f f e r e n t c o u r s e when t h e i s o p r e n y l s i d e chain i s reduced. 362
(E),
CH 3COCHCH2N+EtzMe
I
CH3
2 97 -
I-
+
t
COCH2COOC2H5
298 -
-
COOC2H5
0
0
296 -
I
Fenchone 299
*
-
CH3
H2S04 /HOAC
&.. 300 -
The p-Menthanes
115
The 3-Oxygenated M e n t h a n e s I n d e a l i n g w i t h thymol (301) and i t s reduced n a t u r a l p r o d u c t s ( l i s t e d i n Scheme 44) i t i s c o n v e n i e n t t o i n c l u d e t h e d e r i v a t i v e s of 3,9-dioxygenated menthanes, s i n c e t h e s e are u s u a l l y Scheme 44
P
$OR
’
O
$0
H
$.
CH20R
R = COCHMe2
30336 3 , 3 6 4
-
Thymol
Piperitone
301 -
250 -
9:Q 13.Piperitenone
OMe
305 -
Ref. 365
Menthofuran
321* -
Piperitols
302 -
Pulegone
P Qu l e g o l s H
Men @OH t h o 1s
307 -
*Two isomers ( a t l e a s t ) of t h i s s u b s t a n c e have been i s o l a t e d from n a t u r a l p r o d u c t s (see Refs. 366 and 367).
116
The S y n t h e s i s o f Monoterpenes
Evodone
Isopulegone
Menthones
332 -
found i n c y c l i z e d form, menthofuran (302) being t h e b e s t known member of t h e group. Some of t h e s e s u b s t a n c e s , however, have been found by Bohlmann e t a l . i n v a r i o u s Helenium s p e c i e s and i n Doronicurn austriacum a s uncyclized e s t e r s ( e . g . , 303) .363, 36 4
Many of t h e s e 3-oxygenated menthane d e r i v a t i v e s have been s y n t h e s i z e d by c y c l i z a t i o n procedures from open chain a c i d s . One of t h e e a r l i e s t of t h e s e t o be examined i n d e t a i l was t h e t o p i p e r i t e n o n e * (305) 369' y c l i z a t i o n of g e r a n i c a c i d (2) but similar c c l i z a t i o n s of c i t r o n e l l i c acid (306)to pulegone ( 3 0 7 ) , 3 7 ' r 3 7 2 l a v a n d u l i c a c i d (308) t o p i p e r i t e n o n e (305),3 7 2 and d i h y d r o l a v a n d u l i c a c i d (309) t o p i p e r i t o n e These c y c l i z a t i o n s occur ( 2 5 0 ) 3 7 2 have a l s o been d e s c r i b e d . g e n e r a l l y w i t h a small a m u n t of s u l f u r i c a c i d i n a c e t i c anh y d r i d e , b u t c e r t a i n c y c l i z a t i o n s o f open c h a i n aldehydes occur simply on h e a t i n g , and t h e r e l a t i o n s h i p between t r a n s c i t r a l , i s o p i p e r i t e n o l , and c i s - c i t r a l , f o r example, have been discussed by O h l o f f g 9 ( s e e a l s o i n t h e s e c t i o n on t h e open chain aldehydes , above)
.
304 -
305 -
308 -
*This c y c l i z a t i o n i v e s o t h e r products of c o n s i d e r a b l e i n t e r e s t , s e e BeereboomI6' and t h e s e c t i o n on f i l i f o l o n e (below).
The p-Menthanes
306 -
117
"1
307 -
An i n t e r e s t i n g c y c l i z a t i o n of c i t r o n e l l o l i s t h a t des c r i b e d by V a n Bruggen; when t r e a t e d w i t h a t - b u t y l peroxide, t h e a l c o h o l forms c i t r o n e l l y l r a d i c a l s t h a t c y c l i z e t o a mixt u r e of menthols. 373 T h y m o l (301). Thymol and i t s methyl e t h e r both occur n a t u r a l l y ; t h e phenol i s very widely d i s t r i b u t e d , and i s of some commercial importance. I t i s u s u a l l y s y n t h e s i z e d by r e a c t i o n of rn-cresol (310) w i t h propylene i n a F r i e d e l - C r a f t s - t y p e reaction, and the p r i n c i p a l d i f f i c u l t y i s i n s e p a r a t i n g t h e thymol from t h e d i f f e r e n t isomers t h a t a r e formed i n t h e rea c t i o n . 3 3 7 Thymol i s a well-known example of a cryptophenol (one t h a t i s n o t s o l u b l e i n aqueous a l k a l i , nor methylated with dimethyl s u l f a t e i n b a s e , see Ref. 374) , and t h i s f a c t can sometimes be used i n its p u r i f i c a t i o n .
30 1 -
The S y n t h e s i s of Monoterpenes
118
Piperitenone (305). T h i s compound i s of i n t e r e s t a g a i n n o t only f o r i t s e l f , b u t because it would, i f r e a d i l y a v a i l a b l e , make t h e o t h e r more reduced compounds a l s o e a s i l y a c c e s s i b l e . The most obvious way t o make p i p e r i t e n o n e , condensation of m e s i t y l oxide (311) w i t h methyl v i n y l k e t o n e , h a s caused a c e r t a i n amount of c o n t r o v e r s y i n t h e l i t e r a t u r e ; r e f e r e n c e s a r e given by Beereboom,368 who a l s o g i v e s p r e c i s e c o n d i t i o n s using d r y potassium hydroxide i n t e t r a h y d r o f u r a n t o g i v e only 2 2 % formation of t h e i n t e r f e r i n g i s o x y l i t o n e (312). The two substances are d i f f i c u l t t o s e p a r a t e by d i s t i l l a t i o n , and t h e b e s t method i s t h a t of Naves and Papazian, u s i n g t h e f a c t t h a t i s o x y l i t o n e forms a w a t e r s o l u b l e b i s u l f i t e compound. 3 7 5 This s y n t h e s i s , a s w e l l a s t h e p r e p a r a t i o n of menthone and menthol from p i p e r i t e n o n e h a s a l s o been more r e c e n t l y s t u d i e d by Ohshiro and Another method t h a t raises t h e amount o f p i p e r i t e n o n e i n t h e mixture t o 50% used m e s i t y l oxide (g), and i n s t e a d of methyl v i n y l k e t o n e , t h e Mannich b a s e (313) of a c e t o n e , using T r i t o n B a s t h e condensing a g e n t i n b o i l i n g e t h e r . 3 7 7 When p r e c a u t i o n s a r e n o t t a k e n i n t h i s basec a t a l y z e d c o n d e n s a t i o n , some i d e a of t h e complex i s o x y l i t o n e l i k e p r o d u c t s t h a t a r e formed can be gained from t h e work of Furth and Wiemann. 378
9 P 0
"
Lippion e " 314 -
Menthones
The p-Menthanes
119
P i p e r i t e n o n e 1.2-epoxide (314, " l i p p i o n e " ) is a l s o a cons t i t u e n t of v a r i o u s Mentha s p e c i e s , and h a s been s y n t h e s i z e d from pulegone (307).3 7 9 (See a l s o t h e s e c t i o n on dioxygenated p-menthanes f o r compounds r e l a t e d t o 314.)
(z z) .
P i p e r i tone (250), cis- and t r a n s - P i p e r i to1 and Syntheses o f p i p e r i t o n e (250) are g e n e r a l l y v a r i a t i o n s of t h e o r i g i n a l one of W a l k e r , 3 8 v h a t c o n s i s t e d i n allowing 4chlorobutan-2-one a methyl v i n y l ketone e q u i v a l e n t ) t o r e a c t w i t h i s o p r o p y l e t h y l a c e t o a c e t a t e (317, R = E t ) when t h e p i p e r i t o n e system i s formed d i r e c t l y , t h e f r e e ketone being o b t a i n e d a f t e r h y d r o l y s i s i n base. Lawesson e t a l . 381 used t h e t - b u t y l a c e t o a c e t a t e (317 R = t-Bu) , adding methyl v i n y l ketone by b a s e c a t a l y s i s , and t h e n o b t a i n i n g t h e p i p e r i t o n e by p y r o l y s i s . F i n a l l y , Stepanov and Myrcina used a somewhat s i m i l a r method t o Walker's, b u t s t a r t i n g w i t h the a p p r o p r i a t e malonic ester. 382
(316, (2)
ClCH2CH2COCH3
316 CH3COCCOOR 0I CHMe2
317
.1
*-Po-
J
COOEt
A
9; 250 -
lrCocH3 CH2CH2COCH3 I
CH3COk-COOC (CH3) 3
I
CHMe 2
315b -
1
LiAlH4
315a -
The corresponding a l c o h o l s are o b t a i n e d by metal hydride r e d u c t i o n of p i p e r i t o n e , t h e cis- and trans-isomers are separ-
120
The S y n t h e s i s of Monoterpenes
a b l e by d i s t i l l a t i o n , 3 8 3 b u t c a r e must be t a k e n , and t h e author has o c c a s i o n a l l y encountered seemingly i n e x p l i c a b l e deh y d r a t i o n s (probably c a t a l y z e d by t r a c e s of a c i d ) o c c u r r i n g on s t o r a g e , p a r t i c u l a r l y of t r a n s - p i p e r i t o l . ( I n t h i s conn e c t i o n , see t h e d i s c u s s i o n i n Ref. 384 concerning t h e preparat i o n and decomposition of t h e p i p e r i t o l s . ) A d i f f e r e n t prepa r a t i o n o f p i p e r i t o n e u t i l i z e d Birch r e d u c t i o n of thymol methyl e t h e r (3191, followed by d i l u t e o x a l i c a c i d cleavage of t h e e n o l e t h e r formed ( 3 2 0 ) . 384
Na/NH 3
-
Q
+
0
I
OH-
//
250 -
Pulegone, Isopulegone, t h e P u l e g o l s , Menthofuran, and R e l a t e d Compounds. Pulegone (307) o c c u r s i n s e v e r a l s p e c i e s of p l a n t , p a r t i c u l a r l y i n c e r t a i n Mentha s p p . ; i s o p u l e g o l i s a l s o found i n p l a n t o i l s , b u t i n view of i t s ready i n t e r c o n v e r s i o n w i t h c i t r o n e l l a l , with which it i s always found, it i s very l i k e l y t o be an a r t e f a c t . Menthofuran o c c u r s i n v a r i o u s peppermint and o t h e r o i l s , t o g e t h e r w i t h i t s a u t o x i d a t i o n p r o d u c t , 321 (see Scheme 44), t h e s t r u c t u r e of which was e s t a b l i s h e d by Woodward and Eastman i n 1950.305 In view of t h e l a r g e s u p p l i e s of n a t u r a l pulegone, t h e r e h a s n o t been e x t e n s i v e e f f o r t expended on s y n t h e s e s ; i t can be made from 3-methylcyclohexanone (322)by p r e p a r i n g t h e
The p-Menthanes
121
B-ketoester (323) (with d i e t h y l o x a l a t e ) , p r o t e c t i n g t h e ketone group as t h e e t h y l e n e k e t a l (3241, t h e n adding t h e methyl groups w i t h excess methyl magnesium i o d i d e and h y d r o l y s i s with c o n c e n t r a t e d h y d r o c h l o r i c a c i d . The mixture of pulegone (307) and isopulegone (325) t h u s o b t a i n e d can be converted i n t o p r a c t i c a l l y pure pulegone with sodium e t h o x i d e i n e t h a n o l . 386 Ohloff e t a l . have shown t h a t p y r o l y s i s causes t h e o p p o s i t e rearrangement t o t a k e p l a c e , isoisopulegone (=) being formed i n 38% y i e l d from pulegone.387
322 -
325a -
Qo- GI f COOEt
COOEt
32 3 -
307 -
324 -
325 J
Pulegone can a l s o be prepared from aromatic sources. Wolinsky h a s shown how r e d u c t i o n of t h e c r e s o l i c a c i d methyl ester (326) l e a d s t o a mixture of cyclohexanol esters (327) t h a t a r e converted t o a mixture of g l y c o l s (328) with methyl l i t h i u m . Oxidation of t h e secondary a l c o h o l (Jones r e a g e n t ) and d i s t i l l a t i o n o f t h e product w i t h a t r a c e of i o d i n e y i e l d s pulegone. 3'8
COOCH 3
326 -
Y
COC
327 -
122
The Synthesis of Monoterpenes
Pulegone is converted by metal hydride reduction to the pulegols, but the latter dehydrate very easily to mentha-3,8diene The easiest method of making menthofuran (302) from pulegone (307) is still probably the classic one of T r e i b ~ , ~ ” who obtained the sultone (329) with sulfur trioxide, pyrolysis of which led to menthofuran (302).Other methods are, however, occasionally described; Zalkow, for example, has reported that lead tetraacetate oxidation of pulegone leads to unlike the oxidation with mer4-acetoxyisopulegone curic acetate that gives the acetate on the other side of the carbonyl group. The 5-acetoxyisopulegone can be pyrolyzed to a mixture of menthofuran (302) and mentha-4,8-dien-3-one
.
(z),
a
(331).3 9 1
9 0
3 30 -
331 -
The p-Menthanes
123
The l i g h t - i n d u c e d o x i d a t i o n of menthofuran t o t h e hydroxyb u t e n o l i d e (321)has been worked o u t i n d e t a i l by SchulteE l t e 3 9 2 (see, a l s o , Ref. 393). Evodone r e l a t e d t o menthofuran, h a s been i s o l a t e d from t h e l e a v e s of Evodia hortensis, 366 394 and t h e r e is a r e p o r t of a n a b o r t i v e s y n t h e s i s , t h a t s t a r t e d from t h e Birch r e d u c t i o n product (334) of 3,5-dimethoxytoluene (333) Cond e n s a t i o n of (=) with B-bromopropionaldehyde a c e t a l u s i n g potassium amide i n l i q u i d amnonia w a s d e s c r i b e d , b u t such bromoacetals a r e w e l l known t o be extremely r e l u c t a n t t o r e a c t i n t h i s t y p e of condensation.395 A t any r a t e t h e t r e a t m e n t of t h e supposed product (316) w i t h h y d r o c h l o r i c a c i d d i d n o t l e a d t o anything t h a t could be c o r r e l a t e d w i t h evodone. 396
(z),
.
33 3 -
334 -
3 35 -
2-Hydroxy-3-methylene-6-methylbenzofuran. Bohlmann h a s found this benzofuran i n Helenium s p e c i e s , and h a s s y n t h e s i z e d i t s
methyl e t h e r (336) from t h e 6-methylcomaranone r o u t e shown i n Scheme 45.365
(337)by
Scheme 45
I
MeMgI
#
the
124
$- (b
The Synthesis of Monoterpenes
/
Me0
OMe
OMe
Menthones and Menthols. These compounds are very important constituents of various mint oils. Both menthone (338)and isomenthone (339) occur naturally, but there are few, if any, syntheses that lead to a single isomer only, the equilibrium mixture being about 60:40 menthone:isomenthone.
339 -
3 38 -
Menthone
342 -
Menthol
34 3 -
Neomenthol
Isomenthone
340 -
341 -
Isomenthol
Neoisomenthol
Menthones are conveniently made by reduction of one of the more oxidized 3-oxygenated menthanes, for example, piperitenone or thymol, the menthols being available from the menthones. The amount of work that has been done on these reductions is
The p-Menthanes
125
enormous; some i d e a of i t i s o b t a i n e d by c o n s u l t i n g Ref. 397. I t i s s u f f i c i e n t t o say t h a t c a t a l y t i c r e d u c t i o n of thymol completely t o t h e a l c o h o l s g e n e r a l l y r e s u l t s i n a high y i e l d o f isomenthol ( 3 4 0 ) ; t y p i c a l f i g u r e s are t h o s e o b t a i n e d w i t h Raney c o b a l t : 39r84. 7 % isomenthol ( 3 4 0 ) , 9.8% neoisomenthol (341), and 2 . 7 % each of menthol ( % a n d neomenthol ( 3 4 3 ) . Reductions of menthone t h a t d o n o t cause e x t e n s i v e e n o G a t i o n , f o r example, metal hydride r e d u c t i o n s i n e t h e r , e t c . , l e a d t o mixtures of menthol (342) and neomenthol (E), while g i v e s i s o - (340) and neoisomenthols (341). isomenthone (2) Menthone and isomenthone are r e a d i l y s e p a r a t e d by gas chromatography, b u t t h e s e p a r a t i o n of t h e f o u r menthols i s more d i f f i c u l t , t h e b e s t column i s probably H y p r o ~ e . P~ i ~ p e~r i t o l i s a t t h e same o x i d a t i o n s t a g e a s menthone, and Bhati has shown how d i s t i l l a t i o n of p i p e r i t o l w i t h potassium hydroxide, a r e a c t i o n based on a discovery of O h l o f f I 4 ' l e a d s t o (k) menthone. 4o
The 7-Oxygenated Menthanes The n a t u r a l l y o c c u r r i n g 7-oxygenated menthanes a r e shown i n Scheme 4 6 , and t h e oxidation-reduction r e l a t i o n s h i p s between
9
Scheme 46
CH2OH
Cuminaldehyde (and Acid) 360 -
Q c -P
344
A 1dehyde
Perilla
CH20H
346 Phe l G d r a l CH20H
34 5 -
Alcohol
126
The S y n t h e s i s o f Monoterpenes
C HO
CHO
them can b e deduced from t h e f o r e g o i n g s e c t i o n s . The aromatic compounds have been known s i n c e t h e l a s t c e n t u r y , and l i t t l e new c o n c e r n i n g t h e i r t o t a l s y n t h e s i s h a s a p p e a r e d i n t h e p a s t 20 y e a r s . P e r i l l a a l d e h y d e (344) and a l c o h o l (3451, and t h e reduced p h e l l a n d r a l (346) a r e , however, o f c o n s i d e r a b l e i n t e r e s t , n o t o n l y f o r t h e i r own s y n t h e s e s , b u t a l s o b e c a u s e t h e a-oxime* o f p e r i l l a aldehyde i s a p o w e r f u l sweetening a g e n t . 4 0 2 A conv e n i e n t t y p e o f s y n t h e s i s s t a r t s from t h e p i n e n e s k e l e t o n . I n 1 9 4 7 , Toshio e t a l . d e s c r i b e d how m y r t e n a l (347) ( o b t a i n a b l e from a-pinene by a v a r i e t y of o x i d a t i o n p r o c e d u r e s ) is conv e r t e d by h e a t w i t h o r w i t h o u t c a t a l y s t i n t o p e r i l l a a l d e h y d e ( 3 4 4 ) , 4 0 3 and f o u r y e a r s l a t e r a J a p a n e s e p a t e n t a p p e a r e d conc e r n i n g a s i m i l a r t r a n s f o r m a t i o n of m y r t e n o l (=) from t h e selenium d i o x i d e o x i d a t i o n o f a - p i n e n e , t o g e t h e r w i t h m y r t e n a l ( 3 4 7 ) , i n t o p e r i l l a a l c o h o l (345) .404 I n 1959, a French pat e n t d e s c r i b e d t h e r i n g opening of B-pinene e p o x i d e (349) w i t h a c e t i c a n h y d r i d e t o y i e l d t h e d i a c e t a t e (350) t o g e t h e r w i t h some p h e l l a n d r a l , and t h i s d i a c e t a t e c o u l d b e p y r o l y z e d t o t h e a c e t a t e (351) o f p e r i l l a I n none of t h e s e des c r i p t i o n s was t h e s t e r e o c h e m i s t r y made c l e a r , and Keenan h a s shown t h a t i n t h e c a s e of t h e $-pinene r e a c t i o n , s t a r t i n g w i t h (-)-B-pinene r e s u l t s i n the (-)-alcohol I t has also been shown t h a t a n o t h e r of t h e B-pinene o x i d a t i o n produ c t s , n o p i n i c a c i d (=) i s c o n v e r t e d by acid f i s s i o n e i t h e r i n t o p e r i l l i c a c i d (353) o r i n t o m e n t h a - l , + d i e n o i c acid
-
(14)
(z).406
*The c o n f u s i o n i n t h e l i t e r a t u r e a b o u t t h e syn or a n t i nomenc l a t u r e f o r t h e oxime, and i t s e x a c t s t r u c t u r e , have been c l a r i f i e d by Acton e t a l . 4 0 1
The p-Menthanes
127
CHO
CHO
-
___c
Myrtenol 34 8
-
14 -
34 9 -
I( OAC 350 -
CH 2 OH
(354)
A
Myrtenal 347
SeOp
344
c
\
345 -
CH20Ac
a c c o r d i n g t o t h e c o n d i t i o n s . 4 0 7 ~ 4 0 8 The moving of t h e
C-8 double bond i n t o t h e r i n g i s common t o a l l doubly un-
s a t u r a t e d monoterpenes h a v i n g an i s o p r o p e n y l group ( a s we have mentioned above i n t h e case of l i m o n e n e ) , and p e r i l l a compounds are n o t e x c e p t i o n , as t h e v a r y i n g p r o d u c t s of this
128
The S y n t h e s i s of Monoterpenes
n o p i n i c a c i d r e a c t i o n show, and as h a s been shown t o o c c u r w i t h p e r i l l a aldehyde.4o9 COOH
Nopinic Acid 352
-
COOH
35 3 -
COOH
A 354 -
One might t h i n k t h a t a c o n v e n i e n t p r o c e d u r e f o r a r r i v i n g a t 7-oxygenated menthanes would b e by some o x i d a t i o n method from p-cymene, and a l t h o u g h m i c r o b i a l o x i d a t i o n ( e . g . , w i t h Pseudomonas ~ p p . ~ l Oi )s known t o l e a d t o cumin a l d e h y d e , m o s t methods ( p h o t o - o x i d a t i o n , e t c . ) c a u s e o x i d a t i o n i n t h e isop r o p y l group. The o x i d a t i o n of one of t h e p r o d u c t s (355) of menth-lene (247) p h o t o - o x i d a t i ~ n w ~ i~t h~ sodium b i c h r o m a t e i n sulf u r i c a c i d l e a d s t o p h e l l a n d r a l (346),411 b u t t h i s r e a c t i o n might n o t b e so e a s i l y accomplished i n t h e p e r i l l a series i n view of t h e l a b i l i t y o f t h e i s o p r o p e n y l group t o a c i d (see, a l s o , Ref. 345 f o r d i f f e r e n c e s i n o x i d a t i o n of menth-1-ene and l i m o n e n e ) .
I
A 247 -
9 CHO
A 355 -
346 -
The remaining compounds (356 t o 359) l i s t e d above are found i n cumin s e e d s and o i l and Varo and Heinz have d e s c r i b e d t h e i r l a b i l i t y . 4 1 2 Mentha-1,4-dien-7-al (356), f o r example, i s c o n v e r t e d by d i s p r o p o r t i o n a t i o n t o cumin aldehyde (360) and menth-3-en-7-al (359) merely by i n j e c t i o n i n t o a g a s chromatograph. Mentha-l13-dien-7-al (357) h a s a l r e a d y been mentioned as a r i s i n g from p e r i l l a aldehyde w i t h a c i d . 4 0 9
The p-Menthanes
129
+
359 -
356 -
360 -
The 9-Oxygenated Menthanes
It is a curious fact that most of the compounds of this group have only relatively recently been discovered in natural materials; indeed, Gildermeister-Hoffmann lists none at all. and Hunter and Moshonas discovered two of the alcohols (=)I in cold pressed Valencia orange the diol uroterpinol (363) was found414,415 and identified416 as the glycoside (364) in human urine, probably from dietary limonene metabolism,* and the two possible diastereomers of meth-l-en-9In addition to the a1 (365) have been found in rose synthesis of these natural products that is mentioned below, the series of papers by Camps and Pascua1418-419a should be mentioned; they describe the synthesis of a number of saturated and unsaturated rnenthane 9- (and some 7-) alcohols, not yet reported in nature together with their stereochemistry.
[(s)
361 -
Uroterpinol I
363 -
,
probably because *The natural compound is not optically dietary limonene is not optically pure.EYEe’
The S y n t h e s i s of Monoterpenes
130
D e r i v a t i v e s of mentha-l,8-dien-lO-o1 (361) are a c c e s s i b l e from s e v e r a l o x i d a t i o n s of limonene, t h e b e s t known b e i n g t h a t of l e a d t e t r a a c e t a t e o r i t s e q u i v a l e n t , r e d l e a d ( P b j O 4 ) i n ~ ~ was ’ a c e t i c a c i d . T h i s was f i r s t recorded by A r ~ ~ t a n i ,and used by Ruegg e t t o make o p t i c a l l y a c t i v e mentha-1,8dien-10-01, s i n c e t h e limonene used r e t a i n s i t s assymetry during the reaction. The i n i t i a l compound formed (Scheme 4 7 ) i s Scheme 47
3H - /
:
‘YH~OAC
367 -
Glycoside
4
- 0’ OAc
CH20Ac
A C H 2 O H
361 -
366 -
The p-Menthanes
131
t h e 8 , 9 - d i o l i n t h e form of i t s monoacetate (367) and it was t h i s d i o l t h a t Dean e t a l . used f o r making t h e g l y c o s i d e , 364.416 Acetylation of t h e o t h e r hydroxyl group ( t e r t i a r y ) from , which and p y r o l y s i s l e a d s t o t h e d i e n y l a c e t a t e ( g ) t h e f r e e alcohol is obtained i n t h e usual way. The monoa c e t a t e of t h e d i e n o l i s a l s o one of t h e main compounds obt a i n e d by selenium dioxide oxidation of limonene i n a c e t i c anhydride,288 and i s i t s e l f a n a t u r a l product, occurring i n t h e o i l of C i t r u s n a t ~ u d a i d i C. , ~ ~u ~n i s h ~ and , ~ ~ Valencia ~ orange o i l . 424 A d e t a i l e d d i s c u s s i o n of t h e stereochemistry of t h e 9oxygenated menth-1-enes has been given by Ohloff e t a1.,417 and t h i s i s very important, s i n c e e a r l p u b l i c a t i o n s on t h i s t o p i c were obscure. Albaigss e t al.41' pointed o u t t h a t t h e r e (3621, and a mixture were two diastereomers of menth-1-en-9-01 of t h e two can be obtained by h y d r o b ~ r a t i o n ~ -o ~ r *by~ addit i o n of aluminum a l k y l t~o ~limonene, ~ ~ during which t h e c h i r a l i t y c e n t e r a t C-4 i s , of course, maintained. The two isomers can be separated by f r a c t i o n a l c r y s t a l l i z a t i o n of t h e 3,5-dinitrobenzoates, and from t h e pure a l c o h o l s it i s p o s s i b l e t o make t h e two isomers of t h e aldehyde.417
-
D i - and P o l y o x y g e n a t e d Menthanes, C i n e o l s
,Pinol,
etc.
Some of t h e dioxygenated menthanes have a l r e a d y been described, notably t h e 3,9-diols and t h e i r dehydration products (menthofuran d e r i v a t i v e s ) , and t h e 8 , g - d i o l s . Some of t h e remaining n a t u r a l products of t h i s type a r e given i n Scheme 48. Loss of Scheme 48
373 trans-Terpin
370 Sobrerol
371 Pinol ( n o t n a t u r a l l y occurring)
132
The S y n t h e s i s o f Monoterpenes
1,4-Cineol
374 -
376 -
368 -
36 9 -
1,8-Cineol
Ascaridole
Mullilam D i o l
,.%OH
QH
O H $' '
p:
A
n
380 -
381 -
384 -
Ho5? 2
O l e u r o p i c Acid
P
O
378 -
H
OH
379 -
w a t e r between t h e hydroxyl groups of t h e well-known h y d r a t i o n p r o d u c t s of p i n e n e , t e r p i n h y d r a t e , o r o f t h e h y d r o x y l g r o u p s i n m e n t h a n e - l l 4 - d i o I g i v e s t h e c i n e o l s , 1,8-(=) and 1,4(E), r e s p e c t i v e l y . I n t h e same way, s o b r e r o l (2) , known s i n c e t h e e i g h t e e n t h c e n t u r y , l o s e s water t o g i v e p i n o l (=).* T h i s l i s t i s by no means e x h a u s t i v e , and t h e r e i s some quest i o n a s t o how " a u t h e n t i c " some n a t u r a l p r o d u c t s of t h i s n a t u r e r e a l l y are. F o r example, it i s known t h a t t e r p i n o l e n e i s a u t o x i d i z e d t o menth-3-ene-l,2-trans-8-triol (372),429
(z)
*Pin01 i t s e l f i s n o t known as a n a t u r a l p r o d u c t .
The p-Menthanes
3
133
and t h i s may indeed c r y s t a l l i z e i n b o t t l e s of t e r p i n o l e n e ( i n which i t i s n o t very s o l u b l e ) . Thus, i f it were t o be found i n a n a t u r a l product containing a t t h e same t i m e t e r p i n o l e n e ,
51 -
02
@ O H
37 2 -
t h e q u e s t i o n would always a r i s e concerning t h e way t h e n a t u r a l product had been s t o r e d . A f u r t h e r d i f f i c u l t y i s t h e thermol a b i l i t y of c e r t a i n compounds. For many y e a r s t h e a u t h e n t i c i t y of t r a n s - t e r p i n (373) was i n doubt, b u t it was r e c e n t l y ident i f i e d a s c e r t a i n l y a s i s p o s s i b l e a t p r e s e n t i n I l l i c u m verum and i n f e n n e l o i l (Foeniculurn vulgare var. dulce M) , 4 3 0 a l though it l o s e s water a t 70°-800--to g i v e , of course, a v a r i e t y of t h e well-known t e r p i n e o l s we have a l r e a d y discussed. Peyron e t a l . , who made t h i s o b s e r v a t i o n , a l s o r e f e r t o t h e d i f f i c u l t y of e x t r a c t i o n on account of t h e water s o l u b i l i t y of t r a n s - t e r p i n ; 1 g d i s s o l v e s i n 32 g of water a t 1 0 0 ° . 4 3 0 The c i n e o l s a r e f a i r l y commonly encountered i n n a t u r a l p r o d u c t s , f o r example 1 , 4 - c i n e o l (369) is a v i t a l component f o r t h e f l a v o r of l i m e j u i c e ( C i t r u s medica L . , v a r . a c i d a ) 4 3 1 and 1 , 8 - c i n e o l i s one of t h e main oxygen-containing terpenes of v a r i o u s Melaleucia s p e c i e s ( t e a t r e e s ) .432 Finding e t h e r s and u n s a t u r a t e d a l c o h o l s r a t h e r than d i o l s makes one wonder n o t only how a u t h e n t i c known polyoxygenated compounds a r e , b u t how many have been missed by loss of water o r water s o l u b i l i t y during workup. I n t h i s s e c t i o n , t h e d i s c u s s i o n w i l l be l i m i t e d t o those compounds mentioned i n Scheme 48. The compounds of t h e f i r s t l i n e of t h e l i s t (371 t o do n o t m e r i t a long d i s c u s s i o n h e r e , s i n c e t h e i r s y n t h e s i s has been known f o r a long t i m e (see, e . g . , Ref. 433). 1,4-Cineol (369) has g e n e r a l l y been synthesized i n t h e p a s t by reduction of t h e n a t u r a l product, a s c a r i d o l e * (374) [obtainable by photo-oxidation of a-terpinene (=)I t o c i s - l I 4 - t e r p i n (375),
373)
*An i n t e r e s t i n g new source of s i n g l e t oxygen is made from phosphite e s t e r s and ozone. I t s s t r u c t u r e i s r e p o r t e d t o be (RO)BP:E;O,
terpinene.
and it g i v e s a s c a r i d o l e i n 60% y i e l d from a34
134
The S y n t h e s i s of Monoterpenes
and t r e a t m e n t of t h e l a t t e r w i t h o x a l i c a c i d , 4 3 5 b u t t h i s react i o n i s b y no means as clean a s Wallach e v i d e n t l y b e l i e v e d , and c a r e f u l p u r i f i c a t i o n of t h e c i n e o l , o b t a i n e d i n only mode r a t e y i e l d , i s n e c e s s a r y . 4 3 6 A mixture of b o t h c i n e o l s ( 1 , 4 and 1,8-) i s o b t a i n e d d i r e c t l y from i s o p r e n e when t h i s is t r e a t e d a t 30’ i n a n i t r o g e n atmosphere with 50% s u l f u r i c a c i d . A 2 3 % y i e l d of d i s t i l l a b l e product i s o b t a i n e d , cons i s t i n g of 2 8 % 1 , 4 - c i n e o l [=) and 2 5 % of 1 , 8 - c i n e o l I n a d d i t i o n t o t h e c l a s s i c a l methods of making 1 , 8 - c i n e o l , t h e method of hydroboration i n t h e presence of mercuric acet a t e 4 3 8 when ap l i e d t o a - t e r p i n e o l (39) y i e l d s 90% of 1 , 8 c i n e o l (368) .4 38
(z).4
-
226 -
374 -
375 -
369 -
“Mullilam d i o l “ i s t h e name t h a t Mathur e t a l . gave t o t h e 1 , 4 - c i n e o l - 2 , 3 - d i o l (376) t h a t they i s o l a t e d from Zanthoxylium r h e t ~ a . ~ ~The ’ complete s t e r e o c h e m i s t r y i s n o t c e r t a i n , b u t t h e d i o l arrangement i s trans. The compound was o b t a i n e d many y e a r s p r e v i o u s l y a s a product from t h e p e r a c i d o x i d a t i o n of sabinene (233).441 An isomer with a c i s - d i o l arrangement has been made using t h e r e d u c t i o n of a s c a r i d o l e with f e r r o u s s u l f a t e . 4 4 2
9
H3?
The p-Menthanes
135
HO
376 -
2 33 -
Oleuropic a c i d (377) was i s o l a t e d from t h e hydrolyzate of a b i t t e r p r i n c i p l e from v a r i o u s p a r t s of t h e o l i v e t r e e (Olea europaea), and a f t e r i n i t i a l assignment of an i n c o r r e c t s t r u c t u r e , 4 4 3 t h e c o r r e c t formula was determined by Mechoulam e t a l . , and t h e compound s y n t h e s i z e d from cyclohexanone-4-carb o x y l i c a c i d by t h e r o u t e shown i n Scheme 4 9 , 4 4 4 and by Her2 and Wahlborg from (-)-B-pinene ,408 t h e l a t t e r leading t o o p t i c a l l y a c t i v e oleuropic acid.
(14)
() KC2H
Scheme 49
HOoS
t-BuOH
6OOH
COOH
CGQH
1. H+ 2. N a I O
311 -
A I
Several steps
AoH
600H
I
COOMe
1. E s t e r i f y 2. Ketalize
136
The Synthesis of Monoterpenes
Apart from the "classic" diols (such as sobrerol and the terpins), there are some newer diols that have been isolated: menth-8-ene-1,2-diol (378) from cold-pressed Valencia orange the menthane 2,5-diol shown (379)from Japanese peppermint oil (Mentha arvensis, var. piperasceus) ,445 some isomers of menth-l-ene-3,6-diol ( 3 8 0 ) from Eucalyptus dives446 and Chinese star anise oil , 4 4 7 n d trans-menth-2-ene-1,I-diol (381) ( - ) -rnenthane-l13-diol (382)and a menthane-2 ,3-diol , the latter three all from Mitcham peppermint These diols are generally synthesized by some means of oxidation of suitable hydrocarbons; for example, the peracid oxidation of a-phellandrene (228) gives a mixture of three possible isomers of the menth-l-ene-3,6-diols (all of which are present in Eucal y p t u s dives, and the structures of which have been estabon the other hand, l i ~ h e d . Piperitone ~~~ epoxide (+)-(=),
go HO
228 -
( 3 isomers)
___c
f
OH
384
383
382 -
The m-Menthanes
137
can be converted by l i t h i u m aluminum h y d r i d e r e d u c t i o n f o l lowed by c a t a l y t i c r e d u c t i o n i n t o t h e n a t u r a l l y o c c u r r i n g ment h a n e - l 1 3 - d i o l (=) . 4 4 8 P i p e r i t o n e epoxide (=) i s a natur a l p r o d u c t , t o o , and i s r e a d i l y converted by a c i d c a t a l y s i s i n t o one of t h e more " c l a s s i c " dioxygenated menthanes, d i o s phenol (384). 4 4 9 The more u n s a t u r a t e d diosphenolene (385) i s s i m i l a r l y a v a i l a b l e from p i p e r i t e n o n e oxide ( " l i p p i o n e ," 314, see above) ,450 o r by aluminum c h l o r i d e c a t a l y z e d r i n g opening of verbenone epoxide (386), t h a t l e a d s f i r s t t o i s o p i p e r i t e n one epoxide (387) and t h e n with a c i d , t o diosphenolene
(385). 4 5 1
387 -
38 5 -
The s a t u r a t e d menthane-1,2-diols a r e obtained by hydrat i o n o f limonene epoxides (see t h e comprehensive a r t i c l e of Royls and Lef f i n g ~ e ll l) , ~ b~u t t h e paper on t h e i s o l a t i o n 4 does n o t make it c l e a r p r e c i s e l y which isomers were found. F i n a l l y , Klein and Dunkelblum have s y n t h e s i z e d two menthane t r a n s - 2 , 3 - d i o l s (386) from t h e hydroboration of p i p e r i t o n e (250)1 4 5 2 b u t they do n o t appear t o be t h e same a s t h e menthane-2 ,3-diol i n Mitcham peppermint o i l 1 4 4 8 s i n c e t h e m e l t i n g p o i n t s r e p o r t e d a r e completely d i f f e r e n t . 9.
THE m-MENTHANES
It was considered f o r a long time t h a t t h e only rn-menthane
138
The S y n t h e s i s of Monoterpenes
d e r i v a t i v e s encountered i n n a t u r e were a r t i f a c t s a r i s i n g from t h e a c i d - c a t a l y z e d r i n g opening of A3-carene v i a sylv e s t r e n e d i h y d r o c h l o r i d e (388). N e v e r t h e l e s s , Bardyshev e t a l . have i s o l a t e d in-menthenol (389) from t h e high b o i l i n g f r a c t i o n of Russian t ~ r p e n t i n e ~ ~ - a d m i t t e one d l y t h a t contains A3-carene. However t h i s may b e , t h e s y n t h e s i s of t h i s type of compound i s g e n e r a l l y from s y l v e s t r e n e . For example, the d i h y d r o c h l o r i d e (cis + t r a n s , 388) , on t r e a t m e n t w i t h s o a p , w a t e r , and steam, y i e l d s 30.7% of hydrocarbons, and 22.5% of m-menth-1-en-8-01 (390) 36% of which is " n a t u r a l " (+I -m-menth5-en-8-01 ( 3 8 9 ) , f o r m e r l y known a s " s y l v e t e r p i n e o l " ) . 4 5 4
(2)
a
-
cis- + trans-
164 -
388 -
(-)
10. A.
-390
(+)
-389
1,1,2,3-TETR?METHYLCYCLOHEXANES Safranal
(391)
l-Formyl-2,6,6-trimethylcyclohexa-1,3-diene ( s a f r a n a l , 391) i s a breakdown p r o d u c t of t h e b i t t e r p r i n c i p l e o f s a f r a n , and can be considered a s being r e l a t e d e i t h e r t o t h e ionones, where t h e s i d e chain h a s been l o s t , o r t o t h e monoterpenes a s a dehydrogenated c y c l o c i t r a l . Indeed, i t s s y n t h e s i s i s g e n e r a l l y from B - c y c l o c i t r a l (392) by o x i d a t i o n with selenium d i o x i d e 4 5 5 or N-bromosuc~inirnid~~
The 0-Menthanes
392 -
Sa f r a n a l 391 -
139
393 -
(393) has been i s o l a t e d from a s p e c i e s of Mexican compositae, P i q u e r i a trinervia , Cav. ,457 b u t no synt h e s i s i s reported. An e t h o x y s a f r a n a l
B.
(394)
Karahana Ether
This substance (3941, i s o l a t e d from Japanese hops ("Shinshuwase") ,458 can be considered a s a 2,2,6-trimethylbenzyl der i v a t i v e , although i t i s a t t h e same t i m e a t e t r a h y d r o f u r a n . I t has been synthesized by Coates and Melvin from g e r a n i o l , t h e a c e t a t e of which was f i r s t c y c l i z e d with benzoyl peroxide, c u p r i c benzoate, and c u p r i c c h l o r i d e i n a c e t o n i t r i l e following t h e technique of Breslow e t a 1 . 4 5 9 The r e s u l t i n g mixture was hydrolyzed t o t h e corresponding d i o l s , from which t h e d e s i r e d c i s - d i o l (395) was s e p a r a t e d by c a r e f u l chromatography. Rea c t i o n of t h i s d i o l w i t h one e q u i v a l e n t of p-toluenesulfonyl c h l o r i d e i n p y r i d i n e a t room temperature y i e l d e d racemic karahana e t h e r . Coates and Melvin suggest t h a t t h i s may a l s o r e p r e s e n t t h e b i o e n e t i c pathway f o r t h e formation of n a t u r a l karahana e t h e r . 46?
1. CU++, 2.
OH-
BZ perox. HO
&I+
0
395
Karahana Ether 394 -
11.
THE 0-MENTHANES
Although a number of o-menthane d e r i v a t i v e s have been i s o l a t e d as n a t u r a l p r o d u c t s , 4 5 7 , 4 6 1 * 4 6 2none of t h e s e has been synthesized. Entry t o c e r t a i n o-menthatrienes i s p o s s i b l e by
140
The S y n t h e s i s of Monoterpenes
p y r o l y s i s of verbenene. 4 6 3 12.
CYCLOHEPTANES
T h u j i c Acid ( 3 9 6 ) , Shonanic Acid and Karahanaenone(399)
A.
(397), Eucarvone (398),
These compounds a r e d e r i v a t i v e s of 1,1,4-trimethylhepta-2,4,6t r i e n e , and u n t i l r e l a t i v e l y r e c e n t l y , t h e r e was a l i n g e r i n g doubt a s t o t h e i r s t r u c t u r e , l a r g e l y owing t o c e r t a i n of t h e i r r e a c t i o n s t h a t c o u l d b e a s s o c i a t e d w i t h d e r i v a t i v e s of b i c y c l o [ 4 . l . O ] h e p t a n e s ( c a r e n e s ) . The d o u b t s were f i n a l l y res o l v e d i n t h e c a s e of t h u j i c a c i d (=) by measurement of t h e NMR s p e c t r u m 4 6 4 and t h e c r y s t a l s t r u c t u r e o f t h e p-bromophena c y l e s t e r . 4 6 5 T h u j i c a c i d o c c u r s i n t h e wood o i l s of v a r i o u s Thuja and o t h e r s p e c i e s , i n c l u d i n g Libocedrus formosana i n which i t i s accompanied by a reduced ( c a l l e d shonanic a c i d when i t w a s f i r s t i s o l a t e d , 4 6 7 t h e c y c l o h e p t a d i e n e s t r u c t u r e of which w a s a t t r i b u t e d f i r s t by E r d t ~ n a n . ~ ~Although * t h e r e a p p e a r s t o be no t o t a l s y n t h e s i s o f t h u j i c a c i d , i t s r e l a t i o n t o s h o n a n i c a c i d h a s been d i s c u s s e d by P a s t o , who showed t h a t the r e d u c t i o n of t h u j i c a c i d g i v e s i n i t i a l l y a dihydrocompound t h a t i s r e a r r a n g e d by base t o a m i x t u r e of t h r e e f u r t h e r a c i d s (401a, 40lb, and 401c) , none of which i s i d e n t i c a l t o shonanic a c i d .
(z),
-
COOH
COOH
I
I
400 -
396 -
401a -
T h u j i c Acid
1. H B r 2. KOH/EtOH
401b -
CB
Cycloheptanes
Q
141
COOH
39 7 -
398 -
Shonanic Acid
Eucarvone
401c -
Eucarvone (398) was r e p o r t e d i n t h e o l d e r l i t e r a t u r e t o occur i n Asurum Sieboldii, v a r . ~ e o u l e n s i s ,b~u t~ ~t h i s i s t h e o n l y r e p o r t of i t s occurrence a s a n a t u r a l product. I t i s n e v e r t h e l e s s r e a d i l y a v a i l a b l e by t h e s y n t h e s i s of Bayer from carvone (281),470 and a s t u d y of i t s v a r i o u s r e a c t i o n s ? i n c l u d i n g a c o n s i d e r a t i o n of i t s r e l a t i o n s h i p w i t h t h e carane d e r i v a t i v e s ? h a s been given by Corey and Burke.471 The t o t a l s y n t h e s i s of eucarvone h a s been c a r r i e d o u t by Barnes and Houlihan (Scheme 5 0 ) , who o b t a i n e d an a p p r e c i a b l e amount of c a r v a c r o l i n t h e l a s t dehydrobromination s t a g e . 4 7 2 Eucarvone is a l s o o b t a i n e d i n low y i e l d by dehydration of 2-hydroxyisopinocamphone (402)
.
Scheme 50
1. B r 2 2. Lutidine
N- B r omo-
succinimi.de
1
The S y n t h e s i s of Monoterpenes
142
I -HBr
(very easy)
/ @OH
Br
278 -
398 -
4
Karahanaenone ( 2 , 2 , 5 - t r i m e t h y l c clohept-4-enone, 399) was i s o l a t e d from hop o i l i n 1 9 6 8 , ~ ~and ’ i t s synthesis followed s h o r t l y a f t e r w a r d s by Demole and E n g g i s t , who t r e a t e d l i n a l o o l (6) w i t h N-bromosuccinimide, when they o b t a i n e d t h e f u r a n (403) t h a t on r e f l u x i n g i n c o l l i d i n e l o s t hydrogen bromide. The i n t e r m e d i a t e (404) was n o t i s o l a t e d , b u t conv e r t e d d i r e c t l y by h e a t t o karahanaenone A full d e s c r i p t i o n of t h i s s y n t h e s i s h a s a l s o appeared.475
(z).474
-6
Q
0
399 -
403 -
1I
Reflux collidine
1
a P
404 -
Karahanaenone Gas phase p y r o l y s i s o f pulegone epoxide g i v e s 2,2,5t r i m e t h y l c y c l o h e p t a - 1 ,3-dione , 76 b u t t h i s approach h a s n o t been used t o make any n a t u r a l p r o d u c t s .
Cycloheptanes B.
143
Nezukone and The T h u j a p l i c i n s
These compounds a r e n o t i s o p r e n o i d , b u t can c l e a r l y be d e r i v e d
from t h e isopropylbicyclo[3.1.Olhexane system of t h e t h u j a n e s o r t h e bicyclo[4.1.0]heptane system of t h e caranes (see below).
Nezukone (405) i s , i n f a c t , found i n t h e Japanese nezuko t r e e ( T h u j a s t a n d i s h i i ) t o g e t h e r with a- and $ - t h u j a p l i c i n and 406b) . 4 7 7 Syntheses of t h e s e molecules are n o t numerous, b u t Birch has made nezukone from t h e sodium i n ammonia r e d u c t i o n (407) product of p - i s o p r o p y l a n i s o l e , u s i n g a d d i t i o n of d i c h l o r o then t r e a t m e n t with s i l v e r b o r o f l u o r i d e t o carbene ( t o 4&) g i v e t h e product (405).478 The t r o p o l o n e s a r e n o t conveni e n t l y t r e a t e d i n a c h a p t e r on monoterpene s y n t h e s i s , b u t i t might be mentioned t h a t a - t h u j a p l i c i n (B) has been synt h e s i z e d by t e r Borg e t a l . from 2-chlorotropone (409) by rea c t i o n of isopropylmagnesiumbromide , followed by h e a t . 4 7 9
(s
-
-
c1
c1
c12c :
407 -
408 -
1
I
1. 2 equiv. >-MgBr -70° 2. H 2 0
405
Nezukone
H O @
+
1
heat
-
406b -
f3 Thuj ap li c i n
(Hinokit i o 1)
The Synthesis of Monoterpenes
144
406a -
a-Thujaplicin BICYCLO [ 3 . 2 . 0 ] HEPTANES
13.
A.
Filifolone
2,6,6-Trimethylbicyclo[3.2.0]hept-2-en-7-one (filifolone, 2) is the only naturally occurring representative of this class of compound. It occurs in the (+)-form in the Australian plant Zieria srni t h i i , and as the (-)-form in Artemisid f i l i folia (from Arizona) ,480 and the racemate has been synthesized by B e e r e b o ~ m ~from ~ ~ geranic t ~ ~ ~ acid (304).
+ NaOAc
reflux 16 hr 26%
5% 304 -
410 28%
Filifolone It might have been thought that filifolone
(2) could
b e made by the cycloaddition of dimethylketene (411) to methylcyclopentadiene which exists as a rapidly equilibrating 2- (412b), and 5-methyl (%) mixture of the 1- (%),
-
Bicyclo[3.l.O]hexanes
145
isomer^.^^^,^^^ Huber and Dreiding have shown, however, that this reaction leads mainly to the isomeric bicyclo [ 3.2 .O] heptenone together with a second isomer (414) and small amounts of unidentified byproducts .485 Filifolone is obtained from chrysanthenone (see bicyclo[3.l.l]heptanes below) by the action of acetic acid.485a
(s),
0
OCH3 Q 412a -
CH3
+
412b -
::
CH 3
411 -
CH3
CH3 414 -
14. BICYCLO[3.1.O]HEXANES
Po 9*
This class of compounds includes sabinene, 2-thujene, umbellulone, and related substances. The parent hydrocarbon, 1isopropyl-4-methylbicyclo-[3.l.0]hexane (415) is called thujane, both stereoisomers of which can be made by carbene addition to pulegene (416)486 accessible from pulegone (=) via a Favorskii rearrangement.2531 4 8 7
~
__c
307 -
(+) -Pulegone
“COOH
Pulegenic Acid
__c
416 Pulegene
:CH2
146
The S y n t h e s i s o f Monoterpenes
415b -
415a -
trans
cis Thu j a n e s
There are n o t many s a t i s f a c t o r y s y n t h e s e s o f this c l a s s of compound. One o f t h e e a r l i e s t , i n v o l v i n g supposed1 t h e d i b r o m i n a t i o n of menthone (338) and r e a c t i o n w i t h zincf8' h a s been shown489 r 4 9 0 t o l e a d o n l y t o 4-oxygenated menthones The f i r s t t o t a l s y n t h e s i s of t h e n a t u r a l p r o d u c t s i s F a n t a and E m a n ' s s y n t h e s i s of s a b i n e n e (233)and s a b i n a k e t o n e b u t a l l other members of t h e s e r i e s e x c e p t s a b i n o l (419) a r e a c c e s s i b l e from t h e s e compounds (see Scheme 5 1 ) .
(c).
(s),491
P 338 -
k
Scheme 51
o$
24 %1 N / 2a OhH r/ E treufl$ O :H
O\
I
LiAlH4
Bicyclo[3.1.0]hexanes
147 OH
420a cis-
Sabinene
420b -
trans-
Hydrates
4
233 Sabinene
SabinXtone
I
-
\\\\ Na/NH3
423
cisSabin01 (not naturally occurring)
/-
2 - T422 mene
-
426 Salvan
&
3-Tgene
n 419 S A G 1
1
148
The S y n t h e s i s of Monoterpenes
A second s a b i n e n e s y n t h e s i s h a s been d e s c r i b e d b y Vig e t a l . f 4 9 2 and almost s i m u l t a n e o u s l y Mori e t a l . made s a b i n a k e t o n e by t h e same method.493 The k e t o n e (418) i s made by copper c a t a l y z e d r i n g c l o s u r e of t h e a p p r o p r i a t e d i a z o k e t o n e , and s a b i n e n e i s made i n t h e same way as Erman‘s s y n t h e s i s using the Wittig reaction:
(em,
Thus t h e s a b i n e n e h y d r a t e s and both n a t u r a l l y o c c u r r i n g ) a r e o b t a i n e d by t h e r e a c t i o n o f methyl l i t h i u m o r methylmagnesium i o d i d e on s a b i n a k e t o n e .494 I n t h i s r e a c t i o n , t h e trans-compound (*) predominates , b u t t h e cis-hydrate forms a l a r g e r p r o p o r t i o n of t h e m i x t u r e o b t a i n e d from s a b i n e n e (233)by t h e oxymercuration-demercuration proced ~ r e .2-Thujene ~ ~ ~ i s accessible from s a b i n e n e u s i n g acid c a t a l y s i s ( i . e . , w i t h i o n exchange r e s i n s 4 9 6 ) o r base c a t a l y sis ( p o t a s s i u m t - b u t o x i d e 4 ” ) Hydroboration t e c h n i q u e s make the naturally occurring thujones and -) acces~ i b l i 4e9 ’ ~ from ~ ~2 - t h u j e n e (422), from which p h o t o - o x i d a t i o n y i e l d s t r a n s - s a b i n e n e h y d r a t e as the major p r o d u c t a f t e r red u c t i o n of t h e d o u b l e bond of t h e a l c o h o l (423) produced a f t e r b i s u l f i t e r e d u c t i o n o f t h e h y d r o p e r o x i d e . 486,ur8 Chromic a c i d o x i d a t i o n of t h i s same u n s a t u r a t e d a l c o h o l (423) leads t o umbellulone t h e main c o n s t i t u e n t of t h e mountain l a u r e l , Umbellularia c a l i f ~ r n i c a . ~ 3-Thujene ~ ~ (425) i s n o t c e r t a i n l y n a t u r a l l y o c c u r r i n g , b u t h a s been p r e p a r e d i n two l a b o r a t o r i e s from t h u j o n e p-toluenesulfonylhydrazone .499 r 5 0 0 F i n a l l y , t h e h y d r o c a r b o n , 2-methyl-3-methylenehept-5-ene (426, “ s a l v a n “ ) , i s o l a t e d from v a r i o u s S a l v i a s p e c i e s , 5 0 1 1 5 0 2 and b e l i e v e d a t f i r s t t o b e t h u j a n e b u t shown by B r i e s k o r n and c a n be made from t h u j o n e by D a l f e r t h t o be as shown (426), photochemical d e c a r b o n y l a t i o n . and i t s a c e t a t e ( b o t h ocAlthough t r a n s - s a b i n o l c u r r i n g i n Juniperus s a b i n a , “ s a v i n o i l “ ) are c o n v e r t e d b y sodium i n l i q u i d ammonia r e d u c t i o n t o 2 - t h u j e n e , 4 8 6 r 5 0 5 there i s no method y e t known o f l i n k i n g s a b i n o l s y n t h e t i c a l l y w i t h t h e o t h e r n a t u r a l l y o c c u r r i n g members o f t h e group. I n view of t h e f a c t t h a t s a v i n o i l i s no l o n g e r an a r t i c l e o f commerce, t h e r e would seem t o be a need f o r a s y n t h e s i s of t h i s alcohol.
(a)
.
(a
(z),
(2)
Bicyclo[2.2.l]heptanes 15.
149
BICYCLO[2.2.1]HEPTANES
Among i t s n a t u r a l l y occurring members, t h i s group of compounds i n c l u d e s norbornanes with t h e following methyl s u b s t i t u t i o n s : 2,2,3-(camphene, 427) , 1 , 7 , 7 - ( b o r n e o l s , camphor, 224, e t c . ) , 1 , 3 , 3 - , 2,5,5-, and 2,7,7- (fenchane d e r i v a t i v e s ) , b u t synt h e s e s of r e c e n t d a t e a r e t o o r a r e t o warrant s u b d i v i s i o n of t h e s e c t i o n . This was n o t always t h e c a s e , however, and i n t h e days when t h e s t r u c t u r e of camphor was s t i l l of v i t a l importance (one might r e c a l l t h a t B r e d t ' s r u l e d a t e s from t h i s t i m e ) , it was h a r d l y p o s s i b l e t o open a volume of L i e b i g ' s Annalen without f i n d i n g some attempt a t some p a r t i a l s t r u c t u r e of t h e s e r i e s . Today, t h e emphasis has passed t o mecha n i s t i c s t u d i e s , although even here t h e unique rearrangements a s s o c i a t e d with t h e bicyclo[2.2.1]heptane s t r u c t u r e a r e h i s t o r i c a l l y f i r m l y anchored t o t h e f a s c i n a t i n g and f r e q u e n t l y i n e x p l i c a b l e f a c t s t h a t t h e chemists of t h e l a t e nineteenth century were discovering. An a d d i t i o n a l spur t o work i n t h i s group of compounds was always t h e unique p r o p e r t i e s of camphor, a compound known from t h e dawn of c i v i l i z a t i o n by t h e odor it imparted t o woods and o i l s t h a t contained i t , and l a t e r because of t h e abnormally high cryoscopic constant r e s p o n s i b l e f o r t h e e x c e p t i o n a l p r o p e r t i e s observed when physic a l measurements became fashionable a s new instrumentation was developed.* The f i r s t t o t a l s y n t h e s i s of t h e group was t h e c e l e b r a t e d one of camphor by Komppa507,508 and, a p a r t from h i s t o r i c a l i n t e r e s t , t h e r e was a small p o i n t t h a t remained unresolved u n t i l r e c e n t l y , namely, t h e e x a c t s t r u c t u r e of t h e product t h a t Komppa claimed t o have obtained from compound 428, and which he wrote a s 429. This a s p e c t was r e c e n t l y examined by Agharomurthy and L e w i s , 5 0 9 who found t h a t Komppa's s u p p o s i t i o n of a C-methylated r a t h e r than an 0-methylated compound was c o r r e c t (although both 428 and 429 a r e , i n f a c t , e n t i r e l y i n t h e enol form--a f a c t t h a t Komppa c e r t a i n l y susp e c t e d ) , and t h e r e f o r e t h a t t h e camphor s y n t h e s i s , which depends on p r e c i s e l y t h i s p o i n t , is q u i t e c o r r e c t .
-
*One might s t i l l make a case o u t f o r t r y i n g camphor i n any new p h y s i c a l technique--the use of s o l v e n t dependenc of NMR chemi c a l s h i f t s was f i r s t demonstrated w i t h camphorlZo6 because it i s a very r e a d i l y a v a i l a b l e r i g i d molecule having s t e r i c a l l y well-defined s u b s t i t u e n t s i n f i x e d p o s i t i o n s from carbonyl group.
150
The S y n t h e s i s o f Monoterpenes
Methylate
H $3;
@3
-
1
0
COOCH 3
COOCH 3
COOCH I 3
‘COOCH3
The more r e c e n t s y n t h e s e s o f b i c y c l o [ 2 . 2 . 1 ] h e p t a n e s u s e t h e D i e l s - A l d e r r e a c t i o n most f r e q u e n t l y , and have as t h e i r a n c e s t o r , so f a r as n a t u r a l p r o d u c t s are c o n c e r n e d , t h e synfrom 1,1,2t h e s i s o f b o r n y l a c e t a t e (430) and camphor trimethylcyclopentadiene (431) and v i n y l acetate followed by reduction. Epicamphor (432) is a l s o o b t a i n e d from t h i s rea c t i o n . 510
(224)
2. Hydrolyse 3. Oxidize
-
+
2 24 -
4 30 Bornyl Acetate
4 31 -
2. Hydrolyse 3. O x i d i z e U
bAc 432 -
Bicyclo [ 2.2.11 heptanes
151
Similar techniques (Scheme 52) were used by Vaughan and Scheme 52
COCH 3
COCH 3
(tendo)
b0 & &
c.HC1
436 -
+~III;II~~~
4 35 CH3MgI
HzNH2
!OH
4 34 Resolved with (+)-tartaric acid
433
_ .
-& Ester
Camphene 427 -
2CONH2
152
The S y n t h e s i s of Monoterpenes
The Perry i n o r d e r t o make o p t i c a l l y a c t i v e ~ a m p h e n e . ~ ~ acetamide ( 4 3 3 ) , o b t a i n e d by t h e r o u t e shown (Scheme 5 2 ) was r e s i s t a n t t o a c i d h y d r o l y s i s , b u t potassium hydroxide conv e r t e d it t o camphenylamine (=) t h a t was r e s o l v e d with ( + ) t a r t a r i c a c i d . Using t h e Sommelet r e a c t i o n (hexamine and formaldehyde), o p t i c a l l y a c t i v e camphenilone (435) was obt a i n e d . A f t e r a Grignard r e a c t i o n , t h e a l c o h o l was converted t o an e s t e r f o r p y r o l y s i s . Vaughan and P e r r y used p y r o l y s i s of t h e x a n t h a t e , b u t when they used t h e same means t o p r e p a r e 3C-labeled camphene, Friedman and Wolfs1‘ p r e f e r r e d t o use Roberts and Yancey ’ s benzoate p y r o l y s i s method ,5 1 s i n c e t h e y found t h e r e were l e s s t r a c e s of u n d e s i r a b l e i m p u r i t i e s i n the product ( x a n t h a t e p y r o l y s i s l e a v e s some s u l f u r i n t h e camphene) A small p o i n t a r i s e s i n connection w i t h i n i t i a l DielsAlder r e a c t i o n between m e s i t y l oxide (311)and cyclopentad i e n e . Vaughan and P e r r y s u posed t h a t t h e endo-ketone (436) was t h e p r i n c i p a l product,51e b u t it h a s l a t e r been shown t h a t a c t u a l l y 60% of t h e product i s This does n o t a f f e c t t h e s y n t h e s i s , of c o u r s e , s i n c e t h e carbon a t t h i s p o s i t i o n becomes t r i g o n a l a t t h e camphenilone s t a g e , b u t it m a k e s t h e a t t r i b u t i o n of e n d o - s t r u c t u r e s t o t h e i n t e r m e d i a t e s ( a s Vaughan and Perry d i d * ” ) very d o u b t f u l . A recent s y n t h e s i s of camphor i s i n t e r e s t i n g i n t h a t i t p u r p o r t s t o follow a p o s s i b l e b i o g e n e t i c r o u t e . F a i r l i e e t a l . converted (+)-dihydrocarvone [(+)-*I t o a mixture of i t s e n o l a c e t a t e s (Eand and found t h a t t r e a t m e n t of one of them (-) with boron t r i f l u o r i d e i n methylene c h l o r i d e gave camphor (224) i n h i g h y i e l d , b u t unexpectedly, it was racemic. The o t h e r e n o l a c e t a t e g i v e s carvenone (295) under t h e s e c o n d i t i o n s .
-
.
e),
5 -
( + ) -2 9 4
(e)
___c
P/O
A
4 37a -
c
iBF3
+
A
&OAC
4 37b -
Bicyclo L2.2. l l h e p t a n e s
153
Camphor i s produced on a very l a r g e s c a l e commercially, b u t using pinene as s t a r t i n g m a t e r i a l , t h a t i s , it i s once again only a p a r t i a l s y n t h e s i s . The r o u t e followed517 (Scheme 53) i s g e n e r a l l y u s i n g t h e Wagner-Meerwein rearrangement, Scheme 53 P o s s i b l e I n d u s t r i a l Routes t o Camphor
427 -
440 -
(s),
4 39 -
Tricyclene
which l o s e s hydrogen o r i g i n a l l y t o bornyl c h l o r i d e c h l o r i d e t o g i v e camphene (427). The l a t t e r can be converted v i a an i s o b o r n y l e s t e r t o camphor. There are many modificat i o n s of t h i s r o u t e ; one o f t h e o l d e s t i s perhaps t h e d i r e c t c a t a l y t i c conversion of pinene t o camphene. This was f i r s t
154
The S y n t h e s i s of Monoterpenes
d e s c r i b e d by Tishchenko and Rudakov i n 1933,518 b u t similar work h a s c o n t i n u e d , e s p e c i a l l y i n R u s s i a , r i g h t up t o t h e p r e s e n t ( s e e , f o r example, a r e c e n t l y u b l i s h e d p a t e n t t h a t u s e s t i t a n i u m d i o x i d e as t h e There a r e a l s o v a r i a n t s i n t h e camphene t o camphor s t a g e , f o r example, camphene ( o r t r i c y c l e n e , w i t h which “ s y n t h e t i c ” camphene i s u s u a l l y contaminated t o t h e e x t e n t of 10-20%) can be converted t o 2-methoxybornane (440) by methanol i n t h e p r e s e n c e of a methanol-wetted s t r o n g c a t i o n exchange r e s i n i n t h e H-form a t 60°, and 2-methoxybornane can be o x i d i z e d t o camphor by a mixture of n i t r o g e n d i o x i d e and oxygen a t 10°-150. 5 2 0 The f i r s t t o t a l s y n t h e s i s of fenchone (299) was t h a t o f R u ~ i c k a , ” ~b u t s i n c e 1935 , when Komppa and K l a m i p u b l i s h e d an improved method, 5 2 2 t h e r e has been no f u r t h e r s y n t h e t i c work c a r r i e d o u t . a-Fenchol (4411, t h e main p r o d u c t from t h e metal h y d r i d e S 2 and m e t a l - a r r o n ~ n i a r~e~d ~u c t i o n s of fenchol* i s , t o g e t h e r w i t h i t s a c e t a t e , a l s o a widely d i s t r i b u t e d natur a l p r o d u c t , and i s u s u a l l y o b t a i n e d i n small amounts d u r i n g manipulations of a-pinene t h a t i n v o l v e a c i d s ( i n a d d i t i o n t o Ref. 289, quoted above, s e e a l s o Valkanas and I c o n o r n o ~ i~ ~ ~ ) even s u l f u r d i o x i d e i s s u f f i c i e n t t o cause a s m a l l amount of isomerization. Cyclofenchene i s one of t h e p r o d u c t s formed i n t r a c e s when a-pinene i s i r r a d i a t e d i n u l t r a v i o l e t l i g h t . 5 2 7
=,
Fenchone
16.
a-Fenchol
BICYCLO[3.1.1]HEPTANES
Of a l l t h e groups of monoterpenes t h a t have been l i s t e d i n t h i s c h a p t e r , t h i s i s c e r t a i n l y t h e one i n which t h e d i f f e r e n c e between a v a i l a b i l i t y a s n a t u r a l p r o d u c t s and a s synt h e t i c p r o d u c t s i s t h e g r e a t e s t . a-Pinene (17) i s probably t h e most common of t h e monoterpene hydrocarbons, y e t it has never been s y n t h e s i z e d d i r e c t l y . $-Pinene was synthe, s i z e d o n l y r e l a t i v e l y r e c e n t l y by i r r a d i a t i o n of myrcene (2)
(14)
*But n o t aluminum i s o p r o p y l a t e r e d u c t i o n which l e a d s t o t h e o t h e r isomer. 5 2 4
BicycloI3.1.1]heptanes
155
(g),
which Crowley found t o product mainly t h e cyclobutene B-pinene being formed i n only 10%y i e l d 5 2 8 1 5 2 9 ( t h e s e n s i t i z e d i r r a d i a t i o n of myrcene follows a d i f f e r e n t p a t h 5 3 0 ) . This n e v e r t h e l e s s r e p r e s e n t s a t o t a l s y n t h e s i s of t h e whole group of compounds, s i n c e they a r e a l l a v a i l a b l e from B-pinene or a-pinene, which can be made from 6-pinene by l i t h i u m i n e t h y l by t h e a c t i o n of i r o n pentacarbonyl ( t h e e n e d i a m i x ~ e ; ~or~ ~ l a t t e r g i v e s a 97% o t i c a l y i e l d of (-)-a-pinene, I&, from 532 (-)+-pinenel &).
hv
A
+
14
( st e r e o z e m i s t r y undefined )
14a -
li
12 -
442 -
17a
_.
A c t u a l l y , most monoterpene s y n t h e s i s s t a r t i n g from t h e pineries* r e q u i r e t h e s l i g h t l y l e s s common B-pinene, and t h i s i s a l s o o b t a i n a b l e from a-pinene by hydroboration and p y r o l y s i s of t h e organoborane. 534 A b r i e f summary of r e a c t i o n s l e a d i n g from t h e pinenes t o
o t h e r members of t h e pinane group t h a t a r e n a t u r a l l y occurring i s given below i n Scheme 54. The l e a d t e t r a a c e t a t e r e a c t i o n from a-pinene p a s s e s through t h e s t a g e of t h e 2-acetate (443) l e a d i n q f i n a l l y t o trans-verbenyl a c e t a t e (444).534a From t h e l a t t e r compound, verbenone (445) and cis-verbenol (446) are o b t a i n a b l e . The s t e r e o c h e m i s t r y of t h e s e compounds i s f a i r l y e v i d e n t from t h e r e a c t i o n s involved, and has been taken as a matter of course i n most l a b o r a t o r i e s concerned w i t h monoterpenes, b u t t h i s h a s n o t prevented s e v e r a l d e t a i l e d d i s c u s s i o n s of t h e s t e r e o c h e m i s t r y of cis- and t r a n s verbenol d e r i v a t i v e s from appearing i n r e c e n t y e a r s ( s e e , e.g., Ref. 93, 535-537).
(17)
_ I
*For a review of t h e various o t h e r monoterpenes a v a i l a b l e from t h e pinenes, s e e Ref. 533.
156
The Synthesis of Monoterpenes Scheme 54
448 PinocGhones 449 1. NaOAc 2. Hydrolyse 3' mo2
6'
reduce
44 3 -
Pinocampheols*
34 7 Myxnal
447 ChryGthenone
450 trans-Gbenol
445 VerGone
\
1-
452
$
OH
451 trans-Pinecarveol
444 -
446
cis - v x e n ol
*For a full description of the structures and s ectra of the different pinocampheol isomers, see Teisseire. 5%
Bicyclo[4.1.O]heptanes
157
Hurst and Whitham have shown how verbenone is converted i n t o cyrhsanthenone (447) by u l t r a v i o l e t i r r a d i a t i o n , 38 t h e y i e l d of which can reach 67%.539 The n a t u r a l l y occurring pinocamphones (448) can be prepared from a-pinene epoxide by conventional r i n g opening r e a c t i o n s of epoxides. 540 542 The r e a c t i o n of B-pinene with N-bromosuccinimide y i e l d s t h e 7brominated a-pinene d e r i v a t i v e (449) t h a t can be converted i n t o myrtenal (347) 543 The r a d i c a l o x i d a t i o n of a-pinene with t - b u t y l perbenzoate i n t h e presence of cuprous bromide y i e l d s 30% of a l c o h o l s , 30% of t h i s mixture being t r a n s verbenol (450) and 19% trans-pinocarveol (=);544 b u t one of t h e most e f f e c t i v e methods f o r making trans-pinocarveol (451, t h a t occurs n a t u r a l l y i n t h e e s s e n t i a l o i l of camomile545) i s by s e n s i t i z e d photoxygenation of a-pinene, 546 which l e a d s t o 95% trans-pinocarveyl hydroperoxide (452) and 0.56 cis-pin-3ene 2-hydroperoxide. 547
.
17.
BICYCLO[4.1.O]HEPTANES
The most important n a t u r a l product of t h i s group i s A3-carene (=), t h e main c o n s t i t u e n t of some t e r p e n t i n e s , notably from Eastern Europe and I n d i a (Pinus l o n g i f o l i a , from Indian Chir t r e e s ) . Since t h i s i s r e a d i l y a c c e s s i b l e , most work i n t h i s group has been t h a t of conversion of A3-carene t o some o t h e r more u s e f u l compound, b u t t h e r e a r e a few syntheses of t h e s k e l e t o n t h a t w i l l be b r i e f l y mentioned here. A2-Carene (453) a l s o occurs n a t u r a l l y , and t h e two carenes a r e i n t e r c o n v e r t i b l e with ethylenediaminolithium;* Ohloff e t a l . found t h a t t h e a c i d catalyzed isomerizations r e p o r t e d e a r l i e r were e r r o n i o ~ s . Most ~ ~ ~of t h e syntheses of t h e s t r u c t u r e use an o l d r e a c t i o n of Kishner, who found t h a t pulegone (307) can be converted t o t h e imidazoline (454) with hydrazine, then h e a t i n t h e presence of b a s e , and copper s u l f a t e converts t h i s t o trans-carane 5 5 1 The same r e a c t i o n c a r r i e d o u t on p i p e r i t e n o n e (305) r e s u l t s i n t h e synt h e s i s of ( 5 )-A2-carene (453) 5 5 2 Although n o t a n a t u r a l product, caran-2-one i s r e a d i l y synthesized from dihydrocarvone hydrobromide with a l c o h o l i c potassium hydroxide ,5 5 and has a l s o been made more r e c e n t l y by t o t a l s y n t h e s i s from 4methylpent-3-enyl bromide (456) following Scheme 55. 554
(c).550
.
*This i s o m e r i z a t i o n a l s o occurs under hydrogenation condit i o n s . s49
*q 5
9
8
164 -
305 -
453 -
~~-carene t
454 -
307 -
455 -
S c h e m e 55
I
456 -
COOEt
-
COOEt COOEt 3 .
COOH
___c
1.
soc12
2 . CH2N2
KOH / a 1coho1
____c
+ some
158
Furan Monoterpenes 18. A.
159
FURAN MONOTERPENES 3-Methyl-2-substituted and 3-Substituted Furans
Apart from the menthofuran derivatives (see above), the following furan monoterpenes with a 3-substituent occur in nature (the reference given under each formula refers to the correct structural identification of the compound):
457 -
458 -
Elsholtzione55 5 (Elsholt z i a c r i s t a t a ) and others
Naginata Ketone556r557 Perilla frutescens, & Elsholtzia cristata
459 -
Rose F ~ r a n ~ ~ * Rose o i l
460 -
~erillene56" Perilla frutescens and elsewhere
461 -
Elsholt~idiol~ 59 Elsholzia densa (synthesis not yet reported)
Perilla Ketone561 P . frutescens
462 -
Egomaketone5 P . frutescens (synthesis not yet reported)
160
The S y n t h e s i s of Monoterpenes 0
463 -
464 -
1soegornaketone~6 P. frutescens
B a t a t i c Acid564
The e a r l i e s t s y n t h e s i s i n t h e g r o u p i s t h a t of R e i c h s t e i n e t al., who made e l s h o l t z i o n e by c o n v e r t i n g 3-methylfuran (465) t o t h e 2-formyl compound (466) w i t h hydrogen c y a n i d e , t h e n d e h y d r a t i n g t h e oxime of t h i s w i t h a c e t i c a n h y d r i d e and thereby c a r r y i n g o u t a G r i g n a r d r e a c t i o n on t h e n i t r i l e o b t a i n i n g t h e s a t u r a t e d k e t o n e (457). 5 6 5 N a g i n a t a k e t o n e (458)
(s),
CH3
6457 -
467 -
-
CH 3 COCH 3 / N a H
468 -
1. N H 2 0 H 2 . AcgO
CH 3MgI
OH
0
Furan Monoterpenes
heat
457 -
1
161
'CH 3
469
458 -
t h a t had already been reduced t o e l s h o l t z i o n e (457) c a t a l y t i c a l l y , 5 5 6 r 5 5 7was synthesized very simply by Bilchi e t a l . , using t h e r e a c t i o n of 3-methyl-2-furoic e s t e r (468) with acetone i n t h e presence of sodium hydride, followed by r e a c t i o n with methyl magnesium i o d i d e and deh d r a t i o n by h e a t i n g t h e t e r BUchi's aim, however, was t i a r y a l c o h o l r e s u l t i n g (469).5'8 t o s y n t h e s i z e rose furan (4591, and reduction of t h e carbonyl group of n a g i n a t a ketone proved t o be an insuperable o b s t a c l e , s o f o r r o s e furan another s y n t h e s i s was c a r r i e d o u t . Merc u r a t i o n of 3-methylfuran and replacement of t h e mercuri c h l o r o group by l i t h i u m l e d t o 2 - l i t h i a t e d 3-methylfuran (G), t h a t could be r e a c t e d with p r e n y l bromide t o give r o s e furan (459). 5 5 8
-
4 70 -
I
4 59
The s t a r t i n g m a t e r i a l f o r t h e remaining f u r a n s l i s t e d above, t h a t a r e s u b s t i t u e d only i n t h e 3-positionI i s genera l l y a 3 - f u r o i c a c i d d e r i v a t i v e , and t h e r e i n l i e s one of t h e chief d i f f i c u l t i e s of s y n t h e s i s on any s c a l e above t h a t of t h e
162
The S y n t h e s i s of Monoterpenes
r e s e a r c h l a b o r a t o r y . The s y n t h e s e s u s u a l l y s t a r t with t h e p r e p a r a t i o n of 3 - f u r o i c a c i d (471) from t h e sodium d e r i v a t i v e of o x a l a c e t i c e s t e r (a comnercial p r o d u c t ) , b u t t h e s u c c e s s i v e s t e p s (bromination, c o n c e n t r a t e d s u l f u r i c a c i d t r e a t m e n t , h y d r o l y s i s of t h e f u r a n t e t r a c a r b o x y l i c t e t r a e t h y l e s t e r , and e s p e c i a l l y t h e f i n a l p y r o l y s i s , 5 6 6 i n which 3co2 a r e l o s t from a molecule t h a t l e a v e s o n l y 5 carbon atoms) make t h e y i e l d from above 1 kg of s t a r t i n g m a t e r i a l r a r e l y over 50g. A l though r e c e n t l y t h e r e have been two Diels-Alder r e a c t i o n s des c r i b e d t h a t l e a d t o f u r a n c a r b o x y l i c e s t e r s [one from methyl 2-furoate (472),567 and one from w i t h dimethyl butyne d i o a t e ( 4 7 3 ) ) ( s e e Scheme 561, t h a t a r e i n p r i n c i p a l converti b l e t o the 3 - s u b s t i t u t e d a c i d , 5 6 9 t h e c o s t s of p r e p a r i n g any q u a n t i t y of t h e a c i d f o r f u r t h e r s y n t h e t i c work a r e s t i l l r e l a t i v e l y high.
OR
Scheme 56
COOMe +
COOMe
looo
__c
473 -
&C0OMe
COOMe
i
H2
I
1. H C 1 2 . P y r o l y s i s over Cu-bronze
CCQH
Furan Monoterpenes
163
Once t h e acid has been obtained, t h e r o u t e s t o the v a r i For example, t h e s y n t h e s i s of p e r i l l e n e (460),5 7 0 involves h e a t i n g 3-furylmethanol (474) with 1-ethoxy-2-methylbutadiene i n t h e presence of mercuric a c e t a t e t o form t h e diene e t h e r ; t h e
ous 3 - s u b s t i t u t e d f u r a n s a r e r e l a t i v e l y s t r a i g h t f o r w a r d .
0
CH20H
1. L i A l H 4 2 . L i A l H 4 on
Tosylate 460 -
475 -
l a t t e r then rearranges i n a double Claisen-Cope r e a c t i o n t o y i e l d an aldehyde (475) t h a t can be converted, v i a l i t h i u m aluminum hydride reduction of t h e t o s y l a t e of t h e correspondi n g a l c o h o l , t o p e r i l l e n e (=). P e r i l l a ketone (=) was synthesized by MatsuuraS7’ a s follows: 3-furoyl c h l o r i d e (476) was allowed t o r e a c t with the organocadmium compound obtained from isopentylmagnesium h a l i d e (Scheme 5 7 ) :
164
The S y n t h e s i s of Monoterpenes Scheme 57
4 76 -
461 0
COCH2Br
477 -
6 HNMe 2
}
478 -
463
Isoegomaketone (Mannich r e a c t i o n )
I
COOEt
I COOEt
COOEt
COCH2CH2NMe2 CH3-C-
480 -
The c o r r e s p o n d i n g dehydro compound, isoegomaketone (463) was also made from 3 - f u r o i c a c i d . The l a t t e r was c o n v e r t e d t o 3 - a c e t y l f u r a n (477), which was t h e n brominated ( t o 478). The phosphorane, made from t h e bromide (478) and t r i p h e n y l p h o s p h i n e , was c o n v e r t e d by t h e W i t t i g r e a c t i o n t o isoegomaketone (463). 5 7 2 The i s o m e r , egomaketone ( E )d,o e s n o t appear t o
Furan Monoterpenes
165
have been s y n t h e s i z e d . The s y n t h e s i s of b a t a t i c a c i d (464) a l s o s t a r t s from 3a c e t y l f u r a n , which i s converted i n t o i t s Mannich b a s e (479) w i t h formaldehyde and dimethylamine, and t h i s base i s then condensed w i t h t h e sodium d e r i v a t i v e of d i e t h y l methylmalona t e , a f t e r which t h e u s u a l h y d r o l y s i s and p y r o l y s i s of t h e malonic e s t e r (480) l e a d s t o b a t a t i c a c i d (464) .568r573 B.
2 , 5 , 5 - S u b s t i t u t e d Tetrahydrofurans
“ L i n a l o o l o x i d e s ” have been known f o r many y e a r s t o occur i n c e r t a i n e s s e n t i a l o i l s , b u t t h e d e f i n i t e s t r u c t u r e was establ i s h e d o n l y i n 1963 by F e l i x e t a1.574 S i m i l a r r e s u l t s were published by Klein e t a ~ . ’ ~ ’ The former paper i n p a r t i c u l a r g i v e s a f u l l d i s c u s s i o n of t h e o x i d a t i o n products of l i n a l o o l o b t a i n e d by t h e r e a c t i o n with p e r a c i d s , and s u g g e s t s t h a t t h e name l i n a l o o l oxide be r e s e r v e d f o r t h e cis- and trans-isomers o f formula This p e r a c i d o x i d a t i o n l e a d s f i r s t t o a d i a s t e r e o m e r i c p a i r of u n s t a b l e 6,7-epoxides (482) t h a t a r e conv e r t e d by h e a t o r a c i d t o t h e l i n a l o o l o x i d e s (= and *). There i s a small amount of t h e corresponding tetrahydropyran d e r i v a t i v e s (483) formed a t t h e same time, L i n a l o o l oxide can a l s o be made from c i t r a l diepoxide (484)576 u s i n g t h e Wharton r e a c t i o n (hydrazine on an epoxyketon’eS77), o r from g e r a n y l a c e t a t e epoxide (485) with a c i d i n an i n e r t s o l v e n t . 5 7 8 Whether t h e n a t i v e product i n t h e p l a n t i s t h e i n i t i a l l y formed epoxide (482) o r t h e t e t r a h y d r o f u r a n (481) i s n o t c e r t a i n . I t h a s been maintained t h a t t h e compound i s n o t formed from t h e o x i d a t i o n o f l i n a l o o l by a i r , 5 7 9 b u t p r a c t i c a l l y a l l samples o f l i n a l o o l t h a t t h e a u t h o r has examined c o n t a i n t r a c e s of l i n a l o o l oxide ( c f . Ref. 580) , and Ohloff h a s i n d i c a t e d 5 8 1 t h a t whereas r o s e oxide o c c u r s i n t h e p l a n t a s a s i n g l e i s o m e r , l i n a l o o l oxide i s always p r e s e n t a s a mixture of cisand trans- forms. 2-(But-2-en-2-yl)-5,5-dimethyltetrahydrofuran (486) was i s o l a t e d by S t r i c k l e r and Kovsts from lime o i l , and i s formed by t r e a t m e n t o f l i n a l o o l (6) w i t h d i l u t e s u l f u r i c a c i d , t o g e t h e r w i t h t h e corresponding t e t r a h y d r o p y r a n (=) 582
*.
.
Peracid
-6 Acid
d i l . H2SO4
/Et
483
isomers)
19.
166
OXETONES
Tetrahydropyrans
167
-
0
H+
NaOEt
Heat
0
491 -
490 Although n o t s t r i c t l y monoterpenes, w e might i n c l u d e two s p i r o d i h y d r o f u r a n d e r i v a t i v e s (488 and 489) t h a t i s o l a t e d from hop o i l by Naya and Kotaka. The f u l l y genated d e r i v a t i v e (*) w a s s y n t h e s i z e d by r e a c t i o n e t h y l a t e on 4-methyl-4-hydroxy e n t e n o i c a c i d l a c t o n e followed by h e a t i n g w i t h a c i d . 3
P*
20.
TETRAHYDROPYRANS
h
CH2 COCH 3
487
I _
492 2-Acetonyl-Gethyltetrahydropyran
cis-
496a -
Rose Oxide
trans496b
-
here the have been hydroof sodium
(491)
168
The Synthesis of Monoterpenes
2,6,6-Trimethyl-2-vinyltetrahydropyran (487), isolated from lime oil and synthesized by the action of acid on l i n a l o 0 1 ~ ~ ~ has been treated in the last section. The nor-terpene, 2acetonyl-4-methyltetrahyd1opyran (4921, occurring in geranium oil, has been synthesized as the racemate from 4-methyldihydropyran (493)584 by the route shown585 (Scheme 58), further
Scheme 58
I
.
30b Ace tylate
t
\
494 -
p +p H2S04
I
A C H 2 0 A c
.i I
495 -
1. HC03H 2. Acetylate
AcO OAc
496a -
496b
CH3COCH2 497 -
CH3COCH3
492
Hexahydrobenzofuran-2-ones
169
r e a c t i o n of methylmagnesium i o d i d e and dehydration leading t o r o s e oxide.586 The l a t t e r substance, occurring i n both rose587 and geranium5B8 o i l s , i s , however, much more conveniently made b t h e s e n s i t i z e d photooxidation of ( - ) - c i t r o n e l l o 1 (30b) . 5 8 9 r 540 A f t e r r e d u c t i o n of t h e i n t e r m e d i a t e hydroperoxides, t h e mixture i s t r e a t e d with s u l f u r i c a c i d a t room temperature, under which c o n d i t i o n s t h e secondary a l c o h o l (494, 40% of t h e 60% of mixture) i s unchanged, while t h e t e r t i a r y a l c o h o l (2, t h e mixture) i s converted t o a 1:l mixture of n a t u r a l cis(496a) and t r a n s - (=) r o s e oxides. Other o x i d a t i v e techniques have been c a r r i e d o u t on c i t r o n e l l o l ; f o r i n s t a n c e , a c e t y l a t i n g t h e performic acid o x i d a t i o n product of c i t r o n e l l y l a c e t a t e y i e l d s a t r i a c e t a t e (497) t h a t can be converted by p y r o l y s i s and h y d r o l y s i s t o t h e d i e n e a l c o h o l (498). Treatment of t h e l a t t e r with 30% s u l f u r i c a c i d y i e l d s a 9 : l mixture of cis- and t r a n s - r o s e oxides.591
-
21.
HEXAHYDROBENZOFURAN-2-ONES
499
500
501
Act i n x o 1i d e
Dihydroaczidioli.de
LolTide
502
Ac t x d o 1
s t i t u t e d double bond, s e e Ref. 592).
170
The S y n t h e s i s o f Monoterpenes
These t e r p e n o i d compounds a r e i n t e r e s t i n g i n t h a t t h e y c o n t a i n trimethylcyclohexane r i n g A o f t h e higher terpenoids. L e s t t h i s s h o u l d immediately g i v e r i s e t o a supposed r e l a t i o n s h i p , l e t i t be s a i d t h a t t h e i r r e l a t i o n w i t h t h e i o n o n e s and carot e n o i d s i s much c l o s e r t h a n w i t h t h e t r i c y c l i c d i t e r p e n e s and t h e t r i t e r p e n e s . I n d e e d , i t h a s been shown t h a t 8 - i o n o l (503) and B-carotene (504) are b o t h c o n v e r t e d by dye s e n s i t i z e d p h o t o - o x i d a t i o n i n t o d i h y d r o a c t i n i d i o l i d e (500) and t h e a l l e n e (505) .593 A c t i n i d i o l i d e ( 4 9 9 ) and a c t i n i d o l (502) have been found i n Actinidia p l y g a m p 4 t h e dihydrocompound (500) i n s e v e r a l p l a n t s ( a l i s t o f which i s g i v e n by Demle e t a n 5 ) and l o l i o l i d e h a s a l s o been i s o l a t e d from s e v e r a l s o u r c e s ( c f . Ref. 5 9 6 ) . The f i r s t t h r e e of t h e compounds have b e e n synt h e s i z e d a s r a c e m a t e s from homosafranic a c i d (506) by D e m o l e and E n g g i ~ t , ’by ~ ~t h e r o u t e s shown i n Scheme 59. S a k a n had a l r e a d y u s e d 8 - c y c l o h m o g e r a n i c acid (507) t o s y n t h e s i z e (t)d i h y d r o a c t i n i d i o l i d e . 594
’\
503
sens
1-
V
500
505 -
OCHO 1
Scheme 59
fiT0
HO
HCN
506 Homosafranic A c i d I
i
(ycoo:,,.I 499 -
H2/Pt
Py r i d i n e
507 6-C y z h o m o g e r a n i c A c i d
(y
0
0
Pyridine
1
500
L OH
171
172
The S y n t h e s i s of Monoterpenes
REFERENCES
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53. 54. 55 *
56.
57. 58. 59. 60. 61. 62. 63.
64. 65. 66. 67. 68. 69. 70.
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The S y n t h e s i s of Monoterpenes Komppa, B e r . , 36, 4332 ( 1 9 0 3 ) . Komppa, Annalen, 370, 209 ( 1 9 0 9 ) . K. Aghoramurthy and P . M. L e w i s , T e t . Letters, 1415 (1968). K. Alder and E. Windmuth, A n n a l e n , 543, 4 1 (1939). W. R. Vaughan and R. P e r r y , J r . , J . Am. C h e m . SOC. , 7 5 , 3168 ( 1 9 5 3 ) . L. Friedman and A. P. Wolf, J . Am. C h e m . S O C . , 80, 2424 (1958). J . D. Roberts and J. A. Yancey, J . Am. C h e m . S O C . , 75, 3165 ( 1 9 5 3 ) . W. R. Vaughan and R. P e r r y , J r . , J . Am. C h e m . SOC. , 74, 5355 ( 1 9 5 2 ) . A . F. Thomas and B . Willhalm, Helv. C h i m . A c t a , 5 0 , 826 (1967). J . C. F a i r l i e , G . L. Hodgson, and T. Money, C h e m . C o r n . , 1196 ( 1 9 6 9 ) . D. M e r k e l , i n D i e A t h e r i s c h e O l e (Gildemeister-Hoffmann) (Akademie-Verlag, B e r l i n , 19631, Vol. I I I c , p. 310. V . E. Tishchenko and G . A . RudaJcov, Zhur. P r i k l . K h i m . , 6 , 691 ( 1 9 3 3 ) . S . Ya. Korotov, V. A. Vyrodov, E . A . A f a n a s ' e v a , A . I . Kolesov, 2 . L . Maslakova, T. D. O b l i v a n t s e v a , P. K. Chirkov, P. I . Zhuravlev, and 0. I . Minaeva, U.S.S.R. P a t e n t N o . 238,541 (Appl. Oct. 20, 1 9 6 2 ) ; [ C h e m . A b s . , 71, 39216 (1969) I . B . J . Kane and R. M. A l b e r t , U . S . P a t e n t N o . 3,383,422 (Appl. J a n . 27, 1 9 6 5 ) ; [ C h e m . A b s . , 69, 44063 ( 1 9 6 8 ) l . L. Ruzicka, B e r . , 50, 1362 ( 1 9 1 7 ) . G . Komppa and A . K l a m i , B e r . , 68, 2001 ( 1 9 3 5 ) . P . H i r s j ' d r v i , A n n . A c a d . S c i . Fennicae, Se r. A II, 81 (1957). A . Coulombeau and A . Rassat, Bull. SOC. C h i m . F r a n c e , 3338 ( 1 9 6 5 ) . G . Valkanas and N . Iconomou, Helv. C h i m . A c t a , 46, 1089 (1963). B . Burczyk and M. Bukala, C h e m . S t o s o w a n a , 7 , 245 ( 1 9 6 3 ) . R. Mayer, K. Bochow, and W. Z i e g e r , 2. C h e m . , 9, 348 (1964). K . J . Crowley, Proc. C h e m . SOC., 334 ( 1 9 6 2 ) . K . J . Crowley, Proc. C h e m . SOC., 245 ( 1 9 6 2 ) . R. H . S . Liu and G . S . Hammond, J . Am. Chem. S O C . , 8 9 , 4936 ( 1 9 6 7 ) . B . N . J o s h i , R. S e s h a d r i , K . K . C h a k r a v a r t i , and S . C . B h a t t a c h a r y y a , T e t r a h e d r o n , 20, 2911 ( 1 9 6 4 ) . P . A. Spanninger and J . L. von Rosenburg, J. O r g . C h e m . , 3 4 , 3658 ( 1 9 6 9 ) .
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.
Total Synthesis OfNatural Products, Volume2 Edited by John Apsimon Copyright © 1973, by John Wiley & Sons, Inc.
TOTAL SYNTHESIS OF SESQUITEWENES
Clayton H. Heathcock Department of Chemistry u n i v e r s i t y of C a l i f o r n i a Berkeley, C a l i f o r n i a
1. Introduction 2. Acyclic Sesquiterpenes A. Farnesol, Nerolidol B. Juvenile Hormone C. Sinensals D. Torreyal, Neotorreyol, Dendrolasin, Ipomeamarone (Ngaione) 3. Monocarbocyclic Sesquiterpenes A. Sesquiterpenes Related to Bisabolene B. 6-Bisabolene, y-Bisabolene, Lanceol, Isobisabolene, Bisabolol C. Curcumenes, Zingiberene D. ar-Turmerone E. Nuciferal F. Cryptomerion G. Todomatuic acid, Juvabione H. Perezone I. Bilobanone J. Furoventalene K. Elemanes L. Elemane (Tetrahydroelemene) M. Tetrahydrosaussaurea Lactone, Saussaurea Lactone N. Tetrahydroelemol, 8-Elemene, Elemol 0. Furopelargone-A, and Furopelargone-B P. Nootkatin, Procerin Q. Germacrane, Dihydrocostunolide R. Humulene
199 200 200 207 222
227 233 233 2 34 241 247 250
251
253 262 263 264 265 266 267 269 274 276 277 2 80
197
198
Total Synthesis of Sesquiterpenes
Bicarbocyclic Sesquiterpenes, Hydronaphthalenes A. Eudesmanes B. a-Cyperone , B-Cyperone C. a-, 0 - , and y-Eudesmol D. a- and 8-Selinene E. Costol, Costal, Costic Acid F. a- and B-Agarofuran, Nor-ketoagarofuran G. Epi-y-Selinene H. Chamaecynone, 4a-Hydroxyisochamaecynone I. Occidol, Occidentalol J. Atractylon and Lindesterene K. Santonin L. Ar temis in Alantolactone, Isoalantolactone, Telekin M. N. Cadinanes; Calamenene, E-Cadinene, Vetacadinol, Veticadinene 0. Drimanes; Drimenol (Bicyclofarnesol), Drimenin, Farnesiferol A (Biogenetic Routes) P. Drimanes; Drimenin, Isodrimenin, Conterifolin, Drimenol, Isoiresin, Winterin Q. Vale ranone R. Eremophilanes; Isonootkatone (a-Vetivone), Nootkatone, Valerianol, Valencene, Eremoligenol, Eremophilene, Fukinone Tricyclic Sesquiterpenes Having a Decalin S. Nucleus with an Additional Cyclopropane Ring 5. Other Bicarbocyclic Sesquiterpenes A. Guaiazulenes; Bulnesol, a-Bulnesene, and Kessane B. Guaianolides; Arborescin, Geigerin, Desacetoxymatricarin, and Achillin C. Tricyclic Hydroazulenes Containing a Cyclopropane Ring; Aromadendrene, Cyclocolorenone D. Cyperolone E. 8-Himachalene, Widdrol Sesquicarene, Sirenin F. G. a- and 8-cis-Bergamtene Chamigrene 11. I. Cuparene , 8-Cuparenone , Aplysin, Debromoaplysin J. Carabrone K. Helminthosporal L. 8-Vetivone, Hinesol, Epihinesol ( Agarosp iro1) M. Caryophyllene, Isocaryophyllene N. a-Santalol, 0-Santalol, a-Santalene, 8-Santalene
4.
282 282 285 289 296 299 300 304 305 308 310 315 324 326 330
338 34 5
353
36 1 380 395 395 412 417 422 424 428 446 449 453 459 463 466 474 481
Introduction 6.
T r i c a r b o c y c l i c Sesquiterpenes P a t c h o u l i Alcohol, a-Patchoulene, 8-Patchoulene B. Seychellene C. Cedrol, Cedrene D. E p i z i z a n o i c Acid E. Longifolene F. Copaene , Ylangene G. S a t i v e n e , Cyclosativene H. Culmorin I . a- and 8-Bourbonene J. I l l u d i n M K. T r i c y c l i c Rearrangement Products A.
1.
199 49 2 49 2 499 504 514 517 520 525 528 530 5 34 540
INTRODUCTION
The group o f n a t u r a l l y o c c u r r i n g s u b s t a n c e s c o n t a i n i n g 1 5 c a r bon atoms and d e r i v a b l e b i o g e n e t i c a l l y from mevalonic a c i d v i a f a r n e s y l pyrophosphate' ( s e s q u i t e r p e n e s ) , o f f e r s a t r u l y remarkable v a r i e t y of s t r u c t u r a l g o a l s t o t h e s y n t h e t i c chemist. Within t h i s r a t h e r r e s t r i c t e d c l a s s of o r g a n i c compounds, one f i n d s s u b s t a n c e s w i t h s t r u c t u r e s ranging from t h e commonplace Acyclic, monocyclic , b i c y c l i c , t r i c y c l i c , and t o t h e exotic.' even t e t r a c y c l i c compounds a r e r e p r e s e n t e d . Various s e s q u i t e r penes are known which c o n t a i n t h r e e - , f o u r - , f i v e - , s i x - , seven-, nine-, ten-, and eleven-membered carbon c y c l e s . A high degree of s t e r e o c h e m i c a l s u b t l e t y i s encountered, a s memb e r s o f t h e c l a s s are known which p o s s e s s as many a s e i g h t asymmetric carbon atoms. Because o f t h i s wide d i v e r s i t y of s t r u c t u r a l t y p e s , both s k e l e t a l and s t e r e o c h e m i c a l , t h e sesq u i t e r p e n e f i e l d i s an e x c e l l e n t a r e n a f o r t h e t e s t i n g and ref i n i n g o f new s y n t h e t i c methods and concepts. I n t h i s c h a p t e r , w e document t h e a c t i v i t y i n t h i s a r e a through t h e middle of 1970. W e have attempted complete coverage of a l l s e s q u i t e r p e n e t o t a l s y n t h e s e s . Formal t o t a l synt h e s e s are included when t h e p r e c u r s o r n a t u r a l m a t e r i a l had been p r e v i o u s l y prepared by t o t a l s y n t h e s i s ( i n o p t i c a l l y a c t i v e form, i f r e l e v a n t ) and when f a i r l y e x t e n s i v e s t r u c t u r e m o d i f i c a t i o n i s involved. Thus, t h e mere i n t e r r e l a t i o n of s e s q u i t e r p e n e s by minor chemical changes w i l l n o t be covered, even i f t h e s t a r t i n g m a t e r i a l happens t o have been prepared p r e v i o u s l y by t o t a l s y n t h e s i s . L i k e w i s e , t h e t o t a l s y n t h e s i s of a given s e s q u i t e r p e n e does n o t w a r r a n t t h e a d d i t i o n a l inc l u s i o n o f a l l p r i o r chemical t r a n s f o r m a t i o n s o f t h a t subs t a n c e which l e a d t o o t h e r s e s q u i t e r p e n e s . Wehavenot attempted t o be e x h a u s t i v e i n o u r coverage of
200
Total Synthesis of Sesquiterpenes
p e r i p h e r a l s t u d i e s , such as t h e s y n t h e s i s of model compounds, h y d r o g e n a t i o n p r o d u c t s , and d e g r a d a t i o n p r o d u c t s . These t o p i c s have been i n t r o d u c e d mainly when t h e y o f f e r s p e c i a l i n s i g h t i n t o t h e problems e n c o u n t e r e d w i t h s p e c i f i c s t r u c t u r a l t y p e s , o r when complete s o l u t i o n s t o v a r i o u s s y n t h e t i c problems have n o t y e t b e e n a c h i e v e d . W e have i n c l u d e d several t o t a l s y n t h e s e s of materials which are n o t a c t u a l l y n a t u r a l p r o d u c t s , mainly t r i c y c l i c m a t e r i a l s r e s u l t i n g from a c i d catalyzed rearrangements of sesquiterpenes (a-caryophyllene a l c o h o l , i s o l o n g i f o l e n e , c l o v e n e ) . T h i s d e c i s i o n i s less a r b i t r a r y t h a n i t a p p e a r s , s i n c e t h e r e is growing r e a l i z a t i o n t h a t many compounds l o n g r e g a r d e d as of n a t u r a l o r i g i n are i n f a c t a r t i f a c t s of t h e i s o l a t i o n p r o c e s s ( i n t e r a l i a , elemol, elemene) I n any e v e n t , t h e main t h r u s t of t h e c h a p t e r j u s t i f i e s t h e i n c l u s i o n of s u c h t o p i c s , s i n c e t h e y t y p i f y t h e approaches which have c l a s s i c a l l y been t a k e n toward s e s q u i t e r pene s y n t h e s i s .
.
2.
ACYCLIC SESQUITERPENES
A.
Farnesol, Nerolidol
The s e s q u i t e r p e n e a l c o h o l s -1rneso1 and n e r o l i d o l o c c u r i n n a t u r e mainly as t h e trans,trans and t r a n s - i s o m e r i d e s (1and 2 , r e s p e c t i v e l y ) , a l t h o u g h c i s , t r a n s - f a r n e s o l (2) is r e p o r t e d to occur n a t ~ r a l l y . ~ R u z i c k a ' s s y n t h e s i s of f a r n e s o l and nerolidol reported i n 1923, w a s t h e f i r s t sesquiterpene t o t a l
-
1 synthesis.
-2 Scheme 1 o u t l i n e s R u z i c k a ' s s y n t h e s i s .
-3 The problem
Acyclic Sesquiterpenes Scheme 1.
201
Ruzicka's S y n t h e s i s of Farnesol and Nerolidol
-4
-6
5 -
-2
of e s t a b l i s h i n g a uniform s t e r e o c h e m i s t r y a t t h e 6,7-double bond, which was then unknown, was circumvented by s t a r t i n g w i t h n a t u r a l g e r a n i o l 4 , which had been prepared by t o t a l synt h e s i s v i a l i n a l o o l (gp o r c i t r a l (9),7 although probably
-8
CCHO 9 -
202
Total Synthesis of Sesquiterpenes
n o t i n a s t e r e o c h e m i c a l l y homogeneous s t a t e . S t a n d a r d convers i o n o f g e r a n i o l (4) v i a g e r a n y l c h l o r i d e (2) a f f o r d e d g e r a n y l a c e t o n e ( g ) , which w a s c o n v e r t e d i n t o 1 , 2 - d e h y d r o n e r o l i d o l w i t h sodium i n m o i s t w i t h sodium a c e t y l i d e . Reduction o f e t h e r gave ( + ) - n e r o l i d o l (2), which was i s o m e r i z e d by a c e t i c a n h y d r i d e i n p e t r o l e u m e t h e r t o g i v e 1. As h a s been mentioned above, t h e geometry o f t h e o l e f i n i c l i n k a g e s was n o t known a t t h e t i m e o f R u z i c k a ' s s y n t h e s i s . I n f a c t , Ruzicka c o n s i d e r e d n a t u r a l f a r n e s o l t o be a m i x t u r e of a l l f o u r s t e r e o i s o m e r s of 1 and proposed t h a t h i s ( 2 ) - n e r o l i d o l was t h e trans isomer (2) and t h a t h i s s y n t h e t i c f a r n e s o l was e i t h e r t h e trans,trans o r cis,trans m o d i f i c a t i o n (1or 2 ) . I s l e r and co-workers were t h e f i r s t t o a p p l y t h e b a s i c Ruzicka sequence ( e t h y n y l a t i o n , s e l e c t i v e h y d r o g e n a t i o n , conv e r s i o n of t h e v i n y l c a r b i n o l t o an a l l y l i c h a l i d e , and acet o n y l a t i o n ) , which c o n s t i t u t e s a method f o r t h e r e p e t i t i v e a d d i t i o n o f i s o p r e n e u n i t s , f o r t h e complete s y n t h e s i s of ( ? I n e r o l i d o l from a c e t o n e The combined R u z i c k a - I s l e r scheme i s o u t l i n e d i n Scheme 2 . By t h i s method, t h e c e n t r a l d o u b l e bond
1
.'
Scheme 2 .
R u z i c k a - I s l e r Scheme f o r t h e S y n t h e s i s o f N e r o l i d o l Br
10 -
11 -
12 -
13 -
Acyclic Sesquiterpenes
203
was c l e a r l y n o t introduced s t e r e o s p e c i f i c a l l y , and dienone 6 was s e p a r a t e d from i t s isomer v i a i t s semicarbazone d e r i v a t i v e . I t was l a t e r r e p o r t e d t h a t t h i s method of s y n t h e s i s gives a mixture of trans and cis n e r o l i d o l s c o n t a i n i n g 65% of t h e trans isomer. 9 Nazarov, Gussev and Gunar r e p o r t e d a thorough study of r e a c t i o n c o n d i t i o n s i n t h e Ruzicka-Isler scheme and introduced several modifications t o f a c i l i t a t e the large-scale applicat i o n of t h e sequence. l o The Nazarov s y n t h e s i s of (t)- n e r o l i d o l and f a r n e s o l i s given i n Scheme 3. The major modification Scheme 3 .
Nazarov Modification of t h e Ruzicka-Isler S y n t h e s i s
12 -
15 -
FK-"".". 0
x
Ether
-6
-8
7 -
2. 1. KOAc-DMF HBr 3 . KOH-HzO
-2
Pd-SrC03
-
1,
HO * I
introduced was t h e d i r e c t a c e t o n y l a t i o n of a l l y l i c a l c o h o l s was accomplished by h e a t i n g a mixture of t h e a p p r o p r i a t e a l c o h o l and a c e t o a c e t i c ester a t approximately ZOO0 f o r s e v e r a l hours. A l t e r n a t i v e l y , t h e transformation of 12 to o r 8 t o 6 was c a r r i e d o u t by r e a c t i o n of t h e a l l y l i c a l c o h o l with gaseous hydrogen bromide, followed by condensat i o n of t h e r e s u l t i n g h a l i d e with s o d i o a c e t o a c e t i c e s t e r and
1 2 and 8,which -
14
204
T o t a l S y n t h e s i s of S e s q u i t e r p e n e s
s a p o n i f i c a t i o n , o r by r e a c t i o n o f t h e a l l y l i c a l c o h o l w i t h diketene, followed by p y r o l y s i s o f t h e r e s u l t i n g a c e t o a c e t i c e s t e r a t 170-200°.10 The a u t h o r s r e p o r t complete s t e r e o c h e m i c a l homogeneity i n t h e i r s y n t h e t i c p r o d u c t s , reg a r d l e s s of t h e method of s y n t h e s i s , b u t no d e f i n i t i v e evidence i s presented t o r e i n f o r c e t h i s a s s e r t i o n . The b a s i c Ruzicka method of c o n v e r t i n g g e r a n y l c h l o r i d e i n t o ( + ) - n e r o l i d o l and f a r n e s o l h a s been r e p o r t e d subsequently by o t h e r w o r k e r s , 1 2 f 1 3 although no f u r t h e r d e t a i l s on s t e r e o s p e c i f i c i t y were given. Radio-labeled f a r n e s o l h a s been s y n t h e s i z e d from transg e r a n y l acetone (6) by Popjak, C o r n f o r t h , and co-workers, by t h e method given i n Scheme 4 . 1 4 The cis,trans and trans,trans Scheme 4 .
-Y
Popjak-Conforth S y n t h e s i s of F a r n e s o l
Br-CH2 -C02Me
1
Zn
C02Me
Pocl3 C5H5N
17 -
6
C02Me
+
(18
LiAlH4 __c
19)
and were o b t a i n e d i n a r a t i o o f 1:l methyl f a r n e s a t e s and were s e p a r a t e d , p r i o r t o t h e i r r e d u c t i o n , by p r e p a r a t i v e vapor phase chromatography (vpc) J u l i a , J u l i a , and Guegan i n t r o d u c e d an e l e g a n t method f o r t h e c o n s t r u c t i o n o f p o l y i s o p r e n o i d c h a i n s which u t i l i z e s methylcyclopropyl ketone (El a s t h e b a s i c b u i l d i n g u n i t . I 5
.
Acyclic S e s q u i t e r p e n e s
205
The a p p l i c a t i o n of t h e J u l i a scheme f o r t h e s y n t h e s i s of ( ? I n e r o l i d o l i s o u t l i n e d i n Scheme 5. Cyclopropyldimethylcarbinol Scheme 5.
J u l i a S y n t h e s i s of N e r o l i d o l 1. Mg
OH
20 -
21 -
23 -
22 -
1. Mg
24 -
2 -
(21) r e a c t s with 48% HBr t o y i e l d t h e homoallylic bromide 2, t h e Grignard r e a g e n t o f which reacts w i t h methyl cyclopropyl ketone t o y i e l d a l c o h o l 23. Opening of 21 i n t h e same manner g i v e s t h e t r a n s o l e f i n 24, along w i t h approximately 25% o f i t s cis isomer. l6 A c l e a r l y s t e r e o s p e c i f i c s y n t h e s i s o f f a r n e s o l was proThe Corey s y n t h e s i s vided i n 1967 by Corey and co-workers. (Scheme 6 ) b e g i n s with t r a n s - g e r a n y l acetone (51, which was
’
Scheme 6.
6 -
Corey S y n t h e s i s of t r a n s , t r a n s - F a r n e s o l
25 -
206
T o t a l S y n t h e s i s of S e s q u i t e r p e n e s
k
f i r s t converted i n t o t h e dienyne 25. Hydroxymethylation of t h e p r o p a r g y l i c a l c o h o l 26, which was reduced w i t h L i A l H b , i n t h e p r e s e n c e of sodium methoxide. The i n i t i a l l y formed vinylaluminum compound was i o d i n a t e d t o y i e l d s o l e l y t h e trans-isomer 27, which r e a c t e d s t e r e o s p e c i f i c a l l y w i t h lithium dimethylcuprate t o a f f o r d t r a n s ,trans-farnesol In 1969, Vig and c o l l a b o r a t o r s r e p o r t e d t h e s y n t h e s i s o f f a r n e s o l and n e r o l i d o l which i s summarized i n Scheme 7.18 The
25 gave
(1) .
Scheme 7 .
Vig S y n t h e s i s of F a r n e s o l
Acyclic Sesquiterpenes
207
0
1I
(Et0)2P-CH2C02Et
NaH
3
key s t e p i s u t i l i z a t i o n of t h e C l a i s e n rearrangement t o e s t a b l i s h geometry a t t h e c e n t r a l double bond. I t i s claimed t h a t t h e r e a c t i o n l e a d s exclusively t o t h e t r a n s isomer S t e r e o s p e c i f i c i t y was n o t o b t a i n e d i n t h e modified W i t t i g r e a c t i o n , although e t h y l t r a n s - f a r n e s a t e (36) predominates.
(2).
B.
J u v e n i l e Hormone
J u v e n i l e hormone, t h e hormonal substance r e s p o n s i b l e f o r arr e s t i n g development a t t h e pupal s t a g e i n t h e Cecropia moth, i s n o t a c t u a l l y a s e s q u i t e r p e n e . However, i t s c l o s e s t r u c t u r a l resemblance t o t h e a c y c l i c s e s q u i t e r p e n e s warrants i t s i n c l u s i o n i n t h e p r e s e n t d i s c u s s i o n . The hormone was i d e n t i f i e d a s methyl trans,trans,c~s-lO-epoxy-7-ethyl-3,ll-dimethyl-2,6t r i d e c a d i e n o a t e (2) by R G l l e r , Dahm, Sweeley, and T r o s t i n 1967.l' Since t h a t t i m e , no less than t e n s y n t h e s e s o f t h e substance have appeared. 2 0 - 2 9
C02Me
The f i r s t s y n t h e s i s , r e p o r t e d i n 1967 by t h e Wisconsin group o f D a h m and W l l e r (zoology) and T r o s t ( c h e m i s t r y ) , 2 0 was n o n s t e r e o s e l e c t i v e , a f f o r d i n g mixtures of isomers a t each s t a g e where new s t e r e o c h e m i s t r y i s i n t r o d u c e d (Scheme 8 ) .
Juvenile Hormone--The
S c h e m e 8.
0
+
Base
(MeO) 2P-CH2C02Me I1
L C O 2 M e 38 -
LAo
1;;@lz)
b0
1.
4
Wisconsin S y n t h e s i s
,
Base
C 0 2Et
1
+
39 -
CO2Me
1. L i A l H 4 2. PBr3-CsH5N
A
2 . OH-,
Br
41
40 -
0
II
2PCH2C02Me
uco2M 3*),,~~2~b 1. L i A l H 4 2 . P B r 3 , CgHgN
42 -
Base
4 . OH-,
+
-
208
C02Me
* u
0
A
o
I I
-
44 0
(MeO) 2 P C H z C 0 2 M e
II
C o gM e
Acyclic Sesquiterpenes
209
Although s y n t h e t i c a l l y " i n e l e g a n t , " such an approach o f f e r s t h e important advantage of making u n n a t u r a l isomers a v a i l a b l e f o r p h y s i o l o g i c a l s c r e e n i n g . Methyl cis-3-methyl-2-pentenoate (38) was prepared i n 11%y i e l d by t r e a t i n g 2-butanone with t h e sodium s a l t of trimethylphosphonoacetate. The corresponding t r a n s isomer (39) w a s a l s o produced, i n 6% y i e l d . A f t e r f r a c t i o n a t i o n o f t h e mixture o f e s t e r s , t h e pure cis e s t e r w a s reduced t o t h e a l l y l i c a l c o h o l , which was converted i n t o cis bromide 40 by P B r 3 i n p y r i d i n e . A l k y l a t i o n of e t h y l 3-0x0p e n t a n o a t e with 40, followed by a l k a l i n e h y d r o l y s i s and dec a r b o x y l a t i o n a f f o r d e d enone 41. A p p l i c a t i o n of t h e Emmons r e a c t i o n t o 41 gave t h e t r a n s ,cis- and cis ,cis-esters 42 and 43 i n y i e l d s o f 27% and 12%, r e s p e c t i v e l y . R e p e t i t i o n of t h e above sequence ( L i A l H b , P B r 3 , a l k y l a t i o n of a c e t o a c e t i c e s t e r ) on t h e t r a n s , c i s - i s o m e r 42 gave dienone 44 i n 23% y i e l d . When 44 was submitted t o t h e Emmons r e a c t i o n , t h e c i s , t r a n s , c i s and t r a n s ,trans ,cis-C17-methyl esters 45 and 46 were produced i n y i e l d s o f 5 % a n d 2 5 %r,e s p e c t i v e l y . Epoxidation o f s w i t h m chloroperbenzoic a c i d g a v e racemic j u v e n i l e hormone (2) in40% y i e l d , a l o n g w i t h l O % o ft h e 6,7-epoxy compound a n d l o r b o f t h e 6 , 7 , l0,ll-bisepoxide. Three ingenious s t e r e o s e l e c t i v e s y n t h e s e s of j u v e n i l e hormone q u i c k l y i s s u e d from Harvard (Corey), Stanford (Johns o n ) , and Syntex ( S i d d a l l and Edwards). Corey's s y n t h e s i s , o u t l i n e d i n Scheme 9," handled t h e s t e r e o c h e m i s t r y of the
-
-
Scheme 9.
J u v e n i l e Hormone--Harvard OH
.,_ 1. T s C 1 ,
I
47 -
48 1. T s C l 2. Li-C-CCH20THP
WH
3. H ~ O +
1. L i A l H 4 NaOMe CECCH20H 2. I 2 3 . Et2CuLi
\ so -
1. PBr3 2. L i - C H 2 - C X - S i OH
Synthesis
(Me) 3 c
3 . Ag', t h e n CN4. n-BuLi, t h e n C H 2 0
210
Total Synthesis of Sesquiterpenes 1. L i A l H 4 N aOMe 12
3.
(Me)pCuLi
C-CCH 2 0 H
CH20H
2 46
-
2.
C02Me
-
hexane 2 . Mn02-NaCN MeOH
1. HOBr
____c
2 . i-Pro-
CO2Me
p o t e n t i a l epoxide r i n g by s e l e c t i v e s c i s s i o n of a cyclohexadiene t h u s g e n e r a t i n g t h e d e s i r e d c i s - o l e f i n i c l i n k a g e . Ozon i z a t i o n of d i e n e 47, o b t a i n e d r e a d i l y from Birch r e d u c t i o n of p-methoxytoluene, gave an aldehydo e s t e r , which was reduced by NaBH4 t o t h e hydroxy e s t e r 48. Compound 48 was c o n v e r t e d t o a l l y l i c a l c o h o l 2 by r e d u c t i o n o f t h e d e r i v e d p-toluenesulfonate ester with L i A l H 4 . The e s s e n t i a l t r a n s - s t e r e o c h e m i s t r y o f t h e 2 , 3 - and 6,7l i n k a g e s was e s t a b l i s h e d by a p p l i c a t i o n of C o r e y ' s method f o r s t e r e o s p e c i f i c a l l y s y n t h e s i z i n g t r i s u b s t i t u t e d a l k e n e s , which had p r e v i o u s l y been a p p l i e d t o t h e s y n t h e s i s o f f a r n e s o l (see Scheme 6 ) . Two d i f f e r e n t methods were used t o p r e p a r e t h e r e q u i s i t e p r o p a r g y l i c a l c o h o l s (50 and 52). Alcohol 2 w a s extended by f i r s t c o n v e r t i n g it i n t o i t s p - t o l u e n e s u l f o n a t e e s t e r , which was used t o a l k y l a t e t h e l i t h i u m s a l t of p r o p a r g y l t e t r a h y d r o p y r a n y l e t h e r . Hydrolysis of t h e r e s u l t i n g a c e t a l Alcohol 2 was c o n v e r t e d gave t h e p r o p a r g y l i c a l c o h o l i n t o t h e corresponding bromide w i t h P B r 3 i n e t h e r a t O", which was coupled w i t h t h e 3 - l i t h i o d e r i v a t i v e of l - t r i m e t h y l s i l y l propyne. The t r i r n e t h y l s i l y l group was rermved by t h e method of Arens30 and t h e r e s u l t i n g alkyne was hydroxymethylated t o
so.
