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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.S c , Un i v e r s i t y of 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 the Department of Chemistry We accept t h i s t h e s i s as conforming to the required standard THE UNIVERSITY OF BRITISH COLUMBIA December, 1968 In p r e s e n t i n g t h i s t h e s i s i n p a r t i a l f u l f i l m e n t o f t h e r e q u i r e m e n t s f o r an a d v a n c e d d e g r e e a t the U n i v e r s i t y o f B r i t i s h C o l u m b i a , I a g r e e t h a t t h e L i b r a r y s h a l l make i t f r e e l y a v a i l a b l e f o r r e f e r e n c e and S t u d y . I f u r t h e r a g r e e t h a t p e r m i s s i o n f o r e x t e n s i v e c o p y i n g o f t h i s t h e s i s f o r s c h o l a r l y p u r p o s e s may be g r a n t e d by the Head o f my Department o r by h i s r e p r e s e n t a t i v e s . It i s u n d e r s t o o d t h a t c o p y i n g o r p u b l i c a t i o n o f t h i s t h e s i s f o r f i n a n c i a l g a i n s h a l l n o t be a l l o w e d w i t h o u t my w r i t t e n p e r m i s s i o n . D e p a r t m e n t o f L -VN^OT^ <•< The U n i v e r s i t y o f B r i t i s h C o l u m b i a V a n c o u v e r 8, Canada Date 2- "5 ^ oc&»JL (1 ; ]  ( i i ) • - ABSTRACT The n a t u r a l l y occurr ing sesquiterpene, eremophilene, has r e c e n t l y been formulated as (+)-78-eremophil-3,11-diene 2_. The t o t a l synthesis of (± ) 2_, reported h e r e i n , was achieved by the fo l lowing sequence. React ion of the hydroxymethylene d e r i v a t i v e of 3- isopropenylcyclohexanone 130 with 1 - d i e t h y l -amino-3-pentanone methiodide 122 i n the presence of base (Robinson annelat ion reac t ion ) r e a d i l y a f f o r d e d , a f t e r a l d o l r i n g c l o s u r e , l - m e t h y l - 7 - i s o p r o p e n y l -1 9 A ' - o c t a l - 2 J o n e 127. React ion of compound 127 with e thereal l i t h i u m dimethylcuprate 135 r e s u l t e d i n the s e l e c t i v e conjugate a d d i t i o n of a methyl group to octalone 127, 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 product ( ± ) - 7 3 - e r e m o p h i l - l l - e n - 3 - o n e 128. The r e l a t i v e s tereochemistry o f the eremophilane d e r i v a t i v e 128 was confirmed by chemical c o r r e l a t i o n with hydroxydihydroeremophilone 2>0_ of known absolute c o n f i g u r a t i o n . React ion of the tosylhydrazone d e r i v a t i v e of compound 128 with sodium ethylene g l y c o l a t e i n r e f l u x i n g ethylene g l y c o l (Bamford-Stevens reac t ion) afforded (+) 2. Comparison of compound (t) 2_ with a sample of authent ic eremophilene c l e a r l y e s tab l i shed that the s t r u c t u r a l assignment (2) o r i g i n a l l y proposed f o r eremophilene was i n c o r r e c t . Dehydration o f the n a t u r a l l y occurr ing eremoligenol 28^  with t h i o n y l c h l o r i d e and p y r i d i n e af forded (+)-eremophil-1(10) ,11-diene 3 which was shown to be i d e n t i c a l with authent ic eremophilene. Thus the s t r u c t u r e and stereochemistry of eremophilene i s c o r r e c t l y represented by formulat ion 3_. The synthes is of eremophi l -3 ,11-diene 2_ reported here in e s tab l i shes a s t e r e o s e l e c t i v e synthe t i c entry into the eremophilane c lass o f s e squi terpenoids . • . (iii) T A B L E OF CONTENTS Page Title page . . (i) Abstract (ii) Table of Contents (iii) List of Figures (iv) Acknowledgements (v) Introduction 1 Discussion . 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 facilities. 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 is expressed to both Mr. H. Hanssen and Miss D. Johnson for their interest and efforts throughout the prepara-tion of this thesis. INTRODUCTION S e s q u i t e r p e n e s a r e a c l a s s o f i s o p r e n o i d compounds w h i c h n o r m a l l y c o n t a i n f i f t e e n c a r b o n atoms. They a r e p a r t o f a l a r g e r group o f b i o g e n e t i -c a l l y r e l a t e d s u b s t a n c e s , c o l l e c t i v e l y r e f e r r e d t o as t h e t e r p e n e s . The 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 wide d i s t r i b u t i o n t h r o u g h o u t n a t u r e , o c c u r r i n g i n a v a r i e t y o f p l a n t s and t r e e s , and f o r t h e i r c o n s i d e r a b l e s t r u c t u r a l d i v e r s i t y . These compounds e x h i b i t a l a r g e v a r i e t y o f m o n o c y l i c , b i c y l i c , t r i c y l i c and t e t r a c y l i c c a r b o n s k e l e t o n s and i n d e e d i t i s on t h i s b a s i s , t h a t i s t h e n a t u r e o f t h e c a r b o n s k e l e t o n , t h a t s e s q u i t e r p e n e s a r e o f t e n c l a s s i f i e d . One such c l a s s o f s e s q u i t e r p e n e s i s t h e e r e m o p h i l a n e group which p o s s e s s t h e b a s i c c a r b o n s k e l e t o n 1_. 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 d i m e t h y l system f o u n d a t C-4 and C-5 o f r i n g A, and t h e t h r e e c a r b o n " i s o p r o p y l - t y p e " s i d e c h a i n a t t a c h e d t o r i n g B a t C-7. The numbering system shown i n 1_ i s t h a t n o r m a l l y employed f o r t h i s c l a s s o f compounds. U n t i l t h e e a r l y 1960's few members o f t h i s c l a s s o f s e s q u i t e r p e n e were known. However, s i n c e , t h e n , t h e number o f known e r e m o p h i l a n e s has grown r a p i d l y t o t h e f o r t y f i v e o r so t h a t have been r e p o r t e d t o d a t e ( 1 ) . I n t e r e s t i n t h e e r e m o p h i l a n e s e s q u i t e r p e n e s i s , a p a r t from t h e s t r u c t u r a l and f u n c t i o n a l d i v e r s i t y f o u nd w i t h i n t h i s c l a s s , p r i m a r i l y due t o t h e f a c t t h a t t h e c a r b o n s k e l e t o n - 2 -1 i s "non- i soprenoid". In f a c t , f o r sometime the f i r s t i s o l a t e d members of t h i s group represented the only known exceptions to the "isoprene r u l e " i n the sesquiterpene f i e l d (2) . In the past few years t h i s l aboratory has been concerned with the synthes i s of s evera l c lasses o f sesqui terpenes , and r e c e n t l y , a t t e n t i o n was d i r e c t e d to the eremophilane sesquiterpenes . The a t t r a c t i o n was i n part due to the group'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 , and i n part due to the fac t t h a t , at that t ime, none o f the eremophilanes had been * t o t a l l y synthes ized (4). Thus, the s p e c i f i c object o f the work reported i n t h i s t h e s i s was to e s t a b l i s h a general s y n t h e t i c entry i n t o the eremophilane c la s s o f sesquiterpenes and, i n p a r t i c u l a r , to e f fec t an unambiguous synthes is o f one member of the group, eremophilene. Eremophilene, a C 1 5 H 2 4 hydrocarbon, was f i r s t i s o l a t e d from the roots o f Pe tas i t e s o f f i c i n a l i s MOENCH (5) and P. albus (L . ) GAERTN (6) by Herout E a r l y workers, most noteably Ruz icka , observed that the b a s i c s k e l e t a l s t r u c t u r e s possessed by the terpenes could formal ly be considered to be constructed i n m u l t i p l e s o f isoprene u n i t s i_ jo ined e i t h e r i n a regu lar h e a d - t o - t a i l manner, or i n an i r r e g u l a r manner. These s t r u c t u r a l requirements came to be known as the "isoprene r u l e " (2) and thus def ined the "terpenes". In subsequent years however numerous terpenoid compounds were i s o l a t e d whose s t r u c t u r e disobeyed the isoprene r u l e i n as much as t h e i r b a s i c carbon skeletons could not formal ly be regarded as a sequence of isoprene u n i t s . To account for these "non-i sopreno id" substances i n terms of a u n i f i e d d e f i n i t i o n of terpenes, the isoprene r u l e was rev i s ed (3). This v e r s i o n , "the b iogene t i c isoprene r u l e " , simply amends the isoprene r u l e d e f i n i t i o n o f terpenes so as to inc lude those terpenes which have undergone carbon s k e l e t a l rearrangement i n the course o f t h e i r b i o s y n t h e s i s . head t a i l - 3 -H 1 2 3 and coworkers i n 1962. Subsequently the s k e l e t a l and stereochemical features of eremophilene were e l u c i d a t e d by Hochmannova and Herout (7) , who i n 1964, on the bases of chemical r e a c t i o n , i n f r a r e d ( i . r . ) and nuc lear magnetic resonance ( n . m . r . ) spectra and a chemical c o r r e l a t i o n with hydroxy-dihydroeremophilane of known absolute c o n f i g u r a t i o n formulated eremophilene as 2_. However i t should be noted here that r e c e n t l y as a r e s u l t of 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) , t h i s s t r u c t u r a l assignment was shown to be i n c o r r e c t and the r e v i s e d s t r u c t u r e 3_ was e s tab l i shed f o r eremophilene. That formulat ion 3_ i s indeed correc t was very r e c e n t l y confirmed by the exce l l en t t o t a l synthesis of ( i) 3_ by Coates and Shaw (10) . TERPENOID BIOSYNTHESIS A number of references to the b i o g e n e t i c a l l y anomalous eremophilane carbon ske le ton have been made i n the forego ing , and i n subsequent d i s c u s s i o n , c o n s i d e r a t i o n w i l l be given to a proposed " b i o g e n e t i c a l l y s t y l e d eremophilane synthes is" . Thus to c l a r i f y these and other ensuing points r e l a t e d to the b iosynthes i s of t h i s group, i t i s expedient to introduce here a d i s c u s s i o n o f the b i o s y n t h e s i s of terpenes i n general and the eremophilane sesquiterpenes i n p a r t i c u l a r . Throughout the past twenty years s u b s t a n t i a l progress has been made i n e l u c i d a t i n g the b iosynthes i s o f terpenoid compounds. Much of 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 w h i c h 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 con-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 i n t r o d u c e d i n t o p l a n t and a n i m a l systems l e a d -i n g , i f t h e p r e c u r s o r s a r e * a u t h e n t i c , t o an i n c o r p o r a t i o n o f t h e r a d i o - l a b l e 2 i n t h e s u b s e q u e n t l y i s o l a t e d t e r p e n e s . Thus.by such l a b e l l i n g s t u d i e s i t has 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 p r o c e e d s from a c e t i c a c i d , o r i t s b i o s y n t h e t i c e q u i v a l e n t a c e t y l coenzyme A 4_, as s u m m a r i l y r e p r e s e n t e d i n F i g u r e 1_ ( 1 1 ) . The s u c c e s s i v e s e l f c o n d e n s a t i o n o f t h r e e m o l e c u l e s o f a c e t a t e 4_ a f f o r d s , a f t e r p a r t i a l h y d r o l y s i s g - h y d r o x y - $ - n i e t h y l g l u t a r y l coenzyme A S_. R e d u c t i o n w i t h picotinamide - a d e n i n e d i n u c l e o t i d e p h o s p h a t e (NADPH) l e a d s t o t h e m e v a l o n i c a c i d 6_ - m e v a l o n o l a c t o n e 7_ system 3 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 a d e n i n e t r i p h o s p h a t e (ATP) p h o s p h o r y l a t i o n and subsequent d e c a r b o x y l a t i o n . Rearrangement o f t h e t e r m i n a l d o u b l e bond o f 8_ r e s u l t s i n t h e f o r m a t i o n o f d i m e t h a l l y l p y r o -3 p h o s p h a t e w h i c h on c o n d e n s a t i o n w i t h a m o l e c u l e o f A * - i s o p e n t e n y l p y r o -p h osphate ( p r o t o n 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. I t i s t h i s i m p o r t a n t i n t e r m e d i a t e and i t s c i s - d o u b l e bond i s o m e r n e r y l p y r o p h o s p h a t e t h a t a r e t h e b i o s y n t h e t i c p r e c u r s o r s o f t h e monoterpenes, t h a t i s t h e c l a s s o f t e r p e n o i d s w h i c h ( n o r m a l l y ) c o n t a i n t e n c a r b o n atoms. I n a p a r a l l e l manner t h e a d d i t i o n o f one m o l e c u l e o f t h e 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 t o f a r n e s y l p y r o p h o s p h a t e _11_, whereas t h e c o n s e c u t i v e a d d i t i o n o f two m o l e c u l e 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 g e r a n y l p y r o p h o s p h a t e 1_2_. F a r n e s y l and g e r a n y l g e r a n y l p y r o p h o s p h a t e s 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 (11) as b i o s y n t h e t i c p r e c u r s o r s o f t h e s e s q u i t e r p e n e s (C-15) and d i t e r p e n e s (C-20) r e s p e c t i v e l y . 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 o f s p e c i f i c r e s u l t s o f l a b e l l i n g s t u d i e s w i l l n o t 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 f o r d e t a i l s . 9 MONOTERPENES SESQUITERPENES DITERPENES 1 f 4 F i g u r e 1_ - 6 -s q u a l e n e J_3, w h i c h i s t h e b i o s y n t h e t i c p r e c u r s o r o f t h e t r i t e r p e n e s (C-30) and t h e s t e r o i d s ( 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 ) . The b a s i c c a r b o n s k e l e t o n , and t o an i n c r e a s i n g extent t h e c o n f i g u r a t i o n a l f e a t u r e s , o f v i r t u a l l y a l l o f t h e s e s q u i t e r p e n e s can be a c c o u n t e d f o r by c o n s i d e r i n g t h a t t h e s e s u b s t a n c e s a r e b i o s y n t h e t i c a l l y d e r i v e d from c i s , and t r a n s - f a r n e s y l p y r o p h o s p h a t e , 14_ and 11_, v i a t h e a p p r o p r i a t e c y c l i z a t i o n s o f c a t i o n s L5 t o 20_ ( F i g u r e 2)_ ( 1 1 , 12) . C a t i o n s 15 t o 20 a r i s e from c i s - and t r a n s - f a r n e s y l p y r o p h o s p h a t e upon 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 t h e a p p r o p r i a t e r i n g c l o s u r e s . These i o n s s h o u l d o f c o u r s e be r e g a r d e d i n a f o r m a l s e n s e , as t h e b i o s y n t h e t i c c y c l i z a t i o n s o f f a r n e s y l p y r o p h o s p h a t e a r e e n z y m a t i c a l l y c o n t r o l l e d and, as s u c h , may be e f f e c t e d i n a p a r t i a l o r c o n c e r t e d manner ( 1 1 ) . 