Volume 2 the total synthesis of natural products

THE TOTAL SYNTHESIS OF NATURAL PRODUCTS Total Synthesis Of Natural Products, Volume 2 Edited by John Apsimon Copyright © 1973, by John Wiley & Sons, Inc.. Total Synthesis Of Natural Pro

THE TOTAL SYNTHESIS

OF NATURAL PRODUCTS

Total Synthesis Of Natural Products, Volume 2

Edited by John Apsimon Copyright © 1973, by John Wiley & Sons, Inc

Total Synthesis Of Natural Products, Volume 2

Edited by John Apsimon Copyright © 1973, by John Wiley & Sons, Inc

The Total Synthesis

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 11s to 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 I Title

ISBN 0-471-03252-2 (V.2)

Printed in the United States of America

10 9 8

Contributors

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 ever- developing 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

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 view- point and as such have added more to our overall knowledge of the syn- thetic process

A third volume in this series will consider diterpenes and various alka- loids, 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

The Synthesis of Triterpenes

J W APSIMON AND J W HOOPER

Naturally Occurring Aromatic Steroids

THE TOTAL SYNTHESIS

THE SYNTHESIS OF MONOTERPENES

Substances Derived from Chrysanthemic Acid

B The Artemisyl Skeleton

C The Lavandulyl Skeleton

Total Synthesis Of Natural Products, Volume 2

Edited by John Apsimon Copyright © 1973, by John Wiley & Sons, Inc

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 themselves 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

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

On the whole, t h e r e are t h r e e r e a s o n s for s y n t h e s i s The

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 race- mate, b u t t h e c o r r e c t o p t i c a l antipode, 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 of 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 implies 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 least 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 products, no matter 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

t i m e t o t i m e , and which might be c a l l e d t h e "building 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 use a s an i n t e l l e c t u a l ex- ercise (such syntheses 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 For t h i s reason, such syntheses have been included i n t h i s chapter 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)

Many of t h e uses of

There i s a f o u r t h type of s y n t h e s i s t h a t appears from

2 THE TELOMERIZATION OF ISOPRENE

The ready a v a i l a b i l i t y of isoprene 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 involving t h e a d d i t i o n of halogen a c i d s (see, f o r exam-

p l e , t h e next s e c t i o n on methylheptenone) are described else- where i n t h i s chapter, 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 dimeriza-

t i o n t o dipentene 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 dimerization and simul- taneous hydroxylation of isoprene, and considerable 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 Synthesis of Monoterpenes

Estonia and Japan The mixtures obtained are of considerable 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 journals

t h a t a r e d i f f i c u l t t o o b t a i n , including a review of t h e t e l o - merization using 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 fraction

can contain a s much a s 45% of geranyl chloride.**

a c i d t e l o m e r i z a t i o n of isoprene g i v e s a-terpinene and a l l o -

ocimene a s t h e main C10 hydrocarbons, together with geraniol

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 phos- phoric 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 , lavandulol, 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 reac-

t i o n s of isoprene t h a t lead t o mixtures containing 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 with magnesium i n t h e presence of L e w i s a c i d s , and t h e complex t h u s obtained g i v e s adducts with aldehydes b u t again only a s mixtures.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 , passing oxygen through t h e mix-

t u r e g i v i n g then 30 t o 40% of C10 alcohols and 30% of C10

g l y c o l s Although t h e a l c o h o l s include 10% each of 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 products.8

c i t r a l and i t s d e r i v a t i v e s I n view of i t s key p o s i t i o n , it 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 take i n t o ac- count 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 under-

go c y c l i z a t i o n s t o hydrogenated xylenes and tetrahydropyrans,

f o r example, during t h e decomposition of i t s semicarbazone by acid

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 electro-

6-Methylhepg-5-en-2-one 5

obtained undergoes t h e Carrol r e a c t i o n , 1 2 r e s u l t i n g i n a €3- ketoacid through a r e a c t i o n akin t o t h e Claisen rearrange- ment,13 and t h i s ketoacid then l o s e s carbon dioxide under t h e

r e a c t i o n conditions t o y i e l d t h e product (2) An e a r l i e r tech- nique f o r t h i s type of r e a c t i o n consisted i n mixing t h e alcohol with diketene;13 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