Acyclic Sesquiterpenes
211
2.
N o comment was made a s t o how much stereochemical give homogeneity w a s l o s t i n t h e P B r 3 and coupling s t e p s , t h e i m p l i c a t i o n being t h a t t h e p r o c e s s i s s t e r e o s p e c i f i c . A l l y l i c a l c o h o l 53, r e s u l t i n g from a second a p p l i c a t i o n of t h e Corey sequence, was oxidized d i r e c t l y t o methyl e s t e r 46 by an unusual method developed f o r o x i d a t i o n of a l l y l i c alcoh o l s t o u,B-unsaturated e s t e r s without cis,trans i s o m e r i z a t i o n . The t e r m i n a l o l e f i n i c l i n k a g e was s e l e c t i v e l y epoxidized by van Tamelen's method, 3 1 a f f o r d i n g racemic. j u v e n i l e hormone (52% y i e l d ) . The h i g h l y imaginative Syntex s y n t h e s i s (Scheme 10) l e d
Scheme 10.
'0
9
J u v e n i l e Hormone--Syntex Synthesis
1. NaBH4 -EtOH 2 . 0 , H '
-
opt-Bu0'-Me1
57
-
56 -
(0-Bu-t) 3
I
59
-
I. L i A l H 4 HO
NaH
THF
OH
60 -
61 -
212
Total Synthesis of Sesquiterpenes
H+
\
\
OH 2 . MeLi
NaH-THF ___c
4. T s C ~ - C ~ H ~ N HO
63 -
62 -
fi.22
The geometry of t h e two o l e t o t h e Wisconsin d i e n o n e f i n i c l i n k a g e s was e s t a b l i s h e d by Grob f r a g m e n t a t i ~ no~f ~1,3d i o l m o n o t o s y l a t e s 61 and 63. C o n s i d e r a t i o n o f t h e known s t e r i c c o u r s e o f similar fragmentation^^^ r e q u i r e d t h a t t h e e t h y l g r o u p b e cis t o t h e t o s y l a t e g r o u p i n b o t h 61 and 63. The s y n t h e s i s of compound 61 i s a m a s t e r p i e c e o f asymmetric i n d u c t i o n . The f i v e c e n t e r s o f asymmetry were i n t r o d u c e d s e q u e n t i a l l y , a s o u t l i n e d i n t h e scheme, f o l l o w i n g sound p r i n I n two s t e p s (=-+ c i p l e s of k i n e t i c c o n t r o l i n e a c h c a s e . + E),s t e r e o s p e c i f i c i t y w a s o b t a i n e d by t a k i n g ad57 and v a n t a g e o f t h e s t e r i c h i n d r a n c e e x e r t e d by t h e a n g u l a r e t h y l group. The second s e c o n d a r y h y d r o x y l g r o u p w a s formed by reducing t h e corresponding ketone with l i t h i u m tri-tert-butoxyaluminum h y d r i d e , a r e a g e n t which i s known t o g i v e predomin a t e l y t h e e q u a t o r i a l a l c o h o l . E p o x i d a t i o n o f 2 w i t h mc h l o r o p e r b e n z o i c a c i d i n e t h e r gave o n l y a - e p o x i d e due t o t h e a f o r e m e n t i o n e d s t e r i c b u l k of t h e a n g u l a r s u b s t i t u e n t . However, i n methylene c h l o r i d e , t h e same o x i d a n t a f f o r d e d t h e Although t h e s t e r e o c h e m i s t r y o f 8-epoxide 60 i n 50% y i e l d . t h e t e r t i a r y h y d r o x y l g r o u p i n 61 would n o t be r e f l e c t e d i n t h e geometry o f t h e f r a g m e n t a t i o n p r o d u c t , it was found t h a t d e r i v e d from e p o x i d e 64 gave m a i n l y t h e e p i m e r i c a l c o h o l (E), o x e t a n e 66 u n d e r t h e f r a g m e n t a t i o n c o n d i t i o n s .
-
64,
Acyclic Sesquiterpenes OH
HO
I
,
213
NaH-THF
b .+" TsO
64 -
66 -
65 -
The s t a n f o r d group, headed by Johnson, e s t a b l i s h e d t h e s t e r e o c h e m i s t r y a t t h e epoxide r i n g and t h e two double bonds by t h r e e d i f f e r e n t methods of s t e r e o s e l e c t i v e s y n t h e s i s , 2 3 The s t a r t i n g p o i n t was 1-ethyl-1-acetylcyclopropane (70). This ketone was carbonated and t h e r e s u l t i n g k e t o e s t e r was a l k y l a t e d with methyl trans-4-bromo-3-methylbutanoate (2) This a l l y l i c h a l i d e , which r e p r e s e n t s t h e e v e n t u a l 2,3-double bond i n j u v e n i l e hormone, was prepared by t h e n o n s p e c i f i c bromination of % , % - d i m e t h y l a c r y l i c a c i d (67).A mixture of cis and trans isomers (Eand 2) is produced, b u t on workup, the c i s bromo a c i d spontaneously l a c t o n i z e s , l e a v i n g t h e des i r e d trans isomer a s t h e only a c i d i c m a t e r i a l .
.
NBS_
&, hr
67 -
2H
+
L
68 -
C
0
2
69 -
H
-p -
A f t e r h y d r o l y s i s , decarboxylation and r e - e s t e r i f i c a t i o n , t h e u n s a t u r a t e d cyclopropyl ketone 73 was obtained. This subs t a n c e i s t h e key t o t h e S t a n f o r d s y n t h e s i s . Johnson had prev i o u s l y developed a h i g h l y s t e r e o s e l e c t i v e modification16 of t h e J u l i a o l e f i n s y n t h e s i s . 1 5 The method involves t h e
Scheme 11.
J u v e n i l e Hormone--Stanford
1. NaH, (MeO)gC=O
0
70 -
1. Ba(OH)2,
&COzMe
MeOH
_____L
0
Br
71 -
Synthesis
72 -
2. H ~ O + 3. CH2N2
T o t a l S y n t h e s i s of S e s q u i t e r p e n e s
214
u
C
0
2
0
b
l
e
-
2. PBr3- G
C
collidine
73 -
0
2
M
e
ZnBr2-ether
Br
_____c
14 1. NaI-HMPA
Br
0
Base
75 -
p
o
0
76 ,
1. MeMgBr _____c
2.
K2CO3-
MeOH
rearrangement of a c y c l o p r o p y l c a r b i n y l bromide (74) t o a homoa l l y 1 bromide (75) under t h e i n f l u e n c e of z i n c bromide i n e t h e r . I f one assumes t h a t r i n g opening i s concomitant w i t h i o n i z a t i o n , and t h a t an a n t i p e r i p l a n a r arrangement of t h e C-Br and breaking c y c l o p r o p y l C-C bond i s n e c e s s a r y , t h e n conformers 74a and 74b must be considered. Conformer 3,which l e a d s t o t h e d e s i r e d trans p r o d u c t 2 i s c l e a r l y l e s s h i n d e r e d t h a n 14b, which would g i v e t h e cis analog 2. A l t e r n a t i v e l y , t h e rearrangement may proceed by a t t a c k of bromide on a puckered bicyclobutonium i o n ( 2 ) . Conformer should be p r e f e r r e d s i n c e t h e bulky group can occupy a q u a s i - e q u a t o r i a l over I n t h e e v e n t , bromide 74 undergoes smooth r e a r r a n g e position. ment t o 7s w i t h o v e r 95% s t e r e o s p e c i f i c i t y , t h u s e s t a b l i s h i n g the d e s i r e d s t e r e o c h e m i s t r y a t t h e e v e n t u a l 6 , 7 double bond.
-
z,
2
Acyclic S e s q u i t e r p e n e s
215
Br
H
75 -
H
Br R
H
Br-
79a t 75 -
7 9b
The s t a g e was now s e t f o r t h e i n t r o d u c t i o n of t h e epoxide moiety of j u v e n i l e hormone. I n t h i s r e s p e c t , t h e Stanford s y n t h e s i s d i f f e r s from t h e e a r l i e r s y n t h e s e s , which r e l i e d on s e l e c t i v e e p o x i d a t i o n i n a p e n t u l t i m a t e s t a g e t o achieve t h i s f u n c t i o n a l i t y . The p l a n was t o u t i l i z e C o r n f o r t h ' s method f o r t h e s t e r e o s e l e c t i v e s y n t h e s i s of t r i s u b s t i t u t e d o l e f i n s . 34 The Cornforth method i n v o l v e s t h e formation o f a chlorohydrin by a d d i t i o n of a Grignard r e a g e n t t o an a - c h l o r o ketone. One of t h e two p o s s i b l e d i a s t e r e o m e r s i s u s u a l l y produced i n preTheref o r e t h e epoxide dominance i n a p r e d i c t a b l e manner. which r e s u l t s from base c a t a l y z e d c y c l i z a t i o n i s produced s t e r e o s e l e c t i v e l y , by asymmetric i n d u c t i o n i n t h e f i r s t s t e p
T o t a l S y n t h e s i s of S e s q u i t e r p e n e s
216
o f t h e sequence. I n a p p l i c a t i o n s o f t h e C o r n f o r t h scheme t o o l e f i n s y n t h e s i s , t h e e p o x i d e i s c o n v e r t e d i n t o a n a l k e n e by a p r o c e s s which r e t a i n s t h e geometry o f t h e c a r b o n s k e l e t o n . However, f o r t h e problem a t hand, i t i s n e c e s s a r y t o p r o c e e d only t o t h e epoxide s t a g e . The method whereby t h e r e q u i s i t e c h l o r o k e t o n e w a s produced i s e x t r e m e l y i m a g i n a t i v e . Bromide = w a s used t o alkyla t e 3 , 5 - h e p t a n e d i o n e I g i v i n g t h e B-diketone 76. T h i s substance was c h l o r i n a t e d by t h e method o f K o ~ o w e rand ~ ~ the resulting c h l o r o d i k e t o n e was d e a c y l a t e d w i t h barium h y d r o x i d e i n e t h a n o l . C h l o r o k e t o n e 2 was t r e a t e d w i t h methylmagnesium b r o mide a t -75" ( i t h a v i n g p r e v i o u s l y been found t h a t low t e m p e r a t u r e s g r e a t l y enhance t h e s t e r e o s e l e c t i v i t y o f t h e p r o Base t r e a t m e n t c e s s ) l6 t o y i e l d an intermediate chlorohydrin. y i e l d e d r a c e m i c j u v e n i l e hormone, c o n t a m i n a t e d w i t h 8% of t h e trans,trans,trans i s o m e r . TVo n o n s t e r e o s e l e c t i v e s y n t h e s e s o f j u v e n i l e hormone accomplished a t t h e U . S . Department o f A g r i c u l t u r e Entomology Research S t a t i o n i n B e l t s v i l l e , Maryland are o u t l i n e d i n Schemes 1 2 and 1 3 . 2 4 Both s y n t h e s e s l e a d t o a m i x t u r e o f a l l
, Scheme
85 ( c -
12.
J u v e n i l e Hormone--Beltsville
and t )
OH
-
87 (c and t )
Synthesis A
86 ( c and -
88 ( c -
t)
and t )
Acyclic Sesquiterpenes
217
1) H O B r 2 ) i-Pro46 -
( e i g h t isomers) C02Me 37 -
Scheme 13.
L
J u v e n i l e Hormone--Beltsville
Synthesis B
&-
B 80 ( c -
( e i g h t isomers)
r
and t )
89 ( c -
and t ) MeMg I
DMSO
90 ( f o u r -
9 1 (four
isomers)
isomers)
0
\
II
\
(MeO)2PCH2C02Me
-
NaH 44 (eight -
isomers) C02Me
46
( e i g h t isomers)
e i g h t s t e r e o i s o m e r s of t h e n a t u r a l hormone. Although t h i s method i s c l e a r l y u n s u i t a b l e f o r p r e p a r i n g a s i n g l e isomeride i n good y i e l d , it does make a c t i v e m a t e r i a l f a i r l y r e a d i l y a v a i l a b l e f o r entomological research. Two f u r t h e r n o n s t e r e o s e l e c t i v e s y n t h e s e s o f t h e hormone, o r i g i n a t i n g i n t h e Department of A g r i c u l t u r a l Chemistry a t t h e U n i v e r s i t y of Tokyo25 and t h e Department of Chemistry a t t h e U n i v e r s i t y of New Brunswick26 a r e summarized i n Schemes 1 4 and 15. The Tokyo s y n t h e s i s i s p a t t e r n e d a f t e r t h e c l a s s i c a l Ruzicka-Isler f a r n e s o l s y n t h e s i s ( s e e Scheme 2 ) , a s modified by K i m e l . l 1 ' 3 7 The s y n t h e s i s l e a d s , i s a s t r a i g h t f o r w a r d
218
Total Synthesis of Sesquiterpenes Scheme 1 4 .
-
9 2 ( c and t )
93 -
J u v e n i l e Hormone--Tokyo
dO2Et
41 -
6H
Synthesis
( c and t )
0 2 CCH2COMe
94 -
( c and t ) 0
II
(c and t )
-
(Et0)2PCHzC02Me 44 -
( f o u r isomers)
NaH
46 ( e i g h t
isomers)
manner, t o a l l s t e r e o i s o m e r s o f t h e C 1 7 - t r i e n i c e s t e r 46, which was e p o x i d i z e d by t h e van Tamelen p r o c e d u r e . 3 1 Vpc a n a l y s i s of t h e enone 41 showed t h a t i t w a s 70% trans, 30% c i s . D i enone 44 was found t o have t h e composition: 16% c i s , c i s ; 35% cis ,trans ; 17% trans ,cis; 32% trans ,trans. The New Brunswick s y n t h e s i s (Scheme 1 5 ) u t i l i z e s t h e This C l a i s e n r e a r r a n g e m e n t t o p r e p a r e u n s a t u r a t e d aldehyde?. method had been i n t r o d u c e d e a r l i e r by Saucy and Marbet f o r t e r p e n e ~ y n t h e s i s . ~ ' The C l a i s e n method g i v e s a m i x t u r e of s t e r e o i s o m e r i c y , & - u n s a t u r a t e d a l d e h y d e s c o n t a i n i n g 60% and 4 0 % cis i s o m e r s . Vpc a n a l y s i s o f d i e n o n e 44 r e v e a l e d it t o be a m i x t u r e o f 15% c i s , c i s ; 23% trans,cis; 25% cis,trans; and 37% trans,trans isomers ( s e e a b o v e ) , By p r e p a r a t i v e vpc a t v a r i o u s s t a g e s , a l l f o u r isomers o f d i e n o n e 44 were obt a i n e d i n a p u r e s t a t e . The transleis isomer was c o n v e r t e d i n t o racemic j u v e n i l e hormone by t h e method o f D a h m , T r o s t , and R t i l l e r (see Scheme 8 ) .
Acyclic Sesquiterpenes
219
&-, ky, LCH Scheme 15.
Juvenile Hormone--New Brunswick Synthesis
A H3P04
95
41 (c and
96
97 (c and t)
98 -
t)
44 (four isomers)
Schultz and Sprung, at Schering AG in Berlin, have reported an economical synthesis of the hormone, which gives a mixture of all isomers (Scheme 16).27 Unsaturated ketal 100 Scheme 16. Juvenile Hormone--Schering Synthesis
99 -
U0 41 -
100 -
I 101 -
41 -
220
Total Synthesis of Sesquiterpenes
was o b t a i n e d i n 69% y i e l d by c o u p l i n g phosphorane E w i t h 2butanone. The c i s isomer (63% of t h e m i x t u r e ) w a s c o n v e r t e d t o k e t o n e 41, which was t r e a t e d w i t h phosphorane 101 t o y i e l d 102 (50% trans,cis; 50% c i s , c i s ) i n 7 0 % y i e l d . H y d r o l y s i s of t r a n s , c i s - E ( o b t a i n e d i n 29% y i e l d by f r a c t i o n a t i o n o f t h e m i x t u r e ) gave d i e n o n e 44. Compound 44 r e a c t e d w i t h phosphorane 103 t o g i v e 4 1 % of t r a n s , t r a n s , c i s - s , a l o n g w i t h 35% o f t h e cis,trans ,cis isomer. S e l e c t i v e e p o x i d a t i o n of 46 gave racemic j u v e n i l e hormone i n 43% y i e l d . Anderson, H e n r i c k , and S i d d a l l a t Zoecon2’ and van Tamelen and McCormick a t S t a n f o r d 2 ’ u t i l i z e d an i n t e r e s t i n g homologat i o n sequence f o r t h e n o n s t e r e o s p e c i f i c c o n v e r s i o n of f a r n e s o l t o t h e hormone. The f i r s t s y n t h e s i s i s b a s e d on the o b s e r v a t i o n by Crabbg3’ t h a t l i t h i u m d i m e t h y l c u p r a t e r e a c t s w i t h a l l y l i c a c e t a t e s t o y i e l d homologated o l e f i n s . The Zoecon s y n t h e s i s (Scheme 2)b e g i n s w i t h t h e photoScheme 17.
J u v e n i l e Hormone--Zoecon
Synthesis
-
1. 0 2 , h v , s e n s C02Et
2. P (OMe) 3 3. Ac20
36 C02Et
(Me)2CuLi
____c
OAc
OA c
104 -
105 -
108 -
-
%C02Et 106
+
C -OzEt
107
s e n s i t i z e d o x y g e n a t i o n of methyl f a r n e s a t e (2).A f t e r red u c t i o n of t h e i n t e r m e d i a t e b i s h y d r o p e r o x i d e w i t h t r i m e t h y l phosphite, t h e d i o l w a s e s t e r i f i e d with a c e t i c anhydride.
Acyclic Sesquiterpenes
221
Compound 104 r e a c t e d with l i t h i u m dimethylcuprate i n e t h e r t o g i v e t r i e n e s 107, and 106 i n y i e l d s of 7 6 , 1 4 , and 8% r e s p e c t i v e l y . When t h e r e a c t i o n was c a r r i e d o u t i n t e t r a hydrofuran, t h e mixture of t r i e n e esters contained "apprecia b l e amounts" of isomer 108. The corresponding methyl e s t e r (46) had p r e v i o u s l y been converted t o j u v e n i l e hormone. Van Tamelen and McCormick (Scheme 18) converted f a r n e s y l
105,
Scheme 18.
, 0 -
\
J u v e n i l e Hormone--van Tamelen S y n t h e s i s 1. MCPA 2.
\
____c KOH
-
109 -
LiN (CzH5 12
110 -
p-TsC1 LiCl OH
OH
112 -
1. (Me)gCuLi OC43
c1
c1
2. HC1
113 1. MnOg-hexane 2 . Mn02-NaCN-MeOH
H O?
114 (4 -
isomers)
46 ( 4 -
isomers)
222
T o t a l S y n t h e s i s of S e s q u i t e r p e n e s
110
into the t r i s - a l l y l i c trio1 a c e t a t e ( l o g ) , v i a bis-epoxide T h e p r i m a r y h y d r o x y l w a s p r o t e c t e d by t h e t r i t y l group, and t h e t w o s e c o n d a r y a l c o h o l s were r e p l a c e d by c h l o r i n e . A l k y l a t i o n of b i s - c h l o r i d e 113 w i t h l i t h i u m d i m e t h y l c u p r a t e gave, a f t e r d e p r o t e c t i o n of t h e p r i m a r y h y d r o x y l , a m i x t u r e of T h i s w a s o x i d i z e d by C o r e y ' s g e o m e t r i c i s o m e r s of t r i e n o l method4' t o g i v e a m i x t u r e o f isomers o f 46. The isomer d i s t r i b u t i o n was d e t e r m i n e d by g l p c t o be 40% t r a n s , c i s , t r a n s ; 2 0 % t r a n s , t r a n s , t r a n s ; 2 0 % t r a n s , c i s , c i s ; and 2 0 % t r a n s , t r a n s , cis ( d e s i r e d isomer).
111.
114.
C.
Sinensals
(115)
(116)
and 8 - s i n e n s a l are i n g r e d i e n t s of t h e a-Sinensal e s s e n t i a l o i l of t h e Chinese o r a n g e . The s y n t h e s i s of t h e s e compounds a g a i n c a l l s f o r methods o f s t e r e o s e l e c t i v e l y genera t i n g a t r a n s - t r i s u b s t i t u t e d d o u b l e bond.
115 -
116 -
The problem w a s f i r s t s o l v e d by Thomas w i t h a b r i l l i a n t combination of t h e C l a i s e n and Cope r e a r r a n g e m e n t s , as o u t l i n e d i n Scheme 1 9 . 4 1 Selenium d i o x i d e o x i d a t i o n of myrcene
(117)
Scheme 1 9 .
Thomas S y n t h e s i s of f3-Sinensal
k- -vcHd 117 -
-
Rotation
Acyclic Sesquiterpenes
223
116 -
120 -
=.
gave a l l y i c a l c o h o l 118,along w i t h t h e correspon i n g t r a n s aldehyde, which could be reduced t o When a mixture of 118 and l-ethoxy-2-methyl-l,3-butadiene was h e a t e d with m e r curie a c e t a t e and sodium a c e t a t e a t 98' f o r 50 h r , f3-sinensal was produced i n 43% y i e l d . The t r a n s f o r m a t i o n presumably occurs i n t h e following manner: mercuric i o n c a t a l y z e d t r a n s which undergoes a C l a i s e n r e etherification, yielding arrangement t o y i e l d g,which undergoes a second thermal r e o r g a n i z a t i o n t o form 116. Stereochemically, t h e Thomas s y n t h e s i s seems t o produce o n l y t r a n s , t r a n s - 6 - s i n e n s a l , t h e n a t u r a l isomer. This r e s u l t can be r a t i o n a l i z e d i n terms of t h e known s t e r e o c h e m i s t r y of t h e Cope rearrangement. 42 Using a c h a i r l i k e , f o u r - c e n t e r t r a n s i t i o n s t a t e , t h e C l a i s e n rearrangement (=-+ 120) can be written as
-
=,
120 -
119 -
120
Diastereomer can r o t a t e i n t o a s u i t a b l e conformation f o r subsequent Cope rearrangement i n two ways: YHO
R
I
-
OHC I
CH3
\
120a
CH3
/&fCH3 CH 3
I
120b
H
224
T o t a l S y n t h e s i s of S e s q u i t e r p e n e s
OHC%
-
OHC
121
% eH R
H
122 (121), w h i l e
-
Conformer should give trans,cis-isomer conformer s h o u l d g i v e a c i s , t r a n s - i s o m e r (=). Furthermore, conformer s h o u l d b e p r e f e r r e d , on t h e grounds t h a t t h e b u l k y s u b s t i t u e n t s (CH3 and R) occupy p s e u d o - e q u a t o r i a l p o s i t i o n s . Thus, t h e 7,8 d o u b l e bond s h o u l d b e t r a n s . However, i t i s q u i t e l i k e l y t h a t the 2,3 double bond would isomerize t o t h e more stable t r a n s t r r a n g e m e n t d u r i n g t h e r e a c t i o n . A l t e r n a t i v e l y , d i a s t e r e o m e r 123 might be produced i n t h e C l a i s e n r e a r r a n g e m e n t . The p r e f e r r e d conformer of t h i s isom e r would l e a d d i r e c t l y t o t r a n s , t r a n s - B - s i n e n s a l .
a
123 -
H
I.
116 -
Blichi and W U e s t have d e s c r i b e d a s y n t h e s i s of 6 - s i n e n s a l (Scheme 20) which a l s o b e g i n s w i t h t h e s e l e n i u m d i o x i d e oxidat i o n of m y r ~ e n e . Alcohol ~~ 118 w a s c o n v e r t e d , by PBr3 i n Scheme 20.
Biichi-WUest S y n t h e s i s o f B-Sinensal
A 117 -
124 -
118 -
CI H 3 CH 3CH’N-C-CH 3
I
125
.Br
CH 3
LiN (i-Pr) 2
CI H 3
CHZ=CH-N-C-CH~ I 1 L i CH3
-
1. 124
2. H30+
Acyclic Sesquiterpenes
k
C
H
YH
CH~CH~CHZN-C-CH
0
225
LiN (i-Pr)2
I
127 -
CH3
126 CH3 I CH~CHZCH-N-C-CH~
1. 126
2. H ~ O +
! I
L1 CH3
hexane, to allylic bromide 124. This halide was used to alkylate the lithium salt of Schiff’s base 125 (Stork’smethod),44 yielding the C-12 aldehyde 126 after hydrolysis. Compound 126 was treated with the lithium salt of Schiff’s base 127, in an application of Wittig’s “directed aldol condensationat4 to yield B-sinensal. Bertele and Schudel have recorded a s nthesis of Bsinensal which is summarized in Scheme 21.y6 Ozonolysis of
-
Scheme 21.
Bertele-Schudel Synthesis of B-Sinensal
‘CHO
C1
CH20H
c1
to; +
1. n-BuLi
I
CH20H
0
?OHC‘ 129 -
130 -
131 -
132 -
226
Total Synthesis of Sesquiterpenes
134 -
133
_.
11 7 -
2.
135 -
137
OEt
;11 CHO
126
-
+
:
H+
----.c
1. n-BuLi
+3P=C
( c and t )
/CHO
\
CH3
139 -
___c
i":?.i-116 -
myrcene, followed by d i m e t h y l s u l f i d e workup, y i e l d s d i e n e aldehyde 128. T h i s aldehyde is condensed w i t h t h e y l i d der i v e d from phosphonium s a l t 132 t o y i e l d a mixture of s t e r e o i s o m e r i c t r i e n e a c e t a l s 136 c o n t a i n i n g 40% cis- and 60% t r a n s isomers. A l t e r n a t i v e l y , t h e myrcene ozonide may be reduced with sodium borohydride t o a f f o r d a l c o h o l 133. Subsequent
Acyclic Sesquiterpenes
227
c o n v e r s i o n o f t h i s a l c o h o l i n t o phosphonium s a l t 135, followed by c o n d e n s a t i o n of t h e d e r i v e d y l i d w i t h 5,5-diethoxy-2pentanone y i e l d s a m i x t u r e of isomeric t r i e n e a c e t a l s in a r a t i o o f 30% t r a n s and 70% cis. The a c e t a l mixtures 136 and 137 were s e p a r a t e d by p r e p a r a t i v e v p c , t h e major isomer b e i n g r e a d i l y o b t a i n e d i n e a c h case. H y d r o l y s i s of p u r i f i e d t r a n s respectively. The s t e r 136 and cis-= a f f o r d e d 126 and e o c h e m i s t r y was e s t a b l i s h e d f o r t h e two isomers by an examinat i o n o f t h e NMR s p e c t r a . Condensation o f 126 w i t h y l i d 139 yielded trans,trans-6-sinensal, i d e n t i c a l with t h e n a t u r a l material. The same a u t h o r s s y n t h e s i z e d a - s i n e n s a l from i n t e r m e d i a t e 126 by t h e r o u t e shown i n Scheme 22. Condensation of 126 w i t h
137
-
=,
-
-
Scheme 22.
Bertele-Schudel S y n t h e s i s of a - S i n e n s a l
1-carbethoxyethyldinetriphenylphosphorane gave t h e t e t r a e n e ester 140. Treatment of t h i s e s t e r w i t h rhodium c h l o r i d e i n e t h a n o l 4 7 r e a r r a n g e d t h e 1,3-diene system t o a m i x t u r e o f 9 , l O c i s , t r a n s i s o m e r s (70% t r a n s ) . When t h e m i x t u r e was h e a t e d with i r o n pentacarbonyl a t 180°, t h e proportion of transisomer i n c r e a s e d t o 95%. 4 8 Reduction of t h e e s t e r , followed by o x i d a t i o n o f t h e r e s u l t i n g a l l y l i c a l c o h o l gave a - s i n e n s a l . D.
T o r r e y a l , N e o t o r r e y o l , D e n d r o l a s i n , Ipomeamarone (Ngaione)
-
T o r r e y a l (141) , n e o t o r r e y o l (E), d e n d r o l a s i n (E), and ipomeamarone ( n g a i o n e , 144)are s e s q u i t e r p e n e s u b s t a n c e s
T o t a l S y n t h e s i s of S e s q u i t e r p e n e s
228
141-
c o n t a i n i n g a B - a l k y l a t e d f u r a n r i n g . The d o u b l e bonds i n trans, and t h e s y n t h e t i c problem i s t h e r e f o r e s i m i l a r
143 a r e -
141 142
143 -
R=CHO R=CH20H R=CH3
t o t h a t f a c e d i n t h e s y n t h e s i s of f a r n e s o l , j u v e n i l e hormone o r s i n e n s a l . I n f a c t , t h e s t r u c t u r a l s i m i l a r i t y between Bs i n e n s a l and t o r r e y a l i s s t r i k i n g , t h e l a t t e r b e i n g s i m p l y an o x i d a t i o n p r o d u c t o f t h e former. Ipomeamarone p r e s e n t s a somewhat d i f f e r e n t s y n t h e t i c c h a l l e n g e , t h e problem of double bond geometry b e i n g r e p l a c e d by one o f r i n g geometry. Thomas h a s a p p l i e d h i s e l e g a n t Claisen-Cope combination sequence t o t h e s y n t h e s i s of 141-143 from 3 - f u r f u r y l a l c o h o l (Scheme 2 3 ) . 4 9 I n t h i s a p p l i c a t i o n , t h e r e a c t i o n i s u t i l i z e d Scheme 23. Thomas S y n t h e s i s o f T o r r e y a l , N e o t o r r e y o l , and D e n d r o l a s i n
LiAlH4 ___c
141 (cis,trans -
and trans ,trans)
a s a method f o r t h e r e p e t i t i v e a d d i t i o n o f t w o i s o p r e n e u n i t s , a f t e r r e d u c t i o n o f t h e i n i t i a l l y formed aldehyde (147). The
>
Acyclic Sesquiterpenes
229
1. TsCl 2. L i A l H 4
142 -
s y n t h e t i c t o r r e y a l was converted, v i a n e o t o r r e y o l , i n t o dend r o l a s i n by t h e i n d i c a t e d sequence. Stereochemically, t h e Thomas s y n t h e s i s g i v e s aldehydes 147 i n a t r a n s : c i s r a t i o of 2:l. However, a p p l i c a t i o n of t h e sequence t o t h e d e r i v e d a l cohol mixture 148 gave only t r a n s l t r a n s - and cis l t r a n s - t o r r e y a l i n a 4 : l r a t i o , t h e former being i d e n t i c a l with t h e n a t u r a l substance. The conversion of both cis- and trans-= t o a compound c o n t a i n i n g a trans-6,7-double bond deserves comment. The s t e r e o s p e c i f i c conversion of trans-= t o 6 , 7 - t r a n s - S is understandable i n terms of t h e conformational arguments presented p r e v i o u s l y (p. 2 2 3 ) . The 6 , J - c i s isomer of 148 can and r e a c t with t h e ethoxydiene t o g i v e two ethers (E which should g i v e diastereomers and respectively. The p r e f e r r e d " c h a i r l i k e " conformations of both diastereomers
(141)
ml
148a -
149a and
148b -
(e.g.,
3)
149a -
149b -
t h e conformations having two of t h e groups
CH3, v i n y l , and R i n pseudo-equatorial p o s i t i o n s ) lead t o i s o -
mers of
141 c o n t a i n i n g
a trans-6,7-double
bond.
230
ow-
Total Synthesis of Sesquiterpenes
+fa2 CH3
CH3
149a -
R
CH3
R + C H O H
trans,trans-141
149b
R
CHO
cis,trans-= Parker and Johnson report a synthesis of dendrolasin based o n Johnson’s modification.of the Julia olefin synthesis (Scheme 2 4 ) 3-Bromomethylfuran (150) was used to alkylate Scheme 24.
Parker-Johnson Synthesis of Dendrolasin 0
f i0 B r & % +C02Et - + 6 - 3. H ~ O + 150 -
OH
151 -
@
1. P B r :
153 -
rB 152 -
2 . ZnBr2
’*
154 -
2. NaOH
cco Acyclic Sesquiterpenes
231
1. L i A l H 4
c 2 . CrO3*2CgHgN
-
FCH 143 -
156 -
B-keto e s t e r 151. A f t e r h y d r o l y s i s and d e c a r b o x y l a t i o n , cyclop r o p y l k e t o n e 152 w a s reduced t o c a r b i n o l 153. This m a t e r i a l was s u b m i t t e d t o the two-stage PBr3-ZnBr2 t r e a t m e n t t o y i e l d (p. 2 1 4 ) . A f t e r n i t r i l e c h a i n e x t e n h o m o a l l y l i c bromide s i o n , t h e remaining t h r e e c a r b o n s were added b y a W i t t i g r e a c t i o n of isopropylidinetriphenylphosphorane on aldehyde 156. A s i n J o h n s o n ' s j u v e n i l e hormone s y n t h e s i s (see Scheme ll), t h e c e n t r a l double bond w a s g r e a t e r t h a n 95% t r a n s . I n 1956, Kubota and Matsuura cormnunicated a s y n t h e s i s of f+)-ipomeamarone which is summarized i n Scheme 25.51
154
(144)
Scheme 2 5 .
Kubota-Matsuura S y n t h e s i s of Ipomeamarone C02Et
I
02. =*co2R?158 -
157 -
159 -
2 . A 1 (OPr-i) 3
160 -
161 -
232
Total Synthesis of Sesquiterpenes
#
-
CH2C02H
162
1. NaOMe
2.
(COC112
"
16 3 -
\
165 -
AczO-KOAc
0
144 -
166 -
C l a i s e n condensation of e t h y l a c e t a t e and e t h y l 3 - f u r o a t e (157)gave €3-keto e s t e r 9, which was a l k y l a t e d w i t h e t h y l 4-bromo-3-methylbutanoate (p. 213) , a convenient i s o p r e n e e q u i v a l e n t , t o g i v e k e t o d i e s t e r 159. Hydrolysis and decarbo x y l a t i o n a f f o r d e d t h e c r y s t a l l i n e a c i d 160, presumably as t h e pure trans-isomeride. E s t e r i f i c a t i o n of I@, followed by Meerwein-Pondorf-Verley r e d u c t i o n gave hydroxy e s t e r 161 ( a mixture o f i s o p r o p y l and methyl e s t e r s ) , which upon h y d r o l y s i s a f f o r d e d a mixture of d i a s t e r e o m e r i c a c i d s 162. The d e r i v e d a c i d c h l o r i d e mixture 163 r e a c t e d w i t h isobutylcadmium t o undergoes i n t r a n w l e c u l a r y i e l d 164 and 165. Presumably cis-= F r i e d e l - C r a f t s a c y l a t i o n , g i v i n g 165, w h i l e trans-= reacts normally with t h e cadmium r e a g e n t t o g i v e 164. Compound 164 was found n o t t o be i d e n t i c a l w i t h ipomeamarone, although t h e i n f r a r e d s p e c t r a were q u i t e s i m i l a r . However, r i n g opening , t o 166, followed by r e c l o s u r e gave (f)-ipomeamarone suggesting t h a t t h e l a t t e r substance i s t h e cis-diastereomer. F u l l d e t a i l s of t h i s s y n t h e s i s have n o t y e t appeared, s o t h a t
(144)
Monocarbocyclic Sesquiterpenes
233
t h e s t e r e o s e l e c t i v i t y i n t h e r i n g opening-reclosure sequence cannot be a s s e s s e d . 3.
MONOCARBOCYCLIC SESQUITERPENES
A.
Sesquiterpenes Related t o Bisabolene
l a r g e number of s e s q u i t e r p e n e s a r e r e l a t e d t o t h e bisabolenes 3 ) which probably a r i s e i n vivo by t h e c y c l i z a t i o n of "he members of t h i s c l a s s cis-A*-Tarnesyl pyrophosphate
A
(2 and
(1).
@-$?+@ -1
-3
2
(A),
which have been s y n t h e s i z e d a r e a-curcumene ar-tumerone ( 5 ) , n u c i f e r a l (k), 6-curcumene ( I ) ,y-curcumene (51, azTngiberene (9), 8-bisabolene y-bisabolene (21, i s o b i s a bolene (10) , l a n c e o l (11) , a - b i s a b o l o l (12) , cryptomerion ( 2 1 , todomatuic a c i d , juvabione , dehydrojuvabione (16) , and bilobanane Most of t h e s y n t h e s e s i n t h i s a r e a begin with a preformed six-membered r i n g and c e n t e r about v a r i o u s approaches t o t h e a d d i t i o n of t h e C-8 s i d e chain. Stereochemistry i s n o t a t y p i c a l problem i n t h i s s e r i e s ; only t h r e e of t h e compounds are capable of cis-trans isomerism. s y n t h e s i z e d (3, 6, Diastereomers a r e p o s s i b l e with a-zingiberene todomatuic a c i d (141, juvabione (g) , and dehydrojuvabione (2). However, t h e s y n t h e s e s t o d a t e have n o t reckoned w i t h t h i s d i f f i c u l t y . The recorded p r o g r e s s i n t h e a r e a c o n s i s t s mainly of v a r i o u s approaches to t h e carbon s k e l e t o n and methods f o r c o n t r o l l i n g t h e o x i d a t i o n l e v e l of v a r i o u s p o s i t i o n s on t h e b a s i c s k e l e t o n .
(14) (z).
(z),
(g)
11)
(z),
CHO
4 -
5 -
6
7 -
234
T o t a l S y n t h e s i s of S e s q u i t e r p e n e s
OH
10 -
14 15 -
R=H R=CH3
B. 8-Bisabolene, Bisabolol
11 -
13 -
12 -
16 y-Bisabolene,
17 -
Lanceol, Isobisabolene,
I n a p i o n e e r i n g p a p e r i n t h e area of s e s q u i t e r p e n e s y n t h e s i s , Ruzicka reported i n 1925 t h a t ( + ) - n e r o l i d o l (11-2, p . 200) i s dehydrated by acetic anhydride t o y i e l d a hydrocarbon mixture, from which h e succeeded i n p r e p a r i n g a c r y s t a l l i n e t r i s h y d r o c h l o r i d e , m.p. 79°-800.52 T h i s s u b s t a n c e w a s i d e n t i c a l w i t h t h e t r i s h y d r o c h l o r i d e o b t a i n e d from n a t u r a l b i s a b o l e n e . Treatment of t h e s y n t h e t i c t r i s h y d r o c h l o r i d e w i t h sodium acetate i n a c e t i c a c i d gave s y n t h e t i c b i s a b o l e n e , “ . . . w i e n a t l i r l i c k zu e r w a r t e n war, m i t dem a n a l o g a u s Naturprodukten i s o l i e r t e n Kohlenwasserstoff i d e n t i s c h
Monocarbocyclic S e s q u i t e r p e n e s
c1
-2
18 -
235
-3
Seven y e a r s l a t e r , Ruzicka r e p o r t e d a second s y n t h e s i s of y - b i s a b o l e n e , which i s summarized i n Scheme l.53 l-methylScheme 1.
R u z i c k a ' s Second B i s a b o l e n e S y n t h e s i s
19
-+ 20 -
LcozEt 1. N a
Br
2. BrCHzCH2Br
C02C2H5 22 -
0
OH
23 -
ir 25 -
24 -
26 -
21 -
1. H 3 0 + , A
_____c
2 . KOH
236
Total Synthesis of Sesquiterpenes
Cl
27 -
18 -
4 - a c e t y l c y c l o h e x e n e ( g )was l s y n t h e s i z e d by ozonolysis-dehyTo t h i s k e t o n e was added t h e d r a t i o n of B-terpineol G r i g n a r d r e a g e n t d e r i v e d from 2-methyl-5-bromo-2-pentene which w a s p r e p a r e d i n a s t r a i g h t f o r w a r d manner b e g i n n i n g w i t h , a c e t o a c e t i c e s t e r . The r e s u l t i n g a l c o h o l I " b i s a b o l o l " (2) r e a c t e d w i t h HC1 i n e t h e r t o g i v e b i s a b o l e n e t r i s h y d r o c h l o r i d e (la), which had p r e v i o u s l y been c o n v e r t e d t o " b i s a b o l e n e . I' M a n j a r r e z and Guzman r e p o r t a s y n t h e s i s of B-bisabolene b y c o u p l i n g t h e G r i g n a r d r e a g e n t d e r i v e d from bromide 2 w i t h a c i d c h l o r i d e 28, f o l l o w e d by W i t t i g m e t h y l e n a t i o n of t h e res u l t i n g k e t o n e 3.54
(19).
(g),
x Vig h a s r e p o r t e d two s y n t h e s e s of (f)-B-bisabolene , which a r e o u t l i n e d i n Scheme 2 . 5 5 1 5 6 The f i r s t s y n t h e s i s , r e p o r t e d i n 1966, b e g i n s w i t h 1-methyl-4-acetylcyclohexene (11) Alkyl a t i o n o f t h e d e r i v e d B-keto e s t e r 0w i t h 4-bromo-2-methylwhich was c o n v e r t e d i n t o d i e n o n e by hy2-butene gave 2, d r o l y s i s and d e c a r b o x y l a t i o n . W i t t i g m e t h y l e n a t i o n a f f o r d e d 2-Sisabolene. The second Vig s y n t h e s i s i s l o n g e r and was act u a l l y accomplished only as an a d j u n c t t o a s y n t h e s i s of
.
z
Scheme 2 .
JQ*
Vig's a - B i s a b o l e n e S y n t h e s e s F i r s t Synthesis
(Et:C)C=z
(EtO)2 C
30 -
21 -
31 -
32 -
.;.-'o,
2 -
Second S y n t h e s i s C02Et
H2-Pd/C
___c
33 -
NaBHlf_
34 -
CN
237
Total Synthesis of Sesquiterpenes
238
l a n c e o l , f o r which t h e l o n g e r r o u t e is n e c e s s a r y . The s y n t h e s i s b e g i n s w i t h c y a n o a c e t a t e 33, which w a s p r e p a r e d i n 4 1 % y i e l d by t h e KF-catalyzed c o n d e n s a t i o n of e t h y l c y a n o a c e t a t e and 4-methyl-3-cyclohexenone. The n e u t r a l cond e n s i n g a g e n t p r e v e n t s t h e r i n g d o u b l e bond from m i g r a t i n g i n t o conjugation with t h e a,B-unsaturated carbonyl function. Compound 33, which i s r e p o r t e d t o b e a v i s c o u s l i q u i d , i s p r e sumably a m i x t u r e of g e o m e t r i c a l isomers. The c o n j u g a t e d d o u b l e bond was t h e n s a t u r a t e d i n a most remarkably s e l e c t i v e h y d r o g e n a t i o n t o g i v e 34, which w a s reduced w i t h sodium borohydride t o g i v e g . Standard conversions transformed 2 i n t o 38, which w a s t r a n s e t h e r i f i e d w i t h e t h y l v i n y l ether t o 39. C l a i s e n r e a r r a n g e m e n t of 2 gave d i e n e a l d e h y d e 2, which was c o n v e r t e d i n t o (?I)-B-bisabolene b y t h e W i t t i g r e a c t i o n . F o r t h e s y n t h e s i s of ( ? ) - l a n c e o l (2) I a l d e h y d e 40 was condensed w i t h triethylphosphonopropionate t o g i v e a , B u n s a t u r a t e d e s t e r 41,r e p o r t e d l y formed e x c l u s i v e of t h e cis isomer. 5 6 Hydride r e d u c t i o n of y i e l d e d ( + ) - l a n c e o l (11).
-
41
0
1 I
( E t O ) 2P-CHC02Et
I
-
LiAlH4
CH3 40 -
OH
Monocarbocyclic Sesquiterpenes
239
(?)-Lance01 had p r e v i o u s l y been s y n t h e s i z e d by Manjarrez , Rios, and G ~ z m a nby ~ ~a r o u t e which unambiguously determined t h e geometry (then unknown) of t h e o l e f i n i c l i n k a g e . The synt h e s i s (Scheme 3) s t a r t s from enone (prepared by Diels-Alder Scheme 3.
Manjarrez-Rios-Guzman
S y n t h e s i s of
30 -
1. KOH-EtOH 2. H30' 3. CH2N2
-
( + ) -Lance01
42 -
@
CH20H
I
1. C H ~ O H , H +
2. LiAlHt, 3. H30'
C02Me
43 0
1. AcpO
2. $3P=CH2 3. L i A l H 4
p 44 -
OH
45
OH
11 -
condensation of i s o p r e n e and methyl v i n y l k e t o n e ) . Carbetho x y l a t i o n gave 0, which was a l k y l a t e d with methyl y-bromot i g l a t e , of known trans-geometry, t o y i e l d k e t o d i e s t e r 43. Hydrolysis, decarboxylation and r e - e s t e r i f i c a t i o n then afforded 44. A f t e r p r o t e c t i n g t h e k e t o n i c carbonyl a s i t s dioxolane d e r i v a t i v e , t h e e s t e r grouping was reduced, l e a d i n g t o k e t o a l c o h o l 45. W i t t i g methylenation of t h e d e r i v e d a c e t a t e gave, a f t e r removal of t h e a c e t y l p r o t e c t i n g group ( 2 ) - l a n c e o l (GI. Vig's group has r e p o r t e d a s y n t h e s i s of i s o b i s a b o l e n e (lo)which i s somewhat d i f f e r e n t from o t h e r work i n t h e c l a s s , s i n c e t h e six-membered r i n g i s n o t t h e s t a r t i n g p o i n t (Scheme 4 ) .50 Methyl heptenone (11-14) was carbethoxylated t o y i e l d
-
T o t a l S y n t h e s i s of S e s q u i t e r p e n e s
240
Scheme 4 .
Vig's Isobisabolene S y n t h e s i s
B r m C O g E t
( E t O ) 2C=O
NaH
11-14
46 -
C02Et
-
CH20H
I
1. H30'
CH20H __c
2. EtOH, H+
H+
48 -
41 -
Na
B-keto e s t e r 46. N o comment i s made r e g a r d i n g t h e apparent c l e a n s e l e c t i v i t y f o r t h e methyl group. However, a l l of t h e i n t e r m e d i a t e s i n t h e s y n t h e t i c sequence are l i q u i d s , and no c r y s t a l l i n e derivatives are reported. I t is therefore l i k e l y t h a t some i s o m e r i c m a t e r i a l s may be p r e s e n t a s s i d e p r o d u c t s . Keto e s t e r 46 was a l k y l a t e d with two e q u i v a l e n t s of e t h y l
Monocarbocyclic S e s q u i t e r p e n e s
241
8-bromopropionate, g i v i n g k e t o t r i e s t e r 47, which w a s hydrolyzed, decarboxylated, and r e - e s t e r i f i e d t o o b t a i n k e t o d i e s t e r 48. A f t e r k e t a l i z a t i o n , a Dieckman c y c l i z a t i o n y i e l d e d 50, which w a s hydrolyzed t o dione 5-1. The s y n t h e s i s of ( ? I i s o b i s a b o l e n e (10) was completed by a double W i t t i g r e a c t i o n . Kuznetsov and Myrsina r e p o r t t h a t ( f ) - b i s a b o l o l may be prepared from tetrahydro-p-toluonitrile (52) by t r e a t i n g it with 4-methyl-3-pentenylmagnesium bromide. The r e s u l t i n g d i enone (2) was t r e a t e d w i t h methylmagnesium bromide t o give ( ? ) - b i s a b o l o l (2) , presumably a mixture of d i a s t e r e o m e r ~ . ~ ~
-
(12)
0
1. L M g B r
NC\/\
C.
MqI
c
Curcumenes, Zingiberene
Perhaps t h e s i m p l e s t s e s q u i t e r p e n e r e l a t e d t o t h e b i s a b o l e n e s , from a s y n t h e t i c s t a n d p o i n t , i s a-curcumene The subs t a n c e occurs i n n a t u r e along w i t h i t s double bond isomer and t h e i s o l a t e d mixture of 4 and 53 h a s been r e f e r r e d t o a s (-)-a-curcumene. To avoid confusion w e s h a l l r e f e r t o 4 a s Most s y n t h e t i c work a-curcumene and 53 a s iso-a-curcumene. i n t h e a r e a h a s been d i r e c t e d toward t h e s y n t h e s i s of a mixt u r e of 4 and 53 which approximates t h e composition of t h e n a t u r a l l y d e r i v e d mixture.
(A).
-4
(z),
53 -
I n 1940, Simonsen, Carter, and W i l l i a m s synthesized acurcumene and iso-a-curcumene by t h e r o u t e shown i n Scheme 5.60 F r i e d e l - C r a f t s a c y l a t i o n o f t o l u e n e by g l u t a r i c anhydride g i v e s k e t o a c i d 54 i n l o w y i e l d . This substance was e s t e r i f i e d and t r e a t e d w i t h methylmagnesium i o d i d e t o give c r y s t a l l i n e a c i d 11,probably t h e trans isomer. Reduction of 55
242
T o t a l S y n t h e s i s of S e s q u i t e r p e n e s
Scheme 5 .
Simonsen S y n t h e s i s of a-Curcmene 0
1. MeOH, H
+
2 . MeMgI 3 . H30+ C02H
H2-Pd
1. MeOH, H+ 2 . MeMgI
OH
53 -
57 -
-4
y i e l d e d 56. Due t o t h e l o w y i e l d i n t h e f i r s t s t a g e , t h i s a c i d w a s a l s o p r e p a r e d by n i t r i l e c h a i n e x t e n s i o n of e t h y l y-p-tolyl-n-valerate. A d d i t i o n of G r i g n a r d r e a g e n t t o t h e which w a s c o r r e s p o n d i n g methyl e s t e r gave an a l c o h o l d e h y d r a t e d t o a m i x t u r e o f 5 and On t h e b a s i s o f o z o n i z a t i o n s t u d i e s , i t w a s concluded t h a t t h e l a t t e r isomer p r e dominated, w h i l e t h e n a t u r a l l y i s o l a t e d m i x t u r e i s m o s t l y t h e i s o p r o p y l i d i n e isomer (4). B i r c h and M u k h e r j i , i n a 1949 p a p e r p o i n t i n g o u t t h e u t i l i t y of d i s s o l v i n g metal r e d u c t i o n s i n s y n t h e s i s , r e c o r d s y n t h e s e s of a - , 8 - , and y-curcumene (Scheme 6 ) .61 Condensat i o n of p-tolylmagnesiwn bromide w i t h methylheptenone (11-14) S t e p w i s e h y d r o g e n o l y s i s and r e d u c t i o n of the gave a l c o h o l a r o m a t i c r i n g l e d t o ( ? ) -a-curcumene (4) and (?)-B-curcumene (1).F o r t h e s y n t h e s i s o f y-curcumene (2), methylheptenone w a s added t o t h e G r i g n a r d r e a g e n t d e r i v e d from p-bromoanisole. The r e s u l t i n g a l c o h o l w a s r e a d i l y d e h y d r a t e d upon workup w i t h
z.
z.
(z),
Monocarbocyclic Sesquiterpenes Scheme 6.
-
11-14
Birch Synthesis of t h e Curcumenes
58
11.
243
4 -
I
2. H30'
Na-NH3-EtOH
OMe
@
OMe
-7
59 -
Na- NH 3 -E t O H
2.
60 -
61 -
soc12-
-0
aqueous ammonium c h l o r i d e . Diene 2 was reduced t o t h e t e t r a hydro s t a g e , and t h e r e s u l t i n g enol e t h e r E w a s hydrolyzed t o g i v e dienone 61. Compound 61 was formulated a s t h e B,yisomer because of i t s l a c k of a b s o r p t i o n i n t h e 220-280 mp region. Addition of methylmagnesium bromide t o 61 and dehydrat i o n of t h e r e s u l t i n g a l c o h o l gave (f)-y-curcumene (8). I n t h r e e 1965 p a p e r s , Rao and Honwad r e p o r t e d t h e synt h e s e s of a-curcumene o u t l i n e d i n Scheme 7 . 6 2 1 6 3 I n t h e s i m p l e s t , 6 2 Rao reduced methylheptenone (obtained by r e v e r s e
Total S y n t h e s i s o f Sesquiterpenes
244
Scheme 7 .
co, 14 -
62 -
Rao's a-Curcumene
Syntheses
63 -
4 -
&p...pL@ +-p 6-
2 . EL ti O AH l H, 4 H+
@
PBr3-
@.
w5
2 . CH3-
C02H
COCH 3
Br
OH
64
66
HOAc
57
/
4 -
c1
OH
67
53 -
+(
P +3p=c<:;
CHO
OH
65 -
68 -
-4
a l d o l i z a t i o n of p u r i f i e d c i t r a l ) with LiAlHt, t o o b t a i n alcohol The d e r i v e d p - t o l u e n e s u l f o n a t e e s t e r w a s treated w i t h ptolylmagnesium bromide t o g i v e ( + I -a-curcumene i n approxim a t e l y 1 0 %y i e l d . I n c o n j u n c t i o n w i t h a s t u d y which e s t a b l i s h e d t h e absol u t e c o n f i g u r a t i o n o f (-)-a-curcumeneI6 Honwad and Rao synt h e s i z e d a m i x t u r e of ('1-a-curcumene and (+)-iso-a-curcumene (53) from Rupe's y - p - t o l y l - n - v a l e r a t e (64). 6 4 A f t e r e s t e r i f i c a t i o n and h y d r i d e r e d u c t i o n , a l c o h o l w a s o b t a i n e d . The G r i g n a r d r e a g e n t d e r i v e d from t h e c o r r e s p o n d i n g bromide w a s added t o a c e t o n e t o y i e l d a l c o h o l 57. T h i s a l c o h o l w a s
62.
(fl)
Monocarbocyclic S e s q u i t e r p e n e s
245
converted i n t o c h l o r i d e 67,which was dehydrochlorinated w i t h sodium a c e t a t e i n a c e t i c a c i d t o i e l d 4 and 53. I n a s e p a r a t e c o m u n i c a t i o n , f 3 it was r e p o r t e d that alcoh o l 65 may be o x i d i z e d by S a r e t t ' s r e a g e n t t o y i e l d aldehyde 68. Treatment of 68 with isopropylidinetriphenylphosphorane g i v e s ( 2 ) -a-curcumene (4) Although Birch61 and Rao62,63 had prepared pure ( + ) - a curcumene, uncontaminated with (+)-iso-a-curcumene, Vig was t h e f i r s t t o s y n t h e s i z e each isomer i n a p u r e s t a t e (Scheme 8 ) .65 Rupe's a c i d (64)6 4 was converted, by hydride r e d u c t i o n
-
.
Scheme 8.
64
-
ro,
V i g ' s S y n t h e s i s of (+I-a-Curcumene and ( + I -iso-a-Curcumene
Me-N I
I
69 -
68 -
6
COOEt
65 -
I 1. L i A l H t ,
1
2. P B r 3
4 -
ro\ Br
66 -
of i t s N-methylanilide (2) i n t o aldehyde 68. A l t e r n a t i v e l y , gave an a l c o h o l , which was r e d u c t i o n of t h e e t h y l e s t e r converted i n t o bromide 66. A c e t o a c e t i c e s t e r s y n t h e s i s on 66 gave methyl ketone 2. Appropriate W i t t i g r e a c t i o n s on 68 and 70 gave t h e i s o m e r i c a-curcwnenes.
-
246
T o t a l S y n t h e s i s of S e s q u i t e r p e n e s
I n 1968, J o s h i and K u l k a r n i r e p o r t e d a s y n t h e s i s of ( - ) z i n g i b e r e n e ( 9 ) and ( - ) -a-curcumene (4) from ( + ) - c i t r o n e l l a 1 (Scheme 9 ) .66- C i t r o n e l l a 1 (2) w a s c o n v e r t e d , by S t o r k ' s Scheme 9.
J o s h i - K u l k a r n i S y n t h e s i s of a-Curcumene
po 71 -
72 -
MeMgI
H2C204
___c
A
73 -
2.
75 -
a 53 -
-4
enamine method, i n t o cyclohexenone 2. The s u b s t a n c e i s presumably a m i x t u r e of d i a s t e r e o m e r s . When t h i s enone was t r e a t e d w i t h methylmagnesium bromide and t h e r e s u l t i n g a l c o h o l (2) d e h y d r a t e d w i t h o x a l i c a c i d , a hydrocarbon m i x t u r e (75) w a s o b t a i n e d . The a u t h o r s s t a t e t h a t vpc a n a l y s i s o f the mixt u r e shows t w o compounds, i n a r a t i o o f 7 : 3 , b u t t h a t t h e i n f r a r e d s p e c t r u m o f the m i x t u r e i s s u p e r i m p o s a b l e on t h a t of n a t u r a l (-1-zingiberene. I n any e v e n t , d e h y d r o g e n a t i o n of m i x t u r e 75, by p y r o l y s i s o f i t s maleic a n h y d r i d e a d d u c t o v e r a f r e e f l a m e , gave a m i x t u r e o f 4 and Although t h i s synt h e s i s of t h e curcurnene isomers i s p r o b a b l y v a l i d , t h e unc e r t a i n t y s u r r o u n d i n g t h e r e l a t i v e s t e r e o c h e m i s t r y o f t h e two asymmetric c e n t e r s i n t h e J o s h i - K u l k a r n i " z i n g i b e r e n e " remains. I n an p r o b a b i l i t y , t h e a c t u a l s y n t h e t i c material w a s
2.
Monocarbocyclic Sesquiterpenes
247
a mixture of all possible isomers. Other nonstereospecific syntheses of zingiberene had previously been reported by Mukherji and Bhatta~haryya~~ and Banerjee.6 8 For the Mukherji-Bhattacharyya synthesis (Scheme lo), the starting point was the enone 61 utilized by Mukherji Scheme 10. Mukherji-Bhattacharyya Synthesis of Zingiberene
61 -
73 -
9 -
and Birch in the synthesis of y-curcumene (Scheme 6 ) . From this point, the synthesis is identical to that of Joshi and Kulkarni, which it predates by 15 years. The synthetic mixture gave an ultraviolet spectrum quite similar to that of isolated zingiberene. Banerjee's 1962 synthesis is also identical to the earlier Mukherji-Bhattacharyya synthesis.
D.
ar-Tunnerone
Rupe has synthesized (+I-ar-turmerone (2) as outlined in Scheme 11. r 7 0 Reformatsky reaction of ethyl bromoacetate Scheme 11.
Rupe's Synthesis of (2)-ar-turmerone
___c
.___c
2 . Me2Zn
70 -
NaOMe
79 -
-5
T o t a l S y n t h e s i s of S e s q u i t e r p e n e s
248
and p-methylacetophenone gave c r y s t a l l i n e a l c o h o l 76, which was d e h y d r a t e d b y f o r m i c a c i d t o t h e d i m e t h y l cinnamic a c i d 77. Hydrogenation over n i c k e l gave a c i d 78. T r e a t m e n t o f the d e r i v e d a c i d c h l o r i d e w i t h d i m e t h y l z i n c gave, i n q u a n t i t a t i v e y i e l d , (+)-curcumone ( E ) ,i t s e l f isolable from n a t u r a l s o u r c e s . When t h e s y n t h e t i c curcumone was condensed w i t h acet o n e , i n t h e p r e s e n c e o f sodium methoxide, a v e r y l o w y i e l d of ( f ) - a r - t u r n e r o n e (2) w a s o b t a i n e d . The same group h a s p r o v i d e d t h r e e d i f f e r e n t s y n t h e s e s o f dihydro-ar-turmerone (80)which were i n s t r u m e n t a l i n e s t a b l i s h i n g t h e s t r u c t u r e of t h e s e ~ q u i t e r p e n e . ~The ~ Rupe r o u t e s t o t h e d i h y d r o m a t e r i a l are d i s p l a y e d w i t h o u t f u r t h e r comment i n Scheme 1 2 .
-
Scheme 1 2 .
h+-
’ c1
0
!+
Rupe’s S y n t h e s e s of (+)-Dihydro-ar-turmerone
IZnT
0
/
80 -
+
h+ C02Et
I
Na-C-COzEt I
0/
dH
/\
CH3
___t
H 30+ ~
80 -
CH3
Colonge and Chambion, i n 1 9 4 6 , r e p o r t e d t h e u s e of Rupe’s a c i d (2) i n a s u c c e s s f u l s y n t h e s i s of ( f ) - a r - t u n n e r o n e . Treatment o f t h e d e r i v e d a c i d c h l o r i d e ( g )w i t h i s o b u t y l e n e i n t h e p r e s e n c e of aluminum c h l o r i d e gave ( e l - a r - t u r m e r o n e i n 50% y i e l d . ’ l
0
81 -
Monocarbocyclic Sesquiterpenes
249
I n 1947, Mukherji provided an "unambiguous" s y n t h e s i s ,72 s t a r t i n g w i t h aldehyde 82 (Scheme 13), which i s prepared from p-methyl-acetophenone. Compound was reduced with z i n c i n a c e t i c a c i d t o a l c o h o l 83. The Grignard r e a g e n t d e r i v e d from t h e corresponding bromide (84) was added t o t h e p i p e r i d i d e of 3-methyl-2-butenoic a c i d t o o b t a i n (&)-ar-turmerone. Scheme 13.
Mukherji's S y n t h e s i s of (5)-ar-turmerone
82 -
83 -
84 -
Twelve y e a r s l a t e r , Gandhi, Vig, and Mukherji provided a n o t h e r "unambiguous" s y n t h e s i s of (+) -ar-turmerone , o u t l i n e d i n Scheme 14.73 Scheme 1 4 .
Gandhi-Vig-Mukherji S y n t h e s i s of ( ? ) -ar-Tumerone
NH4 OAC
H2-Pd-C
___c
EtOH HOAc
Total S y n t h e s i s of Sesquiterpenes
250
1.
soc12
2 . Me2Cd C02H
70 ( E t O ) 2C=O
CH20H
I
I
Nuciferal
E.
N u c i f e r a l (6) h a s been s y n t h e s i z e d by Vig and c o - ~ o r k e r s , ’ ~ Honwad and Ra0,63 and by BUchi and W i l e ~ t . ’ ~ The Vig and the Honwad-Rao s y n t h e s e s a r e i d e n t i c a l (Scheme 1 5 ) and b e g i n w i t h
ro,
Scheme 1 5 .
I
p
Vig-Honwad-Rao
II I
+ (Et0)2P-CHC02Et
68 -
91 -
-
0 CH3
CHO
OH
S y n t h e s i s of N u c i f e r a l
LiAlH4
p2E
__c
NaH
Mn02=_
CHO
6
Monocarbocyclic Sesquiterpenes
251
aldehyde 68, which w a s t h e key i n t e r m e d i a t e i n t h e s y n t h e s i s of a-curcumene (Schemes 7 and 8 ) . Condensation of t h i s aldehyde w i t h triethylphosphonopropionate gave e x c l u s i v e l y t h e trans ester El which was reduced by L i A l H 4 t o a l l y l i c a l c o h o l 91. Oxidation of 2 with manganese d i o x i d e gave ( + ) - n u c i f e r a l The BUchi-WUest s y n t h e s i s (Scheme 16) a l s o proceeds v i a
-
Scheme 16.
BUchi-WUest N u c i f e r a l S y n t h e s i s
0 0
0
92 -
0
93 -
0
L/
94 -
aldehyde E l which w a s prepared by adding t h e Grignard rea g e n t from bromide 92 t o p-methylacetophenonel hydrogenolysis of t h e r e s u l t i n g b e n z y l i c a l c o h o l (93)and h y d r o l y s i s of t h e a c e t a l grouping. The remaining t h r e e carbons were added s t e r e o s p e c i f i c a l l y by a W i t t i g d i r e c t e d a l d o l condensation ( c f . BUchi's s y n t h e s i s o f s i n e n s a l , Scheme 201, y i e l d i n g racemic nuciferal. F.
Cryptomerion
Vig and c-workers have r e p o r t e d t h e s y n t h e s i s of ( + ) - c r y p t o merion (2) which i s o u t l i n e d i n Scheme 17.76 The theme of t h i s s y n t h e s i s , u t i l i z a t i o n of t h e C l a i s e n rearrangement t o elaborate a five-carbon a l d e h y d i c s i d e - c h a i n which i s converted i n t o t h e r e q u i s i t e i s o p r o p y l i d i n e moiety by a W i t t i g r e a c t i o n , i s s i m i l a r t o t h e approach used i n t h e s y n t h e s i s of 6-bisabolene (Scheme 2 ) 6-Methyl-2-cyclohexenone (96)I obtained by w a s converted Birch r e d u c t i o n of o-cresol methyl e t h e r i n t o k e t o d i e s t e r 91 by Michael a d d i t i o n of d i e t h y l malonate.
.
(z)
Scheme 1 7 .
V i g ' s S y n t h e s i s of
95 -
(+I-Cryptomerion
96 -
99 -
100 -
(+J?
OH
101 -
&
"
102 -
CHO
103 -
104 -
1. PTAB
2. CgHgN,A
25 2
e0
-
Monocarbocyclic Sesquiterpenes
253
After ketalization, the diester was selectively hydrolyzed to give acid 2. This material was subjected to a Mannich reaction to give unsaturated ester E l which was reduced with LiA1Hb to give allylic alcohol E. After chain extension via vinyl ether E,the resulting aldehyde (103)was treated with isopropylidinetriphenylphosphorane to give diene 104. The protecting group was removed by hydrolysis and the resulting ketone brominated with phenyltrimethylammonium perbromide (PTAB). Dehydrobromination afforded (f)-cryptomerion (13).The selectivity in the last two stages of the synthesis is remarkable. No isomeric products are reported to be formed in either the bromination or dehydrobromination steps.
G.
Todomatuic Acid and Juvabione
Todomatuic acid was first isolated in 1940 from a byproduct of the sulfite pulp industry in Japan.77 The correct structure (14)was assigned in 1941 by M ~ r n o s e . ~In~ more recent years, the methyl ester of todomatuic acid ("juvabione," 15) and the related dehydrojuvabione (16) have been isolated from balsam fir and shown to have high juvenile hormone activity.79f80 A n early synthesis of ( 2 ) -desoxotodomatuic acid (106) has been followed by four syntheses of juvabione (15)82-85
14: R=H 15: R'CH3
106 -
16 -
and a nonstereoselective synthesis of dehydrojuvabione (16) ,86 The Nakazaki-Isoe synthesis of (f)-desoxotodomatuic acid (106)carried out in order to confirm Momose's structure assignment, is outlined in Scheme Anisole was acylated Scheme 18. Nakazaki-Isoe Synthesis of (+)-Desoxytodomatuic Acid
254
T o t a l S y n t h e s i s of S e s q u i t e r p e n e s
HI
OMe
OMe
108 -
109 -
110 -
Po
111 -
KCN
OAc
__c
--
1. 600' 2 . NaOEt
Ac20
112
HOAc
.A 11 3 -
3 . H+ CN
w i t h 5-methylh x a n o y l c h l o r i d e t o y i e l d k e t ne 107,which I S t r e a t e d w i t h methylmagnesium bromide t o a f f o r d a l c o h o l 108. This a l c o h o l was d e h y d r a t e d and t h e r e s u l t i n g a l k e n e hydroDemethylation gave p h e n o l genated t o give phenyl e t h e r 110, which was hydrogenated t o g i v e a l c o h o l (diastereomeric which r e a c t e d w i t h KCN m i x t u r e ? ) . O x i d a t i o n of 111 gave i n a c e t i c a n h y d r i d e t o g i v e cyanohydrin a c e t a t e 113. P y r o l y s i s of 113, f o l l o w e d by a l k a l i n e h y d r o l y s i s gave a r a c e m i c desoxotodornatuic a c i d (106).Although t h i s m a t e r i a l is most proba b l y a d i a s t e r e o r n e r i c m i x t u r e , from i t s mode of s y n t h e s i s , i t s i n f r a r e d spectrum w a s "superimposable on t h a t of (+) -desoxotodornatuic a c i d , " o b t a i n e d by Wolff-Kishner r e d u c t i o n o f ( + ) todomatuic a c i d .
-
*.
112,
111
Monocarbocyclic Sesquiterpenes
255
The Mori-Matsui synthesis of todomatuic acid and juvabione (Scheme 19)follows an outline similar to most work on Scheme 19. Mori-Matsui Synthesis of (f.)-TodomatuicAcid and ( 2 )-Juvabione
1. Zn, BrCH2C02Et OMe
114 ~
h
C02Et
H2-Ni
2. H30'
115 -
-
1. KOH, EtOH
OMe 2. SOC12
Me2NH
eOMe 116
117 -
LiAlH (OEt)3
118 -
HO
-
-:;1Q. 120 -
HO
CHO
OMe
122
OMe
OMe
-
119
32%
121 -
-
Ho+o
123 -
256
AcO
Go-+ T o t a l S y n t h e s i s of S e s q u i t e r p e n e s
C g H g N AcO
124 -
CN
125
+
A
127 -
bisabolane-type compounds (attachment of t h e C-8 s i d e c h a i n o n t o a p r e e x i s t i n g r i n g , followed by o x i d a t i o n - r e d u c t i o n chemi s t r y t o e s t a b l i s h t h e p r o p e r f u n c t i o n a l i t y ) .82 The s y n t h e s i s i s n o t s t e r e o s e l e c t i v e , l e a d i n g t o a mixture of (+)-todomatuic acid and i t s d i a s t e r e o m e r ( 1 2 7 * ) . However, t h e workers c l e a n l y s e p a r a t e t h e two r a c e m a t Z ( v i a t h e i r semicarbazones) and g i v e some u s e f u l information r e g a r d i n g t h e s p e c t r a l and chromatographic p r o p e r t i e s of such d i a s t e r e o m e r s . Although i s c r y s t a l l i n e (m.p. 65D-660) and i s not, the infrared s p e c t r a of t h e two racemates a r e almost i d e n t i c a l . The corresponding methyl e s t e r s , ( + ) - j u v a b i o n e and i t s d i a s t e r e o m e r , could n o t be s e p a r a t e d b y vpc. These o b s e r v a t i o n s r e l a t e t o
(14)
127
14
*At t h e time of t h i s s y n t h e s i s , t h e s t e r e o c h e m i s t r y of todomatuic a c i d and juvabione w a s n o t c o r r e c t l y known. Todomatuic a c i d had been i n c o r r e c t l y assigned s t r u c t u r e 127 on t h e b a s i s of molecular r o t a t i o n . ' l The c o r r e c t s t e r e o c h e m i s t r y was l a t e r deduced by t h e Hoffman-LaRoche group . 8 4 b
Monocarbocyclic S e s q u i t e r p e n e s
257
t h e stereochemical homogeneity of t h e s y n t h e t i c z i n g i b e r i n e of J o s h i and Kulkarni (Scheme 91, Mukherji and Bhattacharyya (Scheme 10) and t h e s y n t h e t i c desoxo-todomatuic a c i d of Nakaz a k i and I s o e (Scheme 1 8 ) . In t h e s e v a r i o u s c a s e s , l i q u i d p r o d u c t s were o b t a i n e d which were assayed by i n f r a r e d s p e c t r a and vpc. I f t h e o b s e r v a t i o n s r e g a r d i n g t h e d i a s t e r e o m e r i c todomatuic a c i d s and juvabiones a r e extended t o t h e s e s i m i l a r systems, then one e x p e c t s l i t t l e d i f f e r e n c e i n t h e s p e c t r a l and chromatographic p r o p e r t i e s of such diastereomers. I t i s t h e r e f o r e h i g h l y l i k e l y t h a t t h e above-mentioned s y n t h e s e s a r e nonstereoselective. S h o r t l y a f t e r t h e Mori-Matsui s y n t h e s i s w a s announced, Ayyar and Rao r e p o r t e d an e s s e n t i a l l y i d e n t i c a l s y n t h e s i s (Scheme 20) .86 Ayyar and Rao o b t a i n e d t h e racemate m e l t i n g a t Scheme 20.
Ayyar-Rao S y n t h e s i s of (2)-Todomatuic Acid and ( 2 )-Juvabione
U
128 -
OMe
OMe
129 See Scheme 16 HO
-
1 4 + 127 -
65'-66O, corresponding t o t h e r e l a t i v e s t e r e o c h e m i s t r y i n (+)-todornatuic a c i d , by r e g e n e r a t i o n of t h e a c i d from i t s p u r i f i e d S-benzylthiouronium s a l t . They d i d n o t i s o l a t e t h e o t h e r p u r e racemate, although i t was undoubtedly produced by t h e i r route. I n 1968, a group a t Hoffmann-LaRoche, headed by Beverly A. Pawson, r e p o r t e d an e l e g a n t t r a n s f o r m a t i o n of R-(+)-limonene (130) i n t o (+)-todomatuic a c i d and ( + ) - j u v a b i o n e , which e s t a b l i s h e d t h e a b s o l u t e c o n f i g u r a t i o n i n t h e two s e s q u i t e r p e n o i d s a s 4 (R) , 8 ( S ) . 8 4 The s y n t h e s i s , o u t l i n e d i n Scheme 2 1 , begins with t h e s e l e c t i v e hydroboration of R- ( + ) -1imonene (130)with disiamylborane. The r e s u l t i n g mixture of 4 ( R ) , 8 ( R ) - and 4 ( R ) ,8( S )-p-menth-1-3-en-9-01~ was p u r i f i e d by r e c r y s t a l l i z a t i o n o f t h e corresponding 3 , s - d i n i t r o b e n z o a t e s . The l e s s solub l e e s t e r was hydrolyzed t o g i v e t h e u n s a t u r a t e d a l c o h o l 131.
Total Synthesis of Sesquiterpenes
258
Scheme 2 1 .
Hof fman-LaRoche S y n t h e s i s of (+) -Todomatuic Acid and ( + ) -Juvabione 1. T s C l
CH3 CH3
+
I
I
(CH3CH-CH)zBH
___c
OH
130 -
CN 132 -
2. NaCN
---C
131 1. 0 2 , hv, s e n s 2. cr03 3. AgqO
2. H ~ O + 133 -
I
This a l c o h o l w a s determined by x-ray a n a l y s i s t o be t h e 4 ( R ) , 8 ( R ) i s o m e r , 8 7 i n c o n t r a d i c t i o n t o t h e p r e v i o u s assignment.*' The corresponding p - t o l u e n e s u l f o n a t e was d i s p l a c e d w i t h sodium cyanide t o g i v e n i t r i l e 132, which r e a c t e d w i t h i s o b u t y l l i t h i u m t o g i v e , a f t e r h y d r o l y s i s , t h e u n s a t u r a t e d ketone This s u b s t a n c e was o x i d i z e d s u c c e s s i v e l y w i t h s i n g l e t oxygen, chromic a c i d , and s i l v e r o x i d e t o y i e l d (+)-todomatuic a c i d (m.p. 64.Oo-65.5O), which y i e l d e d (+)-juvabione on esterificat i o n . The e x a c t mechanism of t h e o x i d a t i o n sequence i s obs c u r e , and probably i n v o l v e s t h e following s t e p s :
133.
The juvabione s y n t h e s i s r e p o r t e d by Birch and co-workers
Monocarbocyclic Sesquiterpenes
is outlined in Scheme 22.85
The relative stereochemistry at
a+&XW& Scheme 22.
Birch's Juvabione Synthesis Me
OMe
136 -
135 -
134 -
[ @1 HO
' 0
HO
7
@ 139 -
138 -
HCN
HC1 MeOH
__c
__c
dH
142 -
143 -
+ 144 -
OH
lo
137 -
mo2
140 -
141 -
259
145 -
260
T o t a l Synthesis of Sesquiterpenes
1. Ca-NH3 ____c
146 -
A
15 -
t h e t w o a d j a c e n t asymmetric c a r b o n s i s e s t a b l i s h e d by a D i e l s Alder r e a c t i o n between l-methoxy-l13-cyclohexadiene (formed by i n s i t u i s o m e r i z a t i o n o f t h e 1 , 4 - i s o m e r ) and trans-6-methyl(135) Unformtunately , t h e " a n t i " and "syn" hept-2-en-4-one adducts and 137 are o b t a i n e d i n e q u a l amunts, a l t h o u g h a c o n s i d e r a t i o n of t h e A l d e r - S t e i n r u l e p r e d i c t s t h a t the des i r e d d i a s t e r e o m e r 137 would b e t h e p r e p o n d e r a n t p r o d u c t . However, t h e r i g i d i t y of t h e b i c y c l i c skeleton provides s u f f i c i e n t difference i n t h e physical p r o p e r t i e s of the t w o diastereomers t h a t t h e y may b e s e p a r a t e d by f r a c t i o n a l d i s t i l l a t i o n . Isomer 137 i s t r e a t e d w i t h a c i d , whereupon a t y p e of " r e v e r s e a l d o l c o n d e n s a t i o n " o c c u r s t o y i e l d d i k e t o n e 138, a s a s t e r e o c h e m i c a l l y homogeneous s u b s t a n c e . Sodium b o r o h y d r i d e r e d u c t i o n gave 139, a d i a s t e r e o m e r i c m i x t u r e , which w a s oxid i z e d by manganese d i o x i d e . The e x p e c t e d k e t o a l c o h o l 140 w a s n o t o b t a i n e d , due t o i n t r a m o l e c u l a r c o n j u g a t e a d d i t i o n of t h e hydroxyl group o n t o t h e enone system. The a c t u a l p r o d u c t isoand 142. Although b o t h l a t e d was a m i x t u r e of k e t o ethers d i a s t e r e o m e r s can y i e l d j u v a b i o n e , s i n c e t h e s t e r e o c h e m i s t r y of t h e i s o b u t y l s i d e - c h a i n w i l l be l o s t i n a p e n t u l t i m a t e s t e p , o n l y t h e major isomer ( o f unknown c o n f i g u r a t i o n a t t h a t cent e r ) was c a r r i e d on. The d e r i v e d cyanohydrin (143)w a s conv e r t e d by m e t h a n o l i c H C 1 i n t o a hydroxy e s t e r (=), which w a s dehydrated t o y i e l d a mixture of and 146 i n a r a t i o o f 1 : 2 . The l a t t e r s u b s t a n c e was r e d u c t i v e l y opened w i t h calcium i n l i q u i d ammonia t o g i v e an a l c o h o l , which was o x i d i z e d t o ( + ) - j u v a b i o n e (15). The B i r c h s y n t h e s i s , w h i l e n o t s t e r e o s e l e c t i v e i n t h e f i r s t s t e p , p r o c e e d s w i t h good s t e r e o s e l e c t i v i t y a f t e r 136 and 1 3 7 have been s e p a r a t e d , and p r o v i d e s p u r e samples o f 14 ( a n d , i n theory, of i t s diastereomer). A s h o r t e r , nonstereoselec(1) t i v e s y n t h e s i s p r o c e e d s from 138 by t h e f o l l o w i n g steps: h y d r o g e n a t i o n of t h e d o u b l e bond, ( 2 ) s e l e c t i v e r e a c t i o n of the cyclohexanone c a r b o n y l w i t h HCN, (3) c o n v e r s i o n o f t h e n i t r i l e g r o u p i n t o a methyl e s t e r , and ( 4 ) d e h y d r a t i o n of t h e a-hydroxy e s t e r w i t h POC13.
136
.
141
145
-
Monocarbocyclic Sesquiterpenes
261
It is interesting that, although the synthesis provides authentic juvabione in a stereorational manner, the authors did not recognize that the accepted stereochemistry of the hormone was in error. The oversight apparently came about through an error in formulating the ring opening reaction of intermediate 137. In their communication, Birch and co-workers formulate the reaction as follows:
A
137 -
147 -
148 -
Intermediate 147 would indeed have given a juvabione of structure 148. The Mori-Matsui s nthesis of (5)-dehydrojuvabione (16)is outlined in Scheme 23.tj6 The synthesis proceeds in a straightScheme 2 3 .
Mori-Matsui Synthesis of (*)-Dehydrojuvabione
149
117 -
MeMgBr
C02Et 150
-
HO
OMe CO2Et 151 -
)p-Po-
262
HO
T o t a l S y n t h e s i s of S e s q u i t e r p e n e s
OMe
.:.;p.OH
HO
1. L i - N H 3 HO
152 -
1. HCN
AcoJpo
___c
2. ~ 0 ~ 1 3 C5H5N
OAc
pcN 154 -
OH
AcO
153 -
OH
155 -
C02H
-Ho+
OAc
156 -
OH
1. CrO3
2. HC1-12 3 . CH2N2
157 -
forward f a s h i o n , t h e r e l a t i v e s t e r e o c h e m i s t r y b e i n g e s t a b l i s h e d n o n s e l e c t i v e l y i n t h e cyanohydrin dehydration s t a g e . A mixture of ( f ) - d e h y d r o j u v a b i o n e and d i a s t e r e o m e r 158 was s u r e l y obt a i n e d , b u t was n o t s e p a r a t e d . H.
Perezone
P e r e z o n e i s t h e o n l y known s e s q u i t e r p e n e q u i n o n e . The i n i t i a l and i n 1942 Yamaguchi s t r u c t u r e a s s i g n e d t o p e r e z o n e was r e p o r t e d a n unambiguous s y n t h e s i s of 1 6 0 , t h e d i h y d r o d e r i v a t i v e o f 159.89 However, l a t e r w o r k g o m h a s shown t h a t perezone i s c o r r e c t l y r e p r e s e n t e d by s t r u c t u r e 161.
159,
Monocarbocyclic S e s q u i t e r p e n e s
160 -
159 -
263
161 -
I n 1965, C o r t e s , Salmon, and Walls r e p o r t e d an i n e f f i c i e n t s y n t h e s i s of (?)-perezone, which i s o u t l i n e d i n Scheme 2 4 . 9 2 The l i t h i o d e r i v a t i v e of 3,5-dimethoxytoluene (162) was
-
Scheme 24.
Walls-Salmon-Cortes
S y n t h e s i s of (+I-Perezone
-
1. n-BuLi
1. S i O g
2 . Na-NH3
Me0
162
@- @ OMe
163 5% H2S04
____c
$$,
I OMel
164 -
165 -
10"
I
161 a l c o h o l 163 i n
t r e a t e d w i t h 6-methylhept-5-en-2-one t o give 18%y i e l d . This b e n z y l i c a l c o h o l was dehydrated ( s i l i c a g e l ) and t h e r e s u l t i n g alkene reduced t o y i e l d t h e d i e t h e r 164. This s u b s t a n c e was o x i d i z e d , i n 7% y i e l d t o t h e methyl e t h e r of perezone (1651, which w a s demethylated i n 4 % y i e l d by s t i r r i n g with d i l u t e s u l f u r i c a c i d .
I.
Bilobanone
(x)
Bilobanone h a s been s y n t h e s i z e d i n o p t i c a l l y a c t i v e form by BUchi and WUest (Scheme 25)P3 (+)-Carvone was oxid i z e d by selenium d i o x i d e i n e t h a n o l t o k e t o aldehyde 167 i n 60% y i e l d . Compound 167 r e a c t e d with 3-methyl-1-butynyl-
(166)
264
T o t a l S y n t h e s i s of S e s q u i t e r p e n e s Scheme 25.
BUchi-WUest Bilobanone S y n t h e s i s
A168
magnesium bromide t o g i v e a l c o h o l 168,which r e a r r a n g e d i n m i n e r a l a c i d t o isomer 169. M e r c u r i c s u l f a t e c a t a l y z e d cyc l i z a t i o n o f 169 a f f o r d e d (+) - b i l o b a n o n e (E)
.
Furoventalene
J.
The C-15 b e n z o f u r a n f u r o v e n t a l e n e (1771 i s i n t e r e s t i n q i n t h a t i t s i s o p r e n o i d s k e l e t o n is a p p a r e n t l y n o t d e r i v e d from f a r n e s y l p y r o p h o s p h a t e . The compound w a s s y n t h e s i z e d by Weinheimer and Washecheck a s o u t l i n e d i n Scheme 26. 9 4 m-bromophenoxyacetone Scheme 26.
Weinheirner-Washecheck
O0y
S y n t h e s i s of F u r o v e n t a l e n e
+
Br
170 -
0
1. Mg
_ I
Monocarbocyclic S e s q u i t e r p e n e s
175 -
OH
174 -
&T$-a-{+ 176 -
265
isomers 177 -
(170)w a s c y c l i z e d w i t h p o l y p h o s p h o r i c a c i d t o g i v e a m i x t u r e of bromobenzofurans and 172. The minor isomer, was c o n v e r t e d i n t o t h e c o r r e s p o n d i n g Grignard r e a g e n t , which was added t o 4,4-ethylenedioxypentanal (173)t o g i v e a l c o h o l Compound w a s hydrogenolyzed, w i t h concommitant r e d u c t i o n of t h e f u r a n r i n g . A f t e r d e h y d r o g e n a t i o n , k e t o n e = w a s obt a i n e d ( t h e k e t a l h a v i n g been h y d r o l y z e d d u r i n g t h e hydrow a s condensed w i t h methylg e n o l y s i s s t e p ) . Compound magnesium bromide and t h e r e s u l t i n g a l c o h o l d e h y d r a t e d . The p r o d u c t of t h e d e h y d r a t i o n was f u r o v e n t a l e n e (E), its term i n a l double bond isomer and a t r i c y c l i c a l k y l a t i o n p r o d u c t .
171
172, 174.
174
175
K.
Elemanes
S e s q u i t e r p e n e s o f t h e elemane class [ i . e . , 8-elemene (E), elemol (179) , s a u s s u r e a l a c t o n e (180) 1 were o r i g i n a l l y t h o u g h t t o a r i s e b y i n v i v o Cope rearrangement of c y c l o f a r e s y l c a t i o n . ’ However, t h e o b s e r v a t i o n t h a t t h e a c t u a l c y c l o d e c a d i e n e
178 -
179 -
180 -
266
T o t a l S y n t h e s i s of S e s q u i t e r p e n e s
p r e c u r s o r s "co-occur" w i t h v a r i o u s elemanes and t h a t any app l i c a t i o n of h e a t d u r i n g t h e i s o l a t i o n p r o c e s s i n c r e a s e s t h e " y i e l d " of elemanes h a s r a i s e d a doubt a s t o whether members of t h i s class a r e bona f i d e p l a n t product^.^ However, t h e synt h e t i c problems a r e o f i n t e r e s t and w e s h a l l a c c o r d i n g l y d i s cuss elemane s y n t h e s i s a t t h i s p o i n t . Of t h e compounds i n t h e group which have been s y n t h e s i z e d (178, 179, 1 8 0 ) , t h e former two c o n t a i n t h r e e asymmetric cent e r s and can t h e r e f o r e e x i s t a s f o u r racemates. S a u s s u r e a l a c tone (=) h a s f i v e c e n t e r s of asymmetry and s i x t e e n racemates are p o s s i b l e . ?tro approaches have been taken t o t h e problem o f e l a b o r a t i n g t h e g r o s s s k e l e t o n . Tetrahydrosaussurea l a c tone (=) , 9 5 s a u s s u r e a l a c t o n e I g 6 B-elemene and elemolg7 have a l l been prepared by r e l a y s y n t h e s i s from s a n t o n i n (1821, i n which most of t h e r e l a t i v e s t e r e o c h e m i s t r y h a s been establ i s h e d . Both B-elemeneg8 and elemolg9 have been s y n t h e s i z e d
i n a n o n s t e r e o s e p c i f i c c o u p l i n g of 1,lO-dibromo-2,8-decadienes. Direct s t e r e o r a t i o n a l r o u t e s t o members of t h e group have h o t y e t been found,
L.
Elemane (Tetrahydroelemene)
The f i r s t s y n t h e t i c work on t h e elemanes was t h e s y n t h e s i s of elemane i t s e l f (hexahydroelemene, 190) r e p o r t e d by t h e Czech group i n 1954."' Carvomenthone (183)was t h e s t a r t i n g p o i n t . I n o r d e r t o i n t r o d u c e an e t h y l group a t t h e more s u b s t i t u t e d s i d e of t h e carbonyl f u n c t i o n , t h e ketone was f i r s t "blocked" by u s i n g t h e s e c - b u t y l e t h e r o f t h e d e r i v e d hydroxymethylene d e r i v a t i v e 184. A f t e r e t h y l a t i o n , t h e b l o c k i n g group was removed t o y i e l d ketone presumably a s a mixture of b o t h d i a s t e r e o m e r s . The second i s o p r o p y l group was i n t r o d u c e d by t h e sequence + 188 + 189 * 190 (Scheme 2 7 ) . The t h i r d asymmetric c e n t e r i s i n t r o d u c e d i n t h e l a s t s t e p by c a t a l y t i c hydrogenation. Although t h e s y n t h e t i c elemane was r e p o r t e d t o have an i n f r a r e d spectrum i d e n t i c a l with t h a t o f elemane produced by t o t a l r e d u c t i o n of elemol, i t must be a mixture of four diastereomers.
187
=,
Monocarbocyclic Sesquiterpenes Scheme 27.
S y n t h e s i s of Elemane, Sykora-Cerny-Herout-Sorm
2. O H',
0 CHOCLHq
H20
CHOCqHg
190 -
189 M.
267
Tetrahydrosaussaurea Lactone, Saussaurea Lactone
The n e x t s u c c e s s i n t h e elemane a r e a came i n 1963, when Simono v i c , Rao, and Bhattacharyya r e p o r t e d t h e s y n t h e s i s of t e t r a from s a n t o n i n (Scheme 28) hydrosaussaurea l a c t o n e (=) This i s a c l a s s i c example o f a r e l a y s y n t h e s i s , i n l i g h t of t h e f a c t t h a t s a n t o n i n had p r e v i o u s l y been s y n t h e s i z e d i n o p t i c a l l y a c t i v e form (see p . 322). Hydrogenation of s a n t o n i n (182) over p a l l a d i z e d carbon g i v e s t e t r a h y d r o isomers 191 and 192 i n 22% and 56% y i e l d s , r e s p e c t i v e l y . Isomer 192, "a-tetrahydros a n t o n i n , " had p r e v i o u s 1 been converted i n t o keto-oxide 195 The A r i n g was cleaved by an adapby t h e i n d i c a t e d r o u t e . t a t i o n of Johnson's method ( o z o n o l y s i s of the d e r i v e d benzyli d i n e or f u r f u r i l i d i n e d e r i v a t i v e ) I o 2 The r e s u l t i n g d i a c i d
.'
.
268
Total Synthesis of Sesquiterpenes Scheme 28.
S y n t h e s i s of T e t r a h y d r o s a u s s u r e a Lactone-Simonovi c- Rao-Bhattacharyya
182 CH20H
I
1. LiAlH4
CH20H
____c
2. H ~ O +
T
H+
1. $CHO,OH-
1 95 -
194 -
197 -
196 -
198 -
181 -
was c o n v e r t e d t o i t s d i e s t e r and r e d u c e d w i t h h y d r i d e t o g i v e d i o l 197. T h i s w a s c o n v e r t e d i n t o a d i t o s y l a t e , which was reduced by h y d r i d e t o o x i d e O x i d a t i o n of 198 gave t e t r a -
=.
hydrosaussurea l a c t o n e i n high y i e l d .
Monocarbocyclic Sesquiterpenes
269
I n a subsequent paper, Honwad, S i s c o v i c , and Rao r e p o r t e d t h e conversion of intermediate 197 i n t o saussurea l a c t o n e i t s e l f (Scheme 29) . 9 6 Diol 197 was converted v i a i t s d i t o s y l a t e , Scheme 29.
Honwad-Siscovic-Rao Synthesis of Saussurea Lactone
i n t o i o d i d e 199. This was dehydrohalogenated by potassium tbutoxide i n DMSO t o y i e l d oxide 200. Oxidation of 200 with chromium t r i o x i d e i n a c e t i c a c i d gave saussurea l a c t o n e i n 15%y i e l d . N.
Tetrahydroelemol, B-Elemene, Elemol
formal t o t a l s y n t h e s i s of tetrahydroelemol (2141, i s a v a i l a b l e through t h e combined e f f o r t s of H a l s a l l , Theobald, and Walshaw i n England and Rao's group i n I n d i a (Scheme 3 0 ) . The
A
Scheme 30. Synthesis of Tetrahydroelemol (Halsall-Theobald-Rao)
c1
270
T o t a l S y n t h e s i s of S e s q u i t e r p e n e s
210 -
211 -
OH
212 -
213 -
I
(212)
B r i t i s h group p r e p a r e d e l e m a n - 2 , 3 , 1 1 - t r i o l s t a r t i n g from (-1 -dihydrocarvone (204) I o 3 A l k y l a t i o n of t h i s s u b s t a n c e with 1-chloro-+pentanone gave k e t o l 205. The r e l a t i v e s t e r e o chemistry of t h e a n g u l a r methyl group and t h e i s o p r o p e n y l group i s e s t a b l i s h e d i n t h e a l k y l a t i o n s t a g e . Dehydration of ketol a f f o r d e d 7-epi-cyperone (206), which was reduced by l i t h i u m i n m o n i a t o y i e l d k e t o n e 207. The d e r i v e d e n o l acet a t e (=) was ozonized, w i t h o x i d a t i v e workup, t o y i e l d a k e t o d i a c i d . The methyl e s t e r was epimerized by t r e a t m e n t w i t h n e t h a n o l i c HC1 t o a f f o r d 209. Reduction of t h e corresponding k e t a l w i t h L i A l H 4 gave, a f t e r removal of t h e p r o t e c t i n g group, k e t o d i o l 211. This substance w a s c o n v e r t e d by methylmagnesium bromide i n t o e l e m a n - 2 , 3 , l l - t r i o l ( 2 1 2 ) , which may a l s o be o b t a i n e d by hydroboration of e l e m o l F 3 Rao reduced t h e d i t o s y l a t e 213 with L i A l H 4 t o o b t a i n t e t r a h y d r o elemol (214). l o 4 A formal s y n t h e s i s of 8-elemene (178) and elemol (179) , by Rao and c o - w ~ r k e r s ,i~s ~o u t l i n e d i n Scheme 3 1 . Keto-acid
.
205
(210)
Monocarbocyclic S e s q u i t e r p e n e s Scheme 31.
271
Rao's S y n t h e s i s of 8-Elemene and Elemol
OH
179 -
219 -
215, prepared from a-santonin (182) by t h e r o u t e shown,lo5 was o x i d i z e d by n i t r i c a c i d and ammonium vanadate t o y i e l d t r i a c i d 216. The corresponding t r i e s t e r w a s reduced t o eleman-2,3,12t r i o 1 (217). The primary triiodj.de 218 was o b t a i n e d by sodium i o d i d e displacement on t h e t r i t o s y l a t e . Base c a t a l y z e d dehydroiodination of gave 8-elemene (178). S e l e c t i v e epoxid a t i o n , followed by hydride r e d u c t i o n , gave elemol (179)and secondary a l c o h o l 219. Vig has r e p o r t e d a s y n t h e s i s o f B-elemene,98 based on Corey's o b s e r v a t i o n t h a t l,lO-dibromo-2,8-decadienes c y c l i z e under t h e i n f l u e n c e of n i c k e l carbonyl. O6 The s y n t h e s i s (Scheme 32) b e g i n s w i t h u n s a t u r a t e d e s t e r 220. The r e q u i s i t e ten-carbon chain i s b u i l t up i n a c l e v e r f a s i o n , u t i l i z i n g a C l a i s e n rearrangement and two modified W i t t i g r e a c t i o n s t o add s i x carbons. The f i r s t W i t t i g r e a c t i o n (223+. 224) is s t e r e o -
2
T o t a l S y n t h e s i s of S e s q u i t e r p e n e s
272
Scheme 32.
220 -
V i g ' s S y n t h e s i s of 8-Elemene
222 -
221 0 CH3
II I
CHO
H30'
( E t O ) 2P-CH-CO2Et
NaH
P
C
O
Z
E
t
2 24 -
223 -
227 -
178 224. The
s p e c i f i c , y i e l d i n g o n l y t h e t r a n s isomer second W i t t i g , u s i n g triethylphosphonoacetate (225 * 226) y i e l d s t r a n s - t r a n s isomer 226, a l o n g w i t h some t r a n s - c i s isomer. The mixture of isomers w a s used t o complete t h e s y n t h e s i s . Vig r e p o r t s t h a t h i s s y n t h e t i c B-elemene i s o n l y one of t h e four p o s s i b l e racemates, as judged hy t h e f a c t t h a t t h e s y n t h e t i c hydrocarbon h a s I R and NMR s p e c t r a which a r e i d e n t i c a l with I n t h i s r e s p e c t , t h e work d i f f e r s those of n a t u r a l 8-elemene.
Monocarbocyclic Sesquiterpenes
273
from the observations of Corey and Broger (below). Corey and Broger prepared (?)-elem01 by a route which also involved nickel carbonyl catalyzed coupling of a bisallylic 1,lO-dibromide.99 The requisite dibromide (235)was prepared as outlined in Scheme 33. The interesting isoprene
v0TBr Scheme 33.
Corey's Synthesis of (+)-Elem01
228 -
1. NaH
1. NaH
I
KOH
2 3U
DIBAL
_c
HO 231 -
THpo-
THPO
THp THPO
-
C02Me
232
CHO NaOMe CO2Me
1. H ~ O + PBr3-
___c 2.
THPO
Ni (CO)4
C02Me
ether
274
Total S y n t h e s i s of Sesquiterpenes
p,. “‘CO 2 M e
238 -
e q u i v a l e n t s 228 and 229 were used t o s u c c e s s i v e l y a l k y l a t e malonic e s t e r , y i e l d i n g d i e n e 2. T r a n s e s t e r i f i c a t i o n of 230 i n methanol gave 231, which w a s f u r t h e r c o n v e r t e d i n t o b i s - t e t r a h y d r o p y r a n y l e t h e r 232. S i n c e 232 i s o b v i o u s l y acid s e n s i t i v e , h y d r o l y s i s and d e c a r b o x y l a t i o n o f t h e m a l o n a t e w a s accomplished by r e d u c t i o n w i t h d i i s o b u t y l a l u m i n u m h y d r i d e , f o l l o w e d by b a s e c a t a l y z e d d e f o n n y l a t i o n o f t h e r e s u l t i n g aldehyde (233). S t a n d a r d t r a n s f o r m a t i o n s gave d i b r o m i d e 235, which was c y c l i z e d w i t h n i c k e l c a r b o n y l i n N-methyl-pyrrolidone. Isomers 236-240 were o b t a i n e d i n y i e l d s o f 11%,24%, 3 % , 3%, and 24%, respectively. T r e a t m e n t o f isomer 240 w i t h methylmagnesium bromide gave c r y s t a l l i n e ( f ) - e l e m o l . The o b s e r v e d nons t e r e o s p e c i f i c i t y i n t h e c y c l i z a t i o n s t a n d s i n marked c o n t r a s t t o V i g ‘ s c l a i m i n t h e a f o r e m e n t i o n e d s y n t h e s i s o f 8-elemene. The geometry o f the o l e f i n i c l i n k a g e s i n 236 was a s s i g n e d on t h e b a s i s o f i t s t h e r m a l b e h a v i o r . The d i e n e w a s stable a t 100” f o r l o n g p e r i o d s of t i m e , even though t r a n s , t r a n s - 1 , 5 c y c l o d e c a d i e n e undergoes f a c i l e Cope r e a r r a n g e m e n t a t this t e m p e r a t u r e . A t 2 8 5 ” compound 236 r e a r r a n g e d t o a m i x t u r e o f 237 and 238; no 239 or 240 w a s produced, From the known s t e r e o c h e m i s t r y of t h e Cope r e a r r a n g e m e n t , t r a n s , t r a n s - = s h o u l d r e a r r a n g e t o 239 and 240.
-
0.
Furopelargone-A and Furopelargone-B
The BUchi-WUest s y n t h e s i s o f f u r o p e l a r g o n e s A and B (248 and i s o u t l i n e d i n Scheme 3 4 . I o 7 The s y n t h e s i s of t h e s e molecules r e q u i r e s t h e s t e r e o s e l e c t i v e formation o f a 1,2,3t r i s u b s t i t u t e d c y c l o p e n t a n e p r e c u r s o r , c o n s t r u c t e d i n such a manner t h a t i t c a n b e c o n v e r t e d i n t o d i k e t o a l d e h y d e 247. I t was a n t i c i p a t e d t h a t 247 would undergo d e h y d r a t i o n t o y i e l d furopelargone-A (2481, rather t h a n t h e more s t r a i n e d s y s t e m
249)
Monocarbocyclic S e s q u i t e r p e n e s Scheme 34.
275
Biichi-Wiiest S y n t h e s i s of t h e Furopelargones
241 -
24 2 e
B
r
.___c
NaH, DMF
C02Bu-t
C02Bu-t 243 -
244 -
246 -
245 -
\
L
NaOCH 3
A
I
250.
247 -
248 -
I
249 -
The i n i t i a l o b j e c t i v e w a s achieved b y t a k i n g advantage of t h e w e l l known p h o t o c y c l i z a t i o n of c i t r a l (241). Photocitral-A (*) i s produced i n 20% y i e l d , along w i t h photowhen c i t r a l i s i r r a d i a t e d i n a l c o h o l i c s o l u c i t r a l - B (=), t i o n . The s t e r e o c h e m i s t r y of 242 w a s a s s i g n e d on the b a s i s of
276
Total Synthesis of Sesquiterpenes
e q u i l i b r a t i o n s t u d i e s . Compound 242 was e l a b o r a t e d i n t o t h e d e s i r e d diketoaldehyde 247 by the i n t e r e s t i n g r o u t e i n d i c a t e d i n t h e c h a r t . Reformatsky r e a c t i o n on 242 gave t h e B-hydroxy This e s t e r 243, which was oxidized t o a 8-keto e s t e r compound was a l l y l a t e d w i t h a l l y 1 bromide and sodium hydri.de t o g i v e 245. The e s t e r grouping was removed by p y r o l y s i s a t 280'. The choice of a t - b u t y l e s t e r was d i c t a t e d by a need t o remove t h i s group under nonbasic and n o n a c i d i c c o n d i t i o n s so a s t o avoid e p i m e r i z a t i o n o r double bond m i g r a t i o n . Ozonol y s i s of d i e n y l ketone 246 gave t h e d e s i r e d diketoaldehyde (247) which underwent a c i d c a t a l y z e d c y c l i z a t i o n t o f u r o p e l a r gone-A. Base c a t a l y z e d e p i m e r i z a t i o n of furopelargone-A (248) gave an e q u i l i b r i u m mixture c o n s i s t i n g of 9 4 % furopelargone-A and 6 % furopelargone-B. The l a t t e r isomer was s e p a r a t e d by p r e p a r a t i v e vpc.
(244).
P.
Nootkatin, P r o c e r i n
Kitahara has r e p o r t e d s n t h e s e s of t h e troponoid s e s q u i t e r , I o 9 which a r e sumpenes n o o t k a t i n (258)lo' and p r o c e r i n marized i n Scheme 35. The two t r o p o t o n e s 252 and 253 were
(259)
Scheme 35.
K i t a h a r a ' s S y n t h e s i s of Nootkatin and P r o c e r i n
254 255 -
R=CH (CH3) 2
R=C=CH2
I
CH3
Monocarbocyclic Sesquiterpenes
I
277
R
R
a l k y l a t e d with B,B-dimethylallyl c h l o r i d e t o g i v e mixtures of tropotone e t h e r s . P y r o l y s i s of t h e e t h e r mixture gave nootk a t i n (258)o r p r o c e r i n (259) i n 5 7 % y i e l d . Q.
Germacrane, Dihydrocostunolide
The f i r s t s y n t h e t i c success i n t h e germacrane a r e a was Sorm's s y n t h e s i s of germacrane i t s e l f (2601, which was r e p o r t e d i n 1958.110 Although n o t i t s e l f a n a t u r a l p r o d u c t , t h e substance may be considered t h e p a r e n t hydrocarbon of t h e germacrane family. The only o t h e r s y n t h e s i s i n t h i s a r e a i s Corey's r e l a y s y n t h e s i s of dihydrocostunolide (261) from s a n t o n i n . l 1
260 -
261 -
The primary problem which must b e faced i n t h e s y n t h e s i s of germacranes i s e l a b o r a t i o n of t h e cyclodecane r i n g . This t a s k , f o r which t h e r e a r e few r e l i a b l e methods a v a i l a b l e , i s a m p l i f i e d by t h e s u b s t i t u t i o n p a t t e r n i n more complicated members of t h e c l a s s . One o f t h e few r e l i a b l e methods f o r p r e p a r i n g medium r i n g s i s t h e a c y l o i n condensation. An a n a l y s i s of germacrane i n d i c a t e s t h a t it may be o b t a i n e d by reducing t h e a c y l o i n der i v e d from d i e s t e r s and 263. I n t e r m e d i a t e 262 appears t o
210
T o t a l S y n t h e s i s of S e s q u i t e r p e n e s
be more e a s i l y a c c e s s i b l e , s i n c e i t may be d e r i v e d by homlogat i o n of 268, which i s t h e h a l f - e s t e r of a symmetrical d i a c i d . This m a t e r i a l r e p r e s e n t s t h e c r i t i c a l i n t e r m e d i a t e i n t h e Sorm s y n t h e s i s of germacrane, which i s o u t l i n e d i n Scheme 36. Scheme 36.
Sorm's S y n t h e s i s of Germacrane
268 -
262 -
OH
Diethyl 8 - i s o p r o p y l g l u t a r a t e (264) was reduced t o d i o l 265, which was converted i n t o a d i i o d i d e (266)with triphenoxyphosphonium methiodide. Compound was used t o a l k y l a t e d two moles of d i e t h y l methylmalonate, y i e l d i n g a t e t r a e s t e r which w a s hydrolyzed and decarboxylated. The r e s u l t i n g d i a c i d (267) was s e l e c t i v e l y e s t e r i f i e d with diazomethane ( y i e l d n o t r e Homologation t o 262 was accomplished ported), affording by t h e A r n d t - E i s t e r t sequence. C y c l i z a t i o n proceeded normally, y i e l d i n g a c y l o i n 269, which was reduced t o germacrane undoubtedly a s a mixture of d i a s t e r e o m e r s .
266
=.
(E),
Monocarbocyclic Sesquiterpenes
279
Corey's synthesis of dihydrocostunolide (261)is outlined in Scheme 37. The overall concept embodies a scheme for Scheme 37.
Corey's Synthesis of Dihydrocostunolide
- Q:HC1
H2
0
182 -
0
= H
270
b
192
_.
A1 (OPr-i)3 A
-
Q,,,,i i a
-180
0
274 -
CgHgN-Al203
280
Total Synthesis of Sesquiterpenes
e l a b o r a t i o n of a medium r i n g which h a s g r e a t promise, b u t h a s n o t y e t been used e x t e n s i v e l y i n n a t u r a l p r o d u c t s y n t h e s i s . The b a s i c i d e a i n v o l v e s t h e s c i s s i o n o f t h e c e n t r a l bond i n a 1 , 2 - f u s e d b i c y c l i c s y s t e m , l e a d i n g t o a new r i n g c o r r e s p o n d i n g i n s i z e t o t h e p e r i p h e r y of t h e o l d b i c y c l i c compound. The t e c h n i q u e , which i s c e r t a i n t o f i n d wide a p p l i c a t i o n i n t h e germacrane c l a s s , was e x e c u t e d i n t h i s case by p h o t o l y s i s o f t h e c r u c i a l d i e n e 274, which w a s p r e p a r e d from s a n t o n i n b y t h e s t r a i g h t f o r w a r d method o u t l i n e d i n t h e scheme. The i n i t i a l l y formed c y c l o d e c a t r i e n e which i s exc e e d i n g l y t h e r m o l a b i l e , w a s hydrogenated o v e r Raney n i c k e l a t -18' t o y i e l d d i h y d r o c o s t u n o l i d e .
(E),
R.
Humulene
C o r e y ' s s y n t h e s i s of humulene ( 2 9 2 ) , an eleven-membered r i n g t r i e n e , i s o u t l i n e d i n Scheme 3 c 2 A s w i t h t h e germacrane Scheme 38.
C o r e y ' s S y n t h e s i s o f Humulene
C02Me LiAlH4
C02Me
____c
~ 1 ~ 1 3
276 -
277 -
$CH2NMef 1. OH-
270 -
H+
219 -
OTHP
$3P
__c
F
O
T
H
P$3+Br280 -
c1
282 -
281 -
kco;OCOAr283
P
Monocarbocyclic S e s q u i t e r p e n e s
284 -
285 -
281
286 -
bCOAr
2
E
-
1. DMSO-
L
1. L i A l H 4
T ArCOZ ; "
'
288 -
Ho%
PBrL
O
a
1%
2 . MeOH H+
Ni(CO)k
no 289 -
290 -
( y &
y 2 . -
29 1 -
(& 292 -
family, t h e c h i e f s y n t h e t i c problem h e r e i s c o n s t r u c t i o n of t h e eleven-membered r i n g . Double bond geometry, which appears t o be an added complication, i s a c t u a l l y no problem, s i n c e humul e n e i s known t o be t h e most s t a b l e of t h e v a r i o u s isomers. For t h i s r e a s o n , one may d e s i g n a s y n t h e s i s l e a d i n g t o any of t h e isomers and then e q u i l i b r a t e i n t h e f i n a l s t e p .
282
Total Synthesis of Sesquiterpenes
corey's synthetic plan called for synthesis of the 1,11dibromoundecatriene 2Ef which could be cyclized with nickel carbonyl to humulene isomer =.Io6 Although cyclization of 1,lO-dibrom-2,8-decadienes gives mainly divinylcyclohexanes in preference to cyclodecadienes (p. 273), cyclization of 1,11dibrom0-2~9-undecadienes yields predominately the cycloundecadiene. The requisite dibromoundecatriene was prepared by a Wittig reaction of the ylid derived from phosphonium salt 281 and aldehyde 287, yielding triene 288. After removal of the protecting groups, the resulting diol (289) was converted to dibromide 290, which was cyclized with nickel carbonyl in Nmethylpyrrolidone. The initial product, 4,5-cis-humulene was isomerized to humulene by irradiation with diphenyldisulfide in cyclohexane.
(z),
4. BICARBOCYCLIC SESQUITERPENES, HYDRONAPHTHALENES A.
Eudesmanes
In the bicyclic sesquiterpene area, by far the most synthetic effort has been directed toward eudesmanes. Naturally occurring compounds in this group which have been prepared by total synthesis are a-cyperone (1) , 6-cyperone (2), carrisone (2), a-eudesmol (41, B-eudesmol (21, y-eudesmol (5), aselinene ( I ) ,6-selinene (8) , costol (21, costal (lo),costic , 6-agarofuran (21,nor-ketoagaroacid (G),a-agarofuran (12) furan (14) , 7~,10a-selina-4,1l-diene (2) , 58 ,76 ,l0a-selina3,ll-diene (16) , chamaecynone (17) , 4a-hydroxyisochamaecynone (18) , occidol (19) , occidentalol (20), atractylon ( 2 1 , lindestrene (22), a-santonin (231, 6-santonin (24), astemisin (2 5 ) , alantolactone (26), isoalantolactone (2) , and telekin
(2).
-2
1 -
-4
5 -
3 -
6 -
-7
8 -
15 -
16 -
17 -
“‘OH
18 -
10 -
9 -
OH
19 -
20 -
283
284
Total Synthesis of Sesquiterpenes
25 -
24 -
26 -
A l m o s t i n v a r i a b l y , workers i n t h e f i e l d have c o n s t r u c t e d t h e 9 - m e t h y l d e c a l i n n u c l e u s by t h e Robinson a n n e l a t i o n sequence. The t h r e e c a r b o n s i d e c h a i n may, i n some cases, be p r e s e n t i n t h e s t a r t i n g methylcyclohexanone; i n o t h e r cases it i s added a t a l a t e r s t a g e . S t e r e o c h e m i c a l c o n t r o l is n o t a major problem w i t h most of t h e compounds i n t h i s c l a s s . Many of t h e eudesmanes have a t r a n s d e c a l i n n u c l e u s , w i t h t h e t h r e e carbon f u n c t i o n i n an e q u a t o r i a l p o s i t i o n , so t h a t thermodynamic c o n t r o l may b e e x e r t e d . Those members which have t h e a n g u l a r methyl group and t h e t h r e e c a r b o n group t r a n s have been s y n t h e s i z e d by way o f 7-epi-cyperone the kinetic a l l y formed isomer i n c o n d e n s a t i o n o f d i h y d r o c a r v o n e (2) w i t h e t h y l v i n y l k e t o n e (2) , o r its equivalent.
(z),
Base 0
0
29 -
31
30 -
I
The wide v a r i a t i o n i n s y n t h e t i c approaches h a s b e e n mainly aimed a t a l l o w i n g f o r t h e v a r i e t y o f f u n c t i o n a l i t y i n members o f t h e c l a s s . I t s h o u l d b e n o t e d t h a t nor-ketoagarofuran , chamaecynone and 4a-hydroxyisochamaecynone (E)are C-14 compounds, a p p a r e n t l y d e g r a d a t i o n p r o d u c t s o f s e s q u i t e r p e n e s . O c c i d o l (19) , although nonisoprenoid, i s probably a rearrangement product of o c c i d e n t a l o l .
(14)
(c)
B i c a r b o c y c l i c S e s q u i t e r p e n e s , Hydronaphthalenes B.
a-Cyperone,
285
8-Cyperone
I n t h e e a r l i e s t p a p e r on a b i c y c l i c s e s q u i t e r p e n e s y n t h e s i s , Adamson, M c Q u i l l i n , Robinson, and Simonsen r e p o r t e d t h e synt h e s i s o f " s u b s t a n c e s s t r u c t u r a l l y i d e n t i c a l w i t h a- and 8cyperones. " l 1 The s y n t h e s i s i n v o l v e d c o n d e n s a t i o n of (-) dihydrocarvone (2) w i t h t h e methiodide of l-diethylaminopentan-3-one (2). The r e s u l t i n g p r o d u c t , k e t o l 34* was deh y d r a t e d w i t h sodium e t h o x i d e i n benzene t o g i v e "a-cyperone." Later work h a s shown t h a t t h i s p r o d u c t i s a c t u a l l y a m i x t u r e of compounds 35 and 36 w i t h t h e former predominating.
-
b,+
0
% '
/
NaNH2
I
Me
32 -
34 -
1
H2S04
31 -
+
35 -
+
ojp f 36 -
-.L Dehydration of k e t o l x w i t h 50% s u l f u r i c a c i d gave 6cyperone (2+ 2). From t h e known s t e r e o c h e m i s t r y o f t h e Michael r e a c t i o n of t h i s s e r i e s , i t may b e concluded t h a t t h i s sample w a s a m i x t u r e of approximately 80% 37 and 20% 2 Howe and McQuillin l a t e r r e i n v e s t i g a t e d t h i s work. *The a u t h o r s e r r o n e o u s l y c o n s i d e r e d t h i s s u b s t a n c e t o be t h e uncyclized diketone.
T o t a l S y n t h e s i s of S e s q u i t e r p e n e s
286
(+)-Dihydrocarvone (2) was condensed w i t h compound 33 t o g i v e a m i x t u r e c o n s i s t i n g mainly of k e t o l 2 and a-cyperone (L). A f t e r p u r i f i c a t i o n v i a i t s oxime, a-cyperone was o b t a i n e d i n 3% y i e l d .
29 -
-1
38 -
The p r o d u c t i o n of isomer 8 as t h e major p r o d u c t i n t h i s r e a c t i o n seems t o be t h e r e s u l t o f a x i a l a l k y l a t i o n o f the more s t a b l e ( i s o p r o p e n y l e q u a t o r i a l ) e n o l a t e of k e t o n e 2. T h i s r e s u l t i s i n v a r i a b l y o b t a i n e d i n Michael r e a c t i o n s on s u c h d i a l k y l a t e d cyclohexanones.
1-y /
:0
T o 1 -
I
0
-0
1
Roy r e p o r t e d t h a t racemic B-cyperone may be p r e p a r e d b y w i t h Mannich b a s e 33. NO y i e l d condensing carvenone (2) is given.
Q&
B i c a r b o c y c l i c S e s q u i t e r p e n e s , Hydronaphthalenes
’0
%
+ 33
KOH
__c
287
’0
39 -
-2
Since t h e y i e l d of a-cyperone which may be obtained by such d i r e c t a n n e l a t i o n s i s low, P i e r s developed a s y n t h e s i s of t h e t e r p e n e from a-santonin (3-23) which i s r e a d i l y a v a i l a b l e c o m e r c i a l l y . l 1 6 The P i e r s s y n t h e s i s i s o u t l i n e d i n Scheme 1. Scheme 1.
