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Studies related to the synthesis of eremophilane sesquiterpenes concerning the structure of eremophilene Keziere, Robert John 1968

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STUDIES RELATED TO THE SYNTHESIS OF EREMOPHIIANE SESQUITERPENES. CONCERNING THE STRUCTURE OF EREMOPHILENE.  BY  ROBERT JOHN KEZIERE  B.Sc,  University  o f B r i t i s h Columbia, 1966  A THESIS SUBMITTED IN PARTIAL FULFILMENT OF THE  REQUIREMENTS FOR THE DEGREE OF MASTER OF SCIENCE  i n t h e Department of Chemistry  We accept t h i s required  THE  t h e s i s as conforming  t o the  standard  UNIVERSITY OF BRITISH COLUMBIA December, 1968  In p r e s e n t i n g an a d v a n c e d the  this  degree  Library shall  I further for  agree  scholarly  by  his  of  this  written  thesis  in p a r t i a l  fulfilment  of  at  University  of  Columbia,  the  make  that  it  permission  purposes  may be  representatives. thesis  for  It  for  of  L - V N ^ O T ^ <•<  The U n i v e r s i t y o f B r i t i s h V a n c o u v e r 8, Canada  2- "5 ^ oc&»JL  Columbia  (1 ;  ]  by  the  understood  gain  for  extensive  granted  is  financial  available  permission.  Department  Date  freely  British  shall  Head o f  be  requirements  reference copying  that  not  the  of  I agree and this  or  that  Study. thesis  my D e p a r t m e n t  copying  for  or  publication  allowed without  my  (ii)  •  - ABSTRACT  The n a t u r a l l y o c c u r r i n g s e s q u i t e r p e n e , f o r m u l a t e d as  2_. The t o t a l  (+)-78-eremophil-3,11-diene  r e p o r t e d h e r e i n , was a c h i e v e d by the  eremophilene,  f o l l o w i n g sequence.  Reaction of  reaction)  122 i n the presence  readily afforded, after  o f base  aldol ring closure,  130 w i t h  been  ( ± ) 2_,  synthesis of  hydroxymethylene d e r i v a t i v e o f 3 - i s o p r o p e n y l c y c l o h e x a n o n e amino-3-pentanone m e t h i o d i d e  has r e c e n t l y  the  1-diethyl-  (Robinson a n n e l a t i o n  l-methyl-7-isopropenyl-  1 9 A ' -octal-2 one  127.  J  dimethylcuprate  R e a c t i o n o f compound 127 w i t h e t h e r e a l  135 r e s u l t e d  group t o o c t a l o n e  127,  i n the s e l e c t i v e conjugate  lithium  a d d i t i o n o f a methyl  thus a f f o r d i n g i n good y i e l d the a l l - c i s p r o d u c t  (±)-73-eremophil-ll-en-3-one eremophilane d e r i v a t i v e  128.  The r e l a t i v e  stereochemistry  of  the  128 was confirmed by c h e m i c a l c o r r e l a t i o n w i t h  h y d r o x y d i h y d r o e r e m o p h i l o n e 2>0_ o f known a b s o l u t e  configuration.  Reaction of  the t o s y l h y d r a z o n e d e r i v a t i v e o f compound 128 w i t h sodium e t h y l e n e i n r e f l u x i n g ethylene  glycol  Comparison o f compound (t) established  that  (Bamford-Stevens r e a c t i o n )  afforded  glycolate  (+)  2_ w i t h a sample o f a u t h e n t i c eremophilene  the s t r u c t u r a l assignment  eremophilene was i n c o r r e c t .  (2)  2. clearly  o r i g i n a l l y proposed f o r  D e h y d r a t i o n o f the n a t u r a l l y o c c u r r i n g e r e m o l i g e n o l  28^ w i t h t h i o n y l c h l o r i d e and p y r i d i n e a f f o r d e d  (+)-eremophil-1(10),11-diene  3 which was shown t o be i d e n t i c a l w i t h a u t h e n t i c  eremophilene.  s t r u c t u r e and s t e r e o c h e m i s t r y  c o r r e c t l y r e p r e s e n t e d by  f o r m u l a t i o n 3_.  o f eremophilene  The s y n t h e s i s o f e r e m o p h i l - 3 , 1 1 - d i e n e  establishes a stereoselective synthetic of  is  sesquiterpenoids.  Thus  the  2_ r e p o r t e d h e r e i n  e n t r y i n t o the eremophilane •  class .  (iii) TABLE  OF  CONTENTS  Page (i)  Title page . . Abstract  (ii)  Table of Contents  (iii)  List of Figures  (iv)  Acknowledgements  (v)  Introduction Discussion  1 .  28  Experimental  69  Bibliography  82  (iv)  L I S T OF FIGURES  Figure  Page  1  5  2  16  3  44  4  51  •5  52  6  59  7  60  8  61  9  62  ACKNOWLEDGEMENTS  I should like to record here my substantial indebtedness to Dr. Edward Piers - a stimulating teacher and scientist - for his consistent interest, encouragement and thoughtful guidance throughout the course of this research. Sincere gratitude is also expressed to the Chemistry Department of the University of British Columbia for both a teaching assistantship and the use of the departments research f a c i l i t i e s . Special thanks for numerous and varied discussions are due to the other members of the group:  R.W. Britton, K.F. Cheng, W.M. Phillips, R.D. Smillie,  W. de-Waal, and P. Worster. Finally, my sincere appreciation i s expressed to both Mr. H. Hanssen and Miss D. Johnson for their interest and efforts throughout the preparation of this thesis.  INTRODUCTION  Sesquiterpenes are a c l a s s of isoprenoid contain f i f t e e n cally  c a r b o n atoms.  compounds w h i c h n o r m a l l y  They a r e p a r t o f a l a r g e r group o f  related substances, c o l l e c t i v e l y  biogeneti-  r e f e r r e d t o as t h e t e r p e n e s .  s e s q u i t e r p e n e s as a f a m i l y o f n a t u r a l p r o d u c t s a r e n o t e d f o r t h e i r distribution and  for their  throughout nature, o c c u r r i n g considerable structural  a large variety and  of monocylic, b i c y l i c ,  i n d e e d i t i s on t h i s b a s i s , t h a t  that sesquiterpenes are o f t e n One  such c l a s s  system  f o u n d a t C-4  and C-5  side chain attached to ring  and  group  Of p a r t i c u l a r n o t e i s t h e v i c i n a l  skeleton,  which  possess  dimethyl  o f r i n g A,  and t h e t h r e e c a r b o n  "isopropyl-type"  B a t C-7.  The  shown i n 1_  class  numbering  system  o f compounds.  Until  c l a s s o f s e s q u i t e r p e n e w e r e known.  so t h a t have b e e n r e p o r t e d t o d a t e  (1).  Interest  s e s q u i t e r p e n e s i s , a p a r t from the s t r u c t u r a l this  exhibit  carbon skeletons  i s the nature of the carbon  t h e number o f known e r e m o p h i l a n e s h a s g r o w n r a p i d l y  found w i t h i n  tetracylic  trees,  classified.  t h a t n o r m a l l y employed f o r t h i s few members o f t h i s  tricylic  T h e s e compounds  of sesquiterpenes i s the eremophilane  t h e b a s i c c a r b o n s k e l e t o n 1_.  wide  i n a v a r i e t y o f p l a n t s and  diversity.  The  class, primarily  due  and  the early  1960's  However, s i n c e , t h e n ,  to the forty  i n the  is  five  or  eremophilane  functional  diversity  to the f a c t that the carbon  skeleton  - 2 -  is  "non-isoprenoid".  this  1  In f a c t ,  f o r sometime the f i r s t  group r e p r e s e n t e d the o n l y known e x c e p t i o n s  the sesquiterpene In  the p a s t  synthesis  field  i s o l a t e d members o f  t o the " i s o p r e n e r u l e " i n  (2).  few y e a r s t h i s  l a b o r a t o r y has been concerned w i t h the  of several classes of sesquiterpenes,  d i r e c t e d t o the eremophilane s e s q u i t e r p e n e s .  and r e c e n t l y ,  *  that,  t o t a l l y synthesized this class  (4). T h u s ,  of sesquiterpenes  the s p e c i f i c  object  a general synthetic  and, i n p a r t i c u l a r ,  o f the work r e p o r t e d i n  e n t r y i n t o the  to e f f e c t  eremophilane  an unambiguous  o f one member o f the g r o u p , e r e m o p h i l e n e .  Eremophilene, of  and i n p a r t  at t h a t t i m e , none o f the eremophilanes had been  t h e s i s was t o e s t a b l i s h  synthesis  was  The a t t r a c t i o n was i n p a r t  due t o t h e g r o u p ' s b i o g e n e t i c a l l y anomalous carbon s k e l e t o n , due t o the f a c t  attention  a C  H 1 5  2  4  h y d r o c a r b o n , was f i r s t  P e t a s i t e s o f f i c i n a l i s MOENCH (5) and P. a l b u s  isolated  from the  roots  ( L . ) GAERTN (6) by Herout  E a r l y w o r k e r s , most n o t e a b l y R u z i c k a , observed t h a t the b a s i c s k e l e t a l s t r u c t u r e s p o s s e s s e d by the terpenes c o u l d f o r m a l l y be c o n s i d e r e d t o be c o n s t r u c t e d i n m u l t i p l e s o f i s o p r e n e u n i t s i_ j o i n e d e i t h e r i n a r e g u l a r h e a d - t o - t a i l manner, o r i n an i r r e g u l a r manner.  head  tail  These s t r u c t u r a l requirements came to be known as the " i s o p r e n e r u l e " (2) and thus d e f i n e d the "terpenes". In subsequent y e a r s however numerous t e r p e n o i d compounds were i s o l a t e d whose s t r u c t u r e d i s o b e y e d the i s o p r e n e r u l e i n as much as t h e i r b a s i c carbon s k e l e t o n s c o u l d not f o r m a l l y be r e g a r d e d as a sequence o f i s o p r e n e u n i t s . To account f o r these "noni s o p r e n o i d " substances i n terms o f a u n i f i e d d e f i n i t i o n of t e r p e n e s , t h e i s o p r e n e r u l e was r e v i s e d (3). T h i s v e r s i o n , "the b i o g e n e t i c i s o p r e n e r u l e " , s i m p l y amends the i s o p r e n e r u l e d e f i n i t i o n o f terpenes so as t o i n c l u d e those terpenes which have undergone carbon s k e l e t a l rearrangement i n the c o u r s e o f t h e i r b i o s y n t h e s i s .  - 3 -  H  1  2  and coworkers i n 1962. features  3  S u b s e q u e n t l y the s k e l e t a l  and s t e r e o c h e m i c a l  o f eremophilene were e l u c i d a t e d by Hochmannova and Herout  who i n 1964,  on the bases o f c h e m i c a l r e a c t i o n , i n f r a r e d  magnetic resonance  (n.m.r.)  and n u c l e a r  s p e c t r a and a c h e m i c a l c o r r e l a t i o n w i t h h y d r o x y -  d i h y d r o e r e m o p h i l a n e o f known a b s o l u t e as 2_. However i t  (i.r.)  (7),  c o n f i g u r a t i o n f o r m u l a t e d eremophilene  s h o u l d be noted here t h a t r e c e n t l y as a r e s u l t o f our work  ( 8 ) and a subsequent  r e i n v e s t i g a t i o n by Herout e t . a l .  (9),  this structural  assignment was shown t o be i n c o r r e c t and t h e r e v i s e d s t r u c t u r e 3_ was f o r eremophilene.  That f o r m u l a t i o n 3_ i s  confirmed by the e x c e l l e n t t o t a l  established  i n d e e d c o r r e c t was v e r y r e c e n t l y  synthesis of  (i)  3_ by Coates and Shaw (10) .  TERPENOID BIOSYNTHESIS A number o f r e f e r e n c e s  to the b i o g e n e t i c a l l y  carbon s k e l e t o n have been made i n the f o r e g o i n g ,  anomalous eremophilane and i n subsequent  c o n s i d e r a t i o n w i l l be g i v e n to a proposed " b i o g e n e t i c a l l y synthesis".  Thus t o c l a r i f y  biosynthesis  of this  o f the b i o s y n t h e s i s in  discussion,  s t y l e d eremophilane  these and o t h e r ensuing p o i n t s r e l a t e d t o  group, i t  is  expedient  the  t o i n t r o d u c e here a d i s c u s s i o n  o f t e r p e n e s i n g e n e r a l and the eremophilane s e s q u i t e r p e n e s  particular. Throughout the p a s t twenty y e a r s s u b s t a n t i a l p r o g r e s s has been made i n  e l u c i d a t i n g the b i o s y n t h e s i s  o f t e r p e n o i d compounds.  Much o f t h i s  progress  - 4 has  r e s u l t e d from s t u d i e s i n which p l a u s i b l e b i o g e n e t i c i n t e r m e d i a t e s  t a i n i n g r a d i o i s o p t o p i c atoms a r e ing,  i f the precursors  i n t r o d u c e d i n t o p l a n t and  a r e * a u t h e n t i c , t o an  animal  con-  systems  lead-  i n c o r p o r a t i o n of the r a d i o - l a b l e 2  i n the subsequently has  i s o l a t e d terpenes.  Thus.by such l a b e l l i n g  become q u i t e a p p a r e n t t h a t t h e b i o s y n t h e s i s o f t e r p e n e s  a c e t i c a c i d , or i t s b i o s y n t h e t i c equivalent acetyl represented molecules glutaryl phosphate  i n Figure  of acetate  1_ ( 1 1 ) .  The  successive  4_ a f f o r d s , a f t e r p a r t i a l  c o e n z y m e A S_. R e d u c t i o n (NADPH) l e a d s 3  phosphorylation  s e l f condensation hydrolysis  terminal  acid  from summarily  three  g-hydroxy-$-niethyl  6_ - m e v a l o n o l a c t o n e 7_ s y s t e m  subsequent d e c a r b o x y l a t i o n .  d o u b l e b o n d o f 8_ r e s u l t s  of  i t  w i t h picotinamide - a d e n i n e d i n u c l e o t i d e  to the mevalonic  and  proceeds  c o e n z y m e A 4_, a s  w h i c h i n t u r n g i v e s A - i s o p e n t e n y l p y r o p h o s p h a t e 8_, a f t e r (ATP)  studies  i n the formation  adenine  triphosphate  Rearrangement o f  of  dimethallyl  the  pyro-  3 phosphate phosphate  w h i c h on (proton  intermediate  and  condensation  (normally)  o f one  molecule  o f the monoterpenes, t h a t i s the  c o n t a i n t e n c a r b o n atoms. of the  It is this  In a p a r a l l e l  class of  important  consecutive  terpenoids  a d d i t i o n o f two  to molecules  g e r a n y l p y r o p h o s p h a t e 1_2_.  g e r a n y l pyrophosphates have been e x p e r i m e n t a l l y e s t a b l i s h e d  as b i o s y n t h e t i c p r e c u r s o r s  of the  sesquiterpenes  the  manner t h e a d d i t i o n  i s o p r e n o i d 8_ t o g e r a n y l p y r o p h o s p h a t e l e a d s  o f 8^ t o g e r a n y l p y r o p h o s p h a t e y i e l d s g e r a n y l geranyl  pyro-  i t s c i s - d o u b l e bond isomer n e r y l pyrophosphate t h a t a r e  f a r n e s y l p y r o p h o s p h a t e _11_, w h e r e a s t h e  and  of A*-isopentenyl  l o s s ) y i e l d s g e r a n y l p y r o p h o s p h a t e 1_0.  biosynthetic precursors which  with a molecule  (C-15) and  diterpenes  Farnesyl (11) (C-20)  respectively. R e d u c t i v e d i m e r i z a t i o n o f f a r n e s y l p y r o p h o s p h a t e (12,13) g i v e s . 2 A d e t a i l e d d i s c u s s i o n of s p e c i f i c r e s u l t s of l a b e l l i n g s t u d i e s w i l l not be p r e s e n t e d h e r e i n . The r e a d e r i s r e f e r r e d t o t h e r e f e r e n c e s ' c i t e d for details.  9 MONOTERPENES 1  F i g u r e 1_  SESQUITERPENES  f  DITERPENES  4  -  s q u a l e n e J_3, and  the  basic  features,  carbon skeleton,  that  a l l of  and  the  cations  20_ ( F i g u r e  appropriate formal  triterpenes  2)_  (11,  i n c r e a s i n g extent t h e  ring closures.  be  accounted f o r  b i o s y n t h e t i c a l l y derived 11_, v i a t h e  12) .  the  These i o n s  biosynthetic  c o n t r o l l e d and,  c o n c e r t e d manner  (C-30)  appropriate  C a t i o n s 15  to  configurational  as  by  from c i s ,  cyclizations  20 a r i s e f r o m c i s -  p y r o p h o s p h a t e u p o n l o s s o f a p y r o p h o s p h a t e a n i o n , and  s e n s e , as  enzymatically  t o an  these substances are  p y r o p h o s p h a t e , 14_ and  trans-farnesyl  the  s e s q u i t e r p e n e s can  trans-farnesyl to  p r e c u r s o r of  ( b i o s y n t h e t i c a l l y degraded t r i t e r p e n e s ) .  of v i r t u a l l y  considering  L5  -  which i s the b i o s y n t h e t i c  steroids  The  6  s h o u l d o f c o u r s e be  be  effected  regarded i n  in a partial  of and  the a  c y c l i z a t i o n s of f a r n e s y l pyrophosphate s u c h , may  and  or  (11).  29  are  - 7Robinson (15), some years ago, suggested that the eremophilane sesquiterpenes may be derived from a precursor which possesses the eudesmane carbon skeleton 21_. As depicted below, a 1,2-shift of the angular methyl group of 21 yields cation 22^ which exhibits the characteristic eremophilane carbon skeleton.  The basic eudesmane skeleton _21_ is readily attained via the trans-  annular cyclization of cation 19_, in turn derived from trans-farnesyl pyrophosphate 11.  21  22  A number of specific eudesmanoid derivatives have been suggested in the literature as possible biogenetic precursors of the eremophilane group.  One  of these, the diol 23, has been suggested (15,16) as a plausible precursor of a naturally occurring compound, eremophilone 26, isolated from Eremophila Mitchelli.  The postulated series of Wagner-Meerwein rearrangements indicated  would lead to the trans-eremophilone derivative _2£ which, after ready epimerization, would give the a l l £i_s_-structure 2!5_, characteristic in the eremophilane group. Subsequent oxidation and dehydration would yield eremophilone.  In 1960 Zalkow, Markley and Djerassi (16) suggested that the  naturally occurring g-eudesmol 27_ (17) was also a plausible eremophilone precursor.  An analogous series of 1,2-shifts would lead to the postulated  intermediate 2%_, which after a suitable biosynthetic adjustment of oxidation level, would yield eremophilone 29_, (R=0).  While l i t t l e  i f any e x p e r i m e n t a l work s p e c i f i c a l l y  b i o g e n e s i s o f the eremophilane s e s q u i t e r p e n e s Minato's  1966 i s o l a t i o n o f e r e m o l i g e n o l  (18) and the v e r y r e c e n t (8,10) lends  concerned w i t h  has been r e p o r t e d t o  date,  28, from L i g u l a r i a F i s c h e r i  c o n f o r m a t i o n o f s t r u c t u r e 29_ (I^h^) f o r  support to the above proposed b i o g e n e s i s o f t h e s e  the  Turcz  eremophilene  eremophilanes.  