29 - 7 -Robinson (15), some years ago, suggested that the eremophilane sesqui-terpenes 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 epi-merization, would give the all £i_s_-structure 2!5_, characteristic in the eremophilane group. Subsequent oxidation and dehydration would yield eremo-philone. 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 experimental work s p e c i f i c a l l y concerned with the b iogenes is of the eremophilane sesquiterpenes has been reported to date , Minato 's 1966 i s o l a t i o n o f eremoligenol 28, from L i g u l a r i a F i s c h e r i Turcz (18) and the very recent conformation o f s t ruc ture 29_ (I^h^) for eremophilene (8,10) lends support to the above proposed biogenesis of these eremophilanes. STRUCTURE IN THE EREMOPHILANE SESQUITERPENES As the subject of t h i s thes i s i s concerned with e s t a b l i s h i n g a synthet i c approach to eremophilene and to the eremophilane group per se , i t i s o f importance to consider a number of t o p i c s , a l l of which embrace s t r u c t u r a l aspects of the eremophilanes. S p e c i f i c a l l y , i t i s intended to present i n the fo l lowing sect ions a d i s c u s s i o n o f (a) the s k e l e t a l and c o n f i g u r a t i o n a l - 9 -elucidation of the f i r s t isolated eremophilane-type sesquiterpenes, eremophilone and i t s cogeners, (b) the important structural variations found in the eremophilane group, (c) the o r i g i n a l structural elucidation of eremophilene and f i n a l l y , (d) the salient features of other synthetic approaches to this class of sesquiterpene. (a) The Structure of Eremophilone and Cogeners The f i r s t naturally occurring compounds found which possess the eremo-philane carbon skeleton were isolated i n 1932 by Bradfield, Penfold and Simonsen (19,20). Thus, Simonsen and coworkers iso l a t e d , from the wood of Eremophila  M i t c h e l l i , three closely related sesquiterpenic ketones, v i z . , eremophilone, hydroxydihydroeremophilone and hydroxyeremophilone. In the period between 1932 and 1941, Simonsen's group carried out, by c l a s s i c a l methods of structural elucidation, an investigation into the structure of the three eremophilone sesquiterpenes (20). The enormous amount of work carried out and the pain-stakingly slow progress involved i n the problem render a present detailed discussion of the skeletal elucidation of these compounds quite impractical. Thus, s u f f i c e to say that after considerable effort by these workers, the skeletal features of eremophilone, hydroxydihydroeremophilone and hydroxy-eremophilone were correctly formulated as 26a, 30a and 31a respectively. 26a 30a 31a - 10 -By the mid-1950's it 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). Specifi-cally, ketone 32 was obtained from both eremophilone 26_ by sodium alcohol reduction followed by chromium trioxide oxidation and from hydroxydihydro-eremophilone 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 obtained i n three steps from hydroxyeremophilone 31_ with that obtained i n fourteen steps from the hexalone 34 o f known absolute stereochemistry (16,23). 31 33 34 (b) S t r u c t u r a l V a r i a t i o n s i n the Eremophilane Sesquiterpenes In the fo l lowing s e c t i o n , a t t e n t i o n i s d i r e c t e d . t o the var ious s t r u c t u r a l and c o n f i g u r a t i o n a l features which are encountered i n the n a t u r a l l y o c c u r r i n g eremophilane-type sesquiterpenes . A survey of the known members of t h i s c lass o f compound r e a d i l y revea l s a number of c h a r a c t e r i s t i c stereochemical f ea tures . Of immediate note i s the cons i s tent c i s r e l a t i o n s h i p between the C-14 and C-15 annular methyl groups o f r i n g A. The prevalence of such a c i s geometry i s , of course , i n agreement with the c o n f i g u r a t i o n a l requirements of the 1 ,2-migrat ions postu-l a t e d i n the above mentioned eremophilane b iogenes i s . It i s a l so of i n t e r e s t that the C-7 " i sopropy l - type" three carbon s ide chain of r i n g B i s commonly found e i t h e r c i s or trans to the v i c i n a l methyl s u b s t i t u e n t s . A comparison o f nootkatone 35, i s o l a t e d from C i t r u s p a r a d i s i (24), and eremophilone 2_6_ c l e a r l y demonstrates these s t r u c t u r a l f ea tures . In the frequent ly encountered a l l - c i s geometry, exempli f ied by eremophilone 26, a notable s t e r i c i n t e r a c t i o n occurs between the a x i a l C-5 and C-7 s u b s t i t u e n t s , which i s absent i n the r e l a t e d epimeric system 35_. A fur ther apparent conf i g u r a t i o n a l g e n e r a l i t y , i s - 12 -t h a t o f t h e c i s - f u s e d r i n g j u n c t u r e 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 -i n g a s a t u r a t e d C-10 c a r b o n atom. Of t h e p r e s e n t l y known n a t u r a l l y o c c u r r i n g e r e m o p h i l a n e s , none e x h i b i t t r a n s - f u s e d A and B r i n g s . F u n c t i o n a l l y , t h e s e s e s q u i t e r p e n e s a r e r e l a t i v e l y uncomplex. They 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 e x h i b i t h y d r o x y 1 and k e t o n i c f u n c t i o n a l groups a t one 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 atoms. I t i s i n t e r e s t i n g 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 which e x h i b i t o x y g e n a t e d C - l c a r b o n atoms. A number a r e known w h i c h p o s s e s s a t e r t i a r y h y d r o x y l group a t C - l l , f o r example v a l e r i a n o l 3_6, i s o l a t e d from V a l e r i a n a  o f f i c i n a l i s L. ( 2 5 ) . E r e m o p h i l a n e s c o n t a i n i n g t h e d e h y d r a t i o n r e l a t e d i s o -p r o p e n y l (commonly o c c u r r i n g ) and 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 a r e a l s o known, as i s t h e t o t a l l y s a t u r a t e d i s o p r o p y l s i d e c h a i n m o i e t y . The l a t t e r f u n c t i o n a l i t i e s a r e i l l u s t r a t e d 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 u g a n d e n s i s Sprague ( 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 38., from N a r d o s t a c h y s  j a t a m a n s i D.C. ( 2 7 ) . 