P i e r s ’ S y n t h e s i s of (-)-Cyperone
JQ55
(Relay) Zn-HOAc
’0
23 -
0
40 -
400’
288
Total Synthesis of Sesquiterpenes
( - ) - a - S a n t o n i n (23) was epimerized t o ( - ) - 6 - e p i - a - s a n t o n i n (40)by H C 1 i n dimethylformamide. A f t e r z i n c promoted reducwas t i o n of t h e s i x - a x i a l s u b s t i t u e n t , t h e r e s u l t i n g a c i d e s t e r i f i e d and s e l e c t i v e l y hydrogenated over W i l k i n s o n ' s s o l u b l e c a t a l y s t t o o b t a i n 43. T h i s was reduced t o a m i x t u r e of d i a s t e r e o m e r i c d i o l s 44. S e l e c t i v e o x i d a t i o n of t h e a l l y l i c h y d r o x y l , w i t h d i c h l o r o d i c y a n o q u i n o n e , gave enone-alcohol 45. The r e s u l t i n g c a r b o n a t e e s t e r (46) was pyrolyzed a t 400' t o e f f e c t e l i m i n a t i o n . a-Cyperone was o b t a i n e d i n 61% y i e l d , accompanied by 32% of enone-alcohol S. The f i r s t s y n t h e s i s o f c a r i s s o n e (2) was r e p o r t e d by Mukherji, Singh, and Vig i n 1960 (Scheme 2 ) . 117 The s y n t h e s i s
(41)
(1)
Scheme 2 .
Mukherji-Singh-Vig
S y n t h e s i s of C a r i s s o n e
eh 1. MeMgI
(CH20H) 2 0
C02Et
OH
49
-
C02Et
48
47
0
Ht
2 . H-jO'
OH
proceeds by Robinson a n n e l a t i o n on k e t o - a l c o h o l 49, p r e p a r e d a s i n d i c a t e d , w i t h Mannich b a s e 33. A s one would e x p e c t , t h e condensation i s n o t s t e r e o s p e c i f i c , t h e d e s i r e d stereosomer b e i n g p r o b a b l y a minor p r o d u c t . The 2 , 4 - d i n i t r o p h e n y l h y d r a zone of racemic c a r r i s o n e was i s o l a t e d i n u n s p e c i f i e d y i e l d from t h e r e a c t i o n p r o d u c t . P i n d e r ' s s y n t h e s i s of c a r i s s o n e (Scheme 3 ) was r e p o r t e d i n 1961.118 (+)-a-Cyperone (1) - p r e p a r e d i n 3% y i e l d by t h e method o f Howe and McQuillin, was s e l e c t i v e l y o x i d i z e d a t t h e t e r m i n a l methylene by p e r b e n z o i c a c i d . The r e s u l t i n g epoxide (5 2 ) was reduced by L i A 1 H 4 t o a m i x t u r e of s t e r e o i s o m e r i c d i o l s
Bicarbocyclic S e s q u i t e r p e n e s , Hydronaphthalenes Scheme 3.
289
P i n d e r ’ s S y n t h e s i s of (+) -Carissone
-3
53
(3) which was o x i d i z e d with manganese d i o x i d e t o a f f o r d ( + I c a r i s s o n e (3). C.
a-, 6 - ,
and y-Eudesmol
aH+
Pinder and W i l l i a m s r e p o r t e d t h e f i r s t s y n t h e s i s of a eudesmol i n 1963. ’ l E b T h e i r s y n t h e t i c (+) - c a r i s s o n e was converted i n t o i t s d i t h i o k e t a l (54) which was d e s u l f u r i z e d with Raney n i c k e l t o y i e l d (+) -y-eudesmol (5)
.
Ho * c
’0
-3
54 -
%OH
M a r s h a l l ’ s s y n t h e s i s of B-eudesmol i s o u t l i n e d i n Scheme 4.11’ Octalone was k e t a l i z e d , w i t h c o n c o m i t a n t double bond m i g r a t i o n , t o a f f o r d u n s a t u r a t e d k e t a l 56. Although it was n o t p o s s i b l e t o d r i v e t h i s r e a c t i o n t o completion, c r y s t a l l i n e k e t a l 56 could be o b t a i n e d i n 40% y i e l d . Hydroboration of 56, by Brown’s method,lZ0 gave a mixture c o n t a i n i n g a l c o h o l
-
Scheme 4.
8-Eudesmol--Marshall's
Synthesis
62 -
61 CH2OH
CN CH2
290
Cop H CH2
Bicarbocyclic S e s q u i t e r p e n e s , Hydronaphthalenes
291
57.* Oxidation of t h i s mixture w i t h Jones r e a g e n t , followed by d i r e c t c r y s t a l l i z a t i o n , allowed t h e production of c r y s t a l -
l i n e k e t o - k e t a l 58 i n 30% y i e l d . When t r e a t e d with p-toluenes u l f o n i c a c i d i n r e f l u x i n g t o l u e n e , e q u i l i b r i u m w a s reached between c i s ketone 2 and i t s t r a n s c o u n t e r p a r t 2 with t h e l a t t e r predominating ( t r a n s / c i s = 3/1), D i r e c t c r y s t a l l i z a t i o n gave 2 i n 65% y i e l d . Both 8 and 2 r e a c t e d with methylenetriphenylphosphorane i n DMSO t o g i v e predominately t h e t r a n s fused product. A f t e r h y d r o l y s i s , t h e c r y s t a l l i n e uns a t u r a t e d ketone 60 was o b t a i n e d ( 4 7 % from 2 44% from 59). Lithium aluminum hydride r e d u c t i o n gave predominately t h e e q u a t o r i a l alcohol ( i s o l a t e d i n 83% y i e l d ) , which was conv e r t e d i n t o i t s p - t o l u e n e s u l f o n a t e e s t e r (%). When 62 was t r e a t e d with sodium cyanide i n N-methylpyrrolidone, n i t r i l e 63 was produced i n 64% y i e l d . This w a s hydrolyzed, with con( 6 5 % ) . The commitant e p i m e r i z a t i o n , t o e q u a t o r i a l a c i d corresponding e s t e r (65) was t r e a t e d w i t h methyllithium t o o b t a i n (+-)-6-eudesmol (5). P i n d e r ' s s y n t h e s i s of 8-eudesmol (Scheme 5 ) 1 2 2 begins with a Robinson a n n e l a t i o n of (-)-dihydrocarvone (32) and l - d i e t h y l minobutan-3-one methiodide. A s d i s c u s s e d e a r l i e r , t h e major product i n such r e a c t i o n s i s t h a t produced by a x i a l a l k y l a t i o n on t h e more s t a b l e conformer o f t h e corresponding e n o l a t e . Therefore, t h e r e s u l t i n g k e t o l (E), i s o l a t e d i n 25% y i e l d , h a s t h e undesired t r a n s d i s p o s i t i o n o f t h e a n g u l a r methyl and isopropenyl groups. I n o r d e r t o r e n d e r C-7 epimerizable, k e t o l 67 was ozonized t o diketone E. This m a t e r i a l was
-
5
*Careful a n a l y s i s of t h i s r e a c t i o n i n d i c a t e d t h e following products :
50%
10%
40%
1
OH
Ring-opening o f e t h y l e n e k e t a l s by diborane had been observed previously.121 (However, see p . 405.)
Scheme 5.
69 -
292
8-Eudesmol--Pinder's Synthesis
70 -
B i c a r b o c y c l i c S e s q u i t e r p e n e s , Hydronaphthalenes
293
d e h y d r a t e d , w i t h s i m u l t a n e o u s e p i m e r i z a t i o n , t o o b t a i n endione The u n s a t u r a t e d c a r b o n y l group of 69 r e a c t e d p r e f e r e n t i a l l y w i t h e t h a n e d i t h i o l , a f f o r d i n g c r y s t a l l i n e 70 i n 308 y i e l d . Raney n i c k e l d e s u l f u r i z a t i o n o f t h e d e r i v e d dimethyl c a r b i n o l T h i s was c o n v e r t e d i n t o ( + ) (71) gave nor-y-eudesmol (2). B-eudesmol i n t h e s t r a i g h t f o r w a r d manner shown, An e f f i c i e n t s t e r e o s e l e c t i v e s y n t h e s i s of 8-eudesmol, s u i t a b l e f o r p r e p a r i n g t h e m a t e r i a l i n q u a n t i t y , was r e p o r t e d by Heathcock and K e l l y (Scheme 6 ) i n 1968.123 The s y n t h e s i s
69.
-
c b o- d3-,,Scheme 6.
55
B-Eudesmol--Heathcock-Kelly S y n t h e s i s
7s -
c1 76 -
22% 2.
77 MeLi C02H
70 -
R0* C02Me
79 -
1. H 2 C r 2 0 7
2 . NaOCH3
HO 72 -
73 -
294
T o t a l S y n t h e s i s of S e s q u i t e r p e n e s
begins w i t h methyl o c t a l o n e 55, which was deconjugated by t r e a t i n g t h e d e r i v e d e n o l benzoate (2) with sodium borohydride i n e t h a n o l . The r e s u l t i n g u n s a t u r a t e d a l c o h o l r e a c t e d with PC15 t o g i v e c h l o r i d e Carbonation of t h e corresponding Grignard r e a g e n t gave e x c l u s i v e l y t h e e q u a t o r i a l a c i d 78, which was converted, v i a methyl e s t e r 2, i n t o (+I-nor-y-eudesmol (2).The remainder of t h e s y n t h e s i s is i d e n t i c a l t o t h a t of Pinder i n t h e o p t i c a l l y a c t i v e s e r i e s . The o v e r a l l y i e l d f o r t h e t e n s t e p s was 10%. Vig and co-workers have proposed a m o d i f i c a t i o n of M a r s h a l l ' s s y n t h e s i s (Scheme 7 ) i n which t h e isopropanol s i d e
77.
Scheme 7 . B-Eudesmol--Vig's Modification of t h e Marshall S y n t h e s i s
CH2
60 -
80 -
81 -
83 -
85 -
84 -
5 -
B i c a r b o c y c l i c S e s q u i t e r p e n e s , Hydronaphthalenes
295
c h a i n i s introduced by a W i t t i g r e a c t i o n . 124 The r o u t e appears t o o f f e r l i t t l e advantage over t h e o r i g i n a l Marshall method. Marshall h a s r e p o r t e d a s y n t h e s i s of y-eudesmol ,1 2 5 which begins w i t h a key i n t e r m e d i a t e i n h i s a l a n t o l a c t o n e s y n t h e s i s (Scheme 8 ) . Unsaturated ketone 86 was carbonated t o g i v e Scheme 8.
88 -
90 -
-o,&
M a r s h a l l ' s S y n t h e s i s of y-Eudesmol
I
89 -
91 -
&
OH
f3-keto e s t e r E l which w a s s e l e c t i v e l y reduced t o B-hydroxy e s t e r 88. Treatment of t h e corresponding hydroxy a c i d with methyllithium gave hydroxy ketone 90, which w a s smoothly dehydrated w i t h a l c o h o l i c b a s e t o enone 91. This was hydrogenated t o %, which r e a c t e d w i t h methyllithium t o a f f o r d (+)-y-eudesmol. Pinder r e p o r t s a s y n t h e s i s of a-eudesmol (4) from c a r i s sone (2) which i s o u t l i n e d i n Scheme 9.122b Birch r e d u c t i o n of c a r i s s o n e gave trans-dihydrocarissone which r e a c t e d
(z),
296
Total Synthesis of Sesquiterpenes Scheme 9.
’0
o,qo -
Pinder’s Synthesis of a-Eudesmol
-
J n & OH
93 -
3 -
with p-toluenesulfonylhydrazine in ethanol to yield tosylhydrazone 94. Compound 94 was decomposed with the sodium salt of ethylene glycol to give a-eudesmol (4). D.
a- and 6-Selinene
An early attempt at the synthesis of B-selinene (Banerjee, 1960), which resulted in a mixture of various selinene isomers is outlined without comment in Scheme Scheme 10.
+
Banerjee’s Synthesis of Selinene Isomers
CH3-CH (C02Et)2
NaOEt
(CH20H) 2 ___c
2. CH2N2
C02H
96 -
1. H30’
1. NaOH 2. H-jO’
97 -
/%
1. ( E t 0 ) 2 C = O ,
C02Me
0
Et02C
-
EtO'
2.A
98 -
OEt, Me I C02Me -
0
99 -
NC;CH2C02Et NH40Ac-
Et02C
c
C02Me
100 -
&CN C02Me C02Et
101 -
1. H 3 0 t , A C02Me
NC
103
2 . E t O H , H+
OH-
102 -
-
Zn
1. O E t -
--c
E t 20C
%= C02Et
C02Et
C02Et
1. L i A l H 4 2 . AcgO
550°
C02Et
OAc AcO
107 -
29 7
298
Total Synthesis of Sesquiterpenes
108 -
In connection with his eudesmane program, Marshall synNitrile thesized (f)-B-selinene as outlined in Scheme 11. 'lgb Scheme 11. Marshall's 8-Selinene Synthesis (See Scheme 41
63 was
treated with methyllithium to yield, after hydrolysis of the initially formed imine, the ketone 85. This compound reacted with methylenetriphenylphosphorane to yield ( k ) - B selinene ( g ) . Vig and co-workers have also prepared f? by Wittig reaction on 85.12'+ a-Selinene (1) has been prepared from a-cyperone (1)as outlined in Scheme 12.lZ7 Reduction of a-cyperone with lithium Scheme 12.
1 -
a-Selinene--Bangalore Synthesis
109 -
B i c a r b o c y c l i c S e s q u i t e r p e n e s , Hydronaphthalenes
110 -
299
7
i n ammonia c o n t a i n i n g e t h a n o l o r by sodium and n-propanol gave dihydrocyperol (109). I n o r d e r t o e f f e c t cis e l i m i n a t i o n of t h e . e q u a t o r i a 1 hydroxyl and i t s neighboring t e r t i a r y hydrogen, t h e corresponding metaborate e s t e r (110)w a s p y r o l i z e d by h e a t i n g o v e r a f r e e flame. The r e s u l t i n g hydrocarbon mixture contained predominately a - s e l i n e n e . E.
C o s t o l , C o s t a l , C o s t i c Acid
These r e l a t e d compounds were prepared by Marshall a s o u t l i n e d i n Scheme 13.119br128 The e q u a t o r i a l t o s y l a t e 62 was converted
eOTs -p Scheme 13. M a r s h a l l ’ s S y n t h e s i s of (2)-Costol (21, (+)-Costol and ( f ) - C o s t i c Acid (2)
(g),
OH-
1;
‘““OCHO
CH2
CH2
62 -
111 -
T o t a l S y n t h e s i s of S e s q u i t e r p e n e s
300
10 -
11 -
i n t o a x i a l t o s y l a t e 113 by t h e t h r e e - s t e p sequence shown. Alkylation of malonic e s t e r with t o s y l a t e 113 gave d i e s t e r 1 1 4 . Reduction of t h e corresponding sodium s a l t w i t h l i t h i u m aluminum hydride gave a 3:l mixture of ( + ) - c o s t o l (9) and d i h y d r o c o s t o l . Oxidation of t h e a l l y l i c hydroxyl with a c t i v a t e d manganese d i o x i d e gave ( ? ) - c o s t a l (lo)and f u r t h e r o x i d a t i o n of t h i s substance with s i l v e r oxide gave ( 2 ) - c o s t i c a c i d (2).
-
F.
a-
and 6-Agarofuran, Nor-ketoagarofuran
I n t h e a g a r o f u r a n s (Z-E), t h e a n g u l a r methyl group, and t h e three-carbon s i d e c h a i n a r e trans. T h e r e f o r e , t h e r e a d i l y may be used a s a s t a r t i n g a v a i l a b l e 7-epi-a-cyperone point. I n a s y n t h e s i s designed t o a s c e r t a i n t h e r e l a t i v e s t e r e o chemistry of t h e molecule, B a r r e t t and BUchi p r e p a r e d a-agarofuran from compound 2 a s shown i n Scheme 1 4 . 29 Reduction of
(z)
Scheme 1 4 .
Barrett-BUchi S y n t h e s i s of a-Agarofuran
4%
n,.; HO
31 -
115 -
Basic
116 0
117
I _
Acidic
c,
__c
B i c a r b o c y c l i c S e s q u i t e r p e n e s , Hydronaphthalenes
301
-
ra+ Hop s0cl2
LiAlH4
___c
Ether
Ether
120 -
7-epi-a-cyperone (31) with L i A l H 4 gave a c r y s t a l l i n e a l c o h o l ( s t e r e o c h e m i s t r y undetermined) i n 80% y i e l d . P y r o l y t i c dehyand d r a t i o n o f t h i s a l c o h o l (115)gave a mixture of diene i t s h e t e r o a n n u l a r isomer i n a r a t i o of 3:l. S e n s i t i z e d photooxygenation of 116 gave peroxide t h e s i n g l e t oxygen app a r e n t l y adding predominately from t h e l e s s hindered s i d e of t h e molecule. When peroxide was t r e a t e d with b a s i c alumi n a , it was transformed i n t o t h e c r y s t a l l i n e keto-alcohol which r e a d i l y c y c l i z e d t o k e t o - e t h e r 119 upon exposure t o acid-washed alumina. Compound 119 was reduced by L i A l H 4 t o a mixture of a l l y l i c a l c o h o l s 120. This mixture was deoxygenated by reducing t h e d e r i v e d c h l o r i d e s with L i A l H 4 a-agarofuran and i t s double bond isomer were produced i n equal amounts. Marshall and Pike s y n t h e s i z e d a- and 6-agarofuran as shown i n Scheme 15.’ 30 7-epi-a-cyperone was epoxidized t o
117
(z),
116
=,
* moH 121 (122)
(12)
? , Scheme 15.
123
M a r s h a l l ’ s S y n t h e s i s of t h e Agarofurans
-
__c MCPA
I
___c LiAlH4
’0
31 -
I
-
123 -
AcpO
HO
AcO
124
125
‘OH
__c Li-NH3
221,
302
w,-
Total Synthesis of Sesquiterpenes
OH
MCPA-
SOC12
C5H5N
HO
126 -
127 -
hv
___c
i-PrOH
CH2
12 -
13 -
(probably a mixture of d i a s t e r e o m e r s ) which was reduced t o a The mixture w a s n o t s e p a r a t e d mixture of i s o m e r i c d i o l s b u t was d i r e c t l y a c e t y l a t e d and t h e mixture o f a c e t a t e s r e d u c t i v e l y cleaved w i t h l i t h i u m i n anunonia t o 7-epi-y-eudesmol (126).Treatment of 126 w i t h m-chloroperbenzoic a c i d gave d i r e c t l y t h e n a t u r a l l y o c c u r r i n g 4-hydroxydihydroagarofuran which was dehydrated by t h i o n y l c h l o r i d e i n p y r i d i n e t o a-agarofuran (12).When was i r r a d i a t e d i n i s o p r o p y l a l cohol w i t h xylene a s s e n s i t i z e r , B-agarofuran (13)was produced. The most e f f i c i e n t s y n t h e s i s of a-agarofuran y e t r e p o r t e d i s t h a t of Deslongchamps and co-workers (Scheme 16) . 1 3 1 Ketol
(124).
(g),
(125)
12
q, -oq Scheme 16.
Deslongchamp's S y n t h e s i s of a-Agarofuran
NaOMe
1. Hg(0Ac)g
0
bH
38 -
129 -
__c
2 . NaBH4
bH
OH
128 -
124 -
Bicarbocyclic Sesquiterpenes, Hydronaphthalenes
303
38 (p. 286) was converted i n t o keto d i o l = b y tion-demercuration. Base c a t a l y z e d dehydration
oxymercuray i e l d e d 7epi-carrisone which was reduced t o a mixture of unsaturated diols Treatment of = w i t h p-toluenes u l f o n i c a c i d i n benzene gave a-agarofuran i n 80% y i e l d , along with 20% of keto-ether 130. Kelly and Heathcock reported t h e s y n t h e s i s of nor-ketoagarofuran which i s o u t l i n e d i n Scheme 1 7 . 32 Unsaturated
(g), (124).
(14)
Scheme 1 7 .
Heathcock-Kelly Synthesis of Nor-Ketoagarofuran
131 NaOMe
6-H
MeLi
OH
132 -
6H
OH
134 -
14 -
acid 78, used i n t h e s y n t h e s i s of 8-eudesmol (Scheme 6 ) , was The correoxidized by performic a c i d t o dihydroxy a c i d sponding methyl e s t e r 132 was epimerized and l a c t o n i z e d under c a r e f u l l y c o n t r o l l e d c o n d i t i o n s t o o b t a i n hydroxy l a c t o n e 133.
131.
304
Total Synthesis of Sesquiterpenes
This r e a c t i o n , which is h i g h l y c a p r i c i o u s , proceeds i n y i e l d s ranging from 10-70%. The crude hydroxy l a c t o n e was t r e a t e d which was with m e t h y l l i t h i u m t o y i e l d c r y s t a l l i n e t r i o 1 o x i d i z e d , w i t h concommitant c y c l i z a t i o n , t o nor-ketoagarofuran Although n o v e l , t h e r o u t e i s of l i t t l e p r e p a r a t i v e v a l u e , due t o the u n r e l i a b l e n a t u r e of t h e l a c t o n i z a t i o n s t e p .
(z),
(14).
G.
Epi-y-Selinene
and Like t h e agarof urans and o c c i d e n t a l o l , e p i - y - s e l i n e n e (2) e p i - a - s e l i n e n e (16)have t h e a n g u l a r methyl and t h e t h r e e carbon s i d e c h a i n t r a n s . As mentioned e a r l i e r (p. 286), t h i s s t e r e o c h e m i s t r y may b e e s t a b l i s h e d k i n e t i c a l l y by Robinson a n n e l a t i o n o f e t h y l v i n y l k e t o n e ( o r i t s e q u i v a l e n t ) and d i hydrocarvone. As p a r t o f t h e s t r u c t u r e p r o o f , Klein and Rojahn as o u t l i n e d i n Scheme 18.133 Epi-as y n t h e s i z e d isomer
Scheme 18.
29 -
Klein-Rojahn S y n t h e s i s of Epi-y-Selinene
38 CH2SH
I
CHzSH
___c
31 -
135
was prepared v i a k e t o l 2 by condensation of 1cyperone (2) chloro- 3-pentanone w i t h (+) -dihydrocarvone (2) Deoxygenat i o n was accomplished by Raney n i c k e l d e s u l f u r i z a t i o n o f t h e corresponding d i t h i o k e t a l (135)
.
.
B i c a r b o c y c l i c S e s q u i t e r p e n e s , Hydronaphthalenes H.
305
Chamaecynone and la-Hydroxyisochamaecynone
The chamaecynones a r e a group of b i c y c l i c nor-sesquiterpenes which have been i s o l a t e d from t h e e s s e n t i a l o i l of t h e Benihi t r e e . Chamaecynone (El was s y n t h e s i z e d i n 1967 by t h e Sendai group o f Nozoe, Asao, Ando, and Takase.134 The s t a r t i n g p o i n t w a s a-santonin (23) which w a s converted v i a i t s C-6 epimer i n t o keto-acid 41. Compound 41 was hydrogenated, i n t h e p r e s ence o f 1%NaOH, t o g i v e s a t u r a t e d ketone 136. The configurat i o n a t C-4, which i s e p i m e r i z a b l e , i s t h e more s t a b l e one. Compound was s u b j e c t e d t o chlorodecarboxylation (Kochi' s m o d i f i c a t i o n of t h e Hunsdiecker r e a c t i o n ) t o o b t a i n c h l o r i d e 1 3 7 , undoubtedly a mixture of d i a s t e r e o m e r s . Since t h e n e x t s t e p planned involved t r e a t m e n t w i t h s t r o n g b a s e , and a l d o l condensations must be avoided, t h e carbonyl group w a s tempora r i l y reduced, a f f o r d i n g a mixture of d i a s t e r e o m e r i c chloroa l c o h o l s 138. Base c a t a l y z e d d e h y d r o c h l o r i n a t i o n gave uns a t u r a t e d a l c o h o l mixture 139,which was brominated and dehydrobrominated t o a mixture of a c e t y l e n i c a l c o h o l s Compound was o x i d i z e d t o ketone was Compound brominated and t h e r e s u l t a n t mixture of bromoketones 143 was dehydrobrominated t o g i v e chamaecynone (E)i n 38% y i e l d . Epimerization a t C-4 a p p a r e n t l y occurs d u r i n g t h e bromination stage.
-
136
141
Scheme 19.
141. 142
142.
Chamaecynone--Sendai S y n t h e s i s
136 -
NaBH4 ___c
306
T o t a l S y n t h e s i s of S e s q u i t e r p e n e s
140
141 -
Br
_ I
17 -
In a s u b s e q u e n t paper, t h e same g r o u p reported a s y n t h e s i s of 40,-hydroxyisochamaecynone (g) as o u t l i n e d i n Scheme 20.' 3 5 Scheme 20.
4c(-Hydroxyisochamaecynone--Sendai S y n t h e s i s
Bicarbocyclic Sesquiterpenes, Hydronaphthalenes
*+-,
Br2
=@ o,*
0
OAc
307
“OH
H
“OH
148 -
18 -
The synthesis, which was carried out in order to determine the stereochemistry at C-4, began with acetylenic ketone 142. This material was converted into enol acetate 144,which was epoxidized to oxide 145. Because of the folded nature of the cis-octalin 144,the oxygen is delivered stereospecifically from the convex surface of the molecule. Pyrolytic rearrangewhich was hydrolyzed to ment of 145 gave keto acetate hydroxy ketone 147. The isomeric hydroxy ketone 149 was prepared by direct basic hydrolysis of 145. The formation of isomers 147 and 149 may be depicted mechanistically as follows:
s,
0
’OH 147 -
145 -
T o t a l S y n t h e s i s of S e s q u i t e r p e n e s
308
(147)
Having a r r i v e d a t an i n t e r m e d i a t e c o n t a i n i n g a l l of t h e r e q u i s i t e s t e r e o c h e m i s t r y , it was n e c e s s a r y o n l y t o i n t r o T h i s was accomplished by brominaduce a double bond a t C -1. tion-dehydrobromination t o o b t a i n 4a-hydroxyisochamaecynone (18).
-
I.
Occidol and O c c i d e n t a l o l
The r e a r r a n g e d s e s q u i t e r p e n e o c c i d o l (E)was s y n t h e s i z e d by Nakazaki from s a n t o n i n as o u t l i n e d i n Scheme 21.136 Santonin Scheme 2 1 .
Nakazaki S y n t h e s i s of (+)-Occidol
23 -
150 Zn HOAc
\\
0
1. SOC12
-
+%
2 . MegCd
C02H
154 -
..." *
KOH -
@-
OAc
MeMgI
156 -
(23) was
19 -
OH
converted i n t o oxime (E), which g i v e s hyposantonin r e d u c t i o n w i t h sodium amalgam. Reductive cleavage of ( z i n c d u s t i n acetic a c i d ) g i v e s hyposantonous a c i d was c o n v e r t e d , v i a t h e a c i d c h l o r i d e , i n t o (152).Acid methyl k e t o n e 153. B a e y e r - V i l l i g e r o x i d a t i o n of gave an
(151)upon
151
152
153
B i c a r b o c y c l i c S e s q u i t e r p e n e s , Hydronaphthalenes
309
=,
a c e t a t e (154), which was hydrolyzed t o an a l c o h o l (155). Compound o x i d i z e d t o ketone which gave ( + ) - o c c i d o l when t r e a t e d with methylmagnesium i o d i d e . O c c i d e n t a l o l i s an i n t e r e s t i n g eudesmane i n t h a t t h e decalone system i s c i s - f u s e d and t h e angular methyl and t h r e e carbon groups a r e trans. The s t e r e o c h e m i s t r y must be i n t r o duced s o l e l y by k i n e t i c methods. Hortmann h a s s t a t e d i n a f o o t n o t e 1 3 7 t h a t o c c i d e n t a l o l (20) can be o b t a i n e d , along with isomer 158,v i a p h o t o l y s i s of " t r a n s - o c c i d e n t a l o l (157)" However, t h e s y n t h e s i s of h a s n o t y e t been r e p o r t e d .
=was
.
157
OH
OH
OH
157 -
158 -
20 -
This r e a c t i o n , which must proceed by c l o s u r e of an i n t e r m e d i a t e c y c l o d e c a t r i e n e , i s similar t o t h e key s t e p i n t h e CoreyHortmann s y n t h e s i s of dihydrocustunolide (p. 2 7 9 ) . Heathcock and Amano have r e c e n t l y r e p o r t e d a ( + ) - o c c i d e n t a l o l which i s summarized i n Scheme 2 2 . Scheme 22.
Heathcock-Amano S y n t h e s i s o f O c c i d e n t a l o l
NaOMe
0
-.Q-??.
49 -
29 -
H2-Pd-C
__c HC1
___c
/
THF
0
& 128 -
0
159
OH
HOAc
m,OH
129 -
OH
OH
OH
1. pTsNHNH2
2 . MeLi
-
Br2
OH
160 -
310
Total Synthesis of Sesquiterpenes
Br
OH
OH
Dihydrocarvone (2) was converted into keto-alcohol 49 by oxymercuration-demercuration. Compound 49 was condensed with ethyl vinyl ketone (sodium methoxide in ether) to obtain keto diol 128, in which the angular methyl and isopropanol groups are t r a n s . Dehydration of 128 gave epi-carissone (129).Compound 129 was hydrogenated over palladized carbon in acetic acid to give a 4:l mixture of cis-dihydrocarissone (159) and its t r a n s isomer. Ketone 159 was subjected to Shapiro's modification of the Bamford-Stevens reaction to yield olefin Bromination-dehydrobromination gave a mixture of occidentalol (20) and its isomer 162.
=.
J.
Atractylon and Lindestrene
Atractylon (21) and lindestrene sesquiterpenes.
21 -
(2)are
representative furano-
22 -
Both compounds have been synthesized by Minato and Nagasaki. 39 1 4 0 Scheme 2 3 outlines the atractylon synthesis. 39 The key intermediate in Minato's synthetic plan was methylene decalone 176. It was anticipated that this ketone could be converted into atractylon by a method of furan synthesis previously developed by these ~ 0 r k e r s . l ~It ~ is interesting to compare the route to 176 with Marshall's route to its isomer
Scheme 2 3 .
167 -
M i n a t o - N a g a s a k i S y n t h e s i s of A t r a c t y l o n
169 -
171 -
1. DIBAL 2 . W.K.
311
312
T o t a l S y n t h e s i s of S e s q u i t e r p e n e s CH3
I
1. BrCH-CO2Et 2. H30
i-
-
\
60,
a key i n t e r m e d i a t e f o r eudesmane s y n t h e s i s (p. 2 9 0 ) . This comparison p o i n t s o u t t h e degree of complexity which can be imparted t o a s y n t h e t i c problem by an awkward p a t t e r n of funct i o n a l i t y . While Marshall r e q u i r e d only f i v e s t e p s t o p r e p a r e 6 0 , t h e analogous 2-decalone 2 r e q u i r e s twelve s t e p s . Dienone 165,o b t a i n a b l e from methoxy t e t r a l o n e 163 as i n d i c a t e d , was hydrocyanated by N a g a t a ' s method. Cyanoenones 166 and 167 were o b t a i n e d , each i n 20% y i e l d . Each w a s f u r t h e r hydrocyanated t o o b t a i n t h e trans decalones 168 and 169 r e s p e c t i v e l y , which were converted i n t o k e t o l s and 1 7 1 . The a x i a l cyano group in was epimerized by base t o yield S e l e c t i v e r e d u c t i o n of t h e l e s s hindered n i t r i l e which was converted, over Raney n i c k e l gave primary amine by a type of Leukart r e a c t i o n , i n t o t e r t i a r y amine 173. The a n g u l a r cyano group was converted t o methyl by r e d u c t i o n w i t h diisobutylaluminum h y d r i d e , followed by Wolff-Kishner reduct i o n of t h e r e s u l t i n g aldehyde. P e r a c i d o x i d a t i o n of gave an N-oxide (E), which w a s pyrolyzed t o o b t a i n an u n s a t u r a t e d k e t a l . Hydrolysis t h e n a f f o r d e d t h e d e s i r e d methylene decalone. Compound 176 was a l k y l a t e d , by S t o r k ' s method, w i t h e t h y l a-bromopropionate, t o o b t a i n k e t o e s t e r 178. Dehydration of
-
-
171.
170
170
172,
174
B i c a r b o c y c l i c S e s q u i t e r p e n e s , Hydronaphthalenes
313
t h i s s u b s t a n c e a f f o r d e d b u t e n o l i d e 179,which w a s reduced w i t h diisobutylaluminum h y d r i d e t o a t r a c t y l o n ( g ) . The Minato-Nagasaki s y n t h e s i s of l i n d e s t r e n e i s o u t l i n e d i n Scheme 24,140 "he s t a r t i n g p o i n t was t h e well-known Scheme 24.
Minato-Nagasaki S y n t h e s i s of ( + ) - L i n d e s t r e n e
180 -
181 -
182 -
OH
=
qJ-2183 -
0
\>
1. MCPA
OAc
OH
186 -
y:, OAc
wi20
187 -
,,,QAc
188
OAc
-
CH3
I
Br-CHC02Et
Zn
d
0
OH HO
TsO
191
193 -
CH2
314
195 -
m
U
192
OH
_.
194 -
p+ CH2
196
0-
DIBAL
Bicarbocyclic Sesquiterpenes, Hydronaphthalenes
315
u n s a t u r a t e d hydroxy-ketone 180.14' The secondary a l c o h o l was p r o t e c t e d by base c a t a l y z e d benzylation.* K e t a l i z a t i o n of gave which was converted i n t o a mixture of d i a s t e r e o m e r i c a l c o h o l s by hydroboration. Oxidation with S a r r e t t ' s r e a g e n t gave a mixture o f decalones, which was epimerized by a l c o h o l i c base. The r e s u l t i n g trans-decalone 185 was reduced and t h e dioxolane grouping hydrolyzed t o o b t a i n hydroxy ketone 186. When 186 was t r e a t e d with isopropenyl a c e t a t e , t h e diacet a t e 187 w a s produced. P e r a c i d o x i d a t i o n , followed by a c i d i c h y d r o l y s i s gave 188, which r e a c t e d i n t h e Reformatsky r e a c t i o n t o y i e l d E. Sodium a c e t a t e c a t a l y z e d dehydration gave b u t e n o l i d e 190, which w a s hydrolyzed t o alcohol 191. S a r r e t t o x i d a t i o n of t h e secondary hydroxyl gave 192, which was hydrogenolyzed t o The methylene group was introduced by a The second double bond was Wittig reaction, yielding i n dimethylformamide .t formed by s o l v o l y s i s of t o s y l a t e The r e s u l t i n g t r i e n e (196)was reduced by diisobutyluminum hydride t o (+) -1indestrene (22)
Jg
s,
=.
194.
.
K.
195
Santonin
a-santonin (23) and 6-santonin (24) a r e two of t h e most wellknown and e a r l i e s t s t u d i e d s e s q u i t e r p e n e s . Many y e a r s of s t r u c t u r a l i n v e s t i g a t i o n were culminated i n 1930 when Clem,
23 -
24 -
Haworth, and Walton proposed t h e c o r r e c t s t r u c t u r e s f o r t h e s a n t o n i n i ~ 0 m e r s . l ~I n~ an o u t s t a n d i n g f r a u d , an Indian group claimed i n 1943 t h a t t h e y had e f f e c t e d t h e t o t a l s y n t h e s i s of *Recent a t t e m p t s t o r e p e a t t h i s r e a c t i o n have been unsuccessf ~ 1 . l This ~ ~ is n o t s u r p r i s i n g , due t o t h e w e l l known prop e n s i t y of t h i s type of compound t o undergo vinylogous r e t r o a l d o l condensations. 144 However , compound 182, prepared by another r o u t e 1 4 3 was found t o have t h e same p h y s i c a l propert i e s a s t h o s e r e p o r t e d by Minato and Nagasaki. +This e l i m i n a t i o n i s most remarkable, i n l i g h t of t h e f i n d i n g t h a t t r a n s - d e c a l y l t o s y l a t e s of t h i s type under o predominate s k e l e t a l rearrangement under t h e s e c o n d i t i o n s . J 3
316
T o t a l S y n t h e s i s of S e s q u i t e r p e n e s
o p t i c a l l y a c t i v e s a n t o n i n w i t h o u t t h e a s s i s t a n c e of any d i symmetric r e a g e n t s . 1 4 6 T h i s claim was v i g o r o u s l y d i s p u t e d by v a r i o u s workers. 47 T o t a l s y n t h e s i s of t h e s a n t o n i n isomers was pursued by a number o f groups on account o f t h e powerful a n t h e l m i n t i c act i v i t y p o s s e s s e d by t h e compounds. Success was e v e n t u a l l y r e a l i z e d by a group headed by Abe a t t h e Takeda Pharmaceutical L a b o r a t o r i e s i n Osaka. I n a d d i t i o n t o s y n t h e s i z i n g t h e n a t u r a l s a n t o n i n isomers 23 and 24, t h e Abe group prepared t h e un( + ) - s a n t o n i n B (198) , n a t u r a l isomers ( + ) - s a n t o n i n A ( + ) - s a n t o n i n C (199), and ( 2 ) - s a n t o n i n D (200) .14**
’
(E), -
Because o f t h e i n t e r e s t i n s a n t o n i n c h e m i s t r y , and because n a t u r a l (-)-u-santonin i t s e l f has been used a s t h e starti n g p o i n t i n many formal t o t a l s y n t h e s e s of o t h e r s e s q u i t e r penes ( s e e Schemes 28, 29, 31, and 37 i n s e c t i o n 3; Schemes 1, 1 9 , 2 0 , and 2 1 i n s e c t i o n 4 ; and Schemes 6 , 7 , 9 , and 11 i n s e c t i o n 5), w e s h a l l g i v e a f u l l account o f t h e s y n t h e t i c s t u d i e s c a r r i e d o u t by t h e Takeda group. Scheme 2 5 o u t l i n e s t h e s y n t h e s i s of ( 2 ) - s a n t o n i n A *For t h e sake o f convenience, t h e racemic s a n t o n i n isomers are w r i t t e n i n t h e e n a n t i o m e r i c form w i t h t h e a n g u l a r methyl group B . A t t h e t i m e of the Takeda s y n t h e s i s , no d e f i n i t i v e i n f o r mation on t h e s t e r e o c h e m i s t r y a t C-11 (see formula 197)w a s a v a i l a b l e , and f o r some t i m e t h i s c o n f i g u r a t i o n was i n d i s The c o n f i g u r a t i o n was d e f i n e d i n d e p e n d e n t l y i n 1962 p u t e . l4 by t h r e e groups.
’
Scheme 25.
i
206 -
-HBr
Takeda S y n t h e s i s of
208 -
(+)-Satonin A,
(')-Satonin
-HBr
I
210 -
B , and ( ? ) - S a t o n i n D
c
Q
0
m ,.
rl
u0
=I N
0
a
rn
rl rl
u
0
b( N
a
rl
0
U
318
go m
3:
-8
X-5
0
B i c a r b o c y c l i c S e s q u i t e r p e n e s , Hydronaphthalenes
319
( 1 9 7 ) , 148a ( ? ) - s a n t o n i n B (198) ,148a and (+)-.?,antonin D (200). 148b Keto-ester 201 was condensed w i t h l-diethylaminop z a n - 3 - o n e methiodide (2) i n a Robinson a n n e l a t i o n t o y i e l d a mixture of d i a s t e r e o m e r i c o c t a l o n e s 202 i n 51% y i e l d . A l k a l i n e h y d r o l y s i s o f t h e mixture gave a mixture of a c i d s . F r a c t i o n a l c r y s t a l l i n e y i e l d e d (2)-A-acid (203)i n 21% y i e l d and (2)-B-acid (204) i n 16% y i e l d . Bromination of A-acid (203) with two mole-equivalents of bromine i n e t h e r - a c e t i c a c i d gave a bromo-lactone 207, probably v i a t h e i n i t i a l l y formed dibromo-acid 206. Dehydrobromination of 207 y i e l d e d ( k ) - s a n t o n i n A (197).Analogous t r e a t m e n t of B-acid (2) y i e l d e d ( + ) - s a n t o n i n B (198) , v i a i n t e r m e d i a t e s 208 and 209. A f t e r removal o f t h e c r y s t a l l i n e A- and B-acids, t h e remaining mother l i q u o r s were brominated i n a s i m i l a r manner. C a r e f u l examination of r e a c t i o n mixture a f f o r d e d t h e dibromoa c i d 2 and t h e bromo-lactone 211 i n low y i e l d . Both 210 and 2 1 1 , upon r e f l u x i n g i n c o l l i d i n e , y i e l d e d (+)-saritonin D. From t h e s e r e s u l t s , it may be i n f e r r e d t h a t D-acid (205) i s produced, along w i t h isomers and as a minor product of t h e Robinson a n n e l a t i o n . The f o u r t h u n n a t u r a l s a n t o n i n isomer c o n t a i n i n g a cisfused l a c t o n e r i n g , ( ? ) - s a n t o n i n C (=), was o b t a i n e d , along with ( 2 ) - s a n t o n i n D , by t h e r o u t e shown i n Scheme 26. Hexalone
-
203
Scheme 26.
@
0
204,
Takeda S y n t h e s i s o f ( f ) - S a n t o n i n C and (+)-Santonin D
+
CH3XC02Et NaOEt
___c
H
C02Et
EtOH
T o t a l Synthesis of S e s q u i t e r p e n e s
320
1
2 Br2 Ether-HOAc
1
Etc.
2 00 -
216 -
1
QfB’r
Na2C03
,,,,CH3
0
217 -
1
212 underwent -
Collidine, A
1,6-Michael a d d i t i o n w i t h t h e sodium s a l t of d i e t h y l methylmalonate t o g i v e e x c l u s i v e l y t h e adduct 3,i n which t h e i ncoming group had occupied t h e equatorial p o s i t i o n (69% y i e l d of c r y s t a l l i n e p r o d u c t ) . A l k a l i n e h y d r o l y s i s gave 2 1 4 , which w a s decarboxylated t o a m i x t u r e of keto-acids. From this m i x t u r e , C-acid (215) and D-acid (205) were i s o l a t e d
-
Bicarbocyclic S e s q u i t e r p e n e s , Hydronaphthalenes
321
( i n low y i e l d ) by f r a c t i o n a l c r y s t a l l i z a t i o n . C-acid (215) underwent bromination t o give dibromo-acid 216. This substance was l a c t o n i z e d t o bromo-lactone 217 only upon t r e a t m e n t w i t h sodium carbonate. F u r t h e r dehydrobrominat i o n a f f o r d e d ( + ) - s a n t o n i n C (199). D-acid (205)had a l r e a d y been converted i n t o ( + ) - s a n t o n i n D (200). S e v e r a l noteworthy p o i n t s emerge from a study of t h e s e syntheses. F i r s t l y , we s e e again t h e tendency f o r Robinson a n n e l a t i o n on cyclohexanones of t h e type 201 t o give predomin a t e l y o c t a l o n e s i n which t h e angular methyl group and t h e three-carbon s i d e chain a r e trans ( c f . p . 286). Thus, a c i d s 203 and 204, both having t h e three-carbon group i n t h e unn a t u r a l a x i a l c o n f i g u r a t i o n a r e t h e predominant products. As would be expected, e s s e n t i a l l y no s t e r e o s p e c i f i c i t y i s seen a t t h e side-chain p o s i t i o n (C-11) , with 203 and 204 being produced i n roughly equal amounts. The stereochemistry of t h e l a c t o n e r i n g i s , i n each c a s e , e s t a b l i s h e d by l a c t o n i z a t i o n of a y-bromo a c i d . I t i s l i k e l y t h a t t h e a l l y l i c bromination occurs t o g i v e an a x i a l bromide i n i t i a l l y ( s e e 206 and 208). I n t h e c a s e of 206 and 2 2 , backs i d e displacement by t h e carboxyl group can occur immediately, b e f o r e t h e bromine is epimerized t o t h e more s t a b l e e q u a t o r i a l configuration, giving lactones and 2,r e s p e c t i v e l y . I n t h e case of C-acid (215) o r D-acid (205), backside d i s p l a c e ment on an a x i a l bromide must proceed through a s t r a i n e d t r a n s i t i o n s t a t e . I n t h e s e c a s e s , e p i m e r i z a t i o n of t h e i n i t i a l bromide o c c u r s , and dibromo-acids 216 and 210 may even be i s o l a t e d . L a c t o n i z a t i o n i s now more d i f f i c u l t , a s t h e carboxyl group must approach from an a x i a l d i r e c t i o n . The s t e r e o s p e c i f i c i t y of t h e Michael r e a c t i o n (212+ 213) i s remarkable. Hexalone 212 r e a c t s with d i e t h y l malonate t o give adducts 218 and 2 i n v a r i a b l e amounts, depending upon t h e r e a c t i o n c o n d i t i o n s . With potassium t-butoxide i n tbutanol a t 25' f o r 10 days, c r y s t a l l i n e 218 was obtained i n
-
-
322
T o t a l S y n t h e s i s of S e s q u i t e r p e n e s
51% y i e l d . None of isomer 219 was i s o l a t e d under t h e s e condit i o n s . When t h e r e a c t i o n was c a r r i e d o u t a t r e f l w f o r 1 0 h r , c r y s t a l l i n e isomer 2 was i s o l a t e d i n 39% y i e l d . Examination of t h e mother l i q u o r s i n t h i s case r e v e a l e d t h a t isomer 218 was a minor p r o d u c t . l S 1 These d a t a s u g g e s t t h a t compound 218 i s a k i n e t i c product ( a x i a l a l k y l a t i o n ) and 219 is a thermodynamic product ( e q u a t o r i a l a l k y l a t i o n ) . However, t h e conv e r s i o n of 212 t o 213 was c a r r i e d o u t under mild c o n d i t i o n s (sodium e t h o x i d e i n e t h a n o l a t room temperature) which should favor t h e k i n e t i c p r o d u c t . Scheme 2 7 o u t l i n e s t h e Takeda s y n t h e s i s of a - s a n t o n i n and Scheme 2 7 .
Takeda S y n t h e s i s of a-Santonin and 8-Santonin
213 -
-
220 -
Col 1i d i n e
C02H
4
0
23 -
U
24 -
B i c a r b o c y c l i c S e s q u i t e r p e n e s , Hydronaphthalenes
323
213
B - ~ a n t o n i n . ~Enone ~~ was o x i d i z e d w i t h selenium d i o x i d e i n a c e t i c a c i d t o a dienone 220, which was hydrolyzed t o a d i a c i d 221. Decarboxylation of d i a c i d 221 gave a mixture o f mono-acids 222 and 223. Hydroxylation of t h i s mixture, again w i t h selenium d i o x i d e i n acetic a c i d , gave a mixture of ( 5 ) a-santonin (23) and ( + ) -6-santonin (2) The i n t e r m e d i a t e d i acid was r e s o l v e d a s i t s b r u c i n e of q u i n i n e s a l t . The c a r r i e d through t h e same sel e v o r o t a t o r y a n t i p o d e of =was quence t o a f f o r d (-) -a-santonin and (-) -B-santonin. Scheme 28 o u t l i n e s an a l t e r n a t i v e s y n t h e s i s by Abe’s
.
221
Takeda S y n t h e s i s of a-Santonin
Scheme 28.
C02EtH2 0
C02Et
224 -
213 -
-
Bor& ’co-;
C02Et
0
226 -
225 -
-
1. KOH 2 . H30’
C o l l i d ine
___c
0
A
0 0
228 -
227 -
0
23
324
T o t a l S y n t h e s i s of S e s q u i t e r p e n e s
213
was group which l e d o n l y t o a-santonin.’ 5 2 K e t o - d i e s t e r converted i n t o t h e d i e n y l a c e t a t e % b y a c e t i c anhydride. P e r a c i d o x i d a t i o n o c c u r r e d from t h e f a c e o f t h e molecule oppos i t e t o t h e methyl group, y i e l d i n g (presumably) an a l c o h o l , which l a c t o n i z e d . The i s o l a t e d p r o d u c t was t h e t r a n s fused gave a bromo-ketone 226, l a c t o n e 225. Bromination of which was dehydrobrominated with c o l l i d i n e t o a f f o r d 11carbethoxy s a n t o n i n (227). A l k a l i n e h y d r o l y s i s , followed by a c i d i f i c a t i o n , gave a c i d 228, which decarboxylated t o g i v e only ( t ) - a - s a n t o n i n (23). Compound 228 was r e s o l v e d as i t s b r u c i n e s a l t and t h e l e v o r o t a t o r y a n t i p o d e decarboxylated t o y i e l d (-)-a-santonin.
225
L.
Artemisin
Artemisin (El i s a hydroxy analog of a - s a n t o n i n . Nakazaki and Naemura have r e p o r t e d a s y n t h e s i s of a r t e m i s i n which is c l o s e l y p a t t e r n e d a f t e r t h e Takeda a - s a n t o n i n s y n t h e s i s (see p r e v i o u s s e c t i o n ) . 5 3 The s y n t h e s i s , o u t l i n e d i n Scheme 29 ,
’
Scheme 2 9 .
Nakazaki-Naemura S y n t h e s i s of (?)-Artemisin
HO
0
HO 231 -
2 30 -
229
bc
__c
0
2 32 -
233 -
OAc
2 34 -
2 35 -
B i c a r b o c y c l i c S e s q u i t e r p e n e s , Hydronaphthalenes
[
325
rnHCOZ [H20]
o& , C02Et
__c
H
2 38
Ac20
0 O
'
V
,
,
,t'
2 39 -
H
o*o
DCDQ
I
240 -
0*o-o*
J H
0
24 1
H
5 H% 20
OH
(z),
begins w i t h p-toluoquinone which was hydrogenated t o g i v e t h e cis g l y c o l 230. S e l e c t i v e a c e t y l a t i o n of 230, a f forded monoacetate 231, which was o x i d i z e d t o k e t o - a c e t a t e
326
T o t a l S y n t h e s i s of S e s q u i t e r p e n e s
232. -
Robinson a n n e l a t i o n on t h i s s u b s t a n c e gave t h e o c t a l o n e The d i e n y l a c e t a t e 234, p r e p a r e d b y Abe's brominated and dehydrobrominated t o g i v e t h e acetoxyh e x a l o n e 235. When d i e t h y l methylmalonate w a s added t o 235, compounds 236, 237, and 238 were o b t a i n e d i n u n s p e c i f i e d y i e l d . Hydroxy-ester 238 was hydrolyzed t o t h e c o r r e s p o n d i n g a c i d (2) , which was l a c t o n i z e d b y t r e a t i n g w i t h sodium acet a t e i n a c e t i c a n h y d r i d e . Lactone 240 w a s dehydrogenated t o 241 by d i c h l o r o d i c y a n o q u i n o n e and t h e 6a-hydroxyl g r o u p was t h e n i n t r o d u c e d by o x i d a t i o n w i t h s e l e n i u m d i o x i d e i n a c e t i c a c i d . The r e s u l t i n g h y d r o x y - e s t e r was isomerized t o ( ? I a r t e m i s i n (%) by t r e a t i n g i t w i t h aqueous p o t a s s i u m c a r b o n a t e . No e x p e r i m e n t a l d e t a i l s have been p u b l i s h e d . 233.
was
-
242
Alantolactone, Isoalantolactone, Telekin
M.
The most n o t a b l e s t r u c t u r a l f e a t u r e of a l a n t o l a c t o n e (26) isoa l a n t o l a c t o n e (27) and t e l e k i n (28) i s t h e a-methylenebutyr o l a c t o n e moiety. This g r o u p i n g , commonly found i n many o f t h e more complex s e s q u i t e r p e n e s , p r o v i d e s an added d e g r e e of s y n t h e t i c c o m p l e x i t y which i s n o t e n c o u n t e r e d i n t h e s i m p l e r eudesmanes. With t h e e x c e p t i o n o f t h e Minato-Nagasaki s y n t h e s i s of a t r a c t y l o n (Scheme 2 3 ) , a l l of t h e d e c a l i n s y n t h e s e s d i s c u s s e d s o f a r have u t i l i z e d Robinson a n n e l a t i o n a s t h e method f o r securing t h e hydronaphthalene skeleton. Marshall's e l e g a n t s y n t h e s i s of a l a n t o l a c t o n e (Scheme 30) i l l u s t r a t e s an a l t e r n a t i v e s o l u t i o n o f t h i s problem.' 5 4 Hagemann's e s t e r (=) Scheme 30.
M a r s h a l l ' s S y n t h e s i s of ( ? ) - A l a n t o l a c t o n e
NaH, Toluene
Br
0
243 -
~,
_____c
KOH, E t O H
0
244 -
p' - W' 1. MeLi
HC02H
2. H20
0
245 -
H3C
OH
246 -
? H
/
p9
1. BrCH2C02Et
250 -
249 -
CH2
253 -
CH2
2. H30'
/
254
256 -
255 NaH
___c
MeOCO 2 Me
257 -
250 -
327
328
T o t a l S y n t h e s i s of S e s q u i t e r p e n e s
I
was a l k y l a t e d w i t h 4-bromo-1-butene t o g i v e i n t e r m e d i a t e 244, which was hydrolyzed and d e c a r b o y x l a t e d t o a f f o r d dienone 245. Methyllithiurn gave d i e n o l 246. When 246 w a s d i s s o l v e d i n formic a c i d , f a c i l e n - c y c l i z a t i o n occurred y i e l d i n g p r i m a r i l y t h e b i c y c l i c formate 247. Hydrolysis of t h e e s t e r grouping and o x i d a t i o n of t h e r e s u l t i n g a l c o h o l 248 y i e l d e d t h e d i methyloctalone 249. Ketone 299 formed a p y r r o l i d i n e enamine (250)with t h e double bond p a r a l l e l t o t h e r i n g f u s i o n bond, A l k y l a t i o n of enarnine 250 with e t h y l bromoacetate, f o l lowed by h y d r o l y s i s , gave t h e c r y s t a l l i n e k e t o a c i d 251 i n good y i e l d . Reduction of t h e corresponding methyl e s t e r (252) with methanolic potassium borohydride y i e l d e d l a c t o n e 253 ( 7 4 % ) along w i t h minor amounts of t h e corresponding d i o l (11%) and an e p i m e r i c hydroxy e s t e r (14%, e q u a t o r i a l hydroxyl g r o u p ) . Hematoporphyrin s e n s i t i z e d photooxygenation o f u n s a t u r a t e d l a c t o n e 253 y i e l d e d mainly t h e trans hydroperoxide 254 (53%) along with 2 2 % of i t s c i s a n a l o g . Reduction of 254 gave a l l y l i c a l c o h o l ;155, a key i n t e r m e d i a t e f o r t h e s y n t h e s i s of b o t h a l a n t o l a c t o n e and t e l e k i n . Hydrogenation of a l l y l i c a l c o h o l 255 o v e r Adam’s c a t a l y s t e s t a b l i s h e d t h e a x i a l s t e r e o c h e m i s t r y of t h e new secondary methyl group, y i e l d i n g Dehydration of t h e t e r t i a r y a l cohol with t h i o n y l c h l o r i d e i n p y r i d i n e gave s o l e l y t h e unsaturated lactone The h i g h s e l e c t i v i t y observed i n t h i s r e a c t i o n s u p p o r t s t h e a s s i g n e d s t e r e o c h e m i s t r y of t h e secondary methyl group. The a-methylenebutyrolactone grouping was e s t a b l i s h e d by a method developed e a r l i e r by Marshall f o r t h i s purpose155 and s u c c e s s f u l l y a p p l i e d i n a s y n t h e s i s of 4-demethyltetrahydroa l a n t o l a c t o n e . 1 5 6 Lactone ?57 was carbomethoxylated by h e a t i n g i t w i t h sodium h y d r i d e i n dimethyl c a r b o n a t e . The r e s u l t i n g sodium e n o l a t e (=) was reduced w i t h l i t h i u m aluminum hyd r i d e i n dimethoxyethane t o y i e l d d i o l 259. Oxidation of 259 w i t h a c t i v a t e d manganese d i o x i d e i n benzene gave c r y s t a l l i n e ( 2 ) - a l a n t o l a c t o n e i n 80% y i e l d . For t h e s y n t h e s i s of ( 2 ) - t e l e k i n (Scheme 311, compound 255 i s an i d e a l i n t e r m e d i a t e . 1 5 4 b t 1 5 7 A p p l i c a t i o n of t h e amethylenebutyrolactone s y n t h e s i s t o 255 ( v i a 260 and 261) gave
256.
257.
-
-I*[
Bicarbocyclic Sesquiterpenes, Hydronaphthalenes Scheme 31.
Marshall's Synthesis of (+)-Telekin
$pbH
CH2
255 -
CH2
329
OH CH2
260 -
CH2
261
C02Me
28 -
crystalline (+)-telekin (28). Minato' s synthesis of ( + ) -isoalantolactone (27) is outlined in Scheme 32.158 Methylene decalone, an intermediate in Scheme 32. Minato's Synthesis of (+)-Isoalantolactone 1. BrCH2C02Et
CH7 -
176 -
177 -
263 -
262 -
CH2
264 -
265 -
330
T o t a l S y n t h e s i s of S e s q u i t e r p e n e s
t h e s y n t h e s i s of a t r a c t y l o n (Scheme 2 3 ) was a l k y l a t e d via i t s enamine w i t h e t h y l bromoacetate t o y i e l d , a f t e r hydrolysis, keto acid Borohydride r e d u c t i o n of 262 gave lact o n e 263 i n 66% y i e l d . M i n a t o ' s method of i n t r o d u c i n g the amethylenebutyrolactone grouping involved formylation o f y i e l d i n g t h e hydroxyrnethylene d e r i v a t i v e 264. Reduction of was 264 w i t h b o r o h y d r i d e gave 265. The d e r i v e d t o s y l a t e heated i n pyridine to e f f e c t elimination, thereby yielding ( + ) - i s o a l a n t o l a c t o n e (27).
(177)
=.
=,
(z)
N.
Cadinanes; Calamenene, E-Cadinene, V e t i c a d i n o l , V e t i c a d i n e n e
The o n l y n a t u r a l l y o c c u r r i n g c a d i n a n e s which have been synvetit h e s i z e d a r e calamenene (266),15' c-cadinene (267),I6' c a d i n o l (268) ,161 and v e t i c a d i n e n e (269). I n a d d i t i o n two s y n t h e s e s 7 c a d i n e n e d i h y d r o c h l o r i d e (2) have a p p e a r e d ,
OH
267 -
266 -
269 -
268 -
270 -
one of t h e r a ~ e m a t e land ~ ~ o n e of t h e d e x t r o t a t o r y a 1 1 t i p 0 d e . l ~ ~ S i n c e ( - ) e-cadinene (267)h a s been o b t a i n e d b y dehydrochlor i n a t i o n of ( - ) -cadinene d i h y d r o c h l o r i d e ,165 t h e s e l a t t e r
B i c a r b o c y c l i c S e s q u i t e r p e n e s , Hydronaphthalenes
331
s y n t h e s e s may be considered formal t o t a l s y n t h e s e s of 267. The Ladwa-Joshi-Kulkarni s y n t h e s i s of (+)-calamenene, t h e o p t i c a l a n t i p o d e of t h e more commonly o c c u r r i n g t e r p e n e , i s o u t l i n e d i n Scheme 3 3 . ( - ) -Menthone (271)w a s converted Scheme 3 3 .
Ladwa-Joshi-Kulkarni
Me3N
+" 271 -
2 72 I
"
1. MeMgI
____c
2. A1203
0-
0
2 74 -
27 3 -
275 -
S y n t h e s i s of Calamenene
266 -
272
276 -
i n t o diketoaldehyde by t h e method o f Corey and Nozoe.166 Deformylation with aqueous potassium carbonate gave dione 273, which w a s c y c l i z e d w i t h p y r r o l i d i n e t o enone 274. C o m p o u n d 274 was methylated and dehydrated, a f f o r d i n g a mixture of d i e n e s (275,exo:endo r a t i o = 1 : l ) . Selenium d i o x i d e dehydrogenation of t h i s mixture gave a mixture of (+)-calamenene (266, 60%) and i t s diastereomer (276,4 0 % ) . Rao, Rao, and Dev a t t h e I n d i a n I n s t i t u t e of Science i n Bangalore, re o r t e d a s y n t h e s i s of (?)-cadinene dihydrochloThe s t a r t i n g m a t e r i a l , 4-isopropyl-6r i d e i n 1960. p 6 methoxy-1-tetralone (281)had been p r e v i o u s l y prepared by
-
332
T o t a l S y n t h e s i s of S e s q u i t e r p e n e s
Bardhan and Mukherji (Scheme 34) 1 6 7 and by Rao and Dev (Scheme 35) . 1 6 8 Although t h e l a t t e r s y n t h e s i s i s more l e n g t h y , it i s
/pJCH0Scheme 3 4 .
Bardhan-Mukherji S y n t h e s i s o f T e t r a l o n e
NaOH H20 I
+
Me0
EtOH
0
Ni
Me0
Me0
278 -
277 -
Me0 279 -
A
2 80
Me0
281 Scheme 3 5 .
Rao-Dev S y n t h e s i s of T e t r a l o n e Br
2 82 -
28 3 -
281
3
B i c a r b o c y c l i c S e s q u i t e r p e n e s , Hydronaphthalenes
9-
H3B03
LiAlH4
Me0
333
___c
A
Me0 OH
C02Et
2 88 -
287 Hz-Pd/CaC03 Me0
A
Me0
A
2 90 -
289 -
281 reported t h a t tetralone
on a c i d
282.
281 may
be o b t a i n e d i n 45% y i e l d based
For t h e s n t h e s i s of (?)-cadinene d i h y d r o c h l o r i d e , (Scheme 36) ,I6’ t h e Bangalore group f i r s t reduced t e t r a l o n e 281 t o t h e secondary a l c o h o l 291. Birch r e d u c t i o n of 291 a f forded 292, which was submitted t o Oppenauer o x i d a t i o n t o obt a i n enone 293. Lithium-ammonia r e d u c t i o n o f 293 gave compound 294, which was hydrolyzed t o d i k e t o n e 295. Compound 295 was t r e a t e d w i t h e x c e s s methyllithium t o o b t a i n a gummy d i o l , which r e a c t e d w i t h H C 1 i n e t h e r t o g i v e c r y s t a l l i n e (2)-cadinene d i hydrochloride (270), i d e n t i c a l with t h a t o b t a i n e d from ( ? I - & cadinene. The s t e r e o c h e m i s t r y o f t h e t h r e e c e n t e r s i n c r u c i a l
-
-
’‘’
4
Scheme 3 6 .
Me0
Bangalore S y n t h e s i s of
281 -
4
(+)-Cadinene Dihydrochloride
Na-NH3
LiAlH4
Me0
A
Me0
9-
T o t a l S y n t h e s i s of Sesquiterpenes
334
291 -
OH
Li-NH3
A 1 (1-Pr.Q) 3
Acetone Me0
292 -
29 3 0
Me0
I
H
-
E
A
294 -
295 -
i n t e r m e d i a t e 295 i s e s t a b l i s h e d i n t h e metal-amnonia r e d u c t i o n Mechanistic c o n s i d e r a t i o n s 1 7 0 p r e d i c t t h a t the nwre of 9 . s t a b l e product (294) w i l l be formed predominately. I n any e v e n t , d i k e t o n e 295 was i d e n t i c a l by i n f r a r e d spectroscopy with a sample of t h e l e v o r o t a t o r y d i k e t o n e , obtained by
B i c a r b o c y c l i c S e s q u i t e r p e n e s , Hydronaphthalenes d e g r a d a t i o n of c-muurolene
(297)*
335
by Herout and S a n t a r y . 17'
297 -
6+
I n 1965, S o f f e r r e p o r t e d a more d i r e c t s y n t h e s i s of ( + ) cadinene d i h y c r o c h l o r i d e , which i s o u t l i n e d i n Scheme 37. 164
Scheme 37.
298 -
S o f f e r ' s S y n t h e s i s of (+) -Cadinene Dihydrochloride
/
299 -
295 -
-
OEt
2 . OH-
EtO
300 -
270 -
(-) -Cryptone (298), o b t a i n e d from s y n t h e t i c (+) -cryptone' 7 2 by r e s o l u t i o n o f i t s p-carboxyphenylhydrazone (with q u i n i n e ) , r e a c t e d w i t h 2-ethoxy-1,3-butadiene (299)t o g i v e predominately
*Before 1964, t h e t e r m "c-cadinene" w a s e r r o n e o u s l y a p p l i e d t o s t r u c t u r e 297. W e s t f e l t showed t h a t compound 297 i n f a c t possesses a c i s - r i n g f u s i o n and found t h a t under t r a d i t i o n a l h y d r o c h l o r i n a t i o n c o n d i t i o n s compound 297 y i e l d s (-)-cadinene d i h y d r o c h l o r i d e . 165 However, s i n c e t h e r i n g j u n c t u r e p o i n t a d j a c e n t t o t h e carbonyl group i n 295 is e p i m e r i z a b l e , ozonol y t i c d e g r a d a t i o n o f 297 can s t i l l y i e l d 295
336
Total S y n t h e s i s of S e s q u i t e r p e n e s
t h e o c t a l o n e 300 ( u n s p e c i f i e d y i e l d ) . I t i s expected t h a t t h e diene would a t t a c k mainly from t h e s i d e o f 298 t r a n s t o t h e i s o p r o p y l group, t h u s a s s u r i n g t h e d e s i r e d s t e r e o c h e m i s t r y i n adduct 300. Hydrolysis of t h e e n o l e t h e r and b a s i c epimerizat i o n gave t h e d e x t r o r o t a t o r y a n t i p o d e o f d i o n e 295. This dione was c o n v e r t e d , f i r s t by methyllithiurn, t h e n by H C 1 , i n t o ( + ) -cadinene d i h y d r o c h l o r i d e (270) S o f f e r ' s s y n t h e s i s of E-cadinene (267) i s o u t l i n e d i n Scheme 38. 1 6 0 Octalone 300 was t r e a t e d w i t h m e t h y l e n e t r i -
.
Scheme 38.
S o f f e r ' s S y n t h e s i s of (+)-e-Cadinene
300 -
301 -
267 -
302 -
295 -
phenylphosphorane i n dimethyl s u f o x i d e t o y i e l d t h e transmethylene o c t a l i n Epimerization d u r i n g a W i t t i g r e a c t i o n had been noted p r e v i o u s l y (see p . 291). Acidic h y d r o l y s i s gave methylene decalone 301 which was a g a i n s u b m i t t e d t o W i t t i g methylenation t o o b t a i n (+)-E-cadinene (267). A l t e r n a t i v e l y , 267 could be o b t a i n e d by t h e d i r e c t b i s - m e t h y l e n a t i o n of d i o n e 295. Vig and co-workers r e p o r t e d a s y n t h e s i s of " v e t i c a d i n o l " (268) , o u t l i n e d i n Scheme 39. Relative stereochemistry w0;;ih be e s t a b l i s h e d i n the hydrogenation of compound 304 and i n t h e a c i d c a t a l y z e d e s t e r i f i c a t i o n l e a d i n g t o 308. S i n c e none of t h e i n t e r m e d i a t e s i n Scheme 39 were c r y s t a l l i n e , and s i n c e no comparison was made w i t h a u t h e n t i c v e t i c a d i n o l , t h e r e i s c o n s i d e r a b l e doubt about t h e s t e r e o c h e m i c a l h o m g e n e i t y of t h e f i n a l p r o d u c t . I t i s probably a mixture of 268 and isomers
%.
-
Scheme 39.
Vig's Synthesis of 'I(?)-Veticadinol" C02Et
C02Et HOAc
0
H2-Pd/C
____c
NC
C02Et
303 -
304 NC
KOH-E tOH
C02Et 305
-
1. H30+
___c
2. EtOH,
H+
NC 306 0
307 -
308 -
337
338
Total Synthesis of Sesquiterpenes
OH
OH
311 -
310 -
For the synthesis of "veticadinene" (2691, Vig's group transformed keto ester 308 as outlined in Scheme 4 0 . 1 6 2 The same stereochemical uncertainties exist. Scheme 40. Vig's Synthesis of "(2)-Veticadinene" 0
n
Me2Cd
C02Et
e02H
308 -
312
314 -
:
H
COCl
313 -
269 -
0. Drimanes; Drimenol (Bicyclofarnesol), Drimenin, Farnesi-
ferol
A
(Biogenetic Routes)
The drimane group of sesquiterpenes possesses a bicyclofarnesol skeleton with substitution similar to that typically found in the di- and triterpene families. The probable biogenesis of drimenol (315)from farnesol has stimulated a good deal of
Bicarbocyclic Sesquiterpenes, Hydronaphthalenes
339
study of this and related cyclizations in vitro.
Drimanic sesquiterpenes which have actually been s nthesized by this type of approach include drimenol (315) 11y3,174 the corresponding acid "bicyclofarnesic acid" (316, not natudrimenin (317),176 and farnesiferol A rally occurring) , 1 7 3 r 1 5 5 (318).177 In this section we shalldiscuss these "biogenetically styled" drimane syntheses. In the next, we shall discuss other syntheses of these and related drimanes.
316 -
318 -
317 -
The first work on the cyclization of farnesic acid (319) was reported by Caliezi and Schinz in 1949.173a From the reaction of acid 319 in a formic acid-sulfuric acid mixture, they isolated a crystalline acid (subsequently shown to be bicyclofarnesic acid, 316)175b and a "liquid acid" (subsequently shown to be a mixture). 175 Compound 316 was obtained in 10%
319 -
316 -
315 -
340
Total S y n t h e s i s of Sesquiterpenes
l i t h i u m aluminum h y d r i d e gave a y i e l d . Reduction o f = w i t h racemic a l c o h o l , m.p. 64-65', s u b s e q u e n t l y shown t o be ( ? I drimenol (=). 1 7 5 The " l i q u i d a c i d " gave a " l i q u i d a l c o h o l , " which formed an a l l o p h a n a t e , m.p. 193' Subsequent work showed t h e s e l i q u i d p r o d u c t s t o be m i ~ t u r e s . " ~ The a l l o p h a n a t e m e l t i n g a t 193' c o r r e s p o n d s t o a l c o h o l 321, which must a r i s e from a c i d 320, a minor p r o d u c t i n t h e C a l i e z i - S c h i n z c y c l i z a t i o n . Compound 321 i s t h u s ( ? ) - e p i - d r i m e n o l . CH20H
LiAlH4 ____c
321 -
320 -
S t o r k and B u r g a s t a h l e r examined t h e c y c l i z a t i o n of f a r n e s i c a c i d (%) w i t h BF3 e t h e r a t e . 1 7 5 a They isolated t w o a c i d s , 316 and 320, i n y i e l d s of 35% and 2-5%, r e s p e c t i v e l y . Although t h e s e workers e r r o n e o u s l y concluded t h a t 316 and 320 were c i s - d e c a l i n s , s u b s e q u e n t work' 75b r e v e a l e d t h e t r u e s t r u c trues. I n t h e p r o c e s s of examining i n v i t r o o x i d a t i v e c y c l i z a t i o n s of p o l y e n e s , van Tamelen and co-workers c a r r i e d o u t the sequence of r e a c t i o n s o u t l i n e d i n Scheme 41, which l e d from Scheme 41.
Van Tamelen S y n t h e s i s of and (k)-Epi-Drimenol CH20Ac
CH20Ac
I
OH
322 -
$p
323 -
BF3
___c
C6H6
324 -
(+)-Drimenol
CH20Ac
+ HO
p
CH20Ac
HO
325 -
326 -
I
CH20Ac
QJ
0
H 327 -
328 -
CH2S H C H 2 S H f BF3
CH2SH
i Cl H 2 S H
BF3
CH20Ac
329 -
I
330 -
1. R a n c y Ni 2. L i A l H 4
r;jri CH20H
315 -
1. R a n e y N i 2. L i A 1 H 4 CH20H
321 -
341
342
Total Synthesis of Sesquiterpenes
farnesyl acetate to ( 2 )-drimenol and ( 2 )-epi-drimenol. 74a Farnesyl acetate (322) reacted selectively at the terminal double bond when treated with N-bromosuccinimide in aqueous 1,2-dimethoxyethane to give bromohydrin 323. Treatment of 323 with base yielded the terminal epoxide 324. Cyclization of epoxide 324 with boron trifluoride etherate in benzene gave a mixture of bicyclic unsaturated alcohols 325 ( 8 5 % ) and 326 (15%) in "modest yield." Isomer 325 was converted into (+l-drimenol (315)by the Straightforward route shown in the chart. A similar conversion of the minor isomer (326) into (+)-epi-drimenol (321)was also accomplished. In later work, van Tamelen found that methyl farnesate (331) reacts with N-bromosuccinimide in aqueous THF to yield the bic clic bromides 332 and 333 in minute yield (Scheme 42). 174x Reduction of ?32 and 333 with lithium aluminum Scheme 42.
Van Tamelen's Synthesis of ( 2 )-Drimenol and ( + ) -Epi-Drimenol _COzMe
331 -
333 -
332 -
I
LiAlHh
LiAlH4
hydride in ether gave (+)-drimenol (315) and ( 2 ) -epi-drimenol (321). .-. (2)-Farnesiferol A (318) was s nthesized by van Tamelen in a similar fashion (Scheme 4 3 ) . 17' cis ,trans-farnesyl bramide (34)was condensed with the sodium salt of umbelliferone (335) to obtain cis ,trans-umbelliprenin (336), the required
B i c a r b o c y c l i c S e s q u i t e r p e n e s , Hydronaphthalenes
wr+ Scheme 4 3 .
343
Van Tamelen S y n t h e s i s o f ( + I - F a r n e s i f e r o l A
+
Na
\
1. NBS-HzO 2 . K2CO3 MeOH
3 37 -
-
318 -
s t a r t i n g m a t e r i a l . Terminal epoxidation y i e l d e d t h e oxide which was c y c l i z e d by boron f l u o r i d e e t h e r a t e i n benzene mixture c o n t a i n i n g approximately 2 % of ( + ) - f a r n e s i f e r o l
337, to a A
(318).
(x),
The l a s t b i o g e n e t i c a l l y s t y l e d s y n t h e s i s t o be d i s c u s s e d i n t h i s s e c t i o n i s K i t a h a r a ' s s y n t h e s i s of (2)-drimenin o u t l i n e d i n Scheme 4 4 . 176 Monocyclofarnesic a c i d (338) had p r e v i o u s l y been c y c l i z e d t o drimanic a c i d (316) by S t o r k and B u r g s t a h l e r . 175a K i t a h a r a and co-workers i n c r e a s e d t h e y i e l d o f this c y c l i z a t i o n t o 5 5 % by c a r r y i n g o u t t h e r e a c t i o n with boron f l u o r i d e i n a mixture of e t h e r and benzene a t 30'. The methyl e s t e r (339) d e r i v e d from drimanic a c i d was photooxygenated i n t h e p r e s e n c e of hematoporphyrin o r Rose Bengal.
Total Synthesis of Sesquiterpenes
344
Scheme 44.
Kitahara's Synthesis of (+)-Drimenin
CopH I
C02 H
BF 3 -E tp 0
H 316 -
3 38 -
@ C02Me
1. Op-hv sens
____c
2. K I
3 39 C 0 2 Me
#T H
Q3
C02Me
C02Me
1
",'OH
H
340 -
342 -
H2S04
Dioxane
L
'@ H
317 -
34 3 -
+
Qy H
344
After decomposition of the peroxides with potassium iodide, compounds 3,341, and E w e r e obtained in yields of 33, 23, and 3 3 % , respectively. Hydrolysis and concommittant lactoniza-
B i c a r b o c y c l i c S e s q u i t e r p e n e s , Hydronaphthalenes
345
t i o n o c c u r r e d when hydroxy e s t e r 340 was t r e a t e d w i t h s u l f u r i c a c i d i n d i o x a n e , y i e l d i n g (2)-drimenin (317, 69%) and ( & ) i s o d r i m e n i n (344, 11%). Drimanes; Drimenin, I s o d r i m e n i n , C o n t e r i f o l i n , Drimenol, I s o i r e s i n , Winterin
P.
The s y n t h e s e s of drimenin (317) , i s o d r i m e n i n (%), conterif o l i n (3451, and drimenol (315) by Wenkert are i n t e r e s t i n g , i n t h a t t h e s t a r t i n g m a t e r i a l , d r i m i c a c i d (346) i s a c t u a l l y a d e g r a d a t i o n p r o d u c t of v a r i o u s d i t e r p e n e s 7 ' The Wenkert s y n t h e s i s of (+)-drimenin i s o u t l i n e d i n Scheme 45.
317 -
(p
344 -
H
346 -
315 Scheme 45.
@:.
Wenkert's S y n t h e s i s o f (f)-Drimenin
1. Me2Cd 2 . CH2N2
3. t-BuOK
346 -
345 -
H
Go
347 -
MeOH
__c
348
-
Hf
350 -
349 -
n
351 -
1. KOH
2 . H30'
355 -
I
1
1. H C O z E t , t-BuOK 2 . AcpO, NaOAc
$YoH
346
NH4 C1
@--P H
354 -
353 -
#-(
NaBH4
__c
H
0
B i c a r b o c y c l i c S e s q u i t e r p e n e s , Hydronaphthalenes
E,
347
D r i m i c anhydride o b t a i n e d by h e a t i n g d r i m i c a c i d w i t h a c e t i c anhydride, was t r e a t e d w i t h dimethylcadmium. The r e s u l t i n g k e t o a c i d was methylated and t h e crude product cyc l i z e d w i t h base t o y i e l d t h e 1,3-dione 348. When 348 w a s t r e a t e d with a c i d i c methanol, t h e e n o l e t h e r s 349 and were o b t a i n e d i n 84 and 13%y i e l d s , r e s p e c t i v e l y . Lithium aluminum h y d r i d e r e d u c t i o n , followed by a c i d i c h y d r o l y s i s , converted 349 and 350 i n t o enones 351 and 352. The major product 352 was hydrocyanated by Nagata's method. The r e s u l t i n g cyano ketone shown t o have an a x i a l cyano group, was converted into k e t a l z . Vigorous h y d r o l y s i s of t h e n i t r i l e occurred with p r i o r epimerization t o the e q u a t o r i a l p o s i t i o n . After deketalizat i o n , k e t o a c i d 355 was produced i n good y i e l d . Formylation of k e t o a c i d 355 gave a hydroxymethylene d e r i v a t i v e , which was l a c t o n i z e d by t r e a t m e n t w i t h sodium a c e t a t e i n a c e t i c anhyd r i d e . The r e s u l t i n g p r o d u c t , 7-ketoisodrimenin (=), was reduced t o t h e dihydro analog 357, which w a s f u r t h e r reduced w i t h sodium borohydride t o a l c o h o l 358. When t h e d e r i v e d p t o l u e n e s u l f o n a t e e s t e r was h e a t e d i n dimethyl s u l f o x i d e , ( + I drimenin (=) was o b t a i n e d . Wenkert's f u r t h e r conversions of (+I-drimenin i n t o ( & I isodrimenin, ( + ) - c o n t e r i f o l i n , and ( + ) -drimenol are o u t l i n e d (+)-Isodrimenin, o b t a i n e d by i s o m e r i z a t i o n of i n Scheme 46. (+I-drimenin, was reduced by l i t h i u m aluminum hydride t o d i o l 359. Manganese d i o x i d e o x i d a t i o n of 359 y i e l d e d ( + I - c o n t e r i f o l i n (345) , a l o n g w i t h some (5)-isodrimenin. D i o l 360, obt a i n e d b y h y d r i d e r e d u c t i o n of (?) -drimenin, was a c e t y l a t e d and t h e r e s u l t i n g d i a c e t a t e 361 was reduced by l i t h i u m i n
-
(x),
-
Scheme 46. Wenkert's Conversions of (+)-drimenin i n t o (5)-Isodrimenin, ( 2 )- C o n t e r i f o l i n , and (+)-Drimenol
/
I
317 -
\ f
H
344 LiAlH4
/\ HI
359 -
348
T o t a l S y n t h e s i s of S e s q u i t e r p e n e s &
OH
H
34 5 -
360 -
+
-@ CH20H
1. Li-NH3 2 . NaOH,
H
EtOH
361 ammonia.
(315).
H
315 -
Q9 H
344 -
Subsequent a l k a l i n e h y d r o l y s i s y i e l d e d ( f ) - d r i m e n o l
The drimanic s e s q u i t e r p e n e i r e s i n (362) was t h e f i r s t s e s q u i t e r p e n e i n which t h e b i c y c l o f a r n e s o l s k e l e t o n w a s demons t r a t e d . S y n t h e t i c a l l y , i t p r e s e n t s a much g r e a t e r c h a l l e n g e
bH
362 -
than do the s i m p l e r drimanes p r e v i o u s l y d i s c u s s e d . Although i r e s i n i t s e l f h a s n o t y e t been s y n t h e s i z e d , P e l l e t i e r h a s rep o r t e d a s y n t h e s i s o f i s o i r e s i n d i a c e t a t e (*). Compound i s a d e r i v a t i v e of i s o i r e s i n , which co-occurs w i t h i r e s i n i n
=
Iresin celosioides.
The P e l l e t i e r s y n t h e s i s , o u t l i n e d i n Scheme 47, w a s rep o r t e d i n two s t a g e s . Carbornethoxymethyl v i n y l ketone (363) was condensed with 2-methylcyclohexane-1 ,3-dione (364)
’”
Scheme 47.
e l l e t i e r ' s S y n t h e s i s of ( 2 ) - I s o i r e s i n Diacetate
$ I+
0
C02Me
C02 M e
36 3 -
364 -
365 -
n
@ C02Me
0
n Me I t-BuOK; c6 H6
0
367 -
366 -
LiAlH4
Hg Pd/C
___c
HO'"" C02Me 369 -
368 -
$5
,.-'
HO"
%
IOH
OAc
3 70
371 NaNH? H-CEC-H
I
OAc
-
372 349
HC02H
NaCN
___c
AcO '
__c
EtOH
AcO"
I
OAc
OAc 374 -
313 -
376 -
37s -
C02H
1. NaH
377 -
350
COCl
- --
CN LiAlH ( O h - t ) 3
*..' 378 -
B i c a r b o c y c l i c S e s q u i t e r p e n e s , Hydronaphthalenes CH20H
CH20H
- -
351
DCC ,
DMSO
381 -
382 -
-v
0
385
OAc
386 -
under t h e i n f l u e n c e o f anhydrous potassium f l u o r i d e i n methan o l , y i e l d i n g t h e d i k e t o e s t e r 365 i n 30-50% y i e l d . S e l e c t i v e k e t a l i z a t i o n of 365 a f f o r d e d k e t a l 366, which was methylated s t e r e o s p e c i f i c a l l y t o o b t a i n 367. A f t e r reducing t h e ketone with borohydride, t h e r e s u l t i n g hydroxy e s t e r 368 was c a t a l y t i c a l l y reduced t o y i e l d mainly t h e t r a n s - f u s e d b i c y c l e 369. Lithium aluminum hydride r e d u c t i o n o f hydroxy e s t e r 369 y i e l d e d d i o l 2,which was converted i n t o d i a c e t a t e 371. Hyd r o l y s i s of t h e k e t a l grouping gave k e t o d i a c e t a t e Zpga When k e t o d i e s t e r = w a s condensed with t h e sodium s a l t of a c e t y l e n e , e t h y n y l c a r b i n o l 373 was t h e main product ( 8 1 % ) . Rupe rearrangement o f 373 gave enone 374 i n 48% y i e l d (along with 12% o f t h e corresponding a , $ - u n s a t u r a t e d aldehyde). Hydrocyanation o f 374 occurred when it w a s h e a t e d with a l a r g e excess of sodium cyanide i n e t h a n o l . The r e s u l t i n g product
Total Synthesis o f Sesquiterpenes
352
(375) had s u f f e r e d h y d r o l y s i s of t h e two acetate g r o u p s . Hyd r o c y a n a t i o n i n t h i s c a s e y i e l d s t h e more stable d i a s t e r e o m e r ( d i e q u a t o r i a l ) . D i o l 375 was c o n v e r t e d i n t o an e t h y l i d i n e d e r i v a t i v e (376) by t r e a t m e n t w i t h a c e t a l d e h y d e and f u s e d z i n c chloride. Sodium hypobromite o x i d a t i o n of 376 a f f o r d e d cyan0 acid 377 i n y i e l d s o f 40-60%. When t h e sodium s a l t o f 377 w a s t r e a t e d w i t h o x a l y l c h l o r i d e , an a c i d c h l o r i d e w a s o b t a i n e d (E), which was reduced by l i t h i u m tri-t-butoxyaluminum hyd r i d e t o a m i x t u r e of cyan0 a l c o h o l 379 and imino e s t e r 380. H y d r o l y s i s o f t h i s m i x t u r e gave a hydroxy acid (3811, which was c o n v e r t e d i n t o hydroxy e s t e r 382. M o f f a t t o x i d a t i o n of 382 y i e l d e d aldehyde 383. When 383 was t r e a t e d w i t h p o t a s s i u m c a r b o n a t e i n aqueous methanol, hydroxy l a c t o n e 384 was produced. Dehydration of 384 o v e r p y r i d i n e - i m p r e g n a t e d alumina a f f o r d e d ( + ) - e t h y l i d i n e i s o i r e s i n (385). H y d r o l y s i s of t h e a c e t a l f o l l o w e d by a c e t y l a t i o n gave ( + I - i s o i r e s i n d i a c e t a t e
-
-
(386).
B r i e g e r ' s s y n t h e s i s of ( + ) - w i n t e r i n (392) i s o u t l i n e d i n Scheme 48.lEo The b a s i c approach i s t o c o n s t r u c t t h e B r i n g Scheme 48.
B r i e g e r ' s S y n t h e s i s of ( + ) - W i n t e r i n
387 -
388 -
390 -
389 -
&o& -o
HOAc
39 1 -
392 -
Bicarbocyclic Sesquiterpenes, Hydronaphthalenes
353
(z),
by a Diels-Alder r e a c t i o n . The r e q u i s i t e d i e n e , l - v i n y l 2,6,6-trimethylcyclohexene was prepared by thermal decarboxylation of f3-cyclocitrylidineacetic acid (389). Royals had p r e v i o u s l y shown t h a t t h i s a c i d may be produced from e t h y l c i t r y l i d i n e a c e t a t e (387) by a - c y c l i z a t i o n , followed by a l k a l i n e hydrolysis. When diene 390 was condensed with acetylened i c a r b o x y l i c a c i d , adduct 391 was obtained i n 4 % y i e l d . Catacontaminated with l y t i c hydrogenation gave ( ? ) - w i n t e r i n i t s dihydro d e r i v a t i v e .
(z),
Q.
Valeranone
Valeranone (393) i s a member of an i n t e r e s t i n g c l a s s of sesq u i t e r p e n e s . While i s o p r e n o i d , t h e carbon s k e l e t o n cannot be
d e r i v e d from f a r n e s o l . Since t h e C-10 angular methyl group and t h e t h r e e carbon s i d e chain a t C-7 a r e trans, t h e most promising s y n t h e t i c approach t o t h e s k e l e t o n i s v i a 7-epicyperone (31) o r an analog thereof ( s e e p. 284). The most i n t e r e s t i n g s y n t h e t i c challenge i s t h e second angular methyl
group a t C-9, which must be introduced s t e r e o s p e c i f i c a l l y c i s t o t h e C-10 methyl. Several i n t e r e s t i n g s o l u t i o n s t o t h i s problem have been explored. I n Schemes 49 and 50 a r e o u t l i n e d M a r s h a l l ' s i n i t i a l s y n t h e s i s of t h e antipode of n a t u r a l valeranone. Robinson a n n e l a t i o n of methyl v i n y l ketone and (-)-dihydrocarvone (32) gave k e t o l 67, which was hydrogenated t o k e t o l 394. Acid-catalyzed dehydration afforded enone 395, which possesses t h e proper r e l a t i v e stereochemistry a t t h e two asymmetric centers. I n i t i a l attempts t o introduce t h e second angular methyl
Scheme 49.
Marshall's Valeranone Synthesis--First Variation
67 -
32 -
LiAlH4 0
OH
395 -
394 1. AcpO
HO
396 -
3. CrOg
399 -
_ I
400 -
354
2 . H202
397 -
398
'r 1. B2H6
2. Li, EtNH2
401 -
403 -
402 \
OH-
[
*I
J
HOCH~CHZOH,A
404 Scheme 50.
405 -
Marshall's Valeranone Synthesis--Second Variation t-BuOK, t-BuOH
1. LiAlH4 0
OH
OH 4 06 -
I
HC02H
408 -
407 -
409 -
I
1. NaOH, EtOH 2. CrOg
410 -
355
356
Total Synthesis o f Sesquiterpenes
@!%,r H2-Pd/C
0
OAc
413 -
414
@c ""'f 1. NaBH4
2 . MsC1, C 5H 5N
0
MsO'
%,,
\\+"
OAc
($&
KOH
___c
i-PrOH
OAc
416 -
%,,
0
1. L i A l H 4
4 04 -
2. cro3
417 -
group a t t h i s s t a g e , by c o n j u g a t e a d d i t i o n of methylmagnesium i o d i d e t o 395 were u n f r u i t f u l .182b Subsequent s t u d i e s r e v e a l e d t h a t l i t h i u m dimethylcopper adds t o o c t a l o n e 395, a f f o r d i n g decalone 411 (Scheme 50) i n 10% y i e l d . Because of t h e s e d i f f i c u l t i e s , a l t e r n a t i v e a n g u l a r methyla t i o n procedures were e x p l o r e d . Hydride r e d u c t i o n of 395 gave a mixture of d i a s t e r e o m e r i c a l c o h o l s 396, which were hydrogenolyzed by r e d u c t i o n o f t h e i r a c e t a t e s w i t h l i t h i u m i n ethylamine. The r e s u l t i n g o l e f i n 397 w a s c o n v e r t e d i n t o norby hydroboration-oxidation. Theobald' 8 3 a and valeranone (=)
B i c a r b o c y c l i c S e s q u i t e r p e n e s , Hydronaphthalenes
357
and an Indian group183b have a l s o r e p o r t e d t h e s y n t h e s i s of ketone 398, i n e s s e n t i a l l y t h e same manner. The problem now becomes one o f s t e r e o s p e c i f i c a n g u l a r methylation. To whatever e x t e n t a n g u l a r a l k y l a t i o n o c c u r s , t h e s t e r e o c h e m i s t r y i s p r e d i c t a b l e . Trans a l k y l a t i o n can only occur through one of t h e h i g h l y s t r a i n e d t r a n s i t i o n s t a t e s , t h e incoming methyl group 398a o r 39833. I n one c a s e
(m)
-
39 8b -
398a -
0-
encounters s e v e r e hindrance due t o t h e axial i s o p r o p y l group. I f r i n g B is a d j u s t e d i n t o a t w i s t conformation t o avoid t h i s i n t e r a c t i o n , a price i n t r a n s i t i o n s t a t e energy must be p a i d . The t r a n s i t i o n s t a t e l e a d i n g t o cis a l k y l a t i o n 1-( is not s i m i l a r l y encumbered. However, it had been known f o r some t i m e t h a t 1-decalone undergoes predominant a l k y l a t i o n n o t i n t h e a n g l e , b u t a t I t t h u s became necessary t o t e m p o r a r i l y block C-2, i n C-2.le4 o r d e r t o f o r c e a l k y l a t i o n a t t h e a n g l e . This was r e a d i l y accomplished by t r e a t i n g t h e d e r i v e d hydroxymethylene d e r i v a t i v e 399 w i t h n-butyl mercaptan. The r e s u l t i n g n-butylthiomethylene d e r i v a t i v e 400 was a l k y l a t e d with sodium hydride and methyl i o d i d e i n benzene. Under t h e s e c o n d i t i o n s , e n o l e t h e r 401 and C-alkylated diastereomers 402 and 403 were obtained i n y i e l d s of 56, 1 8 , and 2 % , r e s p e c t i v e l y . Vigorous b a s e c a t a l y z e d hyd r o l y s i s of t h e mixture of 402 and 403 gave (+)-valeranone and i t s s t e r e o i s o m e r 405 i n a r a t i o o f 92:8. An a l t e r n a t i v e s o l u t i o n t o t h e a n g u l a r methyl problem was
-
(404)
358
T o t a l S y n t h e s i s of S e s q u i t e r p e n e s
explored and i s summarized i n Scheme 5 0 . Ketol 394 was reduced and t h e r e s u l t i n g d i o l converted i n t o mono-methanes u l f o n a t e 406. Fragmentation of 406 y i e l d e d t h e b u t e n y l cyclohexanone 407. Treatment of ketone 407 w i t h methyllithium y i e l d e d an a l c o h o l which was t r e a t e d w i t h formic a c i d a t room temperature. There was o b t a i n e d a mixture of b i c y c l i c formates (409) i n 40-50% y i e l d , along w i t h some monocyclic d i e n e (410). Again, t h e s t e r e o c h e m i s t r y of t h e c y c l i z a t i o n process i s p r e d i c t a b l e , a l b e i t only by analogy. Since cyc l i z a t i o n of d i o n e s such as 418 i s known t o y i e l d s o l e l y cis decalones ( e . g . , E),it i s r e a s o n a b l e t h a t c a t i o n *would c y c l i z e i n a s i m i l a r s t e r i c sense.
(e),
4 18 -
67 -
408a -
409 -
In t h e e v e n t , when t h e d i a s t e r e o m e r i c mixture 409 w a s hydrolyzed and o x i d i z e d , cis and t r a n s k e t o n e s 411 and 412 were obtained i n a r a t i o of 87:13. In o r d e r t o c o n v e r t 411 i n t o ( + ) - v a l e r a n o n e , ketone t r a n s p o s i t i o n must be accomplished. I t i s a measure of t h e d i f f i c u l t y of t h i s p r o c e s s t h a t Mars h a l l and co-workers were f o r c e d t o use n i n e s e p a r a t e synt h e t i c s t a g e s t o accomplish it. I n o r d e r t o block u n d e s i r e d r e a c t i o n s a t C-3 (compound 4 1 1 forms a 1:l m i x t u r e of i s o m e r i c e n o l a c e t a t e s ) , bromination-dehydrobromination was f i r s t c a r r i e d o u t . The r e s u l t i n g enone (413) was a c e t o x y l a t e d with l e a d t e t r a a c e t a t e and boron f l u o r i d e i n benzene, t o a f f o r d acetoxy enone 414 i n 2 1 % y i e l d .
-
B i c a r b o c y c l i c S e s q u i t e r p e n e s , Hydronaphthalenes
359
A f t e r c a t a l y t i c hydrogenation, t h e acetoxy ketone was reduced and t h e new hydroxyl e s t e r i f i e d w i t h methanesulfonyl c h l o r i d e . B a s i c h y d r o l y s i s gave a mixture of (+)-valeranone (404)and oxide 417 i x a r a t i o of 16~04. Oxide 417 w a s reduced and t h e r e s u l t i n g secondary a l c o h o l o x i d i z e d t o (+)-valeranone. Wenkert has r e p o r t e d a h i g h l y imaginative s o l u t i o n t o t h e a n g u l a r methyl problem posed by valeranone. l e 5 The Wenkert s y n t h e s i s , o u t l i n e d i n Scheme 51, employs 1,4-dimethoxy-2Scheme 51.
Wenkert's S y n t h e s i s of (-)-Valeranone
OMe
KOH
0
CH30H-
ether
OMe
419 -
4 18 -
,,,,w 420 -
Zn (Cu)
HO"'
0
OMe
OMe
422 -
421 -
W.K.
___c
,+' \\'
HO
Me0
___c
',,'-
5 : 3
42 3 -
424 -
H20-MeOH
425 -
393 -
360
T o t a l S y n t h e s i s of S e s q u i t e r p e n e s
butanone (418) a s an i n s i t u s o u r c e o f methoxymethyl v i n y l ketone i n a Robinson a n n e l a t i o n w i t h (+)-carvomenthone (419). The r e s u l t i n g k e t o l (420) was dehydrated w i t h e t h a n o l i c potassium hydroxide t o o b t a i n methoxy enone 421. Hydride r e d u c t i o n of 421 y i e l d e d predominantly e q u a t o r i a l a l c o h o l 422. Simmons-Smith methylenation o f 422 proceeded s t e r e o s p e c i f i c a l l y , with t h e r e s u l t i n methylene b r i d g e b e i n g cis t o t h e secondary hydroxyl group. 18? Jones o x i d a t i o n gave ketone 4 2 4 , which was reduced by t h e Wolff-Kishner method t o e t h e r 425. Compound 425 underwent s p e c i f i c e l e c t r o p h i l i c cleavage a s expected, y i e l d i n g (-)-valeranone. Recent work by I r e l a n d and co-workers h a s extended t h i s e l e g a n t method t o t h e s y n t h e s i s of t r a n s - f u s e d 9,lO-dimethyldecalones ( e . g . , 426 -+ 428) .I8'
-
-
428 -
421 -
426 -
A second e l e g a n t s o l u t i o n t o t h e problem of v a l e r a n o n e ' s angular methyl groups was r e p o r t e d by I r e l a n d i n 1968.188 The method, which was a p p l i e d t o t h e s y n t h e s i s of desoxy d e r i v a t i v e 434, i s o u t l i n e d i n Scheme 52. Hydride r e d u c t i o n o f
Scheme 52.
I r e l a n d ' s S y n t h e s i s of Desoxyvaleranone OMe CH3-t-NMeZ OMe
L i A l (OBu-t) 3 ~
___c
/
429 -
A
4 30 -
B i c a r b o c y c l i c Sesqui t e r p e n e s , Hydronaphthalenes
433 enone
429
361
4 34 -
(Scheme 49) a f f o r d e d t h e e q u a t o r i a l a l l y l i c a l c o h o l
430 s p e c i f i c a l l y (86% y i e l d ) . Eschenmoser's v a r i a n t of t h e C l a i s e n v i n y l e t h e r rearrangement' 8 9 allowed t h e conversion 430 i n t o u n s a t u r a t e d amide 431. The s t e r e o c h e m i s t r y of t h e
of
new a n g u l a r s u b s t i t u e n t i s decided by t h e geometry of t h e t r a n s i t i o n s t a t e ; it must be a t t a c h e d t o t h e same f a c e of t h e molecule a s t h e d e p a r t i n g oxygen. Lithium diethoxyaluminohydride r e d u c t i o n of amide 432 gave aldehyde 433, which was decarbonylated by t r e a t m e n t with tristriphenylphosphinechlororhodium(1) c h l o r i d e i n benzene. The r e s u l t i n g product (434)i s t h e desoxy analog of ( + I valeranone. An i n t e r e s t i n g photochemical rearrangement d i s c o v e r e d b y Marshall o f f e r s a f u r t h e r s o l u t i o n t o t h e foregoing s y n t h e t i c problem, although i t h a s n o t y e t been a p p l i e d t o t h e s y n t h e s i s of a n a t u r a l p r o d u c t . Upon i r r a d i a t i o n i n a mixture of tb u t y l a l c o h o l and a c e t i c o r formic a c i d , o l e f i n 435 i s conv e r t e d i n t o isomer 436 i n y i e l d s of 40-50%.'90
4 35 -
4 36 -
R. Eremophilanes; Isonootkatone (a-Vetivone) , Nootkatone, V a l e r i a n o l , Valencene, Eremoligenol, Eremophilene, Fukinone
The eremophilane family r e p r e s e n t s an i n t e r e s t i n g nonisoprenoid group of compounds b e l i e v e d t o a r i s e by c a t i o n i c rearrangement of a eudesmanoid p r e c u r s o r . Members of t h e group a r e a l l
362
Total Synthesis of Sesquiterpenes
characterized by cis-vicinal methyl groups at carbons 1 and 9 , although the three-carbon side chain at C-7 may be oriented either c i s or t r a n s to the angular methyl. Successful syntheses have been recorded for isonootkatone (a-vetivone, 4 3 7 ) , l q l nootkatone ( 4 3 8 ) , 1 q 2 r 1 9 3 valencene ,l g 4 ere(439), l q 4 valeriano1 (440),19" eremophilene (441) In addition, synm z g e n o l (=), l q 4 and fukinone (%). theses of tetrahydroeremophilone (444), eremophil-3,lldiene (445), I g 7 and dehydrofukinone (446)l q 8 will be discussed in thissection. Tricyclic eremophilanes will be taken up in Sec. 4 - S .
bk Ltf ,\+'
0
0
4 38 -
437
I _
33i' 440 -
439 -
442 -
441 -
/
H 443 -
0 '
H 0
444 -
445 -
The synthetic problems associated with this group are several. The problem of the cis-vicinal methyl groups has been approached in a variety of ways, and still may not be
B i c a r b o c y c l i c S e s q u i t e r p e n e s , Hydronaphthalenes
363
c o n s i d e r e d t o have been a d e q u a t e l y s o l v e d . With t h e "normal" eremophilanes (C-9 methyl and C-7 i s o p r o p y l c i s ) , t h e stereoc h e m i s t r y a t C-7 i s t h e less s t a b l e ; e i t h e r t h e t h r e e - c a r b o n c h a i n must be a x i a l o r r i n g B must a d o p t a b o a t conformation. The main s y n t h e t i c o b s t a c l e i s a r a t h e r s u b t l e one. The arrangement o f s i d e - c h a i n g r o u p s , combined w i t h f u n c t i o n a l p a t t e r n s , i s n o t e a s i l y accommodated w i t h t h e s t a n d a r d r e p e r t o i r e of s y n t h e t i c methods. The s y n t h e t i c a l l y s i m p l e s t t a r g e t , and t h e f i r s t member t o y i e l d t o s y n t h e s i s , i s i s o n o o t k a t o n e (437). Here t h e o n l y s y n t h e t i c problems are t h e carbon s k e l e t o n i t s e l f and t h e cis d i s p o s i t i o n of t h e two methyl groups. M a r s h a l l ' s s y n t h e s i s i s summarized i n Scheme 53. D i e t h y l isopropylidene-malonate (447) w a s reduced t o d i o l 448, which r e a c t e d w i t h phosphorous t r i b r o m i d e i n ether-hexane-pyridine t o g i v e dibromide 449. Compound 449 was used t o a l k y l a t e t w o moles of d i e t h y l malonate and a f t e r h y d r o l y s i s and d e c a r b o x y l a t i o n , d i a c i d 450 was obt a i n e d . Dieckmann c y c l i z a t i o n of e s t e r 451 a f f o r d e d k e t o e s t e r 452. Compound %was used i n a Robinson a n n e l a t i o n w i t h t r a n s 3-penten-2-one t o o b t a i n o c t a l o n e %. Although f u l l e x p e r i mental d e t a i l s have n o t y e t been p u b l i s h e d , o c t a l o n e 453 i s a p p a r e n t l y t h e major isomer produced i n t h i s r e a c t i o n . A r e l a t e d r e a c t i o n (Scheme 54) used i n t h e s y n t h e s i s of nootkat o n e gave a cis,trans r a t i o of 3 : l . This r e s u l t i s i n t e r e s t i n g , i n l i g h t of o t h e r work w i t h 2-methylcyclohexan-lI3-dione where t h e cis isomer 453 i s t h e minor p r o d u c t when a n n e l a t i o n i s accomplished w i t h KOH-pyrro1idinelg9 o r on t h e p y r r o l i d i n e enamine of 364 i n benzene.200 A t b e s t , isomers 452 and 453 may b e produced i n e q u a l amounts, when t h e r o l i d i n e enamine of 364 i s used i n dimethylformamide. 2 05';
(z),
-
-
45 3 *As C o a t e s h a s p o i n t e d o u t , t h e s t e r e o c h e m i s t r y i n M a r s h a l l ' s a n n e l a t i o n i s determined i n t h e Michael r e a c t i o n o f p52 w i t h pentenone. I n t h e a n n e l a t i o n s w i t h c y c l i c 1 , 3 - d i k e t o n e s such as 364, t h e s t e r e o c h e m i s t r y i s p r o b a b l y s e t i n t h e aldol cond e n s a t i o n of t h e i n t e r m e d i a t e t r i k e t o n e . 214b
Total Synthesis of Sesquiterpenes
364
With the production of 453, the problem now reduces to one of redox chemistry, reduction of the angular carbomethoxyl group to methyl. This was accomplished in straightforward fashion, after protection of the ketonic carbonyl, as outlined in Scheme 5 3 . Marshall‘s Synthesis of (+)-Isonootkatone
Scheme 53. C02Et
LiAlHt,
___c
PBr3
>=(OH
c__c
OH
C02Et
447 -
440 -
450 -
449 -
C02Me
NaH
MeOCH2CH2OMe
C02Me
452 -
45 1 -
CH20H H : ; I F ‘
LiAlH4
___c
___c
c6c6
0 453 -
0 454 -
MsCl
455 -
Li-NHq
EtOH 456 -
-
B i c a r b o c y c l i c S e s q u i t e r p e n e s , Hydronaphthalenes
365
437 -
457 -
Nootkatone (438) h a s been s y n t h e s i z e d by S c h ~ d e l ’and ~~ by M a r s h a l l . l g 3 A r e p o r t e d s y n t h e s i s by Pinder’Ol h a s been Because o f i t s s i m i l a r i t y t o the p r e c e d i n g synretracted.’02 t h e s i s , M a r s h a l l ’ s s y n t h e s i s w i l l b e d i s c u s s e d f i r s t (Scheme when t r e a t e d w i t h e t h y l 5 4 ) . Dimethyl y - k e t o p i m e l a t e idenetriphenylphosphorane i n d i m e t h y l s u l f o x i d e , undergoes W i t t i g r e a c t i o n and Dieckmann c y c l i z a t i o n , a f f o r d i n g 8-keto e s t e r 455 a s a 1:l m i x t u r e o f g e o m e t r i c isomers. Robinson a n n e l a t i o n w i t h trans-3-penten-2-one (potassium t-amyloxide i n t-amyl a l c o h o l ) gave o c t a l o n e 456 and i t s trans isomer (3:l r a t i o ) i n 75% y i e l d . E p o x i d a t i o n o f 456 gave an o x i d e (457), which w a s rearranged t o methyl k e t o n e 458 when t r e a t e d w i t h BF3 e t h e r a t e . A f t e r p r o t e c t i o n o f t h e two k e t o n i c c a r b o n y l g r o u p s , t h e carbomethoxy group w a s reduced t o methyl by h y d r i d e r e d u c t i o n , M o f f a t t o x i d a t i o n of t h e r e s u l t i n g p r i m a r y a l c o h o l (460)t o an aldehyde (461), and Wolff-Kishner r e d u c t i o n of t h e aldehyde t o methyl (462). Acid c a t a l y z e d d e p r o t e c t i o n y i e l d e d a d i o n e (463) from which ( + ) - n o o t k a t o n e was produced by s e l e c t i v e W z i q methylation. The Givaudan s y n t h e s i s (Schudel) , l g 2 summarized i n Scheme Wittig 55, b e g i n s w i t h 4-acetyl-1-ethoxycyclohexene
(e),
(464).
9 & Scheme 54.
M a r s h a l l ’ s (?)-Nootkatone S y n t h e s i s
bCH -
C02Me
C02Me
43z;zCH3-
Me02C
t-AmOK
0
454 -
HCH3 MCPA
0
456 -
455 -
\
o &
- 1. BF3
CHCH3 2 . N a 2 C 0 3
__c
457 -
366
T o t a l S y n t h e s i s of S e s q u i t e r p e n e s
m e t h y l e n a t i o n , f o l l o w e d by h y d r o l y s i s of t h e e n o l e t h e r , a f f o r d e d 4-isopropenylcyclohexanone (465), which was condensed with e t h y l formate t o o b t a i n t h e hydroxymethylene d e r i v a t i v e 4 6 6 . When 466 was t r e a t e d w i t h methyl i o d i d e i n a c e t o n e , e n o l e t h e r 467 and k e t o a l d e h y d e s 468 and 469 w e r e formed i n a r a t i o of 2 7 : 5 5 : 1 8 .
Treatment of t h e m i x t u r e of 467, 468, and 469 w i t h a c e t o n e i n t h e p r e s e n c e of p y r i d i n e and a c e t i c a c i d , f o l l o w e d by m e t h a n o l i c KOH, gave a m i x t u r e of t r i e n o n e s 2 and 471 i n a r a t i o of 5 : l . The problem now r e d u c e s t o t h e s t e r e o s p e c i f i c i n t r o d u c t i o n o f t h e s e c o n d a r y methyl g r o u p of n o o t k a t o n e i n t o dienone 470. L i t h i u m d i m e t h y l c o p p e r a p p e a r s , a t f i r s t examinat i o n , t o b e i d e a l l y s u i t e d f o r t h i s p u r p o s e , s i n c e i t i s known t o add e f f i c i e n t l y t o a , B - u n s a t u r a t e d k e t o n e s , and s i n c e i t s h o u l d s e l e c t t h e l e s s h i n d e r e d a r m of t h e c r o s s - c o n j u g a t e d dienone s y s t e m i n 470. However, a x i a l a l k y l a t i o n , a s i s
B i c a r b o c y c l i c S e s q u i t e r p e n e s , Hydronaphthalenes
367
u s u a l l y e n c o u n t e r e d w i t h such r e a c t i o n s , would l e a d t o a trans d i s p o s i t i o n of t h e t w o methyl groups. I n t h e e v e n t , dienone 470 d i d r e a c t smoothly w i t h l i t h i u m dimethylcopper, a f f o r d i n g 4-epinootkatone (472) i n 85% y i e l d . Compound 472 w a s dehydrog e n a t e d w i t h d i c h l o r o d i c y a n o q u i n o n e (DCDQ) t o dehydronootkat o n e (4731, b u t t h i s compound could n o t be s e l e c t i v e l y reduced a t t h e 3,4-double bond. In order to f a c i l i t a t e reduction of t h i s linkage, k e t o e s t e r 474 was p r e p a r e d by condensing t h e m i x t u r e 467-469 w i t h methyl acetoacetate (see Scheme 5 5 ) . Compound 474 added lithium dimethylcopper c l e a n l y , a f f o r d i n g k e t o e s t e r which was a g a i n dehydrogenated w i t h DCDQ. The 3,4-double bond w a s reduced smoothly w i t h sodium b o r o h y d r i d e i n p y r i d i n e (Michael
-
e,
Scheme 55.
Givaudan S y n t h e s i s o f (k)-Nootkatone
465 -
464 -
<
467 -
468 -
469 I
1. CH3COCH2C02Me, p i p e r i d i n e ,
3. CH2N2
1. Acetone, p i p e r i d i n e , HOAc 2 . KOH, CH30H
368
T o t a l S y n t h e s i s of S e s q u i t e r p e n e s
Me02
438 r e a c t i o n , a x i a l a t t a c k of h y d r i d e ) , y i e l d i n g a B-keto e s t e r which was h y d r o l y z e d and d e c a r b o x y l a t e d t o o b t a i n ( A ) -nootk a t o n e (438). C o a t e s h a s developed an eremophilane s y n t h e s i s which h a s l e d t o t h e p r o d u c t i o n of ( 2 ) - v a l e n c e n e (4391, ( + ) - v a l e r i a n o 1 (f)-eremophilene and ( i ) - e r e m o l i g e n o l (442).1 9 4 The b a s i c scheme (Scheme 56) b e g i n s w i t h 2-methylcyclohexan1,3-dione (364) Robinson a n n e l a t i o n of t h e c o r r e s p o n d i n g i n dimethylformamide enamine (477) w i t h trans-3-pentene-2-one Degave a 1 : l m i x t u r e o f enones 452 and 453 i n 2 7 % y i e l d . * " oxygenation w a s accomplished by r e d u c t i o n of t h e d e r i v e d mixt u r e of d i t h i o k e t a l s w i t h Raney n i c k e l i n e t h a n o l . The r e s u l t i n g m i x t u r e o f O C t a l O h e S 478 and 479 w a s s e p a r a t e d by f r a c t i o n a l
(s), .
(s),
B i c a r b o c y c l i c S e s q u i t e r p e n e s , Hydronaphthalenes
369
.
distillation ” Compound 479, which has t h e d e s i r e d c i s r e l a t i o n s h i p between the two methyl groups, was carbethoxylated and t h e r e s u l t i n g 6-keto e s t e r was a l k y l a t e d w i t h chloromethyl methyl e t h e r i n hexamethylphosphoramide. Under t h e s e c o n d i t i o n s , 0a l k y l a t i o n o c c u r r e d t o t h e complete e x c l u s i o n of C-alkylation. Reduction of e n o l e t h e r 481 with l i t h i u m i n a m o n i a a f f o r d e d t h e u n s a t u r a t e d e s t e r 482 a s t h e s o l e product i n 61% y i e l d . That t h e l e s s s t a b l e ( a x i a l ) isomer was produced was shown by sodium ethoxide-catalyzed e q u i l i b r a t i o n of 482 t o a more s t a b l e isomer (483). The r e d u c t i o n of 481 t o 482 i s an i n t e r e s t i n g and potent i a l l y u s e f u l p r o c e s s which h a s been e x t e n s i v e l y s t u d i e d by C ~ a t e s . ~ ’The ~ probable course of e v e n t s i s o u t l i n e d below:
{bcozEt 1. 2e-2.
r
{
P
O
E
t
-OR-_
[H’]
4 81 1. 2e2.
OEt
[H+]
H+
-
Y Y C O Z E t
The s t e r e o c h e m i s t r y i s determined i n p r o t o n a t i o n of t h e f i n a l e n o l a t e . E v i d e n t l y , k i n e t i c c o n t r o l o c c u r s , with t h e p r o t o n approaching from t h e l e s s hindered f a c e of t h e molecule. Standard methods were t h e n used t o convert 482 i n t o ( ? I eremoligenol (=) and (?)-eremophilene (+). Similarly, the more s t a b l e e s t e r (483) was converted i n t o ( + - ) - v a l e r i a n o 1 (440) and (+)-valencene (439). P i e r s ’ s y n t h e s i s of fukinone (443) i s o u t l i n e d i n Scheme 57.”’ The i n i t i a l phase of t h e s n t h e s i s , s y n t h e s i s of o c t a l o n e 489 was r e p o r t e d e a r l i e r . The approach taken t o the c i s - v i c i n a l methyl s u b s t i t u e n t s h e r e i s i n t e r e s t i n g and c e r t a i n l y d i f f e r e n t from those p r e v i o u s l y d i s c u s s e d . Previous work, both by P i e r s and by Ourisson,206 had shown t h a t 2,3dimethylcyclohexanone (498) may be used i n a Robinson a n n e l a t i o n
”’
Scheme 56.
Coates' Synthesis of (+)-Valencene, (+)-Valerianol, (?)-Ercmophilene, and (2)-Eremoligenol
Q
&9 0
H
T
364 -
0
+
Etzzi2Et
473 -
& -
CH2 SH
H+ 2. Ni
453 -
___c
-
mCoz 1.
o&
452 -
+
/
4 78 -
1. NaH
HMPA
_____c
2. MeOCH2Cl
480 -
OCH70Me C02Et
DMI?
4 7'7
/
&
L
Li
___c
NH3
4 81 -
,C02E t
482 CH3Li
370
B i c a r b o c y c l i c Sesquqterpenes, Hydronaphthalenes
441 -
442 -
371
440 -
4 39 -
w i t h methyl v i n y l k e t o n e . However, P i e r s found t h a t t h e y i e l d of adduct i s low (15%) and t h a t a 3 : 2 r a t i o of s t e r e o i s o m e r s 499 and 500 i s o b t a i n e d .
-
do+ L’-d 2 b +
‘
499 -
‘
0
0
500 -
However P i e r s had f u r t h e r noted t h a t a l k y l a t i o n of 2,3dimethyl-6-n-butylthiomethylenecyclohexanone (484) w i t h m e t h a l l y l c h l o r i d e produced a mixture of k e t o n e s 501 and 502 i n h i g h y i e l d i n a r a t i o o f 4:l. This f i n d i n g suggested an obvious method f o r circumventing t h e c u r r e n t problem.
484 -
501 -
502 -
Ketone 484 was a l k y l a t e d w i t h e t h y l 3-bromopropionate t o was hydrolyzed t o a o b t a i n a mixture of k e t o esters (*)which k e t o a c i d mixture (486). When 486 was r e f l u x e d i n a c e t i c
Total Synthesis of Sesquiterpenes
372
a n h y d r i d e w i t h sodium a c e t a t e , e n o l l a c t o n e s 487 and 488 were obtained i n a r a t i o of 1:9. Isomer *was o b t a i n e d i n 80% y i e l d by f r a c t i o n a l c r y s t a l l i z a t i o n of t h e m i x t u r e . Treatment of 488 w i t h m e t h y l l i t h i u m , f o l l o w e d by b a s e - c a t a l y z e d a l d o l c o n d e n s a t i o n , gave o c t a l o n e 489. Compound 489 w a s f o r m y l a t e d and t h e r e s u l t i n g hydroxywas hydrogenated i n b a s i c medium t o methylene d e r i v a t i v e establish the correct stereochemistry a t the r i n g juncture. In o r d e r t o f o r c e t h e hydroxymethylene g r o u p i n t o t h e a l d e h y d e w a s dehydroform, s o t h a t i t c o u l d be o x i d i z e d , compound g e n a t e d w i t h DCDQ. The r e s u l t i n g a l d e h y d e (492) w a s o x i d i z e d which was m e t h y l a t e d by with s i l v e r oxide t o keto acid t r e a t i n g t h e s i l v e r s a l t w i t h e x c e s s m e t h y l i o d i d e . Keto e s t e r 494 was h y d r o g e n a t e d t o t h e s a t u r a t e d a n a l o g , 495. The carbomethoxyl group w a s c o n v e r t e d i n t o a n i s o p r o p e n y l g r o u p i n g by t r e a t i n g t h e sodium e n o l a t e w i t h m e t h y l l i t h i u m and dehydrating t h e r e s u l t i n g keto alcohol with t h i o n y l c h l o r i d e
(490)
491
493,
-
:c". Scheme 5 7 .