STRUCTURE IN THE EREMOPHILANE SESQUITERPENES As the s u b j e c t  of this  approach to eremophilene  thesis is  concerned w i t h e s t a b l i s h i n g  and to the eremophilane group p e r s e ,  importance t o c o n s i d e r a number o f t o p i c s , a s p e c t s o f the e r e m o p h i l a n e s .  (a)  is  synthetic of  a l l o f which embrace s t r u c t u r a l  Specifically,  following sections a discussion of  it  a  it  is  the s k e l e t a l  i n t e n d e d to p r e s e n t and c o n f i g u r a t i o n a l  in  the  - 9 e l u c i d a t i o n of the f i r s t i s o l a t e d eremophilane-type sesquiterpenes, eremophilone and i t s cogeners, (b) the important s t r u c t u r a l v a r i a t i o n s found in the eremophilane group, (c) the o r i g i n a l s t r u c t u r a l e l u c i d a t i o n of eremophilene and f i n a l l y , (d) the s a l i e n t features of other synthetic approaches to t h i s class of sesquiterpene. (a)  The Structure of Eremophilone and Cogeners The f i r s t n a t u r a l l y occurring compounds found which possess the eremo-  philane carbon skeleton were i s o l a t e d i n 1932 by B r a d f i e l d , Penfold and Simonsen (19,20).  Thus, Simonsen and coworkers i s o l a t e d , from the wood of Eremophila  M i t c h e l l i , three c l o s e l y r e l a t e d sesquiterpenic ketones, v i z . , eremophilone, hydroxydihydroeremophilone and hydroxyeremophilone.  In the period between  1932 and 1941, Simonsen's group c a r r i e d out, by c l a s s i c a l methods of s t r u c t u r a l e l u c i d a t i o n , an  i n v e s t i g a t i o n i n t o the structure of the three eremophilone  sesquiterpenes (20). The enormous amount of work c a r r i e d out and the pains t a k i n g l y slow progress involved i n the problem render a present d e t a i l e d discussion of the s k e l e t a l e l u c i d a t i o n of these compounds quite  impractical.  Thus, s u f f i c e to say that a f t e r considerable e f f o r t by these workers, the s k e l e t a l features of eremophilone, hydroxydihydroeremophilone and  hydroxy-  eremophilone were c o r r e c t l y formulated as 26a, 30a and 31a r e s p e c t i v e l y .  26a  30a  31a  - 10 -  By the mid-1950's i t had become increasingly important, specifically from the point of view of establishing the biosynthesis of the eremophilanes, to determine the relative and absolute stereochemistry of eremophilone and its co-occurring relatives. To this end, hydroxydihydroeremophilone was subjected to an X-ray crystallographic analysis and assigned the relative configuration indicated by structure _3£ (21).  Subsequently, Zalkow, Djerassi and coworkers  proved the relative configuration of eremophilone 26_ and hydroxyeremophilone 31 by a chemical correlation with hydroxydihydroeremophilone (22). Specifically, ketone 32 was obtained from both eremophilone 26_ by sodium alcohol reduction followed by chromium trioxide oxidation and from hydroxydihydroeremophilone 3_0 by treatment of the acetate of 30^ with calcium in liquid  ammonia'. The analogous relative configurational features of hydroxyeremophilone 31 were confirmed on finding that the hydroxy ketone _30 would readily afford hydroxyeremophilone on oxidation with bismuth oxide and acetic acid. The absolute configuration of the three sesquiterpenic ketones was finally established in 1959 by Zalkow, Markley and Djerassi upon comparison of the  r 11 -  decalone  33 o b t a i n e d i n t h r e e  s t e p s from hydroxyeremophilone 31_ w i t h  o b t a i n e d i n f o u r t e e n s t e p s from the hexalone  34 o f known a b s o l u t e  that  stereochemistry  (16,23).  31  (b)  33  34  S t r u c t u r a l V a r i a t i o n s i n the Eremophilane S e s q u i t e r p e n e s In the f o l l o w i n g s e c t i o n ,  and c o n f i g u r a t i o n a l f e a t u r e s eremophilane-type  attention  is  which a r e encountered i n the n a t u r a l l y o c c u r r i n g  sesquiterpenes.  A s u r v e y o f the known members o f t h i s a number o f c h a r a c t e r i s t i c s t e r e o c h e m i c a l the c o n s i s t e n t  d i r e c t e d . t o the v a r i o u s s t r u c t u r a l  cis  c l a s s o f compound r e a d i l y features.  Of immediate note  The p r e v a l e n c e o f such a c i s  agreement w i t h the  c o n f i g u r a t i o n a l r e q u i r e m e n t s o f the  geometry i s ,  l a t e d i n the above mentioned eremophilane b i o g e n e s i s . the C-7 " i s o p r o p y l - t y p e " t h r e e c a r b o n s i d e  found e i t h e r o f nootkatone  cis 35,  isolated  geometry,  It  is  these s t r u c t u r a l f e a t u r e s . 26,  o c c u r s between the a x i a l C-5 and C-7 s u b s t i t u e n t s , r e l a t e d e p i m e r i c system 35_.  also  of  chain of r i n g B is  from C i t r u s p a r a d i s i ( 2 4 ) ,  e x e m p l i f i e d by eremophilone  of course,  1,2-migrations  o r t r a n s t o the v i c i n a l methyl s u b s t i t u e n t s .  c l e a r l y demonstrates all-cis  is  r e l a t i o n s h i p between the C-14 and C-15 a n n u l a r methyl  groups o f r i n g A .  that  reveals  in  postuinterest  commonly  A comparison  and eremophilone 2_6_  In the f r e q u e n t l y a notable which i s  steric absent  encountered interaction in  the  A f u r t h e r apparent c o n f i g u r a t i o n a l g e n e r a l i t y ,  is  - 12 -  that of the c i s - f u s e d r i n g i n g a s a t u r a t e d C-10  juncture  c a r b o n atom.  e r e m o p h i l a n e s , none e x h i b i t  e x h i b i t e d by t h e e r e m o p h i l a n e s p o s s e s s O f t h e p r e s e n t l y known n a t u r a l l y  t r a n s - f u s e d A and B  rings.  F u n c t i o n a l l y , these sesquiterpenes are r e l a t i v e l y g e n e r a l l y c o n t a i n e t h y l e n i c d o u b l e bonds and f u n c t i o n a l g r o u p s a t one is  interesting  oxygenated hydroxyl  propenyl  (25).  f o r example v a l e r i a n o l  Eremophilanes  known, as i s t h e t o t a l l y  Sprague  e x h i b i t h y d r o x y 1 and  A number a r e known w h i c h p o s s e s s a  (commonly o c c u r r i n g ) and  functionalities  containing  saturated isopropyl  are i l l u s t r a t e d  (27).  3_6, i s o l a t e d  from  exhibit  Valeriana  the dehydration r e l a t e d i s o -  side chain moiety.  38., f r o m  are The  also latter  ugandensis  Nardostachys  A l a r g e number o f t h e s e compounds c o n t a i n a t h r e e - c a r b o n suffered  extensive oxidation  t o t h e f o r m a t i o n o f u n s a t u r a t e d y - l a c t o n e s , as e x e m p l i f i e d by e n o l i d e 39_, i s o l a t e d  It  tertiary  by w a r b u g i a d i o n e 37, from W a r b u r g i a  " i s o p r o p y l - t y p e " s i d e c h a i n w h i c h has  as t h e r e c e n t l y  ketonic  i s o p r o p y l i d i e n e m o i e t i e s a t C-7  ( C a n e l l a c e a e ) ( 2 6 ) , and n a r d o s t a c h o n e  j a t a m a n s i D.C.  They  o r more o f t h e s e c o n d a r y a n n u l a r c a r b o n a t o m s .  C - l c a r b o n atoms.  L.  uncomplex.  t h a t v e r y few e r e m o p h i l a n e s have been i s o l a t e d w h i c h  group a t C - l l ,  officinalis  occurring  f r o m P e t a s i t e s h y b r i d u s (30) a n d  isolated  (from Euryops  floribundus  leading  eremophi1-  furan derivatives  ( 2 9 ) ) e u r y o p s o n o l 40.  such  - 13 -  36  37  38  Several eremophilanes are known which contain hydroxyl groups esterified with  vinyl thiolether carboxylic acid moieties, such as the keto ester S-petasin 41, found in petasites officinalis  MOENCH  (30).  Bakkenolide-A 42, recently isolated from the Japanese plant Petasites japonicus (31), is a structurally interesting sesquiterpene.  It appears to  be an eremophilane that has undergone skeletal rearrangement resulting in the contraction of the eremophilane ring B from a six to five membered ring. The numbering system shown is that of the eremophilane group.  There are four  such bakkenolides known at present, varying in the nature of the substituents at C-1 and C-9 (32). While generally regarded as a separate skeletal class of sesquiterpenes, the aristolanes are closely related to the eremophilanes and as such i t is instructive to briefly mention this group here. a-Ferulene 43, from Ferula  - 14 -  .  communis L . ( U m b e l l i f e r a e )  (33)  Aristolochia debilis  et_ Z u c c .  carbon s k e l e t o n .  Sieb.  and t h e e n a n t i o m e r i c a r i s t o l o n e (28)  The a l l - c i s - g e o m e t r y ,  serve to exemplify  and eremophilanes  is  from  the b a s i c  found i n the e r e m o p h i l a n e s ,  a p p a r e n t l y unknown i n the a r i s t o l a n e g r o u p . the a r i s t o l a n e s  44  The s k e l e t a l  is  r e l a t i o n s h i p between  apparent i f one e n v i s i o n s  c l o s u r e o f the eremophilane C-7 i s o p r o p y l - t y p e s i d e  aristolane  a formal  ring  c h a i n , by c a r b o n - c a r b o n  bond f o r m a t i o n between C-6 and C - l l , y i e l d i n g the g e m - d i m e t h y l c y c l o p r o p a n e r i n g and c o n c o m i t a n t l y the  characteristic t r i c y c l i c aristolane skeleton.  s h o u l d be noted however,  even i f somewhat d i g r e s s i v e l y ,  a r e not c o n s i d e r e d to a r i s e b i o g e n e t i c a l l y i t has been proposed t h a t (see  biosynthetic  section),  the a p p r o p r i a t e s e r i e s i l l u s t r a t e d below  from the  that  eremophilanes.  they a r i s e v i a 1 , 3 - d e p r o t o n a t i o n a f f o r d i n g the  of 1,2-shifts  the  It  aristolanes Rather  o f c a t i o n 1_9  cyclopropane moiety,  f o l l o w e d by  l e a d i n g to the a r i s t o l a n e s y s t e m s ,  (11).  H  as  Thus,  i n summary, i t  functional  is  apparent t h a t  group d i v e r s i t y e x i s t s  particularly i f  a considerable  i n the eremophilane  s t r u c t u r a l and  sesquiterpenes,  such " r e a r r a n g e d eremophilanes" as the b a k k e n o l i d e s  and a r i s t -  o l a n e s a r e i n c l u d e d as members o f the g r o u p .  (c)  S t r u c t u r a l E l u c i d a t i o n o f Eremophilane As noted above,  is  eremophilene.  the compound of p r i n c i p a l  Thus,  it  is  synthetic  important to c o n s i d e r the  interest  herein  essential  features  o f the s t r u c t u r a l e l u c i d a t i o n , r e p o r t e d by Hochmannova and Herout i n (7),  which l e d t o the f o r m u l a t i o n o f eremophilene  as  1964  2.  H  Q u a n t i t a t i v e h y d r o g e n a t i o n o f a sample o f n a t u r a l e r e m o p h i l e n e , hydrocarbon,  established  i d e n t i c a l with ation  (18).  The i . r .  spectrum o f eremophilene  ethylenic  double bond ( 5 . 9 9 ,  proton signals  a t T 8.22  double bond ( 6 . 0 6 , 12.36  u).  and x 8.51  two p r o t o n s o f the g e m - d i s u b s t i t u t e d olefin respectively.  bond was e s t a b l i s h e d deactivated  Its  o f known a b s o l u t e  11.23  y)  and a  n . m . r . spectrum gave two  a t x 5.33  and 4 . 7 4 ,  o l e f i n and the  single  of a  tri-substituted three-  methyl  a t t r i b u t e d to  the  p r o t o n o f the t r i -  The p o s i t i o n o f the d i s u b s t i t u t e d  by s e l e c t i v e l y h y d r o g e n a t i n g e r e m o p h i l e n e ,  Raney-nickel i n ethanol.  configur-  i n d i c a t e d the presence  which were a t t r i b u t e d t o v i n y l  groups and two v i n y l i c p r o t o n s i g n a l s  substituted  o f two double bonds and gave a p r o d u c t  (+)-78-eremophilane 45_ ( F i g u r e 2 ) ,  gem-disubstituted ethylenic  the p r e s e n c e  a CjgE^  double  using p a r t i a l l y  The r e s u l t i n g p r o d u c t , d i h y d r o e r e m o p h i l e n e  Figure 2_.  - 17 -  47,  exhibited  an i . r .  doublet  group; moreover the o l e f i n i c e x h i b i t e d by  eremophilene  ing the presence The  crucial  double bond  y) c h a r a c t e r i s t i c o f a gem-dimethyl  carbon-hydrogen  was  absent  deformation absorbance  q u e s t i o n r e g a r d i n g the p o s i t i o n of the  (unconjugated)  was  then considered.  i n eremophilene  compound became p o s s i b l e :  With  tri-substituted  the presence  established, three structures 2_, Z_, and  i n addition to this  3^ and  54.  47_ ( F i g u r e _2) i n e t h y l  by  hydroxy  4_9 r e s p e c t i v e l y .  t i o n o f t h e m i x t u r e f o l l o w e d by product  50_, (R=H)  sought.  acetate at • hydrogen,  contained a keto aldehyde  esterification  of the a c i d i c  bands c h a r a c t e r i s t i c o f m e t h y l  i n the iodoform  ketone  ( 5 . 8 5 , 7.31  test, y)  T h e s e f a c t s w e r e t a k e n - as e v i d e n c e  and  a  Permanganate o x i d a oxidation  w i t h d i a z o m e t h a n e g a v e a C ^ g ^ g O ^ k e t o e s t e r 50_,  This material reacted p o s i t i v e l y  y) g r o u p s .  i.r.  methyl  However,  f o l l o w e d by d e c o m p o s i t i o n o f t h e i n t e r m e d i a t e o z o n i d e w i t h  a f f o r d e d a mixture of products which  6.94  and T 8.51  t h e x 8.22  e v i d e n c e , a c h e m i c a l p r o o f o f s t r u c t u r e was  k e t o n e , f o r m u l a t e d as 48_ and  an  represent-  54 w e r e r e n d e r e d u n s a t i s f a c t o r y .  Ozonolysis of dihydroeremophilene -75°,  of  54.  G i v e n t h e n.m.r. d a t a r e p o r t e d , s p e c i f i c a l l y structures  indicat-  product.  3  group s i g n a l s ,  (11.23y)  i n the dihydro-product, c l e a r l y  o f an i s o p r o p e n y l d o u b l e b o n d i n t h e n a t u r a l  isopropenyl moiety ing this  ( 7 . 2 1 , 7.29  and  (R=Me) .  exhibited  and m e t h y l  ester  substantiating  i.r. (5.75,  structure  - 18 50.  Baeyer-Villiger oxidation of 50_ with perbenzoic acid gave the diester  51 which was then hydrolysed to give a mixture of product containing, in addition to acetic acid, the ^-lactone 55, formed by ring closure of the intermediate 6-hydroxy acid 52.  The critical successful isolation of acetic  acid, identified as the p-bromophenacyl ester, from the reaction mixture clearly discounted structures _3_ and 54, and moreover corroborated the above mentioned n.m.r. evidence for the formulation bf eremophilene as structure 2. Finally, the absolute configuration of eremophilene was established by correlation with hydroxydihydroeremophilone _30, of known absolute configuration (21,23). The hydrogenation product obtained from natural eremophilene, (+)73-eremophilane 45, and the product obtained from the Clemmenson reduction of compound 5_5 (the catalytic hydrogenation product of hydroxydihydroeremophilone 30) were identical in density, refractive index, optical rotation and infrared spectra. Thus, the chemical .and physical experiments demonstrated by these workers"... constituted an unambiguous proof that the trisubstituted double 3  bond in eremophilene is in the A -position and that formula (2_) belongs to this compound" (7) . It should be noted that the only n.m.r. data reported in this structural elucidation was that given for eremophilene. (d) Other Synthetic Approaches to the Eremophilane Sesquiterpenes At this point i t is necessary to mention a number of recently published reports concerning the synthesis of eremophilane sesquiterpenes. Increased interest in the eremophilanes in the past few years is evident from the number of recent reports of syntheses directed toward these compounds. At the conception of our work in 1966, none of the group had been totally synthesized (4). However, there are currently at hand several reports of synthetic approaches to the eremophilanes and these will be the subject of  - 19 -  the following paragraphs. The synthesis of racemic isonootkatone (ot-vetivone) 64_ by Marshall, FaubT and Warne (34) constitutes the f i r s t t o t a l synthesis of a member of the eremophilane sesquiterpenes. The key step i n the sequence was the stereos e l e c t i v e condensation of 2-carbomethoxy-4-isopropylidene-cyclohexanone 57_ with trans-pent-3-en-2-one 56.  In the presence o f sodium methoxide, the  keto ester 5_7_ underwent Michael addition to the pentenone 56_ affording, a f t e r aldol ring closure, a mixture of c i s and trans-octalones, 58 and 5_9, with * the c i s - d e r i v a t i v e 5_8 predominating.  64  . 61_, X=0H 62, X=0MS 63, X=H  6  0  - 20 -  In an e x p l a n a t i o n o f f e r r e d r e g a r d i n g t h e observed M a r s h a l l and coworkers suggested  s t e r e o c h e m i s t r y a t C-4,  t h a t e l e c t r o n i c and s t e r i c c o n s i d e r a t i o n s  would f a v o r a t r a n s i t i o n s t a t e o r i e n t a t i o n r e p r e s e n t e d by 65.  i s apparent  From models i t  t h a t t h e o r i e n t a t i o n o f the methyl group and hydrogen atom  ( a t t a c h e d t o t h e pendent C-4 atom) i n d i c a t e d i n 65b leads t o t h e e s t a b l i s h ment o f a c i s r e l a t i o n s h i p between t h e C-4 and C-5 (eremophilane s u b s t i t u e n t s o f o c t a l o n e _58_.  The s t e r i c a l l y  numbering)  less favorable t r a n s i t i o n state  o r i e n t a t i o n d e p i c t e d in.66 would c o n v e r s e l y l e a d t o t h e t r a n s - o c t a l o n e 59. Subsequent k e t a l i z a t i o n o f o c t a l o n e 5_8 f o l l o w e d by r e d u c t i o n o f t h e carbomethoxy group t o a methyl group h y d r o l y s i s gave a p r o d u c t r e t e n t i o n time vetivert  (60 — » 61^ —> 62^—* 63) and k e t a l  which e x h i b i t e d i . r .  