A f u r t h e r v a r i a n t uses condensation of t h e a l l y 1 alcohol (3)

with an acylmalonic ester (4) a t 130-200°, when alcohol and carbon dioxide 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 type of procedure forms t h e b a s i s of one of the 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 intermediate f o r syntheses of l i n a l o o l ( g ) , t h e ionones (z), and vitamin A , and which is i l l u s t r a t e d i n Scheme

1 l6

Scheme 1

CH3 / L \ OH

6 The Synthesis of Monoterpenes

The thermal rearran ement of ally1 ethers was described

Marbet synthesized methylheptenone from 2-methylbut-3-en-2-01

(2) and ethyl isopropenyl ether (8) : l a

TsH, 14 hr r e f l u x in high bp ligroin; or

H3P04 1 1/2 hr at 125'

3

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 standard ketone s y n t h e s i s from a function-

a l i z e d isoprene is mentioned here 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 isoprene (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 is n o t c a r r i e d through t o c0mp1etion.l~

normal conditions of a d d i t i o n , however, using an excess of

a c i d , t h e main product i s t h e primary c h l o r i d e (2) For example, one mole of isoprene and two t o t h r e e moles of con-

(2) .22

r i d e (2) i s a l s o reported i n a Russian p a t e n t 2 3

Under t h e

Formation of t h e primary c h l o r i d e is a l s o favored by

Direct condensation of acetone with t h e primary chlo-

CH~COCHCO~CZH 5

8 The S y n t h e s i s of Monoterpenes

4 Z16-D1METHYL0CTANE DERIVATIVES

A Hydrocarbons

Myrcene, Ocimene, and Alloocimene

B o t h myrcene (12) and ocimene (&, cis and e, 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

r e a d y t r a n s f o r m a t i o n t o t h e n o n - n a t u r a l l y o c c u r r i n g allo- ocimene (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

plant 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

only cis-ocimene (a) a f t e r s h o r t r e a c t i o n times, b u t with longer periods 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- ously contaminated with dipentene ,32 a s i s t h e case with

t h e pyrol 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 some- what 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 -

a c t i o n of dipentene (g), t h a t gives a 13% y i e l d of p-mentha-

1 0 The Synthesis of Monoterpenes

T o t a l s y n t h e s i s of both myrcene (2) and ocimene (2) gen-

e r a l l y involves p y r o l y s i s of a s u i t a b l e alcohol 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 methyl- heptenone.35 Linalool i t s e l f (6) h a s been known for some

y e a r s t o cjive myrcene (12) by treatment with i o d i n e a t 140- 150', 36

l o s s of a c e t i c a c i d o c c u r s over Chromosorb P* a t temperatures

a s l o w a s 140", t o give the following amounts of t h e d i f f e r e n t

on Chromosorb-W, on which i t i s stable up t o 200'

'This technique, developed by Ohloff4' h a s r e c e n t l y been re- examined by Bhati both f o r alcohol dehydration and isomeriza-

t 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

carbethoxy-5-formyl butanoate (23) It starts with ethyl and follows Scheme 2- 2

Scheme 2 C02C2H5

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 mix-

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

lated from A c h i l l a filipendulina by Dembitskii et a1.45r46

and the first time the substance was certainly isolated is by

dimethylocta-l,3 I 7-triene (2) , the (6.5) -configuration of the

positively rotating isomer of this substance having been

established previously by correlation with (-)-trans-

pinane 5 0 r 5 1

in benzene and a catalytic amount of p-toluenesulfonic acid

shown in Scheme 3, which also gives the synthesis of natural

Early syntheses of "B-hymentherene" were unsuccessfu147~48

Heating this triene ("trans-a-hymentherene," (25)

2,6-Dimethyloctane Derivatives 13

A- OI

trans (aD - 3")

Achillene 27a

-

B (OH) 3

I

Ho CH3

achillene (27a) that Schulte-Elte achieved from cis-8-hymen-

(26a) 49

cently as a natural product,52 but the rotation does not agree with Schulte-Elte' s synthetic material 4 9