+
P i e r s ' S y n t h e s i s of
Br
C02Et
0
(+)-Fukinone
t-BuOK _L_t
t-BuOH
BUS
484 -
2Et
CH20H cH20>& I
2H
KOH, A
BUS
a
ho ho ::::r +
-
NaOAc
406 -
4 85 -
AC20
-
3 . KOH-MeOH
Bicarbocyclic Sesquiterpenes, Hydronaphthalenes
&
2H
hCoz -
&J;:
__c
373
0
H2-Pt02 EtOH
2. CH3Li
in pyridine. The product, isofukinone (497), was isomerized to ( + ) -fukinone (443) by p-toluenesulfonic acid in benzene. Although eremophilone (503) has not been successfully synthesized, Brown has re orted a synthesis of its tetrahydro derivative (Scheme 5 8 ) . l g g Alkylation of keto ester 504 with
374
T o t a l S y n t h e s i s of Sesquiterpenes
(z),
trans-5-bromo-2-pentene gave a k e t o e s t e r which was hydrolyzed and decarboyxlated t o o b t a i n dienone 506. Compound 506 r e a c t e d w i t h methyllithium t o g i v e an a l c o h o l , which was dehydrated t o y i e l d a mixture of t r i e n e s . n - C y c l i z a t i o n , accomplished b y anhydrous formic a c i d a t room temperature, gave a mixture of b i c y c l i c formates 508 and 509 i n 67% y i e l d . The s t e r e o c h e m i s t r y of t h i s p r o c e s s i s of i n t e r e s t . Since t h e s i d e - c h a i n double bond i s trans, e i t h e r 508 o r =may a r i s e through a t r a n s i t i o n s t a t e i n which t h e i n c i p i e n t A-ring has c h a i r l i k e c h a r a c t e r :
-
-
-
On the o t h e r hand, t h e corresponding isomers w i t h trans methyls
can only be formed v i a a b o a t l i k e t r a n s i t i o n s t a t e :
I n any e v e n t , should t h e undesired s t e r e o c h e m i s t r y be o b t a i n e d , t h e s i t u a t i o n may be remedied, s i n c e t h e s y n t h e s i s i s d e s t i n e d t o pass through i n t e r m e d i a t e s i n which t h i s c e n t e r i s e p i merizable ( s e e 512). I t should be noted t h a t t h i s approach, while guaranteeing t h e proper r e l a t i v e s t e r e o c h e m i s t r y of t h e two methyl groups, o f f e r s no c o n t r o l over t h e three-carbon side chain. The mixture o f and 509 was r e d u c t i v e l y cleaved t o a mixture o f a l c o h o l s 510 and 511, which were i s o l a t e d i n a r a t i o of 3:2. The minor isomer was o x i d i z e d and t h e r e s u l t i n g ketone 512 reduced t o o c t a l i n 513. Photo-oxygenation gave a mixture of d i a s t e r e o m e r i c a l l y l i c a l c o h o l s 514, which was c a r e f u l l y ozonized t o o b t a i n k e t o l s 515. Reduction of t h e d e r i v e d acet a t e 516 with calcium i n l i q u i d ammonia a f f o r d e d ( ? ) - t e t r a hydroeremophilone (%) a s has a l r e a d y been n o t e d , i s one of Eremophilene t h e s i m p l e s t members of t h e eremophilane c l a s s . O r i g i n a l l s t r u c t u r e 445 was i n c o r r e c t l y assigned t o t h i s substance. 24;;
. (s),
Scheme 58.
Brown's Synthesis of (2)-Tetrahydroeremophilone
&$%&/@0
I
1. 0 2 , hv, sens.
2. L i A l H 4
-
375
376
Total Synthesis of Sesquiterpenes
k p - &fCH2
0
444 -
516 -
P i e r s s y n t h e s i z e d s t r u c t u r e 445 i n an a t t e m p t e d t o c o n f i r m o r d i s p r o v e the a s s , vnmen t . T h e s y n t h e s i s , which i l l u s t r a t e s an i n t e r e s t i n g approach t o t h e c i s - v i c i n a l methyl problem, i s o u t l i n e d i n Scheme 59. The r e q u i s i t e s t a r t i n g m a t e r i a l , 3-isopropenylcyclohexanone (=), was o b t a i n e d by c o n j u g a t e a d d i t i o n of i s o p r o p e n y l magnesium bromide t o cyclohexenone. F o r m y l a t i o n o c c u r r e d a t C-6 and t h e r e s u l t i n g hydroxymethylene k e t o n e w a s u s e d i n a Robinson a n n e l a t i o n w i t h t h e Mannich b a s e c o r r e s p o n d i n g t o e t h y l v i n y l k e t o n e . A f t e r d e f o r m y l a t i o n and a l d o l c y c l i z a t i o n , o c t a l o n e 520 w a s o b t a i n e d i n 64% y i e l d . The s t e r e o c h e m i s t r y o f 520 i s t h e more s t a b l e o n e , s i n c e t h e a n g u l a r p o s i t i o n i s e p i m e r i z a b l e . Conjugate a d d i t i o n o f m e t h y l , u s i n g l i t h i u m d i m e t h y l c o p p e r , r e s u l t i n g i n t h e format i o n of s o l e l y t h e c i s - f u s e d d e c a l o n e 521. T h i s r e s u l t w a s p r e d i c t a b l e , as M a r s h a l l and co-workers had e a r l i e r demons t r a t e d t h i s s t e r e o c h e m i c a l outcome i n a d d i t i o n s t o v a r i o u s o c t a l o n e s of t h e g e n e r a l s t r u c t u r e 522. 1 8 2 b 1 2 0 8 R
F i n a l l y , Bamford-Stevens r e a c t i o n on d e c a l o n e 521 y i e l d e d t h e d e s i r e d compound, (+)-eremophil-3,ll-diene which w a s found t o be d i f f e r e n t from t h e n a t u r a l s u b s t a n c e .
(s),
B i c a r b o c y c l i c S e s q u i t e r p e n e s , Hydronaphthalenes Scheme 59.
377
P i e r s ' S y n t h e s i s of (+)-Eremophil-3,11-diene
HC02Et
+o
\ t MCgUBCrl
____c
d 511 -
HOC
519 -
___c
NaOMe
518 -
NaOMe 2 . NaOH 3. NaOMe
1. p-TsNHNH2 2.
Na,
(CHZOH)~
a
521 Dehydrofukinone
445 -
(446) was
p r e p a r e d by Okashi (Scheme
60) l q 8 by a r o u t e i n v o l v i n g S t o r k ' s i s o x a z o l e a n n e l a t i o n methHagemann's e s t e r w a s a l k y l a t e d w i t h 4-chloro0d.'09 methyl-3,5-dimethylisoxazole (523). A f t e r h y d r o l y s i s and de-
(243)
c a r b o x y l a t i o n , enone 524 was o b t a i n e d . Hydrogenation y i e l d e d s a t u r a t e d ketone 525, which w a s p r o t e c t e d a t C-6 by t h e i s o propoxymethylene group. A l k y l a t i o n with methyl i o d i d e gave 527, which was d e p r o t e c t e d by a c i d h y d r o l y s i s . The cis isomer 528 was i s o l a t e d i n 40% y i e l d a f t e r chromatography. A l k y l a t i o n of t h e i s o x a z o l e n i t r o g e n , followed by r i n g cleavage, hydrolysis and a l d o l c y c l i z a t i o n , gave a c e t y l o c t a l o n e 529, which e x i s t s i n t h e e n o l i c form i n d i c a t e d . T h i s s u b s t a n c e w a s
-
-
Total Synthesis of Sesquiterpenes
370
converted into an enol ether (530)I which was treated successively with methyllithium, aqueous acid, and POC13-pyridine to obtain (+)-dehydrofukinone (446). Sims has explored a method for the introduction of angular methyl groupsr which, while it has not been utilized as yet in
Eto2cAo Scheme 60.
Ohashi's Synthesis of (f)-Dehydrofukinone
1. NaOEt
____c
2. KOH 3 . H30+, A
+
p>T--ip 524 -
DMF
i-Pro
526 -
1. Et30+ BF; 2.
NaOH-H20 EtOH
525 -
B i c a r b o c y c l i c S e s q u i t e r p e n e s , Hydronaphthalenes
379
i -Pr I Na2CO 3
OH
529 I
I
a n a t u r a l p r o d u c t s y n t h e s i s , o f f e r s promise as an a l t e r n a t i v e s o l u t i o n t o t h e c i s - v i c i n a l methyl group problem.2 l o Scheme 61 o u t l i n e s the s y n t h e s i s of o c t a l i n s 540 and 541 by t h e S i m s method. 4-methyl-1-naphthoic a c i d (531) was c o n v e r t e d i n t o t h e isomeric t e t r a h y d r o a c i d s 532 and 533 (532:533 = 2 : l ) by B i r c h r e d u c t i o n , The i s o m e r i c a c i d s were s e p a r a t e d by f r a c t i o n a l c r y s t a l l i z a t i o n . Hydrogenation of t h e c o r r e s p o n d i n g methyl e s t e r s 534 and 535 gave o c t a l i n s 536 and 537, r e s p e c t i v e l y . Simmons-Smith m e t h y l e n a t i o n g a v e , i n each c a s e , a
pJ
Scheme 61.
p
Sims' Method o f Angular Methyl I n d r o d u c t i o n
__c LiNH3
@J
C02H
C02 H
C02H
531 -
532 -
533 -
534 H2-Pt02
535 -
380
Total Synthesis of Sesquiterpenes
C02Me
C02Me
C02Me
C02Me
5 39 -
5 38 -
1. OH2.
200°
540 -
1. OH2 . 2000
541 -
s i n g l e isomer (538 and 539). A f t e r s a p o n i f i c a t i o n , the res u l t i n g a c i d s were t h e r m a l l y d e c a r b o x y l a t e d , a f f o r d i n g o c t a l i n s 540 and 541. S. T r i c y c l i c S e s q u i t e r p e n e s Having a D e c a l i n Nucleus w i t h an A d d i t i o n a l Cyclopropane Riny
The compounds which w i l l b e d i s c u s s e d i n t h i s s e c t i o n a r e b a s i c a l l y d e c a l i n i c s e s q u i t e r p e n e s which a r e f u r t h e r b r i d g e d so t h a t an a d d i t i o n a l three-membered r i n g i s p r e s e n t . The s e s q u i t e r p e n e s of t h i s s t r u c t u r a l t y p e which have been synt h e s i z e d a r e t h e eudesmane m a a l i o l (542), 2 1 1 t h e e r e m o p h i l a n e s a r i s t o l o n e ( K ) 2 1 2 r 2 1 3 and a r i s t o l e n e (544), 2 1 4 t h e cadinanes B-cubebene and c u b e b o l ( 5 4 6 ) ,216 and thujopsene (547) , 2 1 7 r m which b e l o n g s t o n o n e o f t h e u s u a l decalinic classes.
-
Bicarbocyclic S e s q u i t e r p e n e s , Hydronaphthalenes
543 -
542 -
546 -
54 5 -
381
544 -
547 -
The s y n t h e t i c problems a s s o c i a t e d with t h e s e compounds c l o s e l y p a r a l l e l t h e problems encountered i n t h e r e s p e c t i v e b i c y c l i c series, complicated by t h e n e c e s s i t y of i n t r o d u c i n g t h e cyclopropane r i n g . Biichi's s y n t h e s i s o f maaliol (542) i s o u t l i n e d i n Schemes 62 and 63.'18 The s t a r t i n g p o i n t w a s 7-epi-cyperone (2, see p. 284), which smoothly added H B r i n a c e t i c a c i d t o y i e l d t h e bromide 548. Base c a t a l y z e d dehydrobromination then afforded t h e t r i c y c l i c enone 549 i n 62% o v e r a l l y i e l d . With t h e b a s i c carbon s k e l e t o n i n hand, t h e problem now becomes one of redox chemistry. The carbonyl group must be removed, and, i n a f o r mal s e n s e , water must be added t o t h e double bond i n one spec i f i c o r i e n t a t i o n and cis t o t h e cyclopropane r i n g . As w i l l be s e e n i n t h e s e q u e l , t h e s e problems were n o t adequately s o l v e d , although two d i f f e r e n t r o u t e s l e a d i n g from enone 549 t o m a a l i o l i n poor y i e l d were developed. Wolff-Kishner r e d u c t i o n of enone 549 l e d t o a mixture of o l e f i n s 550 and 551 (550:551 = 15:85) i n 64% y i e l d . Selenium d i o x i d e o x i d a t i o n of t h e mixture gave u n s a t u r a t e d aldehyde 552 i n 6% y i e l d . A second Wolff-Kishner r e d u c t i o n on 552 gave a mixture of o l e f i n s 550, 551, and 553. O s m i u m t e t r o x i d e oxid a t i o n o f t h i s mixture gave a mixture of d i o l s from which Bm a a l i d i o l (554) was i s o l a t e d i n 20% y i e l d . Reduction of t h e d e r i v e d mono-p-toluenesulfonate (555) with l i t h i u m aluminum hydride gave, probably v i a an epoxide i n t e r m e d i a t e , maaliol
--
-
(542).
& Scheme 62.
EUchi's Synthesis of Maaliol--First Variation
/
0
H B rr B * o
KOH
__c
___c
MeOH
HOAc
540 -
31 -
+
549 -
R-
R 551 -
550 -
W.K.-
552 -
OsO4
__c
553
OH
554 -
HO OTs 555 -
382
542 -
550 -
+
551 +
B i c a r b o c y c l i c S e s q u i t e r p e n e s , Hydronaphthalenes
383
A n a l t e r n a t i v e r o u t e (Scheme 63) begins with l i t h i u m ethanol-ammonia r e d u c t i o n of t h e t r i c y c l i c enone From a complex mixture o f p r o d u c t s , a l c o h o l 556 was i s o l a t e d i n 28% pyrolyzed, whereupon a 1:l y i e l d . The d e r i v e d a c e t a t e = w a s mixture of o l e f i n s 558 and 559 was o b t a i n e d i n 74% y i e l d . Osmium t e t r o x i d e o x i d a t i o n gave iso-a-maalidiol (560) i n 5% y i e l d and t h i s d i o l was oxidized by S a r r e t t ' s procedure t o t h e
*.
Scheme 63.
Btichi's S y n t h e s i s o f Maaliol--Second V a r i a t i o n
0
HO
HO
561 -
542 -
a c y l o i n 561 i n 25% y i e l d . Wolff-Kishner r e d u c t i o n of 561 gave m a a l i o l i n 18% y i e l d . The f i r s t r e p o r t e d a r i s t o l o n e (543) s n t h e s i s was t h a t of Ourisson, which i s o u t l i n e d i n Scheme 64. 2Ji2 The p l a n w a s t o i n t r o d u c e t h e i s o p r o p y l i d i n e b r i d g e by a d d i t i o n of a carbene
384
Total Synthesis of Sesquiterpenes
or carbenoid species to an octalone such as 566. 2,3-Dimethylcyclohexanone reacted with methyl vinyl ketone to give isomers 499 and 500 in a ratio of 3 : 2 (see Piers, p. 3 7 1 for yield). Lithium-ammonia reduction of the mixture gave a mixture of decalones 562 and 563. Although this double bond is present in the eventual product, it was temporarily saturated, apparently to avoid the complication to selective reaction in a dienone such as =.* After bromination of the mixture, the crystalline bromo ketone 564 was separated from t h e undesired isomer 565. Dehydrobromination then afforded octalone 566. The crucial stages, introduction of the isopropylidine group, were now encountered. 1,3-Dipolar addition of 2-diazopropane yielded the pyrazoline 567, which underwent ring contraction upon irradiation to give dihydroaristolone (=). Scheme 64. Ourisson’s Synthesis of (+I-Aristolone
498 -
500 -
499 \
I
V
Li-NH3
563 -
L
562 -
I
563 -
Y
Br2-HOAc
*However, such selective reaction would probably succeed; see Scheme 5 5 .
I
B i c a r b o c y c l i c S e s q u i t e r p e n e s , Hydronaphthalenes
385
bo+ H
H
564 -
566 -
565 -
1. PTAB 2. L i B r
H
HMPA
568 -
567 -
Bromination and dehydrobromination of t h i s substance l e d t o ( 5 )- a r i s t o l o n e (543) P i e r s ' s y n t h e s i s of a r i s t o l o n e (Scheme 65) i n c o r p o r a t e s s e v e r a l novel f e a t u r e s . The c i s - v i c i n a l methyl groups were e s t a b l i s h e d by a l k y l a t i n g t h e 6-butylthiomethylene d e r i v a t i v e of 2,3-dimethylcyclohexanone (484) w i t h m e t h y l a l l y l c h l o r i d e (see p . 371). A f t e r d e p r o t e c t i o n of t h e r e s u l t i n g d i a s t e r e o meric m i x t u r e , isomers 569 and 570 were obtained i n a r a t i o of 4:l. E q u i l i b r a t i o n of 569 with p - t o l u e n e s u l f o n i c a c i d i n benzene y i e l d e d a complex mixture from which isomer 571 was i s o l a t e d by f r a c t i o n a l d i s t i l l a t i o n i n 2 2 % y i e l d . * The s y n t h e t i c p l a n c a l l e d f o r t h e i n t r o d u c t i o n of a t h r e e carbon d i a z o ketone chain a t t h e carbonyl p o s i t i o n . I n s e r t i o n of t h e d e r i v e d a-keto carbene i n t o t h e methylpropenyl double bond would t h e n y i e l d t h e a r i s t o l o n e s k e l e t o n , i n a sequence r e m i n i s c e n t of Btlchi's thujopsene s y n t h e s i s (Scheme 7 0 ) .
.
*See Ref. 213, f o o t n o t e 2 f o r an improvement i n t h i s p r o c e s s .
T o t a l S y n t h e s i s of S e s q u i t e r p e n e s
386
Although ketone 571 f a i l e d t o r e a c t w e l l w i t h t h e a n i o n of t r i e t h y l p h o s p h o n o a c e t a t e , probably due t o i t s crowded environment, i t r e a c t e d smoothly w i t h t h e s m a l l e r a n i o n d e r i v e d from d i e t h y l cyanomethylphosphonate i n d i m e t h y l s u l f o x i d e . The p r o d u c t was a m i x t u r e of t h e o l e f i n i c isomers 572. Basic h y d r o l y s i s of t h e cyano group gave a s i n g l e a c i d i n 82% yield, The d e r i v e d a c i d c h l o r i d e was t r e a t e d w i t h diazomethane t o o b t a i n t h e d e s i r e d d i a z o ketone Cupric s u l f a t e - c a t a l y z e d decomposition y i e l d e d a complex mixture cont a i n i n g mainly ( + ) - a r i s t o l o n e (=, 30% y i e l d ) and i t s isomer 576 ( 2 0 % y i e l d ) .
(2)
-
Scheme 65.
Po
P i e r s ' S y n t h e s i s of
-
t BuOK t-BuOH
BUS
4 84 -
571 -
I
F
(+)-Aristolone
+
____c
=.
(573)
BUS
501 -
502 -
5 70 -
569 0
II
( E t O ) ZP-CHZCN DMSO-
1. NaOH
____c
572 -
A
573 -
C02H
2.
(COC1)Z
Bicarbocyclic S e s q u i t e r p e n e s , Hydronaphthalenes
387
For t h e s y n t h e s i s of ( + ) - a r i s t o l e n e ( c a l a r e n e ) , 544, Coates made use o f u n s a t u r a t e d k e t o e s t e r 480, a c r u c i a l i n t e r m e d i a t e i n t h e s y n t h e s i s of s e v e r a l b i c y c l i c eremophilanes (see Scheme 66) .214 The s y n t h e t i c p l a n c a l l e d for i n t r o d u c t i o n of t h e i s o p r o p y l i d i n e group by p y r o l y s i s o f a p y r a z o l i n e r i n g , f i r s t employed by Kishner and Zavodorsky i n t h e s y n t h e s i s of c a r a n e , and l a t e r used by Ourisson i n t h e s y n t h e s i s of (f)a r i s t o l o n e (Scheme 6 4 ) . Keto e s t e r 480 r e a c t e d with methyllithium t o give a hydroxy ketone (E), which was dehydrated by methanolic H C 1 t o o b t a i n dienone 578. This substance r e a c t e d w i t h hydrazine i n e t h a n o l t o y i e l d t h e d e s i r e d p y r a z o l i n e 579. Decomposition was e f f e c t e d by h e a t i n g with powdered potassium hydroxide a t 250'. The product was n e a r l y pure ( + I - a r i s t o l e n e ( 5 4 4 ) . A s i m i l a r d e c o m p l i s i t i o n of p y r a z o l i n e 580 afforded t w o s t e r e o isomers, 581 and 582 i n a r a t i o o f 3 : l . The s t e r e o c h e m i s t r y
580 -
581 -
582 -
of t h e cyclopropane r i n g probably r e f l e c t s t h e thermodynamic s t a b i l i t y of t h e p y r a z o l i n e r i n g . I n both c a s e s , t h e major decomposition product h a s s t e r e o c h e m i s t r y corresponding t o t h a t of t h e more stable p y r a z o l i n e isomer. However, t h e production of s u b s t a n t i a l amounts of 582 i n t h e decomposition of 580 i n d i cates t h a t , i n some unknown manner, t h e s t e r e o c h e m i s t r y of t h e
388
Total Synthesis of Sesquiterpenes
Scheme 6 6 .
C o a t e s ' S y n t h e s i s of
(2)-Aristolene (Calarene)
HC 1
MeOH
577 -
KOH
N2H4
__c
250'
EtOH
570 -
5 79 -
s e c o n d a r y methyl g r o u p i n f l u e n c e s t h e s t e r e o c h e m i c a l outcome of the reaction. The s t r u c t u r e s of B-cubebene and c u b e b o l (545 and 546) are i n t e r e s t i n g i n t h a t t h e c y c l o p r o p a n e r i n g i s found within t h e p e r i p h e r y of t h e b a s i c c a d i n a n e s k e l e t o n . The b i c y c l o [ 3 . 1 . 0 1 hexane a r r a n g e m e n t found i n t h e B and C r i n g s i m m e d i a t e l y sugg e s t s a s y n t h e t i c r o u t e . S t o r k had p r e v i o u s l y e x p l o r e d t h e i n t r a m o l e c u l a r i n s e r t i o n of a - k e t o c a r b e n e s i n t o o l e f i n i c l i n k a g e s as a means of g e n e r a t i n g such s t r u c t u r e s . 2 1 9 The c r u c i a l i n t e r m e d i a t e i s t h u s u n s a t u r a t e d d i a z o k e t o n e 583.
U n f o r t u n a t e l y , s u c h a r o u t e a l l o w s l i t t l e chance f o r s t e r e o c h e m i c a l c o n t r o l . One can o n l y hope t h a t t h e c a r b e n e w i l l add
B i c a r b o c y c l i c S e s q u i t e r p e n e s , Hydronaphthalenes
389
predominately t r a n s t o t h e l a r g e r i s o p r o p y l group, i n which case t h e major cyclopropyl ketone would have t h e proper s t e r e o chemistry. P i e r s ' s y n t h e s i s of ( 2 )-B-cubebene i s o u t l i n e d i n Scheme 67. A mixture of ( k ) -menthone and ( 5 )-isomenthone (584) was formylated and t h e r e s u l t i n g hydroxymethylene d e r i v a t i v e was converted i n t o a mixture of n-butylthiomethylene compounds 585. Sodium borohydride r e d u c t i o n of t h e ketone, followed by a c i d i c h y d r o l y s i s , gave a mixture of aldehydes 586. Reduction w i t h borohydride y i e l d e d a l l y l i c a l c o h o l s 587. While t h e i s o m e r r a t i o a t t h i s p o i n t i s n o t s t a t e d , one e x p e c t s a predominance of t h e isomer having t h e two a l k y l groups t r a n s . Alcohol 587 was converted i n t o bromide 588 and t h i s bromide was used t o a l k y l a t e carbethoxymethylenetriphenylphosphorane. The r e s u l t i n g phosphonium s a l t w a s s u b j e c t e d t o vigorous h y d r o l y s i s t o o b t a i n a mixture of u n s a t u r a t e d a c i d s 589. The d e s i r e d diazoketone, a s a mixture of cis and t r a n s isomers (590), was prepared from 589 i n t h e normal manner. Cupric s u l f a t e - c a t a l y z e d decomposition gave t h r e e isomeric cyclopropyl k e t o n e s 591, 592, and 593, i n a r a t i o of 2 : 3 : 5 . The minor isomer w a s converted by a W i t t i g r e a c t i o n i n t o ( 2 ) $-cubebene (545) Although t h e s t e r e o c h e m i s t r y of isomers 592 and 593 remains o b s c u r e , t h e major isomer should be
*
-
-
-
.
Scheme 67.
P i e r s ' S y n t h e s i s of (?)-$-Cubebene
1. H C 0 2 E t ,
MeOH 2. H ~ O +
585 -
584 -
NaBH4 , Me OH
T o t a l S y n t h e s i s of S e s q u i t e r p e n e s
390
A 588 -
590 -
MeOH
A
589 -
591 -
5 9 2 , 593
f o r m u l a t e d a s i n d i c a t e d b e l o w , i f the a s s u m p t i o n t h a t a l c o h o l 587 is m o s t l y trans i s c o r r e c t .
-
593 3 A n a l t e r n a t i v e s y n t h e s i s of B-cubebene a n d c u b e b o l , d u e t o Y o s h i k o s h i , i s s u m m a r i z e d i n Scheme 6 8 . 2 1 6 While Yoshik o s h i ' s s y n t h e s i s i s a l s o b a s e d o n t h e d e c o m p o s i t i o n of a n uns a t u r a t e d a - k e t o c a r b e n e (5991, t h e r o u t e t o t h i s c r i t i c a l
Bicarbocyclic Sesquiterpenes, Hydronaphthalenes
391
intermediate is quite different. The starting point was ( - ) trans-caran-2-one (E), which reacted with allylmagnesium bromide to give alcohol 595 (stereochemistry unspecified). Hydroboration-oxidation gave a diol (5961, which was further oxidized to the spiro-lactone 597. Pyrolysis of this substance, in the presence of pyridine, yielded the dienic acid 598 in which the methyl and isopropenyl groups are presumably trans, as in the cubebenes. After preparation of the diazoketone 599, copper catalyzed decomposition gave tricyclic ketones 600, 601, and 602 in 11, 13, and 1% overall yields, based on spiro-lactone 597. Isomer =was hydrogenated to the nor-ketone 591, which gave Bcubebene (545) upon treatment with methylenetriphenylphosphorane. Addition of methylmagnesium iodide to 591 gave cubebol Scheme 68. Yoshikoshi's Synthesis of 8-Cubebene and Cubebol
594 -
595 -
0
250-300
a ___c
C5H5N
596 -
597 -
392
Total Synthesis of Sesquiterpenes
601 -
600 -
591 -
602 -
54 5 -
MeMg I
(546) a s
t h e major p r o d u c t ( 4 7 % ) . Thujopsene (547) h a s an u n u s u a l s k e l e t o n which h a s prompted two i n t e r e s t i n g and r a d i c a l l y d i f f e r e n t s y n t h e s e s . I n t h e f i r s t , Dauben c h o s e t o u t i l i z e t h e a l l y l i c a l c o h o l a s a c r i t i c a l i n t e r m e d i a t e (Scheme 6 9 ) . 2 1 7 On t h e b a s i s o f e a r l i e r s t u d i e s , l e 6 it was e x p e c t e d t h a t Simmons-Smith methyle n a t i o n of 607 would o c c u r s t e r e o s p e c i f i c a l l y c i s t o t h e h y d r o x y l g r o u p , t h u s e s t a b l i s h i n g t h e p r o p e r r e l a t i v e stereoc h e m i s t r y i n t h e t h r e e asymmetric c e n t e r s of t h u j o p s e n e . In f a c t , alcohol whichwas p r e p a r e d by t h e s t r a i g h t f o r w a r d route indicated, reacted sluggishly with iodomethylzinc i o d i d e , b u t gave o n l y o n e s t e r e o i s o m e r (608) i n 2 3 % y i e l d . O x i d a t i o n o f 608 y i e l d e d a c y c l o p r o p y l k e t o n e (6091, which was t r e a t e d w i t h methylmagnesium bromide. Upon work-up, t h e resulting c a r b i n o l d e h y d r a t e d s p o n t a n e o u s l y , g i v i n g ( i ) - t h u j o p s e n e (547). B t l c h i ' s s y n t h e s i s (Scheme 7 0 ) i s e l e g a n t l y d e s i g n e d , b u t
607
607,
B i c a r b o c y c l i c Sesquiterpenes, Hydronaphthalenes Scheme 69.
393
Dauben's S y n t h e s i s of (?)-Thujopsene
(p- (po 604 -
603 -
LiA1Hb
Ac20
poH -@ OH
acetone
1. MeMgBr
_____c
2. NH4C1
609 -
547 -
s u f f e r s from an extremely low y i e l d i n t h e f i n a l s t e p . BC y c l o c i t r a l (610) was reduced t o B-cyc o g e r a n i o l (611) whici was converted i n t o v i n y l e t h e r 612. P y r o l y t i c rearrangement o f t h i s m a t e r i a l y i e l d e d aldehyde 613. This s u b s t a n c e , as i t s was allowed t o r e a c t with e t h y l propenyl ethoxy a c e t a l (G), e t h e r t o o b t a i n t h e mixed a c e t a l 615. When 615 was heated w i t h sodium a c e t a t e i n a c e t i c a c i d , a mixture of u n s a t u r a t e d aldehydes 616 and 617 was obtained i n 76% y i e l d . Although one isomer g r e a t l y predominated (12:l r a t i o ) , they were n o t separ a t e d and t h e i r s t e r e o c h e m i s t r y was n o t d e f i n e d . The c o r r e sponding p-toluenesulfonylhydrazones (618 and 619) were irr a d i a t e d , a s t h e i r sodium s a l t s , t o g i v e a complex mixture of products. The hydrocarbon f r a c t i o n r e s u l t i n g from t h i s rea c t i o n (18%)
Scheme 7 0 .
394
BUchi's Synthesis of (+)-Thujopsene
Other B i c a r b o c y c l i c S e s q u i t e r p e n e s
620 -
395
547 -
c o n s i s t e d p r i m a r i l y o f cyclopropene 620 ( 1 0 % ) and ( ? ) -thujops e n e (547, 4 % ) . F i v e u n i d e n t i f i e d hydrocarbons were a l s o observed a s minor p r o d u c t s . 5.
OTHER BICARBOCYCLIC SESQUITERPENES
A.
G u a i a z u l e n e s ; B u l n e s o l , a-Bulnesene,
and Kessane
I n c o n t r a s t t o t h e s y n t h e t i c s u c c e s s which h a s been r e a l i z e d i n t h e d e c a l i n i c area (see Sec. 4 1 , o n l y a few h y d r o a z u l e n i c s e s q u i t e r p e n e s have y i e l d e d t o t o t a l s y n t h e s i s . There are two r e a s o n s f o r t h i s d i s p a r i t y . While t h e r e a r e many r e l i a b l e methods f o r the f o r m a t i o n of t h e hydronaphthalene n u c l e u s (Robinson a n n e l a t i o n , r e d u c t i o n o f n a p h t h a l e n e s , Diels-Alder c y c l o a d d i t i o n , n - c y c l i z a t i o n ) , analogous methods f o r t h e genera t i o n of h y d r o a z u l e n e s a r e r a r e r . Complicating t h i s d e a r t h of methods f o r e l a b o r a t i o n o f t h e b a s i c s k e l e t o n is t h e p o o r l y developed s t a t e o f c o n f o r m a t i o n a l a n a l y s i s i n c y c l o p e n t a n e s and cyclohexanes. Thus, one may c o n f i d e n t l y d e s i g n s t e r e o s e l e c t i v e s y n t h e s e s i n t h e d e c a l i n a r e a , i n which r e l a t i v e s t e r e o c h e m i s t r y i s e s t a b l i s h e d by e i t h e r k i n e t i c o r thermodynamic methods. S t e r e o s e l e c t i v e d e s i g n i n t h e hydroazulene area is much more d i f f i c u l t . As a consequence of t h e s e f a c t o r s , s y n t h e s e s i n t h e h y d r o a z u l e n e area have u n i f o r m l y been accomplished by t h e r e arrangement of a b i c y c l i c p r e c u r s o r p o s s e s s i n g a s k e l e t o n which i s more amenable t o s t e r e o s e l e c t i v e s y n t h e s i s . I n t h i s tz2' s e c t i o n we s h a l l d i s c u s s t h e s y n t h e s i s o f b u l n e s o l (L) a-bulnesene (2) ,221 , 2 2 3 and k e s s a n e (3).224 In t h e f o l l o w i n g s e c t i o n , w e w i l l t a k e up t h e s y n t h e s e s of t h e q u a i a n o l i d e s
396
Total Synthesis of Sesquiterpenes
(A),geigerin (5), desacetoxymatricarin
arborescin achillin derivatives.
(L)#all of which have been prepared
(61, and from santonin
Marshall‘s synthesis of (2)-bulnesol, which proceeds via bicyclo L4.3. lldecane intermediates, is outlined in Scheme 1.’” The synthesis, which is beautifully designed, was based upon the expectation that a bicyclo[4.3.l]decane derivative such as 51 would solvolyze w i t h rearrangement to the hydroazulene 9. Preliminary studies demonstrated the feasibility of the
approach.225 With this knowledge I the problem becomes one of stereospecifically synthesizing an analog of compound S which contains the necessary functionality for incorporation of the isopropylol group. The rearrangement product would then
Other Bicarbocycl i c Se s q u i t e rpenes
39 7
p o s s e s s t h e c o r r e c t s t e r e o c h e m i s t r y (GI. Less d e s i r a b l y , a s u b s t r a t e with t h e s t e r e o c h e m i s t r y i n d i c a t e d i n 1;2 might be
10 -
11 -
employed. The i n i t i a l product (13)might be converted by e p i m e r i z a t i o n t o 2, which could then be converted i n t o b u l n e s o l . A c o n s i d e r a t i o n o f models suggested t h a t t h e e q u i l i b r i u m 13 (X = carbomethoxy) should l i e s t r o n g l y t o t h e r i g h t .
- =G
The startingpointforMarshall's s y n t h e s i s w a s I-carbethoxycycloScheme 1. The d e r i v e d e t h y l e n e k e t a l was reduced by hexanone l i t h i u m aluminum hydride t o primary a l c o h o l ,11. Treatment of t h e corresponding methanesulfonate w i t h sodium p-chlorophenoxide gave e t h e r &, which was hydrolyzed t o k e t o e t h e r Compound 17a r e a c t e d smoothly with e t h y l d i a z o a c e t a t e i n t h e p r e s e n c e o f boron t r i f l u o r i d e t o g i v e t h e ring-expanded Compound 18a r e a c t e d with 6-keto e s t e r J E & i n 79% y i e l d . Acid methyl v i n y l ketone t o y i e l d e x c l u s i v e l y isomer c a t a l y z e d c y c l i z a t i o n , followed by e s t e r h y d r o l y s i s , a f f o r d e d t h e c r y s t a l l i n e k e t o a c i d 3 i n 65% y i e l d . A t t h i s p o i n t , comment on t h e choice of t h e grouping C H 2 0 A r a s t h e p o t e n t i a l i s o p r o p y l o l group i s i n o r d e r . Prel i m i n a r y experiments on t h e r e l a t e d cycloheptanone 23. showed t h a t i n t r a m o l e c u l a r c y c l i z a t i o n competed w i t h t h e d e s i r e d Michael a l k y l a t i o n . The o n l y product i s o l a t e d i n attempted a l k y l a t i o n of 3 w a s t h e k e t o e s t e r 35, which presumably a r o s e by fragmentation of diketone 34. I n o r d e r t o avoid t h i s comp l i c a t i o n , it was decided t o r e p l a c e t h e carbethoxy group with a p r o t e c t e d methylol group. Other c o n s i d e r a t i o n s prompted t h e
(14)
G.
-.
398
T o t a l S y n t h e s i s of S e s q u i t e r p e n e s
r e p l a c e m e n t o f t h e a-methyl group by a n e s t e r g r o u p i n g , which c o u l d l a t e r b e reduced t o t h e d e s i r e d m e t h y l s u b s t i t u e n t . The f i r s t p r o t e c t i n g g r o u p e x p l o r e d was phenoxy. However, i t w a s found t h a t t h i s group was i n c o m p a t i b l e w i t h t h e c o n d i t i o n s req u i r e d f o r c y c l i z a t i o n of t h e d e r i v e d d i k e t o e s t e r . The problem seemed t o l i e i n s u l f o n a t i o n of t h e phenoxy r i n g . I t was t h e r e f o r e r e a s o n e d t h a t t h e i n c o r p o r a t i o n of a d e a c t i v a t i n g group i n t h i s r i n g would s t a b i l i z e i t w i t h r e s p e c t t o t h i s unwanted s i d e r e a c t i o n . As was found i n t h e s e q u e l , t h i s p r e d i c t i o n was a d m i r a b l y b o r n e o u t . The r e m a r k a b l e s t e r e o s p e c i f i c i t y o b s e r v e d i n t h e a l l k y l a i s i n t e r e s t i n g . I f one assumes a t i o n of 8 - k e t o e s t e r " r e a c t a n t - l i k e " t r a n s i t i o n s t a t e , t h e s t e r e o c h e m i s t r y i s exp l i c a b l e i n terms o f s t e r i c h i n d r a n c e t o approach of the rea g e n t ( b e l o w ) . U n f o r t u n a t e l y , t h e r e s u l t i n g p r o d u c t (=) has
18a
9-
0
t h e i n c o r r e c t geometry f o r d i r e c t c o n v e r s i o n i n t o b u l n e s o l . However, as n o t e d p r e v i o u s l y , t h i s s i t u a t i o n may be remedied at a l a t e r stage. With t h e d e s i r e d b i c y c l o [ 4 . 3 . 0 ] d e c a n e s k e l e t o n i n hand, M a r s h a l l and P a r t r i d g e t u r n e d t o t h e problem o f f u r t h e r
Other B i c a r b o c y c l i c Sesquiterpenes
399
e l a b o r a t i o n of compound 20a i n t o a s u i t a b l e p r e c u r s o r f o r t h e s y n t h e s i s o f b u l n e s o l . The f i r s t t a s k , r e d u c t i o n of t h e bridgehead carboxyl t o methyl, was accomplished i n a r e l a t i v e l y s t r a i g h t f o r w a r d manner. Hydride r e d u c t i o n o f k e t o a c i d 20a was accomplished by p a r t i a l removal of t h e aromatic c h l o r i n e . The r e s u l t i n g mixture of d i o l s 21 was converted i n t o t h e c o r r e sponding p - t o l u e n e s u l f o n a t e s 22, which w e r e reduced with l i t h i um aluminum hydride t o hydroxy e t h e r s 23. Birch r e d u c t i o n of 23, followed by h y d r o l y s i s of t h e r e s u l t i n g e n o l e t h e r s , gave t h e s i n g l e c r y s t a l l i n e d i o l 24. The s t e r e o c h e m i s t r y of compound 24 was confirmed by o x i d a t i o n t o k e t o a c i d 36, which was converted i n t o l a c t o n e 37. Reduction o f 37, f o r which t h e
-
24
CrO3
H02C
a
NaBH4
__c
@/-
24
H
H
36 -
iAlH4
0
37 -
s t e r e o c h e m i s t r y i s f i x e d , l e d t o t h e same d i o l
(%).*
*The s t e r e o c h e m i s t r y of t h e secondary a l c o h o l (syn t o t h e f o u r carbon b r i d g e ) i s , of c o u r s e , c r i t i c a l . I n o r d e r for concerted rearrangement t o occur i n t h e d e s i r e d s e n s e , t h e l e a v i n g group must be a n t i - c o p l a n a r with t h e m i g r a t i n g bond:
_____L
The a l t e r n a t i v e isomer would solvolyze t o a d e c a l i n i c system.
400
T o t a l S y n t h e s i s of S e s q u i t e r p e n e s
A f t e r s e l e c t i v e a c e t y l a t i o n of t h e primary h y d r o x y l , t h e double bond w a s reduced c a t a l y t i c a l l y t o a f f o r d compound 26. A t t h i s s t a g e , t h e r e l a t i v e s t e r e o c h e m i s t r y a t t w o of bulnes o l ' s asymmetric c e n t e r s i s f i x e d . Model s t u d i e s had shown t h a t hydrogen i s d e l i v e r e d predominately f r o m t h e exo f a c e of t h e b i c y c l i c system, l e a d i n g t o an e q u a t o r i a l methyl group, a s i n 26.
CH20Ac 25 -
.CH20Ac
26 -
S o l v o l y s i s o f m e t h a n e s u l f o n a t e 27 o c c u r r e d w i t h r e a r r a n g e ment as p l a n n e d , a f f o r d i n g t h e o c t a h y d r o a z u l e n e 28 i n 9 2 % y i e l d . A f t e r removal o f t h e a c e t y l g r o u p , t h e methyl01 group was o x i d i z e d t o c a r b o x y l . The r e s u l t i n g a c i d (0) gave a methyl e s t e r (1 ,) which w a s e q u i l i b r a t e d w i t h m e t h a n o l i c sodium methoxide. Isomer 2 predominated a t e q u i l i b r i u m , a s p r e d i c t e d (32:31 = 7 : 3 ) . The major isomer was s e p a r a t e d by (footnote continued)
The s t e r e o c h e m i s t r y a t t h i s c e n t e r i s e s t a b l i s h e d i n t h e hyd r i d e r e d u c t i o n of k e t o a c i d 3 and may be r a t i o n a l i z e d on s t e r i c grounds. P r e l i m i n a r y s t u d i e s had shown t h a t s i m p l e r k e t o n e s analogous t o 20a are reduced e i t h e r by h y d r i d e or sodium i n a l c o h o l t o a s i n g l e a l c o h o l . A p p a r e n t l y , t h e f o u r carbon b r i d g e e f f e c t i v e l y b l o c k s approach t o t h a t s i d e of t h e carbonyl group.
Other Bicarbocyclic Sesquiterpenes preparative glpc and treated with methyllithium to obtain bunesol (1). Scheme 1.
Marshall's Synthesis of (+)-Bulnesol
OH
0
1. H2SO4
NaOEt
2 . KOH
3 . H30+
18a -
as -
OAr
20a -
LiAlH4
OAr
H
OAr
1. Li-EtOH NH3 2. H3O
-
+ -
401 (?)-
T o t a l S y n t h e s i s of S e s q u i t e r p e n e s
402
OH
Ac
OAc
27 -
29 -
NaOMe
C02H 30 -
(a)
x
= P-Cl-CgHq-;
(b)
x
= CfjH5-
An a l t e r n a t i v e s o l u t i o n t o t h e g u a i a z u l e n e problem, developed by Heathcock and R a t c l i f f e , w a s a p p l i e d t o t h e synt h e s i s of bulnesol and a - b u l n e s e n e (2).221 The HeathcockR a t c l i f f e approach was b a s e d on t h e d i s c o v e r y t h a t b o t h c i s and trans-9-methyl-1-decalyl p - t o l u e n e s u l f o n a t e s undergo solv o l y t i c r e a r r a n g e m e n t t o h y d r o a z u l e n e p r o d u c t s ( i . e . , 38 -+ 3 9 ) .226 C o n s i d e r a t i o n of t h e r e l a t i v e s t e r e o c h e m i s t r y i n
(1)
-
H
Other B i c a r b o c y c l i c S e s q u i t e r p e n e s
403
b u l n e s o l r e v e a l s three d e c a l y l t o s y l a t e s which might y i e l d t h i s type of product upon s o l v o l y t i c rearrangement ( 4 0 - 4 2 ) . The known s t e r e o c h e m i s t r y of t h e Wagner-Meerwein rearrangement p l a c e s an added s y n t h e t i c c o n s t r a i n t on t h e problem. I n c i s - d e c a l i n 40, t h e conformer which h a s t h e t o s y l a t e group and t h e m i g r a t i n g bond a n t i and coplanar (conformer i s hope-
9)
40a -
4Qb -
OTs I
OTs
41a -
I
R
# OTs
4l b -
H
l e s s l y crowded. The a l t e r n a t i v e c h a i r - c h a i r con-Jnner (*) would predominate h e a v i l y . Thus, t h i s m a t e r i a l would proba b l y n o t y i e l d a hydroazulene on s o l v o l y s i s . The c i s - f u s e d d e c a l y l t o s y l a t e 2,however, i s expected t o e x i s t predomin a t e l y a s conformer 2,i n which t h e r e q u i s i t e a n t i - c o p l a n a r r e l a t i o n s h i p i s p r e s e n t . F i n a l l y , t h e trans-fused d e c a l y l t o s y l a t e 42 i s r e s t r i c t e d t o one low-energy conformation, i n which t h e t o s y l a t e group and m i g r a t i n g bond a r e a n t i - c o p l a n a r . The choice of s y n t h e t i c t a r g e t f o r t h i s approach i s t h u s l i m i t e d t o t o s y l a t e s 41 and 42. The Heathcock-Ratcliffe s y n t h e s i s of b u l n e s o l follows t h e t r a n s - d e c a l i n r o u t e (42). A n a l t e r n a t i v e a p p l i c a t i o n of t h i s approach, by Yoshikoshi ,2 2 2 adopts a r o u t e proceeding
404
T o t a l Synthesis of Sesquiterpenes
.
t h r o u g h c i s - d e c a l i n i n t e r m e d i a t e s (41) * Schemes 2 a n d 3 o u t l i n e the H e a t h c o c k - R a t c l i f f e s y n t h e s i s o f ( 5 ) - a - b u l n e s e n c (2) a n d ( + ) - b u l n e s o l , Acetylai n Sec. 4 ) t i o n of unsaturated k e t o alcohol ( s t r u c t u r e g a v e a c e t a t e 45, w h i c h was k e t a l i z e d , w i t h c o n c o m i t t a n t d o u b l e bond m i g r a t i o n , t o g i v e 5. The a c e t y l p r o t e c t i n g g r o u p was necessary t o a v o i d a c i d c a t a l y z e d r e t r o g r a d e a l d o l condensation i n the ketalization step. A f t e r r e d u c t i v e removal o f t h e a c e t y l g r o u p , t h e s e c o n d a r y h y d r o x y l g r o u p i n 47 w a s p e r m a n e n t l y p r o t e c t e d as i t s henzyl ether.? Hydroboration-oxidation o f s t r u c t u r e in S e c . 4 g a v e a m i x t u r e of a l c o h o l s ( s t r u c t u r e i n Sec. 4) w h i c h w a s o x i d i z e d t o a m i x t u r e of k e t o n e s ( s t r u c t u r e 184 i n S e c . 4 ) i n which t h e cis-isomer p r e d o m i n a t e d i n a r a t i o o f 2:l. T h i s m i x t u r e r e a c t e d d i r e c t l y w i t h m e t h y l e n e t r i p h e n y l p h o s p h o r a n e i n d i m e t h y l s u l f o x i d e t o g i v e only the c r y s t a l l i n e t r a n s - f u s e d m e t h y l e n e d e c a l i n 2 i n 07% y i e l d . A c i d - c a t a l y z e d k e t a l h y d r o l y s i s y i e l d e d 49, w h i c h w a s q u a n t i t a t i v e l y r e d u c e d t o a m i x t u r e c o n t a i n i n g 85% of d e c a l o n e 50 and 15% of i t s C - 8 e p i m e r . The c r y s t a l l i n e d e c a l o n e 2, when t r e a t e d w i t h ethylidinetriphenylphosphorane, f o l l o w e d b y h y d r o b o r a t i o n , o x i d a t i o n and a c i d c a t a l y z e d e p i m e r i z a t i o n , q a v e m e t h y l k e t o n e 53. H y d r o g e n o l y t i c r e m o v a l o f the b e n z y l p r o t e c t i n g g r o u p g a v e 3, w h i c h r e a c t e d w i t h methylenetriphenylphosphorane t o give alcohol The d e r i v e d t o s y l a t e (56) w a s s o l v o l y z e d i n b u f f e r e d acetic a c i d t o o b t a i n (5)-a-bulnesene (2). F o r t h e s y n t h e s i s o f b u l n e s o l , m e t h y l k e t o n e (53) was f i r s t t r e a t e d with methyllithium t o obtain a t e r t i a r y alcohol
(1) 180
183
182
z.
*The t h i r d p o s s i b l e a p p l i c a t i o n o f t h i s a p p r o a c h , p r o c e e d i n g t h r o u g h i n t e r m e d i a t e s s u c h as 40, has b e e n d e m o n s t r a t e d b y H e n d r i c k s o n i n t h e r e a r r a n g e m e n t o f compound 4 3 , l e a d i n g t o compounds i n t h e p s e u d o q u a i a n o l i d e s e r i e s . 227-
+Although Minato and Nagasaki r e p o r t t h a t k e t o a l c o h o l ( s t r u c t u r e 180 i n S e c . 4 ) c a n b e b e n z y l a t e d d i r e c t l y , 1 4 ' H e a t h c o c k a n d R a t c l i f f e were u n a b l e t o r e p e a t t h e r e a c t i o n (see p . 3 1 3 ) .
Scheme 2.
Heathcock-Ratcliffe Synthesis of (+)-a-Bulnesene
180 (sec. OAc
4)
45 OH
405
406
Total Synthesis of Sesquiterpenes
TsO
OH
KOAc ___c
HOAc,
(z),
a
which was hydrogenolyzed t o d i o l 2. The c o r r e s p o n d i n g mono-tosylate (2) underwent s o l v o l y s i s t o y i e l d c r y s t a l l i n e (r.)- b u l n e s o l , a l o n g w i t h s e v e r a l minor b y - p r o d u c t s . Y o s h i k o s h i ' s s y n t h e s i s o f b u l n e s o l , which i s s i m i l a r t o t h e H e a t h c o c k - R a t c l i f f e s y n t h e s i s , b u t p r o c e e d s t h r o u g h cisd e c a l i n i n t e r m e d i a t e s , i s o u t l i n e d i n Scheme 4 . 2 2 2 Enone a c e t a t e S w a s c o n v e r t e d i n t o e n o l e t h e r (60)by t h e s t a n d a r d method. T h i s s u b s t a n c e was a l k y l a t e d w i t h V i l s m e i e r ' s rea g e n t t o g i v e immonium s a l t 61 which w a s r e d u c e d t o amine %. The c o r r e s p o n d i n g m e t h i o d i d e (63) w a s hydrogenolyzed by r e f l u x i n g i t i n e t h a n o l w i t h f r e s h l y p r e p a r e d Raney n i c k e l .
(1)
Other B i c a r b o c y c l i c Sesquiterpenes Scheme 3 .
407
Heathcock-Ratcliffe S y n t h e s i s of (+I-Bulnesol
53 -
57 -
KOAc ___c
HOAc
OH
A
Hydrolysis of t h e r e s u l t i n g e n o l e t h e r (64) gave compound 65, i n which t h e s t e r e o c h e m i s t r y a t C-8 i s t h e more s t a b l e one ( e q u a t o r i a l m e t h y l ) . Although hydroxy enone 65 gave a mixture of cis and trans decalones on hydrogenation, t h e corresponding a c e t a t e (66)r e a c t e d with hydrogen i n t h e presence o f p a l l a dium on s t r o n t i u m carbonate t o g i v e almost s o l e l y t h e cis decalohe 67. The d e r i v e d t e t r a h y d r o p y r a n y l e t h e r 69 was reduced w i t h l i t h i u m aluminum hydride t o g i v e e q u a t o r i a l a l c o h o l 70, whose t o s y l a t e (2) r e a c t e d w i t h cyanide, a f f o r d i n g n i t r i l e Basic h y d r o l y s i s , h y d r o l y s i s of t h e p r o t e c t i n g group, and e s t e r i f i c a t i o n then y i e l d e d hydroxy e s t e r 73. The correspondi n g t o s y l a t e (74) solvolyzed with rearrangement t o g i v e e s t e r 32, which had p r e v i o u s l y been ccnverted by Marshall i n t o ( _ f )-bulnesol (1)
12.
-
.
Scheme 4.
Yoshikoshi's S y n t h e s i s of ( + ) - B u l n e s o l
60 -
45 -
OH
OAc
61 -
62 -
____c Ra, N i
+oEt
/
/
\ mef 63 -
OAc
65 -
EtOH, A
&$, ' /
IOA c
-
OH
H30+
___c
OEt
64 -
66 -
OH-
H+
H20
67 -
408
68 -
-
Other B i c a r b o c y c l i c Sesquiterpenes OTHP
OTHP
70 -
69 -
NaCN,
1. KOH,
DMSO , w ,3'
OH
409
(CH20H) 2
t-BuOH
2. H ~ O + CN 3 . CH2N2
OTs
71 -
72 -
-
-
p-TsC1
73 -
KOAc
HOAc, A
h,
'0,
C02CH3
74 -
QQ 32 -
&H
C02CH3
1 -
A m o d i f i c a t i o n of t h i s b a s i c scheme h a s r e c e n t l y allowed t h e s y n t h e s i s of t h e b i c y c l i c hydroazulenic e t h e r kessane ( 2 ) . This s y n t h e s i s , a l s o from Yoshikoshi's l a b o r a t o r y , i s outl i n e d i n Scheme 5 . 2 2 7 The c i s - f u s e d decalone 67was t r e a t e d w i t h methoxymethylenetriphenylphosphorane t o g i v e e n o l e t h e r 75. Acid c a t a l y z e d h y d r o l y s i s gave a mixture of aldehydes (76), which was o x i d i z e d by Jones r e a g e n t t o a 2:3 mixture of epimeric a c i d s 77 and 2. The major isomer (78) was e s t e r i f i e d and t h e r e s u l t i n g e s t e r t r e a t e d w i t h m e t h y l l i t h i m t o o b t a i n d i o l 79. The corresponding monomesylate (E)was
-
410
Total Synthesis of Sesquiterpenes Scheme 5.
Y o s h i k o s h i ' s S y n t h e s i s of
-
(?)-Kessane
OAc
$3P=CH-OMe
__c
CHOMe
75 -
61 OA c
OAc t
CHO
76 -
77 OH
OAc
79 -
70 -
s o l v o l y z e d i n b u f f e r e d a c e t i c a c i d , a f f o r d i n g a t e r n a r y mixt u r e from which ( ? ) - k e s s a n e (2) was i s o l a t e d i n 30% y i e l d . P i e r s h a s r e p o r t e d a r e l a y s y n t h e s i s o f a - b u l n e s e n e , beg i n n i n g w i t h t h e s a n t o n i n d e r i v a t i v e 42 ( S e c . 4 ) (see p. 287).223 I r r a d i a t i o n o f d i e n o n e ( S e c . 4 ) i n aqueous acetic a c i d y i e l d e d t h e p h o t o - p r o d u c t 81, which was a c e t y l a t e d t o g . C a t a l y t i c h y d r o g e n a t i o n of 82 gave s a t u r a t e d k e t o n e 83. A f t e r r e d u c t i o n o f t h e k e t o n i c c a r b o n y l w i t h sodium b o r o h y d r i d e , t h e r e s u l t i n g m i x t u r e of e p i m e r i c a l c o h o l s (84) w a s t r e a t e d w i t h
42
Other B i c a r b o c y c l i c Sesquiterpenes
411
p - t o l u e n e s u l f o n y l c h l o r i d e i n p y r i d i n e t o e f f e c t dehydration. Compound 8s was o b t a i n e d i n 55% y i e l d . Although gave a mixture o f isomers when hydrogenated over platinum oxide, t h e analogous r e d u c t i o n c a t a l y z e d by t h e homogeneous c a t a l y s t t r i s (triphenylphosphine) rhodium( I ) c h l o r i d e was completely s e l e c t i v e , y i e l d i n g isomer Hydride r e d u c t i o n of 86 gave a d i o l (87) which was t r e a t e d with methyl chlorocarbonate t o form t h e carbonate e s t e r a t t h e less-hindered primary p o s i t i o n . Dehydration of a t 400' gave a t h e t e r t i a r y a l c o h o l gave 88. P y r o l y s i s of
s.
Scheme 6.
82 -
P i e r s ' S y n t h e s i s of a-Bulnesene
83 -
(Relay)
412
T o t a l S y n t h e s i s of S e s q u i t e r p e n e s OAc
do2~e
m i x t u r e of o l e f i n s , from which a-bulnesene preparative glpc. (See Scheme 6 . )
(2) was
i s o l a t e d by
Guaianolides; Arborescin, Geigerin, Desacetoxymatricarin, and A c h i l l i n
B.
The q u a i a n o l i d e s a r b o r e s c i n (4), 2 2 8 g e i e r i n (2),229 d e s a c e t h a v e a l l been syno x y m a t r i c a r i n (6),230 and a c h i l l i n t h e s i z e d by r o u t e s o r i g i n a t i n g w i t h s a n t o n i n o r a r t e m i s i n . S i n c e c o n s i d e r a b l e chemical m o d i f i c a t i o n i s i n v o l v e d , and since t h e santonin + isophotosantonic lactone conversion has become an i m p o r t a n t method of p r e p a r i n g h y d r o a z u l e n e s , t h e s e p a r t i a l s y n t h e s e s w i l l be d i s c u s s e d a t t h i s p o i n t .
(z)2Q1
q
Other Bicarbocyclic Sesquiterpenes
0
6 -
7
413
0
The synthesis of arborescin (4) by Suchy, Herout, and Sorm228 is outlined in Scheme 7. a-Santonin (structure 22, Sec. 4 ) was converted into 0-acetyldihydroisophotosantonic lactone (90)by Barton's procedure .232 Borohydride reduction of 90 yielded a mixture of alcohols shown later by White and co-workers to be a 1 : 2 : 4 : 5 mixture, e imeric at the new hydroxyl and the secondary methyl group. 2'o The derived benzoate mixture (92) was treated with BF3 to eliminate acetic acid. The resulting olefin (93) was epoxidized to yield an ether
(z),
Scheme 7 .
Arborescin--Czechoslovak Synthesis (Relay)
hv HOAc
__c
0
HZ-Pd/C
o&
I
,111
0
23 (Sec. 4 )
NaBH4
___c
HO
+COCl
___c
414
T o t a l S y n t h e s i s of S e s q u i t e r p e n e s
2100
(94) which was pyrolyzed a t 210". From t h e p y r o l y s a t e , a r b o r e s c i n (4) was i s o l a t e d by chromatography. For t h e s y n t h e s i s o f g e i g e r i n ( S ) , Barton began w i t h artemisin (structure S e c . 4). G e i g e r i n m e s y l a t e (95) was hydrolyzed by aqueous b a s e t o o b t a i n t h e i n v e r t e d a l c o h o l , which was a c e t y l a t e d t o y - i s o g e i g e r i n a c e t a t e (96). (See Scheme 8 . ) Photochemical rearrangement of 96 y i e l d e d t h e hydroazulene 97. which was d e h y d r a t e d w i t h t h i o n y l c h l o r i d e t o the c o r r e s p o n d i n g o l e f i n . C a t a l y t i c h y d r o g e n a t i o n of t h i s o c c u r r e d s t e r e o s p e c i f i c a l l y t o a f f o r d 98. Reductive c l e a v a g e of t h e l a c t o n e r i n g was accomplished by chromous c h l o r i d e i n 1N h y d r o c h l o r i c a c i d . A f t e r d i g e s t i o n w i t h aqueous s u l f u r i c a c i d , 1 1 - e p i d e o x y g e i g e r i n (99) w a s o b t a i n e d . Base c a t a l y z e d e p i m e r i z a t i o n a t C-11 y i e l d e d d e o x y g e i g e r i n (100)i d e n t i c a l with t h e n a t u r a l l y d e r i v e d m a t e r i a l . Lead t e t r a a c e t a t e a c e t o x y l a t i o n gave mainly t h e 2-acetoxy d e r i v a t i v e 101 (72% y i e l d ) . I s o t o p i c d i l u t i o n experiments showed t h a t g e i g e r i n a c e t a t e (2) was produced i n 0.1-0.3% y i e l d . w h i t e ' s s y n t h e s i s of d e s a c e t o x y m a t r i c a r i n (6)2 3 0 and a c h i l l i n (1)231 i s o u t l i n e d i n Scheme 9. The m i x t u r e of d i a s t e r e o m e r i c a l c o h o l s 91 (see Scheme 7 ) was t r e a t e d w i t h methanesulfonyl c h l o r i d e i n p y r i d i n e a t room t e m p e r a t u r e for 24 h r t o o b t a i n o l e f i n 102 i n 4 5 % y i e l d . A l l y l i c o x i d a t i o n of t h i s m a t e r i a l ( t - b u t y l chromate i n a c e t i c a c i d c o n t a i n i n g
z,
&$ o - * o
Scheme 8.
B a r t o n ' s S y n t h e s i s of G e i g e r i n ( R e l a y )
1. KOH-EtOH
99
100
I
=
0
Pb (OAC ) 4 HOAC Ac20
415
416
T o t a l S y n t h e s i s of S e s q u i t e r p e n e s
AcO
101 -
5 -
sodium a c e t a t e ) gave d e s a c e t o x y m a t r i c a r i n (5) i n 15-20% y i e l d . Epimerization a t C-11 o c c u r r e d , along with a c e t a t e h y d r o l y s i s when l a c t o n e 102 was t r e a t e d with potassium t - b u t o x i d e . The r e s u l t i n g product was an equimolar mixture of isomers and
103
White's S y n t h e s i s of Desacetoxymatricarin and A c h i l l i n (Relay)
Scheme 9.
MsCl
HO
__c
-
91 -
25'
-
1,111'1
0
102 -
0
0
-7
t-Butyl chromate NaOAc
t - b u t y l chromate
n
>
,
Other B i c a r b o c y c l i c Sesquiterpenes 104. -
A l l y l i c oxidation o f
104 f u r n i s h e d
417
a c h i l l i n i n 5% y i e l d .
C. T r i c y c l i c Hydroazulenes Containing a Cyclopropane Ring; Aromadendrene, Cyclocolorenone
(105)
The t r i c y c l i c hydroazulenes aromadendrene and cyclocolorenone (106)p r e s e n t s y n t h e t i c c h a l l e n g e s which a r e q u i t e s i m i l a r t o those encountered i n t h e simpler hydroazulenes. The major s y n t h e t i c t a s k h e r e i s t h e s t e r e o s p e c i f i c e l a b o r a t i o n
of t h e hydroazulene nucleus. I n t h i s s e c t i o n , w e d i s c u s s BUchi's e l e g a n t s y n t h e s i s of (-)-aromadendrene, t h e enantiomer of a s w e l l as t h e s y n t h e s i s of an epimer of compound I&, by BUchi and Narang and Dutta. BUchi's aromadendrene s y n t h e s i s , o u t l i n e d i n Scheme 1 0 , .233 The cyclopropane b e g i n s with ( - ) - p e r i l l a l d e h y d e (2) r i n g was formed by a d d i t i o n of H B r , followed by base c a t a lyzed dehydrobromination. The p r o d u c t , u n s a t u r a t e d aldehyde 109, was condensed with methylenetriphenylphosphorane t o obCompound r e a c t e d with a c r o l e i n t o g i v e a t a i n diene The mixture of aldehydes and i n a r a t i o of 85:15. more abundant isomer was converted i n t o hydrocarbon by s t a n d a r d methods. O s m i u m t e t r o x i d e hydroxylation of gave a s i n g l e d i o l which formed a mono-p-toluenesulfonate e s t e r Compound r e a d i l y underwent p i n a c o l rearrangement when
105,
-
110.
111 111
(z1) , 15 Scheme 1 0 .
110 112
113
113
(115).
BUchi's S y n t h e s i s of (-)-Aromadendrene
418
T o t a l S y n t h e s i s of S e s q u i t e r p e n e s
109 -
110
p+ ZHO
111 -
112 -
1. L i A 1 H 4 2. MsCl 3. LiAlH4
p-
@p 113 -
A120 3
___t
CHCl3
115 -
$3P=CH2
116 -
117 -
t r e a t e d w i t h a c t i v e a l u m i n a i n c h l o r o f o r m . The p r o d u c t , apoaromadendrene (*), w a s c o n v e r t e d i n t o (-)-aromadendrene by a W i t t i g r e a c t i o n . is outlined BUchi's s y n t h e s i s of e p i c y c l o c o l o r e n o n e
(117)
(124)
Other B i c a r b o c y c l i c Sesquiterpenes
419
=.
i n Scheme l l . 2 3 40 - a c e t y l photosantonic l a c t o n e (2) was r e duced with chromous c h l o r i d e i n a c e t i c a c i d t o dienone P a r t i a l hydrogenation gave mainly a dihydro isomer 119 whose methyl e s t e r was reduced w i t h l i t h i u m aluminum hydride t o a d i o l . Reoxidation with dichlorodicyanobenzoquinone gave hyThe d e r i v e d p-bromobenzenesulfonate was droxy enone t r e a t e d with dimethylamine t o o b t a i n an amino ketone (122). Cope e l i m i n a t i o n o f t h e corresponding N-oxide gave dienone
121.
Scheme 11.
BUchi's S y n t h e s i s of Epicyclocolorenone (Relay)
"q,> C02H
'0
118 -
89 -
'%,,,%,\,,
2 . CL12N2LiA1H4
119
C02H
-
,,,,
120
-
OH
DCDQ
42 0
T o t a l S y n t h e s i s of S e s q u i t e r p e n e s
1. H202
o~
___c 1. H B r
____c
0
2.
a
2 . KOH MeOH
$,,I\''
NMe
122 -
123.
123 -
A d d i t i o n of H B r , f o l l o w e d by b a s e c a t a l y z e d dehydrot h e s t a b l e epimer of n a t u r a l c y c l o b r o m i n a t i o n gave colorenone. A sterorandom s y n t h e s i s o f t h e g r o s s c y c l o c o l o r e n o n e s k e l e t o n , by Narang and D u t t a , i s o u t l i n e d i n Scheme 12.235 The s y n t h e s i s b e g i n s w i t h ( ' ) - a - t e r p i n e o l , which w a s o x i d a t i v e l y degraded t o homoterpenyl methyl k e t o n e A f t e r c o n d e n s a t i o n w i t h e t h y l c y a n o a c e t a t e and r e d u c t i o n of t h e d o u b l e bond, i n t e r m e d i a t e was o b t a i n e d . As w i l l be s e e n i n t h e s e q u e l , t h e c r i t i c a l r e l a t i v e s t e r e o c h e m i s t r y of t h e secondary methyl group and t h e p o t e n t i a l c y c l o p r o p a n e r i n g i s i n t r o d u c e d , a p p a r e n t l y i n t h e wrong s e n s e , i n t h i s s t a g e . A l k y l a t i o n of w i t h l-bromo-3-pentanone, f o l l o w e d by h y d r o l y s i s and d e c a r o b y x l a t i o n , y i e l d e d The d e r i v e d k e t a l was s u b j e c t e d t o Dieckmann c y c l i z a t i o n t o o b t a i n c y c l o g a v e 133 which heptanone 132. Mild a l k a l i n e h y d r o l y s i s of gave Aldol c y c l i z a t i o n o f was d e k e t a l i z e d t o d i o n e hydroazulene a s a m i x t u r e o f d i a s t e r e o m e r s . When 1 3 5 was t r e a t e d s u c c e s s i v e l y w i t h H B r and m e t h a n o l i c KOH, a c o T e x m i x t u r e was o b t a i n e d . From t h i s m i x t u r e , a s m a l l amount of c r y s t a l l i n e m a t e r i a l was i s o l a t e d which had t h e g r o s s s t r u c t u r e of c y c l o c o l o r e n o n e . S i n c e t h e substance w a s n o t i d e n t i c a l w i t h e i t h e r c y c l o c o l o r e n o n e o r e p i c y c l o c o l o r e n o n e , the cyclopropane r i n g and t h e s e c o n d a r y methyl group must be c i s . The c o n f i g u r a t i o n a t t h e a n g l e i s u n s p e c i f i e d .
124,
(125)
128
128
135
134.
130. 132
(126).
134
2
Scheme 1 2 .
Narang-Dutta
-
S y n t h e s i s of Cyclocolorenone Isomer
1. KMnO4
OH
126 -
125 -
$7 -;$YEt
H,‘’‘”’
0
Hz-Pd/C
c
t-BuOK
w-
1. H 3 0 + , A 2. EtOH,
*
H+
129 -
C02Et
130 -
ono
421
T o t a l S y n t h e s i s of S e s q u i t e r p e n e s
-@
422
p-TsOH
Ace t o n e
HO
133 -
KOH ___c
H20
134 -
1. HBr, HOAC
-
2 . KOH, MeOH
HO
' 135 -
D.
136 -
Cyperolone
The b i c y c l i c s e s q u i t e r p e n e c y p e r o l o n e (137) may be c o n s i d e r e d a s a r e a r r a n g e m e n t p r o d u c t of t h e epoxy a l c o h o l 136. A synt h e s i s of based o n t h i s a p p r o a c h , was accomplished by
135
HO
q y -
&
136 -
H 137 -
H i k i n o , S u z u k i , and Takemoto i n 1 9 6 6 . 2 3 6 (+)-a-Cyperone (structure Sec. 4 ) w a s reduced t o t h e e q u a t o r i a l a l c o h o l 1 3 8 , which was e p o x i d i z e d by p e r b e n z o i c a c i d t o epoxy a l c o h o l w a s t r e a t e d w i t h BF3 i n benzene, t h e o n l y k e t o 136. When a l c o h o l produced was p r o b a b l y by t h e f o l l o w i n g r o u t e :
1,
-
136
139,
Other B i c a r b o c y c l i c S e s q u i t e r p e n e s
HO
423
J%y 136 -
Oxidation of 136 gave epoxy ketone 140,which w a s rea r r a n g e d w i t h BF3 i n benzene. Diketone w a s produced i n and 25% y i e l d . Hydride r e d u c t i o n gave a mixture of d i o l s i n 49% y i e l d , 143 ( 3 4 % ) . S e l e c t i v e a c e t y l a t i o n of 143 gave
141
-
Scheme 13.
-1 (Sec.
Hikino-Suzuki-Takemoto
142
144
S y n t h e s i s of Cyperolone
138 -
4)
HO
136
140 -
139 -
J
424
Total Synthesis of Sesquiterpenes
OH
%~=*c$PY
NaOH
/ EtOH
AcO
1 45 -
144
144
g a v e c y p e r o l o n e acealong with d i a c e t a t e . Oxidation of t a t e (=), w h i c h was h y d r o l y z e d by o n e e q u i v a l e n t of NaOH i n ethanol to cyperolone ( S e e Scheme 13.)
(137).
E.
B-Himachalene,
Widdrol
(146)
and w i d d r o l The i n t e r e s t i n g s e s q u i t e r p e n e s 8 - h i m a c h a l e n e b o t h p o s s e s s a c a r b o n s k e l e t o n c o n s i s t i n g of fused sixand seven-membered r i n g s . Because o f t h e d i f f e r e n c e s i n
(147)
146 -
147 -
Other B i c a r b o c y c l i c S e s q u i t e r p e n e s
425
s u b s t i t u t i o n , t h e two compounds p r e s e n t q u i t e d i f f e r e n t synt h e t i c c h a l l e n g e s . D e Mayo ' s approach t o the B-himachalene s k e l e t o n was based on h i s discovery t h a t a c e t y l a c e t o n e undergoes photochemical c y c l o a d d i t i o n with cyclohexene, y i e l d i n g an i n t e r m e d i a t e cyclobutanol which can fragment t o a &-diket0ne:~37
The l o g i c a l e x t e n s i o n , use of a c y c l i c B-diketone, l e d t o t h e formation of b i c y c l i c s u b s t a n c e s . 2 3 D e Mayo's a p p l i c a t i o n of t h i s approach t o t h e s y n t h e s i s of B-himachalene i s o u t l i n e d i n Scheme 1 4 . 2 3 8 The k e t a l of
*
Scheme 14.
Q
ow
D e Mayo's S y n t h e s i s o f
(2)-B-Himachalene OAc
+AcoQ'
Et3N
0
O W 0
148 -
149 -
Lf
0
150 -
MeMgI
___c
bMs 151 -
152 -
426
Total Synthesis of Sesquiterpenes t-BuOK t-BuOH
1. CH212
____c
___c
Zn (Cu) 2 . H30’
Me I
154 -
153
Hg-Pt-Rh
___c
HOAC NaOAc
155 -
\,,o”‘
0
156 -
!
158
0
+
\
157 /
Na, i-PrOH, toluene
159 -
*
\
1
146 -
160 ,
P°C13-C5H5N
cyclohexenone (148) was photolyzed in the presence of the enol acetate of 2-methyl-1,3-cyclopentanedione (149).The photoadduct 150 was obtained in 35% yield. Although the full stereochemistry of this adduct is not known, the five-four
Other B i c a r b o c y c l i c Sesquiterpenes
427
r i n g f u s i o n i s probably c i s . Models i n d i c a t e d t h a t reducing a g e n t s should a t t a c k t h e carbonyl group from t h e s i d e cis t o t h e a n g u l a r methyl group. This r e l a t i v e s t e r e o c h e m i s t r y , a l though l o s t i n t h e u l t i m a t e p r o d u c t , i s c r i t i c a l , s i n c e only such an arrangement can l e a d t o concerted fragmentation. The a l t e r n a t i v e d i s p o s i t i o n (methyl and l e a v i n g group c i s ) would , i n t h e o r y , y i e l d a trans-cycloheptene. The high a c t i v a t i o n energy a s s o c i a t e d w i t h such a process would probably p r e c l u d e fragmentation. I n t h e e v e n t , borohydride r e d u c t i o n of 150 gave a s i n g l e a l c o h o l , which r e a c t e d w i t h methanesulfonyl c h l o r i d e i n t r i ethylamine t o g i v e mesylate 151. When t r e a t e d with d i l u t e a l k a l i , 151 underwent h y d r o l y s i s and fragmentation t o g i v e 152. Under t h e s e c o n d i t i o n s , t h e more stable r i n g f u s i o n i s expected t o r e s u l t . Subsequent r e s u l t s revealed t h a t t h e expected t r a n s f u s i o n was p r e s e n t . Upon t r e a t m e n t of with methylmagnesium i o d i d e , an a l c o h o l (153)was produced which r e a c t e d i n a Simmons-Smith r e a c t i o n t o y i e l d t h e t r i c y c l i c substance a f t e r deketalization. Since B-himachalene has o n l y one asymmetric c e n t e r , t h e s t e r e o c h e m i s t r y a t t h e f i v e c e n t e r s i n 154 i s important o n l y i n s o f a r a s they i n f l u e n c e the course of f u r t h e r transformat i o n s . Since t h e s y n t h e t i c p l a n c a l l e d f o r i n t r o d u c t i o n of t h e t e t r a s u b s t i t u t e d double bond of B-himachalene by some type of dehydration o f t h e t e r t i a r y a l c o h o l , a t r a n s arrangement o f t h e hydroxyl group and t h e a d j a c e n t a n g u l a r hydrogen seemed i d e a l . The s t e r e o c h e m i s t r y shown f o r a l c o h o l 153 was assigned on t h e b a s i s of molecular models, assuming a t t a c k by Grignard r e a g e n t t o t h e less hindered f a c e of t h e carbonyl group i n 152. I n l i g h t of t h e dehydration r e s u l t s ( v i d e i n f r a ) , t h i s assignment might be reconsidered. Methylation of 154 gave 155 a s a mixture of d i a s t e r e o m e r s . Hydrogenolysis o v e r a platinum-rhodium c a t a l y s t a f f o r d e d a When t h i s mixture was mixture of k e t o a l c o h o l s and reduced by sodium and i s o p r o p y l a l c o h o l i n t o l u e n e , d i o l s 158-160 were o b t a i n e d i n y i e l d s o f 4 0 , 1 8 , and 26%, respect i v e l y . Upon dehydration with phosphorous oxychloride i n p y r i d i n e , isomers 159 and 160 gave a complex mixture of hydroThe major carbons, c o n t a i n i n g 8 % o f (+)-8-himachalene (@). p r o d u c t s i n each case were isomers 161 and 162, trans-ahimachalene and trans-y-himachalene.
-
152
=,
-
--
156
157.
420
T o t a l S y n t h e s i s of S e s q u i t e r p e n e s
rnO*(pO -
W i d d r o l ( 1 4 7 ) was s y n t h e s i z e d by E n z e l l as o u t l i n e d i n Scheme 1 5 . 2 3 9 Y i m e t h y l o c t a l o n e s t r u c t u r e 605, sec. 4 (see Scheme 6 9 , S e c . 4 ) w a s r i n g ex p an d ed w i t h d i a z o m e t h a n e a nd Scheme 1 5 .
E n z e l l ' s S y n t h e s i s of ( 2 ) - W i d d r o l
CH3Li
aluminum c h l o r i d e t o g i v e a complex m i x t u r e of k e t o n e s , from which t h e d e s i r e d p r o d u c t 163 was i s o l a t e d i n 15% y i e l d . T h i s material reacted with methyllithium to give (5)-widdrol i n 25% y i e l d . F.
Sesquicarene, Sirenin
S e s q u i c a r e n e (164) , t h e s e s q u i t e r p e n e a n a l o g of A 2-c a re ne a n d s i r e n i n (E), an i n t e r e s t i n g p l a n t hormone, h a v e e l i c i t e d w i d e - s p r e a d a t t e n t i o n . F o u r s y n t h e s e s of t h e f o r m e r a nd f i v e s y n t h e s e s of t h e l a t t e r w i l l be d i s c u s s e d i n t h i s s e c t i o n .
I
OH
Other B i c a r b o c y c l i c Sesquiterpenes
429
The bicyclo[4.1.0]heptane s k e l e t o n of sesquicarene and s i r e n i n s t r o n g l y i n v i t e s a s y n t h e s i s based on i n t r a m o l e c u l a r carbene i n s e r t i o n (see Sec. 4 4 , cubebene, thujopsene, a r i s t o lone) :219
A l l n i n e s y n t h e s e s t h u s f a r recorded t a k e t h i s b a s i c approach. Because of t h e known s t e r e o s p e c i f i c i t y of t h i s p r o c e s s , 2 4 0 t h e geometry of t h e t r i s u b s t i t u t e d double bond w i l l be mirrored i n t h e t h r e e asymmetric c e n t e r s of t h e c y c l i z a t i o n product. A t r a n s d i s p o s i t i o n w i l l a f f o r d " n a t u r a l " s t e r e o c h e m i s t r y , while a cis arrangement would l e a d t o i s o s e s q u i c a r e n e or i s o s i r e n i n . Corey's s i x t e e n - s t a g e r o u t e t o s e s q u i c a r e n e from geranyl bromide ( s t r u c t u r e 16, Sec. 2 ) i s o u t l i n e d i n Scheme 16.241 A l k y l a t i o n of t h e l i t h i u m s a l t of p r o p a r g y l tetrahydropyranyl
Scheme 16.
B~
Corey's S y n t h e s i s of (f)-Sesquicarene
1. Li-CZC-CH20T, HP
fJ-&
\'-,
2 . MeOH
CH?.OH
p-TsOH
16 (Sec. -
167 -
2)
166 -
168 -
H2-Ni
-
cusoq ____c
NaH
c
EtOC02Et
171 -
172 -
173 -
174 LiAlH4 AlClq
t-BuOK ___c
C02Et
LiA1H4 THF, 25'
177 4 30
178 -
Other B i c a r b o c y c l i c Sesquiterpenes
431
e t h e r w i t h s t r u c t u r e 1 6 , Sec. 2 , gave, a f t e r h y d r o l y s i s , t h e Reduction of t h e t r i p l e bond, f o l propargylic alcohol lowed by a two-stage o x i d a t i o n , gave a c i d 168. The correspondi n g diazoketone, prepared i n t h e s t a n d a r d manner, was decomposed by h e a t i n g i n cyclohexane w i t h c u p r i c s u l f a t e . B i c y c l i c ketone = w a s o b t a i n e d , as t h e only isomer, i n 60% y i e l d from a c i d From t h i s p o i n t , one must i n t r o d u c e t h e p o t e n t i a l v i n y l methyl group a d j a c e n t t o t h e carbonyl group and change t h e carbonyl group i n t o a double bond. The r o u t e chosen by Corey, although l e n g t h y , was designed so a s t o be a p p l i c a b l e i n a s y n t h e s i s of s i r e n i n ( v i d e i n f r a ) . Carboxylation occurred when 172 was t r e a t e d with sodium hydride i n d i e t h y l carbonate. The r e s u l t i n g 8-keto e s t e r (173)was reduced t o a mixture of which gave t h e corresponding benzoates 8-hydroxy esters Base c a t a l y z e d e l i m i n a t i o n a f f o r d e d u n s a t u r a t e d e s t e r 176, which was reduced t o a l l y l i c a l c o h o l Because of t h e i t s hydrogenolysis was accomplished by an s e n s i t i v i t y of i n t e r e s t i n g new method. Successive t r e a t m e n t with s u l f u r t r i oxide-pyridine complex, followed by l i t h i u m aluminum h y d r i d e , gave (+I-sesquicarene (164). The Mori-Matsui (Scheme 17)2 4 2 and Coates (Scheme 18)2 4 2 syntheses of sesquicarene a r e s i m i l a r i n t h e i r general o u t l i n e .
166.
=,
169.
(z),
(175). -
177,
177.
rBr Scheme 17.
Mori-Matsui S y n t h e s i s o f (+)-Sesquicarene
-
21. . CH3-CH H 3 0 + , a(CO2Me) 2 Base
24 (Sec. -
2)
@
C02H
180 -
1. NaH 2.
(COC1)2
____c
I
181: 182: -
A 5 trans
A s cis
183: 184: -
I
A6 t r a n s A6 c i s
p-TsNHNH2
185 -
186 -
n-BuLi ___c
187
Scheme 18.
6 -
432
(Sec. 2 )
164 Coat s ' S y n t h e s i s of
189 -
188 (f)-S squicarene
Other B i c a r b o c y c l i c Sesquiterpenes
190 -
433
180 -
1. Cu, THF, A 2 . OHcHN2
-
18 3 -
184 -
1. N a H
t
___c
2. A
186 -
164 -
191 -
183,which i s a r r i v e d a t i n d i f f e r e n t r o u t e s . The Mori-Matsui r o u t e i s n o n s e l e c t i v e ; t r a n s : c i s r a t i o s of 2 . 5 : l were observed a t t h e t r i s u b s t i t u t e d double bond. Because of t h i s mixture, Mori and Matsui obt a i n e d n o t o n l y sesquicarone (E), b u t i t s C-7 isomer in a r a t i o of 2 . 4 : l . Coates, working w i t h a pure isomer of d i a z o . & , obtained only 184 ( a s a mixture of methyl epimers) ketone I I n both s y n t h e s e s , t h e double bond was introduced by BamfordStevens r e a c t i o n on p - t o l u e n e s u l f o n y l hydrozone 186. Mori and Matsui decomposed 3 with n - b u t y l l i t h i u m and obtained 164 and 188 i n approximately 20% y i e l d . Coates pyrolyzed t h e sodium s a l t of 186 and o b t a i n e d (2)-sesquicarene (164)and t h e fragmentation product 191 i n 15% and 53% y i e l d s , r e s p e c t i v e l y . S e v e r a l groups have explored d i r e c t r o u t e s t o (5)s e s q u i c a r e n e which a r e based on i n t r a m o l e c u l a r i n s e r t i o n of B o t h proceed through t h e d i a z o ketone
-
T o t a l S y n t h e s i s of S e s q u i t e r p e n e s
434
carbene
192.
164 -
192 -
These r o u t e s I developed by C o a t e s ,2 4 Nakatani ,2 4 4 and C ~ r e y ~ ~ ~ a r e summarized i n Scheme 1 9 . Both C o a t e s and N a k a t a n i p r e p a r e d t h e p - t o l u e n e s u l f o n y l hydrazone o f commercial f a r n e s a l Scheme 1 9 .
N2H4,
Coates-Corey-Nakatani Direct S y n t h e s i s of ( + ) - S e s q u i c a r e n e
E t 3 N , EtOH
MnO2 CH2C12
195 -
h2
196 trans, trans) .
C U I , THF
( m i x t u r e of c i s t r a n s and C o a t e s decomposed t h e t o s y l n y d r a z o n e w i t h copper i n t h e p r e s e n c e of sodium h y d r i d e . ( + ) - S e s q u i c a r e n e was o b t a i n e d i n 5 % y i e l d . Nakatani c a r r i e d o u t t h e c y c l i z a t i o n by p h o t o l y s i s o r p y r o l y s i s o f t h e sodium ( ? ) - S e s q u i c a r e n e and i t s C-7 e p i m e r were o b t a i n e d s a l t of i n 5-15% y i e l d .
194.
Other B i c a r b o c y c l i c Sesquiterpenes
435
Corey f r a c t i o n a t e d commercial f a r n e s o l t o o b t a i n o n l y t h e c i s , t r a n s isomer. Oxidation gave c i s , t r a n s f a r n e s a l (E), which formed t h e hydrazone (195)with hydrazine and t r i e t h y l amine i n e t h a n o l . Oxidation of with excess a c t i v a t e d manganese d i o x i d e gave t h e d i a z o compound 196. Cuprous iodide-catalyzed decomposition of 196 gave (5)-sesquicarene I n a l a t e r study, i n 25% y i e l d , based on c i s , t r a n s - f a r n e s o l . Corey r e p o r t e d t h a t mercuric i o d i d e c a t a l y z e s t h e conversion of both 196 and i t s t r a n s , t r a n s isomer t o ~ e s q u i c a r e n e . ~ ~ ' Using t h i s m o d i f i c a t i o n , t h e commercially a v a i l a b l e mixture of t r a n s , t r a n s - and c i s , t r a n s - f a r n e s o l may be used. The y i e l d r e p o r t e d f o r c y c l i z a t i o n of t h e mixture o f diazoketones t o ( f ) - s e s q u i c a r e n e i s 60%.250 A s w i t h s e s q u i c a r e n e , a l l o f t h e s i r e n i n syntheses a r e based on i n t r a m o l e c u l a r carbene i n s e r t i o n . Rapoport ' s synt h e s i s , which was designed t o y i e l d both ( ? ) - s i r e n i n and ( ? I i s o s i r e n i n f o r b i o l o g i c a l t e s t i n g , i s o u t l i n e d i n Scheme 20.246 Methyl heptenone ( s t r u c t u r e 14, Sec. 2 ) was condensed w i t h t h e y l i d d e r i v e d from phosphonium s a l t s t o y i e l d a mixture o f a c i d s 198 and 169 i n a r a t i o of 3:2. The minor isomer, shown t o p o s s e s s a t r a n s double bond, w a s converted by t h e normal method (see Scheme 1 6 ) i n t o b i c y c l i c ketone The major a c i d (198) w i t h a cis double bond, y i e l d e d b i c y c l i c ketone 200. Rapoport's method f o r changing t h e carbonyl group i n t o t h e r e q u i r e d v i n y l i c hydroxymethyl f u n c t i o n , w a s i d e n t i c a l t o t h a t used by Corey f o r s e s q u i c a r e n e (Scheme 161, except t h a t p i v a l o a t e , r a t h e r t h a n benzoate, was e l i m i n a t e d . Selenium d i o x i d e o x i d a t i o n o f 204 gave a mixture of aldehyde and a l l y l i c a l c o h o l . Oxidation of t h e e n t i r e product with MnO2 y i e l d e d only aldehydo e s t e r 205. When compound was reduced with L i A l H 4 - A l C 1 3 a t O o , ( + ) - s i r e n i n was o b t a i n e d . A s i m i l a r sequence o f r e a c t i o n s converted b i c y c l i c ketone 200 i n t o ( + ) - i s o s i r e n i n . (See Scheme 20.)
195
172.
205
Scheme 20.
+
(?)-Sirenin--Rapoport's
+
$3P-CH2 (CH2) 3C02H Br'
0
14 (Sec. -
2)
197 -
NaH THF-DMSO
Synthesis
c
I
169 -
198 -
1. NaOMe 2. (COCl)2
pcm2 1. NaOMe 2 . (COC1)2 3 . CH2N2
3 . CH2N2
f
i
C
H
I
2
171 -
199 -
CuSO4, A Cyclohexane
I
200 -
N
CUSOL,, A Cyclohexane
172 -
N a H , MeOC02Me,
r
J
NaBH4 i-PrOH, -22'
t-BUCOC1 C5H5N
____c
C02Me
4 36
___c
C02Me
(p
Other B i c a r b o c y c l i c Sesquiterpenes
@
t-BuOK Toluene
___c
C02Me
437
1. Se02, E t O H 2. Mn02 Hexane -
1 :
I
/
C02Me
OCOBu-t 204 -
203 LiAlH4 AlCl7
205 -
OH
165 -
Carey's f i r s t s y n t h e s i s of ( f ) - s i r e n i n (Scheme 2 1 ) 2 4 7 d i f f e r s from Rapoport's i n t h a t t h e s i d e c h a i n i s f u n c t i o n a l i z e d before t h e c y c l i z a t i o n s t e p . A high p r i c e i s p a i d f o r t h i s n o v e l t y , which i s a p p a r e n t l y unnecessary, Corey's synthesis, while s t e r e o s e l e c t i v e (Scheme 2 1 ) o r s t e r e o s p e c i f i c (Scheme 2 2 ) , r e q u i r e s e i t h e r 23 o r 25 s t e p s , with one isomer s e p a r a t i o n r e q u i r e d i n e i t h e r case. A l l y l i c o x i d a t i o n of d i e n i c e s t e r 176 (as i n Rapoport's s y n t h e s i s , Scheme 20; 204 + s y n t h e s i z e d s t e r e o s p e c i f i c a l l y by Corey f o r t h e s y n t h e s i s of s e s q u i c a r e n e (Scheme 1 6 ) , would y i e l d ( + ) - s i r e n i n i n 15 s t e p s . I n o r d e r t o e s t a b l i s h t h e d e s i r e d trans,trans geometry i n d i a z o ketone 217, Corey explored two r o u t e s . The more e f f i c i e n t r o u t e , although n o t s t e r e o s p e c i f i c , i s o u t l i n e d i n
- E),
Scheme 2 1 .
(f)-Sirenin--Carey's F i r s t S y n t h e s i s
Et02C
1
OAc
+
P
O C02Et A
c
OTHP AlCl3
210 -
C02Et
1. MesC1, C5H5N 2. H ~ O +
211 -
-
1. Li-C-C-CH20THP 2. MeOH , p-TsOH
OMe s
CUSOL
2 16 4 38
217 -
NaBH4 E tOH
NaH
____c
____c
Et O C 0 2 Et
C02Et
OMe s
OMe s
218 -
@ H
219 @
___c CgHgN 4COCl
t-BuOK t-BuOH ___c
1 '
C02Et
C02Et
OH
I
H
OCO$
OMe s OMes
220
221 -
LiAlH4
___c
OH
~ 1 ~ 1 3
C02Et
OH
165 -
222 Scheme 22.
207 -
C o r e y ' s A l t e r n a t i v e S y n t h e s i s of Hydroxy E t h e r
A.
H
C1
4 39
T o t a l S y n t h e s i s of Sesquiterpenes
440
225 -
224 -
&Ol'HP
1. n-BuLi
k
2 . CH20
-
+Ol'HP
-
d
1. L i A l H k - A l C 1 3 2 . I2
H
228 -
211 -
229 -
Scheme 2 1 . Geranyl a c e t a t e (206) was ozonized t o g i v e aldehyde 207, w h i c h was condensed w i t h t h e anion of t r i e t h y l p h o s phonopropionate t o give d i e s t e r s 208 and in a ratio 12:88. After s e p a r a t i o n by p r e p a r a t i v e t l c , t h e major d i e s t e r was t r a n s e s t e r i f i e d with e t h a n o l t o y i e l d a hydroxy e s t e r , which was p r o t e c t e d a s i t s t e t r a h y d r o p y r a n y l e t h e r (210). The a,Bu n s a t u r a t e d e s t e r f u n c t i o n was then reduced by L i A l H b - A l C 1 3 t o give the d i f f e r e n t i a t e d d i o l An a l t e r n a t i v e s y n t h e s i s of hydroxy e t h e r 211 i s o u t l i n e d i n Scheme 2 2 . While completely s t e r e o s p e c i f i c , t h e r o u t e i s l e s s e f f i c i e n t i n p r a c t i c e , Reductive i o d i n a t i o n of t h e prop a r g y l l i c a l c o h o l 227 gave a 1 : 2 mixture of p o s i t i o n a l isomers 2 2 0 and 229. Since t h e wrong hydroxyl i s p r o t e c t e d i n compound the f r e e end was e s t e r i f i e d with m e s i t o y l c h l o r i d e and t h e acidl a b i l e t e t r a h y d r o p y r a n y l group removed. The r e s u l t i n g hydroxy e s t e r was converted by P B r 3 i n t o a l l y l i c bromide 213. From
209
211.
-
211
Other Bicarbocyclic Sesquiterpenes
441
this point, the synthesis closely parallels Corey's sesquicarene synthesis (Scheme 16). Grieco, at Columbia University, synthesized sirenin by the method shown in Scheme 23.248 As in Rapoport's synthesis, Scheme 23.
(5)-Sirenin--Grieco's Synthesis
&
A-
eOH p -5
R2BH
-
2 30 -
(Sec. 2)
1. SOC12, CgHgN 2. CH2N2 --
H2Cr20L
6
C02H
2 31 -
CHN2
169 -
Cu Cyclohexane bronze
@
1.
___c 03
2. Me2S
1 :
0
172 -
171 0 Me
-
(EtO)2P-G-CO2Et OHC
232 -
NaH
+
HC02Et
Et02C
C02Et 233 -
2 34 -
442
T o t a l S y n t h e s i s of S e s q u i t e r p e n e s
NaH
i-PrI
- C.o p E t 2 35 -
2 36 -
@ ( /
C02Et
237
LiAlHt,
CHO
OH
1 65 -
f u n c t i o n a l i z a t i o n o f t h e s i d e c h a i n was d e f e r r e d u n t i l a f t e r r i n g closure. Stereochemical i n t e g r i t y a t t h e t r i s u b s t i t u t e d double bond was a s s u r e d by s t a r t i n g w i t h g e r a n y l c h l o r i d e ( s t r u c t u r e 2, Sec. 2 ) . Coupling of t h i s a l l y l i c h a l i d e w i t h allylmagnesium bromide gave t r i e n e 230 i n 90% y i e l d . Hydrob o r a t i o n o c c u r r e d s e l e c t i v e l y a t t h e more exposed d o u b l e bond when d i s i a m y l b o r a n e was u s e d , a f f o r d i n g d i e n o l 231 i n 70% y i e l d . J o n e s o x i d a t i o n o f 231 gave d i e n i c a c i d 169,which w a s t r a n s f o r m e d , v i a d i a z o k e t o n e 171,i n t o b i c y c l i c enone S i d e c h a i n f u n c t i o n a l i z a t i o n was accomplished by conwith t r i e t h y l d e s n a t i o n of t h e d e r i v e d k e t o aldehyde (=) p h o s p h o n o a c e t a t e . Isomers 233 and 234 were o b t a i n e d i n a r a t i o of 8 : 9 2 . The more abundant isomer was f o r m y l a t e d and t h e r e s u l t i n g formyl k e t o n e 0 - a l k y l a t e d w i t h i s o p r o p y l i o d i d e t o g i v e e n o l e t h e r 236. Borohydride r e d u c t i o n , f o l l o w e d by h y d r o l y s i s , y i e l d e d a l d e h y d e 237, which was reduced t o ( ? ) sirenin. Mori and Matsui s y n t h e s i z e d (t)- s i r e n i n and ( ? ) - i s o s i r e n i n by t h e n o n s e l e c t i v e r o u t e o u t l i n e d i n Scheme 24.'"' Homog e r a n y l bromide ( s t r u c t u r e %, Sec. 2 ) w a s condensed w i t h s o d i o d i e t h y l malonate t o g i v e , a f t e r h y d r o l y s i s and decarboxySince halide, l a t i o n , a c i d s 169 and 198 i n a r a t i o of 2 . 5 : l . s t r u c t u r e 2, Sec. 2 , w a s p r e p a r e d by t h e J u l i a o l e f i n synt h e s i s (Scheme 5 , Sec. 2 1 , i t c o n t a i n e d t h e trans and c i s
172.
(234)
443
Other Bicarbocyclic Sesquiterpenes
isomers in approximately this ratio. From this acid mixture, the synthesis follows a line similar in most respects to the Scheme 24.
24 (Sec. 2) -
171: 199:
-
172 -
(f)-Sirenin--Mori-Matsui Synthesis
169: 198: -
% A 5 trans A 5 cis
A6 trans ~6
H O
cis
2 00 -
2 38 -
t
Total Synthesis of Sesquiterpenes
444
0 Me
II I
(Et0)2P-CHC02Et
H5 106
: /
___t
OHC
NaH
C02Et
H
LiAlH4 ___c
C02Et OgEt
OH
165 -
24 3 -
Grieco s y n t h e s i s , except f o r t h e o r d e r o f t h e t r a n s f o r m a t i o n s . A m i x t u r e of ( + ) - s i r e n i n (165)and i t s isomer, ( + ) - i s o s i r e n i n , was o b t a i n e d . The most e x p e d i e n t s y n t h e s i s y e t r e p o r t e d f o r t h e hormone, due t o Corey, is o u t l i n e d i n Scheme 2 5 . 2 5 0 The approach i s p a t t e r n e d a f t e r Corey's " d i r e c t " s y n t h e s i s of s e s q u i c a r e n e from c i s , t r a n s - f a r n e s a l (Scheme 1 9 ) . S i n c e Rapoport had shown t h a t d i e n i c e s t e r 204 may be s t e r e o s p e c i f i c a l l y o x i d i z e d t o an aldehydo e s t e r which y i e l d s s i r e n i n on r e d u c t i o n , t h e synt h e t i c g o a l f o r t h i s approach becomes t h e d i a z o e s t e r 250. This s u b s t a n c e was prepared s t e r e o s p e c i f i c a l l y s t a r t i n g with g e r a n y l bromide ( s t r u c t u r e Sec. 2 ) . Condensation o f
16,
Scheme 25.
16 -
(Sec. 2 )
(+)-Sirenin--Carey's Second S y n t h e s i s
Other B i c a r b o c y c l i c S e s q u i t e r p e n e s
N i (CO) 4
445
CH2N2
-HO* - H HO E t2OA 0H c OH 246 -
245 -
___c
C02Me
THF
2 50 -
249 -
204 -
16,
structure Sec. 2 , w i t h l i t h i o - 1 - t r i m e t h y l s i l lpropyne g a v e , a f t e r t r e a t m e n t w i t h Ag+ and C N', dienyne 244. 2 5 t r The d e r i v e d l i t h i u m s a l t was t r e a t e d w i t h paraformaldehyde t o g i v e prowhich was c a r b o x y l a t e d i n a most i n t e r e s t p a r g y l a l c o h o l *, i n g r e a c t i o n w i t h n i c k e l carbonyl i n HOAc-EtOH-H20 t o y i e l d Methyl e s t e r was i s o l a t e d i n 30% y i e l d hydroxy a c i d based on a l c o h o l 245.
z.
247
Total Synthesis of Sesquiterpenes
446
Oxidation of 247 w i t h a c t i v e Mn02 gave an aldehyde, which Mn02 o x i d a t i o n of 249 gave d i a z o formed a hydrazone ester 250. Cuprous i o d i d e - c a t a l y z e d c y c l i z a t i o n o f 250 gave b i c y c l i c e s t e r 204 i n 50% y i e l d .
(249).
G.
a-
and 6-cis-Bergamotene
The cis-bergamotenes* (251and 252) a r e s e s q u i t e r p e n e analogs of t h e monoterpenes a- and 0-pinene (253 and 254). T h i s a n a l ogy s u g g e s t s a method of s y n t h e s i s , i f one of the methyl groups
251 -
252 -
2 54 -
253 -
i n pinene can be f u n c t i o n a l i z e d , and e l a b o r a t e d i n t o the req u i r e d methylpentenyl s i d e c h a i n . Gibson and Erman accomplished t h i s o b j e c t i v e a s o u t l i n e d i n Schemes 2 6 and 27.255 (+)-Nopinone reacted with methyllithium t o g i v e a l c o h o l 258. Because o f s t e r i c hindrance t o approach, t h e hydroxyl group i n t h i s s u b s t a n c e i s on t h e same s i d e of t h e molecule a s t h e gem-dimethyl grouping. When 258 was t r e a t e d w i t h mercuric oxide and bromide i n r e f l u x i n g p e n t a n e , t r i c y c l i c e t h e r 259 was produced i n 81% y i e l d . a f f o r d e d l a c t o n e 260 i n Oxidation of d i t e r t i a r y e t h e r 72%yield. Hydride r e d u c t i o n , followed by s e l e c t i v e a c e t y l a t i o n , gave hydroxy e s t e r 261. Dehydration of t h i s m a t e r i a l y i e l d e d o l e f i n s 262 and 263, along w i t h e t h e r 259, i n a r a t i o of 15:4:1. Isomer 262 was c o n v e r t e d i n t o t o s y l a t e 264 and
(257)
-
*The p r e f i x e s cis and trans r e f e r t o t h e d i s p o s i t i o n o f t h e more complicated s u b s t i t u e n t on t h e cyclobutane r i n g , r e l a t i v e t o t h e three-carbon b r i d g e . Thus, 251 i s a - c i s - b e r g a m ~ t e n e ~ ~ ~ and 252, n o t y e t found i n n a t u r e , i s 6-cis-bergamotene. The corresponding trans i s o m e r s , and 256,254 a r e b o t h natur a l products.
zZs3
255 -
256 -
Scheme 26.
Gibson-Erman S y n t h e s i s of (+)-a-cis-Bergamotene
258 -
257 -
262 -
26 3 -
259 -
259 -
447
251 Scheme 27.
G i b s o n - E m a n Synthesis of (+)-cis-@-Bergamotene
____c
HgO, Br2
257 -
268 Cog E t
'%,
2. MeOH
2. Pb(OAc)k, NaC1, CgH6 269 -
270 -
273 -
440
1. Na, glyme
-
Other B i c a r b o c y c l i c Sesquiterpenes
449
thence i n t o i o d i d e 265. When i o d i d e 265 was coupled w i t h t h e ethylenediamine complex of l i t h i u m a c e t y l i d e , alkyne 266 was o b t a i n e d i n 50% y i e l d . Hydroboration, with disiamylborane, gave aldehyde This u n s t a b l e aldehyde was condensed d i r e c t l y w i t h isopropylidenetriphenylphosphorane t o o b t a i n ( + ) a-cis-bergamotene i n 5% y i e l d , based on a c e t y l e n e 266. For p r o d u c t i o n o f t h e B isomer 252, a more e f f i c i e n ? method f o r i n t r o d u c t i o n of t h e e x o c y c l i c double bond was developed. Reformatsky r e a c t i o n of 257 gave hydroxy e s t e r 268 i n 57% y i e l d . C y c l i z a t i o n of t h i s m a t e r i a l , again w i t h HgO and B r 2 , gave e t h e r 269. The corresponding a c i d was degraded by a Kochi-Hunsdiecker r e a c t i o n t o c h l o r o e t h e r 270. When t h i s material was t r e a t e d with sodium, fragmentation occurred t o y i e l d u n s a t u r a t e d a l c o h o l 271 i n 48% y i e l d . The s i d e c h a i n was e l a b o r a t e d , a s b e f o r e , t o g i v e (+)-cis-B-bergamotene ( 2 5 2 ) .
267. (251)
-
H.
Chamigrene
Chamigrene (275)and a-chamigrene (276)a r e i n t e r e s t i n g s p i r o s e s q u i t e r p e n e s which p o s s i b l y r e p r e s e n t a l i n k ( a s i o n 277) i n t h e b i o g e n e s i s of thujopsene ( s t r u c t u r e 547, Sec. 4 ) and cuparene (278)2 5 6 Yoshikoshi's s y n t h e s i s of ( + ) - ~ h a m i g r e n e ~ ~ l and ( f ) - a - ~ h a m i g r e n e i~s~ o~u t l i n e d i n Scheme 28.
276 -
275 -
547 (Sec. -
4)
277 -
278 -
Scheme 28.
Yoshikoshi's Synthesis of (?)-Chamigrene and ( + ) -a-Chamigrene
0
H2 -Pd/CaCO 3
279 -
280 -
281 -
G
O 28 3 -
450
282 -
H
p-TsOH
7
OEt
Other B i c a r b o c y c l i c Sesquiterpenes
275 -
-
451
2 89 -
OH I
LiAlH4
291 -
290 -
Diketo e s t e r 279, o b t a i n e d i n 94% y i e l d from m e s i t y l oxide and malonic e s t e r , was converted by known procedures259 Diels-Alder r e a c t i o n o f 284 with 2-ethoxyi n t o enone 1,3-butadiene gave a s i n g l e keto e t h e r (285) i n 20% y i e l d . After hydrolysis, diketone was t r e a t e d w i t h excess methylmagnesium i o d i d e t o g i v e a mixture of epimeric k e t o a l c o h o l s (2871, which was dehydrated t o u n s a t u r a t e d ketone Enone 284 r e a c t e d w i t h i s o p r e n e t o give 288 and i t s isomer 289 i n 20% and 1 2 % y i e l d s , r e s p e c t i v e l y . The c r y s t a l l i n e isomer 288 c o u l d b e o b t a i n e d by seeding t h e mixture of isomers with pure 288. Although t h e h i n d e r e d carbonyl group i n ?88 d i d n o t r e a c t w i t h methyllithium o r methylmagnesium i o d i d e , i t r e a c t e d with rnethylenetriphenylphosphorane i n dimethyl s u l f o x i d e a t 60° f o r 4 8 h r t o g i v e chamigrene (275) i n 70% y i e l d . The epoxide 290, formed from 288 and excess dimethylsulfonium methylide , was reduced by L i A 1 H 4 t o a s i n g l e u n s a t u r a t e d a l c o h o l (291) ( s t e r e o c h e m i s t r y undetermined). Dehydration (BF3 i n e t h e r ) of 291 gave (+I-chamigrene (275) and (+)-cr-chamigrene (276)
z.
-
286
2.
-
-
452
T o t a l S y n t h e s i s of S e s q u i t e r p e n e s
i n y i e l d s of 42 and 35%, r e s p e c t i v e l y . An isomeric hydroc a r b o n formed i n 23% y i e l d i n t h e d e h y d r a t i o n was n o t i d e n t i f i e d , a l t h o u g h i t s s p e c t r a s u g g e s t e d t h a t it i s a r e a r r a n g e m e n t product. A b i o g e n e t i c a l l y s t y l e d s y n t h e s i s of a-charnigrene, due t o K i t a h a r a , i s o u t l i n e d i n Scheme 2 9 . 2 6 0 Dihydro-$-ionone
(292)
Scheme 29.
K i t a h a r a ' s S y n t h e s i s of (2)-a-Chamigrene
2. OH-, H 2 0 3. C H 2 N 2
&& 295 -
293 -
1
LiAlH4
296 -
294 -
LiAlHL
gMe
Other B i c a r b o c y c l i c Sesquiterpenes
453
275 -
was condensed w i t h triethylphosphonoacetate t o give a mixture of e s t e r s , which was hydrolyzed. A f t e r c r y s t a l l i z a t i o n of
trans-monocyclofarnesic a c i d ( a c i d corresponding t o 293) i n 30% y i e l d , t h e remaining a c i d s were e s t e r i f i e d and s e p a r a t e d by chromatography. Esters 293-296 were o b t a i n e d i n r e l a t i v e y i e l d s of 25, 22, 33, and 20%, r e s p e c t i v e l y . Esters and 294 were reduced t o t r a n s - and cis-monocyclofarnesol (297and 298). Treatment of e i t h e r isomer with i o d i n e i n benzene solut i o n gave a mixture of hydrocarbons c o n t a i n i n g 25% ( + ) - a chamigrene (=).
293
I.
Cuparene , $-Cuparenone
, Aplysin , Debromoaplysin
Cuparene (299) and 6-cuparenone (300) a r e t y p i c a l members o f a c l a s s of b i c y c l i c s e s q u i t e r p e n e s produced by t h e o r d e r Cupress a l e s . The compounds p r e s e n t an i n t e r e s t i n g s y n t h e t i c
454
T o t a l S y n t h e s i s of S e s q u i t e r p e n e s
(z),
c h a l l e n g e due t o t h e s t e r i c c o n g e s t i o n a b o u t t h e c y c l o p e n t a n e r i n g . The s y n t h e s i s o f a p l y s i n (301)and debromoaplysin which c o n t a i n t h e same g r o s s carbon s k e l e t o n , w i l l a l s o be discussed i n t h i s section.
301: 302:
-
X = Br X = H
The f i r s t r e p o r t e d s y n t h e s i s of c u p a r e n e was t h a t of Nozoe and T a k e s h i t a (Scheme 30) . 2 6 1 These workers p r e p a r e d Scheme 30.
Nozoe-Takeshita S y n t h e s i s of (k)-Cuparene
l-bromo-1,2,2-trimethylcyclopentane (304) by Hunsdiecker d e g r a d a t i o n of camphonanic a c i d (303). They r e p o r t e d t h a t t h e c o r r e s p o n d i n g l i t h i o d e r i v a t i v e coupled w i t h p-bromotoluene t o g i v e ( + ) - c u p a r e n e (299). S i n c e t h e y i e l d i s n o t s p e c i f i e d , and s i n c e t h e e x p e r i m e n t a l d e t a i l s of t h i s s y n t h e s i s have n o t been forthcoming a f t e r t e n y e a r s , i t i s p r o b a b l y n o t an esp e c i a l l y good p r e p a r a t i o n o f t h e m a t e r i a l . A more p l a u s i b l e s y n t h e s i s of 299 i s o u t l i n e d i n Scheme 31. 2 6 2 3-Methylcyclohex-2-enone and t o l u e n e were condensed i n a F r i e d e l - C r a f t s r e a c t i o n t o g i v e t h e b i c y c l i c k e t o n e 305. The c o r r e s p o n d i n g f u r f u r y l i d i n e d e r i v a t i v e (306) w a s methylwhich w a s o z o n i z e d t o t h e t r i m e t h y l - p ated t o give t o l y l a d i p i c a c i d 308. Dieckmann c y c l i z a t i o n of t h e
=,
Scheme 31.
Raphael's S y n t h e s i s of (+)-Cuparenone and ( 2 ) -Cuparene
Me I
p -
Me02C
H A30'
0
455
T o t a l S y n t h e s i s of S e s q u i t e r p e n e s
456
N2 H4
Na 0 (CHzCH20H)2
0
309a -
299 -
c o r r e s p o n d i n g d i e s t e r gave a 6 - k e t o e s t e r (E), which was h y d r o l y z e d and d e c a r b o x y l a t e d , a f f o r d i n g k e t o n e HuangMinlon r e d u c t i o n of gave ( f ) - c u p a r e n e (299). L a n s b u r y ' s s y n t h e s i s of 6-cuparenone (Scheme 2)u t i l i z e s an i n t e r e s t i n g method f o r c o n s t r u c t i o n of t h e c y c l o p e n t a n o n e
E.
Scheme 32.
L a n s b u r y ' s S y n t h e s i s of ( ? I -6-Cuparenone
311 -
310 -
c1
c1
MeLi
d02Et 31 2 -
HO
4-
313 -
H2S04
Other Bicarbocyclic Sesquiterpenes
457
r i n g . 2 6 3 E t h y l p - t o l y l a c e t a t e (310) was a l k y l a t e d w i t h 2,3d i c h l o r o p r o p e n e and t h e n w i t h methyl i o d i d e t o o b t a i n ester 312 (54% o v e r a l l y i e l d ) . Compound 312 r e a c t e d w i t h methylwhich was t r e a t e d w i t h 90% l i t h i u m t o g i v e an a l c o h o l s u l f u r i c acid. (+)-%-cuparenone (300) was produced i n 34% y i e l d . The c y c l i z a t i o n may b e d e p i c t e d as f o l l o w s :
-
(g),
t
H i r a t a ' s s y n t h e s i s of ( + ) - a p l y s i n (301) and (2)-debromoa p l y s i n (302) i s o u t l i n e d i n Scheme 33. 26L1 4-Bromo-3-methylw a s c o n v e r t e d i n t o t h e 6 - l i t h i o d e r i v a t i v e D? anisole
(314)
Scheme 33.
B
Br
'
v'QMe
QMe
(5)-Aplysin--Hirata's
A
\
OMe
M eI NaH
___f
-
(i
.f
_L
'QMe QMe
315 -
Bre L--c
\
HC03H
OMe
317 -
316 -
318
0
-'
314 -
Synthesis
glyme
MeMgI
___c
\
319
OMe
450
T o t a l S y n t h e s i s of S e s q u i t e r p e n e s
&rB
50% P e nHzS04 tane
_____c
OMe
’
___f
OMe
HCO 3 H
320 -
BBr 3 -L.--c
CH2C12
323 -
322 -
bH
MeMgI
CgHgN
326 -
r e a c t i o n w i t h p h e n y l l i t h i u m a t room t e m p e r a t u r e . A d d i t i o n of c y c l o p e n t a n o n e gave a l c o h o l 316, which d e h y d r a t e d upon d i s t i l l a t i o n . P e r f o r m i c a c i d o x i d a t i o n of gave c y c l o p e n t a n o n e 318, which was m e t h y l a t e d a t t h e b e n z y l i c p o s i t i o n t o o b t a i n T h i s k e t o n e r e a c t e d w i t h methylmagnesium i o d i d e t o g i v e 319. 320. D e h y d r a t i o n , accomplished i n a two-phase medium, gave the cyclopentene which was o x i d i z e d t o c y c l o p e n t a n o n e 322. C h l o r i n a t i o n of 322 a t t h e methine p o s i t i o n was r e a d i l y achieved with s u l f u r y l c h l o r i d e .
317
-
-
321,
Other B i c a r b o c y c l i c S e s q u i t e r p e n e s
459
The a r y l methyl e t h e r was c l e a v e d , w i t h concomitant cyc l i z a t i o n , a f f o r d i n g t h e t r i c y c l i c k e t o e t h e r 324 i n 20% y i e l d . This ketone r e a c t e d w i t h methylmagnesium i o d i d e t o g i v e an a l c o h o l (probably 325) which was dehydrated t o 326. Stepwise hydrogenation gave ( 2 )- a p l y s i n (301) and ( + ) -debromoaplysin
(302).
Carabrone
J.
The s e s q u i t e r p e n e l a c t o n e carabrone (327)may be viewed as a g u a i a n o l i d e which h a s s u f f e r e d s c i s s i o n of t h e five-membered r i n g . W i t h f i v e asymmetric c e n t e r s on t h e simple c a r b o c y c l i c
327 n u c l e u s , carabrone p r e s e n t s an i n t e r e s t i n g problem i n s t e r e o r a t i o n a l s y n t h e s i s . Although t h i s g o a l remains t o b e achieved, Minato h a s r e p o r t e d t h e l e n g t h y s y n t h e s i s o u t l i n e d i n Scheme 34.265
y= Ace\ Scheme 34.
Minato's S y n t h e s i s of (2)-Carabrone __c A
+
C02Et
333 C02Et
OAc
335 -
334 L
336 V
LiAlHL
t
OAc
I
33 7 I
a OH
p-TsC1
NaCN
CgH5N
OTs
____c
34 0 -
34 1 -
H
\."
1. N2CHC02Et,Cu
2. K z C O 3 , MeOH
332 -
C02H
342 -
Et02
1. NaOH
___c
343 -
,,.,..o
H02C
0
344 -
34 5 -
347 -
460
1950
__c
346 -
348 -
1. NaHCO
2
2. (COC1)2 3. n-BUSH 4. Ni
Other Bicarbocyclic Sesquiterpenes
355
461
327 -
Minato's synthetic plan called for construction of the bicyclo[4.1.0]heptane skeleton by adding carbethoxycarbene to a methylcyclohexene (i.e., 328 * 329)
.
462
T o t a l S y n t h e s i s of S e s q u i t e r p e n e s
Et02C
i 329 -
328 -
The s t e r e o c h e m i s t r y i n d i c a t e d was expected t o predominate, s i n c e i t i s known t h a t such r e a c t i o n s l e a d t o t h e l e s s hindered product. Given t h i s b a s i c p l a n , t h e problem devolves i n t o one of c o n s t r u c t i n g t h e proper methylcyclohexene. The i d e a l t a r g e t would seem t o be However, one would t h e n be faced w i t h t h e problem of o r i e n t a t i o n i n t h e carbene addit i o n , s i n c e a t t a c k can o c c w from e i t h e r f a c e of t h e molecule. This problem i s s o l v a b l e , i n t h e o r y , s i n c e b o t h l a c t o n e c e n t e r s can be i n v e r t e d by conversion t o keto-acid 331 ( a t which p o i n t t h e a c e t i c a c i d s i d e - c h a i n would be e p i m e r i z a b l e ) . However, f o r s y n t h e t i c r e a s o n s , t h e t r a n s - l a c t o n e 332 appeared t o be an e a s i e r s y n t h e t i c t a r g e t , and t h i s was adopted a s t h e i n i t i a l goal.