and n.m.r. s p e c t r a and g . l . c .  i d e n t i c a l with that o f n a t u r a l isonootkatone,  acetate  isolated  from  ( 3 5 ) , a commercial e s s e n t i a l o i l .  A somewhat s i m i l a r s t e r e o c h e m i c a l r e s u l t was o b t a i n e d r e c e n t l y by Coates and Shaw (36) upon c o n d e n s a t i o n hexan-l,3-dione  67_ w i t h trans-pent-3-en-2-one 56.  i n good y i e l d a m i x t u r e o f t h i s product  o f t h e p y r r o l i d i n e enamine o f 2 - m e t h y l c y c l o The r e s u l t i n g p r o d u c t  o f t h e c i s and t r a n s - o c t a l o n e s 68.  was found  The c i s : t r a n s  ratio  t o v a r y between 1:1 and 1:10, depending on t h e e x a c t '  r e a c t i o n c o n d i t i o n s used and upon t h e s t r u c t u r e o f t h e cyclohexenone employed.  afforded  reagent  These f i n d i n g s p r o v i d e d an a l t e r n a t e s y n t h e t i c approach t o t h e  - 21 -  OH  74  73  72  characteristic cis-vicinal methyl groups of the eremophilane carbon skeleton and were subsequently utilized in the synthesis of ( ± ) - A * - a r i s t o l e n e (calarene, g-gurjunene) 75_ (37), as indicated below. Selective thioketalization of a 1:1 mixture of the octalones 68, obtained from the reaction of 5_6 and 67_ in a refluxing mixture of formamide, acetic acid and aqueous sodium acetate, gave.the corresponding mixture of the thioketals 69.  This epimeric mixture was then treated with Raney nickel  in absolute ethanol. The resulting product afforded the analogous mixture of  - 22 -  cis  and t r a n s - u n s a t u r a t e d ketones 7_0_ and 71.  successfully  These isomers were then  s e p a r a t e d by f r a c t i o n d i s t i l l a t i o n through a s p i n n i n g - b a n d  column.  R e a c t i o n o f the  presence  o f sodium h y d r i d e i n 1,2-dimethoxyethane gave a m i x t u r e o f keto and  enol tautomers, ethereal mediate  cis-dimethyloctalone  f o r m u l a t e d here as 72.  70 w i t h e t h y l c a r b o n a t e i n  T h i s m a t e r i a l upon r e f l u x i n g  methyl l i t h i u m f o l l o w e d by a c i d c a t a l y z e d tertiary alcohol,  gave the a , g - u n s a t u r a t e d  with  d e h y d r a t i o n o f the ketone 73_.  inter-  A stereo-  s e l e c t i v e i n t r o d u c t i o n o f the r e q u i r e d gem-dimethylcyclopropane moiety e f f e c t e d v i a an i n t e r e s t i n g pyrazolines.  a p p l i c a t i o n o f the thermal d e c o m p o s i t i o n  Treatment o f the a , 8 - u n s a t u r a t e d  the  ketone 7_3 w i t h one  was  of  equivalent  2 of  hydrazine i n r e f l u x i n g absolute  in  turn afforded,  stereochemical^  e t h a n o l gave the  A - p y r a z o l i n e 74_ which  on t h e r m a l d e c o m p o s i t i o n with potassium h y d r o x i d e , a homogeneous p r o d u c t ,  (±)-A*^^-aristolene  75_.  was found t o be chromatographically (g.I.e.) and s p e c t r o s c o p i c a l l y identical  t o the n a t u r a l l y o c c u r r i n g  Recently,  Brown and coworkers  racemic tetrahydroeremophilone  89,  (i.r.,  above,  principal  step a " b i o g e n e t i c - l i k e "  olefinic  Brown u t i l i z e d  (38)  r e p o r t e d the t o t a l  a r e d u c t i o n product o f  a synthetic  synthesis  compound, a p p r o p r i a t e l y d e s i g n e d  77,  m a t e r i a l gave the enone 79_. o b t a i n e d by treatment  the  subsequent  struc-  system. 3-methyl-4-carbomethoxy-5-  was a l k y l a t e d w i t h  76, y i e l d i n g the k e t o e s t e r 78_.  and C o a t e s ,  c y c l i z a t i o n o f an  to y i e l d , a f t e r  starting material for this synthesis,  isopropylcyclohex-2-enone  of  eremophilone.  scheme which i n v o l v e d as  trans-antipara11el  t u r a l m o d i f i c a t i o n the d e s i r e d b i c y c l i c The  n.m.r.)  A*-aristolene.  U n l i k e the Robinson a n n e l a t i o n r e a c t i o n approaches o f M a r s h a l l discussed  This material  trans-l-bromopent-3-ene  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  this  The r e q u i r e d t r i e n e s 80 were then r e a d i l y  o f 79 w i t h methyl  chloride-pyridine dehydration.  l i t h i u m f o l l o w e d by phosphorus  oxy-  The r e p o r t e d o v e r a l l y i e l d o f 80^ from 77_  -  was 22%.  23 -  Ring c l o s u r e was then a c h i e v e d by r e a c t i n g the t r i e n e m i x t u r e 80  85  86,  Ri=CH ,R =H  87,  R =0,R =H  88,  R,=0,R =Ac  2  1  2  89  2  2  w i t h anhydrous f o r m i c a c i d at room temperature  f o r 20 m i n u t e s .  The r e s u l t -  i n g p r o d u c t c o n t a i n e d a m i x t u r e o f e s t e r s 81_ and 82^ which were e p i m e r i c at C - 7 .  Of p a r t i c u l a r importance was the s t e r e o s e l e c t i v e r e a l i z a t i o n o f  the c i s - v i c i n a l methyl group moiety R e d u c t i v e c l e a v a g e o f these formates the r e l a t e d a l c o h o l s  83_ and 84_.  i n the  "eremophilane" r i n g A .  with l i t h i u m aluminum h y d r i d e y i e l d e d  These isomers  were " p a r t i a l l y s e p a r a t e d " on  - 24 -  alumina, and exhibited a ratio 2:3 respectively.  The B-epimer 83, isolated  by chromatography, was oxidized with Jones' reagent to the corresponding ketone, which was then subjected to Wolf-Kishner reduction yielding the all-cis-desoxy derivative 85.  Photooxidation of 85_ followed by immediate  lithium aluminum hydride reduction gave a product containing the epimeric alcohols 86_. Cleavage of the exocyclic double bond of compound 86_ was effected by reaction with one equivalent of ozone-saturated methylene chloride at -70°.  Zinc-acetic acid reduction of the intermediate ozonide  « gave, after appropriate work up, a mixture of the epimeric ketols 87. Finally, removal of the C-10 hydroxyl group of jT7_ was accomplished by calcium. ammonia reduction of the corresponding acetate 88.  The (±)-tetrahydro-  eremophilane 89 thus obtained was found to be identical "in all respects" to the cis-tetrahydroeremophilone derived by known procedures from naturally occurring hydroxydihydroeremophilone. The final synthetic approach to the eremophilanes to be considered herein is that recently outlined by Heathcock and coworkers.  The finding  that the unsaturated acid 90_ on treatment with refluxing anhydrous formic 3 acid gave a 2:1 equilibrium  mixture of lactones 91_ and 92_ suggested that  synthetic entry into this family of natural products could plausibly be realized via a "methyl-migration route" (39). In a preliminary report by Heathcock and Kelly (39) the merits of this possible approach were considered and a number of literature examples of applicable 1,2-methyl migrations were given, further supporting the feasibility of such a "biogenetically styled" eremophilane synthesis. An example cited (39) was the conversion of the diacetoxyhydroxyl steroid 93_ to the rearranged olefin 94. In a subsequent publication, Heathcock and Amano reported the result 3  Treatment of pure 91_ or pure 92_ under identical conditions afforded the same 2:1 mixture.  - 25 -  o f an attempted The hydroxy a c i d on treatment migration.  e x p e r i m e n t a l v e r i f i c a t i o n o f t h e i r proposed approach (40) . 100 was s e l e c t e d as a s u i t a b l y designed  with a c i d , might r e a s o n a b l y g i v e r i s e I t was hoped t h a t  r e l i e f o f the  anticedent  t o the d e s i r e d  1,3-diaxial  steric  between the C - l and C-10 methyl groups o f compound 100 would enhance  the  feasibility  o f the  d e s i r e d rearrangement.  which,  1,2-methyl  interaction energetically  M o r e o v e r , the  r e a r r a n g e d p r o d u c t would be a p p r o p r i a t e l y f u n c t i o n a l i z e d f o r e x t e n s i o n the  eremophilane  to  skeleton.  The s y n t h e s i s o f  100 was accomplished as f o l l o w s .  The r e a d i l y  available  u n s a t u r a t e d a c i d 95 was 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 y i e l d i n g r e l a t e d u n s a t u r a t e d a l c o h o l 96_.  Subsequent  e p o x i d a t i o n o f t h i s compound  with m - c h l o r o p e r b e n z o i c a c i d gave a p r o d u c t c o n t a i n i n g the mixture of epoxy-alcohols  stereoisomeric  97_ and 98 i n a 3:2 r a t i o , r e s p e c t i v e l y .  o f t h i s m i x t u r e w i t h methylmagnesium  the  Treatment  iodide in refluxing tetrahydrofuran  followed by acidic hydrolysis resulted in an opening of the oxirane ring, and readily afforded the diol 99 in 71% yield, base on oxirane 97. Subsequent  conversion to the desired hydroxy acid. 100 was accomplished by chromic acidacetone oxidation of 99. Unfortunately, formic acid treatment of the hydroxy acid 100 under various conditions did not result in the desired methyl migration. Reaction of 100 with formic acid at room temperature smoothly afforded the dehydration product ,101.  The analogous reaction at reflux yielded a complex mixture of  at least seven products. Thus, i t was apparent that the 1,-3-diaxial steric interaction cited above is most efficiently alleviated by simple proton loss, rather than by a 1,2-shift of the C-10 angular methyl group. Similarly, reaction of the y-lactone 102 (obtained by sodium methoxide treatment of the methyl ester of 100) with formic acid at 85° gave a 1:1 mixture of the y-and 6-lactones 104 and 105. unsaturated acid 103.  The reaction was considered to proceed via the In both systems then (100 and 102), the 1,3-diaxial  methyl interactions are relieved immediately by proton loss yielding an  -  100  27 -  >-  unsaturated a c i d ; the o l e f i n i c shift..  acids  a subsequent  r e p r o t o n a t i o n - o f the e t h y l e n i c  101 and 103 does not g i v e r i s e  Hence i t was c o n c l u d e d t h a t  s y n t h e s i s o f eremophilanes, at n a t e l y not p o s s i b l e . In summary t h e n , synthetic  approaches  annelation  double bond o f  to the r e q u i r e d  1,2-methyl  a "methyl-migration"approach t o  l e a s t v i a the above i n t e r m e d i a t e s ,  the  was u n f o r t u -  •  .  the p r e s e n t  l i t e r a t u r e a f f o r d s b a s i c a l l y two  t o . t h e eremophilane s e s q u i t e r p e n e s :  (1)  successful  The Robinson  v a r i a t i o n s r e p o r t e d by M a r s h a l l and C o a t e s , and (2)  the  acid  induced t r i e n e c y c l i z a t i o n method o f Brown.  Each o f t h e s e schemes u n f o r t u n a t e l y  necessitate,  sequence, a r a t h e r  at some p o i n t  i n the  separation of stereoisomer!c  synthetic  products.  difficult  DISCUSSION  As noted i n the was the development  I n t r o d u c t i o n , the o b j e c t of a general  family of sesquiterpenes. eremophilene,  one o f the  Thus,  the  e n t r y i n t o the  f o r t h e development  of such a scheme.  work, the  s t r u c t u r e and a b s o l u t e  herein  eremophilane  stereoselective total  s i m p l e r members o f t h i s  a vehicle  l a t e d as  synthetic  o f the work p r e s e n t e d  synthesis  of  g r o u p , was undertaken as At the  conception of  this  c o n f i g u r a t i o n o f eremophilene were formu-  ( + ) - e r e m o p h i l - 3 , 1 1 - d i e n e 2_ (7).  H  2 The b a s i c this  stereochemical  problems to be r e s o l v e d  s t r u c t u r e were c o n s i d e r e d t o b e :  (1)  the  synthesis  of  i n t r o d u c t i o n o f the v i c i n a l  a n n u l a r methyl groups at C-4 and C-5 o f r i n g A , (2) a c i s - A / B r i n g j u n c t i o n , and (3)  i n the  the e s t a b l i s h m e n t  the e s t a b l i s h m e n t of a  of  cis-relationship  between the a n g u l a r methyl group at C-5 and the C-7 i s o p r o p e n y l g r o u p . The r e a l i z a t i o n o f a c i s - r e l a t i o n s h i p methyl groups w o u l d , o f c o u r s e ,  between the C-4 and C-5 v i c i n a l  be an a d d i t i o n a l r e q u i r e m e n t i n a g e n e r a l  - 29  ,  s y n t h e t i c approach to the The  eremophilanes.  active  i n t e r e s t has  catalysed r e a c t i o n of Grignard reagents systems.  The  Normally,  1,4-adducts.  w i t h a,3-unsaturated  to the unsaturated  (I) s a l t  the otherwise  identical  of copper  o f methylmagnesium  o f copper  (I) c h l o r i d e ,  l e a d s predom-  K h a r a s h and  has  been  Tawney  (41)  (I) c h l o r i d e s i g n i f i c a n t l y  bromide a d d i t i o n to isophorone 1,2-addition products  the product  1,4-adduct, 3,3,5,5-tetramethylcyclohexanone  addition product,  system  (1-5  This f a c t of course,  Thus, the u n c a t a l y s e d r e a c t i o n a f f o r d e d s o l e l y  of the  carbonyl  mole  o f 1 mole p e r c e n t  the presence  1,2-addition  o f a s m a l l amount  t h a t the presence  in  ketone  However, i n the presence  1,4-addition product(s).  course  carbonyl  rather  s i n c e t h e e a r l y o b s e r v a t i o n by  the  copper-  w i t h an a , B - u n s a t u r a t e d  widely recognized  altered  solu-  t h i s r e a c t i o n h e a v i l y f a v o u r s f o r m a t i o n o f 1,2-  o f a copper t o the  i n the  o f compounds d e r i v e d f r o m e i t h e r  or 1,4-addition of the Grignard reagent  percent)  developed  r e a c t i o n of a Grignard reagent  generally affords a mixture  system.  i n the  s y n t h e t i c problems.  I n r e c e n t y e a r s , an  inantly  r  f o l l o w i n g paragraphs o u t l i n e the approach considered  t i o n of these  than  -  106. whereas  mixture  contained  92%  107  8%  1,2-  2,4,6,6-tetramethylcyclohex-l,3-diene  and 108.  of the  -  In the c o u r s e o f subsequent  30  -  investigations  i n t o the n a t u r e o f  these  copper-promoted a d d i t i o n s t o enone s y s t e m s , a d d i t i o n s t o a number o f octalones  were examined, the r e s u l t s  a b i l i t y of this with respect  o f which suggested a p o s s i b l e  r e a c t i o n t o the s y n t h e s i s o f the eremophilanes,  to the s o l u t i o n o f problems  particular interest  (_1) and (2)  was the r e p o r t by M a r s h a l l ,  c o n c e r n i n g a study o f such a d d i t i o n r e a c t i o n s  applica-  specifically  noted above.  F a n t a and Roebke  Of (28)  involving substituted  1 9 A ' -  1 9 octal-2-ones.  Treatment o f the r e a d i l y p r e p a r e d A ' - o c t a l - 2 - o n e  109  (R=H)with an e t h e r - T H F s o l u t i o n o f methylmagnesium i o d i d e and copper a c e t a t e ^ gave,  upon h y d r o l y s i s , a p r o d u c t (80% y i e l d )  the c i s - d e c a l o n e  110  (R=H) • None o f the p o s s i b l e  the C-9 e p i m e r i c t r a n s - d e c a l o n e were d e t e c t e d .  (II)  c o n t a i n i n g 99% o f  1,2-addition products or S i m i l a r treatment  of  10-  19 methylrA  ' -octal-2-one  dimethyldecal-2-one  109  110  109  (R=Me)gave,  a p r o d u c t c o n t a i n i n g 40%  (R=Me)and 60% o f the  110  1,2-adducts  1U  cis-5,10-  (R=Me) . 5  111  Copper ( I I ) i s reduced t o copper ( I ) , i n s i t u , by an e q u i v a l e n t o f the Grignard reagent. See r e f . (10) c i t e d i n J . A . M a r s h a l l and N . H . A n d e r s e n . J. O r g . Chem. 31_, 667 (1966). I n t e r e s t i n g l y , B i r c h and Robinson (42) observed e a r l i e r t h a t the o c t a l o n e 109 (R=Me) underwent e s s e n t i a l l y o n l y 1 , 2 - a d d i t i o n upon r e a c t i o n w i t h methylmagnesium i o d i d e i n the p r e s e n c e o f copper (I) b r o m i d e .  -  Marshall  and h i s  31 -  colleagues explained these r e s u l t s  o f the a l k y l a t i n g reagent  at the  8-carbon atom o f the  c a r b o n y l system must o c c u r p e r p e n d i c u l a r t o the d e p i c t e d i n s t r u c t u r e 112. equally s a t i s f i e d molecule,  Thus, t h i s  by a t t a c k from above  a-Attack of e i t h e r octalone  trans-decalones,  as f o l l o w s .  a,B-unsaturated  IT e l e c t r o n system  (43),  requirement may be  (B) o r below  the p l a n e of  109  (a)  R=H or 109  the  (R=Me),leading to  the  would be p r e c l u d e d due to s t e r i c i n t e r a c t i o n o f the approach  the o t h e r h a n d , B - a t t a c k at C-9 o f the o c t a l o n e hindered s t e r i c a l l y ,  i n the development  109  (R=H)would be  thus r e a d i l y a f f o r d i n g the c i s - f u s e d  (R=H).. 8-Attack on the o c t a l o n e  109  On  less  1,4-addition  (R=Me) ,however would r e s u l t  o f a gauche i n t e r a c t i o n between the incoming "methyl  group" and the a x i a l C-10 methyl s u b s t i t u e n t suggested t h a t t h i s  developing  o f the o c t a l o n e .  1,2-methyl-methyl  Marshall  i n t e r a c t i o n would be  a l l e v i a t e d as the system approached a t r a n s i t i o n s t a t e g e o m e t r i c a l l y to t h a t r e p r e s e n t e d by e n o l a t e conformer 113, methyl group i s  as  stereoelectronic  i n g a l k y l a t i n g r e a g e n t w i t h the a x i a l C - 4 , C-5 and C-7 s u b s t i t u e n t s .  p r o d u c t 110  Attack  i n which the C-9 a n g u l a r  e q u a t o r i a l l y o r i e n t e d with respect  concommitent w i t h t h i s  to the r i n g B-  change would be the development  of s t e r i c  112 between the s u b s t i t u e n t  similar  However, interaction  113 on C - l and the a x i a l s u b s t i t u e n t s  w e l l as between the a x i a l s u b s t i t u e n t  o f C-5 and C-7 as  o f C-3 and t h a t o f C - 5 .  