Achillenol [the alcohol obtained immediately before

Cosmene

The only natural monoterpene tetraene is cosmene, 2,6-dimethyl-

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

evidence for the trisubstituted ethylene is not so certain, in

3,7-Dimethyloct-6-en-l-o1 is one of the most widely distributed

acetate It occurs naturally in both ( + ) - and (-)-forms, al-

most always as the 8-form (i.e., isopropylidene, e.g., s),

2,6-Dimethyloctane Derivatives 15

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

"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

author's opinion that the name should no longer be used at all, and all references be made to citronellol, a-citronellol

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 2,6-

oxidizing51 (the presence of zinc isopropoxide being bene- ficia16')

Another synthesis is important as an illustration of the

16 The S y n t h e s i s of Monoterpenes

use of N-lithioethylenediamine t o d i s p l a c e double bonds This

reagent i s mentioned below i n s i m i l a r connections, 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 dihydrogeraniol

(2) , made from 6-methylheptan-2-one (2) v i a a Reformatsky

All the syntheses of c i t r o n e l l o l from geraniol r e s u l t , of

course, i n t h e racemate, while t h e most important 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 with 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 the 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 value 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 given 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 chemistry

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 oc- cupy in the monoterpene field make a knowledge of their syn- thesis 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 meth- ods 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

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)

5-10%

35

-

18

2,6-Dimethyloctane Derivatives 2 1

I n c e r t a i n regions, notably I n d i a , t h e supply of c i t r a l

(41) is s u f f i c i e n t (from lemongrass) t o make up t h e lack of

l i n a l o o l from t h i s source Thus epoxidation of c i t r a l with

a l k a l i n e hydrogen peroxide followed by treatment of t h e 1 , 2 -

epoxide (f?l) with hydrazine hydrate ( 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

C i t r a l 41 - 42 - 6

A r e l a t e d method uses t h e epoxide (44) of geranyl i o d i d e

(431, which, on treatment with p-toluenesulfonylhydrazine and calcium carbonate i n dimethylsulfoxide, g i v e s a q u a n t i t a t i v e

c h l o r i c a c i d , then methylated with a Grignard r e a c t i o n t o t h e

t e r t i a r y alcohol (47) Dehydration of t h e l a t t e r with 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

t 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 ~ ~ [ t h i o n y l c h l o r i d e , f o r i n s t a n c e , g i v e s o n l y g e r a n y l c h l o r i d e

( 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 so), 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 are

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 mix-

t u r e of methyl g e r a n a t e (%) and methyl n e r o l a t e (=), from

2,6-Dimethyloctane Derivatives 23

t h e Refomatsky reaction7' t o t h e use of dimethoxycarbonyl- methyl phosphonate , 8 o b u t a l l t h e s e a r e standard s y n t h e t i c techniques, t h e d e t a i l of which need n o t be described here 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 type of approach is

t h a t of Weedon's l a b o r a t o r y , s i n c e they confirmed t h e geometry

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 converting 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 acid i n the 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 , dipentene

(18), and terpinolene (z) are obtained 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 (z), n e r o l (221, and a-

t e r p i n e o l (2) a2

t e r p e n e s than 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 geranyl phosphate t o l i n a l y l phos-

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 Prelog and Watanabe 0 7

a c i d i n acetone, y i e l d s R-hotrienol (55) .91 The route f o l - lowed by Nakatani e t a l a l s o s t a r t s from R-linalyl a c e t a t e

(s), r e a c t i o n of N-bromosuccinimide on which gives a mix-

ture of t h r e e bromacetates =, =, and =, from which hydro- gen bromide can be remved by d i e t h y l a n i l i n e , leading t o the

a c e t a t e (57) of t h e R-isomer, from which the alcohol (55) can

be obtained by conventional hydrolysis 09

while t h e R-enantiomorph has

26 The Synthesis of Monoterpenes

2-Methyl-6-methyleneocta-2,7-diene-4-01 (62) and 2-Methyl-6- methylene-oct-7-en-4-01 (63)