=.*
0
C02H
"O,,,,
/
H
330 -
3 31 -
332 -
Diels-Alder r e a c t i o n o f i s o p r e n e and e t h y l B-acetoxya c r y l a t e (333)gave a mixture of a l l p o s s i b l e a d d u c t s (3343 3 7 ) i n 4 8 % y i e l d . The major p r o d u c t s (334 and 335) were found t o be p r e s e n t i n a r a t i o of approximately 3 : l . The cis isomers 336 and 337 were i n f e r r e d t o be p r e s e n t i n "small amounts" from l a t e r o b s e r v a t i o n s . The s y n t h e s i s from t h i s p o i n t i s complicated by t h e f a c t t h a t t h i s mixture was n o t s e p a r a t e d , b u t was c a r r i e d through a s such. I n o r d e r t o avoid c o n f u s i o n , w e s h a l l i l l u s t r a t e t h e s y n t h e s i s w i t h t h e major isomer only (334). Hydride r e d u c t i o n of t h e mixture a f f o r d e d d i o l 338, which was converted, v i a mono-tosylate 339 i n t o hydroxy n i t r i l e 340. Hydrolysis o f 340 gave a hydroxy a c i d
-
*The methylene group was t o be introduced a t a l a t e r s t a g e by Minato's method, s e e s e c . 4-M.
Other B i c a r b o c y c l i c Sesquiterpenes
463
(3411, which l a c t o n i z e d on h e a t i n g a t 200°, a f f o r d i n g t h e d e s i r e d t r a n s - l a c t o n e 332. When t h i s l a c t o n e was t r e a t e d with e t h y l d i a z o a c e t a t e and copper powder i n diglyme a t l 7 O o , and the r e s u l t i n g crude produ c t hydrolyzed w i t h methanolic potassium hydroxide, a mixture of monocarboxylic a c i d s was o b t a i n e d . A t t h i s p o i n t , t h e crude product was t r e a t e d with HC1 i n e t h e r t o g i v e a l a c t o n e f r a c t i o n and an acid f r a c t i o n i n a r a t i o o f 1 : 9 . The l a c t o n e f r a c t i o n contained cis l a c t o n e s d e r i v e d from t h e minor D i e l s Alder adducts 336 and When t h e a c i d f r a c t i o n was heated a t 195', a mixture of l a c t o n e s was o b t a i n e d i n 53% y i e l d . Chromatographic a n a l y s i s i n d i c a t e d t h a t two compounds were p r e s e n t i n a r a t i o of 85:15. S t r u c t u r e 343 was assigned t o t h e major isomer on t h e b a s i s of s p e c t r a l arguments. Alkaline h y d r o l y s i s of 343, followed by a c i d c a t a l y z e d l a c t o n i z a t i o n gave t h e c r y s t a l l i n e a c i d l a c t o n e 344 i n 4 1 % y i e l d . From t h i s p o i n t t h e s y n t h e s i s proceeds with a s i n g l e s t e r e o i s o m e r . Acid 344 was converted, v i a i t s a c i d c h l o r i d e , i n t o a b u t y l t h i o e s t e r , which was d e s u l f u r i z e d by Raney n i c k e l t o aldehyde 345. W i t t i g condensation of 345 w i t h a c e t y l methylenetriphenylphosphorane gave enone 346, which was reduced t o t h e s a t u r a t e d k e t o l a c t o n e 347. A t t h i s p o i n t it was necessary t o i n v e r t the l a c t o n e C-0 bond i n o r d e r t o e s t a b l i s h t h e proper s t e r e o c h e m i s t r y a t t h i s c e n t e r . This was accomplished by a l k a l i n e h y d r o l y s i s of 347, followed by o x i d a t i o n w i t h Jones r e a g e n t . The o i l y k e t o a c i d 348 was reduced by sodium borohydride t o a mixture of d i o l a c i d s (349 and 2). Upon t r e a t m e n t w i t h s u l f u r i c a c i d a t room temperature, one of t h e s e isomers (350)l a c t o n i z e d , g i v i n g c i s - l a c t o n e 351 ( 2 7 % y i e l d ) and unreacted trans-hydroxy a c i d
x.
349. -
352, which
Oxidation of 351 gave k e t o l a c t o n e o f t h e p r o p e r s t e r e o c h e m i s t r y for conversion A f t e r p r o t e c t i o n of t h e side-chain carbonyl, group was introduced by Minato's method (see i n g f i n a l l y ( ? ) -carabrone (327)
.
K.
now h a s a l l i n t o carabrone. t h e methylene s e c . 4-M), y i e l d -
Helminthosporal
Corey's s y n t h e s i s of t h e i n t e r e s t i n g fun a 1 t o x i n helminthos p o r a l (356) i s summarized i n Scheme 35. q 6 6 The compound h a s f o u r asymmetric c e n t e r s , of which two (C-1 and C-5) a r e f i x e d
Total Synthesis of Sesquiterpenes
464
r e l a t i v e t o one a n o t h e r on g e o m e t r i c a l g r o u n d s . The s t e r e o c h e m i s t r y a t C - 8 i s no problem. S i n c e h e l m i n t h o s p o r a l i s known t o r e s i s t a c i d c a t a l y z e d e p i m e r i z a t i o n , t h e formyl group must occupy t h e most s t a b l e c o n f i g u r a t i o n . Thus, t h e o n l y s t e r e o c h e m i c a l f e a t u r e which must b e reckoned w i t h i n a synt h e t i c p l a n i s t h e d i s p o s i t i o n o f t h e i s o p r o p y l g r o u p on t h e cyclohexane r i n g r e l a t i v e t o t h e two-carbon b r i d g e . The n a t u r e of t h e two-carbon b r i d g e i n 356 s u g g e s t s a I f one c o n s i d e r s as an a l d o l i z a method f o r i t s f o r m a t i o n . t i o n p r o d u c t of k e t o aldehyde 358 t h e n t h e r e q u i s i t e i n t e r mediate might b e a v a i l a b l e through o x i d a t i v e c l e a v a g e of t h e b i c y c l o [ 3 . 3 . 1 I nonene
359
357.
The s y n t h e t i c p l a n w a s reduced t o p r a c t i c e a s shown i n t h e scheme. (-)-Carvomenthone ( s t r u c t u r e 419, Sec. 4 ) w a s a c t i v a t e d a t C-6 by c o n v e r s i o n i n t o i t s a-hydroxymethylene derivative Condensation o f 360 w i t h methyl v i n y l ket o n e , f o l l o w e d by d e f o r m y l a t i o n , y i e l d e d d i o n e 361. Treatment of w i t h BF3 i n methylene c h l o r i d e gave b i c y c l i c k e t o n e s 3 6 2 and 363 i n y i e l d s of 8 and 32%, r e s p e c t i v e l y . Although b i c y c l o [ 3 . 3 . 0 ] n o n a n e s such a s 362 and 363 a r e n o r m a l l y o b s e r v e d o n l y a s minor s i d e - p r o d u c t s i n t h e b a s e - c a t a l y z e d Robinson a n n e l a t i o n s e q u e n c e , 26 a c i d c a t a l y z e d h y d r o l y s i s - c y c l i z a t i o n of compound 368 had been g r e v i o u s l y r e p o r t e d t o y i e l d m a i n l y the bridqed product
(360).
361
z.2 '
36 8 -
369 -
Other B i c a r b o c y c l i c S e s q u i t e r p e n e s
465
The r e l a t i v e s t e r e o c h e m i s t r y of t h e i s o p r o p y l group and t h e p o t e n t i a l two-carbon b r i d g e i s e s t a b l i s h e d , s t e r e o s e l e c t i v e l y , i n this s t e p . Although b o t h s u b s t i t u e n t s a t o t h e with c a r b o n y l i n 361 a r e e p i m e r i z a b l e , c y c l i z a t i o n of E, an a x i a l i s o p r o p y l group i n t h e t r a n s i t i o n s t a t e , i s less f a v o r a b l e t h a n c y c l i z a t i o n of
m.
361a -
361b -
362
363 -
t
I -
A f t e r s e p a r a t i o n of t h e two isomers (362 and 363) v i a t h e i r semicarbazone d e r i v a t i v e s , compound 363 was condensed w i t h rnethoxymethylenetriphenylphosphorane t o g i v e an e n o l which was transformed i n t o e t h y l e n e a c e t a l 365. ether Cleavage of t h e double bond y i e l d e d k e t o aldehyde 366, which
(z),
Scheme 35.
Corey’s S y n t h e s i s of (-)-Helminthosporal n
A 419 (Sec. -
EtOH
4)
360 -
Total Synthesis of Sesquiterpenes
466
1. OsO4
____c
2 . Pb(OAc)4
366 -
365 -
was aldolized with ethanolic base, Hydrolysis of the resulting acetal (=) yielded (-)-helminthosporal (=). (See Scheme 3 5 . )
so Hp
L.
5-Vetivone, Hinesol, Epihinesol (Agarospirol)
The spirovetivanes are an interesting class possessing a spiro[4.5]decane skeleton, with two or three asymmetric centers. 6-Vetivone ( 3 7 0 ) , long thought to be a hydroazulene, is The epimeric alcohols hinesol the key member of &-class. (371)and agarospirol (3721 contain an additional chiral center, and thus present more challenging synthetic tasks. #
/
370 -
H
371 -
OH
372 -
Other Bicarbocyclic Sesquiterpenes
467
One obvious approach to compounds of this class is through the spiro[4.5ldecane 375, obtained b Kropp as a solvolysis product of the tricyclic enone 2z9 Enone 374 is a photochemical rearrangement product of the dienone 373. From the stereochemical relationships which had been worked out for the related santonin-lumisantonin rearrangement,2 7 0 compound 375 is known to have the stereochemistry indicated in Scheme 6.
=.
Scheme 36.
Marshall's Synthesis of (2)-B-Vetivone
hv
0
373 -
-
374 -
2.
376 -
375 1. NaBH4 H
CIHO
I
SBu
-
1. HCOzEt, NaOEt
HZ-Pd/C
377 -
4)
MeLi
I
378 1. Li, NH3, EtOH
"o,,
_____c
2. 0
OH
379 -
n-BUSH
3 80 -
CrO3
p - ..* 468
Total Synthesis of Sesquiterpenes
MeLi
8- Ace*
4.
0
381 -
371 -
+
H
OH 382 -
372 -
OAc
304 -
383 -
37 0 -
I f an i s o p r o p y l i d i n e g r o u p c a n b e i n t r o d u c e d a t C-3 i n t h e d i h y d r o d e r i v a t i v e of d i e n o n e t h e n a s t e r e o s p e c i f i c synt h e s i s of 0 - v e t i v o n e i s i n hand. However, a s w i l l b e s e e n from t h e s e q u e l , s u c h a r o u t e o f f e r s no s t e r e o c h e m i c a l cont r o l over an i s o p r o p y l o l group a t t h i s p o s i t i o n . M a r s h a l l ' s s y n t h e s i s of 6 - v e t i v o n e (Scheme 3 6 ) b e g i n s w i t h d i e n o n e 375,which was p r e p a r e d by a n improved p r o c e d~re.*~S ' e l e c t i v e hydrogenation of gave enone 376 which w a s f u n c t i o n a l i z e d a t C - 3 by c o n v e r s i o n i n t o t h e n - b u t y l thiomethylene d e r i v a t i v e Borohydride r e d u c t i o n , f o l l o w e d by a c i d h y d r o l y s i s , y i e l d e d a l d e h y d e 378. T h i s s u b s t a n c e w a s t r e a t e d w i t h m e t h y l l i t h i u m t o o b t a i n 379, a d i a s t e r e o m e r i c m i x t u r e , which was o x i d i z e d t o d i e n o n e 380.
375,
377.
375
Other B i c a r b o c y c l i c Sesquiterpenes
469
D i s s o l v i n g metal r e d u c t i o n o f 380 gave, a f t e r re-oxidat i o n , t h e enone 381 a 3:2 mixture of epimers. This mixture r e a c t e d with methyllithium t o g i v e h i n e s o l and epihines o l ( E l * i n a r a t i o of 5:3. Although 371 and 372 a r e n o t s e p a r a b l e , the corresponding a c e t a t e s (382 and 383) could be s e p a r a t e d by p r e p a r a t i v e g l p c . A l l y l i c o x i d a t i o n of t h e mixt u r e gave k e t o e s t e r mixture which was dehydrated by a known method t o (+)-8-vetivone (370). Although t h i s r o u t e produces s y n t h e t i c $-vetivone i n a s t e r e o r a t i o n a l manner, i t provides no s y n t h e t i c proof of t h e stereochemistry of hinesol. I n o r d e r t o provide t h i s evidence, Marshall c a r r i e d o u t t h e s y n t h e s i s i n Scheme 37.272 The
(371)
=,
Scheme 37.
M a r s h a l l ' s S y n t h e s i s of (+)-Hinesol
____c
2 . Na2CrOq 3. H30'
387: 388: -
C-4 M e 6 ( 2 0 % ) C-4 M e a (80%)
391 (80%) -
389: 390: -
C-4 M e 6 ( 2 0 % ) C-4 M e a (80%)
392 (20%) -
*Compound 372 ( e p i h i n e s o l ) i s very probably a g a r o s p i r o l . A l though samples of a g a r o s p i r o l are no l o n g e r a v a i l a b l e f o r comp a r i s o n , Deslongchamps r e p o r t s t h a t h i s e p i h i n e s o l (Scheme 38) which i s i d e n t i c a l t o M a r s h a l l ' s , gave an epoxide which i s s p e c t r a l l y i d e n t i c a l t o t h a t d e r i v e d from n a t u r a l a g a r o s p i r o l .
oyq oq 1. Br2-HOAc
LiAl(0-t-Bu);H
u
T
393 -
394 -
OH HOP,.,,,
HO..,,,
1. ArCO3H 2.
LiAlHt,
1. M s C l
-
P
2. t-BuOK
--
fl1. L i A l H 4
I
I
H '1
401
2.
CrO3
)f&l
\
A ___c MeLi
m
H
402
T
I
il
470
371 -
Other B i c a r b o c y c l i c S e s q u i t e r p e n e s
471
s y n t h e s i s , w h i l e providing h i n e s o l i n a s t e r e o c h e m i c a l l y unambiguous manner, i t i s n o t s t e r e o s e l e c t i v e . T r i c y c l i c ketone 386 was prepared i n e i g h t s t e p s from 6-methoxy-1-tetralone (385) i n a m o d i f i c a t i o n of t h e r o u t e o r i g i n a l l y employed by Masamune f o r t h e production of t h i s substance from 6-methoxy2 - t e t r a l o n e . 27 3 Addition of l i t h i u m dimethylcopper t o t h e more a c c e s s i b l e double bond of dienone 386 y i e l d e d a mixture of enones 387 and 388 i n a r a t i o o f 1 : 4 . The s t e r e o c h e m i s t r y o f t h e adducts was e s t a b l i s h e d f i r m l y by x-ray a n a l y s i s o f a d e r i v a t i v e of t h e minor ( d e s i r e d ) isomer. The mixture o f enones was converted i n t o a l l y l i c a l c o h o l s 389 and 390 by r e d u c t i o n of t h e corresponding 6 , y - u n s a t u r a t e d isomers. A l l y l i c o x i d a t i o n of t h e corresponding homoallylic a c e t a t e s , followed by e l i m i n a t i o n o f a c e t i c a c i d , y i e l d e d a major and a minor dienone (391 and which were s e p a r a t e d by p r e p a r a t i v e g l p c . The minor isomer was used i n t h e remaining seventeen s t e p s needed f o r t h e produ c t i o n of s y n t h e t i c h i n e s o l . C a t a l y t i c hydrogenation gave a mixture o f isomeric ket o n e s (393), which was converted i n t o enone 394 by bromination-dehydrobromination. Hydride r e d u c t i o n of 394 y i e l d e d a l l y l i c a l c o h o l 395. Reduction of t h e corresponding epoxide gave d i o l 396. Grob fragmentation of t h e d e r i v e d monomethanes u l f o n a t e a f f o r d e d t h e s p i r o [4,5]decane d e r i v a t i v e E. Compound 397 r e a c t e d with methyllithium t o g i v e a mixture o f a l c o h o l s , which w a s a c e t y l a t e d t o o b t a i n u n s a t u r a t e d acetates The corresponding epoxide (=) was reduced with L i A l H 4 and t h e product a c e t y l a t e d t o o b t a i n hydroxy e s t e r 400 ( a mixture of f o u r d i a s t e r e o m e r s ) . Dehydration of t h i s subs t a n c e y i e l d e d u n s a t u r a t e d e s t e r %. The a l c o h o l r e s u l t i n g from L i A l H 4 r e d u c t i o n o f 401 w a s o x i d i z e d t o ketone 402, of unambiguous s t e r e o c h e m i s t r y . Treatment of 402 with methyll i t h i u m gave ( + ) - h i n e s o l (%). Deslongchamps h a s r e p o r t e d t h e e l e g a n t s y n t h e s i s of a g a r o s p i r o l o u t l i n e d i n Scheme 38. 274 The r e a d i l y a v a i l a b l e
-
-
z),
=.
Scheme 38.
403 -
Deslongchamps' S y n t h e s i s o f Agarospirol
404 -
MeOC02Me NaH
410 -
409 -
411 -
'OH
I
I
41 3 -
472
412 -
I OH
I 414 -
Other B i c a r b o c y c l i c S e s q u i t e r p e n e s
473
415 -
enone e s t e r 403 when k e t a l i z e d and then reduced, afforded a l l y l i c a l c o h o l 404. Hydrolysis of t h e k e t a l grouping occurred with concomittant dehydration of y i e l d dienone 405. This m a t e r i a l underwent 1 , 6 a d d i t i o n o f s o d i o d i e t h y l malonate t o y i e l d , a f t e r h y d r o l y s i s , decarboxylation and e s t e r i f i c a t i o n , t h e enone ester 406. Compound 406 was obtained from enone e s t e r 403 i n 4 7 % o v e r a l l y i e l d . K e t a l i z a t i o n again occurred with t h e normal double bond s h i f t t o y i e l d a k e t a l e s t e r , which was s a p o n i f i e d t o o b t a i n k e t a l a c i d 407. The d i a z o ketone 408, obtained i n t h e u s u a l manner, was decomposed i n t h e presence of copper powder t o y i e l d a mixture of t r i c y c l i c ketones 409 and 410 i n a r a t i o of 1:9. The mixt u r e of ketones 409 and 410 was converted i n t o 6-keto e s t e r 4 11. (For t h e sake of convenience, w e i l l u s t r a t e i n t h e scheme with t h e major isomer only. Compounds 411-413 were each contaminated by 10% o f an isomer d e r i v e d from t h e minor t r i c y c l i c ketone 409.) The r e l a t i v e s t e r e o c h e m i s t r y of agaros p i r o l i s e s t a b l i s h e d a t t h i s s t a g e . Nonbonded i n t e r a c t i o n s cause t h e carbomethoxyl group t o be a n t i i n t h e b i c y c l o [ 3 . 1 . 0 ] hexane system.
-
474
T o t a l S y n t h e s i s of S e s q u i t e r p e n e s
Treatment of t h e c o r r e s p o n d i n g a-hydroxy e s t e r w i t h methylmagnesium i o d i d e gave d i o l 413, which r e a c t e d w i t h aqueous a c i d t o a f f o r d t h e c r y s t a l l i n e k e t o a l c o h o l 414. Comw a s r e d u c e d t o d i o l 415, which w a s a c e t y l a t e d t o pound t h e mono a c e t a t e 416. Reduction of 416 w i t h l i t h i u m i n e t h y l amine gave ( f ) - a g a r o s p i r o l (=).* A l t e r n a t i v e l y , d i o l 415 could be reduced i n t h e same manner d i r e c t l y t o ( 2 ) - a g a r o spirol.
414
M.
Caryophyllene, Isocaryophyllene
Caryophyllene (417) and i s o c a r y o p h y l l e n e (418) p o s e t h r e e major s y n t h e t i c problems: c o n s t r u c t i o n of t h e b i c y c l o [ 7 . 2 . 0 ] undecane s k e l e t o n , c o n t r o l of t h e b r i d g e h e a d s t e r e o c h e m i s t r y , and c o n t r o l o f t h e d o u b l e bond geometry. I n C o r e y ’ s approach it was d e c i d e d t o c o n s t r u c t a t r i c y c l i c t o t h e problem,*’’
p r e c u r s e r and g e n e r a t e t h e nine-membered r i n g by s c i s s i o n of t h e i n t e r n a l bond o f a h y d r i n d a n e ( i . e . , 419 420). -f
419 -
420 -
Given t h i s b a s i c a p p r o a c h , t h e problem r e d u c e s t o t h e s y n t h e s i s o f an i n t e r m e d i a t e w i t h t h e g r o s s s k e l e t o n of 419 f u n c t i o n a l i z e d i n such a way a s t o allow t h e f r a g m e n t a t i o n and leave f u n c t i o n a l i t y adjacent t o t h e cyclobutane r i n g f o r i n t r o d u c t i o n o f t h e methylene group. The i n t e r m e d i a t e s h o u l d a l s o a l l o w f o r m a t i o n o f t h e e n d o c y c l i c d o u b l e bond, and s h o u l d p r o v i d e c o n t r o l o v e r i t s geometry. Various c o n s i d e r a t i o n s l e d t o t h e conclusion t h a t t h e *See f o o t n o t e , p . 469.
Other Bicarbocyclic Sesquiterpenes
475
tricyclic diol monotosylates 421 and 423 are ideal intermediates for the purpose. Base catalyzed Grob fragmentation would lead to the bicyclic ketones 422 and 424, respectively.
421 -
422 -
423 -
424 -
Assuming a concerted fragmentation, the geometry of the new double bond is fixed by the relative stereochemistry of the angular methyl group and the leaving group. The products 422 and 424 possess functionality for introduction of the characteristic methylene group and the carbonyl group should allow equilibration of the ketones to the more stable t r a n s ring juncture. Scheme 39 illustrates the application of this approach to the synthesis of (f)-isocaryophyllene. Photoaddition of isobutylene and cyclohexenone gave, after homogenization of the Scheme 39.
0
Corey‘s Synthesis of (2)-Isocaryophyllene
1. hv 2. Al2O3
MeOCO2Me 0
Me02 C OH
0
427 -
426 -
Me02 C
H20 HOAc
l7
F
P
CH (OMe)2
CH (OMe ) 2
428
429 -
1. OH-, H 2 0 2 . CgHgN, A
__.___c
0
OH
“h,
C02Me
4 30 -
4 34 476
431 -
4 35 -
Other B i c a r b o c y c l i c Sesquiterpenes
477
418 -
4 36 -
r i n g j u n c t u r e , t h e b i c y c l o [ 4 . 2 . 0 l o c t a n o n e 425 i n 35-45% y i e l d . This material was converted i n t o t h e e n o l i c B-keto e s t e r 426 i n t h e normal manner ( 8 6 % ) . Methylation of 426 gave a mixture of d i a s t e r e o m e r s 427 i n a r a t i o o f 3 : l (94% y i e l d ) . Although t h e isomers were n o t s e p a r a t e d , and t h e i r s t r u c t u r e s n o t r i g o r o u s l y proven, it seems l i k e l y t h a t t h e major isomer h a s t h e stereochemistry depicted i n S t r u c t u r e 427a would r e s u l t from methylation from t h e less hindered convex f a c e of t h e b i c y c l i c system.
-.
427a Addition of t h e l i t h i u m s a l t of propargaldehyde dimethyl a c e t a l t o t h e mixture 427 gave a mixture of e t h y n y l c a r b i n o l s 428, which was reduced t o 429. Oxidation o f = w i t h chromic a c i d i n aqueous a c e t i c a c i d gave t h e s p i r o - l a c t o n e 430, s t i l l a mixture of d i a s t e r e o m e r s , i n 86% y i e l d . The s t e r e o c h e m i s t r y of t h e new c e n t e r i s based on t h e assumption t h a t t h e l i t h i u m a c e t y l i d e adds from t h e less hindered f a c e of 427. Dieckmann c y c l i z a t i o n o f 430 gave a B-keto e s t e r (431), which was s a p o n i f i e d and decarboxylated t o give a major (m.p. 126-127') and a minor (m.p. 140-141.5') t r i c y c l i c k e t o a l c o h o l . Although no information p e r t a i n i n g t o r e l a t i v e s t e r e o chemistry o f t h e a n g u l a r methyl group was adduced by Corey, f o r t h e reason given above, t h e s t r u c t u r e shown (432) seems most reasonable t o t h i s w r i t e r . F o r t u n a t e l y , t h i s s t e r e o chemical p o i n t i s n o t c r i t i c a l , s i n c e t h e geometry of t h e double bond t o be formed by fragmentation depends only on t h e r e l a t i v e d i s p o s i t i o n of t h i s methyl group and t h e v i c i n a l l e a v i n g group (see above). For purposes of c l a r i t y , w e s h a l l i l l u s t r a t e i n t h e s e q u e l w i t h t h e methyl group t3 o r i e n t e d . The a l t e r n a t i v e s t r u c t u r e , 437, could l e a d , through t h e
-
478
T o t a l S y n t h e s i s of S e s q u i t e r p e n e s
a p p r o p r i a t e i n t e r m e d i a t e s , t o t h e same u l t i m a t e p r o d u c t .
4 37 -
Reduction of t h e c a r b o n y l group i n 432 w i t h v a r i o u s a g e n t s ( N a B H 4 , LiAlH4, LiAl(0-Bu-t) 3 H , Na-H20/ether] l e d t o a s i n g l e d i o l (433). This compound formed a mono-tosylate which r e a c t e d w i t h sodium t - b u t o x i d e i n DMSO t o y i e l d , i n i t i a l l y , t h e c i s - f u s e d u n s a t u r a t e d k e t o n e , 435. E q u i l i b r a t i o n of t h i s s u b s t a n c e y i e l d e d t h e t r a n s i s o m e r % w h i c h rea c t e d w i t h methylenetriphenylphosphorane t o y i e l d ( k ) - i s o caryophyllene. The o b t e n t i o n of i s o c a r y o p h y l l e n e from d i o l 434 demons t r a t e s t h a t t h e r e l a t i v e s t e r e o c h e m i s t r y of t h e s e c o n d a r y hydroxyl and t h e a n g u l a r m e t h y l i s t r a n s . I n o r d e r t o s e c u r e c a r y o p h y l l e n e i t s e l f , i t i s n e c e s s a r y t o o b t a i n t h e isomer o f 4 3 4 i n which t h e s e g r o u p s a r e c i s . This g o a l w a s f i n a l l y a c h i e v e d (Scheme 4 0 ) when it w a s found t h a t k e t o l 432 i s
(s),
-
Scheme 40.
C o r e y ' s S y n t h e s i s of ( + I - C a r y o p h y l l e n e
' "'OH
U 4 32 -
4 38 -
433
439 -
Other Bicarbocyclic Sesquiterpenes
440 -
441 -
479
417 -
r e d u c e d by hydrogen i n t h e p r e s e n c e of Raney n i c k e l t o a 1:l m i x t u r e of d i o l 433 and i t s isomer E. Compound 438 gave a mono-tosylate (439), which on r e a c t i o n w i t h p o t a s s i u m t - b u t o x i d e i n t - b u t a n o l i n i t i a l l y gave t h e c i s - f u s e d k e t o n e , 440 which on e q u i l i b r a t i o n as above gave t h e trans isomer 441. Wittig methylenation provided (2)-caryophyllene. An approach s t a r t i n g from t h e macrocycle humulene ( s t r u c t u r e 279, Sec. 3 ) is d e s c r i b e d by S ~ t h e r l a n d ' ~(Scheme ~ 41). Scheme 41.
279 (Sec. -
Br,,,,
S u t h e r l a n d ' s S y n t h e s i s o f (2)-Caryophyllene from Humulene
3)
~ 0 ~ 1 3 C5H5N
At-
442 -
B r %I,,,,
''J,,,,,
LiAlH4
THF
-3
5
OH
444 -
44 3 -
+
-
+ 417
279 (Sec. -
3)
480
Total Synthesis of Sesquiterpenes
Reaction with N-bromosuccinimide in aqueous acetone gave 20% each of monobromohumulene (442) and hydroxy-bromo compound 443. The latter on dehydration provided 444. Reductive rearrangement of the cyclopropyl system with lithium aluminum hydride was partially successful giving a mixture from which (2)-caryophyllene (417) could be isolated in 30% yield, the other major product being 445. A novel approach starting from 1,2-cyclononadiene (446) has been reported277 (Scheme 4 2 ) . Reaction of the cyclic Scheme 4 2 .
Gras-Maurin-Bertrand Synthesis of
5,6-Dihydro-Nor-Caryophyllene
447 -
446
448 -
449 -
OH
451 -
4 50 -
452 -
453 -
allene with dimethylketone provided the bicyclo[7.2.0lundeceneone 447 as the basic building unit of the caryophyllene
Other B i c a r b o c y c l i c Sesquiterpenes
481
s k e l e t o n . T h i o k e t a l formation t o 448 followed by r e d u c t i o n gave t h e o l e f i n 449. Hydroboration t o 450, followed by oxidat i o n gave t h e u n s t a b l e cis ketone 451 which on e q u i l i b r a t i o n y i e l d e d t h e t r a n s ketone 452. A w i t t i g r e a c t i o n provided 5,6dihydronorcaryophyllene 453. N.
a-Santalol,
$ - S a n t a l o l , a-Santalene, $-Santalene
The c h a r a c t e r i s t i c odor of E a s t I n d i a n Sandalwood o i l , h i g h l y p r i z e d i n perfumery, i s due mainly t o t h e companion a l c o h o l s a- and $ - s a n t a l o l (454 and *), which o c c w i n t h e o i l along with t h e i r hydrocarbon analogs a- and 8-santalene (456 and 457). The r e l a t i o n s h i p of t h e s e s e s q u i t e r p e n e s t o t h e mono-
-
454: 456: -
X = OH
X = H
455: 457: -
X = OH X = H
t e r p e n e s t r i c y c l e n e (458) and camphene (459) provides synt h e t i c analogy f o r c o n s t r u c t i o n of t h e c a r b o c y c l i c nucleus i n each c a s e . The remaining s y n t h e t i c problems a r e t h e introduc-
t i o n o f t h e i s o p e n t e n y l s u b s t i t u e n t , with t h e proper o r i e n t a t i o n i n t h e case of 455 and 457 and t h e geometry of t h e double bond i n t h e c a s e of 454 and 455. The s i m p l e s t t a r g e t , from a s y n t h e t i c s t a n d p o i n t , is a-santalene s i n c e t h e r e i s no s t e r e o c h e m i s t r y t o cont e n d with. Corey w a s t h e f i r s t t o s o l v e t h i s problem, with t h e s y n t h e s i s o u t l i n e d i n Scheme 43. 2 7 a Trans-n-bromocamphor ( E )prepared , from a-bromocamphor (460) by brominationdebromination, was converted i n t o a-bromotricyclene (463) v i a t h e d i a z o compound. The corresponding Grignard r e a g e n t rea c t e d with y , y - d i m e t h y l a l l y l m e s i t o a t e t o g i v e ( + ) - a - s a n t a l e n e
(z),
482
Total Synthesis of Sesquiterpenes
$
Scheme 43.
0
Br
Corey's Synthesis of (2)-a-Santalene
Br2
____c
rB&o
Zn
___c
HSO 3 C1
HBr Br
4 60
461 -
464 -
4 56 -
(456) in 18% yield. The remaining material was mostly the crystalline bi-n-tricyclyl (465). The isopentenyl side-chain
465 -
466 -
could not be efficiently introduced by treatment of 464 with y,y-dimethylallyl bromide, since the resulting a-santalene was accompanied by up to 50% of the isomer 466. In 1962, Corey reported an elegant, stereospecific synthesis of (k)-B-santalene and its epimer, (+_)-epi-Bwhich he showed to be a companion of B-santasantalene (G), lene in sandalwood oil (Scheme 44) . 2 7 9 Norbornanone (467) was
(s),
Other Bicarbocyclic Sesquiterpenes Scheme 44.
483
Corey's Synthesis of (k)-B-Santalene and (2)-epi-B-Santalene
467 -
469 -
1
1. $$Na
&f& -
1. MeLi 2. soc12,
470 -
2. Me1
1. 2 . MeLi SOC12, CgH5N ~
% -
methylated to give the e x o derivative 468. Careful analysis showed that the e x o - e n d o alkylation ratio was greater than 30:l. Alkylation of 468 with 2-methyl-5-chloro-2-pentene yielded solely ketone 469. The tertiary alcohol formed on reaction of 469 with methyllithium was dehydrated to obtain (f)-0-santalene (457). By reversing the order of introduction of the two side-chains, the isomer 472 was prepared, also stereospecifically.
484
T o t a l S y n t h e s i s of S e s q u i t e r p e n e s
Brieger h a s r e p o r t e d an i n t e r e s t i n g , although i n e f f i c i e n t , s y n t h e s i s of a m i x t u r e of t h e t w o B - s a n t a l e n e isomers (Scheme 45) When g e r a n i o l ( s t r u c t u r e 4, Sec. 2 ) was h e a t e d w i t h Scheme 4 5 .
4 (sec. -
474 -
2)
B r i e g e r ' s S y n t h e s i s of ( + ) - B - S a n t a l e n e an d ( k ) - e p i - B - S a n t a l e n e
OH
475 -
Other Bicarbocyclic Sesquiterpenes
485
c y c l o p e n t a d i e n e a t 170' f o r t w o d a y s , a complex m i x t u r e o f Fractional d i s t i l l a t i o n of a d d u c t s and p o l y m e r s w a s p r o d u c e d . t h e m i x t u r e y i e l d e d a m i x t u r e of 473 a n d i n 4% y i e l d . A f t e r s a t u r a t i o n of t h e more a c c e s s i b l e d o u b l e b o n d , t h e corr e s p o n d i n g acetates were p y r o l y z e d t o y i e l d a 3 : 2 m i x t u r e of ( 2 )- B - s a n t a l e n e (457) a n d (k)- e p i - @ - s a n t a l e n e (472) I n a s y n t h e s i s w h i c h was f i r s t a n n o u n c e d i n 1 9 4 7 , a n d f i n a l l y r e v e a l e d i n 1967, Bhattacharyya prepared a - s a n t a l e n e from n - b r o m o t r i c y c l e n e (462) a s o u t l i n e d i n Scheme 4 6 . 2 8 1 The
474
.
Scheme 46.
B h a t t a c h a r y y a ' s S y n t h e s i s of ( ? ) - a - S a n t a l e n e
xco2H rBr% 477 -
462 -
1. 2 . CH2N2 LiA1H4
2.
1. p-TsC1
K
H 2. NaBr
O
481 -
+ 482 -
456 -
486
Total Synthesis of Sesquiterpenes
t e n - s t a g e c o n v e r s i o n , which a f f o r d s a m i x t u r e of ( + ) - a - s a n t a l e n e (456) and i t s isomer 482 o f f e r s l i t t l e advantage o v e r C o r e y ' s o n e - s t e p c o n v e r s i o n , even though t h e l a t t e r p r o c e e d s i n o n l y 18% y i e l d . I n t h e same 1967 a p e r , B h a t t a c h a r y y a r e p o r t e d a s y n t h e s i s of " ( + ) - a - s a n t a l o l . ''28Pb The s y n t h e s i s , which p r o c e e d s t h r o u g h i s o u t l i n e d i n Scheme 47. From t h e tricycloekasantalal
(s),
Scheme 47.
479 -
4 a4 -
Bhattacharyya's Synthesis of
(+)
- (E)-a-Santalol
483 -
485 -
method o f s y n t h e s i s , and from s p e c t r a l d a t a p r e s e n t e d by B h a t t a c h a r y y a , i t seems c l e a r t h a t t h e s y n t h e s i s y i e l d s t h e (El-isomer 486 r a t h e r t h a n n a t u r a l a - s a n t a l o l (454). I t s h o u l d be p o i n t e d o u t t h a t t h e geometry of t h e d o u b l e bond i n n a t u r a l a - s a n t a l o l was n o t c o r r e c t l y known a t t h i s t i m e , it h a v i n g been e r r o n e o u s l y a s s i g n e d t h e (E) geometry (486) by Brieger 282 Colonge and co-workers r e p o r t e d a s y n t h e s i s of a- and 6 - s a n t a l o l (Scheme 48) i n 1966. 2 8 3 n-Bromotricyclene (462) was c o n v e r t e d by a s t a n d a r d homologation sequence i n t o chlor i d e 490. T h i s s u b s t a n c e formed a G r i g n a r d r e a g e n t which
.
Other B i c a r b o c y c l i c Sesquiterpenes Scheme 48.
487
Colonge‘s S y n t h e s i s of a- and 8 - S a n t a l o l ( ? ) CN
KOH
___c
4 89 -
488 -
1. P B r 3
L
2 . KOH
454 (+ -
isomer?)
455 (+ -
isomer?)
r e a c t e d with methacrolein t o y i e l d a l c o h o l 491. Upon t r e a t ment of 491 with P B r 3 , followed by KOH, a mixture of a - s a n t a l o l (454) and 6 - s a n t a l o l (455) was i s o l a t e d . The stereochemical i n t e g r i t y of t h e products h a s been questioned.284 I n 1967, Erman and co-workers, a t t h e P r o c t e r and Gamble L a b o r a t o r i e s i n C i n c i n n a t i , Ohio, provided conclusive evidence t h a t n a t u r a l a - s a n t a l o l indeed has t h e ( 2 ) geometry i n d i c a t e d
T o t a l S y n t h e s i s of S e s q u i t e r p e n e s
488
i n 454. The Erman s y n t h e s i s , w h i c h p r o v i d e s b o t h t h e ( E ) (486) a n d ( 2 ) ( 4 5 4 ) i s o m e r s , is o u t l i n e d i n Scheme 4 9 . 2 8 5 rr-Bromot r i c y c l e n e ( 4 6 2 ) w a s c o u p l e d w i t h t h e e t h y l e n e d i a m i n e complex E r m a n ' s S y n t h e s i s of ( + ) - a - S a n t a l o l a n d I t s ( + ) - ( E ) Isomer
Scheme 4 9 .
Br
LiCE CH __f
DMSO
[
462
I _
I'&
-
+
&+LH
2 . H202
N ayNl eH n2 e , A x
483
494 -
$3P=C-C02Et A
7
4 84 -
\
495 -
Other B i c a r b o c y c l i c S e s q u i t e r p e n e s
489
o f l i t h i u m a c e t y l i d e i n HMPA t o g i v e a mixture of a c e t y l e n i c isomers 492 and 493 i n 80-90% y i e l d . The r a t i o of 492 t o 493 w a s h i g h l y v a r i a b l e , t h e amount o f 493 i n c r e a s i n g with r e a c t i o n t i m e . Homogenization was achieved, i n 63% y i e l d , by r e f l u x i n g t h e mixture with sodamide i n xylene. Terminal a c e t y l e n e 494 r e a c t e d w i t h one e q u i v a l e n t of disiarnylborane t o y i e l d , a f t e r o x i d a t i o n , t r i c y c l o e k a s a n t a l a l (483) This aldehyde r e a c t e d w i t h ( c a r b e t h o x y e t h y l i d i n e )t r i phenylphosphorane t o g i v e u n s a t u r a t e d e s t e r s 484 and 495 i n a r a t i o o f 5:l. The geometry of t h e double bond was, i n each c a s e , a s s i g n e d on t h e b a s i s of NMR spectroscopy. Reduction of t h e major e s t e r (484) gave ( + I - ( E ) - 2 - s a n t a l o l (486). Analogous r e d u c t i o n of t h e minor isomer (495) a f f o r d e d (+)-ai d e n t i c a l w i t h t h e n a t u r a l m a t e r i a l . Analysis s a n t a l o l (*) of e i g h t E a s t Indian sandalwood o i l s and one A u s t r a l i a n sandalwood o i l , a l l from d i f f e r e n t s o u r c e s , r e v e a l e d t h a t isomer 454 i s a c o n s t i t u e n t of a l l , and t h a t t h e ( E ) isomer (486) is a c o n s t i t u e n t of none. By a simple (though e l e g a n t ) m o d i f i c a t i o n of t h e W i t t i g r e a c t i o n , Corey achieved a s t e r e o s p e c i f i c s y n t h e s i s of as a n t a l o l (Scheme 50) 2 8 6 T r i c y c l o e k a s a n t a l a l (*) was t r e a t e d
.
.
Scheme 50.
Corey's S y n t h e s i s of ( + ) - a - S a n t a l o l
KCHO @3P=CHCH3 THF
483
-
-780
-
HO' 496 -
454 -
490
Total Synthesis of Sesquiterpenes
with ethylidinetriphenylphosphorane at -78' to give the betaine This was treated with n-butyllithium at -78", then paraThe product obtained on work-up consisted formaldehyde at Qo. solely of a-santalol (454). In Scheme 51 is outlined Erman's synthesis of the (E) and ( 2 ) isomers of 8-santalol (505 and the latter of which
496.
+ +d++ e),
Scheme 51.
Erman's Synthesis of (2)-6-Santalol and Its (f)-(E) Isomer
MeLi
L-b 0 468
2 . -Br
NaH
-
NaNH2 HMPA
OH
498 -
500 -
502
499 -
501 -
Br
Other Bicarbocyclic Sesquiterpenes
I
503 (80%) -
491
hu
1
504 ( 2 0 % ) I
505 -
455 -
OH
i s i d e n t i c a l with t h e n a t u r a l t e r ~ e n e . The ~ ~ s~y n t h e s i s c l o s e l y p a r a l l e l s Erman's s y n t h e s i s of t h e a - s a n t a l o l isomers (Scheme 4 9 ) Exo-3-methylnorbornanone (468) was a l k y l a t e d with a l l y 1 bromide t o a f f o r d , s t e r e o s p e c i f i c a l l y , t h e ketone -497. This r e a c t e d with methyllithium t o g i v e alcohol 498, which was brominated and then dehydrobrominated t o give t h e hydroxy a c e t y l e n e 500. Dehydration y i e l d e d 501, which was converted i n t o u n s a t u r a t e d aldehyde 502 by Erman's method ( s e e Schemes 2 6 , 2 7 , and 4 9 ) . Aldehyde 502 r e a c t e d with (carbethoxyethylidine)triphenylphosphorane t o give u n s a t u r a t e d e s t e r s 503 and 504 (18%y i e l d ) i n a r a t i o of 5:l. U l t r a v i o l e t i r r a d i a t i o n changed t h e 503:504 r a t i o t o 2 : l . When t h e mixture was r e duced, a mixture of (')-(E)-B-santalol (= major product) and ( t ) - B - s a n t a l o l (455, minor product) was produced. Corey's modification (Scheme 50) could probably be applied t o aldehyde 5 02, providing a s t e r e o s p e c i f i c s y n t h e s i s of 455.
.
-
-
492
Total S y n t h e s i s of Sesquiterpenes
6.
TRICARBOCYCLIC SESQUITERPENES
A.
P a t c h o u l i Alcohol, a - P a t c h o u l e n e , 6-Patchoulene
The h i s t o r y of p a t c h o u l i a l c o h o l , a major c o n s t i t u e n t of E a s t I n d i a n p a t c h o u l i o i l , i s i n d e e d an i n t r i g u i n g one. The s t r u c t u r e of t h e a l c o h o l w a s o r i g i n a l l y a s s i g n e d as by BUchi.288 T h i s s t r u c t u r e was a r r i v e d a t by a r i g o r o u s d e g r a d a t i v e s t u d y of a - p a t c h o u l e n e (21, y-patchoulene (3), and 6 - p a t c h o u l e n e (4). Although 6-patchoulene was t h e s o l e p r o d u c t o b t a i n e d from t r e a t m e n t of p a t c h o u l i a l c o h o l w i t h a c i d s (HzS04 , HCOzH, H3BO3,
1
(4)
-2
4
-3
-4
2, 2, and i n a r a t i o o f 52:46:4 w a s obt a i n e d on p y r o l y s i s of p a t c h o u l i a l c o h o l a c e t a t e . When p a t c h o u l i a l c o h o l w a s d e h y d r a t e d w i t h POC13-pyridineI t h e r a t i o o b t a i n e d was 2:3:4- = 7 0 : 7 : 7 . F u r t h e r m o r e , b o t h 2 and were shown t o g i v e 4, on a c i d t r e a t m e n t . Assuming t h a t must a r i s e by a Wagner-Meerwein r e a r r a n g e ment, and t h a t t h e POC13-pyridine a n d , p a r t i c u l a r l y , t h e acet a t e p y r o l y s i s d e h y d r a t i o n s p r o c e e d w i t h no r e a r r a n g e m e n t , p a t c h o u l i a l c o h o l was t h o u g h t t o b e The assumption was s t r e n g t h e n e d when a - p a t c h o u l e n e (2) was c o n v e r t e d i n t o p a t c h o u l i a l c o h o l by a sequence i n t e r p r e t e d by Biichi as:*" 1 2 ) , a m i x t u r e of
1
4
1.
I
\/
2.
a
T r i c a r b o c y c l i c Sesquiterpenes
493
(z),
With t h i s s t r u c t u r e i n mind, Buchi s e t o u t t o s y n t h e s i z e p a t c h o u l i a l c o h o l v i a a-patchoulene which he had prev i o u s l y converted i n t o p a t c h o u l i a l c o h o l by t h e s t e p s o u t l i n e d above. The BUchi s y n t h e s i s , which i s o u t l i n e d i n Scheme 1, w i l l be d i s c u s s e d s h o r t l y . 2 8 9 I t was o n l y a f t e r t h e s y n t h e s i s had been completed (presumably confirming s t r u c t u r e 1 f o r p a t c h o u l i a l c o h o l ) , t h a t Dunitz and co-workers completed an x-ray i n v e s t i g a t i o n of t h e p a t c h o u l i a l c o h o l d i e s t e r o f chromic a c i d , w i t h t h e i n t e n t of determining t h e C r - 0 - C r bond angle.290 S u r p r i s i n g l y , it was found t h a t p a t c h o u l i a l c o h o l h a s s t r u c t u r e 7-, r a t h e r than 1.
7 -
7 -
I t t h e n became c l e a r t h a t rearrangement had occurred i n p y r o l y s i s of p a t c h o u l i a l c o h o l a c e t a t e (8) t o a-patchoulene:
Amusingly, t h e e x a c t r e v e r s e rearrangement had occurred i n t h e p e r a c e t i c a c i d o x i d a t i o n of a-patchoulene. The conversion of
494
Total Synthesis of Sesquiterpenes
-2 into patchouli as:
alcohol could then be reinterpreted correctly
(3H+
@f CH3C03H
_____c
__c
2 -
9 -
moH
(
',"
11 -
)
As is clear from this discussion, although the correct structure for patchouli alcohol was not known when Blfchi actually set out to accomplish its synthesis, that of a-patchoulene (L) was secure, Since 2 had been converted into patchouli alcohol, albeit by a pathway not understood, any synthesis proceeding through this intermediate was fated for success, even though the structure of the final product would remain obscure. Fortunately, Blichi elected such a synthetic plan, which is outlined in Scheme l.289
Scheme 1. BUchi's Synthesis of (-)-6-Patchoulene, (+)-a-Patchoulene and (-)-Patchouli Alcohol
12 -
13 -
1. L i A l H 4
1. s o c 1 2 P
2. AlC13
-4
$39 dH
20 -
H2-Pt02 ___c
HOAc HCl04
49 5
496
Total Synthesis of Sesquiterpenes
(s),
The p l a n c a l l e d f o r t h e s y n t h e s i s o f 0-patchoulene which could be r e a r r a n g e d t o a a - p a t c h o u l e n e s k e l e t o n . Curio u s l y , t h i s is t h e same t y p e of rearrangement which o b s c u r e d t h e t r u e s t r u c t u r e of p a t c h o u l i a l c o h o l . With this g o a l i n becomes an i d e a l s t a r t i n g p o i n t . mind, homo-camphor Treatment of 2 with allylmagnesium c h l o r i d e a f f o r d e d the a l - and mono-acetate cohol 13,which was c o n v e r t e d , v i a d i o l p 15, i n t o t h e u n s a t u r a t e d a c i d I which was c y c l i z e d v i a i t s a c i d c h l o r i d e t o t h e cyclopentenone Is. Compound 18 rea c t e d with methylenetriphenylphosphorane t o g i v e an u n s t a b l e d i e n e ( 1 9 1 , which was immediately reduced o v e r Raney n i c k e l t o a m i x t u r e of p r o d u c t s . The major p r o d u c t ( 5 3 % ) w a s found t h u s completing t h e t o t a l s y n t h e s i s t o be B-patchoulene (4-1, of t h i s n a t u r a l p r o d u c t . Having a r r i v e d a t 4, t h e n e x t g o a l was t h e rearrangement of t h i s s u b s t a n c e t o a - p a t c h o u l e n e ( 2 ) ,which would complete a t o t a l s y n t h e s i s of t h a t hydrocarbon and e s t a b l i s h a f o r m a l route t o patchouli alcohol. P e r a c e t i c a c i d o x i d a t i o n of B p a t c h o u l e n e gave a s i n g l e epoxide which r e a r r a n g e d upon t r e a t m e n t w i t h BF3 t o t h e u n s a t u r a t e d a l c o h o l 2. Hydroborat i o n of 21 a f f o r d e d d i o l 22. The most e f f i c i e n t method f o r removal of t h e unwanted t e r t i a r y hydroxyl t u r n e d o u t t o b e c a t a l y t i c h y d r o g e n a t i o n i n t h e p r e s e n c e of p e r c h l o r i c a c i d . Compound 23 was o b t a i n e d i n 31% y i e l d . The r e a c t i o n p r o b a b l y p r o c e e d s by p r i o r d e h y d r a t i o n t o 25, which is reduced t o 23. P y r o l y s i s of a c e t a t e 24, o b t a i n e d by a c e t y l a t i o n of a l c o h o l 2 3 , a f f o r d e d a m i x t u r e o f o l e f i n s c o n s i s t i n g mainly ( 8 0 % )of a-patchoulene ( 2 ) . I n l i g h t of t h e p r i o r c o n v e r s i o n of 1. t o
(12)
-
(17)
(z),
I
Tricarbocyclic Sesquiterpenes
497
25 -
patchouli alcohol, a formal total synthesis of the alcohol was established. After the structure of patchouli alcohol became known,290 rational syntheses not proceeding through the patchoulenes could be planned. Such a route, due to Danishevsky, is outlined in Scheme 2.291 Danishevsky's synthetic plan called for Scheme 2 .
Danishevsky's Synthesis of (+)-Patchouli Alcohol
H20 Dioxane
a
HO 31 -
32 -
/
EtOAc
=
NaN02
H
33 -
+
-- k--
Ho&
37 -
1
Na
39 -
+
498
*oH
26 -
THF
1
Naf
THF
T r i c a r b o c y c l i c Sesquiterpenes
499
t h e p r i o r c o n s t r u c t i o n of t h e b i c y c l o [ 2 . 2 . 2 ] o c t a n e moiety ( r i n g s B and C ) , followed by c l o s u r e of r i n g A by r e d u c t i v e a l k y l a t i o n of an c-bromo ketone ( i . e . , E - +2 ) .
The r e q u i s i t e bicyclo[2.2.2]octanone was c o n s t r u c t e d s t a r t i n g with t h e trimethylcyclohexadienone 27, which underwent Diels-Alder a d d i t i o n with methyl v i n y l ketone t o a f f o r d dione i n 93% y i e l d . A f t e r s a t u r a t i o n of t h e double bond, t h e a c e t y l group was epimerized with base. The e q u i l i b r i u m r a t i o of 29:30 was 3:7. By c r y s t a l l i z a t i o n of t h e major i s o mer (30) and e q u i l i b r a t i o n of t h e mother l i q u o r s , isomer 0 w a s obtained i n 65% y i e l d . Dione 30 r e a c t e d with v i n y l l i t h i u m a t t h e more a c c e s s i b l e carbonyl t o y i e l d a l c o h o l which y i e l d e d a l l y l i c c h l o r i d e 2 upon t r e a t m e n t with HC1 i n chloroform. Since c a t a l y t i c r e d u c t i o n of t h e double bond i n 11 was accompanied by c o n s i d e r a b l e hydrogenolysis, t h e h a l i d e was solvolyzed t o o b t a i n a l c o h o l 2. Hydrogenation of this mat e r i a l gave two epimers, 34 and g, which w e r e s e p a r a t e d by chromatography. Isomer 9 gave a bromide ( g )which , was t r e a t e d w i t h sodium i n THF. The p r o d u c t , obtained i n 55% y i e l d , was an equimolar mixture of s a t u r a t e d ketone and Analogous t r e a t m e n t of t h e i s o (+)-patchouli alcohol meric bromide 21. gave almost e x c l u s i v e l y s a t u r a t e d ketone 2, and o n l y a t r a c e of ( t ) - e p i - p a t c h o u l i a l c o h o l (2).
1,
(z).
B.
Seychellene
(s),
The t r i c y c l i c hydrocarbon s e y c h e l l e n e i s o l a t e d from p a t c h o u l i o i l , may a r i s e b i o g e n e t i c a l l y by rearrangement of p a t c h o u l i a l c o h o l . The hydrocarbon h a s r e c e n t l y been synthes i z e d , i n a p e r f e c t l y s t e r e o r a t i o n a l r o u t e , by Piers. 2 9 2
500
T o t a l S y n t h e s i s of S e s q u i t e r p e n e s
A n a l y s i s of t h e t r i c y c l i c s k e l e t o n r e v e a l s v a r i o u s ways i n which i t may b e c o n s t r u c t e d by o n e - r i n g c l o s u r e i n a b i c y c l i c p r e c u r s o r . One method, p r o c e e d i n g t h r o u g h a b i c y c l o [ 2 . 2 . 2 ] o c t a n e w a s i l l u s t r a t e d by Danishevsky i n h i s p a t c h o u l i a l c o h o l s y n t h e s i s . Such a r o u t e s u f f e r s s i n c e it o f f e r s n o c o n t r o l o v e r t h e s t e r e o c h e m i s t r y o f the s e c o n d a r y m e t h y l g r o u p , t h i s c e n t e r b e i n g i n a s i d e c h a i n p r i o r t o c l o s u r e of t h e f i n a l r i n g . A method o f s y n t h e s i s p r o c e e d i n g t h r o u g h i n t e r m e d i a t e s which c o n t a i n this c e n t e r i n a r i n g , p r e f e r a b l y a six-membered r i n g , would be more d e s i r a b l e , s i n c e c o n t r o l o v e r i t s s t e r e o chemistry could then be e x e r t e d . Four r o u t e s t o 40 are p o s s i b l e i n which t h e immediate b i c y c l i c p r e c u r s o r is a d e c a l i n , with t h e secondary methyl group i n one r i n g . Of t h e s e p o t e n t i a l d e c a l i n i c r o u t e s , c i s p r e f e r a b l e , s i n c e o n e of t h e t e r m i n i o f t h e m i s s i n g bond i s a dj a c e n t t o t h e methylene group.
I f one r e c o g n i z e s t h a t a methylene g r o u p is s y n t h e t i c a l l y equivalent t o a carbonyl group, then a l o g i c a l s y n t h e t i c targ e t is the keto t o s y l a t e which c o u l d u n d e r g o i n t r a m o l e c u l a r a l k y l a t i o n t o t h e t r i c y c l i c k e t o n e 42.
s,
%=%Tricarbocyclic Sesquiterpenes
501
TsO
42 -
41 -
40 -
The construction of keto tosylate 41 and its elaboration into (2)-seychellene is outlined in Scheme 3.292 The readily
-a a .Jp Scheme 3.
Piers' Synthesis of (2)-Seychellene
GTHP
QTHP
-- . -.
- -
1. LiCuMe2
0
2. CH3COC1
MCPA
___c
AcO
43 -
44 -
pTHP
- -
Ac
6-
,,,*I"
*
OTHP
-- --
4 3 P=CH2
__c
___c
:
45 -
OAc
46 -
MeLi
____c
502
Total S y n t h e s i s of Sesquiterpenes
54 -
41 -
a v a i l a b l e k e t o e t h e r 43 was t r e a t e d with l i t h i u m dimethylcopper. The r e s u l t i n g e n o l a t e was quenched with a c e t y l chlor i d e t o o b t a i n t h e enol a c e t a t e 44. The process is s t e r e o s p e c i f i c , l e a d i n g t o compound fi i n 10% y i e l d . Epoxidation, followed by thermal rearrangement of t h e acetoxy epoxide,
Tricarbocyclic Sesquiterpenes yielded k e t o a c e t a t e
5.
This m a t e r i a l was t r e a t e d w i t h
methylenetriphenylphosphorane t o g i v e an a l l y l i c a c e t a t e
503
(47),
which was s u b j e c t e d s u c c e s s i v e l y t o hydrogenation, s a p o n i f i c a t i o n , and o x i d a t i o n t o o b t a i n ketone 48. I t i s i n t h e hydrogenation s t e p t h a t t h e r e l a t i v e s t e r e o chemistry a t t h e secondary methyl group i s probably establ i s h e d . Apparently, compound 47 e x i s t s i n t h e conformation 47a, with hydrogen being d e l i v e r e d e x c l u s i v e l y from t h e l e s s hindered f a c e . The p o i n t i s of l i t t l e p r a c t i c a l importance, however, s i n c e t h i s c e n t e r i s epimerizable i n ketone S. Analy s i s r e v e a l s t h a t isomer 48 should be more stable than i t s
-
OTHP
f H
L
47a epimer 49. with base.
I n f a c t , ketone
48 was
unchanged upon t r e a t m e n t
Pp7f OTHP
48
48 r e a c t e d
49
(so),which w a s dehydrated t o o b t a i n t h e e x o c y c l i c o l e f i n 2. Ketone
w i t h methyllithium t o g i v e an a l c o h o l
Hydroboration occurred from t h e more a c c e s s i b l e convex f a c e , l e a d i n g t o primary a l c o h o l 52 which was transformed i n t o tos y l a t e %. A f t e r removal of t h e p r o t e c t i n g group and oxidat i o n , t h e d e s i r e d k e t o t o s y l a t e 41 was i n hand. Base c a t a lyzed c y c l i z a t i o n indeed y i e l d e d t r i c y c l i c ketone 42, which was transformed i n t o ( + ) - s e y c h e l l e n e (40).
T o t a l S y n t h e s i s of S e s q u i t e r p e n e s
504 C.
C e d r o l , Cedrene
The t r i c y c l i c a l c o h o l c e d r o l (55) and i t s companion hydrocarbon 0-cedrene (56) a r e c o n s t i t u e n t s of c e d a r wood o i l . The s y n t h e s i s of t h e s e t r i c y c l i c s e s q u i t e r p e n e s , which p o s s e s s t h e
56 -
55 -
(z),
same b a s i c r i n g s t r u c t u r e ( e x c l u s i v e of s u b s t i t u t i o n ) a s apatchoulene w i l l be d i s c u s s e d i n t h i s s e c t i o n . The f i r s t t o t a l s y n t h e s i s of c e d r o l , by S t o r k , 2 9 3 was begun b e f o r e t h e complete s t e r e o c h e m i s t r y of t h e molecule was known w i t h c e r t a i n t y . The a v a i l a b l e d e g r a d a t i v e e v i d e n c e was s u f f i c i e n t t o l i m i t t h e s t e r e o s t r u c t u r e t o one of f o u r poss i b i l i t i e s (&-A). N o r c e d r e n e d i c a r b o x y l i c a c i d , a d e g r a d a t i o n
a: b: -
R=OH, R ' = M e R=Me , R ' = O H
-dc :: -
R=OH,
R'=Me
R=Me, R'=OH
c.
In order p r o d u c t o f t h e n a t u r a l p r o d u c t , t h u s becomes 5 o r t o c l a r i f y t h i s s t e r e o c h e m i c a l ambiguity by s y n t h e s i s , i t i s n e c e s s a r y t o d e s i g n a r o u t e which w i l l l e a d t o s t r u c t u r e s &-A i n an unambiguous manner. A t t h e o u t s e t , S t o r k d e c i d e d t o f o c u s h i s a t t e n t i o n on
T r i c a r b o c y c l i c Sesquiterpenes
505
norcedrenedicarboxylic a c i d f o r two reasons. F i r s t l y , there a r e o n l y two, r a t h e r than f o u r , p o s s i b l e s t r u c t u r e s f o r this substance. On b i o g e n e t i c grounds, one of t h e s e seemed more l i k e l y than t h e o t h e r (2, 57). Second, it seemed l i k e l y t h a t t h i s d i a c i d would r e p r e s e n t a s u i t a b l e i n t e r m e d i a t e f o r subsequent e l a b o r a t i o n i n t o c e d r o l i t s e l f . N a t u r a l l y d e r i v e d norcedrenedicarboxylic a c i d could then be used a s a r e l a y f o r completing t h e s y n t h e s i s of c e d r o l . The reasoning which l e d t o t h e s y n t h e t i c a t t a c k on d i a c i d 57 was an i n t u i t i v e one. I t was reasoned t h a t " . . . ( s t r u c t u r e e) appeared a p r i o r i r a t h e r more l i k e l y since t h e t r a n s f u s i o n of t h e A/B system i n ( g ) , while n o t impossible, i m p l i e s a deg r e e of s t r a i n which would be s u r p r i s i n g on t h e b a s i s of b i o g e n e t i c speculation^."^^ 3b A s w i l l be s e e n , t h i s i n t u i t i o n turned o u t t o be c o r r e c t . A s a s t a r t i n g p o i n t f o r t h e s y n t h e s i s , Stork chose t h e known cyclopentanone d i e s t e r 8, which was a l k y l a t e d with benzyl a-bromopropionate t o g i v e t h e t r i e s t e r 2) (Scheme 4 ) .
-
-
Scheme 4 . Et02C
Q-
C02Et
0
58 -
-1!3
S t o r k ' s S y n t h e s i s of Cedrol
NaH
C02Et
CH3CH-CO2CH24
I
hr
59 -
!!E":
t-BuOK __c
C02Ett-BuOH
C 0 2 E t ___c 4 . Zn, HOAc
H02C%
60 -
HO
-
H2-Pd/C
WH202C
61 -
57 -
66 -
1. S K 1 2 2 . CH2N2 C02H
t-BUOK
____c
3. H C 1 4.
Zn, HOAc
t-BuOH
Tricarbocyclic Sesquiterpenes
507
C a t a l y t i c hydrogenolysis gave t h e c r y s t a l l i n e k e t o a c i d 60 i n 40% o v e r a l l y i e l d . A t t h i s p o i n t , w e s h a l l comment on t h e s t e r e o c h e m i s t r y of k e t o a c i d 60. Although t h r e e asymmetric c e n t e r s a r e p r e s e n t t h e o n l y c r i t i c a l f e a t u r e is t h e cis d i s p o s i t i o n o f t h e two carbethoxy groups. The secondary methyl group, which i s a d j a c e n t t o a carbonyl f u n c t i o n i s epimerizable. The s t e r e o s e l e c t i v i t y of t h e a l k y l a t i o n s t e p (=+ 2) i s d i f f i c u l t t o assess. Although crude k e t o t r i e s t e r 2 was o b t a i n e d i n 90% y i e l d ( a f t e r d i s t i l l a t i o n ) , no evidence was o b t a i n e d r e l a t i v e t o i t s s t e r e o c h e m i c a l homogeneity. Upon hydrogenolysis, a c i d 60 (presumably t h e major isomer) was obt a i n e d as t h e only c r y s t a l l i n e product i n 45% y i e l d . While a l k y l a t i o n probably proceeds mainly trans t o t h e C-4 carbethoxy group, o t h e r isomers of 2 may be formed i n t h e r e a c t i o n . Keto a c i d 60 was transformed i n t o diketone 61 by an adapt a t i o n of t h e A r n d t - E i s t e r t method ( v i a t h e a c i d c h l o r i d e , d i azoketone and c h l o r o k e t o n e ) i n 79% o v e r a l l y i e l d . The product o b t a i n e d (61) was a mixture of epimers a t t h e secondary methyl group. Closure of ring-A was accomplished by b r i e f exposure of 61 t o t-BuOK i n t-BuOH. The r e s u l t i n g a l d o l (62) w a s dehydrated by a c i d t o y i e l d t h e cyclopentenone 63 i n 80% o v e r a l l yield. C a t a l y t i c hydrogenation of 63 y i e l d e d t h e c r y s t a l l i n e k e t o d i e s t e r 64. The same product was o b t a i n e d by l i t h i u m ammonia r e d u c t i o n o f 63, a p r o c e s s expected t o y i e l d t h e more stable cis r i n g f u s i o n . The carbonyl group w a s removed v i a its dithio ketal y i e l d i n g d i e s t e r 66. S a p o n i f i c a t i o n of 66 y i e l d e d (+)-norcedrenedicarboxylic a c i d t h u s conf i r m i n g t h e s t e r e o c h e m i s t r y assigned t o the secondary methyl group and e s t a b l i s h i n g t h e complete s t e r e o c h e m i s t r y of 55. A f t e r r e s o l u t i o n of 57 v i a i t s q u i n i n e s a l t , the remaining s y n t h e s i s w a s accomplished u s i n g n a t u r a l l y d e r i v e d E. Compound 21 was converted, by p a r t i a l s a p o n i f i c a t i o n of the dimethyl e s t e r , i n t o t h e h a l f - e s t e r The secondary carboxyl of 67 was transformed i n t o a c e t y l by t h e diazoketone r o u t e . C l a i s e n c y c l i z a t i o n of 68 gave 8-diketone 69, which p o s s e s s e s t h e e s s e n t i a l s k e l e t o n o f c e d r o l . Lithium aluminum hydride r e d u c t i o n of 69 gave (remarkably) t h e secondary a l c o h o l 70 i n good y i e l d . Oxidation of 3 gave a ketone which r e a c t e d with methyllithium t o a f f o r d c e d r o l (E). The probable b i o g e n e s i s of c e d r o l and a-cedrene (below) prompted CoreyZg4 and LawtonZg5 t o design s y n t h e s e s s t y l e d on such a c a t i o n i c c y c l i z a t i o n .
-
5,
(z),
67.
T o t a l S y n t h e s i s of S e s q u i t e r p e n e s
508
Both g r o u p s f o c u s t h e i r a t t e n t i o n on c y c l i z a t i o n of s p i r o I 4 . 5 1 d e c a n e s ( l a s t s t e p of p r o p o s e d b i o s y n t h e s i s ) . Corey s n t h e s i z e d t h e c r u c i a l s p i r o d i e n o n e as o u t l i n e d i n Scheme 5 . '94 p-Methoxyacetophenone (2) w a s c o n v e r t e d , by
goMe Scheme 5 .
eoM eoM
Synthesis of Spirodienone
Br
(Corey)
COZMe
p-TsOH
Zn
0
=
O
C02M e
72 -
71 -
Y
CgH6 ?1
M
e
-
1. H B r , HOAc
2 . H C 1 , MeOH
C02Me
02Me 73 -
74 -
Tricarbocyclic Sesquiterpenes
H+ O ?H
D
O
T
C02Me
C02Me
C B0 r 2
p 1. NaOMe (C02Me)2-
2. Br2 3 . NaOMe
76 -
75 -
h
H
509
M
e
Br
C02Me
78 -
77 NaOMe
7
Reformatsky r e a c t i o n with e t h y l y-bromocrotonate, i n t o hydroxy Dehydration, followed by hydrogenation gave e s t e r e s t e r 72. 74. A f t e r demethylation and r e - e s t e r i f i c a t i o n , t h e p h e n o l i c hydroxyl was p r o t e c t e d a s i t s t e t r a h y d r o p y r a n y l e t h e r , Bromination a t o t h e e s t e r group i n 76 was achieved by o x a l y l a t i o n , bromination of t h e r e s u l t i n g s o d i o d e r i v a t i v e and deoxa l y l a t i o n . The r e s u l t i n g a-bromo e s t e r (77) was d e p r o t e c t e d t o y i e l d t h e p h e n o l i c bromo e s t e r 2. Base c a t a l y z e d c y c l i z a t i o n gave an equimolar mixture of t h e cis- and trans-isomers 79 and 80, which was homogenized upon f u r t h e r t r e a t m e n t with base t o o b t a i n isomer 80. S e v e r a l methods which were used t o e l a b o r a t e i n t e r m e d i a t e 80 a r e summarized i n Scheme 6. C a t a l y t i c hydrogenation y i e l d e d
Scheme 6. Conversion of Spirodienone 80 i n t o (f)-Cedrol and (2)-a-Cedrene (Corey)
1
2. MeLi 3. H30+ 4. AcOR, H+
Hz-Pd/C
Go 'z,,
C02Me
83 -
1
I 510
MeLi
1. HCO2H
2 . 400°, ( 8 0 % )
i
BF3, CH2C12
87 -
HC02H (10-20%)
T r i c a r b o c y c l i c Sesquiterpenes
511
t h e t e t r a h y d r o k e t o ester 81, which r e a c t e d with methyllithium t o a f f o r d a mixture of d i a s t e r e o m e r i c d i o l s (82). When t h i s mixture was exposed t o formic a c i d a t room temperature, ( 2 ) ~ cedrene (56) was produced i n 10-20% y i e l d . P a r t i a l hydrogenation of = w a s s e l e c t i v e , y i e l d i n g a s i n g l e dihydro d e r i v a t i v e (83). Enone r e a c t e d with methyll i t h i u m t o g i v e a mixture of d i o l s (%), which was t r e a t e d with formic a c i d . The p r o d u c t , a mixture of t r i c y c l i c f o r mates, was pyrolyzed b r i e f l y a t 400' t o o b t a i n diene 85 i n 80% y i e l d . Reduction of w i t h l i t h i u m i n ethylamine afforded e x c l u s i v e l y (+ ) -a-cedrene (56) A t h i r d r o u t e t o t h e cedrene s k e l e t o n proceeded through t h e e n o l a c e t a t e 5 , prepared i n t h e manner i n d i c a t e d . Comwhen pound underwent c y c l i z a t i o n t o t r i c y c l i c ketone t r e a t e d with BF3. Treatment of 87 w i t h methyllithium y i e l d e d (+) - c e d r o l (55) The s t e r e o c h e m i s t r y of t h e s e c y c l i z a t i o n r e a c t i o n s i s i n t e r e s t i n g . The isomeric e n o l a c e t a t e s and can, i n t h e o r y , l e a d t o isomeric ketones 87 and 88. A s s e e n , ketone 87 p o s s e s s e s t h e s t e r e o c h e m i s t r y of c e d r o l .
.
.
-
88 -
86b -
Isomer 88 would l e a d t o an isomer of n a t u r a l c e d r o l . However, t h e s t r a i n i n h e r e n t i n compound probably p r e v e n t s i t s f o r mation, even though i o n is d o u b t l e s s p r e s e n t . Since i o n s 86a and 86b a r e i n e q u i l i b r i u m , and o n l y t h e former c y c l i z e s ,
-
e
512
Total Synthesis of Sesquiterpenes
t h e p r o c e s s i s q u i t e e f f i c i e n t . S i m i l a r a r g u m e n t s c a n be adv a n c e d for t h e c y c l i z a t i o n of d i o l s 82 a nd 84,a l t h o u g h t h e disparity i n yields is inexplicable. 1 , a w t o n ' s s y n t h e s i s , w h i c h w a s s i m i l a r l y p a t t e r n e d , is D i e t h y l p-benzyloxyphenylmalonate o u t l i n e d i n Scheme 7 . 2 9 Scheme 7 .
Lawton's S y n t h e s i s o f (+)-a-Cedrene
0
89 -
90 -
OH
92 -
91
P
O
H
H tBOr H E
E
t
0
2
C
e
o
H
___c
t-BuOK t-BuOH
93 -
Br
94
1. KOH, EtOH
2. HC1, ether
C02Et 97 -
____c
1. NaOMe 2. CH2N2
, t '
*C02H
C02H
p+p'.,
's
'5
C02Me
C02Me
101 -
100 -
j-
0
102 -
OH 103 -
56 -
513
514
T o t a l S y n t h e s i s of S e s q u i t e r p e n e s
(E)was a l k y l a t e d w i t h methyl v i n y l k e t o n e t o o b t a i n 90, which was reduced t o hydroxy d i e s t e r 2. H y d r o l y s i s of 2 y i e l d e d , a f t e r a c i d i f i c a t i o n and d i s t i l l a t i o n , t h e l a c t o n e 9 2 . C a t a l y t i c d e b e n z y l a t i o n a f f o r d e d p h e n o l i c l a c t o n e 93, whichr e a c t e d w i t h HBr i n a b s o l u t e e t h a n o l t o g i v e bromo e s t e r C y c l i z a t i o n of 94 gave a s i n g l e s p i r o [ 4 . 5 I d e c a d i e n o n e l a s s i g n e d t h e t r a n s s t r u c t u r e 95. The c o r r e s p o n d i n g t e t r a h y d r o k e t o ester 96 r e a c t e d w i t h methylenetriphenylphosphorane t o y i e l d u n s a t u r a t e d e s t e r 97. A f t e r s a p o n i f i c a t i o n of t h e e s t e r , h y d r o c h l o r i n a t i o n of t h e r e s u l t i n g unsaturated a c i d yielded t h e isomeric chloro a c i d s 98 and i n a r a t i o o f 3 : 2 . When t h i s m i x t u r e was n e u t r a l i z e d w i t h sodium methoxide and t h e c a r b o x y l a t e i o n s k e p t a t 35' f o r 2 4 h r , a m i x t u r e of u n s a t u r a t e d a c i d s w a s o b t a i n e d . A f t e r e s t e r i f i c a t i o n , e s t e r s 100 and 101 were o b t a i n e d i n a r a t i o o f 1 : 3 . The preponderance of isomer 101 s u g g e s t s t h a t t h e c a r b o x y l a t e i o n a s s i s t s i n t h e f o r m a t i o n of t h i s i s o m e r :
=.
-
pCH3 p __c
i/0 '/I
-1
'5,
Cog H
The m i x t u r e of u n s a t u r a t e d e s t e r s w a s t r e a t e d w i t h methylmagnesium c h l o r i d e t o o b t a i n a m i x t u r e of a l c o h o l 103 and an u n s a t u r a t e d k e t o n e , which w a s a s s i g n e d s t r u c t u r e 102. When a l c o h o l 103 w a s d i s s o l v e d i n 88% f o r m i c a c i d a t 25O, (?)-ac e d r e n e (=) was produced i n 8 0 % y i e l d .
D.
E p i z i z a n o i c Acid
Zizaene (=), khusirnol (E), z i z a n o i c a c i d (E), and e p i a r e t r i c y c l i c s e s q u i t e r p e n e s of an i n t e r z i z a n o i c a c i d (107) e s t i n g t y p e which o c c u r i n o i l of v e t i v e r . S i n c e e p i z i z a n o i c a c i d (107) h a s been c o n v e r t e d i n t o compounds 104-106,
104 -
Tricarbocyclic Sesquiterpenes
515
C02H
106 -
107 -
Yoshikoshi's synthesis of 107 (Scheme 8) constitutes a formal synthesis of the others. 29r Scheme 8.
Yoshikoshi's Synthesis of Epizizanoic Acid
___c
NaOEt
C02Me
109 -
108 -
110 -
111 1. NaBH4
3. CH2N2
4. C r O 3
0
8 114 -
"C02Me
1. ( CH 2 S H ) 2
2. N i
-
Total Synthesis of Sesquiterpenes
516
t- BuOK
116 -
115 0
0
118 -
117 -
119 -
(108)
107 -
Methyl ( + ) -camphenecarboxylate was reduced t o a l 109,which was o x i d i z e d by M o f f a t t ' s method t o aldehyde 110. Condensation of t h e l a t t e r w i t h a c e t o n e gave t h e trans enone 111. Compound 111 underwent h y d r o c y a n a t i o n and subs e q u e n t o z o n o l y s i s t o g i v e a s i n g l e cyano d i k e t o n e (=) in 45% y i e l d . C y c l i z a t i o n of t h i s 1 , 5 - d i k e t o n e y i e l d e d the cyano enone 113. A f t e r h y d r o l y s i s of t h e cyano g r o u p and e s t e r i f i c a t i o n of t h e r e s u l t i n g a c i d , t h e c a r b o n y l group was removed by Raney n i c k e l d e s u l f u r i z a t i o n of a d i t h i o k e t a l . Osmylation of t h e d o u b l e bond gave a d i o l , whose monounderwent b a s e c a t a l y z e d p i n a c o l r e a r r a n g e m e n t . m e s y l a t e (=) Ketone 117 was produced i n i t i a l l y . Prolonged t r e a t m e n t w i t h and 118 (2:3). Isomer b a s e gave an e q u i l i b r i u m m i x t u r e of 118 was c o n v e r t e d i n t o k e t o a c i d 119. W i t t i g r e a c t i o n on t h e sodium s a l t o f 119 gave e p i z i z a n o i c a c i d (107)i n a p p r o x i m a t e l y 10% y i e l d . cohol
-
117
T r i c a r b o c y c l i c Sesquiterpenes E.
517
Longifolene
(120)
Longifolene p r e s e n t s an i n t e r e s t i n g s y n t h e t i c problem. Although t h e r e i s no s t e r e o c h e m i s t r y t o reckon w i t h , construct i o n of t h e unusual t r i c y c l i c s k e l e t o n i s no t r i v i a l t a s k .
After consideration of various routes t o t h e skeleton of , Corey ~ ’ adopted ~ an approach based on i n t e r n a l Michael a l k y l a t i o n of t h e b i c y c l i c enedione
~ 0
121.
121 -
122 -
A f t e r c o n s t r u c t i o n of t h e b a s i c network, it would t h e n be necessary t o i n t r o d u c e t h e t h i r d methyl group, remove t h e superfluous carbonyl group and transform t h e remaining carbony1 i n t o a methylene group. The i n d i c a t e d i n t r a m o l e c u l a r Michael r e a c t i o n had ample p r e c e d e n t i n t h e known conversion of s a n t o n i n ( s t r u c t u r e 2 i n Sec. 4 ) i n t o s a n t o n i c a c i d which presumably occurs by a s i m i l a r mechanism:
(123),
23 (Sec.
4)
T o t a l S y n t h e s i s of S e s q u i t e r p e n e s
518
dione
The Corey s y n t h e s i s (Scheme 9 ) began w i t h t h e u n s a t u r a t e d 124 which w a s f i r s t t r a n s f o r m e d i n t o monoketal 125. Scheme 9.
C o r e y ' s S y n t h e s i s of (?:)-Longifolene
0
124 -
125 -
n
Q
OkS
129 -
128
Qo
: : -
Et?N
@ 0
121
&?
0
Q
122 -
130 -
1. LiAlH4
____c
2 . WK
0
H2Cr04
MeLi ___c
____c
H
132 -
133
I _
519
520
T o t a l S y n t h e s i s of S e s q u i t e r p e n e s
S i n c e d i r e c t r i n g e x p a n s i o n w i t h diazomethane or d i a z o e t h a n e d i d n o t a p p e a r p r o m i s i n g , a more i n d i r e c t approach was adopted. Diene 126,p r e p a r e d by W i t t i g r e a c t i o n on enone w a s hyd r o x y l a t e d t o g i v e a m i x t u r e of d i a s t e r e o m e r i c d i o l s 127. The c o r r e s p o n d i n g m o n o t o s y l a t e s 128 were s o l v o l y z e d t o g i v e the unconjugated enone 129 i n 41-48% y i e l d . Acid c a t a l y z e d hyd r o l y s i s o c c u r r e d w i t h concommitant d o u b l e bond m i g r a t i o n t o a f f o r d t h e d e s i r e d enedione =.* C y c l i z a t i o n o f compound proved t o b e q u i t e d i f f i c u l t . S t r o n g b a s e s r e s u l t e d i n e x t e n s i v e d e g r a d a t i o n , w h i l e weak b a s e s caused no r e a c t i o n a t t e m p e r a t u r e s up t o 1 0 0 " . I t was f i n a l l y accomplished by h e a t i n g with triethylamine i n e t h y l e n e g l y c o l a t 225" f o r 24 h r . Under t h e s e c o n d i t i o n s , t r i c y c l i c d i k e t o n e 122 w a s o b t a i n e d i n 10-20% y i e l d . A f t e r m e t h y l a t i o n of i t was n e c e s s a r y t o remove t h e l e s s h i n d e r e d c a r b o n y l group. Again, unexpected d i f f i c u l t i e s i n t r u d e d . D i r e c t methods (Wolff-Kishner r e d u c t i o n o f 130, des u l f u r i z a t i o n of t h i o k e t a l 131) were n o t e f f e c t i v e . Moreover, was f i r s t reeven when t h e c a r b o n y l g r o u p i n t h i o k e t a l duced, d e s u l f u r i z a t i o n was n o t s u c c e s s f u l . However, when this hydroxy t h i o k e t a l was r e d u c e d by G e o r g i a n ' s a d a p t a t i o n of the Wolff-Kishner r e a c t i o n , (+I-longicamphenylol (132) w a s obt a i n e d i n good y i e l d . O x i d a t i o n o f 132 y i e l d e d ( + ) - l o n g i camphenylone (1331, which was t r a n s f o r m e d i n t o ( + ) - l o n g i f o l e n e (120)by s t a n d a r d methods.
125,
121
121
122,
131
F.
Copaene, Ylangene
The t r i c y c l i c hydrocarbons copaene (135)and y l a n g e n e (136)may be r e g a r d e d a s t r i c y c l i c i s o p r e n o l o g s o f a-pinene ( s t r u c t u r e 2 5 3 , Sec. 5 1 , o r r i n g - c l o s e d forms of a-trans-bergamotene ( s t r u c t u r e 255, Sec. 5 ) . The major s y n t h e t i c problem p r e s e n t e d
-
135 -
136 -
121
*The s t e r e o c h e m i s t r y of compound was n o t e s t a b l i s h e d . This question i s not of p r a c t i c a l importance, s i n c e t h e cis and t r a n s i s o m e r s are presumably i n e q u i l i b r i u m under t h e c o n d i t i o n s o f t h e Michael r e a c t i o n .
T r i c a r b o c y c l i c Sesquiterpenes
253 (Sec. -
5)
255 (Sec. -
521
5)
by t h e s e s e s q u i t e r p e n e s i s c o n s t r u c t i o n of t h e i n t e r e s t i n g t r i c y c l i c nucleus. Of s u b s i d i a r y importance i s t h e stereochemi s t r y of t h e i s o p r o p y l group, r e l a t i v e t o t h e f u n c t i o n a l i t y i n t h e o t h e r six-membered r i n g . An i d e a l c a n d i d a t e f o r f u r t h e r elaboration into and 136 i s t h e t r i c y c l i c i n t e r m e d i a t e 137, which p o s s e s s e s t h e b a s i c nucleus and h a s d i f f e r e n t i a t e d oxygen f u n c t i o n s . F o r conversion of 137 i n t o copaene o r
-
135
ylangene, two f u r t h e r changes would be r e q u i r e d . The carbonyl group must b e converted i n t o an i s o p r o p y l group, and t h e masked hydroxyl group must be changed i n t o v i n y l methyl. Both operat i o n s should be r o u t i n e . Analysis of t h e carbon network s u g g e s t s t h a t it may be produced by one-bond c l o s u r e of a c i s - d e c a l i n p r e c u r s o r . Since t h e r e are four bonds common t o a l l t h r e e r i n g s , t h e r e are f o u r p o s s i b l e p r e c u r s o r s (5-2). There a r e v a r i o u s reasons f o r choosing an approach based on a type 5 i n t e r m e d i a t e . F i r s t , one o f the new-bond t e r m i n i i s a d j a c e n t t o a carbonyl group. Thus, i n t r a m o l e c u l a r a l k y l a t i o n might be used f o r r i n g c l o s u r e . Second, methyl decalones o f t h i s g e n e r a l type a r e r e a d i l y a v a i l a b l e by Robinson a n n e l a t i o n .
522
Total Synthesis of Sesquiterpenes
The Heathcock s y n t h e s i s , b a s e d on t h i s g e n e r a l s y n t h e t i c p l a n , i s summarized i n Scheme 10.2 9 8 U n s a t u r a t e d k e t o a l c o h o l s t r u c t u r e 180, Sec. 4 , w a s c o n v e r t e d i n t o t o s y l a t e 138,which was hydrogenated t o y i e l d t h e c i s - f u s e d k e t o t o s y l a t e 139. P y r i d i n e - c a t a l y z e d d e h y d r o t o s y l a t i o n gave t h e o c t a l o n e A f t e r p r o t e c t i o n o f t h e c a r b o n y l g r o u p , t h e d o u b l e bond w a s o x i d i z e d by p e r a c i d t o o b t a i n o x i d e The o x i d a t i o n is s t e r e o s p e c i f i c , a t t a c k o c c u r r i n g o n l y from t h e more exposed convex s i d e of t h e u n s a t u r a t e d k e t a l The epoxide r i n g w a s opened b y r e a c t i o n w i t h sodium b e n z y l a t e i n b e n z y l a l c o h o l a t 200'. The r e s u l t i n g a l c o h o l 1 4 3 was changed t o t o s y l a t e and t h e k e t a l g r o u p i n g h y d r o l y z e d t o y i e l d i n t e r m e d i a t e 145. Keto t o s y l a t e 145 reacted w i t h methylsulfinyl carbanion i n dimethylsulfoxide, affording t h e
140.
142. 141.
-
Scheme 10. Heathcock's Synthesis of (+I-Copaene and (+I-Ylangene
180 (Sec. -
*J141
138 -
4)
MCPA
__c
0
@3
4CH20Na
___c
0
4CH20H 200°
14 2 -
TsO
p-TsC1
H~O+
__c
__c
C5H5N
14 3 -
144 -
523
524
Total Synthesis of Sesquiterpenes
I
150 -
152 -
+
135 -
146 i n 96% y i e l d . I n an a l t e r n a t i v e r o u t e t o this c r u c i a l i n t e r m e d i a t e , o c t a l o n e 140 was t r e a t e d w i t h N-bromosuccinimide i n b e n z y l a l c o h o l . A f t e r h y d r o l y s i s of some d i b e n z y l k e t a l and b e n z y l e n o l e t h e r , t h e bromo b e n z y l e t h e r 147 was o b t a i n e d i n a p p r o x i underwent c y c l i z a t i o n t o 146 m a t e l y 4 0 % y i e l d . Compound i n 50% y i e l d . desired t r i c y c l i c k e t o e t h e r
a. 1. NBS
147
Br
. 'CH20"%
@CH20H
2.
140 -
H30+ 1 47 -
Tricarbocyclic Sesquiterpenes
525
146
was debenzylated by t r e a t m e n t with H B r i n Keto e t h e r g l a c i a l a c e t i c a c i d . Keto a c e t a t e 148 was obtained i n 55% y i e l d . Treatment of 148 with i s o p r o p y l l i t h i u m gave a mixture of d i a s t e r e o m e r i c s e c o n d a r y - t e r t i a r y d i o l s , which was oxidized t o a mixture of k e t o a l c o h o l s . Dehydration of t h e l a t t e r mixture gave u n s a t u r a t e d ketone i n 17% y i e l d f o r t h e t h r e e steps. A t t h i s p o i n t , t h e r e l a t i v e s t e r e o c h e m i s t r y was e s t a b l i s h e d . C a t a l y t i c hydrogenation of 149 gave a mixture of s a t u r a t e d ketones 150 and 151,which were s e p a r a t e d by preparat i v e g l p c . Isomer 150 was converted, v i a a l c o h o l 152, i n t o (f)-copaene (135). Isomer 151 was transformed i n a s i m i l a r manner i n t o (+I-ylangene (136).The p r o p o r t i o n of 150 and 151 formed i n t h e hydrogenation r e a c t i o n v a s found t o be cond i t i o n dependent. Thus, when 149 was reduced i n e t h y l a c e t a t e o r methanol, isomers 150 and 151 were produced i n a r a t i o o f 3:7. When t h e r e a c t i o n was c a r r i e d o u t i n hexane, t h e 150:151 r a t i o was 6:4. When enone 149 was f i r s t reduced t o alcohol 154 and t h e l a t t e r hydrogenated, a mixture of isomeric seconda r y a l c o h o l s was o b t a i n e d . Jones o x i d a t i o n o f t h i s mixture
149
-
gave ketones 150 and 151 i n a r a t i o of 9 : l . Thus, by choosing t h e proper hydrogenation c o n d i t i o n s , t h e s y n t h e s i s i s s t e r e o s e l e c t i v e f o r e i t h e r (+)-copaene o r (+)-ylangene. G.
p BI
S a t i v e n e , Cyclosativene
S a t i v e n e and c y c l o s a t i v e n e have been shown t o possess s t r u c t u r e s 155 and 156,r e s p e c t i v e l y . For t h e s y n t h e s i s of 155
526
Total Synthesis of Sesquiterpenes
% McMurry chose a route based on intramolecular alkylation of an enolate ion. The ideal candidate for such a cyclization is keto tosylate 157. The McMurry synthesis is outlined in Scheme ll.299a-
\
OTs
Scheme 11.
125 -
@ 6 - 7 0
OTs
McMurry‘s Synthesis of and (2)-Cyclosativene
-Sativene
-4 158 -
L 4 - E ”
hexane 159 -
(+)
H+
160 -
T r i c a r b o c y c l i c Sesquiterpenes NNHAr
NNHAr
161 -
7
527
162 -
@ - ,,,,@ p-TsC1
\\+'
OH
C5H5N
163 -
CHJ!CHZNa
____c
\i"
DMSO
OTs
157 H2S04
___c
HZ.0
hexane
164 -
165 -
155
156 -
Unsaturated k e t o k e t a l 125 w a s hydrogenated t o g i v e t h e a l o n g w i t h approximately 5% of i t s c i s - f u s e d decalone reacted with isopropyllithium a t t r a n s isomer. Compound which was dehydrated - S O o t o g i v e a mixture of a l c o h o l s by t r e a t m e n t w i t h aqueous s u l f u r i c a c i d . Unsaturated ketone 160 was o b t a i n e d i n 80% y i e l d , based on ketone 158. Since diborane r e a c t e d w i t h t h e carbonyl group f a s t e r
158, 158
-
(z),
T o t a l S y n t h e s i s of S e s q u i t e r p e n e s
528
t h a n t h e double bond, enone 160 was f i r s t t r a n s f o r m e d i n t o i t s 2,4-dinitrophenylhydrazone d e r i v a t i v e 161. A d d i t i o n of d i b o r a n e t h e n proceeded n o r m a l l y , w i t h h i g h s t e r e o s p e c i f i c i t y , t o y i e l d a l c o h o l 162. O z o n o l y s i s s u f f i c e d t o remove t h e blocking group, thus a f f o r d i n g k e t o alcohol The c o r r e s p o n d i n g t o s y l a t e (157) underwent base c a t a l y z e d c y c l i z a t i o n i n the des i r e d manner t o y i e l d t r i c y c l i c k e t o n e 3. T h i s s u b s t a n c e was t r a n s f o r m e d , v i a a l c o h o l 165 i n t o ( + ) - s a t i v e n e (155). Treatment o f 155 w i t h c u p r i c a c e t a t e i n r e f l u x i n g a c e t i c acid gave ( t ) - c y c l o s a t i v e n e (156)i n 32% y i e l d . 2 9 9 b
=.
H.
Culmorin
The mold m e t a b o l i t e c u l m o r i n (166)h a s a c a r b o n s k e l e t o n enant i o m e r i c w i t h t h a t of l o n g i b o r n e o l a rearrangement p r o d u c t of l o n g i f o l e n e (120).Although c u l m o r i n i t s e l f h a s n o t been p r e p a r e d by t o t a l s y n t h e s i s , t h e r e l a t e d d i k e t o n e (168)h a s been s y n t h e s i z e d a s t h e r a c e m a t e by R o b e r t s . 3 0 0 The o p t i c a l l y a c t i v e d i k e t o n e i s r e d u c e d by sodium i n i s o p r o p y l
(x),
OH
OH
120
a l c o h o l t o a m i x t u r e of c u l m o r i n a r a t i o of 3:2.301
169 i n -
(166)and
167 -
t h e isomeric d i o l
Tricarbocyclic Sesquiterpenes
h 2 <
529
OH
i-PrOH
+
HO
OH
166 -
168 -
169 -
Roberts' synthesis of (+)-culmorin diketone is summarized was alkylated with in Scheme 12. Tetrahydroeucarvone (170) Scheme 12.
0
Roberts' Synthesis of (+)-Culmorin Diketone C02Et
Br
ACOZEt
P
NaH
170 -
172 -
II
&?
BrCHZCOzEt NaH
=r
0
174 -
175 -
530
T o t a l S y n t h e s i s of S e s q u i t e r p e n e s OH
RuO4
~ a 1 0 ~ ___c
177 -
176 0
k7
Eto2c%7 HC1
___c
HOAc
a
0
178 -
166 -
171,
e t h y l a-bromopropionate t o o b t a i n k e t o e s t e r a s a mixture I n t r a m o l e c u l a r a c y l a t i o n was w i t h sodium h y d r i d e i n accomplished by t r e a t i n g k e t o e s t e r glyme. Diketone was o b t a i n e d i n 65% y i e l d . Methyllithium added s e l e c t i v e l y t o t h e more a c c e s s i b l e carbonyl, a f f o r d i n g k e t o a l c o h o l 173, which w a s dehydrated t o u n s a t u r a t e d ketone 1 7 4 . A l k y l a t i o n of w i t h e t h y l bromoacetate occurred exelusively cis t o t h e one-carbon b r i d g e , a f f o r d i n g k e t o ester 1 7 5 . Hydroboration gave t r i o 1 176 ( a d i a s t e r e o m e r i c m i x t u r e ) , The corresponding d i which was o x i d i z e d t o k e t o d i a c i d methyl e s t e r was c y c l i z e d w i t h sodium e t h o x i d e t o g i v e d i k e t o e s t e r 178,which was hydrolyzed and decarboxylated t o o b t a i n ( - f ) -culmorin d i k e t o n e (166) of d i a s t e r e o m e r s , i n 30% y i e l d .
172
-
171
174
177.
.
I.
a - and 0-Bourbonene
a-Bourbonene (179)and B-boubornene (180)a r e s e s q u i t e r p e n e s of an i n t e r e s t i n g s k e l e t o n which have been i s o l a t e d from Geranium bourbon. The c e n t r a l cyclobutane r i n g s u g g e s t s a s y n t h e t i c r o u t e based on p h o t o a d d i t i o n of two o l e f i n s . Both recorded bourbonene s y n t h e s e s 3 0 2 30 have been accomplished by a v a r i a t i o n of t h i s b a s i c approach.
Tricarbocyclic Sesquiterpenes
179 -
531
180 -
White's synthetic plan (Scheme 13) called for the synthesis of 1-methyl-3-isopropylcyclopentene (181).Photoaddition of this olefin and cyclopentenone in a well-documented reaction,304 should give tricyclic ketones 182 and/or 183. Although the cis-anti-cis relative stereochemistry about the
cyclobutane ring could be confidently predicted on the basis or head-toof analogy ,304 the orientation (head-to-head, I&, tail, 183) could not. The relative stereochemistry of the isopropyl group is also difficult to predict in such a path, although one would probably expect addition to occur predominately trans to this group. Scheme 13.
+
white's Synthesis of (f)-a-Bourbonene and (k)-Bourbonene
6-
1. EtMgBr 2 . i-PrBr 3 . H30+
HC02Et NaOMe
532
- +--
T o t a l S y n t h e s i s of S e s q u i t e r p e n e s
LiAlH4
SOCl2
ether
187
186
_.
n
_.
LiA1H4 ____c
( i - P r ) 2O
188
-
189 -
___c
-
hv
181
'
180 -
179 -
(184)
The cyclohexylimine of cyclopentanone was a l k y l a t e d with i s o p r o p y l bromide t o g i v e , a f t e r h y d r o l y s i s , 2-isopropylcyclopentanone (185).The corresponding a-hydroxymethylene was reduced by L i A l H + t o a l l y l i c a l c o h o l derivative ( 7 0 % ) . Alcohol reacted w i t h thionyl chloride i n ether t o g i v e rearranged c h l o r i d e which was reduced t o cyclopent e n e 181. When a mixture of 181 and cyclopentenone w e r e i r r a d i a t e d , t r i c y c l i c ketones and E w e r e produced i n a r a t i o o f 1:l. Isomer 190 r e a c t e d with methylenetriphenylphosphorane t o g i v e ( + ) -8-bourbonene Acid c a t a l y z e d i s o m e r i z a t i o n a f f o r d e d t h e more s t a b l e (+)-a-bourbonene Brown's s y n t h e s i s o f -a-bourbonene (Scheme 1 4 ) was a c t u a l l y on o f f - s h o o t from an a t t e m p t t o s y n t h e s i z e copaene (see s e c . 6 ) . The s y n t h e t i c p l a n c a l l e d f o r p r o d u c t i o n of t h e d i e s t e r 191. P h o t o c y c l i z a t i o n of 191 could l e a d t o a copaene p r e c u r s e r (192)o r a bourbonene p r e c u r s e r ( E l . A s w i l l be s e e n , d i e s t e r 191 a f f o r d s e x c l u s i v e l y 193.
(186)
(180) .
187
188,
(179).
ra
Scheme 1 4 . 1.
196 -
198 -
193 -
Brown’s Synthesis of (2)-a-Bourbonene
/k/ -
2. H20
194 -
cH0 192 -
191 -
0
( E ~ O )\I~ P - C H ~ C O Z E ~ = _
NaH
A 195 -
197 -
189 -
533
534
Total Synthesis of Sesquiterpenes
The p i p e r i d i n e enamine of i s o v a l e r a l d e h y d e reacted with methyl v i n y l ketone t o g i v e , a f t e r h y d r o l y s i s , k e t o aldehyde 195 ( 7 9 % ) . This s u b s t a n c e r e a c t e d w i t h triethylphosphonoacet a t e t o a f f o r d d i e s t e r 191,a s a mixture of cis,trans isomers. P h o t o c y c l i z a t i o n of 191 gave a diastereomeric mixture, which was hydrolyzed t o o b t a i n a c r y s t a l l i n e d i a c i d (196)i n 53% y i e l d . Although t h e f u l l s t e r e o c h e m i s t r y of is not known, t h e r i n g f u s i o n must be cis and t h e i s o p r o p y l group must be cis t o t h e a n g u l a r methyl group. Diacid 196 was c o n v e r t e d , by S t o r k ' s method ( s e e Scheme 4 ) , i n t o d i k e t o n e 197. A l d o l i z a t i o n of 197 gave enone 198, w h i c h was reduced t o ( 5 ) -a-bourbonene.
-
J.
193,
196
Illudin M
I l l u d i n S (199) , i l l u d i n M (200) and i l l u d o l (201) a r e produced by t h e J a c k - o ' - l a n t e r n mushroom. Compounds and 200 are t o x i c , a n t i b a c t e r i a l and show a n t i t u m o r a c t i v i t y .
199
199 -
OH
200 -
OH
20 1 -
Matsumoto and co-workers, a t Hokkaido U n i v e r s i t y , have r e p o r t e d a h i g h l y i m a g i n a t i v e , s t e r e o s p e c i f i c s y n t h e s i s of i l l u d i n M I which i s o u t l i n e d i n Scheme 1 5 . 3 0 5 Ethyl dimethyla c e t o a c e t a t e e t h y l e n e k e t a l (202) r e a c t e d w i t h m e t h y l s u l f i n y l carbanion t o y i e l d t h e 8-keto s u l f o x i d e 203. When 203 w a s t r e a t e d w i t h i o d i n e i n methanol a d i a s t e r e o m e r i c p a i r of
Scheme 15.
I l l u d i n M--First
Hokkaido Synthesis
0
iin
CH3 SCHF
DMSO
'Go
7
203 -
202 -
OMe
OMe
1. NaBQ
AcoqI NaH
__c
___c
OMe 2. AcgO
204 -
I2
\
__c
01.le
c6 H6
205 -
206 -
NaOEt
207 -
208 -
210 -
209 -
t-BuOK
Ac20
___c
___c
0
211 -
212 -
5 35
536
Total Synthesis of Sesquiterpenes
214 -
2 13 -
OH 2 00 -
215 -
t e t r a h y d r o f u r a n o n e s (204)w a s produced. Reduction gave a mixt u r e of d i a s t e r e o m e r i c a l c o h o l s , which were a c e t y l a t e d t o g i v e 205. Acid c a t a l y z e d h y d r o l y s i s of 205 gave k e t o aldehyde 206, which was c y c l i z e d t o cyclopentenone 207. Michael a d d i t i o n of 8 - k e t o s u l f o x i d e 208 ( p r e p a r e d from e t h y l 1-acetylcyclopropanecarboxylate e t h y l e n e k e t a l and m e t h y l s u l f i n y l c a r b a n i o n ) and c y c l o p e n t e n o n e 207 gave 209. Pummerer r e a r r a n g e m e n t of 209 gave 210. When 210 was h e a t e d i n ethanol, diketone was produced. C y c l i z a t i o n o f y i e l d e d t h e c r y s t a l l i n e enone which was a c e t y l a t e d t o obtain Methylmagnesium i o d i d e a t t a c k e d 213 s o l e l y a t t h e cyclohexanone c a r b o n y l , y i e l d i n g 214 s t e r e o s p e c i f i c a l l y . Borohydride reduction o f t h e cyclopentanone carbonyl also occurred s t e r e o s p e c i f i c a l l y , a f f o r d i n g 215, which r e a c t e d w i t h m e r c u r i c c h l o r i d e i n aqueous a c e t o n e t o y i e l d ( ? ) - i l l u d i n M (200). An a l t e r n a t i v e s y n t h e s i s , a l s o from t h e Hokkaido g r o u p , i s o u t l i n e d i n Scheme 1 6 . 3 0 6 f 3 0 7 I n t e r m e d i a t e 210 w a s reduced by amalgamated aluminum t o 216, which w a s h y d r o l y z e d t o t r i A l d o l c y c l i z a t o n y i e l d e d d i k e t o d i a c e t a t e 218, ketone which r e a c t e d s e l e c t i v e l y and s t e r e o s p e c i f i c a l l y w i t h methylmagnesium i o d i d e t o a f f o r d %. P a r t i a l h y d r o l y s i s of 2 y i e l d e d mono-acetate 220 (30%), afa l o n g w i t h d i o l and u n r e a c t e d d i e s t e r . O x i d a t i o n of f o r d e d ( 2 ) - d e h y d r o i l l u d i n M (221), i d e n t i c a l w i t h m a t e r i a l d e r i v e d from n a t u r a l i l l u d i n M. The r e m a i n i n g t r a n s f o r m a t i o n s were c a r r i e d o u t on o p t i c a l l y a c t i v e 221. Hydride r e d u c t i o n gave a t r i o 1 ( 2 2 2 1 , which formed a d i a c e t a t e (223). S e l e c t i v e
-
211
213.
212,
211
217.
220
-
Scheme 1 6 .
@ c.$o:
I l l u d i n M--Second
Hokkaido S y n t h e s i s
2 16 -
210 -
-
MeMgI
t-BuOK
0
___c
t- BuOK
\
218 -
217 -
220 -
219 -
222 -
221 -
Ho&
K2C03 =-r
___c H2Cr04
H20-MeOH
OAc
223 -
OAc
2 24 5 37
538
T o t a l S y n t h e s i s of S e s q u i t e r p e n e s
200 -
225 -
hydrolysis occurred cleanly, yielding, after oxidation, i l l u d i n ( 2 2 5 ) , w h i c h w a s s a p o n i f i e d t o o b t a i n i l l u d i n M. A l t h o u g h i l l u d o l (201) h a s n o t y e t been synthesized, the Hokkaido g r o u p h a s r e p o r t e d a n i n t e r e s t i n s y n t h e s i s o f a compound (240) w h i c h h a s t h e b a s i c s k e l e t o n . j o 8 The s y n t h e s i s , which i s o u t l i n e d i n Scheme 1 7 , b e g i n s w i t h a l k y l a t i o n of
M acetate
Scheme 1 7 .
226 -
Hokkaido R o u t e t o t h e P r o t o i l l u d a n e S k e l e t o n
227 -
EtMgBr ____c
&
OEt
~ a 1 0 ~ ___c
OEt
2 34 -
235 -
P Jp-pz-
0
NaBH4
A12° 3
___c
EtO
Et
2 36 -
OEt
238 -
‘OE t
237 -
OEt
239 -
5 39
540
T o t a l S y n t h e s i s of S e s q u i t e r p e n e s
After hydrolysis B-keto e s t e r 226 w i t h 1-bromo-2-butanone. and decarboxylation, d i k e t o n e 227 was o b t a i n e d . Aldol c y c l i z a t i o n gave an enone, which was hydrogenated t o s a t u r a t e d k e tone 2. Compound = w a s obtained i n 4 1 % o v e r a l l y i e l d . The d e r i v e d a-benzylidine d e r i v a t i v e 230 was reduced and a c e t y l a t e d t o o b t a i n a c e t a t e 231. Ozonolysis o f t h e double bond, followed by s a p o n i f i c a t i o n of t h e e s t e r gave t h e a-hydroxy ketone 232. This was oxidized t o an a-diketone, which w a s a c e t y l a t e d . Enol a c e t a t e 233 was o b t a i n e d s p e c i f i c a l l y . When 233 and 1 , l - d i e t h o x y e t h y l e n e were i r r a d i a t e d , a s i n w a s o b t a i n e d i n 50% y i e l d . Comg l e t r i c y c l i c compound (%) pound 234 r e a c t e d w i t h ethylmagnesium bromide t o g i v e a d i o l (235)which was cleaved by p e r i o d a t e t o dione 236. Basic alumina caused e l i m i n a t i o n of e t h a n o l , y i e l d i n g cyclobutenone 237. This r e a c t e d w i t h sodium borohydride t o g i v e a s a t u r a t e d dial which was o x i d i z e d t o dione 239. Aldol c y c l i z a t i o n of 239 gave t h e t r i c y c l i c i n t e r m e d i a t e 240.
K.
(z),
T r i c y c l i c Rearrangement Products
A number o f i n t e r e s t i n g t r i c y c l i c compounds, d e r i v e d by re-
arrangement of s e s q u i t e r p e n e s , have been prepared by t o t a l synt h e s i s . Although t h e s e m a t e r i a l s a r e n o t a c t u a l l y n a t u r a l p r o d u c t s , t h e i r s y n t h e s e s w i l l be d i s c u s s e d i n t h i s s e c t i o n . Included i n t h i s category a r e a-caryophyllene a l c o h o l (2411, a rearrangement product of humulene; i s o l o n g i f o l e n e (2421, a rearrangement product of l o n g i f o l e n e ; and clovene (243), a rearrangement product o f caryophyllene.
241 -
242 -
243 -
a-Carophyllene a l c o h o l (241) i s formed when humulene ( s t r u c t u r e 276, Sec. 3 ) i s t r e a t e d with aqueous a c i d . A probable mechanism f o r t h e t r a n s f o r m a t i o n i s o u t l i n e d below:
Tricarbocyclic Sesquiterpenes
276 (Sec. 3)
245 -
541
244 -
241 -
Although compound 241 itself is rather complicated from a synthetic standpoint, Corey reasoned that tertiary alcohols corresponding to ions 244 and 245 might be more easily derivable. In particular, alcohol 247, which might derive from tricyclic ketone 246 represents an attractive synthetic intermediate. Corey's synthesis of a-caryophyllene alcohol, based on this approach, is outlined in Scheme 113.~'~ Photoaddition Scheme 18. Corey's Synthesis of a-Caryophyllene Alcohol
+
Total Synthesis of Sesquiterpenes
542
0
248 -
246 -
24 9 -
MeLi HO
24 1 -
247 -
of 3,3-dimethylcyclopentene and 3-methy,cyclohexenone gave three isomeric tricyclic adducts (246, 248, and 249) in a ratio The major isomer 246 was purified by preparative of 7 2 : 1 2 : 1 4 . glpc and treated with methyllithium to yield the crystalline tertiary alcohol 247. When alcohol 247 was treated with sulfuric acid in aqueous THF, a-caryophyllene alcohol was obtained in 5 0 % yield. a rearrangement product of longiIsolongifolene folene, has been synthesized by Dev by the route outlined in Scheme 19.310 The synthesis consists of fusing the C-ring
(z),
Scheme 19. Dev's Synthesis of (2)-Isolongifolene
QaZH 250 -
NCCH2C02Et
MeLi
___c
I
NH~OAC
251 -
T r i c a r b o c y c l i c Sesquiterpenes
254 -
543
255 -
242 o n t o camphene. Dev's s t a r t i n g m a t e r i a l , (?I-camphene-1-carbo x y l i c a c i d , obviously p o s s e s s e s t h e necessary f u n c t i o n a l i t y f o r t h i s purpose. For a s y n t h e s i s of e p i z i z a n o i c acid based on a s i m i l a r approach, s e e Scheme 8. Unsaturated a c i d 250 was converted by methyllithium t o enone 251, which was condensed with e t h y l cyanoacetate t o obt a i n intermediate Conjugate a d d i t i o n of l i t h i u m dimethylcopper y i e l d e d 253, which was hydrolyzed t o u n s a t u r a t e d a c i d 254. Ring c l o s u r e was e f f e c t e d by t r e a t i n g t h e d e r i v e d a c i d c h l o r i d e with s t a n n i c c h l o r i d e . Removal of t h e carbonyl group then a f f o r d e d ( + I - i s o l o n g i f o l e n e (242) The e i g h t - s t e p synt h e s i s was accomplished i n 1 7 % o v e r a l l y i e l d . Clovene (243) i s one of t h e p r o d u c t s o b t a i n e d when caryop h y l l e n e i s t r e a t e d with a c i d . I t has an i n t e r e s t i n g carbon s k e l e t o n , with a cyclopentene r i n g fused o n t o a b i c y c l o [ 3 . 3 . 1 ] nonane system. Raphael has d i s c l o s e d a s y n t h e s i s of clovene.311 The Raphael s y n t h e s i s i s o u t l i n e d i n Scheme 20. Since complete d e t a i l s are s t i l l l a c k i n g , t h e s y n t h e s i s i s simply p r e s e n t e d i n t h e c h a r t without f u r t h e r c o m e n t .
252.
-
.
Scheme 20.
Raphael's S y n t h e s i s of (+)-Clovene CHO
256 -
257 -
G
C
O
z
E
t
Q
C
0
.
zn(HgL
H
HC1
MeOH
259 -
258 -
1.
soc12
2 . CH2N2
.C O & iJ
3.
Ag20 MeOH
s-8- Se02
C02Me
HOAc
26 1 -
260 -
LiAlH4
MnOg
___c
GH -8”5
264 -
& 544
1. H 2 - c a t
1. H 3 0 +
____c
@o
2. base
2. 268 -
270 -
-
2. esterification
265
268 -
269 -
02H
[OI
References
Q 0
LiA1H4-
271 -
545
@OH
272 -
@OC02Me
A@
REFERENCES
1.
( a ) W. P a r k e r , J . S. R o b e r t s and R. Ramage, Q u a r t . R e v . , 21, 331 (1967) ; ( b ) R. B. C l a y t o n , i b i d . , 1 9 , 168 (1965); ( c ) J . H. R i c h a r d s and J. B. Hendrickson, B i o s y n t h e s i s of S t e r o i d s , T e r p e n e s a n d A c e t o g i n s (Benjamin, N e w York, 1964).
2.
( a ) G. O u r i s s o n , S. M u n a v a l l i , and C. E h r e t , Data R e l a t i v e t o S e s q u i t e r p e n o i d s (Pergamon Press, Oxford, 1 9 6 6 ) ; ( b ) A. R. P i n d e r , T h e C h e m i s t r y of the T e r p e n e s (Wiley and Sons, I n c . , New York, 1 9 7 0 ) ; (c) J. L. Simonsen and
H. R. B a r t o n , T h e T e r p e n e s , Vol. 111, 2nd ed. (Camb r i d g e U n i v e r s i t y P r e s s , Cambridge, England, 1 9 6 0 ) ; ( d ) J. L. Simonsen and W. C. Ross, T h e T e r p e n e s , Vol. V , addenda t o Vol. I11 ( w i t h P. DeMayo) (Cambridge U n i v e r s i t y Press, Cambridge, England, 1 9 5 7 ) ; ( e ) P. DeMayo, Monoa n d S e s q u i t e r p e n o i d s ( I n t e r s c i e n c e , New York, 1 9 5 9 ) ; (f) F. Sorm and L. D o l e j s , G u a i a n o l i d e s a n d G e r m a c r a n o l i d e s (Holden-Day, I n c . , San F r a n c i s c o , 1 9 6 6 ) . R. V. J o n e s and M. D. S u t h e r l a n d , C h e m . Commun., 1229 (1968); ( b ) K. Morikawa and Y. H i r o s e , T e t . L e t t e r s , 1799 (1969); ( c ) A . S . Rao, A . P. Sadgopal and S. G. Bhattac h a r y y a , T e t r a h e d r o n , 1 3 , 319 ( 1 9 6 1 ) ; ( d ) K . Takeda, H. Minato and M. Ishikawa, J. C h e m . SOC., 4578 ( 1 9 6 4 ) . R. B. Bates, D. M. Gale and B. J. Gruner, J. Org. Chem., 2 8 , 1086 (1963). L. Ruzicka, Helv. C h i m . A c t a . , 6 , 492 ( 1 9 2 3 ) . G . Bouchardat, C o m p t . R e n d . , 116, 1253 ( 1 8 9 3 ) ; ( b ) F. Tiemann and F. W. Semmler, B e r . , 26, 2708 (1893); ( c ) K. Stephan, J. P r a k t . Chem., 5 8 , 109 ( 1 8 9 8 ) ; ( d ) L . Ruzicka and V. F o r n a s i r , Helv. C h i m . A c t a . , 2 , 182 ( 1 9 1 9 ) . D.
J.
3.
4. 5. 6.
546 7. 8. 9. 10. 11. 12. 13. 14. 15. 16. 17. 18. 19. 20. 21. 22. 23. 24.
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SOC. Chim. F r a n c e ,
558 307. 308.
309. 310.
311.
T o t a l S y n t h e s i s of S e s q u i t e r p e n e s T. Matsumoto, H. S h i r i h a m a , A. I c h i h a r a , H . S h i n , S . Kaqawa, and F. S a k a n , i b i d . , 1171 ( 1 9 7 0 ) . S . Kagawa, S . Matsumoto, S. N i s h i d a , S . Yu, J . M o r i t a , A . I c h i h a r a , H . S h i r a h a m a , and T . Matsumoto, i b i d . , 3913 (1969). ( a ) E . J. Corey and S . Nozoe, J . A m e r . C h e m . SOC. , 8 6 , 1652 ( 1 9 6 4 ) ; (b) 8 7 , 5733 ( 1 9 6 5 ) . R. R. S o b t i and S . Dev, T e t . L e t t e r s , 2893 ( 1 9 6 7 ) ; ( b ) T e t r a h e d r o n , 26, 649 ( 1 9 7 0 ) . ( a ) R. D. H . Murry, W. P a r k e r , R. A. R a p h a e l , and D. B . J h a v e r i , T e t r a h e d r o n , 1 8 , 55 ( 1 9 6 2 ) ; (b) P . D o y l e , I. R. MacLean, W. P a r k e r , and R. A . R a p h a e l , Proc. C h e m . SOC., 239 ( 1 9 6 3 ) .
Total Synthesis OfNatural Products, Volume2 Edited by John Apsimon Copyright © 1973, by John Wiley & Sons, Inc.
THE SYNTHESIS OF TRITERPENES
J. W.
ApSimon and J. W. Hooper*
D e p a r t m e n t of C h e m i s t r y , Carleton U n i v e r s i t y O t t a w a , Ontario, Canada Introduction Squalene and Related Compounds A. Squalenoid Compounds by t h e Coupling o f Two I d e n t i c a l Units B. Squalenoid Compounds by t h e Coupling of Two D i f f e r e n t Units C. Stepwise Syntheses of Squalene D. Malabaricanediol 2 E. Ambrein 56 3. T r i t e r p e n e s with S t e r o i d a l Ring Systems A. L a n o s t e r o l and Congeners (Scheme 2 ) B. C y c l o a r t e n o l 60 4. Nonsteroidal P o l y c y c l i c T r i t e r p e n e s A. The Onocerins and Related Compounds B. The Amyrin Group C. S t e r e o r a t i o n a l Syntheses 5. Presqualene Alcohol Acknowledgments 1.
2.
1.
559 560 560 562 562 566 569 569 569
572 574 574 594 610 63 3 635
INTRODUCTION
The t r i t e r p e n e s c o n s t i t u t e a l a r g e t e r p e n o i d c l a s s 1 i n which r e l a t i v e l y l i t t l e s y n t h e t i c work had been r e p o r t e d u n t i l r e c e n t l y . This i s undoubtedly a r e f l e c t i o n of t h e i r complexity and the stereochemical problems i n h e r e n t i n t h e e l a b o r a t i o n of *Present a d d r e s s : Canada
B r i s t o l L a b o r a t o r i e s of Canada, Candiac,
P.Q.,
559
560
The S y n t h e s i s o f T r i t e r p e n e s
such m o l e c u l e s . T h i s c h a p t e r i s d i v i d e d i n t o t h r e e s e c t i o n s : squalene and r e l a t e d compounds; t r i t e r p e n e s w i t h s t e r o i d a l r i n g s y s t e m s ( e . g . , l a n o s t e r o l 2 ) ; and n o n s t e r o i d a l p o l y c y c l i c t r i t e r p e n e s ( e . g . , a - o n o c e r i n 2, @-amyrin 4, hydroxyhopanone 5 , and a l n u s e n o n e 6 ) .