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 " 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 s u f f e r e d e x t e n s i v e o x i d a t i o n l e a d i n g 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 eremophi1-e n o l i d e 39_, i s o l a t e d from P e t a s i t e s h y b r i d u s (30) and f u r a n d e r i v a t i v e s such as t h e r e c e n t l y i s o l a t e d ( f rom Euryops f l o r i b u n d u s (29)) e u r y o p s o n o l 40. - 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 it is instructive to briefly mention this group here. a-Ferulene 43, from Ferula - 14 -. communis L . (Umbel l i ferae) (33) and the enantiomeric a r i s t o l o n e 44 from A r i s t o l o c h i a d e b i l i s S ieb . et_ Zucc. (28) serve to exemplify the bas i c a r i s t o l a n e carbon ske l e ton . The a l l - c i s - g e o m e t r y , found i n the eremophilanes, i s apparent ly unknown i n the a r i s t o l a n e group. The s k e l e t a l r e l a t i o n s h i p between the a r i s t o l a n e s and eremophilanes i s apparent i f one envis ions a formal r i n g c losure of the eremophilane C-7 i s o p r o p y l - t y p e s ide c h a i n , by carbon-carbon bond formation between C-6 and C - l l , y i e l d i n g the gem-dimethylcyclopropane r i n g and concomitantly the c h a r a c t e r i s t i c t r i c y c l i c a r i s t o l a n e ske le ton . It should be noted however, even i f somewhat d i g r e s s i v e l y , that the a r i s t o l a n e s are not considered to a r i s e b i o g e n e t i c a l l y from the eremophilanes. Rather i t has been proposed that they a r i s e v i a 1 ,3-deprotonat ion of c a t i o n 1_9 (see biosynthetic s e c t i o n ) , a f f o r d i n g the cyclopropane moiety, fol lowed by the appropr ia te s er i e s of 1 , 2 - s h i f t s leading to the a r i s t o l a n e systems, as i l l u s t r a t e d below (11). H Thus, i n summary, i t i s apparent that a cons iderable s t r u c t u r a l and f u n c t i o n a l group d i v e r s i t y ex i s t s i n the eremophilane sesquiterpenes , p a r t i c u l a r l y i f such "rearranged eremophilanes" as the bakkenolides and a r i s t -olanes are inc luded as members of the group. (c) S t r u c t u r a l E l u c i d a t i o n of Eremophilane As noted above, the compound of p r i n c i p a l s y n t h e t i c i n t e r e s t here in i s eremophilene. Thus, i t i s important to consider the e s s e n t i a l features of the s t r u c t u r a l e l u c i d a t i o n , reported by Hochmannova and Herout i n 1964 (7) , which led to the formulat ion o f eremophilene as 2. H Q u a n t i t a t i v e hydrogenation o f a sample o f n a t u r a l eremophilene, a C j g E ^ hydrocarbon, e s tab l i shed the presence o f two double bonds and gave a product i d e n t i c a l with (+)-78-eremophilane 45_ (Figure 2 ) , o f known absolute c o n f i g u r -a t i o n (18). The i . r . spectrum of eremophilene i n d i c a t e d the presence of a gem-disubst i tuted e t h y l e n i c double bond (6.06, 11.23 y) and a t r i - s u b s t i t u t e d e thy l en i c double bond (5.99, 12.36 u ) . I ts n . m . r . spectrum gave two t h r e e -proton s igna l s at T 8.22 and x 8.51 which were a t t r i b u t e d to v i n y l methyl groups and two v i n y l i c proton s igna l s at x 5.33 and 4.74, a t t r i b u t e d to the two protons of the gem-disubst i tuted o l e f i n and the s i n g l e proton o f the t r i -subs t i tu ted o l e f i n r e s p e c t i v e l y . The p o s i t i o n of the d i s u b s t i t u t e d double bond was e s tab l i shed by s e l e c t i v e l y hydrogenating eremophilene, us ing p a r t i a l l y deact ivated Raney-nickel i n e thanol . The r e s u l t i n g product , dihydroeremophilene Figure 2_. - 17 -47, e x h i b i t e d an i . r . d o u b l e t (7.21, 7.29 y) c h a r a c t e r i s t i c o f a gem-dimethyl group; moreover t h e o l e f i n i c c a r b o n - h y d r o g e n d e f o r m a t i o n a b s o r b a n c e (11.23y) e x h i b i t e d by e r e m o p h i l e n e was a b s e n t i n t h e d i h y d r o - p r o d u c t , c l e a r l y i n d i c a t -i n g t h e p r e s e n c e o f an i s o p r o p e n y l d o u b l e bond i n t h e n a t u r a l p r o d u c t . The c r u c i a l q u e s t i o n r e g a r d i n g t h e p o s i t i o n o f t h e t r i - s u b s t i t u t e d d o u b l e bond ( u n c o n j u g a t e d ) was t h e n c o n s i d e r e d . W i t h t h e p r e s e n c e o f an i s o p r o p e n y l m o i e t y i n e r e m o p h i l e n e e s t a b l i s h e d , t h r e e s t r u c t u r e s r e p r e s e n t -i n g t h i s compound became p o s s i b l e : 2_, Z_, and 54. 3 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 t h e x 8.22 and T 8.51 m e t h y l group s i g n a l s , s t r u c t u r e s 3^  and 54 were r e n d e r e d u n s a t i s f a c t o r y . However, i n a d d i t i o n t o t h i s 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 sought. O z o n o l y s i s o f d i h y d r o e r e m o p h i l e n e 47_ ( F i g u r e _2) i n e t h y l a c e t a t e a t • -75°, 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 h y d r o g e n , a f f o r d e d a m i x t u r e o f p r o d u c t s w h i c h by i . r . c o n t a i n e d a k e t o a l d e h y d e and a h y d r o x y k e t o n e , f o r m u l a t e d as 48_ and 4_9 r e s p e c t i v e l y . Permanganate o x i d a -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 e s t e r i f i c a t i o n o f t h e a c i d i c o x i d a t i o n p r o d u c t 50_, (R=H) w i t h diazomethane gave a C^g^gO^ k e t o e s t e r 50_, (R=Me) . T h i s m a t e r i a l r e a c t e d p o s i t i v e l y i n t h e i o d o f o r m t e s t , and e x h i b i t e d i . r . bands c h a r a c t e r i s t i c o f m e t h y l k e t o n e (5.85, 7.31 y) and m e t h y l e s t e r ( 5.75, 6.94 y) g r o u p s . These f a c t s were taken- as e v i d e n c e s u b s t a n t i a t i n g s t r u c t u r e - 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 hydroxydihydroeremo-philone 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 it 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 syn-thesized (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 total synthesis of a member of the eremophilane sesquiterpenes. The key step in the sequence was the stereo-selective condensation of 2-carbomethoxy-4-isopropylidene-cyclohexanone 57_ with trans-pent-3-en-2-one 56. In the presence of sodium methoxide, the keto ester 5_7_ underwent Michael addition to the pentenone 56_ affording, after aldol ring closure, a mixture of cis and trans-octalones, 58 and 5_9, with * the cis-derivative 5_8 predominating. 64 . 6 0 61_, X=0H 62, X=0MS 63, X=H - 20 -In an explanation o f f e r r e d regarding the observed stereochemistry at C-4, Marshall and coworkers suggested that e l e c t r o n i c and s t e r i c considerations would favor a t r a n s i t i o n state o r i e n t a t i o n represented by 65. From models i t i s apparent that the o r i e n t a t i o n of the methyl group and hydrogen atom (attached to the pendent C-4 atom) indic a t e d i n 65b leads to the e s t a b l i s h -ment of a c i s r e l a t i o n s h i p between the C-4 and C-5 (eremophilane numbering) substituents of octalone _58_. The s t e r i c a l l y less favorable t r a n s i t i o n state o r i e n t a t i o n depicted in.66 would conversely lead to the trans-octalone 59. Subsequent k e t a l i z a t i o n of octalone 5_8 followed by reduction of the carbomethoxy group to a methyl group (60 —» 61^ —> 62^—* 63) and ketal h y d r o l y s i s gave a product which exhibited i . r . and n.m.r. spectra and g . l . c . r e t e n t i o n time i d e n t i c a l with that of natural isonootkatone, i s o l a t e d from v e t i v e r t acetate (35), a commercial e s s e n