In support  - 32 of this concept is the observation that the copper (II) acetate catalysed reaction of methylmagnesium bromide with either 10-methyl-7a-isopropyl- or 19  10-methy1-7a-isopropeny1-A ' -octal-2-one 114 affords only the 1,2-addition products ,115 and none of the conjugate addition products (28).  R=isopropyl or isopropenyl The above explanation is, of course, a partial one as the role of the copper catalyst in effecting conjugate addition was not considered (28). At this time, no literature precedent had been found which recorded the conjugate addition of a methyl Grignard reagent to a compound contain19 ing the 1-methyl-A ' -octal-2-one moiety 116. However, Theobald has reported (44) the successful Michael addition of cyanide ion to 1,10 1 9  dimethyl^76-isopropenyl-A ' -octalT2-one (a-cyperone) 117.  The reaction  H +  J  - "C0NH  2  119  33  p r o d u c t o b t a i n e d from a r e f l u x i n g e t h a n o l i c  s o l u t i o n of octalone  117,  p o t a s s i u m c y a n i d e and ammonium c h l o r i d e gave a 42:58 m i x t u r e o f the and t r a n s - k e t o  amides  6  118 and 119.  It  is  suggested  pounds a r i s e v i a a 2 - k e t o a s s i s t e d h y d r o l y s i s o f the ketones,  as d e p i c t e d below f o r the t r a n s  case.  (44)  that  cis-  these com-  intermediate  g-cyano  The c y a n i d e i o n i s  evidently  119  sterically  l e s s r e q u i r i n g than the m e t h y l a t i n g reagent  copper-catalysed Grignard additions, trans-isomer  119,  v i a a-attack  involved in  thus a d d i t i o n a l l y g i v i n g r i s e  on o c t a l o n e  two important p o i n t s :  o f the C - l methyl g r o u p , i n t h i s Grignard addition r e a c t i o n ,  is  (1)  to  the  117.  With r e g a r d to the proposed eremophilane s y n t h e s i s , illustrates  the  The u l t i m a t e  this  reaction  stereochemical  r e a c t i o n and i n an analogous  thermodynamically c o n t r o l l e d a s ,  fate  conjugate subsequent  The k e t o amides 118 and 119 are t a u t o m e r i c a l l y r e l a t e d to the hydroxy lactams 120 and 121. I n f r a r e d s p e c t r a , show t h a t the hydroxy lactam form i s h e a v i l y f a v o u r e d , both i n c h l o r o f o r m and i n n u j o l (44).  HO  120  121  -  to carbon-carbon formed i n both  bond f o r m a t i o n a t the 8-carbon atom, an e n o l a t e i o n i s  addition reactions.  a t i o n o f t h e e n o l a t e anions C-9  34 -  Hence, a subsequent thermodynamic p r o t o n -  a s s u r e s a c i s - r e l a t i o n s h i p between the C - l and  substituents of the r e s u l t i n g  decalones  o f the A/B r i n g j u n c t i o n o f t h e conjugate s u c c e s s f u l Michael conjugate  a d d i t i o n o f cyanide  regardless o f the stereochemistry  a d d i t i o n products.  i o n t o o c t a l o n e 1 1 7 suggested  m e t h y l a t i o n o f an eremophilane a n t i c e d e n t such  appropriately  ( 2 ) The  as o c t a l o n e 1 1 6  f u n c t i o n a l i z e d a t C-7, would n o t be p r e c l u d e d due t o an  i n t r a m o l e c u l a r s t e r i c i n t e r a c t i o n i n v o l v i n g the C - l methyl group. if  s u c c e s s f u l , such  all-cis  a methylation  c o u l d be expected  Moreover,  t o a f f o r d the r e q u i r e d  s t e r e o c h e m i s t r y a t C - l , C-9 and C-10 o f t h e r e s u l t i n g  The  that  decalone.  proposed scheme f o r the i n t r o d u c t i o n o f the 73-isopropenyl  group  o f eremophilane remains t o be d i s c u s s e d . The  7 B - i s o p r o p e n y l s u b s t i t u e n t o f eremophilene was c o n s i d e r e d t o be  most c o n v e n i e n t l y r e a l i z e d  i n a manner s i m i l a r t o t h a t employed i n t h e  s y n t h e s i s o f a-cyperone 1 1 7  ( 4 5 ) . As r e p o r t e d by Howe and M c Q u i l l i n ( 4 5 ) ,  Robinson a n n e l a t i o n o f (+)-dihydrocarvone pentanone methiodide c l o s u r e , a mixture densation  1 2 2 i n the presence  o f C-10  122  9  o f base a f f o r d e d , upon a l d o l  epimeric octalones  o f the methiodide  hexanone 1 2 5 , R=H  1 2 3 with l - d i e t h y l a m i n o - 3 -  salt  124.  Analogously,  ring  con-  1 2 2 with t h e known ( 4 6 ) 3 - i s o p r o p e n y l c y c l o -  (or i t s hydroxymethylene  123  derivative  1 2 5 , R=CHOH) would  124  -  be expected to tion  l e a d to the eremophilane a n t i c e d e n t  (and d e f o r m y l a t i o n ) ,  intermediate  35 -  diketone  127.  Following  condensa-  a l d o l c y c l i z a t i o n would l i k e l y p r o c e e d v i a  conformer 126a as the e p i m e r i z i n g c o n d i t i o n s  a l k a l i n e r e a c t i o n medium would c l e a r l y e s t a b l i s h  a cis  the  of  the  r e l a t i o n s h i p between  the e p i m e r i z a b l e "C-10" hydrogen atom and the " C - 7 " i s o p r o p e n y l g r o u p . Moreover,  the C-10 p o s i t i o n o f the p r o d u c t o c t a l o n e  also  epimerizable  thus e n s u r i n g the e q u a t o r i a l o r i e n t a t i o n o f the C-7 i s o p r o p e n y l  substituent.  For reasons c o n s i d e r e d above,  conjugate m e t h y l a t i o n o f o c t a l o n e  would then be expected t o y i e l d the which i n t u r n ,  i n two s t e p s ,  127 i s  all-cis-eremophilone  would a f f o r d  the r a c e m i c m i x t u r e c o r r e s p o n d i n g t o  derivative  (±)-eremophil-3,ll-diene  the proposed s t r u c t u r e o f  127 128  2_,  eremophilene  (7). In summary t h e n , and Theobald (44)  it  from a c o n s i d e r a t i o n o f the r e p o r t s by M a r s h a l l was c o n c l u d e d t h a t  cis-A/B ring junction exhibited conveniently  i n the  be r e a l i z e d s y n t h e t i c a l l y  the  (28)  c i s - v i c i n a l methyl groups and  eremophilane s e s q u i t e r p e n e s might v i a the  conjugate  addition of a  - 36 -  methyl G r i g n a r d reagent to a s u i t a b l y derivative.  This derivative  annelation reaction The  involving  starting material  h e x a n o n e , was  substituted  i n t u r n appeared the r e a d i l y  accessible v i a a  Robinson  available 3-isopropenylcyclohexanone.  f o r the present s y n t h e s i s ,  p r e p a r e d by a p r o c e d u r e e s s e n t i a l l y  r e p o r t e d by H o u s e , L a t h a m and S l a t e r  1 9 ' -octal-2-one  1-methyl-A  (46).  3-isopropenylcyclo-  identical with  Thus, commercial  that  2-cyclohexenone 7  129 u p o n t r e a t m e n t w i t h copper  (I) chloride  isopropenylmagnesium  i n d r y THF,  i s o p r o p e n y l c y c l o h e x a n o n e 130 and  coworkers d i f f e r s  copper  (I) chloride  bromide  and  5 mole p e r c e n t  a f f o r d e d , a f t e r h y d r o l y s i s , the d e s i r e d  i n 70% y i e l d .  i n the use o f copper  c a t a l y s t employed  The  p r o c e d u r e r e p o r t e d by  above.  The  product thus obtained The. i . r .  exhibited  5.85  a strong s a t u r a t e d c a r b o n y l absorbance  and  11.20  and  y a t t r i b u t e d to the s t r e t c h i n g  y  a  spectrum n  x  8.22,  resonance s i g n a l s  a v i n y l methyl group  reported f o r structure evidence i n d i c a t e d  that  An i n t e r e s t i n g  130  a t x 5.22,  (46).  little,  Spectroscopic ( i . r . , i f any,  n.m.r.) a n d  1 , 2 - a d d i t i o n p r o d u c t had  and .important f e a t u r e o f t h i s undergo  reaction  i s the  the hydroxymethylene  derivative  7  Relative  g.l.c.  formed. demonstra-  to that of  aryl  ' >  considered synthetically  Robinson a n n e l a t i o n r e a c t i o n .  and  copper catalysed conjugate  and a l k y l G r i g n a r d r e a g e n t s . i t was  group.  a vinyl proton multiplet,  t o a , 3 - u n s a t u r a t e d k e t o n e s i n a manner a n a l o g o u s  At t h i s p o i n t ,  absorbances  s i n g l e t , were i n agreement w i t h t h e d a t a  t i o n that v i n y l Grignard reagents w i l l addition  d  and d e f o r m a t i o n v i b r a t i o n  o f t h e e t h y l e n i c double bond i n the i n c o r p o r a t e d i s o p r o p e n y l Nuclear magnetic  House  (I) i o d i d e r a t h e r than the  e x h i b i t e d the appropriate s p e c t r o s c o p i c p r o p e r t i e s .  a t 6.12  3-  o f k e t o n e 130  f o r use  Hydroxymethylene  t o t h e number o f m o l e s  efficient i n the  to prepare subsequent  ketones, or 2-formyl ketones  of organo-metallie reagent present.  -  37 -  129  130  have long been used t o a c t i v a t e a  to a carbonyl group.  alkylation reactions o f the  2 - f o r m y l ketone  ketone.,  methylene  The s y n t h e t i c  is  is  treatment  w i t h aqueous  Thus,  a l k y l a t i o n at the  131 i n 75% y i e l d .  o f the p a r e n t ketone  with an a l k y l  after  130 w i t h e t h y l  suitable  following  at 6.02  predominance of the k e t o - e n o l A s t r o n g absorbance at  o f the i s o p r o p e n y l double bond.  11.15  data.  y i n the i n f r a r e d 131b and f o r m y l - e n o l y established  the  The n . m . r . spectrum o f t h i s  pound was p a r t i c u l a r l y i n f o r m a t i v e .  A three-proton singlet  a two-proton unresolved m u l t i p l e t  x 5.25  at  derivative  spectroscopic  and 6.22  formate  work-up and  the d e s i r e d hydroxymethylene  T h i s m a t e r i a l gave the  forms.  activated  to a l k y l a t i o n , may be r e a d i l y removed by  The u n s a t u r a t e d c a r b o n y l absorbances  131c t a u t o m e r i c  parent  a c t i v a t i n g f o r m y l group may be r e a d i l y i n t r o -  i n dry benzene gave,  i n d i c a t e d the expected  base  base.  reduced p r e s s u r e d i s t i l l a t i o n ,  presence  t h a t the c o n j u g a t e  the r e a c t i o n o f 3 - i s o p r o p e n y l c y c l o h e x a n o n e  and sodium methoxide  in  more s t a b l e than t h a t o f the  a facile  condensation  and subsequent  located  u t i l i t y o f these d e r i v a t i v e s  significantly  M o r e o v e r , the  duced, by b a s e - c a t a l y z e d formate e s t e r ,  o r methyl group p r o t o n s  s i m p l y d e r i v e d from the f a c t  hence r e n d e r i n g p o s s i b l e  a - c a r b o n atom.  131  at x 8.26  were r e a d i l y a s s i g n e d  v i n y l methyl group and v i n y l hydrogen atoms o f the C-5 i s o p r o p e n y l  to  comand the  substituent  - 38 -  H  131b  131c  A sharp o n e - p r o t o n s i n g l e t at x - 4 . 0  were a l s o  evident.  at x 1.4  and a v e r y b r o a d o n e - p r o t o n m u l t i p l e t  Assignment o f these resonances  comment on the t a u t o m e r i c e q u i l b r i a r e p r e s e n t e d above. resonance  studies  (47)  requires  brief  N u c l e a r magnetic  o f 2 - f o r m y l c y c l o h e x a n o n e and a number o f  related  compounds, have e s t a b l i s h e d t h a t the e n o l i c tautOmers o f these compounds, e.g.  131b and 131c,  over, tive  are n o r m a l l y predominant t o the e x t e n t o f 99%.  the e q u i l i b r i u m between the two p o s s i b l e to n . m . r .  spectra averaging)  between the f o r m y l k e t o n e , ingly,  a  and  faster  o f the e n o l s  (rela-  than the c o r r e s p o n d i n g e q u i l i b r i a  151a and the two e n o l i c t a u t o m e r s .  the above mentioned x 1.4  of protons H x -4.0  e.g.  e n o l i c forms i s  More-  s i g n a l was d e s i g n a t e d as the s i g n a l 131b and 131c;  analogously,  Accordaverage  the broad  s i g n a l was r e a d i l y a t t r i b u t e d to the hydrogen-bonded hydroxy1  hydrogens o f 131b and 131c.  Simple c a l c u l a t i o n s  (47)  revealed that  e n o l i c m i x t u r e was composed o f a p p r o x i m a t e l y 22% 131c and 78% 131b.  the  - 39  -  C o n s i d e r a t i o n was t h e n d i r e c t e d to the s y n t h e s i s o f o c t a l o n e Robinson a n n e l a t i o n r e a c t i o n methiodide presence  employing  l-diethylamino-3-pentanone  122 and hydroxymethylene d e r i v a t i v e  o f m e t h a n o l i c sodium methoxide  afforded, 132.  (48)  upon a c i d i f i c a t i o n and e t h e r  131 c a r r i e d out i n  isolation,  a crude f o r m y l  The crude d e f o r m y l a t e d m a t e r i a l s u b s e q u e n t l y  a strong saturated  c a r b o n y l absorbance a t  c a r b o n y l absorbance a t  6.02  octalone  127,  5.86  Hence, t o e f f e c t  for five  thus  samples  of this  131.  ring  c l o s u r e t o the  to s i x hours.  The s p e c t r o s c o p i c  s t r u c t u r e 127. (£ =14,600). absorbances  The u l t r a v i o l e t  (u.v.)  6.20  and 11.25  v i n y l protons.  was  properties  at  thus  o r by p u r i -  the  assigned  showed an absorbance at  T 5.26,  A p o o r l y r e s o l v e d q u a r t e t at  refluxed  of a n a l y t i c a l  y and  The n . m . r .  which was a s s i g n e d  T 8.22  ( J = 1.2  and 1.8  to  a t C-10 and C - 8 .  was a t t r i b u t e d t o the t o the v i n y l p r o t o n s .  i s o p r o p e n y l methyl group b e i n g a l l y l i c a l l y coupled  by a d e c o u p l i n g experiment i r r a d i a t e d thus singlet,  effecting  i n which the the  l e a v i n g the x 8.22  collapse  olefinic of the.x  q u a r t e t unchanged.  assignments were  (47)  established  p r o t o n s at x 5.26 8.25  (47)  ( J = 1.2 Hz)  S i m i l a r l y a t r i p l e t at x 8.25  The above c h e m i c a l s h i f t  the  Hz) was  a t t r i b u t e d t o the C - l methyl group which was h o m o a l l y l i c a l l y coupled to the a x i a l p r o t o n s  249.5 my  olefinic  u appeared i n the i . r . spectrum.  spectrum showed an u n r e s o l v e d m u l t i p l e t  desired  127 i n 64% y i e l d ,  oxime 159,. s u b s t a n t i a t e d  spectrum  aldol  The p r o d u c t  An u n s a t u r a t e d c a r b o n y l absorbance at 6.00 at  126,  compound, o b t a i n e d e i t h e r by p r e p a r a t i v e g . l . c .  f i c a t i o n v i a the h y d r o l y s i s o f i t s  showed  i n d i c a t i n g that  o b t a i n e d was f r a c t i o n a l l y d i s t i l l e d a f f o r d i n g o c t a l o n e based on hydroxymethylene  potassium  isolated  t h i s m a t e r i a l , c o n t a i n i n g m a i n l y the d i k e t o n e  w i t h m e t h a n o l i c sodium methoxide  diketone  y and a weak u n s a t u r a t e d  y i n the i n f r a r e d ,  c y c l i z a t i o n was i n c o m p l e t e .  the  at room temperature f o r 48 h o u r s ,  T h i s i n t e r m e d i a t e was then d i r e c t l y t r e a t e d w i t h aqueous  hydroxide.  127.  were  t r i p l e t t o a sharp  As noted above,  assignment  - 40  of  the  -  B - o r i e n t a t i o n o f the C-7 i s o p r o p e n y l group i s made on the  the C-10 p o s i t i o n  is  The e l e m e n t a l  e p i m e r i z a b l e under the r e a c t i o n  analysis  of this  agreement  conditions.  compound (as w e l l as a l l o t h e r  u n r e p o r t e d compounds which have been s y n t h e s i z e d complete  basis t h a t  w i t h the c a l c u l a t e d  herein)  previously  gave r e s u l t s  in  values.  CHO  H  159  127  With the s y n t h e s i s o f the  desired octalone  127 complete,  introduction  8 o f the C-5  a n g u l a r methyl group o f the eremophilane  accomplished.  To t h i s  e t h y l ether s o l u t i o n monohydrate.  127 was t r e a t e d w i t h a t e t r a h y d r o f u r a n -  o f methylmagnesium i o d i d e and copper  The copper a c e t a t e - t e t r a h y d r o f u r a n  employed by M a r s h a l l 8  end, octalone  Unless o t h e r w i s e employed.  system remained to be  (28) noted,  (II)  acetate  system has been  i n the a l k y l a t i o n o f a v a r i e t y o f  successfully  octalones.  eremophilane system numbering w i l l be  henceforth  -  41  -  A f t e r h y d r o l y s i s and w o r k - u p , a p r o d u c t was o b t a i n e d which e x h i b i t e d a weak saturated material g.l.c.  c a r b o n y l peak a t  5.85  u.  A n a l y s i s by g . l . c .  c o n t a i n e d a complex m i x t u r e o f at  isolation  o f one o f t h e s e components  shown t o be i d e n t i c a l t o a u t h e n t i c as s u b s e q u e n t l y  d e s c r i b e d below.  least  10 components.  (i)-eremophil-ll-en-3-one  the  eremophilane d e r i v a t i v e These r e s u l t s  128 p r e p a r e d  v a r i e d somewhat  1,4-adduct  128  the irreproduc-  (10-25%).  Thus  c o p p e r - c a t a l y z e d G r i g n a r d a d d i t i o n approach t o  128 was not s y n t h e t i c a l l y  were i n agreement  despite repeated attempts,  (50) .  the copper  a d d i t i o n o f methyl G r i g n a r d reagent  (I)  the  useful.  w i t h those r e p o r t e d i n a  observed paper by I r e l a n d and c o l l e a g u e s that,  sample  U n f o r t u n a t e l y the c o m p o s i t i o n o f  i b l y both i n c o m p l e x i t y and p e r c e n t o f the  this  Preparative  a f f o r d e d an a n a l y t i c a l  p r o d u c t s o b t a i n e d from a number o f such r e a c t i o n s  i t was c o n c l u d e d t h a t  indicated that  subsequently  These workers r e p o r t e d bromide c a t a l y s e d  t o the k e t a l o c t a l o n e  153 was  conjugate unsuccess-  ful.  133  At t h i s  juncture,  Respess and W h i t e s i d e s copper i n conjugate  attention (51)  was d i r e c t e d to a r e c e n t  c o n c e r n i n g an i n v e s t i g a t i o n  Grignard a d d i t i o n s .  