I.
1 -
5 -
2.
SQUALENE AND RELATED COMPOUNDS
A.
S q u a l e n o i d Compoundsbythe Coupling of ?tro I d e n t i c a l U n i t s
S q u a l e n e 1 o c c u p i e s a key p o s i t i o n i n t h e b i o s y n t h e t i c pathway l e a d i n g t o t r i t e r p e n o i d s and s t e r o i d s . E a r l y s y n t h e t i c work
Squalene and R e l a t e d Compounds
561
c e n t e r e d on t h e c o u p l i n g o f t w o molecules o f f a r n e s y l bromide l i t h i u m t o g i v e a l o w y i e l d of a l l t r a n s - s q u a l e n e 1 a s t h e t h i o u r e a adduct. R e c e n t l y 1 5 a more e f f i c i e n t method h a s been developed and the a n a l o g 8 was coupled u s i n g n i c k e l t e t r a c a r b o n y l t o y i e l d 10.15-bis-norsqualene i n h i g h y i e l d and w i t h 90% s t e r e o s e l e c t i v i t y . Another g e n e r a l l y a p p l i c a b l e c o u p l i n g r e a c t i o n i n v o l v i n g t h e r e a c t i o n of a l l y l i c o r b e n z y l i c a l c o h o l s ( e . g . , 2 t o g i v e lo) w i t h a r e a g e n t formed from methyl l i t h i u m and titanium t r i c h l o r i d e h a s also been r e p o r t e d . T h i s c o u l d presumably b e a p p l i e d t o s q u a l e n e s y n t h e s i s . N o
-7 3 r 4 w i t h
comment h a s appeared as t o t h e mechanism b u t t h e r e a c t i o n can be used €or " c r o s s c o u p l i n g " so t h a t a l c o h o l s and y i e l d e d k e t a l 13,which w a s s u b s e q u e n t l y t r a n s f o r m e d i n t o 15n o r s q u a l e n e . 10-norsqualene and 1 0 ' - n o r s q u a l e n e were a l s o p r e p a r e d from s i m i l a r p r e c u r s o r s . V a r i o u s o t h e r modified s q u a l e n e s , i n c l u d i n g 2 0 , 2 1 - d e h y d r ~ s q u a l e n e ~and 1-norsqualene (cis and t r a n s ) ' have been o b t a i n e d by d e g r a d a t i o n of s q u a l e n e and r e s y n t h e s i s . The v a r i o u s s y n t h e t i c modified s q u a l e n e s were used i n h i g h l y s i g n i f i c a n t t r i t e r p e n e and s t e r o i d b i o s y n t h e s i s i n v e s t i g a t i o n s .g
11
12
+
11 -
12 -
13 -
562 B.
The S y n t h e s i s o f T r i t e r p e n e s S q u a l e n o i d Compounds by t h e Coupling o f Two D i f f e r e n t U n i t s
The u s e - o f t h e W i t t i g r e a g e n t h a s been d e m o n s t r a t e d by f o u r g r o u p s ” who condensed i t w i t h g e r a n y l a c e t o n e 2 and o b t a i n e d a m i x t u r e o f i s o m e r s from which s q u a l e n e was i s o l a t e d i n low
14 -
15 -
y i e l d . Recent r e f i n e m e n t s i n t h e s t e r e o c h e m i c a l c o n t r o l o f t h e W i t t i q r e a c t i o n ” would seem t o make t h i s r o u t e worthy o f reexamination. The c o u p l i n g o f two d i f f e r e n t C-15 u n i t s h a s b e e n r e l a t i v e l y u n e x p l o r e d u n t i l r e c e n t l y when Biellmanl’ r e p o r t e d a method b a s e d on t h e a l k y l a t i o n o f c a r b a n i o n s o f t h e t y p e 16 s t a b i l i z e d by a d o u b l e bond and an a d j a c e n t s u l p h u r atom. These a - c a r b a n i o n s a p p e a r t o s u f f e r v e r y l i t t l e i s o m e r i z a t i o n o f t h e d o u b l e b o n d ( s ) d u r i n g r e a c t i o n . Thus t h e c a r b a n i o n 2, d e r i v e d from f a r n e s y l p h e n y l t h i o e t h e r , was r e a c t e d w i t h f a r n e s y l bromide t o y i e l d t h e c o u p l e d p r o d u c t subsequently d e s u l p h u r i z e d by l i t h i u m i n e t h y l a m i n e t o s q u a l e n e i n 60% overall yield. The method i s g e n e r a l f o r a wide v a r i e t y o f s u b s t r a t e s and would a p p e a r t o be t h e most u s e f u l t o d a t e . Another r o u t e ’ u t i l i z e d t h e sigmatropic rearrangement o f a l l y l i c sulphonoum y l i d s , as i n 19’20, a method s u g g e s t e d a s a p o s s i b l e b i o s y n t h e t i c r o u t e t o s q u a l e n e . Thus, f a r n e s y l n e r o l i d y l s u l p h i d e was r e a c t e d w i t h benzyne t o g i v e t h e y l i d 2 1 which r e a r r a n g e d i m m e d i a t e l y t o 1 2 - p h e n y l t h i o s q u a l e n e 1 8 . N o y i e l d was r e p o r t e d f o r t h i s s e q u e n c e . The c o u p l i n g ofphosphorous y l i d s and a l l y l i c h a l i d e s and r e l a t e d r e a c t i o n s 1 4 a r e important i n t h e s y n t h e s i s of 1,5-dienes. Thus, t h e y l i d o b t a i n e d from t h e t r i b u t y l p h o s p h o n i u m bromide ?2 w a s r e a c t e d w i t h f a r n e s y l bromide 1 t o y i e l d t h e phosphonium s a l t 2 3 r e a d i l y c o n v e r t e d t o s q u a l e n e i n 65% o v e r a l l y i e l d . 1 4 C.
S t e p w i s e S y n t h e s e s of S q u a l e n e
The s t e p w i s e s y n t h e s i s o f s q u a l e n e and similar a c y c l i c t e r p e n o i d s r e q u i r e s a h i g h l y s t e r e o s e l e c t i v e pathway t o t r a n s t r i s u b s t i t u t e d d o u b l e b o n d s , an a r e a which h a s r e c e n t l y e n j o y e d a r e s u r g e n c e of a t t e n t i o n w i t h t h e d i s c o v e r y of t e r p e n o i d i n s e c t hormones. The f i r s t h i g h l y s t e r e o s e l e c t i v e r o u t e t o s q u a l e n e w a s
’
18 R=-SPh + 2 3 R=-PBu3Br
f
E
l
{%
0
3 B I:
56 3
The S y n t h e s i s of T r i t e r p e n e s
564
r e p o r t e d by C o r n f o r t h 1 6 and was based on an asymmetric i n d u c t i o n s t e p f o r t r a n s - t r i s u b s t i t u t e d double bonds. The succ e s s of t h i s r o u t e l i e s i n t h e p r e f e r r e d conformation of an d u r i n g a t t a c k by a Grignard r e a g e n t which, a-chloroketone a c c o r d i n g t o Cram’s r u l e , ” t a k e s p l a c e from t h e l e a s t h i n d e r e d s i d e t o g i v e predominantly 2. Epoxide 26 f o r m a t i o n from t h e c h l o r o h y d r i n can now proceed i n one h i g h l y s t e r e o s e l e c t i v e manner and o l e f i n 27 f o r m a t i o n from t h i s epoxide v i a an iodohydrin p r o c e e d s w i t h g r e a t e r t h a n 80% s t e r e o s e l e c t i v i t y .
4
24 -
25 -
R‘
S
R
L
/o\-
26 -
28 -
Rg L
R
27 -
Squalene and Related Compounds
565
Using t h i s p r i n c i p l e t h e chloroketone E w a s r e a c t e d w i t h t h e Grignard r e a g e n t from 2 t o y i e l d chlorohydrin 2, of c o r r e c t geometry for f i n a l conversion i n t o squalene. Chloride 29 was prepared i n a s i m i l a r way from 2 and 2. The o v e r a l l y i e l d of squalene was 18-20% and a s t e r e o s e l e c t i v i t y of > 7 0 % p e r double bond was achieved. More r e c e n t l y , Brady, I l t o n , and Johnson1* r e p o r t e d even g r e a t e r s t e r e o s e l e c t i v i t y by worki n g a t lower temperatures. An e l e g a n t stepwise t o t a l s y n t h e s i s of squalene has been a c c o n ~ p l i s h e dw~i~t h about 98% s t e r e o s e l e c t i v i t y f o r each doub l e bond formed. The b a s i s o f t h i s method i s a v e r s i o n of t h e C l a i s e n rearrangement i n which a v i n y l e t h e r of t h e type 33 i s formed i n s i t u and thermally rearranged t o 2, t h u s providi n g a t r a n s - t r i s u b s t i t u t e d double bond with pendant funct i o n a l i t y a v a i l a b l e f o r f u r t h e r modification. Similar highly s t e r e o s e l e c t i v e C l a i s e n type p r o c e s s e s have r e c e n t l y been reported2' and t h e s u c c e s s of t h e s e methods probably depends on t h e nonbonded i n t e r a c t i o n s developing i n a c h a i r l i k e s i x membered t r a n s i t i o n s t a t e which f a v o r s 35-t36, l e a d i n g t o a t r a n s - t r i s u b s t i t u t e d double bond, over 7 2 which would lead t o a cis-double bond.
-
-f
34 -
33 -
\q I
p1
OEt
R2
37 -
WR* R1
OEt
38 -
566
The S y n t h e s i s of T r i t e r p e n e s
The s y n t h e s i s of squalene i t s e l f ” s t a r t e d with succinaldehyde 2 which, on r e a c t i o n with 2-propenyllithium, gave t h e diene d i o l 40 a s a mixture of d l and meso forms. On t r e a t m e n t w i t h e t h y l orthoformate and p r o p i o n i c a c i d followed by p y r o l y t i c rearrangement, t h e d i e n e e s t e r g w a s formed with a p u r i t y of 9 7 % . Transformation i n t o t h e corresponding d i aldehyde and r e p e t i t i o n of t h e above sequence of r e a c t i o n s provided t h e t e t r a e n e d i o l 42 and, i n t u r n , t h e t e t r a e n e d i e s t e r 43 ( R = C 0 2 E t ) c o n t a i n i n g about 9% of isomers o t h e r than a l l trans. C r y s t a l l i z a t i o n o f t h e corresponding a l c o h o l 43 (R=CHzOH) allowed removal of unwanted isomers. Reaction of 4 3 (R=CHO) w i t h isopropylidenetriphenylphosphorane a f f o r d e d squalene with 96% p u r i t y with r e s p e c t t o double bond i s o mers. The use of 3-methoxyisoprene f i l q r 2 0 a i n a s i m i l a r C l a i s e n rearrangement i s a p p a r e n t l y e q u a l l y e f f i c i e n t .
-
1
G
CHO
O
H
HO
56%
___c
Et02C
41 -
40 -
39 -
43 -
42 D.
pco
87%-
Malabaricanediol
44 -
45
Attempts t o c y c l i z e squalene 1 o r r e l a t e d compounds t o t e t r a c y c l i c o r g e n t a c y c l i c t r i t e r p e n o i d d e r i v a t i v e s have been f r u i t l e s s , , 2 1 1 2 2 probably due23 t o a t t a c k by t h e a c i d i c r e agents a t s e v e r a l c e n t e r s and/or t o a p r e f e r r e d c y c l i z a t i o n o f t h e type 46 -+ 4 7 . q r 2 4 S h a r p l e ~ stook ~ ~ advantage of t h i s t o s y n t h e s i z e t h e unique t r i t e r p e n e malabaricanediol (Scheme 1 ) . Squalene 1_ was randomly epoxidized with p e r a c e t i c a c i d i n dichloromethane t o g i v e a mixture which, on c o n t r o l l e d hyd r o l y s i s , a f f o r d e d a mixture of 1, squalene-2,3-diol 48, and The i n t e r n a l epoxides 49 t h e isomeric epoxides 49 and
so.
47 -
46 Scheme 1
50 x=o 52 X = ( O H ) 2
53 X=t-OH, -
s-OAC
561
568
The S y n t h e s i s of T r i t e r p e n e s
4 1 % from 0
and were s e p a r a t e d from d i o l 48 by f o r m a t i o n of t h e i r t h i o u r e a c l a t h r a t e s , and from s q u a l e n e by chromatography. Hydrolysis of t h e m i x t u r e of 49 and gave t h e c o r r e s p o n d i n g e r y t b r o - d i o l s 2 and 2 which were s e p a r a t e d by chromatography on s i l v e r n i t r a t e impregnated s i l i c a g e l . The mono-acetate 5 3 of d i o l r e a c t e d w i t h NBS i n t - b u t a n o l t o g i v e (mainly) t h e c y c l i c bromoether 2, t h u s p r o t e c t i n g t h e oxygen f u n c t i o n s Terminal epoxide formation v i a t h e bromoi n t h i s region. h y d r i n ( N B S / H 2 0 and t h e n K2CO3) followed by t r e a t m e n t w i t h z i n c d u s t and a c a t a l y t i c q u a n t i t y of a c e t i c a c i d and subs e q u e n t b a s i c h y d r o l y s i s of t h e a c e t a t e gave t h e r e q u i r e d e p o x y - e r y t h r o - d i o l 55. I f t h e r e d u c t i v e e l i m i n a t i o n o f t h e bromoether were performed with z i n c and l a r g e amounts of a c e t i c a c i d t h e n t h e e p o x i d e group was reduced t o t h e o l e f i n (cis and t r a n s ) , and t h i s r e a c t i o n was shown t o a p p l y t o o t h e r a l i p h a t i c epoxides. Lewis a c i d c a t a l y z e d c y c l i z a t i o n of e p o x y d i o l 55 d i d n o t a f f o r d d e t e c t a b l e amounts of m a l a b a r i c a n e d i o l 45, which was u n s t a b l e under t h e s e c o n d i t i o n s . I t was reasoned t h a t t h e u s e of a n a c i d s t r o n g enough t o p r o t o n a t e e p o x i d e s b u t n o t o l e f i n s was needed. P i c r i c a c i d was used s i n c e i t i s f a i r l y a c i d i c and a l s o h i n d e r e d , and t h e r e f o r e l e s s l i k e l y t h a n o t h e r prot o n i c a c i d s t o a c t a s a nucleophile. T h i s gave a 16% y i e l d of a m i x t u r e of f o u r i s o m e r i c d i o l s . T h e c o r r e s p o n d i n g t r i m e t h y l s i l y l e t h e r s were s e p a r a t e d by p r e p a r a t i v e g.1.c. and d l m a l a b a r i c a n e d i o l 45 was o b t a i n e d a f t e r h y d r o l y s i s .
T r i t e r p e n e s w i t h S t e r o i d a l Ring Systems E.
Ambrein
569
56
Ambrein i s o b t a i n e d from ambergris and h a s n o t as y e t been s y n t h e s i z e d , a l t h o u g h i t s d e h y d r a t i o n p r o d u c t a m b e r t r i e n e 57 h a s been obtained’’ from t h e d e g r a d a t i o n p r o d u c t ambreinolide 58 and dihydro-y-ionone 2, b o t h of which have been independe n t l y synthesized.26
-
58 3.
59 -
TRITEFPENES WITH STEROIDAL R I N G SYSTEMS
Compounds b e l o n g i n g t o t h i s group i n c l u d e l a n o s t e r o l 2 and t h e v a r i a t i o n on i t s methyl s u b s t i t u t i o n p a t t e r n , c y c l o a r t e n o l 60.
570
The Synthesis of Triterpenes
Most of the syntheses depend on the conversion of cholesterol (already totally s y n t h e s i ~ e d1 ~to ~ lanosterol 2, which has been used for the (formal total) synthesis of several compounds.
61 A.
Lanosterol and Congeners (Scheme 2)
Cholesterol 61 was transformed by unexceptional methods2* to the enone 62. Alkylation of the corresponding dienolate anion gave the methyl substituted B,y-enone 63 (63%) thus solving the major synthetic problem, the introduction of the 14ctmethyl group. Wolff-Kishner reduction gave the olefin 64 Scheme 2
BzO
T r i t e r p e n e s w i t h S t e r o i d a l Ring Systems
571
HO 67 68 S i d e -
69
Chain S a t u r a t e d
70 S i d e I
Chain S a t u r a t e d
which i s i n a c i d c a t a l y z e d e q u i l i b r i u m w i t h l a n o s t e n o l 65. There remained t h e problem of i n t r o d u c i n g t h e d o u b l e bond i n t o t h e s i d e c h a i n and t h i s w a s achieved by d e g r a d a t i o n t o 66 and r e s y n t h e s i s t o g i v e l a n o s t e r o l 2. Simple t r a n s f o r m a t i o n s of l a n o s t e r o l have l e d t o t o t a l s y n t h e s e s o f a g n o s t e r o l 67,’’ d i h y d r o a g n o s t e r o l 68, 30 p a r k e o l 69,3 1 and d i h y d r o p a r k e o l 70.3 2 Van Tamelen h a s r e c e n t l y announced“ t o t a l s y n t h e s e s of 2 4 , 2 5 - d i h y d r o l a n o s t e r o l , 24,25-dihydro-A13 (I7) - p r o t o s t e r o l , i s o e u p h e n o l , ( - ) - i s o t i r u c a l l o l and p a r k e o l v i a t h e i n t e r mediacy of t h e nonenzymic c y c l i z a t i o n of t h e e p o x i d e s or t h e i r C-3 epimers.
>
The S y n t h e s i s o f T r i t e r p e n e s
572
B.
Cycloartenol
60
The p u b l i s h e d a p p r o a c h e s t o t h e c y c l o a r t a n e t r i t e r p e n e s a l l depend upon p h o t o l y t i c f u n c t i o n a l i z a t i o n o f t h e C-19 methyl group of l a n o s t a n e d e r i v a t i v e s . Thus, c y c l o a r t a n e 2, t h e p a r e n t hydrocarbon, was obt a i n e d from 1 1 6 - h y d t o x y l a n o s t a n y l a c e t a t e 72. P h o t o l y s i s of t h e n i t r i t e e s t e r of t h e l a t t e r gave t h e C - 1 9 oximino compound 73 which was d e h y d r a t e d and reduced t o t h e a d n e Deaminar e a d i l y cont i o n o f t h i s ave 3B,lla-dihydroxycycloartane v e r t e d t o 2.9 3
-
I& HO
75
74.
-: H71 R=H 7 5 R=OH -
S h a f f n e r e t a l . 3 4 p h o t o l y z e d 1 1 - o x o l a n o s t e n o l 76 and obtained the d i o l which was o x i d i z e d w i t h l e a d t e t r a a c e t a t e t o t h e h e m i a c e t a l 2. T h i s , on t r e a t m e n t w i t h methanes u l p h o n y l c h l o r i d e u n d e r b a s i c c o n d i t i o n s , gave t h e c y c l o p r o panoketone 79 which was r e a d i l y r e d u c e d t o c y c l o a r t a n o l 80.
T r i t e r p e n e s w i t h S t e r o i d a l Ring Systems
w
573
OH
77 -
OH
HO
@} ; c : -
-H
H
H
78 -
79 R=O -
80 R=Hq Barton e t a l . 3 5 have s y n t h e s i z e d c y c l o a r t e n o l 60 i t s e l f (Scheme 3 ) . Thus, r e d u c t i o n of t h e 11-keto compound 81, a v a i l able from l a n o s t e r o l 2 by a simple series of r e a c t i o n s , gave t h e 118-hydroxy compound P h o t o l y s i s of t h e corresponding i n t h e presence o f i o d i n e gave t h e C-19 iodo n i t r i t e ester compound 84 and thence t h e iodoketone E. Treatment of t h i s w i t h base then gave 11-oxocycloartenyl benzoate E w h i c h suff e r e d l o s s of t h e C - 1 1 oxygen f u n c t i o n on r e d u c t i o n with l i t h i u m aluminum hydride t o g i v e c y c l o a r t e n o l 60, i s o l a t e d a s i t s a c e t a t e 87. Scheme 3
82 R=H 83 R=ONO -
574
The S y n t h e s i s of T r i t e r p e n e s
84 85
-
R= HO
R=O
i
60 R=H 0 7 R=Ac 4.
NONSTEROIDAL POLYCYCLIC TRITERE'ENES
A.
The O n o c e r i n s and R e l a t e d Compounds
a - O n o c e r i n w a s shown by B a r t o n a n d O ~ e r t o nt o~ ~h a v e the symm e t r i c a l s t r u c t u r e 2 and t o u n d e r g o a c i d c a t a l y z e d i s o m e r i z a and s u b s e q u e n t c y c l i z a t i o n t o y - o n o c e r i n t i o n to 6 - o n o c e r i n 89. These r e a c t i o n s form t h e b a s i s f o r several t o t a l synt h e s e s i n w h i c h a - o n o c e r i n , whose t o t a l s y n t h e s i s i s d e s c r i b e d b e l o w , was u s e d a s a n a t u r a l r e l a y .
Nonsteroidal P o l y c y c l i c T r i t e r p e n e s
Dinoronocerane
90
575
(Scheme 4 )
Sondheimer and Elad3 have s y n t h e s i z e d t h i s degradation produ c t of a-onocerin ?. Reduction of t h e enedione 91 gave a mixture o f d i o l s 92 which, on o x i d a t i o n w i t h manganese d i o x i d e , a f f o r d e d t h e hydroxyenone 93. A l k y l a t i o n o f t h e corresponding benzoate 94 gave the f3.y-unsaturated ketone 95 which was succ e s s i v e l y reduced by t h e Wolff-Kishner method and hydrogenated t o g i v e t h e t r a n s - d e c a l o l 96. The corresponding ketone 97 was r e a c t e d w i t h sodium a c e t y l i d e and t h e a c e t y l e n i c a l c o h o l 98 so formed was converted t o i t s disodium s a l t and r e a c t e d with a f u r t h e r e q u i v a l e n t of ketone 97 t o g i v e a mixture of meso (m.p. forms of t h e d i o l s . These 210") 99 and dl (m.p. 190') could b e produced d i r e c t l y by r e a c t i o n of two e q u i v a l e n t s o f ketone 97 with a c e t y l e n e dimagnesium bromide. Attack on ketone 97 w a s s t e r e o s p e c i f i c i n both r e a c t i o n s , proceeding by a x i a l a d d i t i o n t o the less hindered a s i d e . The assignment of
100
not
&-a Scheme 4
53%
from
___c
0
91
@..-
0
95 R=Bz -
R2
92 R1=H, R2= (HOH 93 R1=H, R2'0 94 Rl=Bz, R 2 = 0
gl ?, H
79%
93 -
___c
OH
96 R= ( H 97 R=O -
576
The S y n t h e s i s o f T r i t e r p e n e s
@ OH
E
CH
c
111
Ill
C
+
111
c
@ ‘ H
98 -
100 m.p. 190°
/ - -
101 -
99 m . p . -
210°
90 -
d l - and m e s o - s t r u c t u r e s w a s based on t h e assumption t h a t t h e centrosymmetric meso-form would have t h e h i g h e r m e l t i n g p o i n t , a phenomenom known t o h o l d good w i t h v e r y few e x c e p t i o n s . Dehydration of d i o l 100 gave t h e dienyne 101 which was hydrogenated from t h e less h i n d e r e d s i d e t o a f f o r d d l - d i n o r o nocerane This racemate w a s s p e c t r o s c o p i c a l l y i d e n t i c a l w i t h an a u t h e n t i c o p t i c a l l y a c t i v e specimen d e r i v e d from ao n o c e r i n . However, t h e r e s t i l l remained a p o s s i b i l i t y t h a t the s u b s t a n c e o b t a i n e d might be of t h e meso-series s i n c e the i n f r a r e d s p e c t r a showed l i t t l e f i n e s t r u c t u r e . T h i s d o u b t was n o t resolved.
90.
Nonsteroidal P o l y c y c l i c T r i t e r p e n e s The Onoceradienes
102,203 and 104 (Schemes 5
577
and 6 )
Two d i f f e r e n t a p p r o a c h e s 3 8 @ 39 t o t h e o n o c e r a d i e n e s ( i . e . , o n o c e r i n s l a c k i n g t h e C-3 and C - 3 ' hydroxyl g r o u p s ) have l e d t o t h e p r o d u c t i o n of t h e same key i n t e r m e d i a t e Eschenmoser and c o - ~ o r k e r s (Scheme ~~ 5 ) used k e t o - e s t e r 106, o b t a i n e d from t h e t r i e n e - a c i d by a c i d c a t a l y z e d cytwo d i f f e r e n t r o u t e s c l i z a t i o n , t o p r e p a r e t h e enone w i t h l i t h i u m aluminum hyb e i n g employed. Reduction of d r i d e and sodium h y d r i d e gave t h e a l l y l i c a l c o h o l 2 which afforded on o x i d a t i o n . A l t e r n a t i v e l y , r e d u c t i o n of w i t h l i t h i u m aluminum h y d r i d e a l o n e gave a d i o l , t h e monowas o x i d i z e d t o t h e k e t o m e s y l a t e which m e s y l a t e of which a f f o r d e d t h e enone 108 on t r e a t m e n t with b a s e .
105.
107
-
108
108, 106
106
110
Scheme 5
107 C02Me
106 190%
109 185%
1 A
+ isomer m.p. 130' (24%)
112 meso -
113 -
114 1,111
OH *
-
'H
578
105 -
series
Nonsteroidal P o l y c y c l i c T r i t e r p e n e s
579
When = w a s heated i n xylene it underwent a Diels-Alder r e a c t i o n t o g i v e two dimeric products m.p. 172' and m.p. 130" of which t h e former l e d t o a racemic onocerin d e r i v a t i v e and t h e r e f o r e had s t r u c t u r e = w h i l e t h e o t h e r belonged t o t h e meso-series and l e d t o diketone Thus t h e dimers were t h e products of endo a d d i t i o n . Reduction of t h e dimer m.p. 1 7 2 O with sodium i n propanol gave t h e d i o l 113 which w a s r e s o l v e d v i a i t s (-)-menthyloxyacetate. Oxidation of t h e ( + ) - d i o l 113 gave bisnoronoceradione i d e n t i c a l w i t h t h e product obt a i n e d from an ozonolysis of a-onoceradiene 102. F i n a l l y , r e a c t i o n of diketone with methylmagnesium i o d i d e gave t h e diol by a t t a c k from t h e l e s s hindered s i d e , and t h i s was i d e n t i c a l w i t h a sample prepared by Corey3' and described below. Corey and S a u e r s (Scheme 613' a l s o u t i l i z e d a dimerizat i o n , t h e Kolb6 e l e c t r o l y s i s of c a r b o x y l i c a c i d s , i n t h e i r approach. S c l a r e o l 115,which has been t o t a l l y s y n t h e ~ i z e d , ~ ~ was o x i d i z e d t o t h e t r a n s - l a c t o n e 116 which could be isomeri z e d by a c i d t o t h e more s t a b l e c i s - l a c t o n e Both l a c tones have t h e same a b s o l u t e c o n f i g u r a t i o n a s t h e onocerins. Hydrolysis of t h e l a c t o n e s gave t h e corresponding a c i d s 118 and 119. The a c e t a t e 120 of a c i d 118 was a l s o prepared from E l e c t r o l y t i c oxidative s c l a r e o l v i a t h e acetoxy aldehyde decarboxylation (KolbB coupling) of t h e ammonium s a l t s of t h e hydroxy a c i d s 118 and gave t h e dimeric d i o l s ( 1 7 % ) and 123 ( 1 2 % ) , r e s p e c t i v e l y , each accompanied by t h e ketone ( c a . 35%). The l a t t e r was probably formed by f i s s i o n of t h e C-8 t o C-9 bond i n t h e i n t e r m e d i a t e 125 although an i o n i c mechanism cannot be excluded. The d i o l 123 i s i d e n t i c a l with t h a t produced by Eschenmoser and c o - w ~ r k e r s d~e~s c r i b e d above. E l e c t r o l y s i s of t h e a c e t a t e gave t h e dimeric d i o l i n improved y i e l d ( 3 4 % ) and none of t h e ketone was formed. Dehydration of d i o l 122 (hydroxyl groups e q u a t o r i a l ) with phosphorous oxychloride and p y r i d i n e gave a-onoceradiene while s i m i l a r t r e a t m e n t o f d i o l (hydroxyl groups a x i a l and t r a n s - c o p l a n a r with t h e C-9 p r o t o n s ) gave B-onoceradiene 1 0 3 . Treatment of e i t h e r of t h e t e t r a c y c l i c d i o l s 123 w i t h p e r c h l o r i c a c i d i n benzene gave y-onocerene (pentacyclosqualene) 104,i d e n t i c a l with a sample d e r i v e d from n a t u r a l a-onocerin.
112.
105
114
114
=.
-
119
121.
122
124
123
124
122
102
122,
The Onocerins The syntheses described s o f a r r e l a t e t o substances d e r i v e d achieved t h e f i r s t synfrom n a t u r a l p r o d u c t s . Stork e t a l ? t h e s i s of a n a t u r a l l y occurring n o n s t e r o i d a l p o l y c y c l i c t r i terpene (a-onocerin 2). The Stork e t a l . approach u t i l i z e d t h e Kolb6 e l e c t r o l y s i s method used e a r l i e r by Corey3' t o good
Scheme 6
580
Nonsteroidal P o l y c y c l i c T r i t e r p e n e s
126
581
f o r t h e u l t i m a t e sube f f e c t . A simple model compound s t r a t e ( k e t o - a c i d =)w a s coupled t o d i k e t o n e Keto-acid 1 2 7 was f i r s t s y n t h e s i z e d by S t o r k and l a t e r produced by o t h e r workers" r 4 3 u s i n g d i f f e r e n t methods.
s.
-
127
S t o r k ' s Approach t o Acid (Scheme 7 ) .41 Reaction of 6methoxy-1-tetralone 129 w i t h methyl magnesium i o d i d e gave o l e f i n 130 by spontaneous d e h y d r a t i o n of t h e t e r t i a r y b e n z y l i c a l c o h o 1 T E p o x i d a t i o n of t h i s o l e f i n and a c i d c a t a l y z e d
Scheme 7
P 128 -
126 -
doMe 129 -
130 -
131 -
o&oMe
__c 61%
88%
0
132 -
0
133 -
RO
134 -
135 R=H -
136 R=Ac -
582
The S y n t h e s i s o f T r i t e r p e n e s
137 R=H -
139 -
-
1 3 8 R=Me
140 R=Ac 1 2 7 R=H -
r e a r r a n g e m e n t o f t h e m i x t u r e o f d i o l s s o o b t a i n e d , gave t h e B - t e t r a l o n e 131 which, on a n n e l a t i o n w i t h methyl v i n y l k e t o n e , a f f o r d e d t h e t r i c y c l i c enone 132. T h i s gave t h e $,y-unsatur a t e d k e t o n e 133 on geminal d i a l k y l a t i o n w i t h p o t a s s i u m tb u t o x i d e and methyl i o d i d e , and c a t a l y t i c r e d u c t i o n of 133 proceeded from t h e a s i d e (6 f a c e h i n d e r e d by t w o a x i a l methyl g r o u p s ) t o g i v e t h e s a t u r a t e d k e t o n e 134. B i r c h r e d u c t i o n of t h e a r o m a t i c r i n g , w i t h s i m u l t a n e o u s r e d u c t i o n of t h e k e t o n i c group, followed by a c i d h y d r o l y s i s of t h e 1 , 4 - d i e n e so produced gave t h e hydroxyenone The trans-anti stereochemi s t r y i s a s s u r e d s i n c e t h i s i s t h e most stable c o n f i g u r a t i o n and was formed under e q u i l i b r a t i n g c o n d i t i o n s . O z o n o l y s i s of t h e a c e t a t e 136 and o x i d a t i o n of t h e p r o d u c t s , f i r s t w i t h hydrogen p e r o x i d e and a c e t i c acid and t h e n w i t h p e r i o d i c a c i d , gave t h e k e t o - a c i d 137. The k e t o n i c group of t h e correspondi n g e s t e r 138 w a s p r o t e c t e d as t h e k e t a l and t h i s compound w a s t r a n s f o r m e d i n t o t h e k e t o - d i p h e n y l e t h y l e n e 139 by r e a c t i o n w i t h phenylmagnesium bromide, f o l l o w e d by h y d r o l y s i s of t h e k e t a l group and r e a c e t y l a t i o n of t h e 3-hydroxyl group. Oxid a t i o n of t h e d i p h e n y l e t h y l e n e m o e i t y c o u l d be a c h i e v e d by o z o n o l y s i s b u t w a s b e s t performed u s i n g a n o v e l r e a g e n t , ruthenium t e t r o x i d e and sodium p e r i o d a t e i n aqueous a c e t o n e , t o g i v e t h e d , l - a c e t o x y k e t o - a c i d 140. T h i s was r e s o l v e d v i a t h e h a l f hydrogen p h t h a l a t e of t h e methyl e s t e r and i t s s t r y c h n i n e s a l t t o g i v e p u r e samples of t h e (-)-hydroxyketoa c i d 127 and i t s (+)-isomer.
135
=.
Nonsteroidal P o l y c i c l i c T r i t e r p e n e s
127
583
(Scheme 8) . 4 2 The s t a r t i n g Sondheimer’s Approach to Acid m a t e r i a l , t h e hydroxyenone (R=H) (page 575) was hydrogena t e d o v e r platinum t o g i v e t h e d i o l = w i t h a trans-fused r i n g could be consystem. Chromium t r i o x i d e o x i d a t i o n o f d i o l t r o l l e d t o g i v e t h e d e s i r e d k e t o l 142 t o g e t h e r with unchanged The unwanted p r o d u c t s of 1 4 1 , diketone and k e t o l o x i d a t i o n could be reduced back t o d i o l 128 and t h u s recycled.
143,
-
141
144.
Scheme 8
0
95 95 R=H -
OH
141 -
COEt 111
R
0
J$)
’.H
0
The S y n t h e s i s of T r i t e r p e n e s
504
142
w i t h l i t h i u m e t h o x y a c e t y l i d e gave t h e Reaction of k e t o l a c e t y l e n i c d i o l 145 which a f f o r d e d t h e u , B - u n s a t u r a t e d e s t e r 1 4 6 on a c i d t r e a t m e n t f o l l o w e d by a c e t y l a t i o n . Allylic oxidat i o n of t h i s e s t e r w i t h s e l e n i u m d i o x i d e (assumed t o o c c u r from t h e l e s s h i n d e r e d s i d e ) s e r v e d t o i n t r o d u c e t h e needed oxygen f u n c t i o n a t C-8. The u n s a t u r a t e d l a c t o n e s o formed was t r e a t e d w i t h s t r o n g b a s e when double bond m i g r a t i o n , hyd r o l y s i s of b o t h e s t e r g r o u p s and k e t o n i z a t i o n o f t h e e n o l i d e n t i c a l w i t h t h a t preformed gave t h e r e q u i r e d a c i d p a r e d by S t o r k .
147
127,
Ireland's S y n t h e s i s of A c i d
127
(Scheme 9) . 4 3 I r e l a n d ' s obj e c t i v e was t h e p r e p a r a t i o n o f t h e o l e f i n i c hydroxyacid which s h o u l d b e c a p a b l e of t r a n s f o r m a t i o n t o a - o n o c e r i n 3 d i r e c t l y by e l e c t r o l y t i c c o u p l i n g . T h i s o b j e c t i v e w a s n o t resulted instead. a c h i e v e d and a s y n t h e s i s of k e t o - a c i d
148,
127
Scheme 9
/,02,
0
148 -
144 -
95 -
0 0
149 -
A
o
mH2
150 -
-
i
S H
'511
-
p r and o t h e r
-
substances 90%
0
?H
153 -
75%
0
157 C02H
-
-
AcO
R *-
H
1 5 6 R=O 159 R=H2
-
HO
1 63 -
127 -
78%
66%
___c
___c
160 -
162 /C02Me
1 61 585
586
The S y n t h e s i s o f T r i t e r p e n e s
The h y d r o x y e n o n e 95 ( R = H ) w a s h y d r o g e n a t e d t o t h e t r a n s fused product t r a n s f o r m e d b y k e t a l i z a t i o n and o x i d a t i o n o f the k e t a l to t h e ketone R e a c t i o n of t h i s w i t h e t h y l f o r mate and sodium m e t h o x i d e f o l l o w e d by b a s e i n d u c e d O - a l k y l a t i o n , gave t h e isopropoxymethylene k e t o n e Borohydride r e d u c t i o n o f t h i s k e t o n e w a s c o m p l i c a t e d b y 1 , 4 - a d d i t i o n r now Thus, a c i d c a t a l y z e d rearrangement o f known t o b e and s i l v e r t h e product (containing unsaturated alcohol o x i d e o x i d a t i o n of t h e m i x t u r e of k e t o - a l d e h y d e s so o b t a i n e d g a v e , i n a d d i t i o n t o t h e d e s i r e d p r o d u c t 152, a n o i l y k e t o A c i d 152 was e s t e r i f i e d a l c o h o l of p r o b a b l e s t r u c t u r e and, a f t e r p r o t e c t i o n o f t h e k e t o n i c group by k e t a l i z a t i o n , r e d u c e d w i t h l i t h i u m aluminum h y d r i d e t o y i e l d , a f t e r h y d r o l y sis of t h e k e t a l , t h e k e t o - a l l y l i c a l c o h o l This was e q u i l i b r a t e d w i t h e t h y l v i n y l e t h e r and t h e crude u n s t a b l e was r e a r r a n g e d p y r o l y t i c a l l y t o g i v e t h e a c e t a l d e ether I t was t h o u g h t t h a t t h e s t e r e o c h e m i s t r y hyde d e r i v a t i v e a t t h e a c e t a l d e h y d e s i d e c h a i n would b e t h a t d e p i c t e d i n t h a t i s , t h e u n d e s i r e d c o n f i g u r a t i o n f o r a n a - o n o c e r i n precursor, s i n c e the Claisen rearrangement of vinyl e t h e r would p r o b a b l y p r o c e e d v i a a x i a l a t t a c k o n t h e l e s s h i n d e r e d a s i d e (also s t e r e o e l e c t r o n i c a l l y favored) through t r a n s i t i o n state T h i s was c o n f i r m e d when i t was f o u n d t h a t a s i m i l a r r e a c t i o n w i t h e t h e r 158 g a v e a n a l d e h y d e which w a s subsequently transformed i n t o keto-ester This was r e a d i l y e p i m e r i z e d t o t h e more s t a b l e e q u a t o r i a l e s t e r via the e n o l a c e t a t e 162. Aldehyde w a s o x i d i z e d w i t h s i l v e r o x i d e t o the a c i d and t h e c o r r e s p o n d i n g methyl ester w a s r e d u c e d w i t h borohyd r i d e t o g i v e , a f t e r a c e t y l a t i o n , t h e acetoxy ester O z o n o l y s i s o f t h i s a n d a l k a l i n e h y d r o l y s i s of t h e e s t e r g r o u p s r with c o n c o m i t a n t e p i m e r i z a t i o n o f t h e acetic a c i d s i d e c h a i n , gave keto-acid i d e n t i c a l w i t h t h e same compound p r e p a r e d by S t o r k .
144
149.
150.
s)
153.
155
154.
156.
156,
156
157.
160.
156
161
163.
127,
3 - O n o c e r i n from A c i d 127 (Scheme 1 0 ) . 4 1 With t h e s y n t h e s i s of t h e (-)-keto-acid t h e r e r e m a i n e d o n l y the t a s k s o f coup l i n g t w o u n i t s t o g e t h e r a n d c o n v e r s i o n of t h e k e t o n i c r e s i d u e s t o e x o c y c l i c m e t h y l e n e g r o u p s . Thus S t o r k , 4 1 u s i n g cond i t i o n s e s t a b l i s h e d f o r t h e s u c c e s s f u l c o u p l i n g of k e t o - a c i d 1 2 6 , e l e c t r o l y z e d ( - ) - a c i d 127 and o b t a i n e d , a f t e r a c e t y l a t i o n of t h e p r o d u c t , t h e ( - ) - d i a c e t o x y d i o n e identical with a sample d e r i v e d f r o m n a t u r a l a - o n o c e r i n . Attempts t o t r a n s f o r m t h e k e t o n i c g r o u p s of 164 i n t o m e t h y l e n e r e s i d u e s v i a t h e W i t t i g r e a c t i o n f a i l e d , presumably due t o s t e r i c h i n d r a n c e . Instead an i n d i r e c t route w a s used. Reaction o f d i o n e 164 w i t h e t h o x y a c e t y l e n e magnesium b r o m i d e a n d a q u e o u s acid-
127
164
Nonsteroidal Polycyclic Triterpenes
507
Scheme 10
-
32%
28%
HO
(-)-acid 127 -
168 -
AcO 164 /'2
-3
catalyzed rearrangement of t h e d i a c e t y l e n i c d i o l so obtained gave the diacetoxy d i e s t e r 165. The corresponding dihydroxy d i a c i d 166 was then thermally decarboxylated. The mechanism of t h i s r e a c t i o n r e q u i r e s t h e intermediacy of the %,y-unsatur a t e d isomer and it i s known t h a t i n t h e onocerin system t h e isomer shown 167 i s favored. Thus, t h e asymmetric center a t C-9 i s destroyed during t h i s r e a c t i o n . However, it was a n t i c i pated t h a t a-onocerin 2 would n e v e r t h e l e s s be produced ( r a t h e r
588
The S y n t h e s i s o f T r i t e r p e n e s
168
f o r t h e det h a n an i s o m e r ) s i n c e t h e t r a n s i t i o n s t a t e c a r b o x y l a t i o n was e x p e c t e d t o i n v o l v e a x i a l a d d i t i o n of t h e c a r b o x y l p r o t o n t o C-9 ( b e s t o r b i t a l o v e r l a p ) . T h i s proved t o be t h e c a s e and a - o n o c e r i n 2 was o b t a i n e d .
6 and y-Onocerins 75 and 76 (Scheme 11). 4 5 Van Tamelen e t al? a l s o used a c o u p l i n g r e a c t i o n i n s y n t h e s i z i n g the o n o c e r i n s k e l e t o n , t h i s t i m e employing t h e d i m e r i z a t i o n of t h e T h i s bromide w a s produced v i a a b i o a l l y l i c bromide g e n e t i c t y p e c y c l i z a t i o n of an epoxydiene. Thus, methyl t r a n s - t r a n s - f a r n e s a t e 170 was s e l e c t i v e l y e p o x i d i z e d a t t h e Boron t r i f l u o r i d e c a t a l y z e d t e r m i n a l d o u b l e bond t o g i v e c y c l i z a t i o n o f t h i s epoxide yielded s e v e r a l p a r t i a l l y c y c l i z e d p r o d u c t s and a m i x t u r e of hydroxy e s t e r s which w a s shown t o c o n t a i n >90% of t h e e q u a t o r i a l e s t e r and ca. 2 % of t h e axial ester isomerized with The b e n z y l e t h e r of = w a s b a s e t o an e q u i l i b r i u m m i x t u r e o f a,B and B , y - u n s a t u r a t e d e s t e r s . These were s e p a r a t e d by a combination o f chromatography The
169.
171.
172
173.
Scheme 11
170 -
171 -
& C02Me
HO
'H
C02Me
'-H
52% ___c
174 -
1 7 5 R=OH 1 6 9 R=Br -
Nonsteroidal P o l y c y c l i c T r i t e r p e n e s
176 R=Ac 88 R=H -
589
1 7 7 R=Ac 89 R=H -
and s e l e c t i v e h y d r o l y s i s (formic a c i d / s u l p h u r i c a c i d ) of t h e a I 8 - u n s a t u r a t e d e s t e r , t o g i v e t h e a c i d 174. This was r e solved through i t s brucine s a l t and t h e (+)-isomer was reduced t o t h e a l l y l i c a l c o h o l 175 which was r e a d i l y transformed i n t o t h e corresponding bromide 169 using hydrobromic a c i d . Coupling of t h e bromide w i t h magnesium i n e t h e r and cleavage of t h e benzyloxy groups u s i n g sodium i n l i q u i d amnonia gave, a f t e r a c e t y l a t i o n , (+)-B-onocerin d i a c e t a t e 176. Acid t r e a t ment of t h i s a f f o r d e d y-onocerin d i a c e t a t e The convers i o n s of t h e d i a c e t a t e s and t o 8-onocerin 88 and yonocerin 89 a r e w e l l known.
176
Serratenediol
=.
178
179 R=H, 180 R=O
-
177
OAc
178 R=H, 181 R=H, 182 R=O 183 R'H2 -
OH
OAc
A s p r e v i o u s l y mentioned, d e r i v a t i v e s of a-onocerin rearrange
when t r e a t e d with a c i d c a t a l y s t s , f i r s t t o 8-onocerin types and subsequently t o t h e p e n t a c y c l i c y-onocerin s e r i e s . The a-onocerin + B-onocerin t r a n s f o r m a t i o n obviously involves prot o n a t i o n of both of t h e e x o c y c l i c methylene groups. Tsuda e t a l . 4 6 reasoned t h a t i f a bulky a c i d c a t a l y s t were used then
590
The S y n t h e s i s o f T r i t e r p e n e s
onlyone olefinicresiduemightbe affectedand concertedattack of t h e r e s u l t a n t p o s i t i v e l y charged s p e c i e s on t h e remaining u n s a t u r a t e d c e n t e r could occur w i t h t h e p o s s i b l e formation of s e r r a t e n e d e r i v a t i v e s , t h a t i s , 178 c o n t a i n i n g a seven membered C r i n g . I n t h e e v e n t , t r e a t m e n t of a-onocerin d i a c e t a t e 1 7 9 o r a-onocerindienedione w i t h boron t r i f l u o r i d e i n chloroform y i e l d e d s e r r a t e n e d e r i v a t i v e s and 182 which were d e t e c t e d and i d e n t i f i e d by t r a n s f o r m a t i o n t o t h e hydrocarbon 183, followed by g a s - l i q u i d chromatographic (g.1.c.) a n a l y s i s . B and y-onocerin d e r i v a t i v e s were a l s o formed i n t h e s e react i o n s . Serratenedione was i s o l a t e d by f r a c t i o n a l c r y s t a l l i z a t i o n and shown t o be i d e n t i c a l w i t h a sample d e r i v e d from t o which it could be the natural product, serratenediol converted by r e d u c t i o n t h u s completing t h e s y n t h e s i s .
180
-
181
182
178,
Tetrahymanol and the Hopane Group (Schemes 1 2 and 1 3 ) S w i s s workers4' were t h e f i r s t t o t a k e advantage of t h e t r a n s formation of a-onocerin t o p e n t a c y c l i c y-onocerin f o r t h e synt h e s i s of t r i t e r p e n o i d d e r i v a t i v e s o f t h e hopane series. P r e v i o u s l y , Barton and O ~ e r t o nhad ~ ~ shown t h a t y-onocerin d i acetate gave t h e k e t o - d i a c e t a t e 684 (Scheme 1 2 ) on t r e a t reduced t h i s k e t o n e (Wolffment w i t h p e r a c i d . JEger e t a l ? ' Kishner) t o t h e d i a c e t a t e 185 and t h e n p a r t i a l l y o x i d i z e d t h e Treatment of corresponding d i o l 186 t o t h e hydroxyketone t h i s with F u l l e r s e a r t h i n b o i l i n g xylene gave hop-17(21)enone 188, a d e g r a d a t i o n product of hydroxyhopanone 189. Tsuda e t a l . 4 8 have prepared t h e a c e t a t e of 187 by p a r t i a l h y d r o l y s i s of d i a c e t a t e 184 t o t h e hydroxyacetate 176 followed b y o x i d a t i o n t o k e t o a c e t a t e 191. Wolff-Kishner r e d u c t i o n o f t h e hydroxyketone and p u r i f i c a t i o n o f t h e p r o d u c t v i a t h e a c e t a t e gave tetrahymanol 192, a p r o t o z o a l t r e r p e n e . Van Tamelen and co-workers have recently" synthesized by means of t h e a b i o l o g i c a l dl -A12-dehydrotetrahymanol c y c l i z a t i o n of epoxide as i n d i c a t e d ; t h i s w a s t h e n converted i n t o tetrahymanol 192.
177
187.
187
195a -
195b -
Scheme 1 2
177
I
184 R , R ' = A c , 185 R , R ' = A c , 186 R , R ' = H , -
R"=O R"=H2 R"=H2 190 R=H, R ' = A c , R"=H2
-
592
The S y n t h e s i s o f T r i t e r p e n e s
193
and i s o l a t e d Kishi e t a l . 4 9 solvolyzed t h e t o s y l a t e t h r e e p r o d u c t s A , B , and C . P r o d u c t A w a s t h e k e t o - o l e f i n which, on c a t a l y t i c r e d u c t i o n of b o t h t h e d o u b l e bond and the c a r b o n y l group, a f f o r d e d t e t r a h y m a n o l P r o d u c t B was hop-21(22)-enone known a s a d e g r a d a t i o n p r o d u c t o f hydroxyhopanone P r o d u c t C w a s i d e n t i c a l w i t h hydroxyhopanone 189 i t s e l f , a n a t u r a l p r o d u c t o b t a i n e d from dammar r e s i n . S e v e r a l hopane t y p e t r i t e r p e n e s have been s y n t h e s i z e d from hydroxyhopanone 189 (Scheme 1 3 ) . Thus, Wolff-Kishner reduct i o n o f 189 gaveSUTS1 t h e n a t u r a l p r o d u c t d i p l o p t e r o l 196 and t h i s , on t r e a t m e n t w i t h phosphorous o x y c h l o r i d e i n p y r i d i n e , a f f o r d e d a m i x t u r e o f hop-21(22)-ene 197 and t h e o l e f i n i c Oxidation of t h i s mixture with n a t u r a l product diploptene osmium t e t r o x i d e l e d t o i s o l a t i o n o f t h e g l y c o l 199 d e r i v e d from 198 and t h i s , on c l e a v a g e w i t h l e a d t e t r a - a c e t a t e under c o n d i t i o n s m i l d enough t o a v o i d e p i m e r i z a t i o n o f t h e p r o d u c t , gave t h e k e t o n e 200 known a s a d i a n t o n e , a t r i t e r p e n e i s o l a t e d from a J a p a n e s e f e r n . Ketone 200 i s e p i m e r i z e d by b a s e 5 1 1 5 2 t o t h e more s t a b l e isomer 201 t h e e n o l acetate o f which, on o x i d a t i o n w i t h osmium t e t r o x i d e , a f f o r d e d s 2 t h e n a t u r a l prodChromatography o f k e t o l 202 on u c t hydroxyadiantone alumina g i v e s ketohakonanol a compound w i t h which i t cooccurs i n nature.
-
189.
192.
195
198.
=. 203,
Scheme 13
1 8 9 R=O 1 9 6 R'H2 -
-
+
194
Nonsteroidal P o l y c y c l i c T r i t e r p e n e s
-
c
593
202 -
201
Recently, I g u c h i and Kakisawati3 achieved a s y n t h e s i s of t h e n a t u r a l p r o d u c t fern-8-ene (Scheme 1 4 ) . y-Onocerin diacetate was p a r t i a l l y d e a c e t y l a t e d w i t h methylmagnesium and The i o d i d e t o g i v e a mixture of hydroxyacetates mixture o f isomers was n o t s e p a r a t e d u n t i l t h e penultimate s t a g e b u t s i n c e b o t h s e r i e s underwent i d e n t i c a l r e a c t i o n s u n t i l t h e n , o n l y t h e s t r u c t u r e s l e a d i n g t o fern-8-ene a r e d e s c r i b e d and d e p i c t e d . Thus, o x i d a t i o n of 205 t o t h e ketone followed by Wolff-Kishner r e d u c t i o n gave t h e hydroxyolefin 207 which, on t r e a t m e n t w i t h phosphorous p e n t a c h l o r i d e , afforded t h e rearranged d i e n e g . F u r t h e r rearrangement u s i n g F u l l e r s e a r t h i n r e f l u x i n g xylene gave a mixture from which t h e d i e n e 209 was i s o l a t e d as a p u r e compound. This gave fern-8-ene on Birch r e d u c t i o n .
177
204
205
Scheme 14
117 R=R'=Ac 205 R=H, R ' = A c 206 R=Ac, R'=H -
207 -
206.
594
The Synthesis of Triterpenes
209 -
208 -
204 B.
The Amyrin Group
Total synthesis of triterpenes of the amyrin group, including those of natural products which can be derived from 8-amyrin 4 by 1,2-methyl and/or hydrogen shifts (e.g., taraxerol 2 and multifluorenol 2111, are based on three syntheses of olean13(18)-ene 212, and a later partial synthesis of 8-amyrin itself from olefin 212 by Barton.54
210 -
211 -
Nonsteroidal P o l y c y c l i c T r i t e r p e n e s
Olean-l3(18)-ene
212 and
595
Related Compounds
A l l t h r e e s y n t h e s e s o f t h i s type have involved a preformed
AB/DE t e t r a c y c l i c r i n g s stem which was t h e n c c l i z e d by a c i d have proc a t a l y s i s . Corey e t a l . Y 5 and B a r l t r o p e t al."
duced substances formulated a s t h e same t e t r a c y c l i c i n t e r mediate 226 by d i f f e r e n t r o u t e s , and each group transformed t h i s compound i n t o an o l e a n - l 3 ( 1 8 ) - e n e d e r i v a t i v e , a l s o by d i f f e r e n t methods. Sondheimer and Ghera57 used procedures r e m i n i s c e n t of t h o s e a l r e a d y d e s c r i b e d i n t h e i r syntheses of onocerin d e r i v a t i v e s .
Olean-ll,12,13,18-diene 214 (Scheme 15). C ~ r e ys y~n t h ~e s i z e d t h i s d e r i v a t i v e , which had p r e v i o u s l y been transformed i n t o o l e a n - l 3 ( 1 8 ) - e n e , u s i n g a r i n g s ABE -+ r i n g s ABDE + amyrin approach. The key i n t e r m e d i a t e s , t h e AB r i n g s p r e c u r s o r 215 and t h e E r i n g p r e c u r s o r 216, were produced a s follows. The s t a r t i n g m a t e r i a l (+)-ambreinolide 58, a degradation product of ambrein 56 (p. 569), has been t o t a l l y s y n t h e s i z e d S a p o n i f i c a t i o n of l a c t o n e 50 and i n t h e racemic form subsequent m e t h y l a t i o n and dehydration of t h e t e r t i a r y T l c o h o 1 gave t h e o l e f i n i c e s t e r 217 which, on r e d u c t i o n w i t h l i t h i u m aluminum h y d r i d e , a f f o r d e d t h e a l c o h o l 218 and then t h e t o s y l a t e and t h e (+)-bromide g. The a c i d 219 was a l s o prepared from t h e aldehyde 220 o b t a i n e d from s c l a r e o l . Thus, aldehyde 220 w a s converted t o t h e n i t r i l e 221 v i a t h e a l c o h o l and b r o s y l a t e , t h e acetoxy group w a s e x t r u d e d by r e f l u x i n g i n q u i n o l i n e , and h y d r o l y s i s of t h e u n s a t u r a t e d n i t r i l e gave a c i d 219. The Michael adduct 222 from d i k e t o n e 223 and methyl a c r y l a t e was s a p o n i f i e d and cyclodehydration of t h e a c i d gave enoll a c t o n e 224. Hydrogenation of t h e o l e f i n i c bond was accompan i e d by hydrogenolysis o f t h e l a c t o n i c oxygen t o g i v e a ketoa c i d which a f f o r d e d t h e racemic e n o l l a c t o n e 216 on r e c y c l i z a tion. Reaction of t h e Grignard r e a g e n t d e r i v e d from (+)-bromide 215 w i t h t h e racemic enol-lactone 216 gave t h e crude d i k e t o n e s 225 a s an o i l y mixture o f s t e r e o i s o m e r s . Intramolecular a l d o l condensation was achieved by t r e a t m e n t with potassium t - b u t oxide and t h e mixture o f conjugated ketones *was readily s e p a r a t e d from s u b s t a n t i a l amounts of by-products, although s e p a r a t i o n o f t h e two isomers could n o t be achieved. T r e a t ment of ketones 226 with methyl l i t h i u m gave a mixture of t e r t i a r y a l c o h o l s 227 which was used d i r e c t l y f o r t h e a c i d c a t a l y z e d c y c l i z a t i o n . This c r i t i c a l s t e p was expected t o proceed v i a i n i t i a l dehydration t o g i v e , f o r example, t h e t r i e n e 228 which could then p r o t o n a t e t o form v a r i o u s c a t i o n s i n e q u i l i b r i u m , i n c l u d i n g t h e s p e c i e s 229. A d r i v i n g f o r c e
(z).
-
GO
0
a
596
597
598
The S y n t h e s i s of T r i t e r p e n e s
f o r t h e c y c l i z a t i o n of 229 t o t h e s t e r i c a l l y s t r a i n e d pentac y c l i c system should be t h e g e n e r a t i o n of a s t a b i l i z e d a l l y l i c c a t i o n ( e . g . , G ) . Thus, t h e behavior of t h e mixture 227 with a l a r g e number of a c i d i c r e a g e n t s was i n v e s t i g a t e d , d e t e c t i o n of t h e d e s i r e d p r o d u c t being f a c i l i t a t e d by i t s v e r y charact e r i s t i c uv spectrum. Only one of t h e s e r e a g e n t s , hydrogen c h l o r i d e , showed any promise and optimum r e s u l t s using a c e t i c acid a s s o l v e n t gave e s t i m a t e d y i e l d s of about 5 % . ( - ) - d i e n e 2 1 4 , i d e n t i c a l w i t h a sample d e r i v e d from 6-amyrin was eventua l l y obtained i n 1 . 5 % y i e l d a f t e r e x t e n s i v e chromatography,
-
.
Olean-1 3 ( 18) -ene and 18-Olean-12-ene (Schemes 16 and 1 7 ) B a r l t r o p and RogersS6 (Scheme 1 6 ) prepared a t e t r a c y c l i c subs t a n c e assigned t h e same g e n e r a l s t r u c t u r e a s t h e i n t e r m e d i a t e 226 produced by Corey. The approach used was t o couple two u n i t s c o n t a i n i n g t h e preformed AB and DE r i n g systems, t h e l a t t e r fragment being t h e b i c y c l i c ketone 231 p r e v i o u s l y produced by H a l s a l l and Thomas” a s shown. Scheme 1 6
2 32
234 R=CH2,
... OH 2 3 3 R=\Mer
R‘=OH
R’=OH
2 3 5 R=CH2 , R ’ = B r
Nonsteroidal P o l y c y c l i c T r i t e r p e n e s
599
237 R=O OH 238 R= (Me
2 36 -
+ 2 39 241 l7a-Me -
212 240 17a-Me -
The d i t e r p e n e s c l a r e o l 115,which h a s been t o t a l l y syn, was o x i d i z e d under c a r e f u l l y c o n t r o l l e d cont h e s i z e d (*) d i t i o n s t o give t h e enol e t h e r =which, on ozonolysis and hydride r e d u c t i o n o f t h e mixture o f a c i d s and aldehydes produced, a f f o r d e d t h e d i o l 233 and t h e o l e f i n i c a l c o h o l On t r e a t m e n t with phosphorous oxybromide both of t h e s e gave t h e ( + ) - o l e f i n i c bromide t h e p r e c u r s o r of r i n g s A and B. A l k y l a t i o n of t h e anion o f racemic enone 231 with (+)bromide 235 gave a mixture o f epimeric dienones which on Birch r e d u c t i o n a f f o r d e d t h e mixture of o l e f i n i c ketones 237. These w e r e converted by methyl l i t h i u m t o t h e mixture o f a l cohols 238 which w a s cyclodehydrated with aluminum c h l o r i d e t o g i v e a product c o n t a i n i n g about 35% o f p e n t a c y c l i c hydrocarbons. P r e p a r a t i v e g.1.c. o f t h i s m a t e r i a l a f f o r d e d a sample of mixed c r y s t a l s o f (-) -olean-13 (18)-ene 212 and (-) -18aolean-12-ene 239, i d e n t i c a l w i t h t h e same substance o b t a i n e d The o t h e r p e n t a c y c l i c s u b s t a n c e s were assigned from B-amyrin. t h e 1 7 a - s t r u c t u r e s 240 and 241. Sondheimer and G h e r a ' s r s y n t h e s i s (Scheme 16) of t h e t i t a l compounds a l s o s t a r t e d from enone 231 which was t r a n s -
*.
235,
236
600
The S y n t h e s i s of T r i t e r p e n e s
242
by d e s u l p h u r i z a t i o n of t h e t h i o formed i n t o the o l e f i n k e t a l , and t h e n c e t o t h e d e c a l o n e v i a h y d r o b o r a t i o n and o x i d a t i o n . The a c e t y l e n i c a l c o h o l 98, p r e v i o u s l y u s e d i n t h e s y n t h e s i s of o n o c e r i n d e r i v a t i v e s , w a s c o n v e r t e d t o i t s d i magnesium bromide s a l t and r e a c t e d w i t h k e t o n e 243. The d i o l
243
Scheme 1 7
CH
\I1
23 1 -
243 -
242 -
+
t
2 4 7 m.p. -
258'
Nonsteroidal P o l y c y c l i c T r i t e r p e n e s
248 R=H m.p. 249 R=Ac -
245O
ri;) .1.'3
601
250 -
I
239 A-12,18a-H 2 1 2 A-13(18) -
251 -
produced was dehydrated t o g i v e a mixture of t h e dienynes 244 and 245. Formation of t h e r e q u i r e d t r i s u b s t i t u t e d double bond isomers (shown) w a s p r e d i c t e d f o r t h e c i s - f u s e d decalone on t h e b a s i s of conformational a n a l y s i s . I t was thought t h a t t h e t r a n s - f u s e d isomer of 243 would have y i e l d e d compounds cont a i n i n g t e t r a s u b s t i t u t e d double bonds. O s m i u m t e t r o x i d e c a t a l y z e d o x i d a t i o n o f t h e double bonds was followed by hydrogenation o v e r platinum. The l a t t e r rea c t i o n proceeded d i f f e r e n t l y f o r t h e two isomers 244 and 245 g i v i n g compounds l a t e r i d e n t i f i e d a s o l e f i n i c t e t r a - o l 246 and s a t u r a t e d t e t r a - o l 247 m.p. 258'. These were r e a d i l y separated and t h e o l e f i n i c compound 246 w a s f u r t h e r hydrogenated t o t h e isomer of 247, t e t r a - o l 248 m.p. 245". B o t h s a t u r a t e d t e t r a - o l s gave d i a c e t a t e s confirming t h e presence of t r i s u b s t i t u t e d double bonds i n t h e dienynes 244 and 245. Zinc c a t a lyzed S e r i n i r e a c t i o n of t h e d i a c e t a t e 249 gave, a f t e r base c a t a l y z e d e q u i l i b r a t i o n , a mixture presumed t o be mainly t h e isomer 250. Treatment o f t h i s with methylmagnesium bromide and cyclodehydration of t h e d i t e r t i a r y a l c o h o l o b t a i n e d , using p e r c h l o r i c a c i d and a c e t i c anhydride i n benzene, gave a comp l e x mixture i n which t h e presence of oleanenes 212 and 239
602
The S y n t h e s i s o f T r i t e r p e n e s
could b e d e t e c t e d by g . 1 . c . and mass s p e c t r o s c o p y . Selenium d i o x i d e o x i d a t i o n of t h e m i x t u r e a f f o r d e d a sample o f t h e known d i e n e - d i o n e 251 t h u s c o n f i r m i n g t h e s y n t h e s e s of 212 and 239.
-
The s y n t h e s e s of o l e a n - l 3 ( 1 8 ) - e n e o r i t s e q u i v a l e n t s d e s c r i b e d above, and t r a n s f o r m a t i o n s of B-amyrin i n t o o t h e r n a t u r a l p r o d u c t s d e s c r i b e d l a t e r , were o n l y r e c e n t l y l i n k e d b t h e e l e g a n t s e r i e s o f r e a c t i o n s a c h i e v e d by Barton e t al.)54 i n v o l v i n g , t y p i c a l l y , a p h o t o l y t i c p r o c e s s a s t h e key step. B a r t o n ' s s y n t h e s i s (Scheme 1 8 ) w a s i n t w o p h a s e s : t h e f o r m a t i o n o f olean-12-ene 252 from 18a-olean-12-ene 239 and t h e " h y d r o x y l a t i o n " o f o l e f i n 252 a t C - 3 . Although 18a-olean12-ene 239 and o l e a n - l 3 ( 1 8 ) - e n e 212 can be i n t e r c o n v e r t e d by a c i d , olean-12-ene i s n o t p r e s e n t i n t h e e q u i l i b r i u m mixture.
252
Scheme 18
18% ___c
89% __c
253 -
&
4%
256
___c
to
254 -
252 -
255 18a-H 256 1 8 B - H -
HON
30% __c
259 -
257 R=H 258 R=NO
-
262 -
263 -
264 -
60 3
604
The S y n t h e s i s of T r i t e r p e n e s
40%
__c
HO
4
265 -
8-Amyrin
18a-olean-12-ene was converted t o t h e known dienone 253. Birch xeduction of t h i s and a c i d c a t a l y z e d i s o m e r i z a t i o n of t h e product 254 gave a mixture o f t h e e p i m e r i c (C-18) oleanSince t h e s e were r e a d i l y s e p a r a t e d 12-en-11-ones 255 and and t h e 18% compound 256 ha4 p r e v i o u s l y been transformed i n t o olean-12-ene, t h i s completed t h e formal t o t a l s y n t h e s i s of t h a t compound. Oxidation o f olean-12-ene 252 with a novel rea g e n t , N-bromosuccinimide and l e a d t e t r a - a c e t a t e l followed by b a s i c h y d r o l y s i s of t h e a c e t a t e formed, a f f o r d e d t h e l l a a l l y l i c a l c o h o l 257 ( 5 0 % ) . P h o t o l y s i s of t h e corresponding n i t r i t e 258 gave t h e oximino-alcohol 259, t h i s Barton r e a c t i o n b e i n g f a c i l i t a t e d by t h e p r o x i m i t y of t h e C-11 oxygen f u n c t i o n and C-1. Nitrous a c i d t r e a t m e n t transformed t h e oximino funct i o n i n t o a carbonyl group and subsequent hydrogenolysis of t h e a l l y l i c a l c o h o l gave olean-12-ene-1-one 260. Bromination/ dehydrobromination of t h i s ketone produced t h e dienone 261 which smoothly added cyanide ion t o g i v e a mixture of 3-cyano1-ketones 262. Bromination/dehydrobromination of t h i s mixture then gave t h e 6-cyano-enone 263. Reaction of t h i s with e x c e s s methoxide i o n r e s u l t e d i n n u c l e o p h i l i c displacement of t h e n i t r i l e group and t h e methoxy d e r i v a t i v e 264 s o o b t a i n e d was s u b j e c t e d t o h y d r i d e r e d u c t i o n followed by a c i d h y d r o l y s i s t o g i v e t h e 2-ene-3-one 265. Hydrogenation o f t h i s t h e n a f f o r d e d olean-12-ene-3-one which had p r e v i o u s l y been c o n v e r t e d t o Bamyrin. The n i t r i l e 263 was converted t o dienone 265 b y two o t h e r e l e g a n t r o u t e s . Recently, van Tamelen*’ has announced t h a t t h e s t a n n i c c h l o r i d e - n i t r o m e t h a n e induced c y c l i z a t i o n of epoxide 265a l e a d s I n view of e x i s t i n g cont o 8-amyrin ?12 ( 3 B - O H ) i n 8% y i e l d . v e r s i o n s of t h e n a t u r a l compoundl t h i s experiment a l s o l e a d s . t o formal t o t a l s y n t h e s e s of 8-amyrin 4 and germanicol 9
256.
Nonsteroidal P o l y c y c l i c T r i t e r p e n e s
605
265a -
Taraxerol
210
(Scheme 19)
P a r t of t h e s t r u c t u r a l e l u c i d a t i o n of t a r a x e r o l 210 by Spring and c o - w ~ r k e r s involved ~~ t h e p a r t i a l s y n t h e s i s of t h i s t r i t e r p e n e from 6-amyrin. Thus, t h e a c e t a t e 266 was o x i d i z e d t o t h e ketone u s i n g hydrogen p e r o x i d e / a c e t i c a c i d , and t h i s on bromination/dehydrobromination gave t h e u n s a t u r a t e d ketone 268. A f u r t h e r bromination/dehydrobromination proceeded with methyl m i g r a t i o n , presumably v i a a C-13 carbonium i o n , t o y i e l d t h e dienone 269 with a t a r a x e r o l s k e l e t o n . This compound has been prepared by o t h e r methods from 8-amyrin.60 Birch r e d u c t i o n o f t h e conjugated double bond followed by a Wolff-Kishner r e d u c t i o n under f o r c i n g c o n d i t i o n s gave t a r a x e r o l 210.
267,
-
Scheme 19
606
The S y n t h e s i s of T r i t e r p e n e s
Mu1 t i f l o r e n o l
212
(Scheme 2 0 )
Corey e t a1.61 noted t h a t e t h a n o l s o l u t i o n s of B-amyrin d e p o s i t a c r y s t a l l i n e o x i d a t i o n product on prolonged exposure t o a i r and l i g h t . This was o b t a i n e d i n b e t t e r y i e l d by i r r a d i a t i o n of an a c i d i c e t h a n o l s o l u t i o n of 6-amyrin and i t s s t r u c t u r e was e s t a b l i s h e d a s t h e epoxide 270. I t was shown t h a t t h i s probably a r i s e s v i a t h e hydroperoxide 271 which can r e a r r a n g e under a c i d c a t a l y s i s t o t h e l e s s thermodynamically stable t a r a x e r a n e d e r i v a t i v e 270. B o t h of t h e e p i m e r i c 1 1 - a l c o h o l s 2 7 2 and 273, and t h e a c e t a t e 274 gave t h e a-epoxi.de 270 when t r e a t e d with hydrogen p e r o x i d e and a c i d t h u s s u p p o r t i n g t h e which, s i n c e t h e C-0 bond i s o b v i o u s l y intermediacy of cleaved during t h e r e a c t i o n , probably a r i s e s by a t t a c k of peroxide on t h e a l l y l i c carbonium i o n I t was s u g g e s t e d t h a t t h e s e r e a c t i o n s may p a r a l l e l t h e p o s t u l a t e d n a t u r a l p r o c e s s e s whereby t h e less s t a b l e t r i t e r p e n e s k e l e t a l t y p e s a r e d e r i v e d from t h e amyrins, o r t h e i r i o n s , by an o x i d a t i v e p r o c e s s . The o x i d a t i o n i s s a i d t o "power" t h e rearrangement ( s ) t o less s t a b l e s t r u c t u r e s . The t a r a x e r o l s y n t h e s i s d e s c r i b e d a l r e a d y , i n v o l v i n g a bromination with methyl m i g r a t i o n , f a l l s i n t h e
-
271
=.
0
N
N N u RI,"("
a:
x x o
99 b 8 m II I1 I1
s,"y
N
+X
607
m
0
a
HO
277 -
HO
- H 276 -
c1
31 %
AcO
278 -
Nonsteroidal P o l y c y c l i c T r i t e r p e n e s
609
same category. With t h e s e examples i n mind Corey t r e a t e d t h e epoxide 270 w i t h c h l o r i n e and obtained a s one of t h e products t h e rearranged i s probably formed v i a t h e chloronium i o n c h l o r i d e =which 277. Treatment of t h e c h l o r i d e 276 with l i t h i u m i n e t h y l m i n e followed by a c e t y l a t i o n of t h e 3-hydroxyl gave t h e c h l o r i n e f r e e alcohol Oxidation t o t h e ketone and Wolff-Kishner r e d u c t i o n o f t h i s compound t h e n gave m u l t i f l o r e n o l 211.
-
=.
O l e a n o l i c Acid
279
(Scheme 21)
Barton6’ again u t i l i z e d a p h o t o l y t i c s t e p i n t h e conversion of B-amyrin t o i t s n a t u r a l l y o c c u r r i n g C-28 c a r b o x y l i c a c i d , o l e a n o l i c a c i d 2. Careful epoxidation of B-amyrin-3-benzoate gave t h e 12,13-B-epoxide 280. Previous workers had o b t a i n e d only t h e product o f rearrangement of t h i s epoxide, t h e 12ketone. Epoxide 280 was i n e r t toward l i t h i u m aluminum hydride b u t r e d u c t i o n with l i t h i u m i n ethylamine gave, a f t e r a c e t y l a t i o n , a mixture of t h e 3 , 1 2 - d i a c e t a t e 2&, B-amyrin a c e t a t e Scheme 2 1
2 80 -
281 (45%) -
282 R=H ( 2 4 % ) 283 R=NO ( 8 3 % ) -
284 -
610
The S y n t h e s i s of T r i t e r p e n e s
74% RO
285 R=H, 286 R=O -
OH
(84%)
287 R=Ac 279 R=H -
and t h e r e q u i r e d 13-0-hydroxy-3-acetate 282. P h o t o l y s i s of t h e n i t r i t e ester r e s u l t e d i n o x i m a t i o n of t h e C-28 methyl g r o u p b u t , i n t e r e s t i n g l y , n o t t h e s i m i l a r l y d i s p o s e d C-26 m e t h y l group. N i t r o u s a c i d t r e a t m e n t o f t h e c r u d e oxime afforded t h e hemiacetal which was o x i d i z e d t o t h e l a c t o n e 286. Treatment o f t h i s l a c t o n e w i t h d r y hydrogen c h l o r i d e i n c h l o r o f o r m gave an e q u i l i b r i u m m i x t u r e of 286 and o l e a n o l i c a c i d a c e t a t e 287. The l a t t e r was c o n v e r t e d t o o l e a n o l i c a c i d 279.
283
285
-
284
C.
Stereorational Synthesis
General P r i n c i p l e s The common p e n t a c y c l i c t r i t e r p e n e t y p e s c o n t a i n s e v e n o r more t e r t i a r y o r q u a t e r n a r y asymmetric c e n t e r s a t r i n g j u n c t i o n s . Thus t h e s e n a t u r a l p r o d u c t s r e p r e s e n t a f o r m i d a b l e c h a l l e n g e t o t h e o r g a n i c c h e m i s t i n t h a t t h e s y n t h e t i c o b j e c t i v e w i l l be one of ( a t l e a s t ) 1 2 8 i s o m e r s . N o t s u r p r i s i n g l y t h e n , t h e syntheses of t h e s e types already described have involved t h e p r o d u c t i o n of a p l e t h o r a o f i s o m e r s from which t h e r e q u i r e d compound h a s been s e p a r a t e d w i t h v a r y i n g d e g r e e s o f d i f f i c u l t y . A notable exception is S t o r k ' s s y n t h e s i s 4 ' of t h e t e t r a c y c l i c a - o n o c e r i n 2 which i n t u r n l e d t o s y n t h e s e s o f t r i t e r p e n e s of t h e p e n t a c y c l i c hopane s e r i e s . Recent advances i n s y n t h e t i c o r g a n i c methodology, t h e d i s c o v e r y o f new r e a c t i o n s , and e s p e c i a l l y t h e r a t i o n a l i z a t i o n of t h e s t e r e o c h e m i s t r y o f v a r i o u s r e a c t i o n s i n v o l v i n g substit u t i o n b y , o r a t t a c k of a n i o n s i n rigid polycyclic systems had s e t the stage f o r successful stereoselective synthetic assaults on t h e p e n t a c y c l i c t r i t e r p e n e s . A b r i e f d i s c u s s i o n of s u c h r e a c t i o n s is undertaken h e r e using t h e h y p o t h e t i c a l " r i g i d " r i n q s y s t e m 228 a s a c o n v e n i e n t frame of r e f e r e n c e (see Ref. 6 3
Nonsteroidal P o l y c y c l i c T r i t e r p e n e s
611
f o r a comprehensive s u r v e y ) . This w i l l s e r v e t o e x p l a i n t h e p r i n c i p l e s involved so t h a t no f u r t h e r comment need be o f f e r e d when such r e a c t i o n s a r e met i n t h e s y n t h e t i c work d e s c r i b e d i n t h e sequel. A l k y l a t i o n s of e n o l a t e anions o f t h e type 289 (Scheme 2 2 ) have been much I f R be H t h e n a l k y l a t i o n t a k e s p l a c e predominantly from t h e B s i d e t o g i v e 290 ( a x i a l a t t a c k due t o s t e r e o e l e c t r o n i c c o n t r o l i n t h e absence of overwhelming s t e r i c hindrance f a c t o r s . * 6 6 I f R be methyl then s u b s t i t u t i o n t a k e s p l a c e predominantly from t h e a s i d e t o g i v e 291 ( s t e r i c approach c o n t r o l due t o the hindrance of t h e 1 , 3 - a x i a l l y d i s posed B methyl group). The a l k y l a t i o n o f d i e n o l a t e anions of t h e type 292, d e r i v e d from a , @ - u n s a t u r a t e d ketones, i s a l s o However, r e a c t i v e 66 highly stereoselective giving a l k y l a t i n g a g e n t s must be used i f reasonable y i e l d s are t o be obtained.
293.
Scheme 2 2
*G. Stork (IUPAC Conference, Boston, Mass., U . S . A . , June, 1971) h a s suggested t h a t s t e r i c f a c t o r s a l o n e , and e s p e c i a l l y e c l i p s i n g between a C-4 s u b s t i t u e n t and t h e C-6 methylene group i n t h e t r a n s i t i o n s t a t e , may be an a l t e r n a t i v e t o "stereoelectronic considerations."
612
The S y n t h e s i s of T r i t e r p e n e s
295 -
R
292 -
R'
29 3 -
S e v e r a l methods f o r t h e g e n e r a t i o n of s p e c i f i c e n o l a t e anions f o r u s e i n such a l k y l a t i o n s have been developed i n r e c e n t y e a r s . Thus, e n o l a c e t a t e s can be formed from k e t o n e s and adjustment of t h e e x p e r i m e n t a l c o n d i t i o n s 6 8 can l e a d t o a predominance of t h e d e s i r e d isomer. Cleavage of an e n o l acet a t e w i t h two e q u i v a l e n t s of methyl l i t h i u m l e a d s t o t h e lithium e n o l a t e , f o r example, 294,68a l s o o b t a i n a b l e by Birch r e d u c t i o n of t h e corresponding enone 2 9 5 6 4 1 6 5 o r of t h e aacetoxy o r a-haloketone 296.69 Such l i t h i u m e n o l a t e s are r e l a t i v e l y s t a b l e with r e s p e c t t o transformation t o t h e o t h e r p o s s i b l e isomeric anion b u t a r e a l k y l a t e d o n l y slowly by a l l b u t t h e most r e a c t i v e h a l i d e s . The p r o c e s s of Birch r e d u c t i o n followed by a l k y l a t i o n of t h e e n o l a t e anion g e n e r a t e d , developed l a r g e l y by S t o r k , 6 4 a f 6 5 w i l l be r e f e r r e d t o as "reductive alkylation" i n the sequel. A phenomenom r e l a t e d t o t h e a l k y l a t i o n of k e t o n e s , t h e Michael a d d i t i o n of e n o l a t e o r d i e n o l a t e anions t o a c t i v a t e d
Nonsteroidal P o l y c y c l i c T r i t e r p e n e s
613
o l e f i n s , appears t o be governed by s i m i l a r s t e r e o e l e c t r o n i c and s t e r i c approach c o n t r o l f a c t o r s . The g e n e r a l cases a r e given i n Scheme 2 3 . 7 0 1 7 1 Scheme 23 R
I
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o
Z
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R'
X
@ ij H
0
z
n
R X = C N , C 0 2 R I COR, NO2 e t c .
614
The S y n t h e s i s o f T r i t e r p e n e s
&=
CHO H
Rx
OH:
- -
ft
The a l k y l a t i o n of cyclohexane a l d e h y d e s (Scheme 23) i n " r i g i d " systems i s u s u a l l y a h i g h l y s t e r e o s e l e c t i v e p r o c e s s l e a d i n g t o t h e a x i a l a l d e h y d e . Again s t e r e o e l e c t r o n i c (equat o r i a l a t t a c k f a v o r e d ) and/or s t e r i c h i n d r a n c e f a c t o r s are implicated. 72 The Simmons-Smith ~ n e t h y l e n a t i o fn7~4 ~of a l l y l i c a l c o h o l s f o r t h e i n t r o d u c t i o n of a n g u l a r methyl h a s been g r o u p s . S t e r e o s p e c i f i c a t t a c k of t h e o r g a n o z i n c r e a g e n t (Scheme 2 4 ) on t h e same s i d e of t h e molecule as t h e h y d r o x y l group ( w i t h which i t complexes) g i v e s c i s - c y c l o p r o p a n o - a l c o h o l s , f o r example, from 298. O x i d a t i o n of t h e a l c o h o l and B i r c h r e d u c t i o n o f t h e a,B-cyclopropanoketone 299 gives t h e e n o l a t e a n i o n 300 by f i s s i o n of t h e bond h a v i n g m a x i m u m overl a p w i t h t h e c a r b o n y l n o r b i t a l s (Dauben e t a ~ ~ Such ~ ) . e n o l a t e anions a f f o r d e i t h e r the angularly methylated product 301 ( R = H ) on p r o t o n a t i o n o r t h e a d d i t i o n a l l y a l k y l a t e d p r o d u c t 301 ( R = a l k 1) on quenching w i t h a r e a c t i v e a l k y l a t i n g agent, 6 5 A
297
-
&&& Scheme 2 4
HO
/
-c HO
__c0
29 7 -
298 -
300 -
_t
299 -
R
301 -
Nonsteroidal Polycyclic Triterpenes
304 -
30 2 -
615
305 R=NH -
I 307 R=o 0
0
& CN
30 3 The development o f a l k y l aluminumfiydrogen c y a n i d e rea g e n t s by Nagata7’ h a s l e d t o a n o t h e r u s e f u l method f o r t h e i n t r o d u c t i o n o f a n g u l a r methyl groups. These r e a g e n t s add t h e e l e m e n t s o f hydrogen cyanide t o a , B - u n s a t u r a t e d c a r b o n y l compounds ( e s p e c i a l l y k e t o n e s ) and i n many cases t h e r e a g e n t s and c o n d i t i o n s can be v a r i e d t o g i v e a p a r t i c u l a r isomer predominantly, f o r example, 302 o r 303 from enone 304 (Scheme 2 4 ) . C o n t r o l l e d r e d u c t i o n o f t h e n i t r i l e group w i t h l i t h i u m aluminum h y d r i d e o r (best) w i t h di-isobutylaluminum h y d r i d e g i v e s t h e imine 305 which can b e d i r e c t l y reduced (Wolff-Kishner) t o a methyl group 306 o r hydrolyzed t o t h e aldehyde 307 f o r f u r t h e r manipulation.
616
The S y n t h e s i s of T r i t e r p e n e s
Germanic01
308
(Schemes 25 and 26)
The s y n t h e s i s o f g e r m a n i c o l h a s b e e n a c h i e v e d t h r o u g h t h e com~ u s 'e d a~ t o t a l bined e f f o r t s of t w o groups.71 Ireland e t a s y n t h e t i c a p p r o a c h w h i l e the work of Johnson e t a l . l e d t o t h e same k e y i n t e r m e d i a t e 309 v i a d e g r a d a t i o n o f t h e s t e r o i d a l t r i terpene euphol to the lactone The l a t t e r achieved by a series o f r e a c t i o n s a l r e a d y d e s c r i b e d
310
311.
Pg"";;";,
l i t e r a t u r e i n c o n n e c t i o n w i t h the s t r u c t u r a l work o n e u p h o l , w i l l not b e discussed i n d e t a i l here.
The t o t a l s y n t h e s i s s t a r t e d w i t h 2 - m e t h y l c y c l o h e x a n e 1 , 3 - d i o n e 312 (Scheme 2 5 ) w h i c h g a v e t h e d i k e t o n e 313 o n annelation with e t h y l vinyl ketone. Selective ketalization of t h e non-conjugated carbonyl group followed by a n o t h e r annelat i o n w i t h e t h y l v i n y l k e t o n e g a v e t h e t r i c y c l i c d i e n o n e 314 i n w h i c h t h e two a n g u l a r m e t h y l g r o u p s are c o r r e c t l y o r i e n t a t e d . R e d u c t i v e a l k y l a t i o n w i t h m e t h y l i o d i d e gave t h e k e t o n e 315 which was c o n v e r t e d t o the i n t e r m e d i a t e 316 b y s u c c e s s i v e hyd r i d e r e d u c t i o n , a c e t y l a t i o n o f t h e C - 3 h y d r o x y l g r o u p , hyd r o l y s i s of t h e k e t a l g r o u p a n d s t e r e o s p e c i f i c h y d r o g e n a t i o n of t h e d o u b l e bond f r o m t h e l e s s - h i n d e r e d a f a c e . This ketoa c e t a t e was t h e n t r a n s f o r m e d i n t o t h e d i k e t o n e 309 b y t w o d i f ferent routes. I n t h e f i r s t r o u t e t h e d i o s p h e n o l - m e t h y l e t h e r 317 w a s o b t a i n e d v i a b r o m i n a t i o n of 316 a n d s u b s e q u e n t t r e a t m e n t o f t h e d i b r o m i d e w i t h a l k a l i n e m e t h y l s u l p h a t e f o l l o w e d b y rea c e t y l a t i o n a t C-3. This enol e t h e r was c o n v e r t e d t o a s p i r o - e p o x i d e ( d i m e t h y l s u l p h o n i u m m e t h y l i d e ) w h i c h g a v e the aldehyde o n t r e a t m e n t w i t h BF3. M e t h y l a t i o n of t h e a l d e hyde was a c h i e v e d w i t h d i f f i c u l t y , d u e t o i t s h i g h l y conWitg e s t e d environment, b u t s t e r e o s p e c i f i c a l l y t o g i v e t i g r e a c t i o n gave t h e o l e f i n 320 w h i c h w a s s u c c e s s i v e l y hyd r o l y z e d t o t h e k e t o n t . a n d r e d u c e d t o t h e a l c o h o l 321. Hyd r o b o r a t i o n of t h i s compound f o l l o w e d by chromium t r i o x i d e
318
318
317
=.
Scheme 25
312 -
I
313
315 -
314 -
316 -
OMe
318 R=H 319 R=Me
317
34 % from 319 ___c
AcO
S H
617
&1
HO
sR
311 -
310 -
326 -
618
322 R=O H 323 R= (OH
OMe
c
-n..
327 -
Nonsteroidal P o l y c y c l i c T r i t e r p e n e s
619
o x i d a t i o n gave t h e racemic l a c t o n e - a c e t a t e 2. F o r t u i t o u s l y , t h i s c r y s t a l l i z e d a s a racemic mixture which was r e s o l v a b l e by mechanical s e p a r a t i o n . Thus, t h e i d e n t i t y of t h e ( + ) - e n a n t i o mer w i t h t h e same compound o b t a i n e d from euphol 310 was r e a d i l y established. ( + ) - l a c t o n e - a c e t a t e 311 (from euphol) was conv e r t e d i n t o t h e l a c t o n e k e t a l 322 v i a h y d r o l y s i s of t h e a c e t a t e f u n c t i o n , o x i d a t i o n t o t h e ketone and k e t a l i z a t i o n . Reduction with a d i a l k y l b o r a n e gave t h e h e m i a c e t a l 323 which was r e a c t e d with m-methoxyphenylmagnesium bromide. Hydrogenolysis of t h e b e n z y l i c hydroxyl group i n t h e product 324, followed by hyd r o l y s i s and o x i d a t i o n , then afforded t h e key i n t e r m e d i a t e ( + I diketone Racemic d i k e t o n e 309 was o b t a i n e d more conveniently from i n t e r m e d i a t e 316 through a n o t h e r sequence. Thus, r e a c t i o n of 316 w i t h methyl l i t h i u m , followed by dehydration of t h e t e r t i a r y a l c o h o l s o formed, and manipulation o f t h e C-3 oxygen s u b s t i t u e n t , gave t h e o l e f i n 325 i n 86% o v e r a l l y i e l d . This was s u b j e c t e d t o s e n s i t i z e d photo-oxygenation, and hydride red u c t i o n of t h e hydroperoxide so formed followed by o x i d a t i o n o f t h e a l l y l i c a l c o h o l gave t h e enone 326. Such systems undergo conjugate a d d i t i o n w i t h g r e a t f a c i l i t y s o t h a t t r e a t m e n t of 326 w i t h m-methoxyphenylmagnesium bromide followed by t r a p p i n g o f t h e e n o l a t e anion with a c e t i c anhydride gave t h e enol acetate This was cleaved w i t h methyl l i t h i u m (two equival e n t s ) and t h e e n o l a t e anion so formed was s t e r e o s p e c i f i c a l l y a l k y l a t e d w i t h methyl i o d i d e t o g i v e , a f t e r h y d r o l y s i s o f t h e k e t a l f u n c t i o n , t h e racemic diketone 309.
=.
-
-
=.
Scheme 26
__c
__c
330 R=CN
HO
329 -
331 R=Me -
620
The S y n t h e s i s o f T r i t e r p e n e s
from
3 3 3 R=H 3 3 4 R=CH3
-
3 32
_ .
309
C y c l o d e h y d r a t i o n (Scheme 2 6 ) of d i k e t o n e using polyp h o s p h o r i c a c i d p r o c e e d e d smoothly and t h e p r o d u c t 328 was reduced w i t h l i t h i u m and a l c o h o l i n l i q u i d ammonia. T h i s r e s u l t e d i n s a t u r a t i o n o f t h e s t y r e n o i d d o u b l e bond and r e d u c t i o n o f the r i n g s o t h a t a c i d workup gave t h e p e n t a c y c l i c enone 329 (31% The l o w y i e l d i n t h i s s t e p may b e due to t h e profrom d u c t i o n o f s i g n i f i c a n t q u a n t i t i e s of t h e CD c i s - f u s e d p r o d u c t s , p r e v i o u s l y n o t e d i n s i m i l a r s y s t e m s . T r e a t m e n t of 329 w i t h t r i e t h y l aluminum/hydrogen c y a n i d e gave t h e DE-trans-conjugate a d d i t i o n p r o d u c t 330 which w a s t r a n s f o r m e d i n t o t h e k e t o a l c o h o l 331 v i a k e t a l i z a t i o n , h y d r i d e r e d u c t i o n of t h e cyan0 g r o u p , Wolff-Kishner r e d u c t i o n o f t h e imine and h y d r o l y s i s o f t h e k e t a l . Bromination/dehydrobromination of 331 gave the enone 332 which, i n t e r e s t i n g l y , c o u l d n o t be m e t h y l a t e d d i r e c t l y . The d o u b l e bond w a s f i r s t m i g r a t e d by k e t a l f o r m a t i o n , f o l l o w e d by h y d r o l y s i s , and t h e n t h e 8 , y - u n s a t u r a t e d k e t o n e 3 3 3 was m e t h y l a t e d . The p r o d u c t 334 gave r a c e m i c g e r m a n i c o l 308 on Wolff-Kishner r e d u c t i o n . -
328).
-
Alnusenone
6
(Schemes 27-29)
Alnusenone h a s b e e n s y n t h e s i z e d by I r e l a n d e t a 1 . 7 5 u s i n g a scheme i n c o r o p o r a t i n g many e l e g a n t and h i g h l y s t e r e o s e l e c t i v e
Nonsteroidal P o l y c y c l i c T r i t e r p e n e s
621
r e a c t i o n s . The key i n t e r m e d i a t e was t h e p e n t a c y c l i c d i e t h e r t h i s was approached by two r o u t e s , t h e second being developed a s a r e s u l t of low y i e l d s a t l a t e s t a g e s i n t h e f i r s t .
335 and -
I n t h e f i r s t approach75a (Scheme 2 7 ) t h e known t r i c y c l i c ketone 336 was s t e r e o s p e c i f i c a l l y a l k y l a t e d from t h e a s i d e t o g i v e t h e keto-acid Attempts t o hydrogenate e s t e r s of t h i s a c i d l e d t o mixtures i n which t h e undesired cis isomer predominated, probably due t o a q u a s i b o a t conformation i n t h e f l e x i b l e k e t o n i c r i n g C o f 336. Borohydride r e d u c t i o n of ketone 336 gave t h e a l c o h o l 338 i n which t h e p r e f e r r e d equat o r i a l c o n f i g u r a t i o n of t h e hydroxyl group a s s u r e s a q u a s i c h a i r conformation. This compound w a s smoothly hydrogenated t o t h e BC t r a n s product which a f f o r d e d t r a n s - l a c t o n e 339 on a c i d t r e a t m e n t . Reduction of t h i s l a c t o n e w i t h disiamylborane gave n o t t h e d e s i r e d l a c t o l 340 b u t t h e d i o l 341, a p p a r e n t l y because t h e open c h a i n hydroxy-aldehyde s t r u c t u r e is p r e f e r r e d o v e r t h e t r a n s - l a c t o l 340 due t o s t r a i n i n t h e l a t t e r . However, s i n c e experiments with cis-locked l a c t o n e s (less s t r a i n e d ) had given t h e corresponding l a c t o l s , c i s - l a c t o n e 342 was prepared. Treatment o f t h e t r a n s - l a c t o n e 339 with t h e l i t h i u m aluminum s a l t of methylamine gave t h e hydroxyamide 343. Rea c t i o n of t h i s a l c o h o l w i t h methanesulphonyl c h l o r i d e - p y r i d i n e and then w i t h water gave t h e c i s - l a c t o n e 342 (R=O) , presumably v i a t h e iminolactone 342 (R=+NMe) formed by a t t a c k of t h e amide oxygen on t h e mesylate 344 with i n v e r s i o n o f configurat i o n . C i s - l a c t o n e 342 was smoothly reduced t o l a c t o l 345 which, on r e a c t i o n w i t h m-ethoxyphenylmagnesium bromide f o l lowed by hydrogenolysis of t h e b e n z y l i c hydroxyl group and subsequent Jones o x i d a t i o n , gave t h e ketone 346. This was cyclodehydrated (p-toluenesulphonic a c i d ) t o t h e octahydrop i c e n e 347, which was found ( s u r p r i s i n g l y ) t o be one of t h e few o l e f i n s r e s i s t a n t t o hydroboration. Epoxidation y i e l d e d a mixture o f ketones 348 and 349, r e a d i l y e q u i l i b r a t e d ( 9 5 % ) t o t h e t r a n s - a n t i - c i s isomer 349 and t h e k e t o l 350. The l a t t e r was transformed t o g i v e f u r t h e r 348 and 349 by p i n a c o l
337.
h, h,
m
3 39 -
Me0 & O / F O H \
Me0
340
3 36 -
“11,
Me0
\
/
341 -
-
343 R=H 344 R=Ms
337 -
OH
&
i‘---.,__
Me0
mo
Scheme 27
Me0
\
/
88%f r o m
34 5 -
I”
338 -
O -H
342
W
N
m
348 14a-a-H -
349 14a-8-H -
347 -
346 -
624
The S y n t h e s i s of T r i t e r p e n e s
rearrangement of t h e c o r r e s p o n d i n g d i o l , t h u s r a i s i n g t h e y i e l d of t h e d e s i r e d k e t o n e s t o 67%. The e x p e c t e d epoxide could n o t be d e t e c t e d and t h e o x i d a t i o n of p r o d u c t k e t o n e s 348 and 349 t o k e t o l 350 appeared t o be a s f a s t a s t h a t of the o l e f i n . Methylation o f t h e k e t o n e s 348 and was complicated b y predominating e n o l e t h e r f o r m a t i o n and e x t e n s i v e e x p e r i m e n t a t i o n l e d t o an optimum i s o l a t e d y i e l d of 18% of ketone 351 a s t h e o n l y C - a l k y l a t i o n p r o d u c t d e t e c t e d . I n view of t h e low y i e l d s i n t h e l a t t e r s t a g e s of t h i s sequence a l t e r n a t i v e approaches t o t h e decahydropicene !35 were i n v e s t i g a t e d .
349
-
Scheme 2 8
72% ____c
+ Me0 35 3 -
35 2 -
MoEt
p y O E t
M e0
354
3 5 7 R=CN 350 R'CH3
-
97% 355 Ct-CN, 85% 3 5 6 0-CN,
B-H a-H
3 35 -
Nonsteroidal P o l y c y c l i c T r i t e r p e n e s
625
The s u c c e s s f u l approach75b (Scheme 28) used a convergent type s y n t h e s i s . Thus, a n n e l a t i o n of t e t r a l o n e 352 w i t h t h e known v i n y l ketone 353 gave t h e enone 354. Hydrocyanation of t h i s compound u s i n g Nagata's a l k y l aluminum cyanide r e a g e n t s could be c o n t r o l l e d t o g i v e e i t h e r t h e c i s - f u s e d compound 355 ( 9 7 % ) [thermodynamic control-- (C2H5) 2AlCN-benzene] o r t h e t r a n s - f u s e d isomer 356 ( 8 5 % ) [ k i n e t i c control-- ( C 2 H 5 ) 3Al-HCNTHF]. The l a t t e r f a i l e d t o r e a c t w i t h methylenetriphenylphosphorane b u t a d d i t i o n of methylmagnesium i o d i d e followed by dehydration (SOC12-pyridine) o f t h e t e r t i a r y a l c o h o l gave a mixture o f cyano-olefins 357, which was converted t o the mixt u r e o f o l e f i n s 358 by r e d u c t i o n t o t h e imine and subsequent modified Wolff-Kishner r e a c t i o n . This mixture was c y c l i z e d by a c i d t o t h e r e q u i r e d i n t e r m e d i a t e 335 i n an o v e r a l l y i e l d (from t e t r a l o n e 352) of 31%. I n t h e f i n a l s e r i e s of t r a n s f o r m a t i o n s (Scheme 2 9 ) s e l e c t i v e demethylation of t h e d i e t h e r 335, achieved with l i t h i u m diphenylphosphide, was necessary i n o r d e r t o p r o t e c t t h e A r i n g d u r i n g Birch r e d u c t i o n of t h e E r i n g . The l a t t e r p r o c e s s was complicated by t h e i n s o l u b i l i t y o f t h e l i t h i u m phenolate b u t use of a d i l u t e s o l u t i o n and excess l i t h i u m i n ammonia-THF gave, a f t e r r e m e t h y l a t i o n of t h e A r i n g p h e n o l i c moeity and a c i d t r e a t m e n t , t h e enone 359. This was reduced ( d i - i - b u t y l aluminum h y d r i d e ) t o t h e pseudo-equatorial a l c o h o l wpich gave t h e cyclopropylketone 360 a f t e r d i r e c t e d Simmons-Smith cycloproponation and subsequent o x i d a t i o n o f t h e hydroxyl group. Geminal-dialkylation o f 360 gave t h e ketone 361, t h e cyclop r o p y l group s e r v i n g as an e f f i c i e n t b l o c k i n g agent. Lithiumammonia cleavage of t h i s moeity followed by Wolff-Kishner red u c t i o n o f t h e carbonyl group (achieved w i t h d i f f i c u l t y ) gave t h e i n t e r m e d i a t e 362. This was s u b j e c t e d t o Birch r e d u c t i o n followed by a c i d t r e a t m e n t t o g i v e enone 363 which was d i methylated under c o n d i t i o n s which g i v e t h e 4,5-ene, dl-alnusenone 6 , r a t h e r than i t s A-5,lO isomer. Scheme 29
3 35 -
626
The S y n t h e s i s of T r i t e r p e n e s
6%
36 2 -
Lupeol
363 -
364
Lupeol has been s y n t h e s i z e d by S t o r k e t a l . 6 5 ' 8 0 (Schemes 303 3 ) through a r e m a r k a b l e s e r i e s of r e a c t i o n s which r e s u l t e d i n t h e c r e a t i o n of t h e a s y m e t r i c c e n t e r s one a t a t i m e and each i n a highly s t e r e o s e l e c t i v e fashion.
The s t a r t i n g m a t e r i a l , t h e enone 365 (Scheme 30), had p r e v i o u s l y been prepared i n low y i e l d by a n n e l a t i o n of t h e t e t r a l o n e 366 w i t h a methyl v i n y l ketone e q u i v a l e n t . Ketone 365 was obtained" more e f f i c i e n t l y v i a t h e r o u t e shown i n
-
Nonsteroidal Polycyclic Triterpenes
627
which s e l e c t i v e k e t a l i z a t i o n of d i k e t o n e 367 had t o be performed under c a r e f u l l y c o n t r o l l e d c o n d i t i o n s . The transformat i o n of k e t o n e 368 t o enone 365 was achieved by s u c c e s s i v e a c i d and base t r e a t m e n t s . Scheme 30
Me0
Me0
Me0
Me0
Me0
36 7 -
36 8 -
__c
Me0
Me0
369 -
\
/ 3 70 -
371 -
620
The S y n t h e s i s of T r i t e r p e n e s
C a t a l y t i c h y d r o g e n a t i o n of enone 365 r e s u l t e d i n much h y d r o g e n o l y s i s of t h e k e t o n i c group, presumably d u e t o i t s Both h y d r o g e n a t i o n i n t h e p r e s vinylogous benzylic nature. ence o f b a s e ( t o s u p p r e s s h y d r o g e n o l y s i s ) and B i r c h r e d u c t i o n gave m i x t u r e s of cis- and t r a n s - r i n g f u s e d isomers. However, c a r e f u l l y c o n t r o l l e d b o r o h y d r i d e r e d u c t i o n of 365 gave t h e a l l y l i c a l c o h o l 369 which c o u l d b e hydrogenated i n good y i e l d t o t h e t r a n s - f u s e d p r o d u c t 370. B i r c h r e d u c t i o n of t h i s and h y d r o l y s i s o f t h e p r o d u c t t h e n gave t h e hydroxy enone 371 which was used f o r b o t h s t e r o i d " and t r i t e r p e n e s y n t h e s e s . The p r i n c i p a l problem i n t r i t e r p e n e s y n t h e s i s , t h e i n t r o d u c t i o n of t w o v i c i n a l methyl g r o u p s i n a t r a n s - d i a x i a l relat i o n s h i p a t r i n g j u n c t i o n s , was now s o l v e d i n an e l e g a n t f a s h i o n (Scheme 3 1 ) . Treatment o f t h e b e n z o a t e 372 w i t h t r i a l l y l o r t h o f o r m a t e gave the a l l y 1 d i e n o l e t h e r 373 which r e a r r a n g e d Scheme 31 OBz
372
OBz
OB z
d
374
_.
OB z
OBZ
375 R=O
_.
3 7 6 R= -
(:I
377 R=H -
3 7 0 R=Ms
Nonsteroidal P o l y c y c l i c T r i t e r p e n e s OBz
-
OH
I
60%
85%
from
CH~OH
380 -
629
377
379 OH
on h e a t i n g t o t h e a l l y l ketone 2. D i r e c t a l k y l a t i o n of enone 372 w i t h a l l y l h a l i d e s r e s u l t s i n p o l y a l k y l a t i o n , avoided h e r e b y u s i n g t h e C l a i s e n rearrangement. The a l l y l ketone 374 formed t h e trans-anti-trans-cyanoketone 375 on t r e a t m e n t with diethylaluminum cyanide and t h e corresponding k e t a l 376 w a s converted t o t h e primary a l c o h o l 377 v i a t h e imine and aldehyde. Acid h y d r o l y s i s of t h e corresponding mesylate 378 f o l lowed by removal o f t h e benzoate p r o t e c t i n g group gave t h e a, B-cyclopropanoketone 379 d i r e c t l y , This unusual " s o l v o l y t i c c y c l i z a t i o n " may have proceeded through t h e e n o l ether 380 as shown. Reductive a l k y l a t i o n (methyl i o d i d e ) of cyclopropanoketone 379 gave t h e ketone 381 w i t h t h e two newly i n t r o d u c e d methyl groups i n t h e d e s i r e d t r a n s - o r i e n t a t i o n . The c o n s t r u c t i o n of t h e A and B r i n g s of l u p e o l i s shown i n Scheme 32. Hydroboration (disiamylborane) o f t h e benzoate 382 followed by o x i d a t i o n (chromic a c i d ) gave t h e a c i d 383 which was converted t o t h e e n o l l a c t o n e 384. This was t r e a t e d with e t h y l Grignard r e a g e n t and b a s e c a t a l y z e d r e t r o a l d o l / a l d o l r e a c t i o n o f t h e r e s u l t i n g mixture o f k e t o l s 385 afforded t h e t e t r a c y c l i c enone 386. Reductive a l k y l a t i o n ( a l l y l bromide) of t h i s and subsequent p r o t e c t i o n o f t h e hydroxyl group gave
-
630
The s y n t h e s i s o f T r i t e r p e n e s
t h e k e t o n e 387 w i t h t h e m e t h y l g r o u p s c o r r e c t l y o r i e n t a t e d . T h i s was c o n v e r t e d , by a s e r i e s o f r e a c t i o n s similar t o t h a t used f o r t h e c o n s t r u c t i o n of t h e B r i n g , i n t o t h e p e n t a c y c l i c hydroxyenone 388. R e d u c t i v e a l k y l a t i o n ( m e t h y l i o d i d e ) of t h i s a f f o r d e d t h e hydroxyketone 389 whose gross s t r u c t u r e d i f f e r s from t h a t o f l u p e o l 364 o n l y i n t h e E r i n g . Scheme 32
OBz
OBz
OB z
OH
386 -
387 -
Nonsteroidal P o l y c y c l i c T r i t e r p e n e s
631
OH
OH
64% ____c
388 -
389 -
I n connection with t h e e x t e n s i v e use o f r e d u c t i v e a l k y l a t i o n (Birch r e d u c t i o n followed by t r a p p i n g of t h e e n o l a t e anion w i t h an a l k y l a t i n g a g e n t ) , it should be noted t h a t t h e presence o f t h e E r i n g hydroxyl f u n c t i o n w a s e s s e n t i a l f o r the s u c c e s s o f t h e s e r e a c t i o n s , probably due t o s o l u b i l i t y d i f f i c u l t i e s w i t h t h e hydroxyl p r o t e c t e d compounds. *O These were a p p a r e n t l y less s e r i o u s w i t h t h e ( l i t h i u m s a l t of t h e ) a l c o h o l . The f i n a l phase o f t h e s y n t h e s i s , t h e m o d i f i c a t i o n of t h e E r i n g o f 389, i s shown i n Scheme 33. Thus, formation of t h e C-3 k e t a l followed by o x i d a t i o n gave t h e ketone 390 which a f forded t h e e n o l a c e t a t e 391 on t r e a t m e n t with t h e s t r o n g b a s e , sodium hexamethyldisilazane, and then a c e t i c anhydride. Scheme 3 3
H
390 -
ji
OAc
H
391 -
A
632
The S y n t h e s i s of T r i t e r p e n e s
392 R=H 393 R=Ts -
396 R=O OH 364 R= < 'H
394 R=C02Me 395 R=-C (OH) (CH3) 2 -
397 -
Ozonolysis o f t h e e n o l a c e t a t e 391, borohydride r e d u c t i o n of t h e p r o d u c t and e s t e r i f i c a t i o n w i t h diazomethane gave t h e h y d r o x y e s t e r 392, which was c o n v e r t e d t o i t s t o s y l a t e 393. T h i s underwent an i n t r a m o l e c u l a r a l k y l a t i o n when t r e a t e d w i t h s t r o n g b a s e t o g i v e t h e p e n t a c y c l i c e s t e r 394 which h a s t h e most s t a b l e c o n f i g u r a t i o n and t h e c o r r e c t one f o r c o n v e r s i o n t o l u p e o l . Reaction o f e s t e r = w i t h e x c e s s methyl l i t h i u m gave t h e t e r t i a r y - a l c o h o l 395 which, on d e h y d r a t i o n (phosphorous o x y c h l o r i d e / p y r i d i n e ) f o l l o w e d by a c i d t r e a t m e n t a f f o r d e d ketone 396 r e a d i l y reduced t o l u p e o l 364. The y i e l d s o f t h e l a t e r s t a g e s of t h e s y n t h e s i s were n o t known or o p t i mized a t t h e t i m e o f w r i t i n g . Glochidone 397, a n o t h e r n a t u r a l p r o d u c t of t h e l u p a n e s e r i e s , h a s been s y n t h e s i z e d from l u p e o l 364 t h r o u g h a s i m p l e s e r i e s of r e a c t i o n s . "
Presqualene Alcohol 5.
PRESQUALENE ALCOHOL
633
398
The n a t u r a l l y o c c u r r i n g pyrophosphate of t h e cyclopropylc a r b i n o l 398 has been shown by R i l l i n g B 3 t o be an i n t e r m e d i a t e i n t h e b i o s y n t h e s i s of squalene 1 from f a r n e s y l pyrophosphate, hence t h e t r i v i a l name presqualene a l c o h o l . Recent s y n t h e s e s of t h e racemate of = h a v e confirmed t h e s t r u c t u r e .
39 8 The s i m p l e s t ~ y n t h e s i s ' was ~ achieved through a d d i t i o n of t h e carbene d e r i v e d from d i a z o compound 399 t o t r a n s , t r a n s f a r n e s o l 400. The product was a 7 0 : 3 0 mixture of racemic presqualene a l c o h o l 398 and t h e compound isomeric a t t h e carbon marked. The c i s - r e l a t i o n s h i p of t h e methyl and hydroxymethyl groups, expected from a c i s - a d d i t i o n t o t h e trans-double bond of 400, w a s confirmed by NMR spectroscopy. Diazo compound 399 was o b t a i n e d from t r a n s ,trans-farnesaldehyde v i a o x i d a t i o n of i t s hydrazone. 5'
R
A CH3
H
+ isomer
399 -
R =
70 :30
634
The S y n t h e s i s of T r i t e r p e n e s
I n t h e second s y n t h e s i s e 6 r e a c t i o n of t r a n s , t r a n s - f a r n e s o l with g l y o x a l y l c h l o r i d e t o s y l h y d r a z o n e and t r i e t h y l a m i n e a f f o r d e d t h e d i a z o a c e t a t e 401 which gave t h e l a c t o n e 402 on copper-catalyzed d e c o m p o s i t i o n , v i a i n t e r n a l a d d i t i o n of t h e carbenoid s p e c i e s t o t h e a d j a c e n t double bond. The ciss t e r e o s p e c i f i c i t y of t h i s r e a c t i o n and t h e s t e r e o c h e m i s t r y of t h e s t a r t i n g o l e f i n allowed t h e d e f i n i t i o n of t h e r e l a t i v e s t e r e o c h e m i s t r y o f l a c t o n e 402 a s t h a t d e p i c t e d . S u c c e s s i v e h y d r o l y s i s of 402, e s t e r i f i c a t i o n w i t h diazomethane and oxidat i o n of t h e a l c o h o l i c f u n c t i o n w i t h C o l l i n s r e a g e n t , gave the aldehyde 403. T h i s was e p i m e r i z e d t o t h e more s t a b l e isomer 404 on t r e a t m e n t w i t h aqueous b a s e f o l l o w e d by r e - e s t e r i f i c a t i o n of t h e a c i d i c r e s i d u e . The phosphorane 405 p r e p a r e d by reacted with s t a n d a r d methods from g e r a n y l a c e t i c a c i d aldehyde 404 t o g i v e a m i x t u r e o f two compounds i s o m e r i c a b o u t t h e newly formed double bond. T h i s , on r e d u c t i o n w i t h l i t h i u m aluminum h y d r i d e followed by chromatography, a f f o r d e d presqualene alcohol a s t h e major p r o d u c t ( 6 6 % ) .
-
(c),
398
401 -
H
CH3
CHO
I
92%
H
403 -
404 R
'C=PPh
/ Me
57%
3
405 -
5 steps
t
34%
RC02H
406
-
CH3
I
H 398 + isomer 67:33
References
635
The pyrophosphates of samples of p r e s q u a l e n e a l c o h o l obt a i n e d by b o t h s y n t h e t i c r o u t e s were c o n v e r t e d i n t o s q u a l e n e by y e a s t s u b c e l l u l a r p a r t i c l e s i n 66% y i e l d (assuming o n l y one o p t i c a l isomer i s u t i l i z e d ) 8 4
.
ACKNOWLEDGMENTS
W e thank t h e N a t i o n a l Research Council of Canada and t h e C. D. Howe Foundation f o r f i n a n c i a l s u p p o r t , and Mrs. J i l l Hooper f o r secretarial assistance.
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6 36
11.
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13.
14. 15.
16.
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20.
21.
22. 23. 24.
25. 26.
The S y n t h e s i s o f T r i t e r p e n e s
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638
The S y n t h e s i s of T r i t e r p e n e s
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46.
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Total Synthesis OfNatural Products, Volume2 Edited by John Apsimon Copyright © 1973, by John Wiley & Sons, Inc.
NATURALLY OCCURRING AROMATIC STEROIDS
D. Taub
Merck, S h a r p & Dome R e s e a r c h L a b o r a t o r i e s Rahway , New J e r s e y 1. 2.
3.
4.
Introduction Equilenin A. Bachmann Synthesis B. Johnson Syntheses C. Bachmann and Holmen Syntheses D. Robinson-Birch Synthesis E. Horeau Synthesis F. Syntheses from Estrone Intermediates Equilin A. Zderic et al. Synthesis B. Bagli et al. Synthesis C. Stein et al. Synthesis D. Bailey et al. Synthesis E. Marshall and Deghenghi Synthesis Estrone A. Anner and Miescher Synthesis B . Johnson Syntheses C. Johnson's First Synthesis D. Johnson's Second Synthesis E. Johnson-Walker Synthesis F. 2-Methylcyclopentane-1-3-dione G. Syntheses of Smith et al. H. Torgov Synthesis I. Resolution J. Velluz Syntheses K. Miscellaneous
642 642 642 649 654 656 661 662 664 664 665 666 668 669 670 673 679 679 683 687 690 693 698 703 706 711
641
642
1.
N a t u r a l l y O c c u r r i n g Aromatic S t e r o i d s
INTRODUCTION^
The e r a of s t e r o i d t o t a l s y n t h e s i s o r i g i n a t e d i n t h e e a r l y 1930s f o l l o w i n g t h e e s t a b l i s h m e n t o f t h e s t r u c t u r e o f t h e
s t e r o i d r i n g s y s t e m and t h e i s o l a t i o n and c h a r a c t e r i z a t i o n o f t h e s t e r o i d a l s e x hormones. The n a t u r a l l y o c c u r r i n g aromatic e s t r o g e n s were a m n g t h e e a r l i e s t s y n t h e t i c g o a l s . The p r e s ence o f a r o m a t i c r i n g s s i m p l i f i e d t h e s y n t h e t i c d i f f i c u l t i e s and l i m i t e d t h e number o f p o s s i b l e r a c e m a t e s t o f i g u r e s comp a t i b l e with t h e e a r l y nonstereoselective procedures. Init i a l l y t h e b i o l o g i c a l importance of t h e s t e r o i d a l e s t r o g e n s , and l a t e r t h e i r i n c r e a s i n g m e d i c a l and i n d u s t r i a l u t i l i t y , l e n t growing i m p e t u s t o t h e development o f e f f e c t i v e s y n t h e s e s . The s y n t h e t i c e f f o r t which h a s now p r o g r e s s e d some t h r e e and one-half d e c a d e s h a s r e s u l t e d n o t o n l y i n many i n g e n i o u s and p r a c t i c a l r o u t e s , b u t a l s o i n s i g n i f i c a n t enrichment of t h e methodology of o r g a n i c c h e m i s t r y . N a t u r a l l y o c c u r r i n g a r o m a t i c s t e r o i d s , w i t h few except i o n s - - s u c h as t h e r i n g D-aromatic solanum a l k a l o i d , v e r a t r a mine--are l i m i t e d t o t h e s t e r o i d a l e s t r o g e n s t o which t h i s review i s d e v o t e d . 2.
EQUILENIN
A.
Bachmann S y n t h e s i s
The e s t r o g e n i c s t e r o i d ( + ) e q u i l e n i n _1. w a s i s o l a t e d from mare pregnancy u r i n e i n 1 9 3 2 . 2 Because o f i t s s t e r e o c h e m i c a l s i m p l i c i t y (two asymmetric c e n t e r s ) i t w a s a n e a r l y s y n t h e t i c 0
-2
1 -
o b j e c t i v e . I t s s y n t h e s i s i n 1939 by Bachmann, C o l e , and W i l d s , 3 t h e f i r s t of a n a t u r a l l y o c c u r r i n g s t e r o i d , was a m i l e s t o n e i n p r e p a r a t i v e o r g a n i c c h e m i s t r y . The s u c c e s s f u l r o u t e , one o f a number o f a p p r o a c h e s u n d e r g e n e r a l i n v e s t i q a t i ~ n u, t i~l i z e d t h e a d d i t i o n o f t h e e l e m e n t s of r i n g D t o 1-
oxo-7-methoxy-l,2,3,4-tetrahydrophenanthrene
2.