t i a l o i l . A somewhat s i m i l a r stereochemical r e s u l t was obtained recently by Coates and Shaw (36) upon condensation of the p y r r o l i d i n e enamine of 2-methylcyclo-hexan-l,3-dione 67_ with trans-pent-3-en-2-one 56. The r e s u l t i n g product afforded i n good y i e l d a mixture of the c i s and trans-octalones 68. The c i s : t r a n s r a t i o of t h i s product was found to vary between 1:1 and 1:10, depending on the exact' re a c t i o n conditions used and upon the structure o f the cyclohexenone reagent employed. These findings provided an alternate synthetic approach to the - 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 -c i s and trans -unsaturated ketones 7_0_ and 71. These isomers were then s u c c e s s f u l l y separated by f r a c t i o n d i s t i l l a t i o n through a spinning-band column. React ion of the c i s -d imethy loc ta lone 70 with e thy l carbonate i n the presence o f sodium hydride i n 1,2-dimethoxyethane gave a mixture o f keto and enol tautomers, formulated here as 72. This m a t e r i a l upon r e f l u x i n g with e therea l methyl l i t h i u m fol lowed by a c i d ca ta lyzed dehydration o f the i n t e r -mediate t e r t i a r y a l c o h o l , gave the a ,g-unsaturated ketone 73_. A s tereo-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 was e f f ec ted v i a an i n t e r e s t i n g a p p l i c a t i o n o f the thermal decomposition o f p y r a z o l i n e s . Treatment of the a ,8-unsaturated ketone 7_3 with one equivalent 2 of hydrazine i n r e f l u x i n g absolute ethanol gave the A - p y r a z o l i n e 74_ which i n turn a f f o r d e d , on thermal decomposition with potassium hydroxide , a s t e r e o c h e m i c a l ^ homogeneous product , ( ± ) - A * ^ ^ - a r i s t o l e n e 75_. This m a t e r i a l was found to be chromatographically (g.I.e.) and s p e c t r o s c o p i c a l l y ( i . r . , n . m . r . ) i d e n t i c a l to the n a t u r a l l y occurr ing A * - a r i s t o l e n e . Recent ly , Brown and coworkers (38) reported the t o t a l synthesis o f racemic tetrahydroeremophilone 89, a reduc t ion product o f eremophilone. Unl ike the Robinson anne la t ion r e a c t i o n approaches of M a r s h a l l and Coates , d iscussed above, Brown u t i l i z e d a synthe t i c scheme which involved as the p r i n c i p a l step a " b i o g e n e t i c - l i k e " t r a n s - a n t i p a r a 1 1 e l c y c l i z a t i o n o f an o l e f i n i c compound, a p p r o p r i a t e l y designed to y i e l d , a f t e r subsequent s t r u c -t u r a l m o d i f i c a t i o n the des ired b i c y c l i c system. The s t a r t i n g m a t e r i a l f or t h i s syn thes i s , 3-methyl-4-carbomethoxy-5-i sopropylcyc lohex-2-enone 77, was a l k y l a t e d with trans- l -bromopent-3-ene 76, y i e l d i n g the keto es ter 78_. H y d r o l y s i s and decarboxy la t ion of t h i s m a t e r i a l gave the enone 79_. The r e q u i r e d tr ienes 80 were then r e a d i l y obtained by treatment of 79 with methyl l i t h i u m fol lowed by phosphorus oxy-c h l o r i d e - p y r i d i n e dehydrat ion . The reported o v e r a l l y i e l d o f 80^  from 77_ - 23 -was 22%. Ring c losure was then achieved by reac t ing the t r i e n e mixture 80 85 86, Ri=CH 2 ,R 2 =H 89 87, R 1 =0,R 2 =H 88, R,=0,R 2=Ac with anhydrous formic a c i d at room temperature for 20 minutes. The r e s u l t -ing product contained a mixture of esters 81_ and 82^ which were epimeric 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 i n the "eremophilane" r i n g A. Reductive cleavage o f these formates with l i t h i u m aluminum hydride y i e l d e d the r e l a t e d a lcohols 83_ and 84_. These isomers were " p a r t i a l l y separated" 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 -of an attempted experimental v e r i f i c a t i o n of t h e i r proposed approach (40) . The hydroxy a c i d 100 was se l ec ted as a s u i t a b l y designed anticedent which, on treatment with a c i d , might reasonably give r i s e to the des i red 1,2-methyl m i g r a t i o n . It was hoped that r e l i e f o f the 1 , 3 - d i a x i a l s t e r i c i n t e r a c t i o n between the C - l and C-10 methyl groups of compound 100 would e n e r g e t i c a l l y enhance the f e a s i b i l i t y of the des i red rearrangement. Moreover, the rearranged product 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 for extension to the eremophilane ske le ton . The synthes is of 100 was accomplished as fo l l ows . The r e a d i l y a v a i l a b l e unsaturated a c i d 95 was reduced with l i t h i u m aluminum hydride y i e l d i n g the r e l a t e d unsaturated a l coho l 96_. Subsequent epoxidat ion of t h i s compound with m-chloroperbenzoic a c i d gave a product containing the s tereo isomeric mixture of epoxy-alcohols 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 . Treatment o f t h i s mixture with methylmagnesium iod ide i n r e f l u x i n g te trahydrofuran 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 acid-acetone 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, it 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. The reaction was considered to proceed via the unsaturated acid 103. In both systems then (100 and 102), the 1,3-diaxial methyl interactions are relieved immediately by proton loss yielding an - 27 -100 >-unsaturated a c i d ; a subsequent r e p r o t o n a t i o n - o f the e thy l en i c double bond of the o l e f i n i c acids 101 and 103 does not g ive r i s e to the r e q u i r e d 1,2-methyl s h i f t . . Hence i t was concluded that a "methyl-migration"approach to the synthes is o f eremophilanes, at l eas t v i a the above in termediates , was u n f o r t u -nate ly not p o s s i b l e . • . In summary then, the present l i t e r a t u r e affords b a s i c a l l y two success fu l s y n t h e t i c approaches to . the eremophilane sesquiterpenes: (1) The Robinson a n n e l a t i o n v a r i a t i o n s reported by M a r s h a l l and Coates, and (2) the ac id induced t r i e n e c y c l i z a t i o n method of Brown. Each of these schemes unfor tunate ly n e c e s s i t a t e , at some point i n the synthe t i c sequence, a rather d i f f i c u l t separat ion of s tereoisomer!c product s . DISCUSSION As noted i n the I n t r o d u c t i o n , the object of the work presented here in was the development o f a general synthe t i c entry in to the eremophilane fami ly o f sesquiterpenes . Thus, the s t e r e o s e l e c t i v e t o t a l synthesis o f eremophilene, one of the s impler members o f t h i s group, was undertaken as a v e h i c l e for the development of such a scheme. At the conception o f t h i s work, the s t r u c t u r e and absolute c o n f i g u r a t i o n of eremophilene were formu-la ted as (+)-eremophil-3 ,11-diene 2_ (7). H 2 The b a s i c s tereochemical problems to be re so lved i n the synthesis of t h i s s t r u c t u r e were considered to be: (1) the i n t r o d u c t i o n o f the v i c i n a l annular methyl