two e t h e r s o l u b l e methyl c o p p e r - a t e e x h i b i t e d a remarkable s e l e c t i v i t y a d d i t i o n - as opposed t o  In the course  complexes  (52)  toward e f f e c t i n g  1,2-addition  r e p o r t by House,  i n t o the r o l e of t h i s  of  investigation  were p r e p a r e d which preferential  - o f a methyl group t o  conjugate  a,8-unsaturated  - 42 -  ketones. methyl  For example,  reaction of trans-pent-3-en-2-one  copper-tri-n-butylphosphine  afforded  a product containing  one 137.  Of the  134 o r l i t h i u m d i m e t h y l c u p r a t e  > 99% o f the  two complexes,  136 with  1,4-adduct,  either 135  4-methyl-pentan-2-  l i t h i u m dimethylcuprate  135 was p a r t i c u l a r l y  MeCuPBu  134  135  attractive  i n that  o f two e q u i v a l e n t s  it  136  c o u l d be c o n v e n i e n t l y  of ethereal  c o n t a i n i n g one e q u i v a l e n t  methyl  o f copper  137  p r e p a r e d s i m p l y by the  l i t h i u m to a c o l d  (I)  iodide.  addition  ( 0 ° ) ethereal  T h u s , the  selectivity  e x h i b i t e d by t h e s e organo-copper complexes upon r e a c t i o n w i t h ketone and o t h e r a , B - u n s a t u r a t e d  ketones,  135,  a p p l i c a b i l i t y to the  suggested an obvious Thus,  ethereal  it  was found t h a t  desired  127  0 ° and under n i t r o g e n  128.  An a n a l y t i c a l  136  preparation of synthesis.  127 w i t h an excess  a p r o d u c t shown by g . I . e .  73-eremophil-ll-en-3-one  H  at  facile  eremophilene  reaction of octalone  lithium dimethylcuprate,  gave, upon a c i d h y d r o l y s i s ,  i n a d d i t i o n to the  slurry  of  f o r two h o u r s ,  t o c o n t a i n 77% o f sample,  H  128  o b t a i n e d by  the  - 43 -  preparative g . l . c , that  afforded spectroscopic  r e q u i r e d by f o r m u l a t i o n 128.  strong saturated due t o the spectrum  d a t a i n complete  Of p a r t i c u l a r note i n the  c a r b o n y l absorbance observed at  i s o p r o p e n y l double bond a p p e a r i n g at  (Figure  5.86 6.10  a o n e - p r o t o n q u a r t e t at  T 7.17  the C-4 p r o t o n , and a p o o r l y r e s o l v e d t r i p l e t at t o the C-13 v i n y l methyl g r o u p . doublet  at  x 9.11  (J^ ^  = 6.7  Strong i r r a d i a t i o n at  triplet  to a sharp s i n g l e t ,  C-12 and C-13 p r o t o n s . a p a r t i a l collapse  x 8.29  y.  The n . m . r .  assigned  = 6.7  to  Hz) due  the to  readily attributed  Hz) and a s i n g l e t  x 5.33  at  x 9.21,  respectively.  confirmed the c h e m i c a l s h i f t  effected  the  collapse  S i m i l a r l y , s t r o n g i r r a d i a t i o n at  o f the  absorbances  o f the  assign-  x  8.29  thus c o n f i r m i n g a l l y l i c c o u p l i n g between the  x 9.11  T h i s was t a k e n as evidence and x 9.11  and 11.27  the  The C-14 and C-15 methyl groups a f f o r d e d a  Frequency-swept d e c o u p l i n g experiments ments.  y and the  (J^ ^  with  i . r . was  at T 5 . 3 3 ,  3 ) gave a two-proton m u l t i p l e t  C-12 v i n y l p r o t o n s ,  agreement  doublet  x 7.17  to a p o o r l y r e s o l v e d  i n support o f the above assignment  resulted  in  triplet. o f the  x  7.17  signals.  Some mention o f the quenching p r o c e d u r e o f the r e a c t i o n o f o c t a l o n e 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 135 s h o u l d be made.  Subsequent  a d d i t i o n o f a methyl group to a g i v e n a , 3 - u n s a t u r a t e d anion i s  formed which  is  ketone,  the  ammonium c h l o r i d e .  In p r e l i m i n a r y e x p e r i m e n t s ,  t h e s e workers found  faster  to  l e d to a complex m i x t u r e c o n t a i n i n g both mono- and  d i - a l k y l a t i o n products. evidently  al.  saturated  i n v e r s e p r o c e d u r e , a d d i t i o n o f the ammonium c h l o r i d e s o l u t i o n  the r e a c t i o n m i x t u r e ,  is  an e n o l a t e  The quenching p r o c e d u r e g i v e n by House e t .  r e q u i r e d p o u r i n g the r e a c t i o n m i x t u r e i n t o v i g o r o u s l y s t i r r e d  that  conjugate  u l t i m a t e l y k e t o n i z e d by p r o t o n a t i o n d u r i n g the  r e a c t i o n work-up p r o c e d u r e .  aqueous  to  127  K e t o n i z a t i o n o f the  than the  1,4-addition  derived  a c i d d e s t r u c t i o n o f the organo-copper  enolate species,  - 45  -  . h e n c e , the s a t u r a t e d ketone thus formed r a p i d l y undergoes •by 1 , 2 - a d d i t i o n  o f the u n r e a c t e d methyl copper s p e c i e s .  further However,  alkylation applica-  t i o n o f the recommended ammonium c h l o r i d e quenching p r o c e d u r e i n our case gave a complex m i x t u r e o f p r o d u c t s . increase  i n the  Subsequently  was found t h a t  a c i d i t y o f the quenching medium was r e q u i r e d .  a d d i t i o n o f the r e a c t i o n m i x t u r e to v i g o r o u s l y a c i d afforded a considerably d e s i r e d decalone  it  128 and o n l y a s m a l l number o f minor the  An a - c o n f i g u r a t i o n  from an a - r a t h e r than B - a t t a c k Sterically,  t h i s appears  indicated in structure  less  evidence  8-orientation  indicated  at C-4 and C-5 w o u l d , o f c o u r s e ,  likely.  However, the r e l a t i v e  128 was confirmed by chemical  c o r r e l a t i o n of  r e d u c t i o n o f decalone  as d e s c r i b e d below,  which was s u b s e q u e n t l y  r e a c t i o n of  o f know a b s o l u t e  found t o be  (+)-78-eremophilane 45,  eremophilone _30_ by l i t e r a t u r e p r o c e d u r e s The  analytical  sample o f t h i s  i n 65% y i e l d .  d e f o r m a t i o n absorbances spectrum o f t h i s one-  at 5.95  11.20  and 6.40  configur128  led  to  spectroscopically  obtained  from h y d r o x y d i h y d r o  r e a d i l y afforded  y,  the  The i . r . spectrum o f an  c r y s t a l l i n e m a t e r i a l showed,  i s o p r o p e n y l double bond absorbance at  this  128 with s e m i c a r b a z i d e h y d r o -  c h l o r i d e and sodium a c e t a t e i n r e f l u x i n g e t h a n o l 137,  127•  (22).  (±)-eremophil-ll-en-3-one  c o r r e s p o n d i n g semicarbazone  result  stereochemistry  ation.  i d e n t i c a l with authentic  in  o f the a l k y l a t i n g reagent on o c t a l o n e  30,  an e r e m o p h i l a n e ,  given  t o b o t h the C-4  compound w i t h h y d r o x y d i h y d r o e r e m o p h i l o n e Specifically,  the  components.  spectroscopic  C-5 methyl s u b s t i t u e n t s , r a t h e r than the 128.  slow  s t i r r e d 1 M aqueous h y d r o c h l o r  above would not p r e c l u d e assignment o f an a - o r i e n t a t i o n  structure  Thus,  l e s s complex p r o d u c t m i x t u r e c o n t a i n i n g  I t might c o r r e c t l y be argued that  and  an  strong  i n a d d i t i o n to  the  c a r b o n y l and N-H  y, r e s p e c t i v e l y .  The n . m . r .  compound f u r t h e r confirmed s t r u c t u r a l assignment 137.  and t w o - p r o t o n b r o a d m u l t i p l e t s a p p e a r i n g at  x 1.40  and x 4.24  were  The  -  r e a d i l y assigned ively.  Signals  46 -  t o the secondary and p r i m a r y amide hydrogen atoms, due t o the i s o p r o p e n y l group p r o t o n s  respect-  appeared as an  12 unresolved m u l t i p l e t  at T 5.27  (-C  =H ) and a p o o r l y r e s o l v e d t r i p l e t 2  at  13 x 8.27  (-C  H ). 3  A t h r e e - p r o t o n s i n g l e t a t T 9.24 was a t t r i b u t e d to the C-15  a n g u l a r methyl g r o u p . poorly resolved assigned  Finally,  a T.9.06  one-proton quartet  (J^^  = 6.8 Hz) d o u b l e t  a t T 7.25  centered  (J^^  and a  = 6.8 Hz) were  to t h e methyl and t e r t i a r y hydrogen s u b s t i t u e n t s o f C - 4 , r e s p e c t i v e l y .  NH COHNN 2  128  137  45  138  Haung-Minlon r e d u c t i o n upon treatment refluxing  137 (50) was a c c o m p l i s h e d  o f t h i s m a t e r i a l w i t h excess h y d r a z i n e h y d r a t e and base i n  diethylene  glycol.  11-ene 138 i n h i g h y i e l d . olefin  (53) o f the semicarbazone  The r e a c t i o n c l e a n l y a f f o r d e d  (t)-eremophil-  The i . r . spectrum o f an a n a l y t i c a l  138, o b t a i n e d by p r e p a r a t i v e g . l . c ,  e x h i b i t e d the expected  at  6.08 and 11.28 u ,  Both the c a r b o n y l and the N-H absorbances  p r e v i o u s l y observed  stretching  and d e f o r m a t i o n absorbances  r e g i o n were now a b s e n t . multiplet  sample o f olefinic  respectively. i n the 5 . 5 - 6 . 5 y  The n . m . r . spectrum o f 138 showed an u n r e s o l v e d  at T 5 . 3 8 , a t t r i b u t e d to the two C-12 o l e f i n i c  protons  and a t h r e e -  - 47 -  .  proton, poorly resolved triplet at x 8.32 due to the C-13 vinyl methyl group. A singlet appearing at x 9.17 was assigned to the tertiary C-15 methyl group and a x 9.28 (J„ , ,. = 6.5 Hz) doublet was readily attributed to the v  4,14  J  secondary C-14 methyl group. Reduction of the olefin 138 to (±)-7B-eremophilane 45_ was accomplished by hydrogenating an ethanolic solution of compound 138 in the presence of platinum oxide catalyst.  An analytical sample of the resulting product,  isolated by preparative g . l . c , afforded spectroscopic data in complete agreement with that required by structure 4_5. Of particular importance in the infrared spectrum was the absence of the 6.08 and 11.28 u olefinic absorbances and the appearance of a sharp doublet at 7.22 and 7.30 u, characteristic of an isopropyl substituent. Moreover, comparison of the i . r . spectrum of this material with a copy of the i.r. spectrum of authentic 9  (+)-73-eremophilane  suggested that the two substances were indeed identical.  The n.m.r. spectrum of the synthetic eremophilane showed a six-proton doublet centered at x 9.15 ( J ^  12(13)  = 6  Hz  ^ ' attributed to the magnetically  equivalent C-12 and C-13 isopropyl methyl groups. A three-proton singlet appeared at x 9.16 which was assigned to the angular C-15 methyl group. The signal due to the annular C-14 methyl group appeared as a doublet at x 9.28 (J  = 6.5 Hz). 4  It is interesting that, as might reasonably be expected,.  , J.4  hydrogenation of the A^^-double bond in 138 did not significantly influence the chemical shift of the C-14 and C-15 methyl groups. This is apparent upon comparison of the above noted C-14 and C-15 methyl group signal positions in the n.m.r. spectra of 4_5 and 138. Consideration was then directed to the conversion of authentic hydroxydihydroeremophilone 3_0 Dr. to (+)-73-eremophilane This sequence We are indebted to H. Ishii for a copy 45_. of the i . rreaction . spectrum of (+)-73-eremophilane. 9  has been p r e v i o u s l y r e p o r t e d pounds t h e r e i n . upon treatment was i s o l a t e d  (22)  48  -  along w i t h the  c h a r a c t e r i z a t i o n o f the  Thus h y d r o x y d i h y d r o d e r e m o p h i l o n e 3 0 ^ with a c e t i c a n h y d r i d e i n dry p y r i d i n e .  from the r e a c t i o n m i x t u r e w h i c h , a f t e r  a melting point  (68-71°)  and i . r .  spectrum  (3.42,  underwent  acetylation  A crystalline  product  recrystallization,  5.73,  5.80,  com-  exhibited  7.70-8.5,  corresponding to that p r e v i o u s l y reported f o r hydroxydihydroeremophilone  11.10 M) acetate  139. Subsequent ammonia a t  treatment  - 3 3 ° (22),  o f the k e t o a c e t a t e 139 w i t h c a l c i u m i n  f o l l o w e d by a p p r o p r i a t e work-up a f f o r d e d  c o n t a i n i n g the d e a c e t o x y l a t e d  product,  liquid  a crude o i l  (+)-78-eremophil-ll-en-9-one  The v e r y generous sample o f a u t h e n t i c h y d r o x y d i h y d r o e r e m o p h i l o n e from D r . L . H . Zalkow i s g r a t e f u l l y acknowledged.  140.^ obtained  I t i s p e r t i n e n t t o note here t h a t the C-10 p o s i t i o n o f ketone 140 i s e p i m e r i z a b l e , thus i n p r i n c i p l e e n a b l i n g , under the c o n d i t i o n s o f t h i s r e a c t i o n , the f o r m a t i o n o f decalone d e r i v a t i v e s c o n t a i n i n g e i t h e r c i s - o r trans-fused A/B ring junctions. However, i t has been p r e v i o u s l y e s t a b l i s h e d t h a t the c i s - f u s e d A / B r i n g system o f 7 B - e r e m o p h i l - l l - e n - 9 - o n e 140 i s t h e r m o d y n a m i c a l l y f a v o u r e d over the c o r r e s p o n d i n g t r a n s - f u s e d system ( 2 2 ) . t h i s i s p r e d o m i n a n t l y due t o the p r e s e n c e o f the 7 g - i s o p r o p e n y l substituent. Thus upon c o n s i d e r a t i o n o f the t r a n s - f u s e d s t e r e o i s o m e r , i t i s apparent t h a t  the c h a i r - c h a i r conformer 141a n e c e s s i t a t e s a v e r y s u b s t a n t i a l 1,3-diaxial s t e r i c i n t e r a c t i o n between the a x i a l C-5 methyl and C-7 i s o p r o p e n y l substituent. T h i s 1 , 3 - d i a x i a l i n t e r a c t i o n would be absent i n the r e l a t e d c h a i r - b o a t conformer 141b. Of the a l t e r n a t i v e c i s - f u s e d conformers 140a and 140b, the l a t t e r i s f a v o u r e d , p r e d o m i n a n t l y due to the absence of 1 , 3 - d i a x i a l i n t e r a c t i o n between the 3 C-5 and C-7 s u b s t i t u e n t s . As both t r a n s - f u s e d conformers 141a and 141b are o b v i o u s l y thermodynamically l e s s s t a b l e than the c i s - c o n f o r m e r 140b, c i s - 7 g - e r e m o p h i l - l l - e n - 9 - o n e 140 i s the p r o d u c t formed under the a l k a l i n e c o n d i t i o n s o f the above mentioned reaction.  - 49 Repeated chromatography of this crude o i l on Woehlm neutral alumina enabled the isolation of g.l.c. pure 140. This material exhibited an i.r. spectrum (3.45, 5.86, 6.08, 11.20 u) in accordance with that previously reported for (+)-73-eremophil-ll-en-9-one.  In addition, the n.m.r. spectrum of 140  indicated an unresolved multiplet at T 5.26 due to the C-12 vinyl protons and an unresolved triplet at T 8,27 due to the C-13 vinyl methyl group. The C-14 and C-15 annular methyl groups appeared as a three-proton doublet at T.9.23 (J. ... = 5.9 Hz) and a three-proton singlet at x 8.97, respectively. 4,14  Reduction of the C-9 carbonyl function of the thus obtained cis-dihydroeremophilone 140 was effected by Haung-Minlon reduction, as described earlier (22).  The reaction of ketone 140 with excess hydrazine hydrate and base  in refluxing diethylene glycol followed by ether isolation gave a product shown by g.l.c. to contain 65% of the desired cis-olefin (+)-138 and several other relatively minor components. Preparative g.l.c. isolation afforded an analytical sample which exhibited an i.r. spectrum in agreement with that required by structure 138.  -  50 -  Comparisons were then c a r r i e d out which c o n c l u s i v e l y the a u t h e n t i c 138  (+)-78-eremophil-ll-ene  (1)128,  ( d e r i v e d from  index,  as d e s c r i b e d above)  i . r . , n . m . r . and g . l . c .  Figure  138 ( d e r i v e d from  established (+)30)  that  and r a c e m i c  were i d e n t i c a l by r e f r a c t i v e  r e t e n t i o n times on f o u r d i f f e r e n t  columns.  4_ shows the comparison i . r . s p e c t r a o f the " n a t u r a l " and " s y n t h e t i c "  78-eremophil-ll-enes. The f i n a l  s t e p i n the c o n v e r s i o n o f n a t u r a l h y d r o x y d i h y d r o e r e m o p h i l o n e  30 t o (+)-7B-eremophilane  was a c c o m p l i s h e d by c a t a l y t i c r e d u c t i o n o f  eremophil-ll-ene  138 w i t h hydrogen and p l a t i n u m o x i d e .  o f the authentic  (+)-7 8-eremophi l a n e ,  An a n a l y t i c  (+)sample  o b t a i n e d by p r e p a r a t i v e g . l . c ,  exhibited  9 an i . r . spectrum i n accordance w i t h t h a t p r e v i o u s l y determined f o r Subsequent  comparison o f the thus  c o r r e s p o n d i n g r a c e m i c 7 8-eremophilane above) tive  clearly established  index,  columns.  _5  (+)-45_ w i t h the  ( d e r i v e d from d e c a l o n e  128, as d e s c r i b e d  the two m a t e r i a l s were i d e n t i c a l by r e f r a c -  i . r . , n . m . r . . and g . l . c .  Figure  "synthetic"  that  obtained authentic  r e t e n t i o n times on t h r e e  different  shows the comparison i . r . s p e c t r a o f the " n a t u r a l " and  76-eremophilanes  45.  The above c o r r e l a t i o n o f the dextrorotatory and r a c e m i c compounds (i)-l_38 and (+)-45,  (-) -45 c o n c l u s i v e l y  stereochemistry  of  structure  Thus,  128.  synthetic  the s u c c e s s f u l  it  was c o r r e c t l y r e p r e s e n t e d by  s t e r e o s e l e c t i v e conjugate  addition of  127 c l e a r l y enabled a new and c o n -  of the c r u c i a l  sesquiterpenes.  eremophilane d e r i v a t i v e 128  i s worthwhile t o c o n s i d e r a t t h i s  r e a c t i o n by which t h i s  (+)-138_,  that the r e l a t i v e  e n t r y i n t o the eremophilane c l a s s o f  With the s t e r e o c h e m i s t r y established,  established  (i)-7B-eremophil-ll-en-3-one  l i t h i u m d i m e t h y l c u p r a t e 135 t o o c t a l o n e venient  (+)-45.  compound was s y n t h e s i z e d .  