Equilenin
643
The t r i c y c l i c k e t o n e 2. and t h e c o r r e s p o n d i n g p h e n o l had been p r e p a r e d i n 1935 by Butenandt and S c h r a m ’ f o r e s t r o g e n i c a s s a y and as p o t e n t i a l s y n t h e t i c i n t e r m e d i a t e s . T h e i r synthesis of 2 as w e l l as l a t e r s y n t h e s e s are o u t l i n e d i n Scheme 1. By s t a n d a r d p r o c e d u r e s t h e dye i n t e r m e d i a t e , l-aminon a p h t h a l e n e - 6 - s u l f o n i c a c i d ( C l e v e ’ s a c i d ) 2 was c o n v e r t e d i n t o Scheme 1.
1-0~0-7-Methoxy-1,2,3,4-Tetrahydrophenanthrene
Butenandt: NHAc
HO3S
d
Me0
I 55 % Me0
-
(1) Mg/ether ( 2 ) OHC (CH2) 2COOMgI
A
.
-
Cook :
/CH20H
4 -
(1) Mg/ether
(1) P B r 3
( 2 ) CH2-CH2
( 2 ) CH2 ( C O O E t ) 2
‘0’
~ 8 0 %
7 -
(1) OH(2) A
6 6 0 % from
Haher l a n d :
0
CH
9 -
10a -
COOE t
I
CH2
Me0
Na/CH 3 OH
1O b ,CHzOH (1) PBr3
Me0
11 644
( 2 ) CH2 ( C O O E t ) Z / N a / x y l e n e ( 3 ) KOH/HZO/EtOH A
A
1
Me0 &CWH \
83%
12 -
6 -
a::-
Stork :
MeOH/H+
HO
H 2 / N l / E t O H ,AcOH
Me0
14 -
13 -
BrCH2CH=CHCOOMe/Zn
c
4 8 % D i r e c t ( 9 3 % conversion)
Me0
& 9 -
COOMe
Me0
15 -
30% Pd/C
280-290
--+
O
75%
do
Me0
3
645
646
N a t u r a l l y Occurring Aromatic S t e r o i d s
1-iodo-6-methoxy-naphthalene 5. Grignard r e a c t i o n of 4 w i t h t h e magnesium i o d i d e s a l t of s u c c i n i c a c i d h a l f aldehyde gave a c i d 2 i n poor y i e l d . Hydrogenation and F r i e d e l - C r a f t s r i n g c l o s u r e t h e n l e d t o 2. An improved p r o c e d u r e f o r a d d i t i o n of t h e f o u r carbon s i d e c h a i n developed by Cook e t a1.6 involved Grignard r e a c t i o n of 4 with e t h y l e n e o x i d e t o g i v e B (6methoxynaphthyll-ethanol L, f o l l o w e d by malonic e s t e r synt h e s i s on t h e d e r i v e d bromide. With minor m o d i f i c a t i o n s t h i s was t h e scheme u t i l i z e d by Bachmann and h i s co-workers t o obt a i n 2 i n 8% o v e r a l l y i e l d from 2. An a l t e r n a t i v e r o u t e t o 2 s t a r t i n g from 6-methoxytetralone 9' u t i l i z e d t h e Reformatsky r e a c t i o n followed by BouveaultBlanc r e d u c t i o n t o produce t h e 8 - t e t r a l y l e t h a n o l 2, which by t h e malonic e s t e r sequence and dehydrogenation l e d t o t h e y n a p h t h y l b u t y r i c a c i d 6 t h e common p r e c u r s e r t o 2. Stork' i n t r o d u c e d major improvements which made 2 a v a i l able from 8-naphthol i n 30-35" o v e r a l l y i e l d . These i n c l u d e d an improved p r o c e d u r e f o r t h e s e l e c t i v e h y d r o g e n a t i o n of t h e u n s u b s t i t u t e d r i n g of B-naphthyl methyl e t h e r and u t i l i z a t i o n of t h e Reformatsky r e a c t i o n o f 2 w i t h methyl y-bromocrotonate t o i n t r o d u c e t h e four-carbon s i d e c h a i n i n one s t e p , followed by p a l l a d i u m c a t a l y z e d i s o m e r i z a t i o n of t h e s i d e c h a i n double bonds i n t o r i n g B. The v i n y l o g o u s Reformatsky r e a c t i o n had been used i n d e p e n d e n t l y by Bachmann and Wendler i n t h e synt h e s i s of l-oxo-1,2,3,4-tetrahydrophenanthrene from a - t e t r a lone. 9 6-Methoxytetralone 2, an i m p o r t a n t i n t e r m e d i a t e also i n a number of s y n t h e s e s of e s t r o n e ( s e e b e l o w ) , i s g e n e r a l l y p r e p a r e d by chromic a c i d o x i d i a t i o n of 6-metho t e t r a l i n a l t h o u y h t r i s t r i p h e n y l p h o s p h i n e r h o d i u m c h l o r i d y ' and 2,3d i c h l o r o - 5 ,6-dicyanobenzoquinone1 have r e c e n t l y been u t i l i z e d a s novel o x i d a n t s . I n t h e i n i t i a l s t e p s of t h e Bachmann s y n t h e s i s (Scheme 2 )
14,'
Scheme 2 .
Bachmann S y n t h e s i s of E q u i l e n i n COCOOMe
(COOMe)Z/NaOMe
Powdered s o f t glass/
Me0
90-94%
2 -
16 -
COOMe NaOMe
d C 0 0 . e
89-92% Me0
18 -
17 COOMe ( 1 ) SOClg ( 2 ) KOH/EtOH CH2 COOMe
*
G ; Y I I O H
'
H
19 -
20 -
21 -
q Me
.-COOH
H
CHgCOOH
45% a-isomer 22a -
8-series (1) CH2N2 ( 2 ) 1% NaOH/aq.MeOH 80-85%
42% f3-isomer 22b
-
Jq Me
.COOMe
H
23 -
CHgCOOH
Me .* COOMe
( 1 ) SOClg ( 2 ) CH2Ng (3) CH30H/AgOH
80-84%
COOMe-
NaOMe/ c6 H6
95-98%
H 24 -
647
648
N a t u r a l l y O c c u r r i n g Aromatic S t e r o i d s 0
h
-
AcOH HC 1
90-95%
HO
7 c
( 2 )- E q u i l e n i n [Resolved v i a t h e ( - ) m e n t h o x y a c e t a t e ]
-1
0
-
26 ( 2 ) 14-isoequilenin
17)
s u c c e s s f u l i n t r o d u c t i o n of t h e carbomethoxy g r o u p ( c f . was a c h i e v e d by p y r o l y s i s o f t h e c o r r e s p o n d i n g g l y o x y l a t e 2 i n I n t h e a b s e n c e of powt h e p r e s e n c e of powdered s o f t g l a s s . d e r e d s o f t g l a s s p y r o l y s i s was e r r a t i c a n d , i n f a c t , h a d p r e viously f a i l e d i n t w o c l o s e l y r e l a t e d c a s e s . 1 2 D i r e c t carbom e t h o x y l a t i o n employing d i m e t h y l c a r b o n a t e and sodium h y d r i d e i s an a l t e r n a t i v e p r o c e d u r e n o t t h e n a v a i l a b l e ( c f . t h e a n a l o gous s t e p i n t h e C I B A a l d o s t e r o n e s y n t h e s i s l 3 ) . F o l l o w i n g i n t r o d u c t i o n of t h e a n g u l a r methyl g r o u p t h e Reformatsky rea c t i o n gave t h e hydroxy d i e s t e r (m.p. 125-126'1, apparently a s i n g l e compound. T r e a t m e n t o f t h e l a t t e r w i t h h o t a l k a l i i n o r d e r t o produce t h e c o r r e s p o n d i n g u n s a t u r a t e d d i a c i d 20 res u l t e d i n s t e a d i n d e g r a d a t i o n t o t h e 2-methyl d e r i v a t i v e o f 2. The d e s i r e d change w a s accomplished by c o n v e r s i o n of 19 t o t h e c o r r e s p o n d i n g c h l o r i d e p r i o r t o base t r e a t m e n t , which t h e n y i e l d e d t h e u n s a t u r a t e d d i a c i d as a m i x t u r e of g e o m e t r i c isomers 20 and 2. The former r e a d i l y gave a n a n h y d r i d e . Reduct i o n o f e i t h e r a c i d w i t h sodium amalgam i n w a t e r was u n s e l e c t i v e , g i v i n g t h e same r e a d i l y s e p a r a b l e 1:l m i x t u r e of c r y s t a l l i n e reduced d i a c i d s and I t was n o t known which a c i d c o r r e s p o n d e d t o e q u i l e n i n . u n t i l c o m p l e t i o n of t h e s y n t h e s i s ; 22b l e d t o ( C ) e q u i l e n i n 1 and 2 t o ( ? ) - i s o e q u i l e n i n 26. O p t i c a l l y a c t i v e 22a and
19
= =.
z,
Equilenin
649
t h e methyl e t h e r s of cis and t r a n s bisdehydromarrianolic a c i d , were o b t a i n e d l a t e r by h y p o i o d i t e o x i d a t i o n of t h e methyl e t h e r s of (+) i s o e q u i l e n i n and (+) e q u i l e n i n , r e s p e c t i v e l y . l 4 Conversion of 22b t o t h e dimethyl ester followed by select i v e s a p o n i f i c a t i o n w i t h one e q u i v a l e n t of d i l u t e a l k a l i gave t h e primary a c i d 23. A r n d t - E i s t e r t homologation, Dieckmann c y c l i z a t i o n , and simultaneous e t h e r cleavage and decarbomethResolution was accomplished o x y l a t i o n l e d t o (f) e q u i l e n i n by f r a c t i o n a l c r y s t a l l i z a t i o n of t h e d i a s t e r e o m e r i c (-1 menthoxyacetates. Despite t h e n o n s t e r e o s p e c i f i c r e d u c t i o n l e a d i n g t o a c i d s 22a and y i e l d s i n t h e o t h e r s t e p s were s u f f i c i e n t l y h i g h such t h a t about 2.5 g of (t) e q u i l e n i n and an e q u a l amount of (+) 1 4 - i s o e q u i l e n i n were o b t a i n e d from 10 g o f 2.
1.
B.
2,
Johnson Syntheses
Two s y n t h e s e s of e q u i l e n i n were developed by Johnson and h i s a s s o c i a t e s . 1 5 I n hopes of developing a simpler a l t e r n a t i v e t o t h e Bachmann procedure f o r c o n s t r u c t i n g t h e p r o p i o n i c a c i d s i d e chain a t C - 1 (Scheme 2 ) t h e y i n v e s t i g a t e d t h e Stobbe react i o n . 1 6 Previous a t t e m p t s t o add a p r o p i o n i c e s t e r u n i t i n one s t e p t o ketones analogous t o u s i n g Grignard r e a g e n t s d e r i v e d from 8-halopropionic esters had given poor y i e l d s . More r e c e n t l y , moderate y i e l d s of Ply-unsaturated p r o p i o n i c a c i d s have been a t t a i n e d v i a t h e W i t t i g r e a c t i o n by g e n e r a t i o n of y l i d s o f 8-carboxytriphenylphosphonium h a l i d e s i n t h e presence of t h e carbonyl component.” I n i n i t i a l s t u d i e s 1 5 a Stobbe condensation of t h e 8-keto ester 2 with d i e t h y l succinate f a i l e d , possibly f o r s t e r i c r e a s o n s , and t h e only i s o l a b l e product was 28 r e s u l t i n g from k e t o n i c cleavage d u r i n g work-up. COOMe
28 -
27 -
0
(CHZCOOEt) 2
(1) t-BuOK/t-BuOH
650
N a t u r a l l y Occurring Aromatic S t e r o i d s
The r e a c t i o n was then t r i e d with t h e corresponding 6-keton i t r i l e 2 i n which t h e carbonyl group i s s t e r i c a l l y more acc e s s i b l e than i n 27. Condensation occurred and i n f a c t proceeded beyond t h e expected s t a g e t o y i e l d d i r e c t l y t h e t e t r a c y c l i c product 2 i n 60’3 y i e l d . T h e l a t t e r may be formed i n t e r a1 v i a Thorpe condensation of t h e i n t e r m e d i a t e Stobbe product followed by l a c t o n i z a t i o n , e l i m i n a t i o n and decarboxyl a t i o n as formulated. 5a
-p k00Et
NH
COOE t COOE t
COOEt
I t should be noted t h a t analogous 6 k e t o n i t r i l e s do n o t undergo Stobbe condensation i n t h e absence of an aromatic system conjugated t o t h e carbonyl y u p because of competing r i n g cleavage, f o r example, 2 * 2. t64
Equilenin
651
The 6 - k e t o n i t r i l e 36 (Scheme 3 ) was o b t a i n e d from t r i v i a t h e hydroxymethylene k e t o n e z a n d i s o x a z o l e
2
cyclic ketone
Scheme 3.'
J o h n s o n ' s F i r s t S y n t h e s i s of E q u i l e n i n
0
HONH 3C 1
HCOOE t NaOMe
AcOH
___c
96%
97-99%
Me0
-L
QCy
H CH3 I
t-BuOK/t-BuO
92%
0
34 -
Q:" M e
(-CH2COOMe 2 t-BuOK/t-BuOH
B a (OH) 2 _____t 98 %
_______F
79-03%
-
36 -
0
37 -
CsHSN/HC1
& 38 -
\
c
EtOAc
66%
@COOH
Me0
Hg Pd/C
I
39 -
0
+
/
-I
4 0 (63%)
HC1
t98%
98%
N a t u r a l l y O c c u r r i n g Aromatic S t e r o i d s
652
26 -
1 Modification of Banerjee et al.
NaBH4
MeOH
37
99%
OH I
P
C
O
OH
O
H
-@ Glass powder 67-03% 300°
OH
Ba (OH)2
-
COOMe
____t
87%
42 -
The l a t t e r under b a s i c c o n d i t i o n s was c o n v e r t e d t o t h e a n i o n o f t h e c o r r e s p o n d i n g 6 - k e t o n i t r i l e 2 , l 9 which was t h e n m e t h y l a t e d . Following t h e Stobbe s e q u e n c e , s a p o n i f i c a t i o n of 37 o c c u r r e d w i t h c o n c o m i t a n t s h i f t of t h e A-14 d o u b l e bond t o t h e A-15 p o s i t i o n t o g i v e the 146-15-carboxy-A-15-17-ketone 38 a s shown by i t s uv s p e c t r u m and c o n v e r s i o n w i t h diazomethane i n t o a methyl e s t e r d i f f e r e n t from Acid c a t a l y z e d dec a r b o x y l a t i o n of 2 l e d t o 1 4 , 1 5 - d e h y d r o e q u i l e n i n methyl e t h e r 39. Presumably, a c i d 2 i s i n e q u i l i b r i u m w i t h i t s A-14 isomer i n which t h e 3-methoxy g r o u p can f a c i l i t a t e d e c a r b o x y l a t i o n v i a t h e i n d i c a t e d C-15 p r o t o n a t e d form.” 34. -
-
1.”
Equilenin
653
39 C a t a l y t i c hydrogenation of 2 occurred with p a r t i a l stere o s e l e c t i v i t y t o g i v e a 2 : l mixture of ( 2 ) e q u i l e n i n methyl e t h e r 40 and ( k ) i s o e q u i l e n i n methyl e t h e r 41, r e a d i l y separ a t e d by f r a c t i o n a l c r y s t a l l i z a t i o n and hydrolyzed t o t h e and 26 by Bachmann's procedure. By t h i s r e s p e c t i v e phenols s y n t h e s i s 3.3 g of ( 2 ) e q u i l e n i n L w a s o b t a i n e d from 10 g of t r i c y c l i c ketone 2. This was f u r t h e r improved by Banerjee e t a1.21 who showed t h a t t h e hydrogenation s t e p could be made s t e r e o s p e c i f i c i f c a r r i e d o u t on t h e 176-01 42 corresponding t o 2. The u n s a t u r a t e d 17B-01 42 was i n i t i a l l y o b t a i n e d from 37 a s i n d i c a t e d i n Scheme 3 , 2 1 a 0 , b e t t e r , d i r e c t l y from 39.21b An a d d i t i o n a l s y n t h e s i s of e q u i l e n i n v i a 14,15-dehydroe q u i l e n i n 2 based on t h e Stobbe r e a c t i o n of 1-0x0-2-methyl7-methoxy-1,2,3,4-tetrahydrophenanthrene 43 w i t h dimethyl succ i n a t e w a s d e s c r i b e d by Johnson and Stromberglgb (Scheme 4 ) .
I.
-
Scheme 4 .
Johnson's Second S y n t h e s i s of E q u i l e n i n
(-CH2COOMe) 2
t-BuOK/t-BuOH
86% Me0
654
N a t u r a l l y O c c u r r i n g Aromatic S t e r o i d s
45 -
39 -
-1
46 -
The methyl k e t o n e 43 had been o b t a i n e d by m e t h y l a t i o n of t h e s u b s t i t u t e d malonic ester i n t e r m e d i a t e i n t h e s y n t h e s i s of 2 (Scheme 1), f o l l o w e d by s a p o n i f i c a t i o n , d e c a r b o x y l a t i o n , and was s a p o n i f i e d and cyclization.6b The Stobbe p r o d u c t
-
44
COOEt COOE t
S
(1) N a / E t O H / C H 3 B r ( 2 ) KOH ( 3 ) 190° ( - C 0 2 ) ( 4 ) HF
Me0
& bo
Me0
8 -
43 -
decarboxylated t o g i v e t h e endocyclic dihydrophenanthreneprop i o n i c a c i d 45, o b t a i n e d i n d e p e n d e n t l y by Bachmann and Holmen from 43 by A r n d t - E i s t e r t homologation of t h e c o r r e s p o n d i n g Keformatsky product.'' C y c l i z a t i o n of S i n r e f l u x i n g a c e t i c anhydride containing a l i t t l e z i n c c h l o r i d e under c a r e f u l l y d e f i n e d c o n d i t i o n s gave 14-15-dehydroequilenin m e t h y l e t h e r 39 ( 2 3 % ) a s w e l l as 18% o f an i s o m e r i c k e t o n e , p o s s i b l y 46.
-2.
Rachmann and Holmen S y n t h e s e s
Two s h o r t b u t low y i e l d r o u t e s t o 2 o r i g i n a t e d from t h e adand 6d u c t 3 d e r i v e d from d i e t h y l a-methyl-B-oxoadipate methoxy-1-naphthylethyl i o d i d e (Scheme 5 ) . 2 2 C y c l o d e h y d r a t i o n of 47 gave a m i x t u r e of two i s o m e r i c l a c t o n e e s t e r s which
a,
Scheme 5
CH2 I t-BuOK/CGH
COOEt
&
Me0
\
/
COOEt
COOEt H2S04
COOE t
Me0
47 -
1 I
49 -
KOH/MeOH
1650
1
0
-co2
655
656
N a t u r a l l y O c c u r r i n g Aromatic S t e r o i d s
u n d e r Dieckmann c y c l i z a t i o n c o n d i t i o n s y i e l d e d a s o l i d , t e n t a t i v e l y f o r m u l a t e d as 49, t h a t m e l t e d w i t h gas e v o l u t i o n t o g i v e 39. F u r t h e r m o r e , 48 on s a p o n i f i c a t i o n r e a d i l y u n d e r w e n t d e c a r b o x y l a t i o n t o 45 c y c l i z e d a s above t o 9. D.
Robinson-Birch
Synthesis
A n o v e l s y n t h e s i s of t h e 1 3 - n o r e q u i l i n a n e r i n g s y s t e m d e v i s e d by R o b i n s o n 2 3 i n 1 9 3 8 l e d i n 1 9 4 5 t o 1 4 - i ~ o e q u i l e n i n a~n~d i n 1967 t o e q ~ i l e n i n . The ~ ~ key step involved a c i d i c h y d r o l y s i s of t h e f u r f u r y l i d e n e d e r i v a t i v e of 6-methoxy-2-acetylnaphthalene t o t h e dioxo acid (Scheme 6). I t is b a s e d o n the
3
Scheme 6 .
Robinson-Birch
S y n t h e s i s of 1 4 - I s o e q u i l e n i n
CH3 COCl/AlC 13 Me0
HC1 /EtOH/A
%50-60%
Me0
2 % aq. KOH
A
295%
Me 0
@ca” H2/2% Pd/SrCOg
Me0
CH30H %95%
657
658
N a t u r a l l y O c c u r r i n g Aromatic S t e r o i d s
( 2 ) KOH H 20/E t OH
f i n d i n g t h a t t h e f u r f u r y l i d e n e d e r i v a t i v e of acetophenone on r e f l u x i n g i n e t h a n o l i c h y d r o c h l o r i c a c i d y i e l d s 7-phenyl-4,7d i o x o h e p t a n o i c a c i d i n $50% y i e l d . 2 6 T h i s hydro1 t i c f i s s i o n i s general f o r a v a r i e t y of f u r f u r y l f o r examp l e , t h e c o n v e r s i o n of f u r f u r y l a l c o h o l t o l e v u l i n i c a c i d . The s y n t h e s i s a l s o depended on t h e a v a i l a b i l i t y of 2 which was o b t a i n e d i n good y i e l d by F r i e d e l - C r a f t s a c y l a t i o n of a t C-2 i n n i t r o b e n z e n e , 2 8 a l t h o u g h i n less p o l a r s o l v e n t s such a s benzene or carbon d i s u l f i d e a c y l a t i o n o c c u r s a t C-1. The d i o x o a c i d 53 was smoothly c o n v e r t e d t o t h e naphthylcyclopentenone 54 i n w a r m d i l u t e a l k a l i and the l a t t e r hydrog e n a t e d i n h i g h y i e l d t o t h e s a t u r a t e d 0x0 a c i d 55. C y c l i z a t i o n i n r e l a t i v e l y l o w y i e l d t o t h e t e t r a c y c l i c d i o n e 56 w a s b e s t accomplished i n p o l y p h o s p h o r i c a c i d and h y d r o g e n o l y s i s of t h e c a r b o n y l group a t o t h e a r o m a t i c system t h e n gave “x”n o r e q u i l e n i n methyl e t h e r -+ 56 w a s shown t o be The assumed c o u r s e of c y c l i z a t i o n c o r r e c t i n t h e 3-deOw s e r i e s by d e h y d r o g e n a t i o n o f t h e 3deoxy a n a l o g of 56 t o 1,2-~yclopentenophenanthrene. S i n c e C - 1 3 i s an e p i m e r i z a b l e c e n t e r i n 55 and 56 and s i n c e these i n t e r m e d i a t e s were g e n e r a t e d under e q u i l i b r a t i n g c o n d i t i o n s , t h e y s h o u l d p o s s e s s t h e thermodynamically s t a b l e c o n f i g u r a t i o n shown, t h a t i s , trans i n 55 and cis i n 56 (and 57). I n t r o d u c t i o n of t h e a n g u l a r methyl group a t C-13 r e q u i r e d p r i o r b l o c k i n g of C-16. T h i s was accomplished w i t h t h e a i d of t h e m e t h y l - a n i l i n o m e t h y l e n e group2’ developed a s an a l t e r n a t i v e t o t h e more d i f f i c u l t l y removable b e n z y l i d e n e t y p e b l o c k i n g group. O t h e r d e r i v a t i v e s of 2 - h y d r o x p e t h y l e n e k e t o n e s have s i n c e been u t i l i z e d a s b l o c k i n g groups o f which t h e nb u t y l t h i o m e t h y l e n e is one o f t h e most s a t i s f a c t o r y . 3 1 M e t h y l a t i o n of t h e C - 1 6 b l o c k e d k e t o n e 58 o c c u r r e d ent i r e l y i n t h e c i s s e n s e , and f o l l o w i n g removal of the b l o c k i n g
derivative^,'^
z.23
Equilenin
659
group, t h e product was ( ? ) 1 4 - i s o e q u i l e n i n methyl e t h e r 41, a n o t unexpected r e s u l t s i n c e a s i m i l a r sequence on hydrindan1-one l e d e x c l u s i v e l y t o c is 8-methyl-hydrindan-1-one. 24 By c o n t r a s t analogous methylation of a-decalone gave cist r a n s mixtures2' ' 30b i n which t h e t r a n s component, although t h e minor p r o d u c t , could be s e p a r a t e d and transformed t o t r a n s 8-methylhydrindan-1-0ne.~~ This r e s u l t l e d t o a number of s t e r o i d s y n t h e s e s based on i n t r o d u c t i o n o f t h e C-13 methyl group i n t o a C,D decalone system followed by s e p a r a t i o n of t h e t r a n s isomer and c o n t r a c t i o n of r i n g D (see below). I n a l a r g e number of s u b s t i t u t e d decalones cis methylation predominated over t r a n s w i t h t h e s t r i k i n g e x c e p t i o n of t h e A 6 analog. 33,66,71 An important f a c t o r i n determining t h e pref e r r e d d i r e c t i o n of r e a c t i o n between e n o l a t e anion and methyl
cis trans
1.3
ci s trans
> 10
c is %O. 3-0.5 trans
i o d i d e i n t h e s e systems appears t o be t h e r e l a t i v e thermodynam i c s t a b i l i t i e s of t h e methylated p r o d u c t s . Bucourt has r a t i o n a l i z e d t h e r e s u l t s i n terms of minimization of t o r s i o n a l s t r a i n of t h e d i h e d r a l a n g l e s i n v o l v i n g t h e r i n g j u n c t i o n s a s w e l l a s o f t h e r e l a t i v e s t e r i c i n t e r f e r e n c e between t h e angul a r methyl group and t h e p e r t i n e n t a x i a l hydrogens.34 For a number of y e a r s t h e r e was no f u r t h e r development of t h e Robinson approach. However, a p p l i c a t i o n of modern synt h e t i c methods h a s l e d t o completion of two r o u t e s t o e q u i l enin. I n 1967 Birch and Subba Rao25 a p p l i e d S t o r k ' s 3 5 r e d u c t i v e
660
N a t u r a l l y O c c u r r i n g Aromatic S t e r o i d s
m e t h y l a t i o n p r o c e d u r e t o t h e u n s a t u r a t e d 0x0 acid 54 and obt a i n e d t h e 13-methyl 0x0 a c i d 60 a s a 1 : 3 cis:trans m i x t u r e , q u i t e d i f f e r e n t from t h e 3 : l cis:trans r a t i o o b s e r v e d w i t h A9-octal-1-one.35 I n t h e l e a s t s a t i s f a c t o r y s t e p of t h e synt h e s i s 60 was c y c l i z e d ( p o l y p h o s p h o r i c a c i d ) i n $40% y i e l d and
H t h e d i o n e s 61 and 62 s e p a r a t e d c h r o m a t o g r a p h i c a l l y . Hydrog e n o l y s i s of e a c h t h e n gave ( + ) e q u i l e n i n methyl e t h e r 2 and ( z ) i s o e q u i l e n i n methyl e t h e r s.1, r e s p e c t i v e l y . Scheme 7 .
B i r c h S y n t h e s i s of E q u i l e n i n
- trans
54 -
60a
-
(75%)
60b cis ( 2 5 % )
H
Me0
61
M e0 62
Equilenin
661
ye o
Me0
40 -
41 -
Horeau S y n t h e s i s
E.
A s t e r e o s p e c i f i c synthesis of the
trans 13-methyl 0x0 a c i d
60a was d e s c r i b e d i n 1969 by Horeau e t a l ? methoxynaphthalene ( a v a i l a b l e from 8-naphthol
2-Bromo-6i n good y i e l d ) was converted t o t h e corresponding Grignard r e a g e n t 61 i n t e t r a h y d r o f u r a n and t h e l a t t e r condensed with t h e i s o b u t y l e n o l e t h e r o f 2-methylcyclopentanedione-l,3 62 t o g i v e t h e t r i c y c l i c ketone 63. Hydrogenation l e d t o a mixture of methyl ketones 64 which gave t h e a l l y l e n o l e t h e r 65 by an a c i d c a t a lyzed exchange procedure i n v o l v i n g a l l y l a l c o h o l and 2,2-dimethoxypropane. C l a i s e n rearrangement occurred s t e r e o s p e c i f i c a l l y on warming t o g i v e a s i n g l e a l l y l methyl ketone 66 i n good y i e l d . Permanganate o x i d a t i o n t h e n l e d t o t h e 0x0 a c i d 60a converted t o e q u i l e n i n methyl e t h e r % b y t h e p r e v i o u s l y d e s c r i b e d procedures. The s t e r e o s p e c i f i c i t y of t h e C l a i s e n rearrangement may be r a t i o n a l i z e d s t e r i c a l l y - - t h e l a r g e napht h y 1 r e s i d u e impeding bond formation from i t s s i d e of t h e cyclopentane r i n g .
-
Scheme 8.
Horeau S y n t h e s i s of Equilenin
rnMgBr +
Me0
61
i-BuO
H2
Me0
662
N a t u r a l l y O c c u r r i n g Aromatic S t e r o i d s
& a-' 0
CH2=CHCH20H CH3C CH3 MeO' 'OMe
Hf
A
*
----c 80%
Me0
64
Me0
65 -
KMnO4
60a F.
40 -
S y n t h e s i s from E s t r o n e I n t e r m e d i a t e s
A number of r o u t e s t o e q u i l e n i n from i n t e r m e d i a t e s i n e s t r o n e
t o t a l s y n t h e s i s have been d e v i s e d and a r e f o r m u l a t e d below. Dehydrogenation o f 8 - d e h y d r o e s t r o n e m e t h y l e t h e r y i e l d e d e q u i l e n i n methyl e t h e r I n view o f t h e r e a d y a v a i l a b i l i t y of 67 v i a c u r r e n t e s t r o n e s y n t h e s e s (see below) i t s d e h y d r o g e n a t i o n o f f e r s p r o b a b l y t h e s i m p l e s t and s h o r t e s t route t o equilenin y e t devised. Treatment o f t h e t r i c y c l i c D-homo d i o n e 68 w i t h h o t p y r i d i n e h y d r o c h l o r i d e l e d t o D-homoequilenin 69 which had been c o n v e r t e d t o e q u i l e n i n by J o h n s o n ' s method of r i n g c o n t r a c t i o n . 3 8 D-Homoequilenin m e t h y l e t h e r 2 was s i m i l a r l y produced from 70.3 7 b However, v i g o r o u s a c i d t r e a t m e n t o f t h e 5-membered r i n g D - t r i c y c l i c d i o n e 7237co r t h e b i c y c l i c t r i o n e 1137b l e d o n l y t o t h e 1 4 - i s o e q u i l e n i n s y s t e m s 41 and 26. The res u l t s a r e i n accord w i t h t h e d i f f e r i n g r e l a t i v e s t a b i l i t i e s o f t h e r e s p e c t i v e C/D d e c a l i n and h y d r i n d a n e p a r t s t r u c t u r e s .
s.37
67
Me0
& \
0
Se02/t-BuOH
II
or
Cr03/acetone/H+
67 -
Me0
;1
40
steps
Pyr. HC1/18Oo 55%
Me0 68 -
HO h
69 -
66 3
N a t u r a l l y O c c u r r i n g Aromatic S t e r o i d s
664 3.
EQUILIN
E q u i l i n 2 was i s o l a t e d a l o n g w i t h e q u i l e n i n from mare p r e g nancy u r i n e by G i r a r d e t a l . 3 9 i n 1932. Although i t i s a comm e r c i a l l y s i g n i f i c a n t e s t r o g e n and s t e r e o c h e m i c a l l y simpler t h a n e s t r o n e and t h e a n d r o g e n i c s t e r o i d s it w a s i n f a c t t h e l a s t of t h e hormonal s t e r o i d s t o b e s y n t h e s i z e d - - r e f l e c t i n g t h e d i f f i c u l t i e s i n i n t r o d u c i n g and m a i n t a i n i n g a d o u b l e bond i n t h e nonconjuqated A-7 p o s i t i o n . E q u i l e n i n d e r i v a t i v e s , obv i o u s s t a r t i n g materials, have o n l y r e c e n t l y been s u c c e s s f u l l y converted t o e q u i l i n . A.
Zderic e t a l . Synthesis
The f i r s t s y n t h e s i s of e q u i l i n , a c h i e v e d by a S y n t e x g r o u p , i n 1958,40 was n o t a c o m p l e t e l y c h e m i c a l s y n t h e s i s s i n c e it included a microbiological dehydrogenation s t e p . 1 9 - N o r t e s t o s t e r o n e a c e t a t e 75,o b t a i n e d b y B i r c h red ~ c t i o nof~ p~h e n o l i c e t h e r s of e s t r a d i o l (see below for t o t a l s y n t h e s i s ) , w a s c o n v e r t e d t o t h e c o r r e s p o n d i n g 4,6-dien-3-one 77 by b r o m i n a t i o n and dehydrobromination of t h e e n o l e t h e r 76 (Scheme 9 ) .
-
&:-& Scheme 9 .
Z d e r i c e t a l . S y n t h e s i s of E q u i l i n
(1) NBS
0
’
EtO
I5 -
\
\
76 -
@ Ac20, AcCl
1.90% ( c r u d e )
0
( 2 ) CaC03/DMF %70%
& -
AcO
Equilin
NaBH4
MeOH, THF, H20
665
t
%85%
OH A1 (OCH(Me) 2) 3 Cyclohexanone HO 79 -
80 -
'~40%Corynebacterium s i m p 1 ex
Enol acetylation of 77 led to the 3,17L3-diacetoxy-3,5,7-triene on sodium borohydride reduction followed by Oppenauer This two step oxidation gave androsta-4,7-diene-3,17-dione sequence was simplified by Bagli et al.42 who converted enol acetate 78 directly to 80 by brief treatment with sodium bicarbonate in dry methanol. Under these mild conditions the A-7 double bond did not shift into conjugation. Attempted ring A dehydrogenation utilizing dichlorodicyanoquinone (DDQ) by procedures which were successful with 10-substituted-4-en3-ones failed. However, microbiological dehydrogenation with Corynebacterium simplex gave equilin 3 in 40% yield.
78 which
B.
so.
Bagli et al. Synthesis A second synthesis of equilin was completed by Bagli et
666
Naturally Occurring Aromatic Steroids
By utilizing 19-hydroxyandrost-4,6-diene-3,17-dione (obtained from 38-acetoxyandrost-5-ene-17-0ne 3 , as starting material in essentially the Syntex scheme it was possible to aromatize ring A chemically. Treatment of the 19-acetoxy4,7-diene-3,17-dione with DDQ in refluxing dioxane led to the corresponding lI4,7-triene-3,17-dione5 which on retroaldolization gave equilin. al?
-
Scheme 10. Bagli et al. Synthesis of Equilin
AcpO/AcCl Pyridine 56%
AcO
0
&- & OH’/MeOH
85 -
C.
HO
Stein et al. Synthesis
The third synthesis of equilin44a,44b proceeded from 3-methoxy-17B-hydroxyestra-1,3,5(10) ,8-tetraene 86, an intermediate in estrone total synthesis and consisted essentially in transfer of the A-8 double bond to the A-7 position. Synthetic resolved on treatment with m-chloroperbenzoic acid in benzene-hexane gave a mixture of a-oxide 87 and allylic alcohol 88, which was converted entirely to 88 by treatment with benzoic acid in chloroform. Catalytic
Equilin
667
hydrogenation then yielded the ring C saturated diol 89 which with methanesulfonyl chloride in refluxing pyridine gave the A-7 olefin as the expected product of bimolecular trans elimination, contaminated with %lo%of its A-8 isomer. Lithium to the 17B-carbinol 91 and the aluminum hydride converted synthesis was completed by ether cleavage at C-3 and Oppenauer oxidation at C-17. The original 16% overall yield44a was later improved to %38%, principally by utilizing phosphorus oxychloride in dimethylformamide at 0-25' in the elimination step to give the 17-formate in 81% yield (converted to 91 by aqueous methanolic alkali) and only a trace of the A-8 isomer.44b Scheme 11.
Stein et al. Synthesis of Equilin
___c
Me0
Me0
87 -
86 -
OH
OH 1
-
CH3S02C1/ C5H5N/A -EtOH Me0
POCl3/DMF/
Me0
0-25'
R
F T / 4 H ? &
_____c
160"
NaOH/H20-MeOH
Me0
90a R = OS02CH3 90b R = OCHO
-
91 -
668
N a t u r a l l y O c c u r r i n g Aromatic S t e r o i d s
74 -
92 D.
B a i l e y e t al. S y n t h e s i s
The f o u r t h s y n t h e s i s of e q ~ i l i np r~o c~e e d e d from e q u i l e n i n Birch reduction methyl e t h e r 40 o r t h e r e l a t e d 1 7 6 - c a r b i n o l . of similar 6 - n a p h t h y l m e t h y l e t h e r s u t i l i z i n g p o t a s s i u m 4 6 o r sodium47 a s t h e d i s s o l v i n g m e t a l had o c c u r r e d o n l y i n r i n g A . However, s u b s t i t u t i o n of t h e more e f f i c i e n t l i t h i u m 4 * l e d t o a moderate y i e l d of t h e t e t r a h y d r o p r o d u c t 93. Oppenauer o x i d a t i o n and a r o m a t i z a t i o n of r i n g A by t r e a t m e n t w i t h N-bromos u c c i n i m i d e i n aqueous t - b u t a n o l t h e n gave e q u i l i n 2. A l t e r n a t i v e l y , a r o m a t i z a t i o n w i t h p y r i d i n e hydrobromide perbromide produced e q u i l i n m e t h y l e t h e r . Scheme 12.
B a i l e y e t a l . S y n t h e s i s of E q u i l i n
sH
t-BuOH/ THF
40%
Me0
t-BuOH/HzO 4 3%
94 -
74 -
Oppenauer
Equilin E.
669
M a r s h a l l and Deghenghi S y n t h e s i s
The f i f t h s y n t h e s i s (Scheme 1 3 1 , a remarkably e f f i c i e n t conv e r s i o n of e q u i l e n i n t o e q u i l i n , i n v o l v e d low t e m p e r a t u r e Scheme 13.
M a r s h a l l and Deghenghi S y n t h e s i s of E q u i l i n
b
0
96a, -
96b, -
0
(1) NaH/THF
,I
3a-OH 38-OH
97 -
a l k a l i metal r e d u c t i o n o f e q u i l e n i n e t h y l e n e k e t a l 95.49 The naphthoxide a n i o n , g e n e r a t e d i n s i t u o r p r e f e r a b l y by sodium hydride i n tetrahydrofuran before addition t o a solution of l i t h i u m i n l i q u i d ammonia a t - 7 0 ° , was p r e f e r e n t i a l l y reduced i n r i n g B t o g i v e , f o l l o w i n g d e k e t a l i z a t i o n , a 55% i s o l a t e d y i e l d (76% by g.1.c. a n a l y s i s ) o f e q u i l i n 3.By-products i n c l u d e d t h e r i n g A reduced e p i m e r i c a l c o h o l s 96 and i n some r u n s t h e c o r r e s p o n d i n g k e t o n e . The absence of 9 - i s o e q u i l i n i s noteworthy. Compound was i d e n t i c a l w i t h a r i n g B aromatic isomer of e s t r o n e i s o l a t e d from mare pregnancy u r i n e 5 ' and s y n t h e s i z e d v i a c a t a l y t i c hydrogenation o f e q u i l e n i n d e r i v a t i v e ~ . A~t ~ -33' e q u i l i n w a s t h e major p r o d u c t w i t h l i t h i u m o r sodium, b u t p o t a s s i u m l e d t o f3a-estrone 97 by a novel red u c t i o n of t h e unconjugated A-7 double bond. Although B i r c h r e d u c t i o n of p h e n o l s s h o u l d b e more d i f f i c u l t t h a n r e d u c t i o n of t h e c o r r e s p o n d i n g p h e n o l i c e t h e r s because o f t h e presumed i n t e r m e d i a c y of r a d i c a l d i a n i o n s r a t h e r t h a n o f r a d i c a l monoanions, i t h a s been accomplished i n good y i e l d by u t i l i z i n g high c o n c e n t r a t i o n s of l i t h i u m i n l i q u i d
670
N a t u r a l l y Occurring Aromatic S t e r o i d s
ammonia. 5 2 I n t h e p r e s e n t case e l e c t r o s t a t i c r e p u l s i o n of l i k e charges would favor r e d u c t i o n i n r i n g B r a t h e r than i n r i n g A.
4.
ESTRONE
I s o l a t e d from pregnancy u r i n e i n 1 9 2 9 e s t r o n e 98 was t h e f i r s t s t e r o i d hormone t o be obtained i n pure form.S3-It was o r i g i n a l l y b e l i e v e d t o be t h e main e s t r o g e n i c hormone b u t i t has s i n c e been recognized t h a t estradiol-17B 99 i s t h e primary e s t r o g e n s e c r e t e d by t h e ovary. Both compounds have been i n t e r r e l a t e d e n z y m a t i c a l l y a n d chemically w i t h each o t h e r and w i t h a number of s t r u c t u r a l l y s i m i l a r m e t a b o l i t e s , f o r example, e s t r i o l 16a,17B-=. Estrone has been i s o l a t e d from a l l major c l a s s e s of v e r t e b r a t e s a s well a s from h i g h e r p l a n t s and r e c e n t l y from w a t e r b e e t l e s p e c i e s 5 4 along w i t h o t h e r C - 1 8 , C - 1 9 , and C - 2 1 hormonal steroids.
HO
H
\
HO 98 -
99 -
100 -
Estrone
671
The medical importance of e s t r o n e engendered e a r l y i n t e r e s t i n i t s s y n t h e s i s . More r e c e n t l y i t s p o s i t i o n a s a prec u r s e r t o commercially important 19-nor-steroids h a s s t i m u l a t e d development of i n d u s t r i a l l y f e a s i b l e t o t a l l y s y n t h e t i c r o u t e s , a s w e l l a s p a r t i a l syntheses from s t e r o i d a l raw m a t e r i a l s such a s d i o s g e n i n , s t i g m a s t e r o l , o r c h o l e s t e r o l . 5 5 Eight racemates of the e s t r o n e s t r u c t u r e are p o s s i b l e and stereochemical cont r o l i n t h e g e n e r a t i o n of t h e f o u r asymmetric c e n t e r s i s mand a t o r y i n any p r a c t i c a l s y n t h e t i c scheme. One of t h e f i r s t a t t e m p t s t o p r e p a r e t h e e s t r o n e s t r u c t u r e involved t h e Diels-Alder r e a c t i o n between 1-vinyl-6-methoxy3,4-dihydronaphthalene 101 and methylcyclopent-l-en-4,5-dione 102.56 The c r y s t a l l i n e adduct, i s o l a t e d i n low y i e l d , a p r i o r i 103 o r 104 was converted t o an e s t r o g e n i c a l l y i n a c t i v e monoketone m.p. 210' isomeric with e s t r o n e methyl e t h e r .
-
0
Me0
.+
6
0
Dioxane
______c
1 00 O / 5 0 h r
a
Me0
103
104 -
I t was shown l a t e r t h a t t h e c r y s t a l l i n e adduct (23%) has i n f a c t t h e double bond isomerized A - 8 14-methyl s t r u c t u r e 105 and t h a t an e q u i v a l e n t q u a n t i t y of t h e n o n - c r y s t a l l i n e A - 8 13-methyl isomer 106 i s a l s o formed.57 I n any event t h e Diels-Alder r e a c t i o n g e n e r a t e s C/D cis r a t h e r than t h e r e q u i r e d C/D trans s t e r e o c h e m i s t r y .
-
672
N a t u r a l l y O c c u r r i n g Aromatic S t e r o i d s
Me0
M e0
106 -
105 -
I n t h e analogous c o n d e n s a t i o n of d i e n e with citraconic anhydride 107 t h e 13-methyl a d d u c t 108 predominated o v e r t h e 14-methyl a d d u c t by a b o u t 2:1.5aSuccessful examples of t h e D i e l s - A l d e r r e a c t i o n i n s t e r o i d s y n t h e s i s have avoided s t r u c t u r a l ambiguity and p r o d u c t m i x t u r e s by k e e p i n g one of t h e r e a c t a n t s s y m m e t r i c a l , e . g . , t h e Johnson-Walker e s t r o n e s y n t h e s i s ( p . 687).
109
&
Me0 \
d
+
0
101 -
+
108 -
109 -
The e x c l u s i v e f o r m a t i o n of t h e 14-methyl a d d u c t o b s e r v e d and 2,6-xyloi n t h e normal D i e l s - A l d e r c o n d e n s a t i o n of quinone i s a l t e r e d i n favor of t h e d e s i r e d 13-methyl a d d u c t b y boron t r i f l u o r i d e c a t a l y s i s . T h i s r e c e n t f i n d i n g l e d V a l e n t a and h i s c o l l e a g u e s t o a n e f f e c t i v e s y n t h e s i s of (+) e s t r o n e methyl e t h e r =.l1*
Estrone
P
673
BF 3 /E t g 0
i
0
20”
69% (+ 1 4 % 14-methyl adduct)
2 2 % from
A.
101
119 -
Anner and Miescher S y n t h e s i s
The f i r s t s y n t h e s i s of e s t r o n e w a s accomplished by Anner and Miescher i n 1948.59 Their approach followed t h a t envisioned by Robinson d u r i n g t h e n i n e t e e n t h i r t i e s when h e and h i s c o l l a b o r a t o r s s y n t h e s i z e d t h e t r i c y c l i c ketone 110 (R=Et) 6 o and hoped to add t h e elements of r i n g D by r e a c t i o n s analogous t o t h o s e developed l a t e r by Bachmann i n t h e f i r s t e q u i l e n i n synthesis.
N a t u r a l l y O c c u r r i n g Aromatic S t e r o i d s
674
i s o u t l i n e d i n Scheme 1 4 .
The o r i g i n a l s y n t h e s i s of Scheme 1 4 .
Robinson-Walker Ketone--Robinson
Synthesis
c1
I
COOEt
+ Me 0
H3C-C
II
0
-f/
(1) N a / E t 2 0 ( 2 ) aq. KOH
COOEt
(2) NaOEt/Et20
Me0
Me0
Me0
-
111 -
112 -
109'
CH31/K/C6H6 R O ' ' &
&ocmEt Me0
m.p.
\
Me0 m.p.
98-99O
\ 110 ( R = E t ) -
Hydrogenation o f t h e hexahydrophenanthenone 111 gave a m i x t u r e o f d i h y d r o ( k e t o n e ) and t e t r a h y d r o ( a l c o h o 1 ) z o d u c t s . Back o x i d a t i o n o f t h e l a t t e r by t h e Oppenauer p r o c e d u r e and p u r i f i c a t i o n v i a t h e semicarbazone y i e l d e d t h e s a t u r a t e d k e t o n e m.p. 109'. The l a t t e r was f o r m u l a t e d w i t h trans B/C s t e r e o c h e m i s t r y o n t h e b a s i s of i t s s t a b i l i t y t o e p i m e r i z a t i o n and a n x-ray c r y s t a l l o g r a p h i c a n a l y s i s ( p r o b a b l y one of t h e f i r s t of an o r g a n i c s y n t h e t i c i n t e r m e d i a t e ) . I n 1942 Bachmann e t al. succeeded i n s y n t h e s i z i n g an
112,
Estrone
675
isomer of estrone, 0a,l3a-estrone (estrone-A) from the hexahydrophenanthrene ketoester 113. Hydrogenation of the Reformatsky product 113a y i e l d e d a m i x t u r e o f s t e r e o i s o m e r s a .
&ocooM COOMe
Me0
HCOOMe-
Me0
113
113a
I _
m
Me0
113c -
113b -
from which at the final stage was obtained by fractional crystallization. In connection with this work they developed an improved route (Scheme 15) to the Robinson-Walker ketone Scheme 15.
Robinson-Walker Ketone--Bachmann Synthesis
0 C"/CooEt Me0
Br COOEt
COOEt Me0
\ COOEt ClCO (CH2)3COOEt
______t
N a t u r a l l y Occurring Aromatic S t e r o i d s
676
PcooEt COOEt
COOEt
Me0
oYcooH F
C
O
O
H
H2,'Pd-C _____c CH3COOH
Me0
Me 0 &coo"
A
B
C
110 ( -
-
110 -
(R=Me)
m.p. 113-135' m.p. 127-128' m.p. 87- 89'
s t h e methyl e t e r ) which was u t i i z e d by n n e r and Miescher. Since s t r u c t u r e p o s s e s s e s t h r e e asymmetric c e n t e r s , f o u r racemates a r e p o s s i b l e . By simple f r a c t i o n a l c r y s t a l l i z a t i o n from acetone t h e S w i s s workers obtained t h r e e of t h e s e c r y s t a l l i n e . 6 2 Each k e t o - e s t e r 110 was converted i n t o t h e corresponding p a i r of e s t r o g e n i c d o i s y n o l i c a c i d s 114 and isomer A was t h e r e by c o r r e l a t e d s t e r e o c h e m i c a l l y with e s t r o n e 98 a t C - 8 , C-9 and C-13. Furthermore, isomer C was epimerized t o isomer A on t r e a t m e n t w i t h a l k a l i i n conformity with trans B/C stereocherni s t r y for t h e l a t t e r . 6 2
Estrone
677
114 Isomer A was t h e r e f o r e chosen a s s u b s t r a t e €or t h e Bachmann r i n g D sequence (Scheme 1 6 ) , which was c a r r i e d o u t with Scheme 16.
~\ o
c
o
o
Estrone--Anner-Miescher
M
e
Me0
& 110 (isomer -
A)
,COOMe
OH
Me0
\
115 -
CH*CooMe
POC13/pyr.
Synthesis
N a t u r a l l y Occurring Aromatic S t e r o i d s
678
COOMe
Hp /Pd-C
_____c
CHCOOMe
Me0
&
Me0
(1) 0.1N KOH ( 2 ) Arndt-Eistert
CH2 COOMe
( 3 ) KOH
t
\
& 117a 117b
I _
Me0
COOMe
-
m.p. 95-96O m.p. 91-93' COOH
\
Pb (co3 2
COOH
300'
-
Me0
119 -
HO
98
c
m o d i f i c a t i o n of t h e o r i g i n a l p r o c e d u r e (Scheme 2 ) a t t h e deh y d r a t i o n , r e d u c t i o n and c y c l i z a t i o n s t a g e s The s a t u r a t e d diester m.p. 95-96", y i e l d e d e s t r o n e 98 r e s o l v e d as t h e (-1 menthoxyacetate, and d i e s t e r gave 14B-estrone. A s h o r t e r r o u t e from t o e s t r o n e based o n t h e a c y l o i n cond e n s a t i o n was d e v i s e d l a t e r by Sheehan e t a l . ( s e e Scheme 18).69
m,
Estrone
679
Three a d d i t i o n a l racemates of t h e e s t r o n e s t r u c t u r e were a l s o s y n t h e s i ~ e d . ~ ’A~ n endocyclic isomer m.p. 95-97’ of 116 produced a t t h e dehydration s t a g e gave a mixture on hydrogenat i o n which l e d t o 96-estrone ( e s t r o n e d ) and 8aI9B-estrone ( e s t r o n e e ) . Estrone d and e were a l s o o b t a i n e d from t r i c y c l i c keto-ester C ( l l O C ) . A f i f t h racemate, 8 a I l 3 a - e s t r o n e ( e s t r o n e f , Bachmann’s e s t r o n e a ) was o b t a i n e d from t r i c y c l i c The c o n f i g u r a t i o n a l assignments were k e t o - e s t e r B (E). deduced l a t e r by Johnson e t a l . following t h e i r p r e p a r a t i o n of seven of t h e e i g h t p o s s i b l e racemates of t h e e s t r o n e s t r u c exception was e s t r o n e e l t h e s t r u c t u r e of which t ~ r e .The ~ ~ w a s assigned by d i f f e r e n c e . Despite t h e l a c k o f stereochemical c o n t r o l gram q u a n t i t i e s of (+) e s t r o n e were produced by t h e above r o u t e .
-
B.
Johnson Syntheses
Following t h e i n i t i a l s u c c e s s of Anner and Miescher, Johnson and h i s c o l l a b o r a t o r s devised t h r e e d i f f e r e n t approaches t o estrone.63’66 The f i r s t 6 3 r 6 4 and t h i r d 6 6 a p p l i e d Johnson’s method of a n g u l a r m e t h y l a t i o n , which had been developed e a r l i e r i n t h e p r e p a r a t i o n of cis and trans 8-methylhydrindan-1-one from a-decalone3* t o a p p r o p r i a t e t e t r a c y c l i c i n t e r m e d i a t e s . The second s y n t h e s i s 6 5 u t i l i z e d a novel A C -+ B + D approach. C.
Johnson’s F i r s t S y n t h e s i s
In p r e l i m i n a r y work it was e s t a b l i s h e d t h a t a r o u t e analogous t o Johnson’s f i r s t e q u i l e n i n s y n t h e s i s , t h a t i s , Stobbe cond e n s a t i o n on t h e cyanoketones 2 o r *, was i n ~ p e r a t i v e . ~ ~ The hydrochrysene s y n t h e s i s shown i n Scheme 1 7 was then developed.
31 31a -
A-4a(lOa)
qiH3 Scheme 17.
Estrone--Johnson's First Synthesis OH
Me0
0
Me0
0
OH
I
(1) Raney Ni/H2 (2) Na2Cr207/Ht
0
+
CECH
120 -
t - BuOK t-BuOH
____c
0
122 -
& &-
A1C13/C6H6 ____c
Me0
Me0
124
680
C6 H5CHO MeOH/NaOH
125a c1 125b 6 -
isomer cis a n t i trans isomer trans a n t i trans
Estrone
681
0
Me I t-BuOK t-BuOH ____c
n
(1) Og/EtOAc-AcOH ( 2 ) H202
-&
& Me
0
COOH ((1) 2 ) PbC03/300° Pyr.HC1/210"
Me0 HO
128
\
129a t r a n s a n t i c i s . . . 1 3 a - e s t r o n e 129b t r a n s a n t i t r a n s . . .e s t r o n e 98 129c c i s a n t i c i s . . .90,13u-estrone 129d -c i s a n t i t r a n s . . . g B - e s t r o n e
Condensation o f t h e p o t a s s i u m d e r i v a t i v e o f m-methoxyp h e n y l a c e t y l e n e 120 w i t h cis and/or t r a n s decalin-1,5-dione 1 2 1 6 7 gave two a c e t y l e n i c c a r b i n o l s hydrogenated t o t h e c o r r e s p o n d i n g s a t u r a t e d c a r b i n o l s 123. Cyclodehydration o f t h e m i x t u r e or t h e i n d i v i d u a l components l e d t o a dodecahydroHowever, d e h y d r a t i o n o f t h e s a t u chrysenone m . p . 170" rated carbinols =to t h e unsaturated ketone ( 7 0 % from 1 2 1 ) f o l l o w e d by c y c l i z a t i o n gave i n c a . 25% y i e l d two dodecahydrochrysenones, l a r g e l y t h e isomer and a lesser amount o f a B isomer m.p. 155' B. On s u b s e q u e n t r e p e t i t i o n of t h i s s t e p u s i n g v e r y a c t i v e aluminum c h l o r i d e o n l y t h e l a t t e r c o u l d be i s o l a t e d (ca. The B isomer was shown t o have t h e t r a n s a n t i t r a n s c o n f i g u r a t i o n a t t h e B/C and C/D r i n g
122,
-
e.
-
125a
124
682
N a t u r a l l y O c c u r r i n g Aromatic S t e r o i d s
(=%) and 1 3 a - e s t r o n e j u n c t i o n s by c o n v e r s i o n t o e s t r o n e (lumiestrone) Methylation of t h e benzylidene d e r i v a t i v e 126 (8 s e r i e s ) gave p r e f e r e n t i a l l y t h e cis methyl d e r i v a t i v e 1 2 7 ( c i s : t r a n s = 3:l) a s i n t h e d e c a l o n e s e r i e s . 3 2 Ozonizat i o n o f each component t o t h e c o r r e s p o n d i n g d i a c i d pyr o l y s i s o f t h e r e s p e c t i v e l e a d s a l t s and d e m e t h y l a t i o n t h e n l e d t o 13a-estrone and e s t r o n e The dodecahydrochrysene m.p. 170' was shown l a t e r 6 3 t o possess t h e cis a n t i trans c o n f i g u r a t i o n and t h e c o r r e s p o n d i n g e s t r o n e s a r e t h e r e f o r e t h e 98, 13a and t h e 96 racemates. The m e t h y l a t i o n cis:trans r a t i o i n t h i s s e r i e s was
-
=.
-
128,
m. 125c
125d
4:l.
A t h i r d o f t h e fo u r p o s s i b l e C/D t r a n s dodecahydrochryse n o n e s , t h e cis syn t r a n s , y-isomer, m.p. 138', w a s obt a i n e d by h y d r o g e n a t i o n o f t h e t e t r a c y c l i c u n s a t u r a t e d k e t o n e 130a d e r i v e d by a halogenation-dehydrohalogenation sequence on 125a. The c o r r e s p o n d i n g u n s a t u r a t e d k e t o n e i n t h e 8-series (B/C t r a n s ) c o u l d n o t be o b t a i n e d p u r e and i n q u a n t i t y from 125b. I t was p a r t l y e p i m e r i z e d by h o t m e t h a n o l i c a l k a l i t o
125c
-
( 3 ) LiCl/DMF
_____c 40% Me0
Me0 125a -
130a -
-
130a B/C -
cis
0
H?/Pd-C
NaOH/EtOH 60%
Me0
125c
_ L
-isomer cis s y n t r a n s
Estrone
683 n
4 steps
HO 131 -
129e c is s y n 129f c is s y n
-
cis 8 a , 13a e s t r o n e t r a n s 8a e s t r o n e
t h e B/C ci s isomer B, which i n t u r n was stable t o b a s e . Assuming h y d r o g e n a t i o n of from t h e exo f a c e and concomit a n t i s o m e r i z a t i o n i n t h e b a s i c medium l e a d s t o t h e cis s y n t r a n s formulation f o r The l a t t e r was m e t h y l a t e d as t h e furfurylidene derivative t h e m i x t u r e of methyl isomers ( c i s : t r a n s = 11:l) s e p a r a t e d and e a c h c o n v e r t e d t o t h e c o r r e s p o n d i n g e s t r o n e racemate, 8a, 1 3 a - e s t r o n e and 8aestrone respectively. The 8 a - e s t r o n e s t r u c t u r a l a s s i g n ment w a s confirmed by an independent p r e p a r a t i o n o f t h e methyl e t h e r v i a h y d r o g e n a t i o n o f t h e B r i n g of ( 2 ) e q ~ i l e n i n . ~ ~ T h i s s y n t h e s i s t h e r e f o r e l e d t o s i x racemates of the e s t r o n e s t r u c t u r e w i t h t h e d e s i r e d isomer a minor p r o d u c t a t t h e c y c l i z a t i o n (124+ 125) and m e t h y l a t i o n (126+ 127) s t a g e s . The s t r u c t u r e s of t h e t h r e e dodecahydrochrysenones b and were confirmed l a t e r by p r e p a r a t i o n from i n t e r m e d i a t e s of t h e Johnson-Walker e s t r o n e s y n t h e s i s , 6 6 which l e d also t o a f o u r t h isomer, t h e t r a n s s y n c is from which 1 4 6 - e s t r o n e w a s obtained.
=.
131,
129f,
=,
c
D.
J o h n s o n ' s Second S y n t h e s i s
J o h n s o n ' s second s y n t h e s i s 6 Scheme 1 8 .
(Scheme 1 8 ) was c o n s i d e r a b l y more
Estrone--Johnson's
Second S y n t h e s i s
COOMe I
( CI H 2 ) 3
Me0
0
(1) A l C 1 3 / C 2 H 2 C 1 4 ( 2 ) MeOH/H+ 77%
-f
n
C
O
O
(1) Stobbe 62%
I
Me 0
132 -
CH2 COOH
COOMe CH2COOMe
134 -
Me (1) BrCH2COOMe/Zn ( 2 ) HCOOH
H
______c ( 3 ) MeOH/NaOH 40%
CH2COOMe
Me0
135a A r / M e 135b A r / M e -
W \C
H
cis 4 3 %
trans 2 9 % Me
C CH2COOH O O M
e
MeG
,COOMe
(1) H 2 / P d - S r C 0 3 MeG ~
\C
H
C
0
684
O
137 -
O
M
-
(1) Raney Ni/NaOH C-COOH
MeG
H
HOAc/HClOt, e ---T (2) HZ/Pd-SrC03 EtOAc
( 2 ) MeOH/H+
75%
Estrone
:ge&
CH2COOMe Me0
\
NaBH4/
___t MeOH
* h
85-100%
/ 117a -
Me0
685
\ 138 -
OH
0
CsHcjN*HCl
- 2
90% HO
139 -
98 -
s t e r e o s e l e c t i v e than t h e f i r s t and by a m o d i f i c a t i o n l e d a l s o t o a seventh racemate of t h e e s t r o n e s t r u c t u r e - - t h e trans s y n c i s ( 1 4 6 - e s t r o n e ) . I n c o n t r a s t t o t h e previous e s t r o n e synt h e s e s which used meta s u b s t i t u t e d a n i s o l e s t a r t i n g m a t e r i a l s t h e p r e s e n t r o u t e u t i l i z e d a more e a s i l y a v a i l a b l e para subs t i t u t e d derivative, the keto-ester r e a d i l y prepared by F r i e d e l C r a f t s condensation of a n i s o l e with e i t h e r g l u t a r i c anhydride o r t h e corresponding h a l f e s t e r a c i d c h l o r i d e . Stobbe condensation with e t h y l s u c c i n a t e and potassium tbutoxide i n t-butanol a t room temperature followed by saponif i c a t i o n l e d t o t h e u n s a t u r a t e d t r i c a r b o x y l i c a c i d 133. The l a t t e r was reduced and converted t o t h e t r i m e t h y l e s t e r 134 which on Dieckmann c y c l i z a t i o n and methylation gave the k e t o diesters and E. As a p a r t l y e q u i l i b r a t e d cyclohexanone t h e major component 135a would be expected t o have i t s t h r e e bulky groups disposed e q u a t o r i a l l y , and t h i s was shown t o be so by i t s conversion t o e s t r o n e . [The isomer 135b presumably would have l e d t o 13a-estrone d e r i v a t i v e s i n c l u d i n g 13a, 148e s t r o n e ( 8 a , gB-estrone, Anner and Miescher's e s t r o n e e ) t h e one racemate Johnson d i d n o t s y n t h e s i z e . ] Reformatsky r e a c t i o n on 135a followed by l a c t o n i z a t i o n and e l i m i n a t i o n gave the d i e s t e r a c i d which was c y c l i z e d a s t h e a c i d c h l o r i d e to 137. Hydrogenolysis of t h e k e t o group i n t h e l a t t e r and hydrogenation of t h e double bond then l e d t o t h e methyl e t h e r of ( * ) dimethyl m a r r i a n o l a t e 3converted t o e s t r o n e by
=,
136
606
N a t u r a l l y O c c u r r i n g Aromatic S t e r o i d s
A r n d t - E i s t e r t homologation, c y c l i z a t i o n , and d e m e t h y l a t i ~ n . ~ ~ ~ t o (+) e s t r o n e from n a t u r a l l y d e r i v e d b a s e d o n t h e a c y l o i n c o n d e n s a t i o n was d e v i s e d b y S h e e h a n e t al?’. 16-Keto-estradiol methyl e t h e r produced i n h i g h was r e d u c e d t o a m i x t u r e of t r i o l s w h i c h o n y i e l d from f u s i o n with p y r i d i n e h y d r o c h l o r i d e l e d d i r e c t l y t o estrone. H y d r o g e n a t i o n of t h e d o u b l e bond o f = p r i o r to cyclizat i o n o c c u r r e d from t h e s i d e o p p o s i t e t h e a c e t i c a c i d s i d e c h a i n l e a d i n g t o 140 and f i n a l l y t o 1 4 6 - e s t r o n e . A superior route
138
136 -
-
4 COOMe
---c-
Hz/Pd-SrC03 EtOH 70%
‘CHZCOOMe
Me0
CLi2COOH
146-estrone
v i a the cyanoImproved r o u t e s t o t h e k e t o d i e s t e r k e t o e s t e r 1 4 1 have b e e n d e v e l o p e d by B a n e r j e e 7 0 a and by Johnson.70bMe
Me0
CH2COOMe
Estrone E.
687
Johnson-Walker S y n t h e s i s
J o h n s o n ' s method o f i n t r o d u c i n g t h e a n g u l a r methyl group, f o r example, =-+ a l t h o u g h a h i g h y i e l d r e a c t i o n , u n f o r t u n a t e l y produced mainly cis r a t h e r t h a n t h e d e s i r e d trans methyldecalone systems. However, i n 1957 Johnson and Allen71 succeeded i n o b t a i n i n g predominantly t r a n s p r o d u c t s on methyla t i n g t h e A-6 d e c a l o n e system 142 o r t h e e q u i v a l e n t t e t r a c y c l i c It w a s r e a s o n e d t h a t i n t r o d u c t i o n o f t h e double system bond, by e l i m i n a t i n g a 0 - a x i a l hydrogen might f a c i l i t a t e 0f a c e approach o f t h e m e t h y l a t i n g a g e n t . The e s t r o n e s y n t h e s i s o f Johnson, Walker e t a l . w a s d e s i g n e d w i t h t h i s p o i n t i n mind
127,
143.
14 2 -
H
144
145
1 43 -
and t h e decahydrochrysenones and were p r e p a r e d . 6 6 In the l a t t e r t h e e f f e c t o f e l i m i n a t i n g t h e a x i a l 8-0 hydrogen c o u l d be t e s t e d .
144 145 Compounds 144 and 145 were o b t a i n e d v i a t h e Diels-Alder a d d u c t 147 (Scheme 19) of t h e d i e n e 101 and benzoquinone.
T h i s a d d u c t had been p r e p a r e d o r i g i n a l l y by Dane e t a l . i n 1937,72 b u t i t s c h e m i s t r y w a s f i r s t s t u d i e d i n d e t a i l by Robins and Walker c o n s i d e r a b l y l a t e r . 7 3 An improved r o u t e t o d i e n e 101 i n v o l v i n g d i r e c t p r e p a r a t i o n of t h e v i n y l c a r b i n o l 146 by r e a c t i o n o f 6-methoxytetralone 9 w i t h v i n y l magnesium bromide i n t e t r a h y d r o f u r a n developed by Nazarov e t a1.74 as w e l l a s o t h e r p r o c e s s improvements, l e d t o a d d u c t i n 75%
147
Scheme 1 9 .
Estrone--Johnson-Walker
-
Synthesis
0
CH2 =CHMgBr/THF
1 2 /c6
-T
Me0
Me0
9 -
% /A
146 -
Zn/AcOH
____c
Me 0
86%
0
0
101 -
1 4 7 ( 7 5 % from 9) -
148 -
144 -
Me
@
300'
-T
Na/NH 3
( 2 ) Pyr.HCl/
COOH
COOH
151 -
(1) PbC03/
COOH
200°
1 2 8 ( 3 1 . 5 % from -
98 688
Estrone
689
o v e r a l l y i e l d from 2 and thence t o t h e r i n g D s a t u r a t e d adduct The s e l e c t i v e removal of t h e 15-carbonyl group i n 148 was s t u d i e d i n d e t a i l . The b e s t procedure developed involved s e l e c t i v e Meerwein-Ponndorf r e d u c t i o n of t h e 17a-carbonyl group, Huang Minlon-Wolff-Kishner r e d u c t i o n a t C-15 w i t h concomitant i s o m e r i z a t i o n a t C-14 and Oppenauer o x i d a t i o n t o g i v e the C/D t r a n s ketone i n 49% y i e l d from P r o t e c t i o n of t h e 17a-carbonyl group a s t h e dimethyl k e t a l l e d t o i n only 22% y i e l d . Methylation o f t h e f u r f u r y l i d e n e d e r i v a t i v e 149 produced, a s a n t i c i p a t e d , mainly (56%) t h e t r a n s isomer 150 and 33% of i t s cis c o u n t e r p a r t , which were s e p a r a t e d by f r a c t i o n a l c r y s t a l l i z a t i o n ( t h e t r a n s : c i s r a t i o a s determined by nmr was 6 0 : 4 0 ) . Conversion of 150 t o t h e A - 9 (11) homomarrianolic a c i d 151 by h o t a l k a l i n e hydrogen peroxide [ o z o n i z a t i o n a s i n 128 could n o t be used because of t h e 9(11) double bond1 f o l lowed by chemical r e d u c t i o n l e d t o t h e methyl e t h e r o f homop r e v i o u s l y converted t o e s t r o n e . D e marrianolic acid s p i t e t h e s t e r e o s e l e c t i v e i n t r o d u c t i o n o f a l l asymmetric cent e r s t h e low y i e l d i n t h e r i n g D cleavage sequence (=+ 128) l i m i t e d t h e o v e r a l l y i e l d of e s t r o n e from 2 t o 3.7%. The p r e p a r a t i o n of 145 and i t s C/D cis isomer 3a l s o proceeded from 148. Conversion t o t h e monoethylene k e t a l 152 w i t h double bond s h i f t followed by Huang Minlon r e d u c t i o n and a c i d h y d r o l y s i s gave a mixture of c i s and t r a n s ketones 9 and 145, A l k a l i t r e a t m e n t of 152 p r i o r t o hydrazone formation led exclusively t o whereas hydrazone formation b e f o r e a d d i t i o n of a l k a l i l e d t o r e d u c t i o n without e p i m e r i z a t i o n . E i t h e r 145 or produced t h e same 75-80% cis:5-7% t r a n s mixp o i n t i n g up t h e s e n s i t u r e of furfurylidene d e r i v a t i v e s t i v i t y o f t h e C/D c i s : t r a n s r a t i o i n t h e s e systems t o s t r u c tural detail.
148.66
144
-
148.
144
=+
=,
145a
145
=,
n
148 -
145 C/D trans 145a -C/D cis
‘ H
0
152
154 R=H 155 R=Me -
690
N a t u r a l l y O c c u r r i n g Aromatic S t e r o i d s
154
M e t h y l a t i o n o f t h e C/D cis f u r f u r y l i d e n e k e t o n e led i n contrast t o the e x c l u s i v e l y t o t h e cis methyl compound p r e d o m i n a n t l y trans m e t h y l a t i o n o f 2. As d i s c u s s e d e a r l i e r (p. 659) t h e s e r e s u l t s have b e e n r a t i o n a l i z e d i n terms of p r o d u c t s t a b i l i t y - - a n g u l a r m e t h y l a t e d trans and c i s o c t a l i n s y s t e m s p r e f e r r i n g t h e d o u b l e bond i n t h e A-2 and A-1 p o s i t i o n s , r e s p e c t i v e l y , i n o r d e r t o minimize a x i a l s t e r i c i n t e r a c t i o n s and t o r s i o n a l s t r a i n .
155,
F.
2-Methylcyclopentane-1,3-dione
I n t h e s y n t h e s e s o f e q u i l e n i n and e s t r o n e c o n s i d e r e d s o f a r t h e C-13 methyl g r o u p was i n t r o d u c e d e i t h e r p r i o r t o c o n s t r u c t i o n of r i n g D o r f o l l o w i n g assemblage o f t h e t e t r a c y c l i c s y s t e m . U t i l i z a t i o n o f a preformed m e t h y l a t e d r i n g D component or b e t t e r i n t h e form o f 2-methylcyclohexane-lI3-dione h a s b e e n the key f a c t o r i n 2-methylcyclopentane-l,3-dione t h e development o f a number o f r e l a t i v e l y s h o r t i n d u s t r i a l l y f e a s i b l e s y n t h e s e s of e s t r o n e e x e m p l i f i e d by t h e a p p r o a c h e s of S m i t h , Torgov, and V e l l u z .
156,
157,
0
0 156
J5
0
157 -
2-methylcyclohexane-1,3-dione ( a v a i l a b l e i n 60% y i e l d by ) first u t i l i z e d r e d u c t i o n and m e t h y l a t i o n of r e s o r ~ i n o l ’ ~ was i n s t e r o i d s y n t h e s i s i n 1953 by M i e s c h e r e t a l . a s a r i n g D component i n t h e i r p r e p a r a t i o n of D-homoandrostane-3,17ai n e s t r o n e s y n t h e s i s r e q u i r e s subd i ~ n e . S~i n~c e u s e o f s e q u e n t D-ring c o n t r a c t i o n , 2-methylcyclopentane-l,3-dione 1 5 7 a p r i o r i would be t h e r e a g e n t of c h o i c e . However, t h e l a t t e r w a s a r e l a t i v e l y rare s u b s t a n c e u n t i l 1955 when i t became a v a i l a b l e i n 20% y i e l d from butanone-2 by a f o u r - s t a g e s y n t h e s i s , t h e key s t e p o f which was t h e s e l e c t i v e removal o f t h e C-4 c a r b o n y l group o f t h e i n t e r m e d i a t e t r i o n e 2 by Wolff-Kishner r e d u c t i o n of t h e c o r r e s p o n d i n g monosemicarbazone77 (Scheme 20). S i n c e t h e n s e v e r a l s u p e r i o r methods have i s now a r e a d i l y accessible i n t e r m e b e e n d e v e l o p e d and diate.
156
-
157
S c h e m e 20.
157
2-Methylcyclopentane-1,3-dione
Panouse and ~ a n n i 6 7 7 0
COCOOEt
d
(1) NH2CONHNH2 ( 2 ) K/CH20H
0
0
CH20H
159 -
15 7 -
B u c o u r t e t a1.78
CH3
O=
(",
COOEt
1
CH3 CH
' 0
E x c e s s KOBut
xylene A
CH-CH2 I COOEt
O=f
0 f-
1-
CH2
COOEt
160
I_
( 1 ) Aq. KOH (2) A
0
COOEt
161 -
6 0
0
157 -
691
N a t u r a l l y O c c u r r i n g Aromatic S t e r o i d s
692
Grenda e t a l . " 0
r o
1
0
0
Schick e t a1." 0
COOH COOH
(1) A l C 1 3 / C H 3 N O ( 2 ) CH 3CH2CCC1
QCH3
( 3 ) H30' 0
157
B u c o u r t e t a l . d e s c r i b e d an i n g e n i o u s route t o inv o l v i n g an i n t r a m o l e c u l a r a c y l a t i o n o f d i e t h y l p r o p i o n y l s u c a s t h e d i a n i o n f o l l o w e d by s a p o n i f i c a t i o n and decinate c a r b o x y l a t i o n ( y i e l d 7 3 % ) .7 8 However, t h e p r o c e d u r e s o f b a s e d on a n o v e l F r i e d e l Grenda e t a l . 7 9 and S c h i c k e t a1." C r a f t s t y p e a c y l a t i o n r e a c t i o n u t i l i z i n g s u c c i n i c a c i d der i v a t i v e s a r e t h e methods of c h o i c e , Grenda e t a l . o b t a i n e d 1 5 7 i n 80-85'3 y i e l d by r e a c t i n g s u c c i n i c a n h y d r i d e , aluminum c h l o r i d e and 2-acetoxybutene-2 (molar r a t i o 1:3.5:1.5) i n nitrobenzene. Somewhat s i m i l a r p r o c e s s e s were d e v e l o p e d by I n t h e i r b e s t v a r i a n t (1969) s u c c i n i c a c i d was Schick e t a l . t r e a t e d s u c c e s s i v e l y w i t h aluminum c h l o r i d e and p r o p i o n y l in c h l o r i d e (molar r a t i o 1 : 3 : 3 ) i n nitromethane t o g i v e 72-78% y i e l d .
160
157
Estrone
693
S y n t h e s e s of Smith e t a l .
G.
P r e l i m i n a r y a c c o u n t s of two e s t r o n e s y n t h e s e s based on an D -+ ABCD approach and u t i l i z i n g E 8 l and 15737a, respect i v e l y , as D components were p u b l i s h e d i n 1960% Hughes and Smith (Schemes 21 and 2 2 ) . This work was d e s c r i b e d i n d e t a i l i n 196337b a l o n g w i t h a number of r e l a t e d r o u t e s .
A
-f
Scheme 2 1 NaCfCH/
(1) Hz/Pt/EtOH Me0
16 3 -
162 -
CH2 N E t 2
I
111
Me0
164 -
Me0
111
a 166 -
165 -
+
)$j
Me0
167
_c
U
HCl/EtOH ___t
Me0
169 -
170 -
171 -
172 -
Me0 127 -
98 S c h e m e 22
+
(166
I _
+
&’”;
167) KOH/MeOH/A ~
0
157 -
694
Me0 180 -
Estrone
695
dioxane or C6H6
181 -
Me0
OH 0
183 -
119 -
163,
3-m-methoxyphenylpropyl bromide prepared e f f i c i e n t l y from m-methoxycinnamic a c i d 162,was condensed w i t h sodium a c e t y l i d e t o g i v e 5-m-methoxyphenylpentyne 164. The l a t t e r , on Mannich c o n d e n s a t i o n w i t h formaldehyde and d i e t h y l a m i n e followed by h y d r a t i o n of t h e t r i p l e bond and d i s t i l l a t i o n , gave a m i x t u r e o f Mannich base 166 and v i n y l k e t o n e 167 which, i n t h e f i r s t s t e p of a Robinson a n n e l a t i o n r e a c t i o p w a s condensed w i t h 2-methylcyclohexane-1,3-dione 156 t o give t h e A l d o l i z a t i o n t o close t h e C r i n g w a s accomplished trione w i t h triethylammonium b e n z o a t e i n r e f l u x i n g x y l e n e . Hydrog e n a t i o n of t h e d o u b l e bond i n t h e u n s a t u r a t e d d i o n e 169 occ u r r e d s t e r e o s e l e c t i v e l y from t h e s i d e o p p o s i t e t h e a n g u l a r methyl group, and s u b s e q u e n t e p i m e r i z a t i o n o f t h e a l k y l subs t i t u e n t a t o t h e c a r b o n y l group l e d t o w i t h t h e thermodynamically p r e f e r r e d a n t i - t r a n s s t e r e o c h e m i s t r y . A l t e r n a tively, = w a s c o n v e r t e d t o 170 by lithium-ammonia r e d u c t i o n Cyclodehydration i n followed by back o x i d a t i o n a t C-17a. e t h a n o l i c h y d r o c h l o r i c a c i d t h e n gave A9 (11)-dehydro-D-homoe s t r o n e methyl e t h e r 171 reduced t o D-homoestrone methyl e t h e r 172 by p o t a s s i u m - l i q u i d ammonia r e d u c t i o n and back o x i d a t i o n
168.
170
-
696
N a t u r a l l y O c c u r r i n g Aromatic S t e r o i d s
172
a t C-17a. The o v e r a l l y i e l d of from 3-m-methoxyphenylwas 7 . 5 % . The s y n t h e s i s was completed by p r o p y l bromide p r e p a r a t i o n of t h e b e n z y l i d e n e d e r i v a t i v e 1 2 7 , a n i n t e r m e d i a t e i n Johnson's D r i n g c o n t r a c t i o n p r o c e d u r e 6 7 S c h e m e 1 7 ) . 2-Methylcyclopentane-1,3-dione was u t i l i z e d s u c c e s s f u l l y i n t h e above s e q u e n c e w i t h some m o d i f i c a t i o n s t o y i e l d i n 1 4 % y i e l d from 163.37bThe p r i n e s t r o n e methyl e t h e r c i p a l m o d i f i c a t i o n i n v o l v e d h y d r o g e n a t i o n o f t h e k e t o l 174 r a t h e r than the dione which i n c r e a s e d t h e y i e l d of from _173 from 4 0 % t o 6 0 % . (See Ref. 105b f o r f o r m a t i o n o f (+)-= by c l o s u r e o f t h e C r i n g under a s y m m e t r i c c o n d i t i o n s . ) I t i s s t r i k i n g t h a t t h e C-4 s u b s t i t u t e d t e t r a h y d r o i n d a n e s
163
157
119 173
175
173
OH
I
Me0
(1) H C l / E t O H ( 2 ) HZ/Pd-C/EtOH
174
175 -
119 -
and a r e h y d r o g e n a t e d s t e r e o s e l e c t i v e l y t r a n s , whereas t h e unsubstituted tetrahydroindanes and are h y d r o g e n a t e d s t e r e o s e l e c t i v e l y cisezat e z b i n a c c o r d w i t h g e n e r a l e x p e r i e n c e i n t h i s a r e a e 3 [see a l s o V e l l u z s e c o n d e s t r o n e s y n t h e s i s (Scheme 2 6 ) 1.
176
177
Fc
R
Hz/Pd-SrC03/EtOH 0
H
-
1 7 6 , R=B-OH 1 7 7 , R=O
1 7 8 , R=B-OH 1 7 9 , R=O
-
-
Estrone
697
F u r t h e r y i e l d improvement t o 18% of 119 from 163 was achieved a s shown i n Scheme 2 2 . 3 7 a , 37b Cyclodehydration of 180 under more s t r o n g l y a c i d i c c o n d i t i o n s than had been used e a r l i e r l e d t o t h e e s t r a p e n t a e n e I&, a key i n t e r m e d i a t e a l s o o f t h e Torgov r o u t e t o e s t r o n e ( s e e below). The r e q u i s i t e t r a n s a n t i t r a n s s t e r e o c h e m i s t r y was i n t r o d u c e d i n t o 181, which has one c h i r a l c e n t e r , by an e s s e n t i a l l y two s t e p red u c t i v e sequence. Hydrogenation of t h e 14,15 double bond occ u r r e d mainly from t h e cx s i d e ( c f . 14-dehydro-equilenin, Scheme 3) t o g i v e 8-dehydroestrone methyl e t h e r 182, converted by a l k a l i metal-ammonia r e d u c t i o n and back o x i d a t i o n a t C-17 t o e s t r o n e methyl e t h e r 119. Yields were improved by c a r r y i n g o u t t h e chemical r e d u c t i o n of t h e A-8 double bond on the 178-01 183 and l a t e r by c a r r y i n g o u t both s t e p s on t h e 1 7 6 - 0 1 der i v e d from 181 (see Torgov s y n t h e s i s ) . A novel r o u t e t o 167 u t i l i z i n g the inexpensive e s s e n t i a l o i l , eugenol 184, a s s t a r t i n g m a t e r i a l was d e s c r i b e d by Horeau e t a l . i n 1 9 6 p The key i n t e r m e d i a t e , m-methoxyallylbenzene 185, w a s o b t a i n e d from eugenol phosphate. Conversion of 185 t o t h e Grignard r e a g e n t 186 was accomplished d i r e c t l y by titanium t e t r a c h l o r i d e c a t a l y z e d exchange with n-propyl magnesium bromide i n r e f l u x i n g e t h e r , a g e n e r a l r e a c t i o n of terminal 0 1 e f i n s . ' ~ ~Addition of a c r o l e i n and o x i d a t i o n of t h e i n t e r m e d i a t e v i n y l c a r b i n o l completed t h e s y n t h e s i s . The important i n t e r m e d i a t e , 6-methoxytetralone 9 a l s o was obtained from by r e a c t i o n w i t h carbon d i o x i d e followed by Friedel-Craft r i n g closure.
-
-
-
186
184 -
185 -
(1) CH2=CH CHO
m
( 2 ) Cr03/ether-H20
Me0
186 -
167 -
698 H.
Naturally Occurring A r o m a t i c S t e r o i d s Torqov S y n t h e s i s
In t h e Smith s y n t h e s e s j u s t d i s c u s s e d t h e c a r b o n system was assembled by c o n d e n s a t i o n of t h e a n i o n of t h e 8 - d i c a r b o n y l compound o r 157 w i t h t h e v i n y l k e t o n e The Torgov approach had i t s g e n e s i s i n s t u d i e s on a n a l o g o u s b a s e - c a t a l y z e d w i t h a l l y l i c bromides 188. The l a t a l k y l a t i o n s of 156 o r t e r , p r e p a r e d from v i n y l c a r b i n o l s 187 b y a n i o n o t r o p i c rearrangement w i t h hydrogen bromide, were condensed w i t h t h e a n i o n of t h e B-diketone and t h e a d d u c t s 189 c y c l i z e d t o h e t e r o a n n u l a r d i e n e s by h e a t i n g w i t h phosphorus p e n t o x i d e . 8 5
167.
156
157
-
N aOMe/MeOH/lO- 20
c
187 -
188 0
189 -
n = 1, 2
190 -
F o r e s t r o n e s y n t h e s i s by t h i s r o u t e t h e r e q u i r e d v i n y l c a r b i n o l 146 was r e a d i l y a v a i l a b l e from 6 - m e t h o ~ y t e t r a l o n e ~ ~ as d e s c r i b e d e a r l i e r , b u t t h e c o r r e s p o n d i n g p r i m a r y bromide 191 was t o o u n s t a b l e t o b e o b t a i n e d by t h e hydrogen bromide I t was, however, p r e p a r e d l a t e r by W h i t e h u r s t procedure .86 and co-workers u s i n g m i l d e r condition^.^^ R e a c t i o n of w i t h t h e a n i o n of [methanol, one e q u i v a l e n t of T r i t o n B ( b e n z y l t r i m e t h y l a n n n o n i u m h y d r o x i d e ) 70°/24 h r ] gave t h e t r i c y c l i c d i o n e 192 i n p o o r y i e l d and c y c l i z a t i o n of t h e l a t t e r gave t h e e s t r a p e n t a e n e 181 i n o n l y 6 % y i e l d o v e r t h e condensat i o n and c y c l i z a t i o n s t e p s . 07
-
175
191
Estrone
-
CHC~~-C.I~H~N
___c
Me0
-60'
CH?OH/Triton B ?0°/24 h r
Me0
146 -
699
191 -
181 (6% from 191)
192 -
Following t h e i r unsuccessful a t t e m p t s t o p r e p a r e 191 and o t h e r analogous m u l t i u n s a t u r a t e d primary bromides t h e Russian workers i n 1959 condensed t h e p r e c u r s e r b i s - v i n y l c a r b i n o l s 193 w i t h = i n t h e presence of '1.10%T r i t o n B and obtained t h e adducts 194 i n 50% y i e l d . 8 6 This novel r e a c t i o n which l a t e r became known as t h e Torgov reaction" f a i l e d when a p p l i e d t o
-
+
C6HsCH2NMe3 ] OH-/140
O
R
'1.50%
193 -
R=H, M e
156 -
194 -
s i n g l y v i n y l i c c a r b i n o l s . Application t o t h e b i s - v i n y l carb i n o l 146 t h e n l e d t o t h e t r i c y c l i c adduct 195 (Scheme 2 3 ) i n 60% y i e l d (based on 156 consumed) which was c y c l i z e d t o t h e D-homoestropentaene 196 i n high y i e l d . 89 C a t a l y t i c hydrogenat i o n of t h e A-14 double bond followed by potassium-liquid ammonia r e d u c t i o n o f t h e A - 8 17a-ethylene k e t a l 197 produced, a f t e r h y d r o l y s i s , D-homoestrone methyl e t h e r 172 i n 16% overE s t r o n e methyl e t h e r a l l y i e l d from 6-methoxytetralone. w a s o b t a i n e d from i n %50% y i e l d by o x i d a t i o n of t h e f u r f u r y l i d e n e d e r i v a t i v e and p y r o l y s i s o f t h e l e a d s a l t of t h e
172
Scheme 2 3
19 5 -
n
Me0
U
17 2 -
700
Estrone
701
d e r i v e d d i a c i d [procedure of Johnson e t a l . (Scheme 1 9 ) ] i n the U t i l i z a t i o n of 2-methylcyclopentane-l,3-dione above sequence would o b v i a t e t h e n e c e s s i t y f o r r i n g D c o n t r a c t i o n , and f i v e independent s n t h e s e s based on t h i s approach were p u b l i s h e d i n 1963. 3 7 b t 3 Y c r 8 7 r 9 1 Y i e l d s were s i m i l a r t o t h o s e i n t h e D-homo s e r i e s and e s t r o n e methyl e t h e r = w a s produced from 6-methoxytetralone i n e s s e n t i a l l y f i v e s t e p s i n about 20% y i e l d v i a t h e key i n t e r m e d i a t e s 192 and (Scheme 2 4 ) . E s t r a p e n t a e n e 181 had a l r e a d y been c o n v e r t e d t o
157
181
Scheme 24
&-&
Hg /Pd-CaCO 3
Me0 \
HCl/MeOH 85-90% Me0
\
192 -
cr
50-70%
181 -
&- &
Me0
( 2 ) %60% CrO3
\
182 -
Me0
\
119 -
182
e s t r o n e methyl e t h e r 119 v i a by Hughes and Smith37a (Scheme 2 2 ) . Minor v a r i a n t s of t h e r o u t e from 181 have been des c r i b e d . 9 2 Analogous t o t h e e a r l i e r f i n d i n g s i n t h e e q u i l e n i n seriesg1 hydrogenation o f t h e A-14 double bond of t h e e s t r a p e n t a e n e - 1 7 8 - 0 1 ~ ~ ' o r 1 7 8 - a c e t a t e g 3 d e r i v e d from 181 gave a g r e a t e r p r o p o r t i o n (80-90%) of t h e d e s i r e d 14a p r o d u c t than
702
N a t u r a l l y O c c u r r i n g Aromatic Steroids
from t h e 17-ketone (%50-70%). However, c o n t r a r y t o e x p e c t a t i o n s based on s i m p l e s t e r i c c o n s i d e r a t i o n s , h y d r o g e n a t i o n of t h e c o r r e s p o n d i n g 17a-01 ( b u t n o t t h e 1 7 a - a c e t a t e ) o v e r Raney n i c k e l i n dioxane a l s o gave %90%of 1 4 a - p r o d ~ c t . ~ ~ The Torgov r e a c t i o n w a s c o n s i d e r e d o r i g i n a l l y t o be base c a t a l y z e d and w a s g e n e r a l l y c a r r i e d o u t i n t h e p r e s e n c e of a b o u t 10% of t h e q u a t e r n a r y ammonium h y d r o x i d e , T r i t o n B . 3 7 b f However, t h e o b s e r v a t i o n s t h a t c o n d e n s a t i o n d i d n o t o c c u r when a full m o l a r e q u i v a l e n t of b a s e w a s u s e d and a c t u a l l y o c c u r r e d i n h i g h e r ( 7 0 % ) y i e l d i n t h e absence of base t h e n under t h e s t a n d a r d c o n d i t i o n s ( 5 0 - 6 0 % ) showed t h a t t h e r e a c t i o n i s n o t b a s e c a t a l y z e d . I t r e q u i r e s t h e f r e e Bdiketone r a t h e r t h a n t h e c o r r e s p o n d i n g a n i o n . The 1,3d i o n e (pKa 4 . 5 ) presumably f u n c t i o n s as an a c i d - - p r o t o n transf e r t o t h e v i n y l c a r b i n o l 146 f a c i l i t a t i n g i o n i z a t i o n of t h e l a t t e r w i t h g e n e r a t i o n of t h e i o n p a i r 193 and t h e n c e 1 9 2 . 9 4 f 9 5
157
0
146 -
192 -
157 -
193 -
194 -
The p o s s i b i l i t y of an e n o l e t h e r i n t e r m e d i a t e *which could g i v e 192 by Cope r e a r r a n g e m e n t w a s e l i m i n a t e d b y 0 1 8 ~tudies.’I ~na c e t i c acid-xylene a t 120’ 146 and 157 were c o n v e r t e d d i r e c t l y t o 181 i n 60% A major y i e l d improvement r e s u l t e d from p r i o r c o n v e r s i o n of t h e unstable v i n y l c a r b i n o l 146 to t h e c r y s t a l l i n e isot h i u r o n i u m a c e t a t e 195. The l a t t e r coupled w i t h 157 under
Estrone mild conditions (water-ether/25') i n 90% y i e l d . 9 4 p 9 5 a
-'
SC ( N H * ~ ; A c O H d
Me 0 146
t o give t r i c y c l i c dione
S
-
C
<
l
l
703
192
0AcO
]
Me0
195 The above modifications r a i s e t h e o v e r a l l y i e l d of 119 from 6 t o about 3540%. A v a r i a n t of t h e Torgov r e a c t i o n involving r e a c t i o n of t h e p y r o l l i d y l analog of v i n y l c a r b i n o l 146 with 157 i n r e f l u x i n g methanol l e d t o crude in
3
80% yield.96
Me0
196 -
I.
196
n
fi
0
157
MeOH/A/16 h r
-
192
0
Me0
192
_.
Resolution
Conventional r e s o l u t i o n of e s t r o n e i t s e l f 5 9 a and t h e e s t r a pentaen-17B-01 derived from 18137c has been accomplished v i a t h e corresponding 1-menthoxyacetates. I t was subsequently recognized t h a t t h e p r o c h i r a l t r i c y c l i c dione 192 o f f e r e d t h e unique p o s s i b i l i t y of r e s o l u t i o n without enantiomer l o s s , e i t h e r by reconversion of the "wrong" enantiomer t o o r by asymmetric o p e r a t i o n s on 192.
192
N a t u r a l l y O c c u r r i n g Aromatic S t e r o i d s
704
OH I
L i A l H (OBUt) 3/THF
v 85-90%
Me0
75%
+
uvarum
Me
OH I
OH
I
H CCONH2 I OH
MeO197 (-) -
198 (+) -
Reduction of 192 w i t h l i t h i u m t r i - t - b u t o x y aluminum h y d r i d e o c c u r r e d u n d e r r e a g e n t approach c o n t r o l t o g i v e t h e (*) k e t o l (Me/OH t r a n s ) i n h i g h y i e l d . The l a t t e r w a s r e s o l v e d v i a t h e q u i n i n e s a l t of i t s h e m i s u c c i n a t e , and t h e (-1 k e t o l c o n v e r t e d t o (+) e s t r o n e by way of 17a-hydroxy intermediates. The (+) k e t o l = w a s r e c y c l e d by o x i d a t i o n t o 192.94 M i c r o b i o l o g i c a l r e d u c t i o n of w i t h t h e y e a s t , Saccharomyces uvarum, gave t h e (-1 k e t o l (Me/OH c i s ) i n 75% y i e l d , which was c o n v e r t e d t o (+) e s t r a d i o l methyl e t h e r v i a 1 7 8 a c e t o x y i n t e r m e d i a t e s i n 55% y i e l d . 9 3 J e r i v a t i z a t i o n of d i o n e 192 w i t h 1 - t a r t r a m i c a c i d hydraz i d e under e q u i l i b r a t i n g c o n d i t i o n s l e d t o t h e (+) d e r i v a t i v e 198 i n 7 5 - 8 0 % y i e l d . R e v e r s i b l e r e a c t i o n o c c u r s a t e i t h e r c a r b o n y l g r o u p , b u t e q u i l i b r i u m i s d i s p l a c e d i n f a v o r of d i a s t e r e o m e r 198 b e c a u s e of i t s g r e a t e r i n s o l u b i l i t y . C y c l i z a t i o n and h y d r o l y s i s gave ( - ) estrapentaen-17-one 181.97 An a d d i t i o n a l s y n t h e s i s o f ( - ) 181 from a p r o c h i r a l denamely, t h e r i v a t i v e o f 2-methylcyclopentan-1,3-dione Michael a d d u c t of and e t h y l a c r y l a t e , i s o u t l i n e d i n t o t h e monoethylene k e t a l and Scheme 25.98 Conversion of
-
196 196
192 197
-
199
157
157,
199
Estrone
705
Scheme 2 5
n
0
199, R = E t 199a, R=H
0
200 -
-
xfi QjHzMqBr n
n
__t OR-
Me0
0
201 -
Me0 202 -
n
0
H+
___c
Me0
203 s a p o n i f i c a t i o n l e d t o t h e a c i d 200 which w a s r e s o l v e d a s t h e c i n c h o n i n e s a l t . The "wrong" enantiomer w a s r e c y c l e d by hyd r o l y s i s t o E. P r e p a r a t i o n o f t h e e n o l l a c t o n e 201 and Grignard r e a c t i o n w i t h 3-m-methoxyphenylpropyl magnesium broScheme 2 1 ) under c o n d i t i o n s compatible w i t h mide ( c f . which was cyk e t a l f u n c t i o n a l i t y l e d t o the dioxoketal c l i z e d under a l k a l i n e c o n d i t i o n s t o g i v e 203. Acid c a t a l y z e d c y c l i z a t i o n and k e t a l cgeavage t h e n a f f o r d e d (-1
163,
202,
181.
Naturally Occurring Aromatic S t e r o i d s
706
Velluz Syntheses
J.
Velluz and h i s colleagues a t t h e Roussel-Uclaf Laboratories i n P a r i s developed two s t e r e o s e l e c t i v e r o u t e s t o the t r i c y c l i c dione 204, a v e r s a t i l e intermediate from which they s nthesized t h e key aromatic and non-aromatic hormonal s t e r o i d s . 9 4 , 1 0 0 Their work i s c h a r a c t e r i z e d by t h e novel i n c o r p o r a t i o n of OC00
04 2
elements of e a r l i e r syntheses and f e a t u r e s e a r l y r e s o l u t i o n as a p r e r e q u i s i t e f o r p o s s i b l e i n d u s t r i a l p r a c t i c a l i t y . The first s y n t h e s i s (linear--Scheme 2 6 ) i s t o o lengthy f o r indust r i a l c o n s i d e r a t i o n , b u t t h e second (converging--Scheme 2 7 ) i s comparable t o t h e Torgov r o u t e .
Po
Scheme 26
Me0
-9
--&”-
Me I/NaOE t
Me0
-
Me0
206 -
207 -
205 -
-0
( CH2COOMe ) 2 /KOBut
OH
0
(1) BH;
___c
(2) OH-
208 (50% from 2) -
____).
( 2 ) EtOH/
@ C OH \ Me0
(1) Resolution HCl/A
209 (1) @COCl/Pyr. (2) Li/NH3/ether
75%
__T
& 214 -
OC00
204 -
&
(2) AcBr/Ac20/CH2C12 (1) OH(97%)
0
/
215 -
HO
\
99 707
-
OC00
HCl/MeOH
212 -
216 -
5+ob
Scheme 27
Pyridine, toluene A
-b
Ple00C
157 -
219 -
'-,,,,
p-p
0
HOOC
221 -
OAc
Ac20/NaOAc/A
HOOC0
223 -
0
____c 220 -
(1) Resolution
( 2 ) NaBH4
HC1
HOOC
224 -
Hz/Pd/EtOH/HC
-
75%
Estrone
OCOCg H 5
OAc
204 -
22s -
220
709
-
OH
F h i zopus arrhi zus >70%
The 1960 synthesis’’ followed a BC -F D + A scheme. A n e f f i c i e n t r o u t e t o t h e racemic t r i c y c l i c i n t e r m e d i a t e 211 from 6-methoxytetralone 9 d e s c r i b e d by Banerjee i n 195621a was employed and modified t o i n c l u d e r e s o l u t i o n of Construct i o n of r i n g D followed t h e sequence developed by Johnson i n h i s f i r s t e q u i l e n i n s y n t h e s i s (Scheme 3 ) with B a n e r j e e ’ s modif i c a t i o n f o r i n c r e a s e d s t e r e o s e l e c t i v i t y i n t h e hydrogenation of t h e r i n g D double bond (208 + 2 1 1 ) . I n t e r m e d i a t e 209 was r e s o l v e d a s t h e chloramphenicol s z . The a l k y l a t i o n r e a c t i o n l e a d i n g t o r i n g A was s t u d i e d using methyl v i n y l k e t o n e , 3benzyloxybutyl bromide and 1,3-dichlorobutene-2 ( p r e f e r r e d ) with t h e B,y-unsaturated ketone 213 a s w e l l a s with t h e corresponding a,B-unsaturated ketone 216. I n ketone the doubly a c t i v a t e d hydrogens on t h e carbon a t o both t h e c a r bony1 group and t h e double bond a r e c l e a r l y t h e most a c i d i c , and a l k y l a t i o n was d i r e c t e d t o t h i s s i t e . However, it was d i s c o v e r e d l a t e r t h a t a l k y l a t i o n of t h e dienamine derived from 216 was a more e f f i c i e n t r o u t e t o =.Io1 Sulfuric acid h y d r o l y s i s o f t h e v i n y l c h l o r i d e 214 t h e n gave t h e enedione 204. The 9,10-double bond i n t h e l a t t e r i n h i b i t s f u r t h e r a c i d c a t a l y z e d condensation t o a 3,3,1-bic clononene system observed i n analogous s a t u r a t e d c a s e s . I n t h e p r e s e n t example t h e r e s u l t a n t system 218 would v i o l a t e B r e d t ’ s r u l e . 215) was b e s t accomplished with soClosure of r i n g A (*+ dium t-amylate i n benzene. Aromatization of t h e A r i n g by i s o m e r i z a t i o n o f t h e 9,lO-double bond was c a r r i e d o u t c a t a l y t i c a l l y i n 40% y i e l d by palladium on carbon i n r e f l u x i n g
=.
213 217
-
’”
710
N a t u r a l l y O c c u r r i n g Aromatic S t e r o i d s
e t h a n o l . An a l t e r n a t i v e i s o m e r i z a t i o n p r o c e d u r e i n v o l v i n g r e a c t i o n o f 215 w i t h a c e t y l bromide and a c e t i c a n h y d r i d e i n methylene c h l o r i d e a t 20' followed by a d d i t i o n t o a ueous a m n i a l e d t o e s t r a d i o l 17-benzoate i n 97% y i e l d . 193 Saponif i c a t i o n o f t h e l a t t e r t h e n gave e s t r a d i o l 99. The u s e of b e n z o a t e as a p r o t e c t i n g group f o r h y d r o x y l o v e r a c o n s i d e r able v a r i e t y of c o n d i t i o n s i s noteworthy. The 1963 V e l l u z s y n t h e s i s l o o u t i l i z e d a D + C -+ B + A scheme analogous t o a sequence t h a t had been s t u d i e d e a r l i e r w i t h D-homo i n t e r m e d i a t e s . 7 6 ' O 4 Michael c o n d e n s a t i o n under weakly b a s i c c o n d i t i o n s of 2-methylcyclopentane-1,3-dione 157 w i t h methyl 5-0x0-6-heptenoate 229 l e d t o t h e t r i o n e a c i d 220, which a s a b a s e u n s t a b l e 2,2-disubstituted-l,3-diketone was c y c l i z e d t o t h e e n e d i o n e a c i d 221 under a c i d i c c o n d i t i o n s . The l a t t e r w a s r e s o l v e d c o n v e n t i o n a l l y v i a i t s e p h e d r i n e s a l t . However, i t s p r o c h i r a l p r e c u r s e r 220 w a s l a t e r reduced microb i o l o g i c a l l y i n >70% y i e l d t o t h e c o r r e c t o p t i c a l l y a c t i v e enantiomer 226 (methyl/OH-cis) , 0 5 a which w a s c y c l i z e d w i t h h y d r o c h l o r i c a c i d t o 222 i d e n t i c a l w i t h m a t e r i a l o b t a i n e d from 221. A l t e r n a t i v e l y asymmetric c y c l i z a t i o n o f 220 methyl e s t e r to ( + ) - = m e t h y l e s t e r of 64% o p t i c a l p u r i t y w a s accomplished i n t h e p r e s e n c e of L-phenylalanine.' 05b Hydrogenation of t h e l a t t e r o v e r p a l l a d i u m i n aqueous e t h a n o l l e d t o t h e r e q u i s i t e C/D trans p r o d u c t 223 w i t h e q u i l i b r a t e d p r o p i o n i c a c i d s i d e c h a i n i n 75% y i e l d ? E a r l i e r e x p e r i e n c e w i t h t h e C-4 uns u b s t i t u t e d t e t r a h y d r o i n d a n e s 176 and 177 had s u g g e s t e d t h a t h y d r o g e n a t i o n would l e a d t o a C/D cis f u s e d p r o d u c t . 8 2 a Howe v e r , i n most c a s e s w i t h a l k y l s u b s t i t u t i o n a t C-4 t r a n s f u s e d p r o d u c t s were found t o predominate ( c f . 1 7 4 -+ 17537b) . 8 3 b 1 1 1 1 Conversion of i n t o a m i x t u r e of e n o l l a c t o n e s 224 f o l l o w e d by G r i g n a r d r e a c t i o n w i t h 4,4-ethylenedioxypentylmagnesium bromide l e d t o A l d o l c o n d e n s a t i o n t o close r i n g B and concomitant c l e a v a g e of t h e 17-acetoxy group f o l l o w e d by k e t a l h y d r o l y s i s and b e n z o y l a t i o n t h e n gave i n t e r m e d i a t e 204 which had been c o n v e r t e d i n t o e s t r a d i o l i n t h e e a r l i e r s y n t h e s i s . A similar sequence w i t h methyl magnesium bromide l e d t o the
-
223
E.
- -
Estrone
711
1 7 - a c e t a t e of t h e t r i c y c l i c ketone 216 of t h e e a r l i e r synt h e s i s l o 6 ( c f . Ref. 1 0 4 ) . Rea%tion of Grignard r e a g e n t s w i t h e n o l l a c t o n e s followed by c y c l i z a t i o n t o a , b - u n s a t u r a t e d ketones has been a f r e q u e n t l y used a n n e l a t i o n procedure i n t h e s t e r o i d f i e l d l o ' (see a l s o 201 -+ 202). A u s e f u l v a r i a n t involves condensation of e n o l l a c t o n e s with phosphonium o r phosphonate y l i d s . Thus, t h e 17-t-butyl e t h e r of 224 on r e a c t i o n with t h e anion of d i e t h y l 4,4-ethylenedioxypentyl phosphonate followed by t r e a t m e n t w i t h aqueous sodium hydroxide ( l o s s of d i e t h y l phosphate) and aqueous a c e t i c a c i d y i e l d e d t h e t - b u t y l e t h e r of % . l o 8
-
-
OC (Me) 3
( 2 ) Aq. NaOH ( 3 ) Aq. AcOH
0
pC (Me) 3
L P
0
K.
Miscellaneous
A novel AD + ABCD r o u t e t o e s t r a p e n t a e n e 181 involving t r i p l e bond p a r t i c i p a t i o n i n a c c l i z a t i o n sequence was d e s c r i b e d by Hiraoka and Iwai i n 1966. 5-m-Methoxyphenylpentyne 164 (Scheme 21) was converted i n t o the propargyl bromide 227 and the l a t t e r condensed w i t h t h e sodium s a l t of 2-methylcyclopentane-lI3-dione i n dimethylsulfoxide. The a l k y l a t i o n rea c t i o n f a i l e d when attempted i n methanol, dioxane, o r acetone. Treatment of t h e adduct 228 with polyphosphoric a c i d a t room temperature then l e d t o 181 i n 63% y i e l d , p o s s i b l y v i a t h e t r i c y c l i c dione 192 (Scheme 2 4 ) .
log
CH2Br
Ill
I
I
I
( 3 ) PBr3 164 -
Na
DMS0/85"/6.5 67%
hr
712
N a t u r a l l y O c c u r r i n g Aromatic S t e r o i d s
CH2 I
Ill I
-b 0
-& 0
H3POt+-P205 25'/6 hr 63%
Me0
181 -
228 -
181
A further route t o p r o c e e d e d from t h e t e t r a h y d r o indanedione o b t a i n e d i n 70% y i e l d by c o n d e n s a t i o n of 2methylcyclopentane-l,3-dione w i t h methyl v i n y l k e t o n e . l 1 (For an asymmetric s y n t h e s i s y i e l d i n g (+)-= see Ref. 105b.) A l k y l a t i o n of 177 w i t h m-methoxyphenethyl bromide ( ~ - B U O K / C E H ~ 2 5 % )3 7 b r o r t h e d e r i v e d t e t r a h y d r o p y r a n y l e t h e r 229 w i t h m-me thoxyphenethy l-p- t o l u e n e s u l f o n a t e ( t- B u O K / t - B u O c 32 % )87b f o l l o w e d by h y d r o l y s i s and o x i d a t i o n g a v e t r i c y c l i c d i o n e 173. A g e n e r a l l y mre e f f i c i e n t p r o c e d u r e f o r t h e p r e p a r a t i o n of 4 - s u b s t i t u t e d 5,6,7,7a-tetrahydroindan-5-ones i s by a Robinson a n n e l a t i o n sequence i n which t h e s u b s t i t u e n t i s i n + + 219 + corporated i n t h e v i n y l ketone ( e . g . , 157 + 221). C y c l o d e h y d r a t i o n of 1 7 3 i n w a r m p o l y p h o s p h o r i c a c i d led t o 3 i n %50% y i e l d . 8 7 a T c ~ 3 7 b ~ 1 1 1
177
-
-
167 157
=;
Estrone
@
0
177
(1) NaBH4 /E t O H ( 2 ) dihydropyran/H+
*
713
bm
0
229
I
173 -
181 -
Improved y i e l d s r e s u l t e d when a l k y l a t i o n of = w a s carr i e d o u t i n d i m e t h y l s u l f o x i d e . Thus, i n a s y n t h e s i s of t h e t r i c y c l i c enone 232 r e a c t i o n of 229 with 1-bromo-3-pentanone e t h y l e n e k e t a l (DMSO/NaH) l e d t o 58% o f C-alkylated 230 and 32% o f o - a l k y l a t e d p r o d u c t 231 (VPC y i e l d s ) . S e p a r a t i o n and a c i d h y d r o l y s i s of t h e l a t t e r gave r e u s a b l e k e t a l 229a.112a S i m i l a r r e s u l t s were o b t a i n e d w i t h t h e t - b u t y l e t h e r o f 229a.112b
-
714
Naturally Occurring Aromatic Steroids OTHP NaH/DMSO
BrCH2CH2-C-CH2CH3
0
’0
229, K=THP 229a, R=H -
p
229a -
‘0
U
-
-
t
OTHP
HOAc/H20
OH
2 31 -
0
2 32 -
A route to ( 2 ) estrone 2 from the tetrahydroindmone 177 utilized alkylation with 1,3-dichlorobutene-2 f o r generaIt led to ( k ) estra-4,g-diene tion of the B and A 3,17-dione which was aromatized by the Roussel procedure”’ (cf. Scheme 26: 215 + 99).
-
-
177 -
0
40-45%
Estrone 715
-
t-CsH110K toluene/A 0
Annelation of 2-methylcyclopentane-1,3-dione with ethoxycarbonylmethyl vinyl ketone led to the 4-carbethoxytetrahydroindane-dione 241 which was transformed efficiently to (+) estrone methyl ether 119 in eight steps.122
d
/o\ NPg3
@ . . l L @ -
0
COOE t
241
CHO I
(1) Me0
(2) Hz/Pd-C
CH
>
716
Naturally Occurring Aromatic Steroids
A new route to polycyclic systems involving Michael condensation of a cyclic lI3-dione with B-chloroethyl vinyl ketone followed by similar condensation of the adduct with a B-keto t-butyl ester developed by Danishefsky has been applied by h i m to the syntheses of the dienedione 234113a1114and estr-4,8 (14),9-triene-3,17-dione 235. 1 1 3 b 1 m The latter was obtained in 34% yield from 157.
<
",d 0
+
(1) Et20-H20 MeOCH2CH20Me
(2)
0
( 6 0 - 85%)
p
_______c
0
t-BuOK/t-BuOH
233
0
233 -
-
p-TSA/AcOH/78'
COOt-Bu
+
boot-Bu
234 ( 5 2 % from 233) -
(1) t-BuOK/t-BuOH/20°
c1 oot-Bu COOt-Bu
(2) P-TSA/ACOH/~O~
2 35 -
c
Estrone
717
G . Saucy and co-workers a t t h e Hoffmann-LaRoche laborat o r i e s have developed s e v e r a l v a r i a n t s of a novel and e f f i (e.g. c i e n t r o u t e t o ( + ) and (+) 19-nor steroid-4-ene-3-ones 238),'19 which is adaptable t o t h e s y n t h e s i s of e s t r o n e . The following scheme' is i l l u s t r a t i v e .
-
c
CH2MgC1
R
2 36 -
+
---C R
OCH (CH2) 3CHO
0
0
_____c
R
R
&
7 2 % from
8-
AcOH/pyr./toluene A
236
OH
0
OH-
R
o
R
I& 2 37 -
(1) Hz/Pd/THF/Et3N ( 2 ) HCl/MeOH/A
R =
0 '0
0
238
20% from
236
718
N a t u r a l l y O c c u r r i n g Aromatic S t e r o i d s
I n t e r m e d i a t e 237 i s a n a l o g o u s t o 204. Removal of t h e p r o t e c t i n g g r o u p , c l o s u r e of t h e A r i n g , and d o u b l e bond isomerization should y i e l d e s t r o n e . A p p l i c a t i o n of J o h n s o n ’ s conce t s of s t e r o i d s y n t h e s i s v i a biomimetic o l e f i n c y c l i z a t i o n ’ ” l e d t o t h e f o l l o w i n g synthesis of ( + ) e s t r o n e g ( R = H) . 1 2 2
n
RO
U
2 39 -
References
719
I n t h e key c y c l i z a t i o n s t e p some o r t h o c y c l i z a t i o n prodThe p a r a / o r t h o r a t i o was d e p e n d e n t u c t 40 was a l s o produced. on t h e n a t u r e of R and R ' . R Me3Si MejSi Me CgHgCO
R'
H Me3Si H CgHgCO
P/O 8.4 2.6 3.0 1.4
A d d i t i o n a l (somewhat c i r c u i t o u s ) s y n t h e s e s of e s t r o n e have b e e n d e s c r i b e d by B i r c h ' l6 and Miki. REFERENCES
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,
724
N a t u r a l l y O c c u r r i n g Aromatic S t e r o i d s
A k a d . Nauk. S.S.S.R., Ser K h i m , 1 0 3 ( 1 9 5 9 ) . ( a ) D. J. C r i s p i n and J. S . w h i t e h u r s t , Proc. C h e m . SOC., 22 ( 1 9 6 3 ) ; ( b ) D. J . C r i s p i n , A . E . V a n s t o n e , and J. S . W h i t e h u r s t , J. C h e m . SOC. ( C ) 10 ( 1 9 7 0 ) . R e v i e w : J. W e i l l - R a y n a l , B u l l . SOC. C h i m . F r a n c e , 4 5 6 1 88. (1969). S . N . Ananchenko and I . V. Torgov, Ookl. A k a d . N a u k . 89. S.S.S.R., 1 2 7 , 553 ( 1 9 5 9 ) . S . N . Ananchenko, V . N. Leonov, A . V . P l a t o n o v a , and 90. I . V . Torgov, Dokl. & a d . Nauk. S . S . S . R . , 1 3 5 , 7 3 ( 1 9 6 0 ) ; S. N . Ananchenko, V . Y . Limanov, V. N . Leonov, V. N. Rzheznikov, and I . V. Torgov, T e t r a h e d r o n , 1 8 , 1355 (1962). ( a ) S. N . Ananchenko and I . V. T o r g o v , T e t . L e t t e r s , 91. 1 5 5 3 ( 1 9 6 3 ) ; (b) T. B. Windholz, J. H. F r i e d , and A . A . P a t c h e t t , J. O r q . Chem., 2 8 , 1092 (1963). K . K . Koshoev, S . N . Ananchenko, and I . V . Torgov, K h i r n . 92. Prir. S o e d i n . , 1 1 7 2 ( 1 9 6 5 ) . ( a ) H . G i b i a n , K . K i e s l i c h , H. J . Koch, H. Kosmol, C . 93. R u f e r , E . S c h r o d e r , and R. Vos$ing, T e t . L e t t e r s , 2 3 2 1 ( 1 9 6 6 ) ; ( b ) C. R u f e r , E . S c h r E d e r , and H . G i b i a n , A n n . , 7 0 1 , 206 ( 1 9 6 7 ) . C . H . Kuo, D. Taub, and N . L . Wendler, J. O r g . C h e m . , 94. 33, 3126 ( 1 9 6 8 ) . 95. ( a ) C. H . K U O , D . Taub, and N . L. Wendler, A n q e w . C h e m . , 7 7 , 1142 ( 1 9 6 5 ) ; ( b ) D. P. S t r i k e , T . Y. J e n , G . A . Hughes, G . H. D o u g l a s , and H. S m i t h , S t e r o i d s , 8 , 309 ( 1 9 6 6 ) ; (c) A . V. Zakharychev, D . R. L a g i d z e , and S . N . Ananchenko, T e t . L e t t e r s , 803 ( 1 9 6 7 ) . U. K. P a n d i t , F. A. v a n d e r V l u g t , and A. C. v a n D a l e n , 96. T e t . L e t t e r s , 3697 ( 1 9 6 9 ) . R . B U C O U r t , L. Ngdglec, J. C . Gasc, and J. Weill-Raynal, 97. B u l l . SOC. C h i m . France, 5 6 1 ( 1 9 6 7 ) . R . B u c o u r t , M . Vignau and J . W e i l l - R a y n a l , Cornpt. R e n d . , 98. 265C, 834 ( 1 9 6 7 ) . ( a ) L . V e l l u z , G . Nomin6, and J. M a t h i e u , A n q e w . C h e m . , 99. 7 2 , 725 ( 1 9 6 0 ) ; (b) L. V e l l u z , G . Nomin6, J. M a t h i e u , E . Toromonoff, D. B e r t i n , M. Vignau, and Tessier, Compt, R e n d . , 250, 1510 ( 1 9 6 0 ) ; ( c ) S e e also L. L. Chinn and H . L. Dryden, J . O r g . Chem., 2 6 , 3904 (1961). 100. L. V e l l u z , G . Nomin&, G . Amiard, V . T o r e l l i , and J. CgrBde, Compt. R e n d . , 257, 3086 ( 1 9 6 3 ) . 101. ( a ) L. V e l l u z , G . Nomin.6, R. B u c o u r t , A . P i e r d e t , and P. Dufay, T e t . L e t t e r s , 127 ( 1 9 6 1 ) ; (b) F r e n c h P a t e n t No. 1 , 3 0 5 , 9 9 2 ( 1 9 6 2 ) . 102. S e e , f o r example, S. J u l i a , B u l l , SOC. C h i m . F r a n c e , 780 (1954). 103. Roussel-Uclaf , B e l g i a n P a t e n t N o . 634,308 ( 1 9 6 3 ) . 87.