groups at C-4 and C-5 o f r i n g A, (2) the establishment of a c i s - A / B r i n g j u n c t i o n , and (3) the establishment of a c i s - r e l a t i o n s h i p between the angular methyl group at C-5 and the C-7 i sopropenyl group. The r e a l i z a t i o n of a c i s - r e l a t i o n s h i p between the C-4 and C-5 v i c i n a l methyl groups would, of course , be an a d d i t i o n a l requirement i n a general - 29 -, r s y n t h e t i c a p p roach t o t h e e r e m o p h i l a n e s . The f o l l o w i n g p a r a g r a p h s o u t l i n e t h e a p proach c o n s i d e r e d i n the s o l u -t i o n o f t h e s e s y n t h e t i c p r o b l e m s . In r e c e n t y e a r s , an a c t i v e i n t e r e s t has d e v e l o p e d i n t h e c o p p e r -c a t a l y s e d r e a c t i o n o f G r i g n a r d r e a g e n t s w i t h a, 3 -unsaturated c a r b o n y l s y s t e m s . The r e a c t i o n o f a G r i g n a r d r e a g e n t w i t h an a , B - u n s a t u r a t e d k e t o n e g e n e r a l l y a f f o r d s a m i x t u r e o f compounds d e r i v e d from e i t h e r 1 , 2 - a d d i t i o n o r 1 , 4 - a d d i t i o n o f t h e G r i g n a r d r e a g e n t t o t h e u n s a t u r a t e d c a r b o n y l system. N o r m a l l y , 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- r a t h e r t h a n 1,4-adducts. However, i n t h e p r e s e n c e o f a s m a l l amount (1-5 mole p e r c e n t ) o f a copper ( I ) s a l t t h e o t h e r w i s e i d e n t i c a l system l e a d s predom-i n a n t l y t o t h e 1 , 4 - a d d i t i o n p r o d u c t ( s ) . T h i s f a c t o f c o u r s e , has been w i d e l y r e c o g n i z e d 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 K h a r a s h and Tawney (41) t h a t t h e p r e s e n c e o f 1 mole p e r c e n t o f copper ( I ) c h l o r i d e s i g n i f i c a n t l y a l t e r e d t h e c o u r s e o f methylmagnesium bromide a d d i t i o n t o i s o p h o r o n e 106. 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 1 , 2 - a d d i t i o n p r o d u c t s whereas i n t h e p r e s e n c e o f copper ( I ) c h l o r i d e , t h e p r o d u c t m i x t u r e c o n t a i n e d 92% o f t h e 1,4-adduct, 3 , 3 , 5 , 5 - t e t r a m e t h y l c y c l o h e x a n o n e 107 and 8% o f t h e 1,2-a d d i t i o n p r o d u c t , 2 , 4 , 6 , 6 - t e t r a m e t h y l c y c l o h e x - l , 3 - d i e n e 108. - 30 -In the course of subsequent i n v e s t i g a t i o n s i n t o the nature o f these copper-promoted add i t ions to enone systems, addi t ions to a number of octalones were examined, the r e s u l t s of which suggested a p o s s i b l e a p p l i c a -a b i l i t y o f t h i s r e a c t i o n to the synthes is o f the eremophilanes, s p e c i f i c a l l y with respect to the s o l u t i o n of problems (_1) and (2) noted above. Of p a r t i c u l a r i n t e r e s t was the report by M a r s h a l l , Fanta and Roebke (28) 1 9 concerning a study of such a d d i t i o n reac t ions i n v o l v i n g subs t i tu ted A ' -1 9 oc ta l -2 -ones . Treatment o f the r e a d i l y prepared A ' - oc ta l -2 -one 109 (R=H)with an ether-THF s o l u t i o n of methylmagnesium iodide and copper (II) acetate^ gave, upon h y d r o l y s i s , a product (80% y i e l d ) containing 99% of the c i s -deca lone 110 (R=H) • None of the p o s s i b l e 1 ,2 -add i t ion products or the C-9 epimeric trans-decalone were detected . S i m i l a r treatment o f 10-1 9 methylrA ' - oc ta l -2 -one 109 (R=Me)gave, a product conta in ing 40% c i s - 5 , 1 0 -dimethyldecal -2-one 110 (R=Me)and 60% of the 1,2-adducts 1 U (R=Me) 5. 109 110 111 Copper (II) i s reduced to copper ( I ) , i n s i t u , by an equivalent of the Gr ignard 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 . Andersen. J. Org. 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 that the octalone 109 (R=Me) underwent e s s e n t i a l l y only 1 , 2 - a d d i t i o n upon r e a c t i o n with methylmagnesium iod ide i n the presence of copper (I) bromide. - 31 -M a r s h a l l and h i s col leagues explained these r e s u l t s as f o l l o w s . Attack o f the a l k y l a t i n g reagent at the 8-carbon atom of the a ,B-unsaturated carbonyl system must occur perpendicu lar to the IT e l e c t r o n system (43), as depic ted i n s t r u c t u r e 112. Thus, t h i s s t e r e o e l e c t r o n i c requirement may be equa l ly s a t i s f i e d by at tack from above (B) or below (a) the plane of the molecule , a-Attack of e i t h e r octalone 109 R=H or 109 (R=Me),leading to the t rans -deca lones , would be prec luded due to s t e r i c i n t e r a c t i o n of the approach ing a l k y l a t i n g reagent with 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 . On the other hand, B-attack at C-9 of the octalone 109 (R=H)would be less hindered s t e r i c a l l y , thus r e a d i l y a f ford ing the c i s - f u s e d 1 , 4 - a d d i t i o n product 110 (R=H).. 8-Attack on the octalone 109 (R=Me) ,however would r e s u l t i n the development 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 subst i tuent of the oc ta lone . Marsha l l suggested that t h i s developing 1,2-methyl-methyl 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 tate geometr ica l ly s i m i l a r to that represented by enolate conformer 113, i n which the C-9 angular methyl group i s e q u a t o r i a l l y or i en ted with respect to the r i n g B- However, concommitent with t h i s change would be the development of s t e r i c i n t e r a c t i o n 112 113 between the subst i tuent on C - l and the a x i a l subst i tuents o f C-5 and C-7 as wel l as between the a x i a l subst i tuent of C-3 and that of 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 1 9 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 contain-19 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 - "C0NH2 119 33 product obtained from a r e f l u x i n g e thano l i c s o l u t i o n o f octalone 117, potassium cyanide and ammonium c h l o r i d e gave a 42:58 mixture o f the c i s -and t rans -ke to amides 6 118 and 119. It i s suggested (44) that these com-pounds a r i s e v i a a 2-keto a s s i s t e d h y d r o l y s i s of the intermediate g-cyano ketones, as depicted below for the trans case. The cyanide ion i s ev ident ly 119 s t e r i c a l l y less r e q u i r i n g than the methylat ing reagent invo lved i n the copper-cata lysed Gr ignard a d d i t i o n s , thus a d d i t i o n a l l y g i v i n g r i s e to the trans- i somer 119, v i a a-at tack on octalone 117. With regard to the proposed eremophilane synthes i s , t h i s r e a c t i o n i l l u s t r a t e s two important p o i n t s : (1) The u l t imate stereochemical fa te of the C - l methyl group, i n t h i s r e a c t i o n and i n an analogous conjugate Grignard a d d i t i o n r e a c t i o n , i s thermodynamically c o n t r o l l e d as , subsequent The keto 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. Infrared s p e c t r a , show that the hydroxy lactam