point  the n a t u r e o f t h e  A l t h o u g h the mechanism  i n v o l v e d i n the r e a c t i o n o f l i t h i u m d i m e t h y l c u p r a t e 135 w i t h c t , g - u n s a t u r a t e d ketones i s as y e t u n e s t a b l i s h e d ,  an i n t e r e s t i n g  hypothesis  concerning  -  this  53 -  r e a c t i o n has been proposed by House and coworkers  be o u t l i n e d  (51,54)  and t h i s  below.  I t has been suggested by these workers t h a t  the e t h e r  soluble  lithium  d i m e t h y l c u p r a t e complex 155 e x i s t s i n r a p i d e q u i l i b r i u m w i t h methyl and methyl copper 142. ether i n s o l u b l e ,  The l a t t e r  o r g a n o m e t a l l i c compound i s  lithium  a yellow,  and a p p a r e n t l y p o l y m e r i c m a t e r i a l , which may be r e a d i l y  p r e p a r e d by r e a c t i n g equimolar amounts o f methyl l i t h i u m and copper i o d i d e i n dry e t h e r  (52).  As d e p i c t e d i n e q u a t i o n  (1),  (I)  the e q u i l i b r i u m c o n -  c e n t r a t i o n s ' o f both methyl l i t h i u m and the methyl copper s p e c i e s 142  MeLi  +  (MeCu)  ——>  n  n o r m a l l y extremely o f the  lithium)  small i n that  the e q u i l i b r i u m l i e s  a relatively  toward c a r b o n y l f u n c t i o n s  has been r e p o r t e d  of equilibrium  (51)  low r e a c t i v i t y  (51,54).  complete  ethereal  (relative  Moreover, n . m . r .  to  data,  l i t h i u m dimethylcuprate  which s u p p o r t s both the e x i s t e n c e and p o s i t i o n  the a d d i t i o n o f  ketone proceeds  l i t h i u m d i m e t h y l c u p r a t e t o an  v i a a one-electron  or p a r t i a l t r a n s f e r o f an e l e c t r o n  ate-complex  The  (1).  House has s u g g e s t e d t h a t a,g-unsaturated  f a r t o the r i g h t .  e q u i l i b r i u m was e v i d e n c e d by the o b s e r v a t i o n t h a t  o b t a i n e d from v a r i a b l e temperature s t u d i e s o f the system,  Q)  2  155  lithium dimethylcuprate exhibits methyl  are  Me Cu L i  142  position  will  t r a n s f e r mechanism.  from the copper  (I)  The  atom o f  155 t o the a , B - u n s a t u r a t e d c a r b o n y l system 156 would l e a d t o  f o r m a t i o n o f an a n i o n - r a d i c a l 144 o r a charge t r a n s f e r complex.  Such  t r a n s f e r from the copper atom o f 135 would l i k e l y be enhanced by the n e g a t i v e charge o f the complex from the t r a n s i e n t  (52) .  Subsequent  d i m e t h y l copper ( I I )  species  t r a n s f e r o f a methyl 143 to the  the the  electron net radical  B-position of anion-  -  54 -  •>-  Li  +  < (I)Cu-CH  Li 0' +  136 3  135  radical  142  143  144,  o r the c o l l a p s e  o f the  charge t r a n s f e r complex would y i e l d  a l k y l a t e d e n o l a t e 145 and methyl copper 142. work-up would then a f f o r d the f i n a l p r o d u c t , Although i t a,g-unsaturated  from the e t h e r e a l (51).  K e t o n i z a t i o n 145 d u r i n g 137.  remains to be e x p e r i m e n t a l l y e s t a b l i s h e d ketone system, reaction of  c l e a r l y i n d i c a t e d the presence  f o r the  above  some support f o r House's p o s t u l a t e  is  derived  l i t h i u m dimethylcuprate with fluorenone  The e l e c t r o n s p i n resonance  (e.s.r.)  .spectrum o f t h i s green  o f the r e l a t i v e l y s t a b l e  an e . s . r .  solution  a n i o n - r a d i c a l 147.  spectrum and simply l e d to  the 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 i o n a f f o r d e d d i o l reaction product.  148 as a  Thus the i m p l i c a t i o n was t h a t d i o l  these f i n d i n g s tenuous.  significant  148 was formed v i a a generated  As House has s u g g e s t e d , the a p p l i c a b i l i t y of  to a d i s t i n c t l y d i f f e r e n t m o l e c u l a r system i s  However i t  146  9-methylfluorenol,  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 the a n i o n - r a d i c a l 147 which had been by the organocopper r e a g e n t .  of  course  does i n d i c a t e t h a t such i o n - r a d i c a l systems may be  g e n e r a t e d by l i t h i u m d i m e t h y l c u p r a t e .  .  146  Moreover, u n l i k e the r e a c t i o n o f e t h e r e a l methylmagnesium bromide with which f a i l e d to e x h i b i t  the  - 55 -  146  147  148  Assuming t h a t the r e a c t i o n o f l i t h i u m d i m e t h y l c u p r a t e w i t h a , ^ - u n s a t u r a t e d ketones proceeds as d e s c r i b e d above, the s t e r e o s e l e c t i v i t y  observed  i n the a d d i t i o n o f t h i s  most  p r o b a b l y due t o s t e r i c  organocopper reagent t o o c t a l o n e factors.  from the a s i d e o f o c t a l o n e  127 i s  T h u s , approach o f t h e a l k y l a t i n g reagent  127 would r e s u l t i n s i g n i f i c a n t s t e r i c  interaction  12 between the incoming r e a g e n t and the a x i a l C - 4 , C-5 and C-7  hydrogens.  8-Approach on the o t h e r hand would be s i g n i f i c a n t l y l e s s h i n d e r e d . or p a r t i a l  Complete  t r a n s f e r o f an e l e c t r o n from a m o l e c u l e o f l i t h i u m d i m e t h y l -  c u p r a t e s i t u a t e d on the r i n g A 3-face o f the o c t a l o n e ,  127a, would a f f o r d  t h e a n i o n - r a d i c a l o r charge t r a n s f e r complex r e p r e s e n t e d by s t r u c t u r e 149. Subsequent t r a n s f e r o f a methyl r a d i c a l  t o t h e C-9 p o s i t i o n o f 149,  c o l l a p s e o f the charge t r a n s f e r complex would g i v e the e n o l a t e 150. hydrolysis,  150 would y i e l d the a l l - c i s - d e c a l o n e  The numbering employed h e r e i s  or Upon  128a.  t h a t o f the A ' - o c t a l - 2 - o n e  system.  - 56 -  OLi 128a  •  C o n v e r s i o n o f decalone  150  128 i n t o  s i d e r e d to be most e f f i c i e n t l y d e r i v a t i v e o f ketone  (i)-eremophil-3,11-diene  a c c o m p l i s h e d by s u b j e c t i n g  128 to the Bamford-Stevens r e a c t i o n  t o a sequence i n v o l v i n g metal h y d r i d e r e d u c t i o n o f ketone d e h y d r a t i o n o f the r e s u l t i n g recently  reported that  ethylene glycolate  alcohol.  tosylhydrazone  i n ethylene g l y c o l  the (56)  2_ was  tosylhydrazone r a t h e r than  128 and  i t was s u g g e s t e d t h a t  (17)  upon h e a t i n g w i t h sodium  (Bamford-Stevens  reaction),  a f f o r d e d an i s o m e r i c a l l y homogeneous p r o d u c t shown to be a-eudesmol Thus,  subsequent  Humber, P i n d e r and W i l l i a m s 151,  con-  cleanly 152.  a p p l i c a t i o n o f the Bamford-Stevens r e a c t i o n  in  - 57 -  TsHNN'  152  the  eremophilane  case might enable  the  specific  i n t r o d u c t i o n of  the  3  r e q u i r e d A -double bond.  128  To t h i s  153  end, decalone  128 was r e f l u x e d with m e t h a n o l i c  h y d r a z i n e thus y i e l d i n g the c r y s t a l l i n e t o s y l h y d r a z o n e spectrum o f t h i s compound e x h i b i t e d bands a t t o the  6.10,  6.25  a r o m a t i c double bond s t r e t c h i n g v i b r a t i o n s . t o the S=0 s t r e t c h i n g  153.  11.2  y i s o p r o p e n y l double bond absorbance was a l s o p r e s e n t .  assigned  t o the  quartet  x 2.44  (J , ^  o f the t o s y l m o i e t y .  The n . m . r .  8 H z , ( 6 , - 6 ) ^ 58 Hz) D 3. The i s o p r o p e n y l  a t h r e e - p r o t o n p o o r l y r e s o l v e d t r i p l e t at x  due t o the C-13 methyl g r o u p , and a t w o - p r o t o n u n r e s o l v e d m u l t i p l e t at assigned  t o the C-12 v i n y l p r o t o n s .  at  The c h a r a c t e r i s t i c  3-D  four aromatic protons  group p r o t o n s appeared as  frequency.  c e n t e r e d at  Z  u attributed  A s t r o n g absorbance  y was a s s i g n e d  Z  The i . r .  and 6.92  8.58  spectrum showed an A„B  p-toluenesulphonyl-  A poorly resolved one-proton  8.32, x  5.36,  quartet,  - 58 -  a p p e a r i n g a t x 7.37  (J.  x 9.12  Hz) w e r e a t t r i b u t e d t o t h e h y d r o g e n  (J 4,14  o f C-4,  =6.5  respectively.  = 6.5  Finally,  Hz)  and a t h r e e - p r o t o n d o u b l e t c e n t e r e d a t  a s i n g l e t a t x 7.61  a r o m a t i c methyl group  a n d a s i n g l e t a t x 9.43  methyl group  The  noteworthy. ketone The  128  a t C-5. The  chemical s h i f t  signals  r e l a t i v e l y high f i e l d  137  appear  x 9.43  C o n v e r s i o n o f t o s y l h y d r a z o n e 153  refluxing yellow major  component  greater retention was  times.  absorbances  The  "  s i g n a l suggests the  (±)-eremophil-3,11-diene 2_ was  w i t h sodium After  ethylene glycolate  i n Figure  unresolved multiplets  to contain  T h i s compound e x h i b i t e d  1_,  significantly  component the  expected  y i n t h e i . r . s p e c t r u m , shown i n  the spectrum  a t x 4.70  as a p o o r l y r e s o l v e d t r i p l e t The  latter  groups, r e s p e c t i v e l y .  one  •  vinyl protons, respectively.  a t x 8.40.  in  a p p r o p r i a t e work-up a p a l e  u n i d e n t i f i e d components o f  11.28  operation  methyl protons  shown by g . l . c . a n a l y s i s  several  and  respectively.  n.m.r. s p e c t r u m o f compound _2 p r o v e d t o b e p a r t i c u l a r l y  indicated  appeared  x 9.24,  An a n a l y t i c a l s a m p l e o f t h e m a j o r  a t 6.11  F i g u r e 6_.  As  and  i s o l a t e d by p r e p a r a t i v e g . l . c .  olefinic  into  hours.  i s o l a t e d w h i c h was  ( c a . 90%)  and  related  group.  the hydrazone  e t h y l e n e g l y c o l f o r two  l i q u i d was  a t t r i b u t e d to the angular  (47) i n v o l v i n g t h e C-15  system o f the t o s y l  t h e n e f f e c t e d by r e a c t i n g  assigned to the  protons i n the  a t x 9.21  methyl group  of a diamagnetic s h i e l d i n g e f f e c t  was  substituent  o f the l a t t e r methyl group i s  a t t r i b u t e d t o t h e C-15  and s e m i c a r b a z o n e  a n d t h e TT e l e c t r o n  was  and m e t h y l  a n d x 5.35  The  showed o n e -  and  a t x 8.30  ( J - 1 Hz)  and  a s a s h a r p x 8.96  s i g n a l s due singlet.  e x p e r i m e n t s were p e r f o r m e d w h i c h  t o t h e C-5  signals  and  C-12  appeared  an u n r e s o l v e d m u l t i p l e t  s i g n a l s w e r e a s s i g n e d t o t h e C-13 The  two-proton  a t t r i b u t e d t o t h e C-3  two v i n y l m e t h y l g r o u p  informative.  a n d C-14  angular methyl  methyl group  A number o f f r e q u e n c y - s w e p t d e c o u p l i n g  c o n f i r m e d t h e above c h e m i c a l  shift  Figure 9. Nuclear Magnetic Resonance Spectrum of Natural Eremophilene.  - 63 -  assignments and supported the structural assignment 2_ for the Bamford-Stevens reaction product.  Irradiation of the C-12 vinyl protons at T 5.35 resulted  in the collapse of the x 8.30 triplet to a sharp singlet, thus confirming allylic coupling between the C-12 olefinic and C-13 methyl protons. Strong, irradiation of the C-3 vinyl proton at x 4.70 effected a substantial sharpening of the x 8.40 multiplet thus confirming allylic coupling between the 14 protons at C-3 and C-14.  A corresponding irradiation of the C  multiplet  at x 8.40 resulted in a sharpening of the x 4.70 multiplet, further confirm* ing coupling between the C-3 and C-14 protons. The reaction mechanism of the Bamford-Stevens reaction merits brief comment. It has been recognized for some time that in the presence of alkoxide bases the thermal decomposition of tosylhydrazones of aromatic or aliphatic ketones and aldehydes proceeds via initial anion formation followed by an elimination of the tosylate anion, affording an intermediate diazo compound, as depicted below (56,58).  -CH-C=NNHTs I I  The fate of this intermediate normally  -CH-C=N-N-Ts II"protic medium"  -CH-C=N=N + Ts "aprotic medium"  H  -C=CH  [-C-CH]  -C=CH  depends upon the nature of the reaction solvent. Thus, in an "aprotic" medium (e.g.; diglyme, diethyl Carbitol) the thermally unstable diazo compounds decompose via carbenes affording the appropriate carbon-hydrogen insertion products.  In proton-donating solvents (e.g., ethylene glycol,  diethylene glycol) the diazo intermediates are competitively protonated thus  -  giving rise  to decomposition predominantly v i a c a t i o n i c  (diazonium c a t i o n s  a n d / o r carbbnium i o n s )  upon r e a c t i o n w i t h the s o l v e n t , loss  (57).  64 -  intermediates  which are s u b s e q u e n t l y  Wagner-Meerwein rearrangement a n d / o r p r o t o n  For s i m p l i c i t y , b o t h pathways i n the above scheme are  as t e r m i n a t i n g w i t h o l e f i n  formation.  Bamford-Stevens r e a c t i o n .  Suffice  to say here t h a t  of  the clearly  (57)  a function of and t h e  the a l i p h a t i c or a r o m a t i c moiety o f the t o s y l h y d r a z o n e d e r i v a t i v e  Thus, of  system  effort  c a r b e n o i d and c a t i o n i c  i n a g i v e n Bamford-Stevens r e a c t i o n i s  b o t h the p r o t o n d o n a t i n g a b i l i t y o f the s o l v e n t  of  t h i s work has  demonstrated t h a t the b a l a n c e between the c o m p e t i t i v e processes operative  represented  In r e c e n t y e a r s c o n s i d e r a b l e  has been expended toward e l u c i d a t i n g the m e c h a n i s t i c d e t a i l s  '  neutralized  i n l i g h t o f the e x i s t i n g  relevant  literature  t o s y l h y d r a z o n e 153 i n t o e r e m o p h i l - 3 , 1 1 - d i e n e  tions  c i t e d above most  (17,57),  the  Comparison o f a sample o f the  l o s s o f the C-4 p r o t o n o f synthetic  (58,59).  conversion  2_ under the r e a c t i o n c o n d i -  l i k e l y proceeded v i a a c a t i o n i c pathway,  f o r m a t i o n r e s u l t i n g due t o a f a c i l e  nature  olefin  153.  ( ± ) - 7 g - e r e m o p h i 1 - 3 , 1 1 - d i e n e 2_ 13  w i t h an a u t h e n t i c  sample o f n a t u r a l eremophilene  t h a t the two s e s q u i t e r p e n e s  were not i d e n t i c a l .  unambiguously  established  T h i s was immediately apparent  upon comparison i . r . s p e c t r a o f these compounds; t h e i . r . s p e c t r a o f and  (±)-2_  n a t u r a l eremophilene are r e p r o d u c e d i n F i g u r e s 6^ and 8_ r e s p e c t i v e l y . 14  S i m i l a r l y the n . m . r . s p e c t r a i n d i c a t e d marked d i f f e r e n c e s ,  o f the two o l e f i n s ,  shown i n F i g u r e s 7_ and 9_,  p a r t i c u l a r l y i n the 8 t o 9.5  tau r e g i o n .  Finally,  13 ' A sample o f a u t h e n t i c eremophilene o b t a i n e d from D r . J . K r e p i n s k y i s g r a t e f u l l y acknowledged; a copy o f the n . m . r . and i . r . spectrum o f t h i s compound was o b t a i n e d from D r . R . B . B a t e s , to whom g r a t i t u d e i s a l s o expressed. 14 The n . m . r . spectrum o f a u t h e n t i c eremophilene shown i n F i g u r e 9 i s i n complete agreement w i t h t h a t r e c e n t l y r e p o r t e d f o r t h i s compound (9). Note t h a t the C-14 methyl group d o u b l e t c e n t e r e d a t T 9.15 ( J ^ ^ = 6 Hz) i s p a r t i a l l y hidden i n t h i s spectrum. ' ' •  the  - 65 natural  and s y n t h e t i c  eremophilenes  exhibited non-identical g . l . c .  times which f u r t h e r c o r r o b o r a t e d the Subsequently,  pyridine  Thus, (18)  evidence.  the a v a i l a b i l i t y o f a sample o f the r e c e n t l y  e r e m o l i g e n o l _28_ ( 1 8 ) ^ philene.  above  enabled the  isolated  c o r r e c t s t r u c t u r a l assignment  dehydration of eremoligenol  of  i s o l a t i o n a f f o r d e d an a n a l y t i c a l sample o f the major  found t o be s u p e r i m p o s a b l e upon t h a t o f a u t h e n t i c  8^  ) which was  eremophilene.  Moreover,  the i d e n t i t y o f these s u b s t a n c e s was f u r t h e r demonstrated by t h e i r retention  times  on t h r e e d i f f e r e n t  columns.  apparent the o r i g i n a l s t r u c t u r a l assignment  Hence, i t  identical  was c l e a r l y  f o r eremophilene r e q u i r e d  that r e p r e s e n t e d by 3_.  The v e r y r e c e n t  total  (10)*^ has c o n f i r m e d the for eremoligenol  s y n t h e s i s o f r a c i m i c 2_8 and 3_ by Coates and Shaw  c u r r e n t s t r u c t u r a l and s t e r e o c h e m i c a l  and e r e m o p h i l e n e .  assignments  The s y n t h e s i s o f these compounds was  The g i f t o f an a u t h e n t i c e r e m o l i g e n o l g r a t e f u l l y acknowledged. ^  olefins.  3  T h i s compound e x h i b i t e d an i . r . spectrum ( F i g u r e  r e v i s i o n to  i n dry  a f f o r d e d a l i q u i d p r o d u c t which c o n t a i n e d a m i x t u r e o f  Preparative g.l.c,.  g.l.c.  eremo-  28_ w i t h t h i o n y l chloride  28  isomer.  retention  The author g r a t e f u l l y acknowledges by P r o f e s s o r C o a t e s .  sample from D r . H . I s h i i  a preprint of this  is  work forwarded  -  r e a l i z e d v i a the g e n e r a l  synthetic  66 -  approach to the eremophilane  p r e v i o u s l y developed by these workers i n the s y n t h e s i s o f 75.  The s t a r t i n g m a t e r i a l i n the e r e m o l i g e n o l  was the carbethoxy ketone  154,  A^  and eremophilene  o b t a i n e d as d e s c r i b e d i n the  Treatment o f the sodium s a l t o f 154 w i t h a c e t y l c h l o r i d e a f f o r d e d the c o r r e s p o n d i n g carbethoxy enol  sesquiterpenes  a c e t a t e 155.  