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 synthesized by Reece e t a l 9 3

gested by Corey and S e e b a ~ h ? ~ ~ ~ ~ and c o n s i s t e d i n coupling bromomethylbutadiene (z)96 with t h e t h i o k e t a l anion (2, o r

i t s dihydro-compound) The t h i o k e t a l (60) thereby obtained was converted t o t h e ketone (61) with s i l v e r n i t r a t e , o r , i n the case of t h e dihydro-compound, with mercuric c h l o r i d e - cadmium carbonate The ketones were t h e n reduced t o t h e corre- sponding a l c o h o l s with sodium borohydride

The i n i t i a l r e a c t i o n followed a procedure sug-

The aldehyde c i t r o n e l l a 1 (65) i s again a widely o c c u r r i n g

n a t u r a l product, and can be made by conventional o r g a n i c tech- niques from t h e corresponding a l c o h o l , c i t r o n e l l o l (see above),

o r by reduction of 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)9Yf98 y i e l d s t h e

2,6-Dimethyloctane Derivatives 27

valuable hydroxycitronellal* (66) t h a t i s n o t , however, r e - ported a s being n a t u r a l l y occurring A study of t h e dehydra-

t i o n of hydroxycitronellal t o a mixture of a- (67) and 6-

c i t r o n e l l a l s has been published by Eschinazi 57-Since c i t r o -

n e l l a l can be made by p y r o l y s i s of isopulegol (64) , q 9 r 1 0 0 any

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 the two pos-

s i b l e isomeric forms, c i t r a l a (=geranial, e) and c i t r a l b ( = n e r a l , z) The two isomers have been well 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 mix-

t 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 pre- dominating 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 isomerization 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 higher temperatures and under t h e

*The conditions necessary f o r high conversion t o t h e hydrate have been examined by s e v e r a l authors ( s e e , e g , Ref 9 8 )

2 8 The Synthesis of Monoterpenes

influence 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 , then steam d i s t i l l i n g , i s reportedlb4 t o give 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 6 th 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 O6

Oxidation of geraniol o r nerol 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 highly dependent on t h e sample of manganese dioxide 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 possible t o oxidize geranyl bromide (691, o b t a i n a b l e from

l i n a l o o l (6) with hydrogen bromide a t -5" (see above), with

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

41

-

69

-

There a r e many o t h e r ways of synthesizing c i t r a l from

methylheptenone, and only a b r i e f survey w i l l be given here

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 terpene syntheses One type involves 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 ap- peared.l1°

thus obtained (z)t l e a d s t o c i t r a l l 1 l Another method of adding a two-carbon u n i t d i r e c t l y t o methylheptenone repre-

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 pre- viously The product of t h e r e a c t i o n between methylheptenone and acetylene (dehydrolinalool, 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 cyclizations (see, e.g., p-isopropenyl-

cessive additions of one carbon, first by formation of the

cumbersome If one-carbon units must be added, then it would

of the use of the Prins reaction by Suga and Watanabe, when

the reaction of formaldehyde in acetate anhydride with 2,6- dimethylhepta-l,S-diene (76) l 6

Prins reaction in the case of these open chain olefins leads

to complex mixtures that are not always easy to separate and

Generally speaking, the

30 The Synthesis of Monoterpenes

(77) from 200 g of the diene [z), and from this, by h drolysis

Ta ye tones

T a g e t e s g l a n ~ i u l i f e r a ~ ~ ~ and other Tagetes spp

been synthesized by Boehm, Thaller, and Whiting,’18 and by

a1.120,121 and by the same French authors.l19

(compositae) ,

Di-

P

The main substance i n Tagetes g l a n d u l i f e r a is cis-

tagetone (=), although small amounts of t h e trans-isomer

(z) occur, and it i s the l a t t e r t h a t Boehm e t a l synthe-

s 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 the 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 reaction of i s o b u t y l bromide with the 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 cata-

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 dioxiae The l a s t s t e p did 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 con-

sists i n again making t h e carbon skeleton by an organometallic

r e a c t i o n on a 3-methylhexyl oxygenated compound They pre- pared 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 chloride (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 dihydrotage- tone121 a r e shown i n Scheme 7

( C U I )

0

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),