form i s h e a v i l y favoured, both i n chloroform and i n n u j o l (44). HO 120 121 - 34 -to carbon-carbon bond formation at the 8-carbon atom, an enolate ion i s formed i n both addition reactions. Hence, a subsequent thermodynamic proton-ation of the enolate anions assures a c i s - r e l a t i o n s h i p between the C-l and C-9 substituents of the r e s u l t i n g decalones regardless of the stereochemistry of the A/B rin g junction of the conjugate addition products. (2) The successful Michael addition of cyanide ion to octalone 117 suggested that conjugate methylation of an eremophilane anticedent such as octalone 116 appropriately f u n c t i o n a l i z e d at C-7, would not be precluded due to an intramolecular s t e r i c i n t e r a c t i o n involving the C-l methyl group. Moreover, i f successful, such a methylation could be expected to a f f o r d the required a l l - c i s stereochemistry at C - l , C-9 and C-10 of the r e s u l t i n g decalone. The proposed scheme for the introduction of the 73-isopropenyl group of eremophilane remains to be discussed. The 7B-isopropenyl substituent of eremophilene was considered to be most conveniently r e a l i z e d i n a manner s i m i l a r to that employed i n the synthesis of a-cyperone 117 ( 4 5 ) . As reported by Howe and McQ u i l l i n ( 4 5 ) , Robinson annelation of (+)-dihydrocarvone 123 with l-diethylamino-3-pentanone methiodide 122 i n the presence of base afforded, upon ald o l r i n g closure, a mixture of C-10 epimeric octalones 124. Analogously, con-densation of the methiodide s a l t 122 with the known (46) 3-isopropenylcyclo-hexanone 125, R=H9 (or i t s hydroxymethylene der i v a t i v e 125, R=CHOH) would 122 123 124 - 35 -be expected to lead to the eremophilane anticedent 127. Fol lowing condensa-t i o n (and de formyla t ion ) , a l d o l c y c l i z a t i o n would l i k e l y proceed v i a the intermediate diketone conformer 126a as the epimeriz ing condi t ions o f the 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 c i s r e l a t i o n s h i p between the epimerizable "C-10" hydrogen atom and the "C-7" i sopropenyl group. Moreover, the C-10 p o s i t i o n o f the product octalone 127 i s a lso epimerizable thus ensuring 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 sopropenyl subs t i tuent . For reasons considered above, conjugate methylat ion of octalone 127 would then be expected to y i e l d the a l l - c i s - e r e m o p h i l o n e d e r i v a t i v e 128 which i n t u r n , i n two s teps , would a f f o r d ( ± ) - e r e m o p h i l - 3 , l l - d i e n e 2_, the racemic mixture corresponding to the proposed s t r u c t u r e o f eremophilene (7) . In summary then, from a cons idera t ion of the reports by M a r s h a l l (28) and Theobald (44) i t was concluded that the c i s - v i c i n a l methyl groups and c i s - A / B r i n g j u n c t i o n exh ib i t ed i n the eremophilane sesquiterpenes might convenient ly be r e a l i z e d s y n t h e t i c a l l y v i a the conjugate a d d i t i o n o f a - 36 -1 9 m e t h y l G r i g n a r d r e a g e n t t o a s u i t a b l y s u b s t i t u t e d 1-methyl-A ' - o c t a l - 2 - o n e d e r i v a t i v e . T h i s d e r i v a t i v e i n t u r n appeared a c c e s s i b l e v i a a R o b i n s o n a n n e l a t i o n r e a c t i o n i n v o l v i n g t h e r e a d i l y a v a i l a b l e 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 . The s t a r t i n g m a t e r i a l f o r t h e p r e s e n t s y n t h e s i s , 3 - i s o p r o p e n y l c y c l o -hexanone, was 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 i d e n t i c a l w i t h t h a t r e p o r t e d by House, Latham and S l a t e r ( 4 6 ) . Thus, commercial 2-cyclohexenone 7 129 upon t r e a t m e n t w i t h i s o p r o p e n y l m a g n e s i u m bromide and 5 mole p e r c e n t c o p p e r ( I ) c h l o r i d e i n d r y THF, a f f o r d e d , a f t e r h y d r o l y s i s , t h e d e s i r e d 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 130 i n 70% y i e l d . The p r o c e d u r e r e p o r t e d by House and coworkers d i f f e r s i n t h e use o f copper ( I ) i o d i d e r a t h e r t h a n t h e copper ( I ) c h l o r i d e c a t a l y s t employed above. The p r o d u c t t h u s o b t a i n e d e x h i b i t e d t h e a p p r o p r i a t e s p e c t r o s c o p i c p r o p e r t i e s . The. i . r . s p e c t r u m e x h i b i t e d a s t r o n g s a t u r a t e d c a r b o n y l a b s o r b a n c e and 5.85 y a n d a b s o r b a n c e s a t 6.12 and 11.20 y a t t r i b u t e d t o t h e s t r e t c h i n g 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 d o u b l e 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 group. N u c l e a r m a g n e t i c r e s o n a n c e s i g n a l s a t x 5.22, a v i n y l p r o t o n m u l t i p l e t , and x 8.22, a v i n y l m e t h y l group s i n g l e t , were i n agreement w i t h t h e d a t a r e p o r t e d f o r s t r u c t u r e 130 ( 4 6 ) . S p e c t r o s c o p i c ( i . r . , n.m.r.) and g . l . c . e v i d e n c e i n d i c a t e d t h a t l i t t l e , i f any, 1 , 2 - a d d i t i o n p r o d u c t had formed. An i n t e r e s t i n g and .important f e a t u r e o f t h i s r e a c t i o n i s t h e demonstra-t i o n t h a t v i n y l G r i g n a r d r e a g e n t s w i l l undergo copper c a t a l y s e d c o n j u g a t e a d d i t i o n 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 an a l o g o u s t o t h a t o f a r y l and a l k y l G r i g n a r d r e a g e n t s . ' > At t h i s p o i n t , i t was c o n s i d e r e d s y n t h e t i c a l l y e f f i c i e n t t o p r e p a r e the h y d r o x y m e t h y l e n e d e r i v a t i v e o f k e t o n e 130 f o r use i n t h e subsequent R o b i n s o n a n n e l a t i o n r e a c t i o n . H y d r o xymethylene k e t o n e s , o r 2 - f o r m y l k e t o n e s 7 R e l a t i v e t o t h e number o f moles o f o r g a n o - m e t a l l i e r e a g e n t p r e s e n t . - 37 -129 130 131 have long been used to a c t i v a t e methylene or methyl group protons located a to a carbonyl group. The s y n t h e t i c u t i l i t y o f these d e r i v a t i v e s i n a l k y l a t i o n reac t ions i s simply der ived from the f a c t that the conjugate base o f the 2-formyl ketone i s s i g n i f i c a n t l y more s tab le than that o f the parent ketone., hence rendering p o s s i b l e a f a c i l e a l k y l a t i o n at the a c t i v a t e d a-carbon atom. Moreover, the a c t i v a t i n g formyl group may be r e a d i l y i n t r o -duced, by base -ca ta lyzed condensation of the parent ketone with an a l k y l formate e s t e r , and subsequent to a l k y l a t i o n , may be r e a d i l y removed by treatment with aqueous base. Thus, the r e a c t i o n of 3- isopropenylcyclohexanone 130 with e t h y l formate and sodium methoxide i n dry benzene gave, a f t er s u i t a b l e work-up and reduced pressure d i s t i l l a t i o n , the d e s i r e d hydroxymethylene d e