in  -aristolene synthesis  Introduction. dimethoxyethane  Reduction of  the  u n p u r i f i e d e n o l a c e t a t e 155 w i t h l i t h i u m i n l i q u i d ammonia f o l l o w e d by EtO  treatment  w i t h ammonium c h l o r i d e gave the e s t e r 157,  from 154.  I t was suggested by Coates and Shaw t h a t  reaction  l i k e l y p r o c e e d v i a an a , 3 - u n s a t u r a t e d  upon f u r t h e r r e d u c t i o n would y i e l d the considered that  this  rather  e s t e r e n o l a t e anion 156.  sterically  i n support o f the  yield  interesting  ester intermediate  the t h e r m o d y n a m i c a l l y u n f a v o u r a b l e B - o r i e n t a t i o n  carbethoxy s u b s t i t u e n t 156 from the  i n 34% o v e r a l l  which It  was  of  the  r e s u l t e d by way o f a k i n e t i c p r o t o n a t i o n o f a n i o n l e s s h i n d e r e d a - s i d e o f the i n t e r m e d i a t e .  B-stereochemical  assignment  was d e r i v e d from the  Evidence fact  t h a t , as i n d i c a t e d b e l o w , ponding a-epimer. group the  A  e s t e r 157a u n d e r w e n t e p i m e r i z a t i o n t o t h e c o r r e s -  d i a m a g n e t i c s h i e l d i n g ' due  i n 157a r e s u l t e d i n t h e o b s e r v a t i o n  angular  methyl group.  Equilibration  157a  epimer  158  shielding effect  angular  methyl group  the  28•  identical  chemical  shift for  t o t h e more s t a b l e e q u a t o r i a l  as r e f l e c t e d  signal  was  i n d i c a t e d by t h e  i n the appearance  at lower f i e l d ,  (i.r.,  158  epimerization)  e s t e r 157 w i t h e x c e s s m e t h y l  shown t o be  o f a x 9.18  carbethoxy  -  ( p r e s u m a b l y by base  of this  to the a x i a l  lithium  x 9.05.  of the  Subsequent  corresponding reaction of  i n e t h e r g a v e an a l c o h o l i c  n.m.r.) w i t h a s a m p l e o f a u t h e n t i c  D e h y d r a t i o n o f t h e a l c o h o l 28_ w i t h t h i p n y l  gave, a f t e r g . l . c . p u r i f i c a t i o n ,  absence  product  eremoligenol  c h l o r i d e i n dry p y r i d i n e  a compound w h i c h e x h i b i t e d n.m.r. and i . r .  s p e c t r a w h i c h w e r e i n d i s t i n g u i s h a b l e f r o m t h o s e o f a u t h e n t i c e r e m o p h i l e n e 3_. T h u s i n c o n c l u s i o n , t h e s t r u c t u r e 2_ o r i g i n a l l y p r o p o s e d e r e m o p h i l e n e h a s b e e n shown t o b e i n c o r r e c t .  Moreover,  ted herein that eremophilene i s r e l a t e d to eremoligenol as s u c h , t h e s t r u c t u r e a n d represented  by  stereochemistry  f o r m u l a t i o n 3_.  described  i n this  t h e s i s has  selective  synthetic entry  The  (7) f o r  i t has been  demonstra-  by d e h y d r a t i o n  and  of eremophilene i s c o r r e c t l y  synthesis of  (±)-eremophil-3,ll-diene 2_  concommitently e s t a b l i s h e d a remarkably  i n t o the eremophilane c l a s s of  stereo-  sesquiterpenoids.  - 68 -  The g e n e r a l i t y o f t h e above c o n j u g a t e a d d i t i o n approach t o t h e e r e m o p h i l a n e sesquiterpenes i s c u r r e n t l y being investigated i n t h i s  laboratory.  I t i s worthwhile t o note here that l i t h i u m dimethylcuprate i s a reagent which o f f e r s a c o n s i d e r a b l e  synthetic u t i l i t y .  The use o f l i t h i u m  dimethyl-  cuprate i n the s e l e c t i v e conjugate m e t h y l a t i o n o f a,3-unsaturated ketones a f f o r d s a marked advantage over p r e v i o u s l y  a v a i l a b l e methods.  Moreover,  t h i s c o p p e r - a t e complex, as w e l l as a number o f o t h e r l i t h i u m d i a l k y l - and divinylcuprate  complexes ( e . g . , t h e d i e t h y l - , d i - n - b u t y l - , d i p h e n y l - , and  di-l-propenylcuprate  a n a l o g u e s ) have r e c e n t l y been s u c c e s s f u l l y p r e p a r e d and  employed i n a number o f o t h e r i n t e r e s t i n g and s y n t h e t i c a l l y u s e f u l (63).  reactions  There c a n be l i t t l e doubt t h a t t h e s e organo-copper r e a g e n t s possess  an i n t r i g u i n g p o t e n t i a l a p p l i c a b i l i t y t o t h e f i e l d o f n a t u r a l synthesis general.  products  i n p a r t i c u l a r , and c e r t a i n l y t o s y n t h e t i c o r g a n i c c h e m i s t r y i n  EXPERIMENTAL  Except where o t h e r w i s e  detailed,  r e p e a t e d e x t r a c t i o n w i t h the s o l v e n t then c o n s e c u t i v e l y parentheses,  the r e a c t i o n p r o d u c t s were i s o l a t e d by specified,  the combined e x t r a c t s  washed and d r i e d w i t h the r e a g e n t s i n d i c a t e d i n  concentrated  a t vacuum pump p r e s s u r e  (1-10  mm).  A l l melting points  Infrared spectra  were r e c o r d e d on a P e r k i n - E l m e r I n f r a c o r d model 137 P e r k i n - E l m e r model 421 G r a t i n g s p e c t r o p h o t o m e t e r , latter  were determined on a  U l t r a v i o l e t s p e c t r a were r e c o r d e d i n  methanol on a Cary 14 r e c o r d i n g s p e c t r o p h o t o m e t e r .  (n.m.r.)  instrument.  a l l comparison i . r .  N u c l e a r magnetic  A u t o p r e p , model 700, 85 ml min  Signal positions  1/4"  x 10'  in  parentheses.  a flow r a t e o f  80-  60/80  A , 20% SE30; B, 20% A p i e z o n - J  C, 20% FFAP; D, 10% FFAP; E , 15% Q F - 1 ; F , 20% Carbowax. with column t e m p e r a t u r e ,  are given  columns were employed u s i n g  mesh Chromsorb W. as an i n e r t p a c k i n g s u p p o r t :  are noted,  in  a  was c a r r i e d out with an Aerograph  u s i n g h e l i u m as a c a r r i e r gas a t  .The f o l l o w i n g  spectra  (tetramethylsilane  the T i e r s x s c a l e w i t h m u l t i p l i c i t y and p r o t o n assignment G a s - l i q u i d chromatography ( g . l . c . )  or a  resonance  and r e c o r d e d on a JEOLCO C-60-H s p e c t r o m e t e r ,  V a r i a n A-60 o r V a r i a n HA-100 s p e c t r o m e t e r .  (i.r.)  spectrophotometer  s p e c t r a were determined i n d e u t e r i o c h l o r o f o r m  as i n t e r n a l s t a n d a r d )  the  i n i t i a l l y at water a s p i r a t o r p r e s s u r e and f i n a l l y  K o f l e r b l o c k and are u n c o r r e c t e d .  were o b t a i n e d u s i n g the  were  i n parentheses.  The g . l . c .  columns  M i c r o a n a l y s e s were  performed by M r . P. B o r d a , M i c r o a n a l y t i c a l L a b o r a t o r y , U n i v e r s i t y o f  -  70 -  B r i t i s h C o l u m b i a , Vancouver.  3-Isopropenylcyclohexanone  130  The p r o c e d u r e employed was e s s e n t i a l l y  that  o f House, Latham and S l a t e r  (46). A solution  o f i s o p r o p e n y l magnesium bromide (from 12.7 g (0.53 mole)  magnesium t u r n i n g s , tetrahydrofuran cooled to 0 ° .  87.4 g (0.74 mole)  of  o f 2-bromopropene i n 70 ml o f d r y  (THF)), under n i t r o g e n , was d i l u t e d with 350 ml o f d r y THF then To t h i s  s t i r r e d s o l u t i o n was added 2.61 g (26.4 mmoles)  of  anhydrous CuCl f o l l o w e d by the dropwise a d d i t i o n o f 24.2 g (0.25 mole)  of  2- cyclohexenone  i n 150 ml o f THF over 20 m i n .  The r e a c t i o n m i x t u r e was  s t i r r e d a t 0 ° f o r 2 h r , then poured i n t o a s t i r r e d aqueous chloride-ammonium h y d r o x i d e with ether  (pH 8) a t 0 ° .  ( d i l . NH^OH, w a t e r ,  brine).  gave 24.54 g (70.5%) o f e s s e n t i a l l y cyclohexanone 1.4749 n.m.r., 8.24  (lit.  4 6  x 5.22  (singlet,  130, b . p . 6 8 - 7 2 ° 1.4743-1.47.49).  T h e . r e a c t i o n p r o d u c t was  (7.5mm)  pure  (lit.  (column A , 1 5 0 ° ) 3 - i s o p r o p e n y l 80.5-84°  4 6  Infrared (film), =CH ), 2  A  7.62  (8mm)), n ^  5.85, 6.12,  0  11.20 u ;  (broad m u l t i p l e t ,  hydroxymethylene  a-CH ), 2  131 g i v e n by Sorm e t .  To a s t i r r e d s l u r r y c o n t a i n i n g 31.6 g (0.58 mole)  al.  i n 160 ml o f d r y benzene.  (60).  o f sodium methoxide  160 ml o f d r y benzene was added a s o l u t i o n o f 43.3 g (0.58 mole) The system was then c o o l e d  w i t h i c e t o c a . 0 ° then a s o l u t i o n o f 26.4 g (0.20 mole) cyclohexanone  ,  3  The p r o c e d u r e employed i s s i m i l a r t o t h a t  formate  6  -CH ).  3- I s o p r o p e n y l c y c l o h e x a n o n e  in  isolated  D i s t i l l a t i o n o f the r e s u l t i n g o i l  g.l.c.  (unresolved m u l t i p l e t ,  s o l u t i o n o f ammonium  of ethyl  externally  of 3-isopropenyl-  130 i n 160 ml o f d r y benzene was added dropwise over 20 m i n .  The r e a c t i o n m i x t u r e was p l a c e d under n i t r o g e n ,  the system a l l o w e d t o come  g r a d u a l l y t o room temperature then s t i r r e d -for 50 h r .  To the r e s u l t i n g  yellow  -  colloidal  times with 7% aqueous  alkaline  were a c i d i f i e d  extracts  the p r o d u c t i s o l a t e d  red-brown o i l .  Ultraviolet, T163t T  sodium h y d r o x i d e .  (water,  brine)  D i s t i l l a t i o n gave 20.65 g (75%) 60-76°  283 my; i . r .  X  (0.03  (broad m u l t i p l e t ,  it  was  The combined  (film),  o f the hydroxymethylene  6.02,  X  cooled  a f f o r d i n g 27.58 g o f  mm), 1 0 1 - 1 0 2 °  HI 3.X  8.26  s t i r r i n g well  (pH 3) with 12 M h y d r o c h l o r i c a c i d ,  with ether  as a p a l e y e l l o w o i l , b . p .  n.m.r.,  -  system was added 500 ml o f water; a f t e r  extracted several  and  '  71  6.22  (4 mm), n * 9  (broad),  131  1.5198.  3  11.15  y;  III 3.X  (singlet, a-l^),  1.4  -CHg),  5.25  (singlet,  (unresolved m u l t i p l e t ,  -CHO),  -4.0  =CH2),  7.7  (very b r o a d m u l t i p l e t ,  =CH0H). 19 l-Methyl-7B-isopropenyl-A  ' -octal-2-one  127  The p r o c e d u r e employed was s i m i l a r to t h a t and  Bhattacharya  14.6  15.9 g (0.10  mole)  mole)  o f f r e s h l y d i s t i l l e d methyl i o d i d e .  was s t i r r e d f o r 3 h r at  0 ° then s t o r e d  use  methiodide  s a l t was d i s s o l v e d  i n the Robinson a n n e l a t i o n The  11.70  g (70.4  mmoles)  60 ml o f m e t h a n o l .  0 ° was added dropwise The r e a c t i o n m i x t u r e  the r e s u l t i n g  After  viscous  i n 40 ml o f methanol f o r  subsequent  reaction.  above m e t h a n o l i c m e t h i o d i d e  t o a s t i r r e d s o l u t i o n o f 2.41  1-diethylamino-  in a r e f r i g e r a t o r overnight.  e v a p o r a t i n g the benzene and excess methyl i o d i d e , colorless  o f commercial  i n 70 ml o f dry benzene under n i t r o g e n at  g (0.10  Chatterjee  (49).  To a s t i r r e d s o l u t i o n o f 3-pentanone  g i v e n by B a n e r j e e ,  g (44.7  s o l u t i o n was added dropwise over 20 min mmoles)  o f sodium methoxide  o f 3-isopropenylcyclohexanone  and  hydroxymethylene  ' 131  The r e a c t i o n m i x t u r e was s t i r r e d under n i t r o g e n at room  temperature f o r 26 h r then poured i n t o a c o l d s a t u r a t e d aqueous ammonium sulfate The  s o l u t i o n which had been f u r t h e r a c i d i f i e d w i t h h y d r o c h l o r i c a c i d .  resulting  in  c o l l o i d a l system was t h o r o u g h l y e x t r a c t e d w i t h e t h e r ;  the  '  combined e x t r a c t s  yielded  16.12  g o f crude p r o d u c t a f t e r  D e f o r m y l a t i o n was e f f e c t e d by s t i r r i n g the c o n c e n t r a t e aqueous  i n 630 ml o f 2%  sodium h y d r o x i d e f o r 1 h r a t room temperature under n i t r o g e n .  r e s u l t i n g a l k a l i n e s o l u t i o n was a c i d i f i e d with ether  (water,  brine)  this material exhibited unsaturated  (6.02  by r e f l u x i n g the in  concentration.  y)  giving  14.52  (pH 6)  and the p r o d u c t  g of yellow o i l .  a significantly  isolated  The i . r . spectrum o f  stronger saturated  c a r b o n y l absorbance.  (5.86  y)  T h u s , r i n g c l o s u r e was  crude p r o d u c t i n a s o l u t i o n o f 0.5  The  than  completed  g o f sodium methoxide  125 ml o f d r y methanol f o r 5-6 h r at which time the u n s a t u r a t e d c a r b o n y l  absorbance o f a c i d quenched a l i q u o t s maximum i n t e n s i t y  o f the r e a c t i o n m i x t u r e had a t t a i n e d a  (starting material present).  50 ml o f water added, the system a c i d i f i e d the crude p r o d u c t i s o l a t e d t i o n gave 10.56 (5mm); (IV)  (II)  1.17  g of pale yellow  2.25  g,  g,  110-128°  132-178°  (0.3  3-isopropenylcyclohexanone c o n t a i n e d 92, g.l.c.  64%.  J  J  r  127-131° .  (e = 1 4 , 6 0 0 ) ; i . r .  (0.3  (unresolved m u l t i p l e t , 1.8  1.2  Hz, a l l y l i c coupling  2  Hz, homoallylic coupling  methyl groups were e s t a b l i s h e d olefinic  6.00,  X  (47)).  protons  g,  (I)  127-131°  0.59  Fractions IT, III  of octalone  6.20,  to  and IV  hydroxymethylene  of octalone  127 were  Ultraviolet, X max 11.25,  11.82  (triplet,  The chemical s h i f t s  249.5 my  -CH3, J -  1.2  isopropenyl -CH^, J =  assigned  by a d e c o u p l i n g experiment  o f the i s o p r o p e n y l group ( T 5.26)  (column B ,  y ; n . m . r . , T 5.26  (poorly resolved quartet,  ( 4 7 ) ) , 8.25  73.80°  127 as determined by  y i e l d , based on the  1.5320.  g,  (0.3mm);  oxime 159 and by p r e p a r a t i v e g . l . c .  =CH ) > 8.22  and  Fractional d i s t i l l a -  was shown to be i d e n t i c a l  A n a l y t i c a l samples  mm), n £ 3 . 5 ' D  (film);  6.55  g.l.c).  The o c t a l o n e  obtained v i a h y d r o l y s i s of i t s 230°), b.p.  (III)  mm). F r a c t i o n (I)  94 and 95% r e s p e c t i v e l y  131 was thus  brine).  l i q u i d i n four f r a c t i o n s :  (i.r.,  evaporated,  (pH 5) w i t h h y d r o c h l o r i c a c i d and  (water,  (0.3mm);  130  (column B , 2 3 0 ° ) .  derivative  with ether  The methanol was  to the  i n which  vinylic  the  were s t r o n g l y i r r a d i a t e d  thus e f f e c t i n g T 8.22  collapse  o f the  q u a r t e t remained  Anal.  Calcd.  for C  1 4  x 8.25  t r i p l e t t o a sharp s i n g l e t ,  while  the  unaffected. H  2 0  O:  C , 82.30; H , 9.87.  Found:  C , 8 2 . 4 3 ; H , 10.03.  19 1-Methyl- 7 - i s o p r o p e n y l - A To an aqueous  ' -octal-2-one  s o l u t i o n o f 0.170  c h l o r i d e and 0.333 g (2.95 0.500 g (2.45 until  mmoles)  mmoles)  oxime  g (2.45  mmoles)  o f the a,8-unsaturated  ketone  analytical X 2.82, in 3.x  crystals.  Methanol was added  f i l t r a t i o n and d r y i n g ,  m  3  Calcd.  7 6 . 8 4 ; H , 9.55;  N,  5.30  for C  (singlet, H  1 4  2 1  0.370 g  R e c r y s t a l l i z a t i o n from methanol a f f o r d e d an  sample, m.p. 1 6 3 - 1 6 5 ° . Ultraviolet, ^ 243 my; i . r . 3 . 1 0 , 3 . 4 4 , 6 . 0 8 , 1 0 . 5 0 , 11.18 y; n . m . r . , x 8 . 1 5 , 8.26  v i n y l i c C H groups), Anal.  127.  The r e a c t i o n m i x t u r e was then s t i r r e d  o v e r n i g h t at room temperature y i e l d i n g , a f t e r of colorless  o f hydroxylamine h y d r o -  o f sodium a c e t a t e t r i h y d r a t e was added  a c l e a r s o l u t i o n was o b t a i n e d .  (69%)  159  0N:  =CH ), 2  1.63  a  x  (CHClj), (singlets,  (broadened s i n g l e t ,  C , 76.66; H , 9.65;  N , 6.39.  =N0H).  Found:  C,  6.21. 19  1-Methyl-7-isopropenyl-A  ' -octal-2-one  127 from i t s  oxime  H y d r o l y s i s o f the oxime 159 t o the a , 8 - u n s a t u r a t e d r e a l i z e d by r e f l u x i n g f o r 25 hr a s o l u t i o n o f 0.183 o f o x a l i c a c i d and 2.7 ml o f 37% aqueous  ketone  (water,  brine).  127 was  g o f the oxime,  formaldehyde d i s s o l v e d  m e t h a n o l , 4 ml o f water and 5 ml o f 8 0 - 1 0 0 ° petroleum e t h e r . was i s o l a t e d w i t h e t h e r  159  i n 9 ml o f  The p r o d u c t  127,  the d a t a f o r which i s  above. 128  The p r o c e d u r e employed i s Whitesides  (51).  g  Reduced p r e s s u r e d i s t i l l a t i o n gave  a s m a l l a n a l y t i c a l sample o f pure o c t a l o n e  (i)-78-Eremophil-ll-en-3-one  0.46  s i m i l a r to that  o f House, Respess and  given  -  74 -  To a s t i r r e d s l u r r y c o n t a i n i n g 6.02 i o d i d e i n 120 ml o f anhydrous e t h e r at 1.59  M (62.6  mmoles)  g (31.3  cooling,  o f copper  2  o f e t h e r e a l methyl l i t h i u m by i n j e c t i o n from a d r y slightly  l i t h i u m d i m e t h y l copper reagent  then a s o l u t i o n  tan c o l o u r e d  m i x t u r e was s t i r r e d a t  c o n t a i n i n g 2.00 g (10.4  0 ° f o r an a d d i t i o n a l 1.75  mmoles)  of octalone  (water,  l i q u i d which was found by g . l . c .  decalone  128  (yield ca.  80%)  u n i d e n t i f i e d components.  brine)  127  in  The r e a c t i o n  h r then s l o w l y added t o  800 ml o f v i g o r o u s l y s t i r r e d 1.2 M aqueous h y d r o c h l o r i c a c i d . p r o d u c t was i s o l a t e d w i t h e t h e r  solution  was s t i r r e d f o r 5 min w i t h  80 ml o f anhydrous e t h e r was added dropwise over 15 m i n .  yellow  (I)  0 ° and under N , was added 39.4 ml o f  s y r i n g e . .' The r e s u l t i n g e s s e n t i a l l y c l e a r , c o n t a i n i n g the  mmoles)  giving  2.185  The r e a c t i o n  g of a pale  (column C , 2 1 5 ° ) to c o n t a i n 77%  i n a d d i t i o n to 5% s t a r t i n g m a t e r i a l and s e v e r a l  An a n a l y t i c a l sample was o b t a i n e d by p r e p a r a t i v e 19 2n n  g.l.c.  (column C , 2 1 5 ° ) ,  (film),  \  5.86,  b.p.  6.10,  6.93,  123.5-124.5 10.59,  (0.03mm),  11.27  1.5041.  p ; n . m . r . , . x 5.33  Infrared  (unresolved  IH3-X  multiplet, triplet,  =CH ), 2  -C  -C^Hj) .  1 3  H ), 3  7.17  (quartet,  -C H,  9.11  (doublet,  -C  effecting  the c o l l a p s e  The o l e f i n i c o f the  s t r o n g i r r a d i a t i o n o f the o f the x 9.11  doublet  x 8.29  x 7.17  H , 3  J  4  J  4  4  H z ) , 8.29  Calcd.  p r o t o n s at T 5.33 triplet  for C  1 5  H  2 4  0:  (poorly  = 6.7 H z ) , 9.21  quartet r e s u l t i n g  resolved  (singlet,  frequency-swept were i r r a d i a t e d  to a sharp s i n g l e t .  to a poorly resolved t r i p l e t ,  o f c o u p l i n g between the  Anal. H,  1 4  1  The c o u p l i n g assignments were confirmed by two  decoupling experiments.  evidence  = 6.7  4  in a partial  Similarly, collapse  which was taken  as  C-4 and C-14 p r o t o n s . C , 81.76; H , 10.98.  Found:  C , 81.61;  10.71.  (1)-78-Eremophil-ll-en-3-one tosylhydrazone The p r o c e d u r e employed i s  153  s i m i l a r to that g i v e n by D j e r a s s i e t .  al.  (61).  To a s o l u t i o n several (9.08  c o n t a i n i n g 2.00  drops o f a c e t y l  mmoles)  g (7.36  by  0°.  of p-toluenesulfonylhydrazide.  The y e l l o w i s h  filtration.  colorless 8.58, ^  crystals  159-161°.  y; n . m . r . , T 9.43  = 6.5  H z ) , 8.32  a r o m a t i c C H ^ ) , 7.37  g  The system was p l a c e d under  t o c o o l to room temperature and  (1.977 g)  thus a f f o r d e d were  R e c r y s t a l l i z a t i o n from methanol gave 1.656  n e e d l e s , m.p.  11.2  128 and  7  c h l o r i d e i n 16 ml o f methanol was added 1.680  n i t r o g e n , r e f l u x e d f o r 40 m i n , allowed ally to  mmoles]'"' o f decalone  Infrared (CHC1 ), 3  (singlet,  -C  (poorly resolved  H ),  1 5  3  triplet,  (poorly resolved quartet,  9.12  X  (doublet;  13 - C H ) , 7.61 3  -C^H,  ^  separated  g (58%) 6.10,  ffiax  fin-  of  6.25, -C  1 4  6.92,  H , 3  (singlet,  = 6.5  Hz),  5.36  12 (unresolved m u l t i p l e t ,  =C  H ) , 2.44  (A2B2 q u a r t e t ,  2  f o u r aromatic p r o t o n s ,  J , ^8 H z , ( 6 , - 6 ) ^ 58 Hz) . ab b a v  Anal. Found:  Calcd.  for C  H 2 2  32 2 2  C , 68.22; H , 8.41;  0  N  S :  N , 7.41;  (±}-76-Eremophil-ll-en-3-one  C  '  6  S,  8  t  0  0  '  ti  >  8  -  3  semicarbazone  ethanol u n t i l a s l i g h t  thus  semicarbazone  8.25.  g o f decalone  c l e a r the  was  128  in  established.  s o l u t i o n and 5.00  g of  g o f sodium a c e t a t e were added.  system was r e f l u x e d f o r 30 min then c o o l e d crystals  S,  137  permanent c l o u d i n e s s  A few drops o f e t h a n o l were added to j u s t s e m i c a r b a z i d e h y d r o c h l o r i d e and 7.50  ' H , 7.21;  8.11.  Water was added dropwise to a s o l u t i o n o f 5.00 50 ml a b s o l u t e  0  The  t o room temperature and the  formed were s e p a r a t e d by f i l t r a t i o n y i e l d i n g 5.222 g o f crude 137.  R e c r y s t a l l i z a t i o n from e t h a n o l gave,  a f t e r vacuum d r y i n g ,  18 3.205 g. (64.8%)  of colorless  X  5.95,  6.92,  4.24  (broad m u l t i p l e t ,  ni3.x  17 18  6.40,  11.20  plates,  m.p.  191.5-194.5°.  y ; n . m . r . , T 1.40  -C0NH ), 2  5.27  S t a r t i n g m a t e r i a l 81% decalone S t a r t i n g m a t e r i a l v/as 82% decalone  Infrared (CHC1 ), 3  (broad m u l t i p l e t , =N-NH),  (unresolved m u l t i p l e t ,  =C  1 2  H ), 2  7.25  - 76 (poorly resolved quartet, -C H), J 4  ... ^ 6.8 Hz), 8.27 (poorly resolved 4,14  triplet, -C H ), 9.06 (doublet, -C H , J 13  14  3  3  4  u  ^ 6.8 Hz), 9.24  (singlet,  -C H ). 15  3  Anal. Calcd. for C^H^ON • C, 69.27; H, 9.81; N, 15.15. Found: C, lo  l i b  69.20; H, 9.98; N, 15.05. [X)-7 B-Eremophil-3,11-diene 2_ The Bamford-Stevens reaction procedure employed was similar to that given by Corey and Sneen (62) To a stirred solution obtained from the gradual addition of 10.0 g of sodium metal to 100 ml of ethylene glycol was added 1.500 g (3.87 mmoles) of tosylhydrazone 153. for 2 hr.  The system was placed under nitrogen then refluxed  The flask and contents were cooled until slightly warm then the  reaction mixture was poured into 200 ml of water. The product, isolated with ether (water, brine), yielded 0.896 g of yellow liquid which was shown by g.l.c. (column D, 120 and 135°) to contain a single major component (ca. 90%) and several considerably more polar components which were not identiAn analytical sample of (i)-eremophil-3,11-diene 2_ was collected by  fied.  19 preparative g.l.c. (column D, 170°), b.p. 85-88° (bath temp.) (0.4 mm) 20 n  1.5052. Infrared (film), X  u D  6.11, 6.95, 7.32, 11.28, 12.03, 12.48 ; v  n.m.r., T 4.70 (unresolved multiplet, -C%), 5.35 (unresolved multiplet, =C H ), 8.30 (triplet, -C H ), 8.40 (multiplet, -C H ), 8.96 (singlet, 12  13  2  -C^H ). 3  14  3  3  The above proton signal assignments were confirmed by frequency-  swept decoupling experiments.  Irradiation at x 5.35 resulted in an observed  collapse of the poorly resolved triplet at x 8.30 to a sharp singlet, thus establishing allylic coupling between the C-12 and C-13 protons/ Similar This value obtained from a separated run of this reaction  -  77 -  i r r a d i a t i o n o f the C-3 v i n y l p r o t o n at multiplet.  • T 4.70  This r e s u l t ,  effected  ing  o f the  T 8.40  the  T 4.70  m u l t i p l e t upon, i r r a d i a t i o n o f x 8.40  Calcd.  for C  (+)-78-Eremophil-11-ene  1 5  H  2 4  :  c l e a r l y demonstrated a l l y l i c  C , 88.16; H , 11.84.  138 from semicarbazone  For an analogous p r o c e d u r e see  Church,  A s t i r r e d s o l u t i o n c o n t a i n i n g 2.00 137,  1.8.2 m l ' ( 3 2 . 2 mmoles)  Found:  C , 88.36; H ,  I r e l a n d and S h r i d a r  (30.9 mmoles)  (t.l.c.)  indicated l i t t l e  g (7.5 mmoles)  (50).  o f 85% h y d r a z i n e h y d r a t e , 1.87  and thus m a i n t a i n e d f o r 21 h r .  11.98  137  semicarbazone  160-165°  190-195°  2.  of  p o t a s s i u m h y d r o x i d e i n 20 ml d i e t h y l e n e  i n c r e a s e d to  sharpen-  and the observed s h a r p e n i n g o f  c o u p l i n g between the C-3 and C^14 p r o t o n s o f s t r u c t u r e Anal.  a substantial  g l y c o l was g r a d u a l l y heated  of  to  As t h i n - l a y e r chromatography  o r no p r o d u c t f o r m a t i o n the temperature was  and thus r e f l u x e d f o r 24 h r .  The r e a c t i o n m i x t u r e  was then c o o l e d t o room temperature then poured i n t o 100 ml o f w a t e r .  The  product,  which  i s o l a t e d with ether  was shown by g . l . c .  (water,  b r i n e ) was a y e l l o w o i l  (column D, 1 4 0 ° ) t o be 97% o l e f i n 138_ (91% y i e l d ) .  These c o n d i t i o n s were employed i n c o l l e c t i n g was found t o be i d e n t i c a l  an a n a l y t i c a l sample which  (n^, i . r . , n . m . r . , g . l . c .  r e t e n t i o n times  columns A , 1 8 0 ° ; B , 1 8 0 ° ; C , 1 6 8 ° ; E , 1 2 0 ° ) w i t h a sample o f (+)-78-eremophil-ll-ene 30,  as d e t a i l e d Anal.  138 d e r i v e d from  Calcd.  for C  ( t ) - 7 B - E r e m o p h i l a n e 45  l r  H ,: 0  authentic  (+)-hydroxydihydroeremophilone  C , 8 7 . 3 0 ; H , 12.70.  Found:  C , 87.02; H ,  12.79  lb  .  A s o l u t i o n c o n t a i n i n g 648 mg (3.15 0.70  on  below.  ID  and  (1.466 g)  g of platinum oxide  mmoles)  of  (t)-eremophil-11-ene  138  i n 25 ml o f e t h a n o l was s t i r r e d at room temp-  e r a t u r e under hydrogen o v e r n i g h t .  The r e a c t i o n m i x t u r e was f i l t e r e d and  c o n c e n t r a t e d y i e l d i n g 596 mg o f a c o l o r l e s s  o i l shown by g . l . c .  (column D,  -  135°)  t o be 95% ( ± ) - 7 B - e r e m o p h i l a n e  78  -  45_.  An a n a l y t i c a l  sample was  collected  23 6 by p r e p a r a t i v e g . l . c .  (column D, 1 3 5 ° ) ,  A  7.30,  " 3.4,  6.90,  6.82,  7.22,  n  10.00,  Q  '  1.4820.  10.81  Infrared  (film),  u ; n . m . r . , T 9.15  (doublet,  IT13.X  -C  H  1 2  and - C  3  1 3  H  J  3 >  1  n  2  ^  3  j  = 6 H z ) , 9.16  (singlet,  -C  1 5  H ), 3  9.28  (doublet,  14 -C  H ,  ^  3  n.m.r.,  = 6.5  and g . l . c .  with authentic 30,  T h i s m a t e r i a l was found to be i d e n t i c a l  retention  time on columns A , 1 5 8 ° ; C , 1 5 8 ° ; E ,  (n , Q  i.r.,  120°),  (+)-73-eremophilane 45_ d e r i v e d from h y d r o x y d i h y d r o e r e m o p h i l o n e  as d e t a i l e d Anal.  Hz).  below.  Calcd.  for C  1 5  H  2 g  :  C , 86.46; H , 13.54.  Found:  C , 86.34; H ,  13.26. (+)-Hydroxydihydroeremophilone The p r o c e d u r e f o l l o w e d A solution 4.25 in  of  1.000  Acetate  is  that  g (4.68  o f D j e r a s s i , Mauli and Zalkow  mmoles)  ml o f a c e t i c a n h y d r i d e d i s s o l v e d  a r e f r i g e r a t o r f o r 2 days.  139  of hydroxydihydroeremophilone  i n 8.5 ml o f dry p y r i d i n e was  with c h l o r o f o r m (1.2  acid,  brine)  sodium b i c a r b o n a t e ,  c r y s t a l l i z e d on s t a n d i n g  at  0°.  water,  giving  1.188  30,  stored  The r e a c t i o n m i x t u r e was then poured  15 ml o f water and the p r o d u c t i s o l a t e d dilute  (22).  into  M hydrochloric g of o i l  which  R e c r y s t a l l i z a t i o n from methanol gave 416 mg  o f the k e t o a c e t a t e 139 as c o l o r l e s s p l a t e s , m.p. 6 8 - 7 1 ° . Infrared (CHC1 ), A - 3 . 4 2 , 5 . 7 3 , 5 . 8 0 , 7 . 9 0 - 8 . 5 , 11.10 u . An a d d i t i o n a l 658 mg o f the max • crude k e t o a c e t a t e was r e c o v e r e d from the mother l i q u o r ( y i e l d c a . 90%). 3  (+)-73-Eremophil-ll-en-9-one The p r o c e d u r e f o l l o w e d  140 is  that  o f D j e r a s s i , M a u l i and Zalkow  To a v i g o r o u s l y s t i r r e d s o l u t i o n of  l i q u i d ammonia at  mg  (3.02  mmoles)  o f 7.45  - 3 3 ° was added dropwise  of keto acetate  g o f c a l c i u m metal  (22). i n 185 ml  over 25 min a s o l u t i o n o f  139 i n 15 ml o f dry t o l u e n e .  m i x t u r e was thus s t i r r e d f o r a f u r t h e r 10 min then 7.45  ml o f  765  The r e a c t i o n bromobenzene  -  was added dropwise of  water.  chloroform oil.  (exothermic)  79 -  f o l l o w e d by t h e c a r e f u l a d d i t i o n o f 36 ml  The ammonia was then evaporated and the p r o d u c t i s o l a t e d  with  (0.6 M h y d r o c h l o r i c a c i d , water,  yellow  The crude e r e m o p h i l - l l - e n - 9 - o n e  thus  b r i n e ) g i v i n g 706 mg o f o b t a i n e d was found to be  i c a n t l y contaminated w i t h an u n i d e n t i f i e d a r o m a t i c i m p u r i t y , as by  t.l.c.  and i . r .  activity  I)  subsequently  was s l i g h t l y *  Successive  a f f o r d e d 84 mg o f t h e d e s i r e d ketone  contaminated and 129 mg o f p r e c i o u s g . l . c .  (+)-eremophil-ll-en-9-one  6.08,  11.20 vi n . m . r . , T 9.23  (doublet,  this  1 4  H , 3  g l y c o l was r e f l u x e d f o r 2 h r , then the excess h y d r a z i n e was o f f s l o w l y by d r a i n i n g the water condenser and a l l o w i n g the  temperature f o r 8 h r .  to 2 0 5 - 2 1 5 ° .  After cooling,  The system was then  The c o l o r l e s s  liquid  3  1.4933.  6  with ether  n.m.r., -C  1 3  H ), 3  T 5.36 9.16  -C  1 5  H ), 3  9.26  =C  H ) , 8.30 2  (doublet,  -C  1 4  g.l.c.  138 ( y i e l d c a . 53%).  X 3 . 4 , 6.08, 6.90, max ' ' 12  (unresolved m u l t i p l e t , (singlet,  (water,  (145 mg) thus o b t a i n e d was shown by  Infrared (film),  refluxed  the r e a c t i o n m i x t u r e was  An a n a l y t i c a l sample was o b t a i n e d by p r e p a r a t i v e g . l . c .  D  140  0.75 g o f potassium h y d r o x i d e i n 10 ml o f  (column D, 1 4 0 ° ) to c o n t a i n 65% o f t h e d e s i r e d o l e f i n  nj '  (unresolved  ( + ) - e r e m o p h i l - 1 1 - e n - 9 - o n e i n 2.0 ml  d i l u t e d w i t h 20 ml o f water and the p r o d u c t i s o l a t e d brine).  5.86,  = 5.9 H z ) , 8.97  3^  13 - C H ^ ) , 5.26  triplet,  c o n t a i n i n g 190 mg o f  temperature t o g r a d u a l l y i n c r e a s e at  -C  3.45,  m  138 from ( + ) - 7 g - e r e m o p h i l - l l - e n - 9 - o n e  85% h y d r a z i n e h y d r a t e ,  distilled  Infrared (film), >  (column E ,  2  A solution  diethylene  pure  140 which  12 =C H ) .  (+)-7B-Eremophil-ll-ene  of  140.  15 - C H ^ ) , '8.27 ( u n r e s o l v e d  multiplet,  indicated  column chromatography (Woehlm n e u t r a l a l u m i n a ,  205°)  (singlet,  signif-  (column D , 1 4 0 ° ) ,  7.28, 7.23, '  11.28 u j  (poorly resolved H , 3  3^  u  triplet,  = 6.6 H z ) .  -  80 -  (+)-78-Eremophi lane 45_ A solution of  c o n t a i n i n g 94 mg o f  platinum oxide  (+)-7g-eremophil-ll-ene  i n 4 ml o f a b s o l u t e  t u r e o v e r n i g h t under h y d r o g e n .  e t h a n o l was s t i r r e d a t room tempera-  The r e s u l t i n g s o l u t i o n was f i l t e r e d and  c o n c e n t r a t e d y i e l d i n g 80 mg o f c o l o r l e s s (column F , 1 4 0 ° ) t o  c o n t a i n 78% o f  An a n a l y t i c a l sample was c o l l e c t e d n P ' D '  1.4820.  6  10.81 9.16  Infrared ( f i l m ) ,  y ; n . m . r . , T 9.15 (singlet,  -C  1 5  H ), 3  o i l which was shown by  g.l.c.  (+)-78-eremophilane 45_ ( y i e l d by p r e p a r a t i v e g . l . c .  X 3.4, max  (doublet, 9.28  138 and 94 mg  -C  1 2  H  (doublet,  6.90,  6.82, J  U  3  -C  1 4  H ,  3^  3  (column F ,  7.30,  and - C H ,  3  ca.  n  7.22,  1 2 (  -  1 3 )  64%). 140°),  10.00,  = 6 Hz),  = 6.5 H z ) .  u  Eremophilene _3 from e r e m o l i g e n o l 28_ The  p r o c e d u r e employed i s  To a s o l u t i o n o f 44.1 dry  p y r i d i n e at  minutes and  at  Tozyo and Minato  mg (0.198 mmole o f e r e m o l i g e n o l  0 ° was added 0.05  for  1 hr.  (18).  28_ i n 0.5 ml o f  ml o f t h i o n y l c h l o r i d e .  After  several  I t was then quenched i n s e v e r a l m i l l i t e r s  and the p r o d u c t i s o l a t e d  sodium b i c a r b o n a t e , w a t e r , b r i n e ) analytical  Ishii,  0 ° the r e a c t i o n m i x t u r e was allowed t o come to room temperature  thus r e a c t  ice-water  that of  sample,  collected  i n f r a r e d spectrum i d e n t i c a l  (l)-78-Eremophil-ll-en-3-one  with ether  (2 N s u l f u r i c a c i d ,  y i e l d i n g 34.4  by g . l . c .  mg o f y e l l o w o i l .  (column B , 1 8 0 ° ) ,  to t h a t o f n a t u r a l  128 by copper  (II)  exhibited  of  dilute An an  eremophilene.  acetate  catalyzed  Grignard addition To a s t i r r e d e t h e r e a l (2.94 iodide  s o l u t i o n of methylmagnesium  mmoles)' o f magnesium t u r n i n g s , i n 3.2 ml o f anhydrous e t h e r )  0.19 ml (3.04 at  200 mg (0.980 mmole)  of octalone  mmoles)  - 1 0 ° under N  c o n t a i n i n g 48.8 mg (0.245 mmole) o f copper  (II)  iodide  2  (from 71.4 mg o f methyl  was added a  solution  a c e t a t e monohydrate,  127 i n 4.8 "ml o f dry t e t r a h y d r o f u r a n  -  dropwise over 30 m i n .  81 -  The c o l d b a t h was then removed and the  yellow  c o l l o i d a l r e a c t i o n m i x t u r e a l l o w e d t o come t o room temperature and thus remain o v e r 4 h r .  A f t e r r e f l u x i n g f o r 1.5  geneous system was poured s l o w l y acid.  h r the r e s u l t i n g g r e y h e t e r o -  i n t o v i g o r o u s l y s t i r r e d 1.2 M h y d r o c h l o r i c  The p r o d u c t was i s o l a t e d w i t h e t h e r  ( d i l u t e sodium b i c a r b o n a t e ,  w a t e r , b r i n e ) g i v i n g 190 mg o f orange o i l . strong saturated carbonyl  (5.85  absorbance and was s u b s e q u e n t l y tain  25% o f the d e s i r e d decalone  i n a d d i t i o n t o at decalone  least  u) and weak u n s a t u r a t e d c a r b o n y l shown by g . l . c . 128  from t h i s  (6.00)  (column D, 1 8 0 ° ) to c o n -  (peak enhancement),  14 o t h e r components.  128 was i s o l a t e d  12% s t a r t i n g m a t e r i a l  An a n a l y t i c a l sample o f  r e a c t i o n m i x t u r e by p r e p a r a t i v e  (column D, 1 6 0 ° ) and e x h i b i t e d an i n f r a r e d that of authentic  This material exhibited a  g.l.c.  spectrum superimposable upon  (i)-78-eremophil-ll-en-3-one.  It s h o u l d be noted  that  the p r o d u c t c o m p o s i t i o n s o b t a i n e d from a number o f such r e a c t i o n s v a r i e d somewhat  irreproducibly  i n c o m p l e x i t y and p e r c e n t  1,4-adduct  (10 t o ^ 2 5 % ) .  -  82 -  BIBLIOGRAPHY  1.  For a l i s t (incomplete) o f t w e n t y - f o u r eremophilane s e s q u i t e r p e n e s see C H . Heathcock and T . R . K e l l y . T e t r a h e d r o n 24, 3753 (1968). See a l s o . G. O u r i s s o n , S. M u n a r a l l i and C E h r e t . International t a b l e s of S e l e c t e d C o n s t a n t s , 15, Data R e l a t i v e to S e s q u i t e r p e n o i d s , Pergamon P r e s s , New York (1966).  2.  L . Ruzicka.  3.  L . R u z i c k a , A . Eschenmoser, 38, 1890 (1955).  4.  J . M . M e l l o r and S. M u n a v a l l i .  5.  J . Hochmannova, 1870 (1962).  6.  Ibid.,  7.  J . Hochmannova and V . H e r o u t .  8.  E . Piers  9.  J . K r e p i n s k y , 0. M o t l , L . D o l e j s , L . Novotny, V . 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