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N. K.
Total Synthesis OfNatural Products, Volume2 Edited by John Apsimon Copyright © 1973, by John Wiley & Sons, Inc.
COMPOUND INDEX 3PAcetox andros Sene-YTone, 666 2-Acetoxyiutene-i; 692 Acetyl bromide, 710 0-Acetyldehydroiso~hotsantonic lactone, 4 13 Acetylene dicarbox'ylic acid, 353 4-Acetyl-l ethoxycyclohexene, 365 1-Acetyl4-isopropenyl-l-cyclopentene, 87 Acetylmethylenetriphenylphosphorane,463 0-Acetyl photosantonic lactone, 419 Achillene, 12,13 Achillenol, 1 3 Achillin, 412-417 Acrolein, 697 Actinidiolide, 170 Actinidol, 170 Adiantone, 592 GAgarofuran, 300-303 PAgarofuran, 301 Agarospiron (Epihinesol), 466-474 Agnosterol, 571 (f)-Alantolactone, 326 - 328 Aldosterone, 646 Alloocimene, 9 Alnusenone, 560,620-626 Ambertriene, 569 Ambrein, 569,595 Ambreinolide, 569,595 1-Amino-naphthalene-6-sulfonicacid (Cleve's acid), 643 Amyrins, 594-610 PAmyrin, 560 PAmyrin acetate, 609 PAmyrin-3-benzoate, 609 6-Amyrin, 602 Androsta4,7-diene-3,17dione, 665 Aplysin, 453-459 Apoaromadendrene, 41 8 Arborescin, 412-417 Aristolene, 380-395 Aristolone, 380-39 5 Aromadendrene, 41 7-422 Artemisia alcohol, 42 Artemisia Ketone, 40 (*)-Artemisin, 324,412,414 Atractylon, 310-31 3 Batatic acid, 165 Benzyl Gbromopropionate, 505 3-Benzyloxybutyl bromide, 709 ecis-Bergamotene, 446-449 &is-Bergamolene, 446-449 atrans-Bergamotene, 5 20 Biiyclbfarnesic acid, see Farnesic acid Bicyclofarnesol, see Drimenol Bilobanone, 264 Bisabolenes, 2 33-238 (+)-Bisabolol, 241 cs! and trans Bisdehydromanianolic acid., 649 Bnnoronoceradione, 5 79 Boll Weevil pheromone, 58 Bornyl acetate, 150 Boschnia lactone, 77 GBpurbonene, 530-534
PBourbonene, 530-534 trans-n-Bromocamphor , 4 8 1 2-Bromod-methoxyn0phthalene,66 1 1-Bromo-3-pentanone ethylene ketal, 715 trans-l-Bromo-3-pentene,374 n-Bromotricyclene, 481,485 1-Bromo-l,2,2-trimethylcyclopntane,454 Bulneool, 395-412 GBulnesene, 395-412 Butenolide, 312 Kadinene, 330,336 (f)Cadinene dihydrochloride, 330-3 36 (+)Calamenene, 331 Camphene, 151,153 (*)Camphene-l -carboxylic acid, 543 Campholenic aldehyde, 88 Camphonanic acid, 454 Camphor. 150-1 53 Carabrone, 459-463 fruns-Carane, 157 (-)-truns-Caran-2-one, 39 1 4Carbethoxycyclohexanone, 397 (+)-AWarene, 157 Carissone, 288,289 7.epi-Carissone, 302,303 C a d o n e , 157 Carvacrol, 104,105 Carvacryl trifluoroacetate, 104 Carvenone, 114,152 Carveols, 106,109 Carveyl acetate, 110 Carvomenthols, 106 Carvomenthones, 106,360,464 Carvone, 112 Carvotanacetols, 106,109 Carvotanacetone, 106, 111 Caryophyllene, 474-481 aCaryophyllene alcohol, 540-545 Cedrene, 504-514 Cedrol, 504-514 Chamaecynone, 305 Chamene, 59 Chamigrene. 449-453 &G%foroethyl vinyl ketone, 71 7 4Chloro-methyl-3,5dimethylesoxazole,3-7 Cholesterol, 671 Chretien-Bessiere monoterpene, 36, 39 Chrysanthemic acid, 37,49,50,54-56 Chrysanthemic esters, 53 Chrysanthemol, 47 Chrysanthemum dicarboxylic acid, 54 Chrysanthenone, 156 1,4€ineol, 133 1,8Cieol, 134 1,4€ineol-2,3d)ioI, 134 Citraconic anhydride, 672 Citral, 28 Citral epoxide, 21 Citronellal, 27 (+)Citronellol, 15 (+)a€itronellol, 15 Clovene, 540-545 127
728
Compound Index
(*)-Conterifolin, 347, 348 Copaene, 520-525 Cosmene, 14 Costal, 299 Costic acid, 299 Costol, 299 (+)-Cryptomerion, 25 1 Cryptone, 97, 98 w u b e b e n e , 380-395 Cubebol, 380-395 Culmorin, 528 - 530 Cuminaldehyde, 128 Cuparene, 453-459 Pcuparenone, 453-459 ccCurcumene, 241-246 -)-aCurcumene, see Isoa-curcumene bc urcumene, 241 Curcumene, 24 2 - 24 3 +)-Curcumone, 247-248 Cycloartenol, 572 -574 w y c l o c i t r d , 393 ~yclocitrylidineaceticacid, 35 3 Cyclocolorenone, 417-422 wyclogeraniol, 393 wyclohomogeranic acid, 171 &Cyclolavandulal, 48 ~ y c l o l a v a n d u l i cacid, 48 Cyclolavandulols, 48 1,2-cyclononadiene,480 1,2~cyclopentenophenanthrene,658 Cyclosativene, 525-528 Cyperolone, 422-424 Cyperolone acetate, 424 ( + ) M y p e r o n e , 422 a-cyperone, 285-288 w y p e r o n e , 285,286 7-epi-Cyperone, 2 6 9 , 2 7 0 , 2 8 4 , 3 8 1
t
Debromoaplysin, 453-459 cis and from Decalin-1 S d i o n e , 681 a-Decalone, 357.679 Dehydroagnosterol, 571 14,15-Dehydroequilenin, 65 3 14,15-Dehydroequilenin methyl ether, 65 2, 654 8-Dehydroestrone methyl ether, 662,697 &(l 1)-dehydro-D-homeestronemethyl ether, 695 Dehydrofukinone, 362-380 (+)-Dehydroilleiden M,536 Dehydro-7-ionone, 569 Dehydrojuvabione, 253, 261,262 24,25-Dehydrolanosterol, 571 Dehydrolinalool, 28 1,2-DehydronerlidoI, 202 Dehydroparkeol, 571 ?0,2 1-dehydrosqualene, 5 6 1 dl-A1 2-Dehydrotetrahymanol, 590 Dendrolasin, 228-231 Desacetoxymatricarin, 41 2-41 7 (+)-Desoxotodomatuic acid, 253, 254 Desoxyvaleranone, 360 2-Diazo-propane, 384 1,3-Dichlorobutene-2, 709,716
2,3-Dichloro-5.6-dicyanobenzoquinnne, 646 biethyl p-benzyloxyphenylmalonate, 5 12 Diethyl cyanomethylphosphonate,386 Diethyl4.4ethylenedioxypentyl phosphonate Diethyl isopropylidene-malonate, 363 Diethyl a-methylpoxoadipate, 654 Diethylpropionylsuccinate, 692 Dihydroactinidiolide, 170 Dihydroagarofuran, 4-hydroxy, 302 Dihydroaristolone, 384 Dihydrocarveols, 1 0 6 , 1 1 3 Dihydrocarvones, 1 0 6 , 1 0 8 , 1 1 3 , 1 1 4 , 3 5 3 Dihydrocostal, 300 Dihydrocostunolide, 277,279 Dihydropionine, 452 5.6-Dihydronorcar o hillene, 481 24 ,ZS-Dihydro-Al 6)-protosterol, 57 1 Dihydrotagetone, 31 -34 (k -Dihydro-ar-turmerone, 248 3d.l la-Dihydroxycycloartane, 572 1,4-Dirnethoxy-2-butanone, 359 ,'pDimethylallyl mesitoate, 481 ,3-Dirnethyl-6-n-butylthiomethylenecyclohexanone, 371 2,3-Dimethylcyclohexanone, 384 3 ,3-DimethylcyclopenteneI542 Dimethyl-y-Ketopimelate, 365 3,7-Dimethylocta-l,3diene-5-one, see Tagetone 2,6-Dimethylocta-l,3,5,7-tetraene. 13 cis-2,6-Dimethylocta-1,4 ,7-triene, see Achillene 2,6-Dirnethylocta-2,4,7-triene, 11 3,7-Dimethyloct- 6en-1-01.15 3,7-Dirnethyloct-7en-l-ol, 15 Dime thylstyrene, 92 -9 3 Dimethyl succinate, 653 2.5-Dimethyl-3-Vinylpent~en-2-o1,see Chrktien-Bessikre monoterpene Dinoronocerane, 575 Diosgenin, 671 Dipentene, 8 , 2 3 Diplopterol, 592 Diprenyl ether, 41 Dolichoidial. 78 Drimanic acid,-343 (k)-Drimenin, 343-347 (f)-Drimenol. 339-342. 347.348 (+)epi-Drimenol, 339 -342
x(
1
Elemane, 266, 267 PElemene, 2 69 - 272 Elemol, ZbY-Z'/1,273, 274 Elsholtzione, 160 Epicamphor, 150 7-Epicyperone, 353 11-Epideoxygeigerin, 4 14 Epihinesol (Agarospirol), 466-474 4-Epinootkatone, 367 Epizizanoic acid, 514-516 Equilenin, 64 2 -663 Equilenin ethylene ketal, 669 Equilenin methyl ether, 6 5 3 , 6 6 0 , 6 6 2 , 6 6 8 Equilh, 664-670
Compound Index Eremoligenol, 361-380 Eremophil-3,l ldiene, 362-380 Eremophilene, 361-380 (k)Estra4,9diene 3, l’ldione, 716 Estradiol, 664 Estradiol-170, 670 Estrapentaene, 701, 71 3 Estrial 16U,17@,670 Estrone, 646,662,670-718 B~Estrone,683 8~,13~-Estrone (estrone-A), 675,683 13GEstrone (lumiestrone), 682 8~9/.%Estrone (estronee), 679 13~,14PEstrone,685 9/.%Estrone(estroned), 679 14PEstrone, 685 Estrone methyl ether, 696,699 Estr4,8( 14),9-triene-3,17dione, 71 7 Ethyl pacetoxyacrylate, 462 Ethyl 1-acetylcyclopropanecarboxylate ethylene ketal, 536 Ethyl 7-bromocrotonate, 509 Ethyl dimethylacetoacetate ethylene ketal, 5 34 Ethyl p-tolyacetate, 457 Eucarvone, 140,141 a-Eudesmol, 295-296 PEudesmol, 289-294 7-Eudesmol, 289, 295 Eunenol. 697 Euihol, 6 1 6 Evodone, 116,123 Exo-3-methylnorbornanone,491 trans, trans-Farnesaldehyde, 633 (+)-Farnesiferol A, 342-343 Farnesol, 200-206,353 cis, trans-Farnesol, 435,444 trans, trans-Farnesol, 435,633,634 Farnesyl bromide, 561,562 Famesyl nerolidyl sulphide, 562 Farnesyl phenyl thioether, 562 Farnesyl pyrophosphate, 633 Fern-gene, 593 Filifolone. 144. 145 Fukinone; 361-380 3-Furoic acid, 162 Furopelargone, 70, 72,274-276 Furoventalene, 264 Geigerin, 4 12 -4 17 Geigerin mesylate, 414 Genepin, 84 Genipic acid, 85 Genipinic acid, 85 Geraniol, 17,23,201,484 Geranyl acetate, 440 Geranylacetic acid, 634 Geranylacetone, 201 -205,562 Geranyl bromide, 429 Geranyl chloride, 202 Germacrane, 277,278 Germanicol, 604,616-620
729
Glochidone, 632 Glyoxalyl chloride tosylhydrazone, 634 Helrninthosporal, 463 -466 trans-a-Himachalene, 427 PHimachalene, 424-428 trans-7-Himachalene14 27 Hinesol, 466-474 Hinokitiol, see Thujaplicins
D-Homoandrostane-3,17adione, 690
Homocamphor, 496 cis-Homocaronic acid, 51 D-Homoequilenin, 662 D-Homoequilenin methyl ether, 662 D-Homoestrone methyl ether, 695,699 Homosafranic acid, 171 Homoter enyl methyl ketone, 420 H o p 2 1(f2)ene, 5 92 Hop-1 7 (2 1)enone, 590 Hop-21(22)enone, 592 Hotrienol, 25 Hotrienol acetate, 25 Humulene, 280,479 Hydroxyadientone, 592 19-Hydroxyandrost4,6diene-3,1 7dione, 666 Hydrobuyenolide, 123 Hydroxycitronellal, 27 8-Hydroxy-PCy mene, 103 Hydroxyhopane, 560 Hydroxyhopanone, 590,592 4a-Hydroxyisochamaecynone, 306 1lfiydroxylanostenyl acetate, 572 1-Hydroxymenth-Zene, 90 2Nydroxy-3-methylene-6-methylbenzofuran, 123 Hymentherenes, 12 Hyposantonin, 308 Hyposantonous acid, 308 Illudin M. 534-540 Illudin S,-534 Illudol, 534 1-1odo-6-methoxv-naphthalene. 646 - . Ionones, 5 Ipomeanarone, 231 Iresin, 348 Iridane, 59 Iridodial, 72,74,78 Iridomyrmecins, 74,75 (f)-Isolantolactone, 329 Isobisabolene, 239 -24 1 Isobutylene, 475 Isocaryophyllene, 474-481 Isoa-curcumene, 241,244-246 Isodihydrocarveol, 113 (+)-Isodrimenin. 344, 345, 347.348 Isoegomaketone, 164 (+)-Isoequilenin, 648 14-lsoequilenin,65b (k)-Isoequilenin methyl ether, 653,660 9-Isoequilin. 669 Isoeuphenol, 571 7-Isogeigerin acetate, 414
730
Compound Index
(f)-lsoiresin diacetate, 348-352 Isoiridomyrrnecin, 74.75 Isolavandulol, 43 Isolongifolene, 540-545 Isomenthol, 124, 125 (*)-lsomenthone, 389 Isonepetalactone, 71 Isonootkatone (a-Vetivone), 361 -380 Isophotosantonic lactone, 412 lsopiperitenone epoxide, 137 3-Isopropenylcyclohexanone, 376 4-lsopropenylcyclohexanone,366 (+)4-Isopropylcyclohex-2en-l-one, see Cryptone 4-lsopropylcyclohex-3-enone,96-99 4-Isopropylidenecyclohexanone, 96, 97 Isopropyiidenetriphenylphosphorane,566 4-Isopropyl-6-methoxy-1 -tetralone, 331 333 Isopulegone, 12 1 cis-Isopyrethric acid, 51 (+)-lsosirenin, 435 Isoterpinolene, 90 Isothujone, 147 (-)-lsotirucallol, 571 fsovaleraldehyde, 534 Isoxylitone, 118 luvabione, 253,255-261 Juvenile Hormone, 207-222 Karahana Ether, 139 Karahanaenone, 142 Kessane, 395 - 4 12 Ketohakonanol, 592 Khusimol, 514 (2)-Lanceol, 238, 239 Lanosterol, 560, 569, 571 Lavandulol. 34,43-48 Lavandulyl acetate, 46 Lavandulyl bromide, 45 Lavandulylic acid, ethyl ester of, 45 Levulinic acid, 658 Limonene, 89 Linalool, 5, 17, 20, 21, 23 Linalool acetate, 22 Linalyl phosphate, 24 Lindestrene, 313-315 Lippione, 1 19 Loganin, 81 Loganin acetate, 82 Loliolide, 170 Longiborneol, 528 (*I-Longicamphenylol, 520 (f)-Longicamphenylone, 520 Longifolene, 528,517-520 Lumisantonin, 467 Lupeol, 626-632 Lyratol, 36, 39 Maaliol, 380 Matatabiether, 80
p-Mentha, 1(7), Bdiene, 9 Mentha-l,3dien-7al, 126, 128 Menthadienes, 24,89 Mentha-1.3dienoic acid, 126
hans-Mentha-l(7),8dien-2-01,110 Mentha-l,8dien4-01,100,101,109
Mentha-l,8dien-l0-01, 130 Mentha4,8dien-3-one, 122 Menthane-l,3diol, I37 Menthan-8-01, cis and trans, 93,94 1,3,8-Menthatriene, 91 Menth-1 en-9-al, 129 Menth-1 en4-01, 100 Menth-1(7)en4-01,100 rn-Menth-len-8-ol, 138 Menth-len-9-01, 131 trans-Menth-2en-l-01,94 Menth-Zen-8-01, 103 Menth-3en-l-01,96 Menth4(8)en-2-0l.l06 rn-Menth-Sen-8-01, 138 Menth-3*n-l,2-truns-8-triol, 132 Menthofuran, 122 Menthols, 115, 124 Menthones, 124,125,389 Methacrolein, 487 p-Methoxyacetophenone, 508 6-Methoxy-2-acetylnaphthalene, 656 m-Methoxyallylbenzene, 697 2-Methoxyborane, 154 m-Methoxycinnarnic acid, 695 3-Methoxy-17&hydroxyestra-l,3,5(10),8tetraene, 666 3-Methoxyisoprene, 566 P(-6-Methoxy-naphthyI)ethanol, 646 6-Methoxy-1-naphthylethyliodide, 654 m-Methoxy-phenyl-acetylene, 681 rn-Methoxyphenethyl bromide, 714 5-m-Methoxyphenylpentyne,695,713 3-m-Methoxyphenylpropyl-bromide, 695, 696
3-rn-M;thox yphenylpropyl magnesium
bromide. 705 6-Methoxytetralin, 646 6-Methoxy-l-tetralone, 471,581,646,687, 701,709 Methyl 7-bromocrotonate, 646 3-Methylbut-2enol,47 Methyl (+)samphenecarboxylate, 5 16 3-Methylcyclohex-2enone,454 2 MethyLcyclohexan-l,3dione,363,616, 690-717 2-Methylcyclopentane-l,3dione, 661,69069 3 Methylcyclopent-1 en4,5dione, 67 1 rruns-Methyl-1 decalyl p-toluenesulphonate, 402 Methyl trans, trans, cis-l0epoxy-7ethyl-3, 11,dimethyl-2,6-tridecadienoate, see Juvenile Hormone Methyl-trans-rrans-farnesate, 588 Methyl geranate, 22, 23 6-Methylhept-5 en-2-0ne, 4
Compound Index cis 8-Methyl-hydrindan-l-one,659 trans 8-MethylhydMdan-l-one, 659 2-Methyl-5-Isopropenylanisole, 103 1-Methyl-3-isopropylcyclopentene, 5 31 2-Methyl-3-methylenehept-5*ne,see Salvan 2-Methyld-methyleneocta-2,7diene4-o1, 26 2-Methyld-methylene-ooct-7en4-ol,26 7-Methyl-3-methyleneoct-6~nylacetate, 29 4-Methyl-1-naphthoicacid, 379 Methyl nerolate, 22,23 Methyl 5-0xod-heptenoate~7 10 3-Methylpent4enal,31 trans-Monocyclofarnesicacid, 45 3 Mullilam Diol, see 1,4-Cineol-2,3diol Multifluorenol. 594.606-609 , Hduurolene, 335 Myrcene, 8 , 1 0 , 1 1 Myrtenal, 126,127,156 Myrtenol, 126,127 Naginate ketone, 160 &Naphthol, 646 y-Naphthybutyric acid, 646 Neodihydrocarveol, 113 Neoisodihydrocarveol, 113 Neoisomenthol, 124,125 Neomatatabiols, 78 Neomenthol, 124,125 Neonepetalactone, 73 Neotorreyol, 228 Nepetalactone, 69,71,72 Nepetalic acid, 70,72 (*)-Nepetalinic acids, 76 cis, trans-Nepetonic acid, 71 trams, cis-Nepetonic acid, 70 Nerd, see Citral h Nerol, 17,23 Nerolidoi, 200-206 Neryl didphenyl phosphate, 24 Nezukone, 143 Nickel tetracarbonyl, 561 Nootkatin, 276 Nootkatone, 361-380 Nopinic acid, 126,128 Norbornanone, 482 Norcedrenedicarboxylicacid, 504,507 “X”-Norequilenin methyl ether, 658 Nor-’y-Eusdesmol, 292-294 Nor-Keto-agarofuran, 303 1-Norsqualene, 56 1 10-Norsqualene, 561 10‘-Norsqualene,561 15-NorsquaIene,561 10,15-bis-Norsqualene (cis and trans), 561 (+) 19-Nor steroid4ene-3-ones, 71 1 (*I 19-Nor steroidQene-3-ones, 71 1 19-Nortestosterone acetate, 664 Norvaleranone, 356 Nuciferal, 250,251 PNymenthrene, 12 Occidentalol, 309 Occidol, 282-284, 308
731
Ocimene, cis and trans, 8,lO OIean-l1,12,13,18diene, 595 Olean-l Zene, 602 18aIean-l2ene, 598 (-)-184ean-lZene, 599 18a-Olean-l2ene, 602 Olean-l3(18)ene, 594,595,598,599,602 Olean-lZene3-one, 604 Oleanolic acid, 609 Oleanolic acid acetate, 610 Oleuropic acid, 132,135 Onoceradienes, 577-579 aanoceradiene, 579 mnoceradiene, 579 yanocerene, 579 Onocerins, 574-594 aanocerin, 560,574 mnocerin, 574 anocerin, 574 +)@nocerin diacetate, 589 y-Onocerin diacetate, 589,590,593 aanocerindienedione, 590 Osmane, 59 Il-Oxocycloartenyl benzoate, 573 Il-Oxolanostenol, 572 1~xo-7-methoxy-l,2,3,4-tetra.hydrophenanthrene, 642 1-Oxo-2-methyl-7-methoxy-l,2,3,4-tetrahydrophenanthrene, 65 3 l-Oxo-l,2,3,4-tetrahydrophenanthrene, 646
I
Parkeol, 571 a-Patchoulene, 492-499 PPatchoulene, 492-499 Patchoulene, 492 atchouli alcohol, 492-499 (*)+pi-Patchouli alcohol, 499 Patchouli alcohol acetate, 493 trans-3-Pentene-2-one,363,365, 368 Peracetic acid, 566 Perezone, 262,263 Perilla alcohol, 125-127 acetate of, 126,127 Perillaaldehyde, 125-127,417 oxime of, 126 Perilla Ketone, 163 Perillene, 163 Perillic acid, 126,128 Phellandral, 125,126,128 a-Phellandrene, 89,90 PPheUandrene, 89,90 7-Pheny14,7dioxoheptanoicacid, 658 12-Phenylthiosqualene,562 Photocitrals A and 8, 60 Picric acid, 568 trans-Pinecarveol, 156 Phocampheols, 156 Pinocamphones, 156 Pinol, 131,132 Pinonic acid, 5 1 Piperitenone, 107,118 Piperitol, cis and trans, 119 Piperitone, 11
8-
732
Compound Index
Plinols, 60,61 Prenyl alcohol, see 3-Methylbut-2enol Presqualene alcohol, 633-635 Rocerin, 276 Ropargaldehyde dimethyl acetal, 477 Pseudoionone, 6 Pulegene, 145 Pulegenic acid, 72 Pulegone, 120,121 Pyrethric acid, 49,57,58 Pyrethrum, 49 Pyrocine, 5 8
Rhodinal, 15 Rhodinol, 15 Rose furan, 161 Rose Oxides, cis and trans, 168
Sabinaketone, 146,147 Sabinene, 146- 148 Sabinene hydrates,cis and trans, 147,148 cis-Sabinol, 147 Safranal, 138 Salvan, 147,148 a-Santalene, 481 -491 Psantalene, 481-491 (f)epi@Santalene, 482,485 a-Santalol, 481 -491 bSantalol. 481 -491 Santolinairiene, 34,36,37 Santonin, 410,412 (+)-Santonins, A,B,C,D, 316-322 (f)a-Santonin, 322-324,413 (+)&antonin. 322 Sa.ntonic acid ,'517 Sativene, 525-528 Saussaurea Lactone, 267, 269 Sclareol, 579,595,599 a-Selinene, 298 pselinene, 296-298 Epi-'y-Selinene, 304 Serrantenediol, 589-590 Sesq uicarene, 428-446 Seychellene, 499-503 Shonanic acid, 140, 141 a-Sinesal, 222,227 PSinesal, 222-227 Sirenin, 428-446 Sobrerol, 131, 132 Squalene, 560 trans-Squalene, 56 1 Squalene-2,3-diol, 566 Stigmasterol, 671 Strychnine, 582 Succinaldehyde, 566 Sylvestrene dihydrochloride, 138 Sylveterpineol, 138 Tagetone, cis and trans, 30-34 Taraxerol, 594,605 (f)-Telekin, 328 cis-l,4-Terpin, 133 PTerpinene, 89.90
'y-Terpinene, 88 a-Terpineol, 23, 102,420 BTerpineol. cis and trans, 94,96 Terpineol, 96,97 Terpmeol, ' 101,102 Terpin -len-ol, 102 Terpinolene, 23 7-Terpinyl acetate, 97 Tetrahydroelemol, 269,270 Tetrahydroeremophilone, 362-380 Tetrahydrosaussaurea Lactone, 267,268 Tetrahyrnanol, 590-594 &Tetralone, 582 Thujane, 145,146 a-Thujaplicin, 143,144 2-Thujene, 147 3-Thujene, 147 Thujone, 147 'Ihujopsene, 380-395 Thujyl alcohol, 147 Thujyl toluenesulfonate, 60 Thymol, 117 Todornatuic acid, 255-258 Torreyal, 228 Tricycloekasantalal, 486,489 Triethyl phosphonoacetate, 386,453
1:
2,2,5-Trimethylcyclohept4enone, 142 2,2,3-Trimethylcyclopent-3ene acetaldehyde, see Camphonelic aldehyde 2,6,6-Trimethyl-2-Viyhetrahydropy1an,168 (f)-ar-Turmerone, 247-250 Umbelliferone, Sodium salt, 343 cis, rruns-Umbelliprenin, 342 Umbellulone, 147 Uroterpinol, 129 glycoside of, 129
Valencene, 361-380 Valeranone, 35 3 -361 Valerianol, 361-380 Veratramine, 642 Verbenalin, 85 Verbenalol, 85-87 Verbenol, cis and trans, 156 Verbenone, 156 li)-Veticadinene, 338 +)-Veticadinol, 336,337 Vetivone, 466-474 Vitamin A, 5 l-Vinyld-methoscy-3,4dihydronaphthalene,
671 l-Vinyl-2,6,6-trimethylcyclohexane, 35 3
Widdrol, 424-428 (*)-Winterin, 352,353
2,6-Xyloquinone, 672 Y langene, 520-5 25 Yomogi alcoho1,42,43 Zingiberene, 246-247 Zizaene , 514 Zizanoic acid, 514
Total Synthesis OfNatural Products, Volume2 Edited by John Apsimon Copyright © 1973, by John Wiley & Sons, Inc.
REACTION INDEX Acetals, acid elimination of acetic acid, 41 3 claisen rearrangement, 393 elimination of ethanol, 393 oxidation, 477 reaction with vinylethers, 28, 29,52 Acetates, elimination of acetic acid, 409 hydrolysis of, 416,424,568 with LAH, 496 pyrolysis, 48,96, 101, 109, 122, 130, 485,490 reduction with lithium-ethylamine, 474 transesterification, 440 Acetonylation of 1,2-diols, 86,87 Acetoxy dienones, retroaldolization, 666 Acetoxy epoxides, thermal rearrangement, 502 a-Acetoxyketones, pyrolysis of, 122 Acetylation, 5 36 selective of, diols, 400,423,473,496 triols, 5 36 cu-Acetylybutyrolactone, 21 hydrochlorination of, 22 Acetylenes, 205, 306 alkylation, 206,210 carboxylation, 445 condensation with acetone, 5 cyclization, 713 formylation, 205 homogenization, 689 hydration, 695 hydroboration, 449,489,491 hydrogenation, 30,687 iodination, 206,440 lithium salts, reaction with, bromides, 489 iodides, 449 ketones, 417 paraformaldehyde, 445 reaction with Raney Nickel, 431 reduction of, 5, 30, 39 Acetylenic alcohol, acetate, pyrolysis of, 29 Acetylenic ethers, 33 claisen rearrangement, 33, 34 reaction with Acid, 44 Acetylide, potassium, addition to ketones, 135 Acetyls, epimerization of, 499 Achilla Filipendulina, 12 Acid catalysed rearrangement, of caryophyllene, 543 of cyclohexanols, 542 of diacetylenic diols, 587 of dienes, 593 of humulene, 540 of hydroperoxides, 606 of longifolene, 528 of 18cu-olean-l2-ene, 602 of (+)-P-onocerin diacetate, 589 of (+)-y-onocerin diacetate, 590 of (+)-a-onocerin dienedione, 590 of spiro[4,5] decalenes, 514 of spiro-decane diols, 5 11 of trienes, 595-596
of tricyclic diols, 474 Acid chlorides, 57 cyclizations of, 386 in dehydrations, 648 reaction with, diazomethane, 386 olefins, 41 organocadmium compounds, 32,164 Acrylonitrile, addition to substituted ethylacetoacetate, 99 Actinidia polygam, 63,64,65,67,68,78, 80,170 Acylation, Friedel-Crafts, 658 intramolecular, 530,692 Acyloin condensation, 277,278,678,686 Acyloins, reduction of, 383 a-Agarofuran, 300-303 double bond isomer of, 301 photochemical irradiation of, 302 Alcohols, bromination, 599 dehydration, 265, 267, 287,414,619, 625 hydrogenolysis, 356 inversion of configuration, 414 Moffatt oxidation, 365, 516 Oppenauer oxidation, 665,667,689 oxidation, 374,400,442,496,586,593, 600,614,616,619,631,634,695 promoting effect in reductive alkylations, 631 motection as and regeneration from. acetate esters, 404,-410,414, 471,496, 582,593,616,619 benzoate esters, 298,413,431,629, 709.710 benzyl ethers, 404,406,514,588,589 brosylate esters, 595 esters, pyrolysis of, 151 mesylate esters, 359,577. 629.667 phenoxy ethers, 398 silvl ethers. 568 teirahydropyranyl ethers, 407,440, 503,509,714 tosylate esters.. 595.632 . removal of, 495 replacement with bromine, 487 replacement with chlorine, 221 selective acetylation, 324, 325,400 dehydration, 667 oxidation, 525 with hydrobromic acid, 420 with mercuric oxide, 446 with phosphorous tribromide, 363 p-Alcohols, oxidation of, 431 protection of, 221,270, 273 replacement with bromine, 499 tosylation, 503 s-Alcohols, dehydration, 410,414 oxidation, 359,404,423,424,463,468, 469,471,503,507,525 protection, 3 13 t-Alcohols, dehydration, 13,22, 27, 100, 353, 360, 372, 374, 378, 387. 392,
-
733
734
Reaction Index
411,440,451,458,459,471,483, 491,496,503,509,525,527,530, 595.632 protection as phenyl urethane, 90 Aldehydes, 27 alkylation, 566,616 conversion to nitriles, 160,595 condensation with, acetone, 516 methylacetoacetate, 367 triethylphosphonoacetate, 442 decarbonylation, 36 1 dehomologation of, 55 epimerization, 464,634 formylation, 393 from pyrolysis of homoallyl alcohol, 27 Jones oxidation. 409 ketalization, 75 oxidation with, oxy en, 55 silver oxide, 74, 3f2.431 reduction, 85, 112, 125, 163. 365,442, 6 29 Wittig reaction, 11,43,440,463,491, 6 34 6-Aldehydoacid, cyclization of, 70,71, 73 Aldehydoesters, lactone from, 57 Aldehydoketal, Wittig reaction on, 32 Alder-Stein rule, 260 Aldols, dehydration of, 507 Aldol cyclizations, 372, 376, 377.420,507, 695,709 Alkyl aluminium-hydrogen cyanide reagents, 615 Alylation of, aldehydes, 616 ally1 alcohols, 206 angular position in ketones, 357, 379 benzylic positions, 458 benzylidene blocked ketones, 682 blocked ketones, 683 carbet hoxymethylenetriphenylphosphorane, 389 conjugate addition, 376 cycloheptanes, stereospecificity in, 398 cyclohexals, 614 cyclohexanones, 47 1 cyclohexylimines, 532 cyclopropyl, as blocking group in, 625 a-decalones, 659 dienamines, 709 dienolate anions, 569, 61 1 dienones, 3 19 ðyl p-benzyloxyphenylnalonate,5 12 diethyl malonate, 363 pdiketones, 698,702 enamines, 5 34 enol acetates, 619 enolate anions, 61 1 enolic p-Keto esters, 477 enol lactones, 372 enones, 625, 715. stereospecificity in, 502 esters, 457, 632, 685 FridelCrafts reaction, 154 furfurylidene blocked ketones, 454,683, 689 gem diesters, 158 geminal triketones, 625
internal during solvolysis, 399 internal Michael, 5 17 isoxazoles, 377,652 ketones, 141, 374,377,520,530,624, 625,648,690 0-keto esters, 208, 369, 397, 538 lithio salt of 4-bromo-3-methyl anisole, 457 (+)-nopinone, 446 norbornanone, 483 olefins, 206, 210 reductive, 6 I 2 reductive, ketones, 616 sodio ethylmalonate, 442 tetrahydroeucarvone, 529 crp-unsaturated ketones, 21 1, 326,575, 599.621 using Triton B, 698,699 via butylthiomethylene derivative, 82 Alkylations with, ally1 bromides, 491,698 benzyl a-bromopropionate, 505 3-benzyloxybutyl bromide, 709 bis-vinyl carbinols, 699 l-bromo-2-butanone, 538 1-bromo-3-pentanone, 420 trans I-bromo-3-pentene, 374 l-bromo-l,2,2-trimethyl cyclopentane, 454 1-chloro-methyl-3,5dimethylisoxazole, 37 7 1,3dichlorobut-2ene, 709,7 16 2,3 dichloropropene, 457 dimethylsulfoxide as solvent, 715 ethyl a-bromopropionate, 37 1,529 isopropyl bromide, 532 lithium dimethyl co per, 366,502 methallyl chloride, f 7 1 6-methoxy-I-na thylethyl iodide, 654 methyl iodide, 827, 582 4-methyl-3-pentenyl chloride, 483 methyl vinyl ketone, 384,514,534,709 propargyl bromide, 61 3 propargyltetrahydropyranyl ether, 429 2-propenyllithium, 566 Vilsmeiers reagent, 406 hydroxymethylenes, 442 p-keto esters, 369 Alkynes, see Acetylenes Allene acetate, 29 alkaline hydrolysis of, 29 Allenone, 33 isomerization with base, 33,34 Ally1 acetates, 22 elimination of acetic acid, 47 I homologation of, 220 hydro enation of, 503 hydrofysis of, 130 pyrolysis of, 10 reaction with lithium dimethyl copper, 220 reduction of, 40, 348 AUyl alcohol, I2. 21, 42. 43, 48. I28, 163, 207, 221, 2-58, 327, 344, 499, -561, 666 acetonylation, 203
Reaction Index acetylation, 201 alkylation, 206 carbene addition, 147 cleavage with osmic acid, periodate, 59 conversion to, acetate, 22 bromide, 208,210,224,281,589 chloride, 201, 221,301 a,@-unsaturatedester, 210, 211, 221 cyclization during oxidation, 328, 329, 347 dehydration with alkali, 10 exchange reaction with ketone, 661 hydrogenation, 321,499,628,667 hydrogenolysis, 431,604 isomerization, 12,128,264 methylenation, 614 pnitrobenzoate, pyrolysis of, 12 oxidation, 12,31,79,81, 107,109, 127, 128,147,150,156,210,287,299, 328,329,334,347,435,446,577, 619 phenylurethane derivative, pyrolysis of,
90
rearrangement, during acetylation, 201 during thermal dehydration, 46 to allylic chloride, 499,532 reaction with, diketene, 204 enamine, 39,40 hydrobromic acid, 589 phosphorous trilbromide, 389 sulphur trioxide-pyridme, 431 thionyl chloride, 532 vinyl ether, 6,206 reduction, 14, 147,431 Simmons-Smith reaction, 392 AUyl bromides, addition to p-ketoesters, 45 in alkylations, 698 base treatment, 487 oxidation to a,@-unsaturatedaldehyde, 28 AUyl chlorides, 499 reduction, 532 solvolysis, 499 Ally1 dienol ether, thermal rearrangement,
735
reduction of, 36, 39,40,361 Amines, oxidation of, 39,40,419 Amine salts, hydrogenolysis of, 406 Amyrin group, 594 Angular methylation, directional effects of double bonds, 687 in estrone synthesis, 679 Anhydrides, 56 Pdiketones from, 345 Crignard reaction on, 56 reaction with dimethylcadmium, 345 Anisornropha buprestoides, 65 Annelations, 581,616 via enol-lactones, 7 11 Anthonomus grandis Bohemn, 58 Arens’ method, for removal of trimethylsilyl group, 209,210 Amdt-Eistert reaction, 507,649,654,685 Aromatization, 668, 709, 710 Artemisia alcohol, 41, 4 2 acetate of, 41 Arternisia filifolia, 144 Artemisyl skeleton, 40 conversion to santolinyl skeleton, 37 from trans-chrysanthemic acid, 34 Arylmethyl ethers, cleavage of, 459 Ascaridole, 132,133 reduction of, 133, 134 Aspidosperm in dole alkaloids, 81
Baeyer Villiger oxidation, 308 Bamford-Stevens reaction, 376,433 Barton reaction, 604 Base catalysed rearrangement, of santonin, 517 Beckman reaction. on oxime of bicvclol3.1. O j -hexan-2-one, 50 Benzaldehyde, in the protection of 1.2-diols asacetal. 38 Benzaldehyde acetals, reaction wtih n-butyl lithium, 38 Benzoates, elimination, 431 pyrolysis, 4 14 628 Benzofuran system, 264 Grignard reaction, 123 AUyl halibes, coupling with phosphorous reduction in, 265 ylids, 562 Benzyl alcohols, dehydration, 263 Allvlic oxidation. 381.414.417,469 hydrogenolysis, 619,621 AUilic sulfonium ylids, r k a n g e m e n t of, with methyl lithium and titanium trichlo41 ride, 561 sigmatropic rearrangement of, 562 Benzyl ethers, hydrogenolysis of, 55,507 AUyl iodides, conversion to ally1 alcohol, epoxidation of, 21 Benzylic alkylation. 458 Benzylidenes, 540. 696 AUyl magnesium bromide, in Crignard reacblocking group in ketone alkylation, 682 tion, 391 AUyl sulfones, reaction with, a,@-unsaturated intermediate in M contraction, 696 ester, 54 ozonolysis, 69,548,682 AUyl vinyl ether, thermal rearrangement of, reduction, 540 6,7, 32,36,142,163,206,222,228, Betaines, 490 with n-butyl lithium, 490 238,252,272,277,661 with paraformaldehyde, 490 AUylic carbonium ions, attack by peroxides, Bicvclic enones. 442 606 Biciclization, of diazoketones, 431 Ambergris, 569 Bicyclo 14.3.1 1 decanes, rearrangement of Amides, 3 6 hydroazulenes, 396 from ketones, 15 1 Bicyclo [ 3.1.01 -hem-2-one, oxime, y-hydroxy, cyclization of, 39
. .,.
736
Reaction Index
Beckman rearrangement, 50 Bicyclo 13.3.1 1 nonene, oxidative cleavage of, 464 Biogencsis, a-cedrene, 507 cedrol, 507 squalene, 633 Biogenetic rearrangement, patchouli alcohol, 499 Birch reduction, 379, 593, 599, 604,605, 612,620,625,628,668 allyl alcohol, 147 aromatic rings, 582 carissone, 295, 296 o-cresol, methyl ether, 251 a,p-cyclopro anoketones, 614 a-cyperone, !98 3,5dimethoxytoluene, 210 6-methoxytetralone, 31 1 p-methoxytoluene, 210 phenolic ethers, 664 phenols, 669 protection of aromatic ring during, 625 sabinol, 147 p-substituted anisole, 255 thymol methyl ether, 120 Bis vinyl carbinals, in alkylation of @ diketones, 699 Boric acid, in the dehydration of t-alcohol, 13 Bornylene, from a-pinene hydration, 103 Boron trifluoride, catalysed rearrangements, 452 cleavage of epoxides, 365 cyclization of, diketones, 464 eposydienes, 588 elimination of acetic acid, 469 in the addition of vinylether to acetal, 28, 29.52 rearrangement of, en01 acetates, 5 11 a-onocerindienedione, 590 with spiro epoxides, 616 Boschriiaka rossica, 64 Boschnialactone, 74, 77 stereochemistry of, 76 Bouveault-Blanc reduction, 646 Bredt’s rule, 709 Bromides, alkylation of, p-bromo toluene, 454 lithium salts of acetylenes, 429 elimination of hydrogen bromide, 384 internal cyclizations, 509,516 with lithio-I-trimethylsiylpropyne,445 with lithium acetylides, 489 with phenyl lithium, 457 Bromination, alcohols, 363,499 allyl alcohols, 389,440 allylic, 25, 141 with N-bromosuccirnide, 25, 142,480, 568 cyano ketones, 604 facilitation by oxalylation, 509 ketones, 98, 146, 384,616,620 olean-l2ene-l-one, 604 sodio oxalylates. 509 terminal olefms, 381, 417,491
Bromoacetals, in condensation reactions, 123 N-Bromoacetamide, bromination of ketones with, 98 p-Bromobenzenesulphonates, with dimethylamine, 419 a-Bromoketones, 98 dehydrobromination of, 58.98 yBromoketones, in the synthesis of cyclopropanes, 158 c-Bromoketones, internal reductive alkylation of, 499 Bromomethylbutadiene, coupling with thioketal anion, 26 N- Bromosuccinimide, allylic bromination, 25 of a,@-unsaturatedacid, 213 of a,@-unsaturatedketone, 141, 142 aromatizations, 668 cyclization of, dienol, 142 methyl farnesate, 342 formation of bromohydrin, 568 with humulene, 480 oxidation of, @-cyclocitral,138 linalool, 142 linalyl acetate, 25 selective reaction with olefin, 340 a-Bromotricyclene, with lithium acetylides, 489 Building Block Principle, in synthesis, 11, 112 t)-Butyl lithium, reaction with, allylether, 42 benzaldehyde acetals, 38 q-Butyl thioesters, with Raney nickel, 463 q-Butylthiomethylenes, as blocking group, 82,357,385 borohydride reduction, 468 cleavage, 83, 385 hydrolysis, 357 Camphene, from a-pinene hydration, 103 Camphor, 149,150,152, 153 photolysis of, 88 reaction with sulfuric acid, 114 Camphor oil, 6 1 Carbanionic reactants, aldol condensations, 5 95 lithium ethoxyacetylide, 584 methyl lithium, 595,599,619 stabilization of, 562 Carbenes, addition to, ally1 alcohol, 147 farnesol, 633 pulegene, 145 reduction product of p-isopropylanisole, 143 intramolecular insertion, 533 orientation of addition, 633 stereochemistry of addition, 462 Carbomethoxylation, 648 Carbonate esters, pyrolysis of, 41 1 Carbonvl comDounds. reduction of. 616 Carboxilic acihs, Arndt-Eistert homologation, 649 - . _ ,654 -- . converstion to, acid chloride, 57 diazoketone, 50,51, 390,431
Reaction Index decarboxylation, 363,652,653 degradation of, 449,454 esterification with, diazomethane, 55,56, 74,79,87, 135,379 methanol, 84 Grignard reaction on, 94 magnesium iodide salts of, 646 pyrolysis of lead salts of, 699 reaction with, q-butyl thiol, 463 diethylcarbonate, 431 methyl lithium, 543 thermal decomposition of, 353 A’carene, 54,157 acid, catalysed ring opening in, 138 epoxide, 54 ozonolysis, 55 Carissone, 288, 289 Birch reduction, 296 Carrol reaction, 5 Carvacrol, 104, IOS, 106,141 methyl ether, 104, 106 oxidation of methyl ether, 103 synthesis from p-cymene, 104 trifluroacetate, 104 Carvenone, 106,114, 286 from dihydrocarvone, 152 Carvomenthone, 266 alkylation, 267 formylation, 267 Carvone, 105,107,109, 112 conversion to eucarvone, 141 epoxidation, 107 interconversion, 107 oxidation to carvacrol, 105 reduction products, 105,113 selective oxidation, 263, 264 Cationic rearrangement, of endesmanoid precursors, 361 Catnip oil, 62, 70 Cecropia moth, 207 Chamaecyparis obtusa (Hinoki), 94,103 Chinese star anise oil, 136 Chlorination, with sulfuryl chloride, 458 y-Chloroesters, cyclopropyl esters from, 5 3 a-Chloroketones, with Grignard reagents, 564 P-Chloroketones, in the condensation reactions, 119 y-Chloroketone, cyclopropane synthesis from, 5 1 Grignard reaction on, 22 2-Chloro-2-methylbut-3ene, 7 isomerization of, 7 l-Chloro4methylpent-3ene, 22 in the synthesis of linalool, 22 Chromatography of, diols, 568 presqualene alcohol, 634 Chromous chloride, in lactone cleavage, 414 on 0-acetyl photosantonic acid, 419 Chrysanthemic acid, 49, 50, 54, 55 conversion t o pyrethric acid, 57 cyclopropane ring fission in, 35 esters of, 54 formation by biogenetic pathway, 36 irradiation of reduction products, 47
737
cis-trans isomerization in the synthesis, 5 1, 56 C’4-labeUcd methyl ester, 58 nitrile, 50 pyrolysis product, 58 Chrysanthemol, 4 7 irradiation of, 48 ffirysanthemum cinerariifolium, 49 ffirysopidae, 62 1,4-Cineole, 132-I34 1,8Cineole, 132-134 Circuitous syntheses of ertrone, 718 Citral a and b, 2 7 conversion to geraniol, 201 cyclization to dimethyl styrene, 42 diepoxide, 165, 166 epoxidation, 21 photocyclization, 60, 275 thermal isomerization, 27 Citronella1 a and 0, 27 conversion to, curcumenes, 246 dolichodiol, 78 isoiridomyrmecin, 75 zingiberene, 246 hydration of, 26 Citronellic acid, cyclization to Pulegone, 116 Citronellol, 15 cyclization, 117 monoacetate, 168 photoxidation, 169 triacetate, pyrolysis, 168 cimcs junes oil, 100 Citrus medico L., bar. acida, 133 citrus natsudaidi, 131 citrus unishu, 1 31 Claisen rearraneement. 5. 31.34.36.44. 112, 163:206,222, 2i8, i38,’25i, 271,393,565,566,586.629.661 Eschenmoser’s variation, 36,’361 Condensation with, bromoacetals, 123 P-chloroketones, 119 ethyl cyano acetate, 420 Mannich bases, 114 sodium acetylide, 695 Condensing agents, sodium acetylide, 695 Conjugate addition, to enones, 353 Cope elimination, on N-oxides, 39,40,419, 420 Cope rearrangement, 36,40,44,163,222, 228,265,274,702 Copper powder, in the cyclization of diazoketones, 50, 148,473 Corynanthe indold alkaloids, 81 Conjnebacterium simplex, 665 Cosmos bipinriatus, O I v , 13 Coupling reaction, allylic bromides, 589 Cram’s rule, 564 (+)-Cryptone, 90, 97, 98 as precursor of, P-phellandrene, 90 cis and trans-0-terpineols, 94 resolution, 100 semicarbazone, 97 (-)-Cryptone, Diels-Alder reaction on, 335 Cryptophenol see Thymol
738
Reaction Index
Cuminaldehyde, 125, 128, 129 Cumin seeds oil. 128 cupric acetate, in cyclizations of terminal olefins, 5 28 Cuprous iodide, in decomposition of diazo compounds, 435 Cyanoesters, selective reduction of, 78 Cyanohydrins, dehydration of, 171 from @,@-unsaturated aldehyde, 171 Cyanoketones, Stobbe condensation, 679 Cyclic ethers, fragmentation with sodium, 449 froml.4-diols, 134 oxidation, 446 Cyclizations, 678,686, 712 of acetylenes, 7 13 of acid chlorides. 685 of 6-aldehydo adds, 70, 71, 73 acid catalysed, 397,595, 625.705.710 aldol condensations, 709 asymetric, 710 base catalysed, 627,705 with boron trifluoride, 588 on cleavage of aryl ethers, 359 of diacids, 56, 97 of I ,Sdialdehyde, 75 of diazoketones. 50,51,148, 158,386, 389 Dieckman, 649 Diels-Alder, 451 of 1,5-dienes, 49 of 1,6-dienes, 1 y pyrolysis, 6 1 of dienoic acic, 144 of dienol with NBS, 142 of diesters. 530 of diketones, 69, 114, 146,464,507,516, 534,536,540 of diols. 579 of dioxocarboxylic acids, 658,660 of epoxides. 571,604 abiololjcal, 590 of epoxydienes, biogenetic like, 31 7 of epoxydiols, with picric acid, 568 FriedelCrafts, 646 of hydrazones, 446 of 6 -hydroxyacids, 76 of 7-hydroxyamides, 39 inhibition of, by olefins, 709 internal Michael reaction, 520 intramolecular, 397 of ketoacids, 55.99 of ketoaldehydes, 55,74, 87, 113,536 of 6-ketoesters, 507 of ketones, 662 of P-ketosulfoxides, 534 of lactoneesters, 656 of cis and fruns monocyclofarnesols, 453 of olefins, biomimetic, 7 12,7 13 terminal, 528 of P-onocerin, 574 of phenolic bromoesters, 509 with phos horous pentoxide, 698 of spiro-18,S 1 -decanes, 508 with sodium t-amylate in benzene, 709 solvolytic, 629
of p-substituted phenols, 5 14 of tosylates, 428,503 of triene carboxylic acids, 577 with triethyl ammonium benzoate, 695 of unsaturated acids, 496,543 dyclization, 353 stereochemistry of, 374 Cycloaddition, of dimethylketene t o methylcyclopentadiene, 144 of ethylene to or@-unsaturated ketone, 58 Cyclobutanol, fragmentation of, 425 Cyclobutanones, elimination of ethanol from, 540 Cyclobutene, synthesis from 1,3-diene, 155 Cyclobutenones. hydride reduction of, 540 CyclobutyUiexenols, acid catalysed rearrangement of, 542 Wyclocitral, oxidation of, 138 Cyclodehydration, 595,697 w t h aluminum chloride, 599,681 with concomittant dechlorination, 457 diketones, 620 r-diols, 601 with ethanolic hydrochloric acid, 695 with polyphosphoric acid, 714 with pyridine hydrochloride, 661 in synthesis of lactone esters, 654 with ptoluene sulphuric acid, 621,697 Cyclodehydrobromination. 420 Cyclofamesyl cation, rearrangement of, 265 Cyclohexanes, oxidation of, 646 Cyclohexanes, with methyl lithium, 511 Cyclopentano pyrans, table of, 63-68 Cyclopentenanes, 457 hydrogenation, 658 with lithio salts, 458 photoaddition, 532 Cyclopro anes, 49-54, 156, 41 7, 420, 467,
48P
cleavage of, 380,427,625 formation from, 7-bromoketones, 156, 158 conjugated dienes, 4 9 , 5 0 diazoketones, 148, 158 a,punsaturated ketones, 156, 158 mode of ring fission in truns-chrysanthemic acid, 35 reductive rearrangement, 480 specific electrophilic cleavage, 360 Cyclopropyl alcohol, 205 conversion to bromide, 214 opening of, 205,214,217 photolysis of, 48 Cyclopropyl carbinyl bromide, from alcohol, 214,230 rearrangement of, 214 Cyclopropyl esters, from ychloroesters, 53 Cyclopropyl ketones, 51, 572,625 alkylation, 213,230,629 carbonation, 213 1,4-dienes from, 147 Grignard reaction, 205, 217 reductive alkylation, 629 Cyclopropyl nitrile, hydrolysis of, 5 0
Reaction Index Cyclopropyl olefis, hydroboration of, 147 ozonolysis of, 57 Qmbopogon, 4 Cymbopogon densiflorus, 11I pCymene, 92 8-hydr0~y,102, I03 microbial oxidation of, 128 photochemical oxidation of, 103,128 in the synthesis of, carvacrol, 104,105 menthatdene, 91 thallation of, 104 a e p e r o n e , 285-288 Birch reduction of, 298 epoxidation, selective, 289 7epi-&-cyperone,269,270,284,304 agarafurans synthesis from, 300,301 deoxygenation of, 304 peracid oxidation of, 301
739
of tertiary alcohols, 22, 100, 360,372, 374,378,387,411,459,471,480, 483,491,496,503,507,509,525, 530,595,619,632 two-phase medium, 458 Dehydrobromination, 46,98,141,142, 420,491 base catalysed, 381 bromocyanoketones, 604 bromoketones, 58,604,620 with HMPT, 384 methyl shift, during, 605 in the synthesis of cyclopropanes, 417 Dehydrochlorination, 47,53,514 Dehydrogenation, ldehydroestrone methyl ether, 662 with DDQ, 367,665,666 hydroxymethylenes, 372 microbiological, 664 Dammar resin, 592 Dehydroiodination, 86, 171 Deacetonylation, 87 Dehydrolinalool, 28 Deacetylation, 446,595 acetate, pyrolysis of, 29 Deamination, 572 Dehydrotosylation, yridine catalysed, 522 Debenzylation, by hydrobromic acid, 525 Deketalization, 11, 75, 79,365,404, Debromination, with alkaline methylsulfate, 420,421,431,473,507,522,536, 616 689,705 by hydrogenation, 459 de Mayo reaction, 83 a-Decslones, cis and truns methylation of, Deoxalylation, 509 659 Desulphurization, lithium in ethylamine, cis Decalones, 601 562 Decarbonylation, by photochemical reacDethioketalization, by Georgian's method, tion. 156 5 20 by reduction of, dithioketal, 516 with mercuric chloridecadmium carbonate, thioketal, 543 26 with silver nitrate, 26 Decarboxylation, 363,368, 374,377, 380, 420,446,456, 530,540,587,649, Diacetates, hydrolysis, selective, 436,538 650.692 from olefms, I68 acidcathysed, 652 pyrolysis, 130 pcyclocitrylideneacetic acid, 353 selective, 109 0-Keto acids, 477 1,s-Dialdehydes, cyclization of, 75 malonic acids, 473 Diazoketones, 391, 441, 473 with trisbiphenyl phosphinechlororhodium decom osition with, copper powder, 391, chloride, 361 4751 Deesterification, 453,473,530 cuprous iodide, 435 with rearrangement, 652 mercuric iodide, 435 Deformylation, 376,464 reaction with, copper catalyst. 391 Dehomologation, of aldehydes, 55 cupric sulfate, 386,389,431 Dehydration, 451,458,678 ring closure of, 148,158 acid catalysed, 353,527 Diazomethane, in esterification, 55,56,74, of acid chlorides, 648 79,87, 104, 135,634 of allvl alcohol. 10.46 ring expansion with, 141 of cykohyd&, 17 1 1,2-Dibromides,reduction to olefms, 97 Dicarboxylic acids, cyclization of, 56,97 of diols, 55,576,601 of diplopterol, 592 Dichlorides, in alkylation of ethyl p-tolylof homoallylic alcohol, 13 acetate, 457 of Phydroxy ketones, 161,171 Dichlorocarbene, addition to en01 ether, 43 of hydroxy olefms, 593 Dieckman cyclization, 241,363,365,420, with mesylchloride/pyridine, 667 454,477,649 of patchouli alcohol, 492,493 dimethyl T-ketopimelate, 365 with phosphorous oxychloride, 427,446, lactone esters. 656 579,667 Diels-Alderreachon, 89, 150, 151, 162, of primary alcohols, 414 259,335,579,671 of secondary alcohols, 414 of acetylene dicarboxylic acid. 353 spontaneous, 392,581 with bdnzoquinone, 687 of terminal alcohols, 463 with borontrifluoride catalyst, 672
h,
740
Reaction Index
citraconic acid, 672 cyclopentadiene, 485 ?-ethoxy-l,3-butadiene, 45 1 ethy1-P-acetoxyacrylate,462 of geraniol, 485 with methyl vinyl ketone, 499 of trimethyl cyclohexadienone, 499 with 2,6-xyloquinone, 672 Dienarnines, alkylation of, 709 Diendiones, hydride reduction of, 536 Dienes, hydroboration, selective, 15 hydroxylation, selective, 130,520 partial hydrogenation, 419 photooxygenation, 133 reduction, selective, 485,51 1 with Raney nickel, 496 I ,3-Dienes, addition of ethyldiazoacetate, of of of of
49
cycloaddition to ketenes, 144,145 cyclobutenes from, 155 Diels-Alder addition to, vinyl acetate, 150 a$-unsaturated ketone, 15 1 epoxidation, selective, 17 1 hydroboration, selective, 171 hydrochlorination, 18 ozonolysis of, 146 reduction, selective, 84 1,4-Dienes. from cyclopropyl ketones, 147 1 ,S-Dienes, 43, 562 cyclization of, 49 photooxidation of, 43 synthesis by Wurtz coupling, 43 1,6-Dienes, pyrolysis of, 61 Dienoic acids, addition of ethyldiazoacetate, 50
cyclization of, 144 Dienols, selective epoxidation, 166 Dienones, 1,6-addition of, sodio diethylmalonate, 324, 325,473 sodio methyl diethyl malonate, 319 Birch reduction, 605 cyanide addition, 604 enol acetylation, 665 hydrogenation, 471,509,511 irradiation, 410 photochemical rearrangement of, 467 photolysis of, 414 reaction with lithium dimethyl copper, 47 1 Dienyne, 576 hydrogenation, 576 Diesters, alkylation of geminal, 158 cyclization, 363,454,530 hydride reduction, 462 partial saponification, 1 1 , 507 Dihydrocarvone, 108, 1 1 3,269,285,291 alkylation, 309 annelation with ethyl vinyl ketone, 284 conversion to camphor, 152 enol acetates, 152 hydrobromide, reaction with alkali, 157 hydroxylation, 309 Dihydrolavandutic acid, cyclization to piperitone, 116 Dihydronepetalactones, 78
reduction, 78 Diketones, cyclization.. 464.536.540.627 . . . fragmentaiion, 397 hydride reduction, 423 reaction with Grignard, selective, 536,579 reduction with sodium-alcohol, 528 selective ketalization, 627 selective reaction with methyl lithium,
530
selective and stereospecific. 536 reaction with Grignard, 536 vigorous acid treatment, 662 a-Diketones, mono enol acetylation of, 540 P-Diketones, 99, 345 alkylation, 698 chlorination, 214, 216 deacylation, 214,216 Grignard reaction with, 160, 161 Michael reaction, 710,717 reaction with, methyl vinyl ketone, 714 propargyl bromides, 7 13 reduction, 517 7-Diketones, 146, 534 cyclizations of, 69, 146,507,534 bDiketones, 83 cyclizations, 5 16,540 Dimethyl acrolein, Grignard reaction with prenyl halide, 42 Dimethyl butynedioate, Diels-Alder reaction with, 162 Dimethylstyrcne, 92,93 in the synthesis of menthatriene, 91 2,5-Dimethyl-3-vinylpent4en-2-ol, 39 formation from chrysanthemic acid, 34 2,4-Dinitrophenylhydrazones,as carbony protecting groups, 428 ozonolytic cleavage of, 428 Diols, acetylation, selective, 423,448,474,
496
cleavage, 84, 87,540 dehydration, 55,427 oxidation, 383, 391,538,540 protection as acetonyls, 86 benzaldehyde acetate, 38 rearrangement in acid, 510,582 selective monomesylation, 47 1, 5 16 selective monotosylation, 41 7,462,478,
479,520
1 J-Diols, monoacetate, pyrolysis of, 48
1,4-Diols, cyclic ethers from, 134 Diones, aldol cyclization of, 420 selective reaction with vinyl lithium, 499 Dioxo carboxylic acids, cyclization, 658 Dipentene, 8,88 irradiation, 9 oxidation with selenium dioxide, 100 1,3-Dipolar addition, of 2-diazo propane,
384
Disiamylborane, in hydroboration, 440,
449,489
Disproportionation, during gas chromatography, 128 Dithio ketals, with Raney nickel, 507 Dolichoderus, 65 Dolichodial, 78
Reaction Index correlation with iridodial, 79 isomers, 80 Doronicum ausmocum, 116 Drimic acid, 345,347 anhydride from, 345,347 Electrocyclic reaction, 4,44 Electrolysis of acetate, 579 Elemol, 269,270 hydroboration of, 270 tetrahydro, 269, 270 Elimination, of tosylate in truns-decalin, 314,315 Elsholtzia cristata, 159 Elsholzia densa, 159 Emmons reaction. 209 Enamines, alkyla&on of, 534 Enediones, reduction, 575 Enol acetates, 55, 73,152, 612, 631 alkylative cleavage, 619 cleavage with methyl lithium, 612 epoxidation, 502 hydrogenation, 73 irradiation in presence of l,l,-diethoxy ethylene, 540 oxidation of, 592 ozonolysis of, 55, 632 rearrangement with boron trifluoride, 5 11 with bicarbonate, 665 Enolates, with acetic anhydride, 619 with acetyl chloride, 502 alkylation, 614 generation, 612 intramolecular alkylation, 526 protonation, 614 Enol ethers, 624 addition of dichlorocarbene, 143 bromination-dehydrobromination, 664 cleavage of, 120 condensation with methyl acetoacetate, 367 consecutive acid-base treatment, 366 with dimethyl sulphonium methylide, 616 with ethylene glycol, 465 with Grignard reagents, 661 hydrolysis, 366, 378,409,451,616 mechanism of reductions, 369 as rotecting group, 378,442 refuction with Uthium-ammonia, 369 with Vilsmeier’s reagent, 406 Enolic P-keto esters, 477 with methyliodide, 417 Enol lactones, with Grignard reagents, 629, 710 hydrogenation of, 595 as intermediates in annelations, 7 11 with methyl lithium, 372 with phosphonium or phosphonate ylids, 711 Enols, 665 borohydride reduction, 665 ketonization, 584 Enones, 451, 682 acetylation, 406 alkylation, 620, 714, 715,716
741
0-alkylation, 7 15 borohydride reduction, 525,628 conjugate addition, 353, 376 dimethylation, 625 dissolving metal reduction, 469 with ethyl cyanoacetate, 543 formylation, 373 with Grignard rea ents, 705,619 with hydrazine, 317 hydride reduction, 422,471,474 hydroboration, 146 hydrocyanation, 516,625,629 hydrogenation, 371,507,540,628,682, 710 hydrolysis, 407 with lithium dimethyl copper, 366, 376 with methyl lithium, 511 reduction, 383, 384,463 reductive alkylation, 629,630 stereospecific angular methylation, 502 stereospecific hydrogenation, 372,527, 695,696 specific reduction, 361 with triallvl orthoformate. 628 with tri-t-iutoxy lithium alluminum hydride, 471 with triethyl aluminum-hydrogen cyanide, 620 Wolf-Kishner reduction, 381 fir-enones, 569 trans-Enyal, Grignard addition to, 30, 31 Epimerization, acetyls, 499 during allylic oxidation, 416 esters, 400 hydroazulenes, 397 ketones, 592, 695 lactone carbonyls, 414 Epoxidation, of &amyrin-3-benzoate, 609 of benzylic olefins, 581 of I ,3-dienes, selective, 171 of dienols, selective, 166 with dimethyl sulfonium methylide, 451 of enolacetates, 306, 313, 502 of homoallylic alcohols, 21 1 of octalones, 522 of olefines, 54, 101, 127, 365,413,422, 471 of ppatchoulene, 496 of squalene, 566 ofqpunsaturated ketone, 107, 137 mono and di. 208 selective, 100, 210, 216, 219, 220, 271, 289,306,588 Van Tamelen method, 219 via aerial oxidation, 606 Epoxides, 208, 210,21I , 214, 216, 217, 219, 221, 564 cleavage, 88, 216, 365 with boron trifluoride, 496 and rearrangement, 422 with sodium benzylate, 522 controlled hydrolysis, 566 conversion to, ally1 alcohols, 221,666 enol acetate, 73 formation of thiourea clathrates, 568
742
Reaction Index
with Grignard reagents, 646 intermediates in cvclization. 57 I rearrangement, to-ketones, 609 with chlorine, 609 reduction of.. 101.. 289.451.471.609 ring opening, to a,&un&turated, ketone, 108 with benzyl alcohol-acid, 54 with dimethylamine, 100 separation from diols, 568 Epoxyacetate, basic hydrolysis of, 307 thermal rearrangement of, 306, 307, 3 13 a,P-Epoxy aldehyde, 21 from epoxidation of citral, 21 in the synthesis of ally1 alcohol, 21 Wharton reaction on, 21, 165 a.BEpoxy Ketones, cleavage of, 95, 107 reduction of, 136 Equilibration. of Ketones, 385, 478 ring junctions, 481 Erythro-diols, 568 Esterification, 400,407.409,419,445, 473,514,516 with diazomethane, 379, 634, 652 with methyl chlorocarbonate. 41 1 with silver oxide-methyl iodide, 373 Esters, alkylation, 457,632,685 axial-equatorial e uilibration, 369 cleavage, 649,68? eoimerization. 400 i t h Grignardreagents, 135, 582 hydrolysis, 363, 368, 371, 374, 377, 397, 442,463. 503. 514. 534. 538. 540. 604,654; 685,692 with methyl lithium, 372, 387,401,409 with methyl magnesium iodide, 473 with methyl sulfinyl carbanion, 534 reduction, 59, 363, 365, 374, 397,411, 4 19,489.649 Ethers, cleavage, 667 exchange, 393 selective cleavage, 625 Ethoxyacetals, with ethyl propenylether, 393 Ethoxyacetylide, addition to ketone, 44 Ethylene acetals, hydrolysis of, 466 Ethyl diazo-acetate addition to, 2,s-dimethylhexa-2,4-diene, 49 2,5-dimethylhexa-2,4-dienoicacid, SO Ethynylation of, Ketone, 201-203 Ethynyl carbinols, (Acelylenic Alcohols), reduction of, 477 Eucalyptus dives, 136 Eucalyptus globulus, 87, 97 Eudesmane group, members of, 282 Evodio hortensis, 123 Exocyclic olefins, hydroboration-oxida tion of, 503 Farnesic acid, bicyclo, 3.39, 340 monocyclo, cyclization of, 343,344 Farnesol, 200, 201. 203, 204, 206 acetate of, cyclization, 340 epoxidation, 221 bromide, 343
cyclization to drimenol, 339 pyrophosphate, cyclization of, 233 Favorskii rearrangement of, (+)-Pulegone, 72,145 Felidae, 6 2 a-Fenchol, from a-pinene hydration, 103 from reduction of fenchone, 154 Fenchone, reaction with sulfuric acid, 114 reduction with lithium aluminum hydride, 154 Fennel oil, 133 Foeniculum vulgare var. duke M., 133 Formylation of, 373 alkynes, 205 hexones, 442 ketones, 376 lactones, 329 menthones, 389 3 methyl furan, 160 7,6-unsaturated ketones, 29 1-Formyl-2,6,6-trimethylcyclohexa-l,3diene, see Safranal Fractional crystallization, 676 Fractional distillation, 368 Fragmentation, bicyclic diol monotosylate, 475 G o b type, of 1,3-diol monotosylate, 21 1. 212,471 hydroxyenone. 3 15 Phydroxy-P-ketoester, 51 monotosylates, 470 Friedel-Crafts reaction, 117, 24 1, 253,454 acylation of methoxy napthalere, 658 of anisole, 685 cyclization, 646 intramolecular in furans, 232 in ring closure, 697 in synthesis of 2 methyl cyclopentan-1,3 dione, 692 Fullers earth, in rearrangements, 590,593 'Furan ring system, 122, 264. 275. 312, 314 oxidative cleavage, 454 Furfurylidenes, as blocking group, 454,683, 689,690 cleavage of, 689 hydrolysis, 656,658 oxidation, 699 Fused ring systems, by hydrogenation, 583, 5 86 stereoselectivity of hydrogenation, 696
Genipa arnericana. 66, 84, 85 Geranial, see Citral a Ceranic acid, cyclization to piperitenone, 116 Geraniol, 200 acetate, 139 acetate oxide, 165 acetonylation, 202 in the biogenesis of, indole alkaloids, 24 Karahana ether, 139 oxidation, 28 phosphate ester in the biosynthesis, 24 Geranyl bromide, 28 oxidation of, 28
Reaction Index Geranyl diphenyl phosphate, 24 allylic rearrangement of, 24 Gingergrass oil, 11 1 Glyoxalyl chloride tosylhydrazone, with trans, trans-farnesol, 634 Glyoxylates, pyrolysis of, 648 Grignard reactions, 579,600,601,621,625 1,4addition to unsaturated ketones, 32, 86,114,619 of ally1 magnesium bromide, 391,442 of 2-bromo-6-methoxy naphthalene, 661 in carbonation, 697 of cycloheptalones, 427 of enol lactone, 595,629,705,710 of n-halotricyclenes, 487 of homocamphor, 496 of 1-iodob-methoxynaph thalene, 646 of isobutylbromide, 30, 31 on acid chloride, 236 on acids, 94 on anhydrides, 56 on benzofuran system, 123 on bicyclic heptanone, 151 on a-chloroketones, 214,564 on ychloroketones, 22 on 2-chlorotropone, 143 on 2-Cyano-3-methyl furan, 160 on cyclopropyl ketone, 205,391 on 0-diketones, 160, 161 on esters, 135, 250,474,514,582 on hemiacetals, 6 19 on Phydroxy ester, 261 on ketal aldehyde, 206 on Pketoacetal, 29 on ketones,47, 92, 96, 97, 151, 168,540 on nitriles, 160, 217, 241 on prenyl halides, 4 2 on protected aldehydo ketone, 29 on 4-substituted methyl cyclopentenes, 103 on tropolone system, 143 on a$-unsaturated acid chloride, 112 on a,punsaturated aldehyde, 30,31 on a,punsaturated ketones, 86,95, 114 selective and stereospecific with diketones, 436 with acrolein, 697 with allylmagnesium bromide, 391,496 with truns-caran-2-one, 391 with 7,ydimethylallyl mesitoate, 481 with ethoxy acetylene magnesium bromide, 587 with ethylene oxide, 646 with phalopropionic esters, 649 with methacrolein, 487 with spontaneous dehydration, 581 Grob fragmentation, see Fragmentation Halogenation of, P-diketone, 214,216 &Halopropionic esters, as Grignard reagents, 649 n-Halotricyclenes, homologation of, 486 Helinium species, 116, 123 Hemiacetals, 572 in Grignard reaction, 619
743
with methane sulphonyl chloride, 572 oxidation, 610 Heptenes, hydroboration, 496 Hexanones, formylation, 442 reduction, 442 Ho leaf oil, 25 Homoallylic acetates, allylic oxidation of, 471 Homoallylic alcohols, dehydration, 13 pyrolysis, 27, 101 synthesis by Rins reaction, 101 Homoallylic chloride, condensation with methyl vinyl ketone, 22 Homogenization, of acetylenic isomers, 689 of ring junctions, 475 Homologation, of n-halotricyclenes, 486 Hop oil, 167 Huang-Minlon reduction, 456,689 Hunsdieker reaction, 454 Hydration, of acetylenes, 69, 695 of alkenes, 27 Hydrazine, with enones, 387 Hydrazones, 435 decomposition with cuprous iodide, 446 cis, tmns-farnesal, 435 of ketones, 689 oxidation, 435,633 Hydrindones, internal bond scission of, 474 Hydride transfer, during pyrolysis of 1,6diene, 6 1 Hydroazulenes, 395, 402, 404 Hydroboration, of acetylenes, 449 of cyclopropyl olefin, 147 of diene, selective, 15 of elemol, 270 of exocyclic olefin, 503 of heptenes, 496 of homodiene, 171 of hydroxyolefins, cyclization during, 134 of methyl heptenone, 146 of olefinic ketal, 290 of olefins, 74,77,356,404,420,528 of olefins, resistant to, 621 of terminal olefins, 391, 530 of cr,P unsaturated ketone, 136 ring opening of ketals, 291 selective, 80 with disiamylborane, 629 with tri-isobutylaluminum, 15 Hydrochlorination, of a-acetyl-ybutyrolactone, 21 of 1,3-dienes, 18 of Isoprene, 7 of Myrcene, 12 of olefinic ketones, 5 1 Hydrocyanation, 311,312,346,347, 350 of enones, 625,629 stereochemical control, 625 Hydrogenation, 353, 392,586,601,604, 674,679 control by neighbouring group, 621,686 in presence of perchloric acid, 496 of acetylenes, 30.681 of ally1 acetates, 503 of ally1 alcohols, 628,667
744
Reaction Index
of aromatic nitro group, I04 of bicyclo olefins, 150, 15 1 of cyclopentenones, 656 of dienes, selective, 419 of dienones, 47 1 selective, 5 11 of dienynes, 576 of enol acetate, 73 of enol lactones, 595 of enones, 377,515,540,628,682,710 of hexenes, 499 of hydroazulenes, 410 of olefins, 353,459, 525, 575, 621,646 of spiro 4.5 decadienones, 514 of spiro 4.5 decanes, 468 of a,P-unsaturated esters, 372 of a,Py,6-unsaturated esters, 509 of a,P-unsaturated ketones, 69, 118,661 over nickel, 646,697, 702 over palladium-calcium carbonate, 697, 699 over palladium-strontium carbonate, 407 of Phenol, 98 over platinum oxide, 379, 583, 601 over tris (triphenylphosphine) rhodium, 411
replacement of bromine, 459 selective, with Wilkinson’s catalyst, 287 stereoselective, 400, 696 stereospecific, 414, 507,522, 525,616, 653,695,696 Hydrogenolysis, of alcohols via their acetates, 356 of amine salts, 406 of benzyl ether, 55 of cyclopropanes, 427 of ketones, 685 selective, of ketones, 658 1,2-Hydrogen shifts, 594 Hydrolysis, of ally1 acetate, 130 of diesters, 507, 590 of cyclopropyl nitrile, 50 of enol ethers, 366, 378,616 of epoxides, 566 of esters, 353, 363, 368,371, 374, 377, 397,442,463,473,503,514,534, 538,540,568,584,586,588,604, 685,692 of ethylene acetals, 466 of 0-hydroxynitrile, 53 of p-keto esters, 69, 456,471 of ketals, 699 of lactones, 463, 579, 634 of malonates, 473 of methyl ethers, 653 of nitriles, 78,385,462, 516, 543, 595, 615 of trifluoroacetate, 105 of trimethylsilyl ethers, 568 of vinyl chlorides, 709 in synthesis of oleon-1 2ene-3-one, 604 partial, of diacetates, 536 Hydrolytic cleavage, of tetrahydrofurans, 5 36 Hydroperoxides, by aerial oxidation, 606
hydride reduction, 61 9 y-Hydroxy acetates, oxidation of, 536 6-Hydroxy acids, cyclization of, 76 y-Hydroxy acids, lactonization, 463,621 y-Hydroxy amides, cyclization, 39 with methane sulphonyl chloride-pyridine, 621 Hydroxy epoxides, cleavage of, 422 2-Hydroxyisopinocamphone, dehydration of, 141 Hydroxy ketal, oxidation of, 32 bHydroxy-Pketo ester, fragmentation of, 51 a-Hydroxy ketones, with calcium-ammonia, 374 oxidation, 540 PHydroxy ketones, dehydration, 161,171 Hvdroxvlation. of dienes., 520..~ 582 bf o l e h s , 84, 86 selective, 130 with osmium tetroxide. 417 1-Hydroxyl group, replacement by chloride, 47 1-Hydroxymenth-2-ene, 90 pyrolysis of phenyl urethane derivative of, 90 Hydroxymethylenes, 532 as blocking group, 82,83,357 with n-butyl mercaptan, 357, 389 0-alkylation, 442 deformylation, 376 with dichlorodicyanoquinone, 372 Cripard reaction on, 29 with hydroxylamine hydrochloride, 65 1 of lactones, 463 with methyl iodide, 367 with methyl vinyl ketone, 464 reduction, 463,532 PHydroxynitrile, lactone during hydrolysis, 53 Hymentherene, 11 isomerization of trans to cis, 13
Ibogu indole alkeloids, 81 lllicum verum, 133 Imidazolines, 158 in the formation of cyclopropanes, 158 Imines. reduction, 620 in synthesis of aldehydes, 629 Iminolactones, 621 Immonium salts, reduction of, 406 Intramolecular alkylation, of tosylates, 632 Iodides, with lithium acetylides, 449 Ips confisus, 26 Iresin celosiodes, 34 8 Lridodial, 72, 74 conelation with dolichodials, 78 Iridoids, table of,63-68 Iridolactones, stereochemistry of, 76 Iridomyrmecin, 74, 77 permanganate oxidation of, 76 stereochemistry of, 76 Iridomyrmex. 62,65 Iridomyrmex conifer, 65 Iridomyrmex defectus, 65
Reaction Index Iridomyrmex humilis, 64 Iridomyrmex nitridus, 64 Isobutene, reaction with acid chloride, 41 cis-Isochrysanthemic acid, double bond isomerization in, 5 1 nitrile of, 50 Isolavandulol, dehydration of, 46 Isomenthone, I24 separation from menthone, 125 Isomerization, in alkaline medium, 676 during hydrolysis of nitriles, 50 of allenones, 33,34 of trans-lactones, 579 of a-onocerin, 574 of terminal olefins, 532 Isonepetalactone, 71,72 conversion to cis, trans-nepetonic acid, 71 isomerization to nepetalactone, 72 Isopiperitenone epoxide, 137 diosphenolene from, 137 Isoprene, dimerization, 89 with formic acid-perchloric acid, 23 with halo-acids, 7 telomerization, 23 Isopropoxymethylenes, as blocking groups, 377 cleavage, 377 Isopropylols, 397 Isopulegol, pyrolysis of, 27 Isopulegone, 116 4-acetoxy, 122 5-acetoxy, 122 conversion to menthofuran, 122 interconversion to pulegone, 121 cis-Isopyrethric acid, 51 cis-trans isomerization, 52 Isoxazoles, alkylation', 377, 652 annelation, 377 cleavage, 377 Japanese hops, 139 Japanese pepper, 100 Japanese peppermint oil, 136 Jones oxidation, 121,621 Juniperus communis, 88, 100 Juniperus sabina, 148 Kentranthus ruber, 6 7 Ketals, hydrolysis, 699, 710 rearrangement, 536 Ketalization, 11,32, 33, 75, 112, 121, 135, 366, 397,404,420,463,473,518, 522, 586,616,619,627,629,631, 689,704 Ketenes, cycloaddition to 1,3-dienes, 144, 145 Keto acids, 127 conversion to enol lactones, 710 cyclization of, 99 decarboxylation, 477 lactonization, 372 reduction, 399 Keto aldehydes, aldolization, 465 cyclizations, 5 5 , 74, 87, 113, 536 enol acylation, selective, 55
745
oxidation, 586 in ring annelation, 366 a-Keto carbenes, with olefins. 388 1 1-Keto compounds, reduction, 573 Keto epoxides, cleavage, 423 0-Keto esters, addition to allylbromides, 45 alkylation, 369 hydrolysis, 69, 456, 477 ketalization of, 32, 121 reaction with methyl vinyl ketone, 397 reduction of, 32,577 in Stobbe condensation, 649 Wittig reaction, 45 Y-Keto esters, intramolecular acylation, 530 6-Keto esters, cyclization of, 507 Ketols, chromatography on alumina, 592 oxidation of, 73 pinacol rearrangement, 621 Ketones, addition of, ethoxyacetylide, 44 methyl lithium, 48 alkylation, 82, 141,371, 385,491, 520 stereospecific, 621,658 angular methylation, 357 Bamford-Stevens reaction, modified, 309 bromination, 98, 141, 146, 384,620 selective, 252, 253 bromination-dehydrobromination,385, 471,481 a-carbethoxylation, 369 carbonation, 295 carboxymethylation, 473 condensation with, aldehydes, 516 methoxyacetylene, 23 conversion to, alkynes, 205 amides, 150 enol acetates, 152 olefins, 296, 390 cyclodehydration, 620 dehydrogenation, 367 epimerization, 695 equilibration, 621 ethynylation, 201-203 formylation, 29, 267, 376 geminal alkylation, 625 Grignard reaction on, 47,92, 96, 97, 151, 168 hydroxymethylation, 357 hydrogenolysis, 685 in Wittigreaction, 59,76, 89, 104, 164, 478 modified 207, 208,216, 217,218 methylation, 427,483, 624 a-oxidation, 4 14 preferential thioketalization, 292 protected as 2.4-dinitrophenylhydrazone, 228
enoiether, 378 reduction, 69, 86,356, 360, 389,407, 410,413,421,431,463,478,514, 536,621 selective, 21 1 b y Meerwein-Ponndorf, 689 Reformatsky reaction on; 204 removal via dithio ketal, 507 selective hydrogenolysis, 6 5 8
746
Reaction Index
separation as semicarbazones, 465 with acetylenic alcohols, 575 with dimethylsulfonium methylide, 45 1 with diethylcyanomethylphosphorate, 3 86 with ethyl magnesium bromide, 540 with isopropyllithium, 525, 527 with lithio acetylides, 477 with methylenetriphenylphosphorane, 451,503 with methyl lithium, 374,404,428, 469, 471,483,491,503,527,530,542, 619 with methyl magnesium bromide, 392 with methyl magnesium iodide, 391,451, 458,459 with Raney nickel, 479 with sodium acetylide, 575 with sodium and isopropyl alcohol, 427 with sodium hexamethyldisilazane, 63 1 with triethylphosphonoacetate, 453 Ketonic cleavage, during work up, 649 pKeto nitriles, in tobbe condensation, 650 p-Keto sulfoxides, cyclization with iodine, 5 34 Kochi-Hunsdiecker reaction, 449 Kolbe electrolysis, 579, 586 Lactols, with m-ethoxyphenylmagnesium bromide, 621 Lactone esters, cyclization of, 656 Lactones, 53, 56,57, 75, 76, 312, 314, 31 7, 320, 322, 323, 325, 327-329. 344, 346, 514, 634 cleavage, 53, 56. 87, 308,414, 514 conversion to furan, 3 14 elimination, 650 epirnerization, 414 formylation, 329 hydride reduction, 77, 399,446 hydrolysis, 420,463, 579,595,634 hydroxy. dehydration of, 351 hydroxymethylenation, 46 1 inversion of C-0 linkage, 463 a-methylene, 326,327-330 reduction, 77, 621 reductive acetylation, 77 self-condensation, 167 with ethyldiazoacetate, 463 with hydrogen chloride, 6 10 with lithium aluminum salt of methylamine, 621 Lactonization, 399,650,685 of hydroxyamides, 621 of Thydroxy acids, 463 of keto acids, 372 specific of yhydroxy acids, 463 with aqueous acid, 4 14 Lanosterol transformations, 57 1 Lavandulybromide, 45 dehydrobromination of, 46 Wurtz Coupling of, 45 Lavandulylic acid, cyclization of, 49, 116 ethyl ester of, 45 Lavandulyl skeleton, 43 formation from, trans-chrysanthernic
acid, 34 prenylbromide, 45 Lead tetraacetate, cleavage of glycols, 592 ketone oxidations, 414 oxidation of a-ketols, 73 selective allylic oxidation, 92 selective cleavage of l.kdiols, 84 Leukart reaction, 311, 312 Liboredrus formosana. 140 Limonene, 88,89 addition of aluminum alkyls to, 131 conversion to menthatriene, 92 dihydrobromination, 97 hydroboration, 13 1, 257 oxidation, 92, 94, 108, 109, 110, 128, 130,131 photooxidation. 94, 111 tribromide, 97 Limonene epoxide, 73 chromatography over alumina of, 108 diacetate from, 109 hydration of, 137 isomerization with Lewis acids, 108 ring opening and contraction in, 74, 87, 96,108 Linalool, conversion to, geraniol, 201 hotrienol, 25 dehydration, 60 from a-acetyl-y-butyrolactone, 21 from citral, 21 from epoxide of geranyl iodide, 21 from a-pinene, 20 oxides of, 165 phosphate ester in biosynthetic pathway, 24 photooxidation, 25 pyrolysis, 6 1 reaction with, acidic reagents, 22, 165 NBS, 142 Linalool acetate, 22 allylic rearrangement in the preparation, 22 chromatography of, 10 conversion to myrcene, 10 pyrolysis of, 10 reaction with N-bromosuccinimide, 25 Lindlar catalyst, for selective reduction of triple bond, 30, 3 1 Lithium aluminum tri-t-butoxide in reductions, 704 Lithium dimethylcopper, alkylation of, alkynes, 206, 210 in 1,4 additions, 376, 543 reaction with, allylic acetate, 220 allylic chloride, 221 Lithium diphenylphosphide, in selective ether cleavage, 625 Lyratol, 39 formation from chrysanthemic acid, 34 Malonic esters, addition to bromides, 646 hvdrolvsis of. 473 Manganhse diohde, in the oxidation of allylic alcohol, 28, 31, 79, 81, 127, 156.575
Reaction Index Mannich bases, 695 in condensation, 114 Mannich condensation, 695 Mare pregnancy urine, isolation of (+) equilenin, 642 Medium ring sesquiterpenes, synthesis, 277282 Melaleucia species, 133 Mentha arvensis, var piperasceus, 136 Mentha-l,4-dien-7-al, 126 disproportionation of, 128 Mentha-1(7),8-dien-2-01,106, I 1 1 acetate of, 110 ethyl ether solvolysis, 114 Mentha-l,8-dien-l@ol, 129,130 derivatives of, 130 glycoside of, 130 Mentha spp., 120 Menth-1-ene, oxidation of, 108, 109,110, 111 photooxidation of, 94, 128 stereochemistry of 9-oxygenated, 131 Menth-l-en-9-01, 131 3,s-dinitrobenzoate of, 131 Menthofuran, 115,116, 120,122 photooxidation of, 123 Menthones. 116,126 dibromination of, 146 formylation of, 331 reduction of, 125 separation of, 125 Mercuric chloride, in cleavage of thio ethers, 26,536 Mercuric iodide, in decomposition of diazo compounds, 435 Mercuric oxide, in ether formation, 446, 449 Meerwein-Ponndorf reduction, selective, of ketones, 689 Mesitoylation, 440 Mesityl oxide, condensation with methyl vinyl ketone, 118 Mesylates, solvolytic rearrangement, 410 solvolytic ring cleavage, 425 Methanesulfonates. with sodium pchlorophenoxide, 397 solvolysis of, 400 Methanesulphonation, selective, of diols, 471 Methane sulphonyl chloride, rearrangement of hemi acetals, 572 Methoxy acetylene, condensation with ketone, 23 Methyl-anilinomethylenes, as blocking group a to a carbonyl, 658 2-Methylbut-3-en-2-01, in the synthesis of methylheptenone, 5 , 6 ttansesterification with ethylacetvacetate, 4 Methyl cyclopropyl ketones, 204, 213, 214 a-Methylenebutyrolactonemoiety, 326,
327-330
Methyl ethers, cleavage of, 685 hydrolysis of,653 selective saponification, 649
747
Methyl group functionalization, 572 6-Methylhept-S-en-2-one,5 acetal, 29 as precursor of,citral, 28 a-curcume, 242 ionones, 5 isobisabolene, 239 lavandulol, 47 linalool, 5 methyl geranate, 23 methyl nerolate, 23 pseudoionone, 6 vitamin A, 5 hydroboration-oxidation,146 reaction with acetylene, 28 Reformatsky reaction, 23 Methyl lithium, addition to, ketones, 48 a,O-unsaturated esters, 43 a,punsaturated ketones, 59 Methyllithium-titanium trichloride, as coupling agent, 561 Methylphenyl ether, cleavage of, 509 1,2-Methyl shifts, 594 Methylsulfinyl carbanion, in internal cyclization of tosylates, 522 Methyl vinylketone, condensation with, homoallytic chloride, 22 mesitvloxide. 118 Michael reaction,’397, 595,612 1,6-addition, 319,324. 325 of Bchloroethyl vinyl ketone, 71 7 of 0-ketosulfoxides, 536 of methyl 5-oxod-heptenoate, 710 of sodiumborohydride, 367 with cyclopentenones, 536 with ethylacrylate, 704 Microbiological dehydrogenation, 664, 665 Mitcham peppermint oil, 136,137 Moffatt oxidation, 351,352, 365 Monotosylation, of diols, 520 Monotropa hypopithys, 67 Myrcene, 10 as precursor in the synthesis of,geraniol,
17
linalool, 17 nerol. I7 @-pinine, I54 P-sinesal, 224, 225 a-terpineol, I7 oxidation, allylic, 224 ozonolysis, 225 Nagata method of, hydrocyanation, 311, 312,346,347,350 Neonepetalactone, 73 conversion from matatabiether, 80 Nepta catanh, 62,63 Nepetalactones, 6 9 optically active stereoisomers of, 70 Nickel carbonyl, carboxylation of acetylenes, 445 cyclization with, 272-274,561 Nickel peroxide, as oxidizing agent, 28 Nitrile groups, 407 epimerization, 3 11
748
Reaction Index
from aldehydes, 160 Grignard reaction, 160 hydrolysis, 78,386,407,420,462, 516,
543,615
introduction by Nagata method, 31 1, 312,
346,347,350
isomerization during hydrolysis, 50 reduction, 620,625,629 replacement with methoxyl, 604 selective reduction, 31 I Nitrite esters, photolysis of, 610 Noriridomyrmecin, see Boschina lactone
N.Oxides, 39, 40 Cope reaction, 39,40,419 [taris-Occidentalol, photolysis of, 309 Octalones, epoxidation, 522 with N-bromosuccinimide, 524 Olea europaea, 135 Olefins. 97, 147, 385, 433, 571, 664 addition of carbenes, 145,462 biomimetic cyclizations, 71 2, 71 3 cleavage, 465 cyclizations with iodine, 453 1 ,?-diacetates from, 168 Diels-Alder reaction, 462 directional effect in angular methylation,
687
epoaidation, 54, 101,127,365,413,422,
471
equilibrium in A “ dehydroequilenin ester,
652
from ketones, 296, 390, 392 hydration. 27. 309 hydroboration, 77,80, 356,404,481,
496,528,600,616
hydrobrornination, 420 hydrochlorination, 5 1 , 514 hydrogenation. 353,459,525,616,621,
646
isonirrization, 227,646,709. 710,71 2 phololytic, 491 mipation, 404,584,620 osmylation, 516 oxidation, 5 1 . 55. 86,208,358,383.458 o ~ o n o l y ~ i5s16 . photochemical addition, 530 iqonierization, 281, 327 oxidation, 258,344, 374,619 rearrangement. 361 rearrangement during hydrolysis, 652 reduction, 367,648 resistant 10 hydroboration, 621 role in angular methylation, 690 selective oxidation, 210 reduction, 496 Simmons-Smith reaction, 360 stereochemistry of photo addition, 532 terminal. by Wittig reaction, 404 bromination, 381,417.491 hydroboration, 391, 530,629 hydrogenation, 414 isomerization, 532 oxidation, 381,661 ozonolysis, 374
trisubstituted, stereospecific synthesis,
206,210, 214, 222
with Q keto-carbenes, 388 with osmium trtroxide, 417 Olive tree, 135 Oppenauer oxidation, 665,667,668,674,
689
Organocadmium Compounds, reaction with acid chloride, 32, 164 Origatiirm Vulgare, 96 Osmium tetroxide-periodate, in the cleavage of ally1 alcohol, 59 Oxalic acid, as dehydrating agent, 100 in enol ether cleavage, I20 Oxalylation, 509 Oxidation of, aerial, of 0-amyrin, 606 alcohols. 121.431. 586. 593.600.606. 6 14,’6 1 9,’631 ,’695 secondary, 359,374,404,423,463, .
.
I
.
468.469.471. 503.507.525
aldehydes, 31’2,431 allylic alcohols, 12, 79, 81, 107-109,127, I
,
128.147. 150.156. 210.577.619
allylic position, 75, 92,’108,’110,’127,
222, 264,322,414,417
amines, 39,40,312,419 benzylic position, 103,333 cyclic ethers, 446 cyclopropyl alcohol, 147 diols, 206,216, 391,540,579 selective, 84,538,590 enone to dienone, 322 cis, trans farnesol, 435 furans, 454 furfurylidenes, 689,699 hemiacetals, 61 0 homo allylic acetates, 471 hydrazones, 435,633 hydroxyacetates, 536,596 hydroxy ketal, 32 ketoaldehyde, 55 a-ketols, 73 ketones, 609 lactones, 87 longicamphenylol, 520 olean-1 2-ene, 604 oletins, 54,55, 86,206 P-patchoulene, 496 sclareol, 579,599 terminal olefins, 400,496,661 tetrahydrofurans, 268 tropolones, 144 a,&unsaturated aldehydes, 74, 139 &,&unsaturated ketones, 135, 141 Oxidation with, bismuth oxide, 540 N-bromosuccinimide and lead tetraacetate,
604
chromic acid, 629,646 chromium trioxide, 399, 583,616 Collin’s reagent, 634 2,3-dicNoro-5,6-dicyanobenzoquinone,
646
hydrogen peroxide, 582,605 hypoiodite, 649 Jones reagent, 360,409,442,463,525,621
Reaction Index
749
lead tetraacetate, 572 of cis to trans double bond, 281 man anese dioxide, 28,435,446, 575 of trans to cis double bond, 12 Idoffat reagent, 516 of diene to triene, 279 nickel peroxide, 28 of endocyclic to exocyclic double bond, Osmium tetroxide, 381,383,417,465, 327 592,601 oxidation of, p-carotene, 170 performic acid, 458 citronellol, 169 periodic acid, 582 p-cymene, 103 ruthenium tetroxide, 530,582 1,5-diene, 43 Sarrett's reagent, 107, 383 homodiene, 300 selenium dioxide, 381,435,584,586,602 trans-a-hymenthrene, 12 tristriphenylphosphine rhodium chloride, 6-ionol, 170 646 limonene, 94,111 Oxidative degradation, of (+)-a-terpineol,420 menth-l-ene. 128 Oximes, with nitrous acid, 604, 610 methyl farnesate, 220 reduction, 572 olefins, 374 0x0-carboxylic acids, cyclization, 658,660 or-pinene, 156 Ozonolysis, 579, 582, 586 a-terpinene, 133 of benzylidenes, 69, 540 terpinolene, 100 of cyclopropyl olefms, 57 2-thujene, 147 of 1,3-dienes, 146 verbenone, 156 of 2,4-dinitrophenylhydrazones,5 28 reaction, in the synthesis of P-amyrin, 602 of enol acetates, 55, 270,632 Photocitrals, A and B, 60, 275, 276 of enol ethers, 599 Reformatsky reaction on, 275 of geranyl acetate, 440 Photolysis of, p-amyrin, 606 of ketobenzylidenes, 682 cyclopropyl alcohol, 48 of terminal olefins, 374, 516 dienones, 410,414 of triene, selective, 225 1,l-diethoxyethylene, 540 of a,p-unsaturated ketone, 56 en01 acetates, 540 of vinyl ether, selective, 209 enones, 467 nitrite esters, 572, 573, 610 Palladium, in isomerization of olefins, 646 olefins, 361 Peppermint oil, 120 1 1-oxolanosterol, 572 Perilla frutescenes, 159, 160 a-santonin, 4 13 Petroselenium sativum, 91 tosylhydrazones, 393 a-Phellandrene, 89,90 Photolytic functionalitation, of C-I9 methperacid oxidation of, 136 yl, 572 0-Phellandrene, 89, 90 Photoperoxides, reduction with sodium sulPhenolic ethers, Birch reduction of, 664 fite, 43 Phenylurethane derivative, of ally1 alcohol, Pinacol rearrangement, 417, 516,621 Pinenes, summary of various reactions on, 90 pyrolysis of, 90 156 Phosphonium salts, vigorous hydrolysis of, Pinene oxide, 60 389 isomerization of, 156 Phosphorus tribromide, with alcohols, 363 a-Pinene, conversion to linalool, 20 Phosphorous ylids, coupling with allylic epoxide, reaction with acid, 60, 88 halides, 562 hydration of, 102 Photochemical, addition of, 3,3-dimethyllead tetraacetate oxidation, 156 cyclopentene, 542 oxidation, 51, 126, 127, 156 isobutylene, 475 Rins reaction on, 102 1-methyl-3-isopropyl cyclopentene, 532 photochemical conversion to cyclofenchene, olefins, stereochemistry of, 532 154 bromination of dibromide, 97 photoisomerizatiori, 9 cleavage of cyclopropyl ketone, 147 photo-oxidation, 156 cycloaddition, of acetylacetone, 425 pyrolysis, 8 of ethylene to a,p-unsaturated ketone, yradiolytic conversion to ocimene, 9 58 reaction with NBS, 156 of 2-methyl-] ,3-cyclopentane dione enol PPinene, 155 acetate, 426 acid treatment of, 89 in the synthesis of loganin acetate, 83 conversion to oleuropic acid, 135 cyclization of, citral, 60, 275 epoxide ring opening of, 126, 127 dia,p-unsaturated esters, 534 hydrochlorination of pyrosylate, 17 decarbonylation of thujone, 148 pyrolysis of, 8 isomerization, induced, 491 reaction with NBS. 156 of trans to cis decalin, 309 pinus lon@folia, 157
750
Reaction Index
Pinus longifolla. 54 Pinus silvestris. 93 Piperitenone, 107, 115, 116,118, 137, 158 diosphenolene from oxide of, 137 epoxide of, I I9 Piperitols, 115 cis and trans. I19 conversion to dl-menthone, 125 dehydration of, I 2 0 Piperitone,lll, 116,119, I20 as precursor of, menth-2-en-1-01, 95 menthane-l,3-diol, 136 diosphenol from, 136 hydroboration of, 136, 137 oxide of, 95, 136 reduction of, 119 Aquvria trinervia, Cav., 139 Polyisoprenoid chains, construction of, 204 Powdered soft glass, in pyrolysis, 648 Renyl halides, Grignard reactions of, 42, 161 in the synthesis of artemisia alcohol, 42 Wurtz coupling of, 42,45 Prim reaction, in the synthesis of, citral, 30 Pcyclolavandulal, 48 cyclolavandulols, 4 8 iridomyrmecin, 75 lavandulol, 4 7 lavandulyl acetate, 47 6-terpineol, 102 Propargyl bromides, in alkylation, 713 Ropionic acids, cyclization, 654 Pseudomoms spp., 128 Pulegenic acid, 72 conversion to iridodial, 73 pyrolysis of, 145 Pule 01 115, 120 deay&ation of, 122 Pulegone, 115,116, 119-121 as precursor in the synthesis of, transcarane, 157 iridodial, 72 isopulegone, 121 menthofuran, 122 epoxide, pyrolysis of, 142 Favorskii rearrangement, 72, 145 imidazoline derivative, 157 lead tetraacetate oxidation, 122 mercuric acetate oxidation, 122 reduction of, 122 sultone of, 122 Pummerer's rearrangement, 536 Pyrazolines, cleavage of, 387 irradiation of, 387 ring contraction in, 384 Pyridine, as dehydrochlorinating agent, 47 as dehydroiodinating agent, 86 Pyridine hydrobromide perbromide, 668 PyroUidenes, in Torgov reaction, 703 Pyrolysis, ofacetates, 10.48, 96, 101, 127, 383,485,496 of acetoxy ketones, 122 of y-aldehydo acids, 70,7 1, 73 of allyl acetate, 10 of allyl alcohol nitrobenzoate, 12
of p a m y M , 609
of benzoates, 414 of carbonate esters, 41 1 of carboxylic lead salts, 682 of diacetates, 109, 130 of 1,6-diene, 61 of 1,3-diol rnonacetate, 4 8 of ester of alcohols, 151 of homoallylic alcohol, 27,101 of patchouli alcohol acetate, 492 of phenylurethane derivative, 90 of a-pinene, 8 of p-pinene, 8 of spirolactones, 391 of sultones, 122 of tricyclic formates, 51 1 of a,&unsaturated ketone, 121 of vinyl ethers, 393 ring contraction during, 96 Pyrolytic rearrangement, 566 Pyrophosphates, conversion by yeast subcellular particles, 635 Racemates, of estrone, 679 Raney Nickel, for desulfurization, 82-84 reduction of, cresolic acid methyl ester, 121 dienol, selective, 100 with n-butyl thioesters, 463 Raspberries, oil of, 94 Rearrangement, during oxidation of allyl alcohol, 147 of allyl esters t h o u enolates, 44 of allyl sulfoniurn y 'ds, 41 with lithium-ethylenediamine, 105 Reduction, Bouveault-Blanc, 646 Huang-Midon reaction, 456 microbiological, 704, 710 novel, of a conjugated olefin, 669 of acetylenes, 5, 30, 39,477 of acid chlorides, 350 of aldehydes, 442,629 of aldehydo ester, 209 of allylic alcohol, 14 of allylic chlorides, 532 of arnides, 36, 39,40 of benzofuran system, 265 of benzylic alcohol, 251,265 of benzylidines, 540 of bicycloketones, 154,156 of cresolic acid methyl ether, 121 of cyano esters, 78 of cyclobutenones, 540 of pcyclocitral, 393 of cyclopropyl ketone, 214 of dienes. 5 11 of dienol, selective, 100 of diesters, 462 of enediones, 575 of enol ethers, 369 of enones, 361,422,463,474 of epoxides, 101, 211,359,451,471 of a,&epoxy ketones, 136 of esters, 32, 59, 363, 365, 397,489 of geminal diesters, 273
P
Reaction Index of hydroperoxides, 6 19 of a-hydroxyketone, 278 of hydroxymethylene, 532 of imines, 620 of immonium salts, 406 of p-keto acids, 399 of 11-keto compounds, 573 of 0-keto esters, 473 of ketones, 69, 356, 360,407,410,419, 427,442,514,536,569,616 of lactones, 308,446,621 of methyl (+kamphene carboxylate, 516 of nitriles, 615,620,625,629 of serratenedione, 590 of tetrahydrofuranones, 536 of thioethers, 536 of thioketals. 482 of tosylates, 381, 399 of a,p-unsaturated aldehydes, 80, 112, 125, 163,389 of a,@-unsaturatedcyanoesters, 420 of a,p-unsaturated epoxides, 13 of +unsaturated esters, 79, 204, 207, 208.473 of a > & a t u r a t e d ketones, 26,119, 269, 270.582 with amalgamated aluminum, 104,536 with amalgamated sodium, 140,648 with did-butyl aluminum hydride, 615, 625
withhydride-aluminum chloride, 431, 435,440 with isourowl lithium. 525. 527 with lithium-aluminum hyhide, 13, 32, 36, 39,40, 80, 154, 156, 573, 577, 586,595,599,604,615,616,634 with lithium aluminum tri-t-butoxide, 39, 704 with lithium diethoxy aluminohydride, 36 I with metal-amine, 105,474,609 with metal-ammonia, 84,98, 120, 123, 147,374,383,384,469,582,593, 599,605,689,695.697.699 with Raney nickel, 82-84, 100, 121,479, 6 86
withsodium borohydride, 69, 80,367, 586,621,628,665 with sodium-alcohol, 113, 528. 579 Reductive alkylation, definition;612 of cyclopropyl ketones, 629 of enones, 629,630 internal, of ebromoketones, 499 of unsaturated oxoacids, 659 promoting effect of alcohols, 631 Reductive dechlorination, with lithium in ethylamine, 609 Reductive elimination, with zinc and acetic acid, 568 Refonnatsky reaction, 23, 247, 275, 276, 313,314,449,508,509,646,648, 654.675.685 Relav svnthesis. of a-bulnesene. 41 0 ~esoiutloonof optical isomers, 5’07,579, 582,589,649,666,703,704,705, 709,710
751
Retroaldol reaction, 629 of acetoxy dienones, 666 vinylogous, 31 5 Rigid ring system, 610 Ring annelation, with acrolein, 417 effect of potassium hydroxide-pyrolidine on, 363 of keto aldehydes, 366 Ring closure, by intramolecular alkylation, 521 Ring contraction, benzylidene intermediate in, 696 during pyrolysis, 96 of pyrazolines, 384, 387 of six-membered carbonium ions, 41 to cyclopentanone, 662 Ring expansion, of bicyclo [4,1,0] system, 143 by solvolysis of tosylates, 520 with diazomethane, 141,428 with ethyl diazoacetate, 397 Ring, fusion, on to camphene, 542 Ring-opening of, lactones, 56 Robinson annelation, 521, 714 of 2,3-dimethyl cyclohexanone, 369 side products in, 464 with (-) dihydrocarvone, 353 with 1,4-dimethoxy-2-butanone, 359 with Mannich bases, 376 with 2-methyl cyclohexane-1,3-dione, 695 with trans-3-pent-2-one, 363, 365, 368 with vinylketones, 371, 615 Rose oil, 129, 159 Rupe rearrangement, 350,35 1 Ruthenium tetroxide, in the cleavage of lactones, 87 Sabinene, peracid oxidation of, 134 pyrolysis of, 89 Sabinol, acetate of, 148 Birch reduction of, 147 trans-cis conversion, 147 Sacchmmyces uvarum, 704 Safranal, 138 ethoxy, 139 reduction of, 139 Salvia species, 148 Santolinyl skeleton, 36 formation from, artemesyl skeleton, 37 trans chrysanthemic acid, 34 yomogi alcohol epoxide, 38 members of, 36 Santonin, 265, 267, 268, 277, 315 aromatization of. 308 epimerization of’a to epi-a, 287, 305 hydroxyanalog, see Artemisin oxime of, 308 reduction of, 271, 279 in the synthesis of sesquiterpenes, 316 tetrahydro, 267 Sarett reagent, in allylic oxidation, 108 Selenium dioxide, 75,435, 584,602 Semicarbazone formation, 674 Serini reaction, 601 Seseli indicum, 4 8
752
Reaction Index
Sesquiterpene quinone, see Perezone Sigmatropic rearrangement, 41 of allylic sulphonium ylids, 562 Silver nitrate, use in, chromatography, 568 dethioketalization, 26 Silver oxide, in the oxidation of a,p-unsaturated aldehyde, 74 Simmons-Smith methylenation, 360, 379, 392,427,614,625 Sodium acetylide, 575 Sodium r-amylate, in cyclopropyl ester formation, 53 Sodium hydride, in the rearrangement of ally1 esters, 45 Sodium sulfite, in the reduction of photoperoxides, 43 Solvolytic rearrangement, of tosylates, 402. 592 Sommelet reaction, 15 1 Spiro 1431 decadienones, 514 hydrogenation of, 5 14 Spiro [4,5] decalenes, acid catalysed rearrangement, 514 Spiro 14,s 1 decanes, cyclization, 508 hydrogenation, 468 Spiro-epoxides, with boron trifluoride, 616 Spiro lactones, 477 pyrolysis, 391 Squalenes, 561 cyclization, 566 degradation, 561 epoxidation, 566 stepwise synthesis, 562 Stannic chloride-nitromethane, in cyclizations, 604 Steric interferance of axial hydrogens, 659 Stereochemistry. of pentacylic triterpenes, 610 Stobbe reaction of, 655 dimethyl succinate, 653 P-keto esters, 649 Crketo nitriles. 650 Structure elucidation, of patchouli alcohol, 492494 of tarhxerol, 605 Strychnos nux Vomica, 65, 81 Sulphur trioxide-pyridine complex, in hydrogenolysis of allylic alcohols, 431 Sulfur ylid, attachment of enzyme to, 36 rearrangement of, 37 Tagetes glandulifera, 30 Tageres spp (compositae), 30 Tagetone, 30 cis-trans conversion, 31 Tea trees, 133 Telomerization, of isoprene, 23 Terminal alcohols, dehydration of,464 Terminal olefin, isomerization of, 373 1,4 Terpin, 100, 131, 133 cis, 133 hydrate method, 93 solubility in water, 133 a-Terpinene, 88 photooxidation of, 133
a-Terpineol, 17, 102 esters of, 102 hydroboration of, 134 trans-0-Terpineol, 94, 96 ozonolysis-dehydration of, 236 YTerpineol, 94, 96, 97 acetate of, 9 7 separation from a-Terpineol, 96 Terpinolene, autooxidation of, 132 epoxide of, 100 photooxidation of, 100 from pyrolysis of terpinyl acetate, 101 7-Terpinyl acetate, 9 7 pyrolysis of, 101 Tetrahydrofurans, 300, 302, 303 hydrolytic cleavage, 536 oxidation, 268, 269 reduction, 536 Tetralones, annelation with vinyl ketones, 625,626 Tetramethylbicyclo [ 3,l ,O]-hexan-2-one, 50 Beckman reaction on oxime of. 5 0 Thermal rearrangement, of acetoxy epoxides, 502 Thioethers, reduction. 536 Thioketal anion. coupling with bromomethylbutadiene, 26 Thioketals, 368, 481 desulphurization, 600 reduction, 368,481 Thiols, acid hydrolysis, 468 Thiourea clathrates, in separation of epoxides, 568 Thorpe condensation, 650 Thujaplicins, Q and p, occurrence, 143 Thuja species, 140 n u j a standishii, 143 Thujene, acid treatment of, 89 hydroboration of, 147 photochemical oxidation of, 147 Thujic acid, 140 p-bromophenacyl ester of, 140 dihydro, 140 n.m.r. spectrum of, 140 reduction of, 140 Thujone, 14 7 photochemical decarbonylation of, 148 reaction with acid, 60 reduction of, 147 Thymol, 104, I 1 7 catalytic reduction of, 124, 125 methyl ether, Birch reduction of, 120 reduced products from, 115 Todomatuic acid, 253,255, 256 diasteromer of, 256 methyl ester, 253, 256 stereochemistry of, 256 P-Toluenesulfonylhydrazine, reaction with iodoepoxide, 21 gToluenesulfonylhydrazones, with n-butyl lithium, 433 with copper-sodium hydride, 434 photochemical decomposition, 393,434 pyrolysis, 434 Torgov reaction, mechanism of, 702
Reaction Index pyrollidenes, 703 Torsional strain in ring junctions, 659 Tosylates, cyclization of, 503 Grob fragmentation, 478 intramolecular alkylation, 500,632 internal cyclization, 528 pinacol rearrangement, 41 7 replacement with cyanide, 407 replacement with iodide, 449 solvolytic rearrangement, 404,406,407 reduction, 381, 399 Tosylation, 446,528 of secondary alcohols, 503,522 selective of diols, 417,462,478 Transesterification, with ethanol, 440 Triallyl orthoformate, with enones, 628 Tricyclic enones, solvolytic rearrangement of, 467 Tricyclic formates, pyrolysis of, 5 11 Trienes, equilibrium in acid, 595 selective hydroboration, 44 2 Triethylammonium benzoate, in aldolization, 695 Triols, oxidation, 530 selective acetylation, 536 Trimethylsilylethers, in preparative gas liquid chromatography, 568 Tristriphenyl phosphinechlororhodium, in the oxidation of menthene, 111 in selective hydrogenation Triton B, in alkylations, 698,699 Trityl chloride, as alcoholic protecting group, 221 Troponoid system, 276, 277 Turpentine, hydration of, 102 6 ,eUnsaturated acids, cyclization, 543 oJ-Unsaturated acid chlorides, Grignard reaction on, 112 a,P-Unsaturated aldehydes, 28, 29 addition to vinyl ether, 75 Grignard addition with prenylhalides, 42 methyl lithium addition to, 468 oxidation with, selenium dioxide, 139 silver oxide, 74,300 reaction with p-toluenesulfonylhydrazine, 373 reduction of, 80, 112, 125, 163,389 reduction, selective, 85 Wittig reaction on, 1 1,43 a,-P,y,fi-Unsaturated aldehydes, 139 Grignard addition, 30 reduction of, 40 @-Unsaturated cyano esters, reduction of, 4 20 a,PUnsaturated epoxides, reduction of, 13 a,@Unsaturated esters, 11, 204, 221, 262 hydrogenation, 372 hydrolysis, 57 methyllithium addition to, 43 photocyclization of, 534 reaction with ally1 sulfone, 54 rearrannement throueh enolates. 45 reduction, 79, 204, 507, 208,431,435, 440,453,473
753
separation from &?by chromatography, 588 a,O-y,6-Unsaturated esters, hydrogenation, 5 09 &$-Unsaturated ketones, 306, 350, 605 addition to vinyl magnesium bromide, 32 alkylation, 575, 582, 599, 709 bromination, 141, 317, 320 cyclopropane ring formation from, 158 deconjugation of, 293,294 Diels- Alder addition to 1,3-diene, 15 1 Diels-Alder reaction with, 89, 335 dienes from, 300 dienones from, 322, 325 epoxidation of, 95,107,137 Grignard reaction, 95 Grignard reaction, 1,4-addition, 86, 114 hydroboration, 136 hydrocyanation, 295 hydrogenation, 69, 295,661 ketalization of, 112, 135, 290 metal-ammonia reduction, 269, 296, 298, 3 34 methyl lithium addition to, 59 oxidation of, 135 ozonolvsis of. 56 photo addition to ethylene, 58 pyrolysis of, 121 reduction, 26, 113, 118, 119, 146, 156 sultones from, 122 synthesis by Rupe rearrangement, 350 thioketalization, 289, 292 Wittig reaction, 90 P,-pUnsaturated ketones, alkylation, 620, 709 reduction, 575,582 Unsaturated lactones, in strong base, 584 a,@Unsaturated 0x0 acids, reductive alkylation, 660 qp-Unsaturated nitriles, conjugate addition to, 543 Valencia orange oil, 129, 131, 136 Verbena officinalis, 67 Verbenone, 137 conversion to cis-verbenol, 156 photochemical oxidation of, 156 from pinenes, 156 Vilsmeiers reagent, with enol ethers, 406 Vinyl acetate, Diels-Alder addition to, 1,3dienes, 150 Vinyl carbinols, anionotropic rearrangement, 698 oxidation, 697 stabilization as isothiuronium acetates, 702 Vinyl chlorides, hydrolysis of, 709 Vinyl ethers, addition to, acetals, 28, 29, 52 a,p-unsaturated aldehyde, 75 Claisen rearrangement, 565 pyrolytic rearrangement, 393 reaction with ally1 alcohol, 112 rearrangement, 361 Vinyl ketones, in Robinson annelations, 695
754
Reaction Index
Vinyl magnesium bromide, addition to ketone. 92 1,4-addition to @-unsaturated ketone, 32 Wagner-Meerwein rearrangement, 403,492 in camphene. 153 in cr-pinene, 153 Wharton reaction, 21, 165 Wittig reaction, 503, 586,616, 649 epimerization during, 336 methylenation, 366, 476 selective, 365 modified, 207, 208 of 3-acyl furan, 164 of aldehydes, 417,440,449,491,634 of aldehydo ketal, 32 of aromatic ketones, 104 of cyclopentenones, 496 of a-cyclopropyl ketones, 147, 148 of diene aldehyde, 11 of enones, 520 of geranyl acetate, 562 of hindered ketones, 451 of p-keto esters, 45 of ketones, 59, 76, 89, 104,418,453, 514 of methyl heptenones, 435 of sodium salt of keto acids, 516 of 3-substituted furans. 164 of tricycloekasantal, 489 ofa,b-unsaturated aldehydes, 11,43 of y.6-unsaturated aldehydes, 206, 231, 272 of a.6-unsaturated ketones, 90 stereochemical control, 562 to give terminal olefins, 392,404
with acetylmethylenetriphenylphosphorane, 463 with (carbethoxyethylidine) triphenylohosphorane. 489.491 with’ ethilidinetnphenylphosphorane, 404,490,520 with isopropylidenetriphenylphosphorane, 566 with methylenetriphenylphosphorane, 478,514,532 with methoxymethylenetriphenylphosphorane, 409,465 with triethylphosphonoacetate,534 Wolf-Kishner reduction, 312, 360, 374, 569, S75,S90,592,S93,609,620.625,689 forcing conditions, 605 of aldehydes, 365 of acyloins, 383 of enones, 381 of imines, 6 15 of ketones, selective, 690 of todomatuic acid, 254 Wurtz coupling, in the synthesis of 1,sdienes, 4 3 of lavandulyl bromide, 45 of prenyl halides, 42 Yomogi alcohol, 34.42 conversion to santolinatriene, 38 epoxides. 37.43 formation from chrysanthemic acid, 35 oxidation of, 42
ZonthoxIium rhetsa, 134 Zieria Smithii, 144