r i v a t i v e 131 i n 75% y i e l d . T h i s m a t e r i a l gave the fo l lowing spectroscopic d a t a . The unsaturated carbonyl absorbances at 6.02 and 6.22 y i n the i n f r a r e d i n d i c a t e d the expected predominance of the keto-enol 131b and formyl -enol 131c tautomeric forms. A strong absorbance at 11.15 y e s tab l i shed the presence o f the i sopropenyl double bond. The n . m . r . spectrum of t h i s com-pound was p a r t i c u l a r l y in format ive . A three-proton s i n g l e t at x 8.26 and a two-proton unresolved m u l t i p l e t at x 5.25 were r e a d i l y assigned to the v i n y l methyl group and v i n y l hydrogen atoms of the C-5 i sopropenyl subst i tuent - 38 -H 131b 131c A sharp one-proton s i n g l e t at x 1.4 and a very broad one-proton m u l t i p l e t at x-4.0 were a lso ev ident . Assignment o f these resonances requires b r i e f comment on the tautomeric e q u i l b r i a represented above. Nuclear magnetic resonance s tudies (47) o f 2-formylcyclohexanone and a number of r e l a t e d compounds, have e s ta b l i s h e d that the e n o l i c tautOmers of these compounds, e . g . 131b and 131c, are normally predominant to the extent of 99%. More-over , the e q u i l i b r i u m between the two p o s s i b l e e n o l i c forms i s f a s t e r ( r e l a -t i v e to n . m . r . spectra averaging) than the corresponding e q u i l i b r i a between the formyl ketone, e .g . 151a and the two e n o l i c tautomers. Accord-i n g l y , the above mentioned x 1.4 s i g n a l was designated as the s i g n a l average of protons H a and o f the enols 131b and 131c; analogously , the broad x -4 .0 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 of 131b and 131c. Simple c a l c u l a t i o n s (47) revealed that the e n o l i c mixture was composed of approximately 22% 131c and 78% 131b. - 39 -Cons idera t ion was then d i r e c t e d to the synthes is of octalone 127. Robinson anne la t ion r e a c t i o n (48) employing l -diethylamino-3-pentanone methiodide 122 and hydroxymethylene d e r i v a t i v e 131 c a r r i e d out i n the presence o f methanol ic sodium methoxide at room temperature for 48 hours , a f f o r d e d , upon a c i d i f i c a t i o n and ether i s o l a t i o n , a crude formyl diketone 132. This intermediate was then d i r e c t l y treated with aqueous potassium hydrox ide . The crude deformylated m a t e r i a l subsequently i s o l a t e d showed a s trong saturated carbonyl absorbance at 5.86 y and a weak unsaturated carbonyl absorbance at 6.02 y i n the i n f r a r e d , thus i n d i c a t i n g that a l d o l c y c l i z a t i o n was incomplete . Hence, to e f f ec t r i n g c losure to the des i red octalone 127, t h i s m a t e r i a l , conta in ing mainly the diketone 126, was re f luxed with methanolic sodium methoxide for f i v e to s i x hours . The product thus obtained 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 octalone 127 i n 64% y i e l d , based on hydroxymethylene 131. The spectroscopic proper t i e s of a n a l y t i c a l samples o f t h i s compound, obtained e i t h e r by prepara t ive g . l . c . or by p u r i -f i c a t i o n v i a the h y d r o l y s i s of i t s oxime 159,. substant ia ted the assigned s t r u c t u r e 127. The u l t r a v i o l e t spectrum (u .v . ) showed an absorbance at 249.5 my (£ =14,600). An unsaturated carbonyl absorbance at 6.00 y and o l e f i n i c absorbances at 6.20 and 11.25 u appeared i n the i . r . spectrum. The n . m . r . spectrum showed an unresolved m u l t i p l e t at T 5.26, which was assigned to the v i n y l protons . A p o o r l y reso lved quartet at T 8.22 ( J = 1.2 and 1.8 Hz) was a t t r i b u t e d to the C - l methyl group which was h o m o a l l y l i c a l l y coupled to (47) the a x i a l protons at C-10 and C-8 . S i m i l a r l y a t r i p l e t at x 8.25 (J = 1.2 Hz) was a t t r i b u t e d to the i sopropenyl methyl group being a l l y l i c a l l y coupled (47) to the v i n y l protons . The above chemical s h i f t assignments were e s tab l i shed by a decoupling experiment i n which the o l e f i n i c protons at x 5.26 were i r r a d i a t e d thus e f f e c t i n g the co l lapse o f the.x 8.25 t r i p l e t to a sharp s i n g l e t , l eav ing the x 8.22 quartet unchanged. As noted above, assignment - 40 -of the B-or ienta t ion o f the C-7 i sopropenyl group i s made on the basis that the C-10 p o s i t i o n i s epimerizable under the r e a c t i o n c o n d i t i o n s . The elemental ana lys i s of t h i s compound (as wel l as a l l other p r e v i o u s l y unreported compounds which have been synthes ized herein) gave r e s u l t s i n complete agreement with the c a l c u l a t e d va lues . CHO H 159 127 With the synthes is o f the des i red octalone 127 complete, i n t r o d u c t i o n 8 o f the C-5 angular methyl group o f the eremophilane system remained to be accomplished. To t h i s end, octalone 127 was t rea ted with a t e trahydrofuran-e thy l ether s o l u t i o n of methylmagnesium iodide and copper (II) acetate monohydrate. The copper ace ta te - te trahydrofuran system has been s u c c e s s f u l l y employed by M a r s h a l l (28) i n the a l k y l a t i o n of a v a r i e t y of oc ta lones . 8 Unless otherwise noted, eremophilane system numbering w i l l be henceforth employed. - 41 -A f t e r h y d r o l y s i s and work-up, a product was obtained which exh ib i t ed a weak saturated carbonyl peak at 5.85 u. Ana lys i s by g . l . c . i n d i c a t e d that t h i s m a t e r i a l contained a complex mixture of at l eas t 10 components. Preparat ive g . l . c . i s o l a t i o n of one of these components af forded an a n a l y t i c a l sample shown to be i d e n t i c a l to authent ic ( i ) - e r e m o p h i l - l l - e n - 3 - o n e 128 prepared as subsequently descr ibed below. Unfortunate ly the composit ion of the products obtained from a number o f such reac t ions v a r i e d somewhat i r r e p r o d u c -i b l y both i n complexity and percent of the 1,4-adduct 128 (10-25%). Thus i t was concluded that the copper-cata lyzed Grignard a d d i t i o n approach to the eremophilane d e r i v a t i v e 128 was not s y n t h e t i c a l l y u s e f u l . These r e s u l t s were i n agreement with those reported in a subsequently observed paper by I re land and col leagues (50) . These workers reported t h a t , despi te repeated attempts, the copper (I) bromide cata lysed conjugate a d d i t i o n o f methyl Grignard reagent to the k e t a l octalone 153 was unsuccess-f u l . 133 At t h i s j u n c t u r e , a t t en t ion was d i r e c t e d to a recent report by House, Respess and Whitesides (51) concerning an i n v e s t i g a t i o n in to the r o l e of copper i n conjugate Grignard a d d i t i o n s . In the course of t h i s i n v e s t i g a t i o n two ether so lub le methyl copper-ate complexes (52) were prepared which exh ib i t ed a remarkable s e l e c t i v i t y toward e f f e c t i n g p r e f e r e n t i a l conjugate a d d i t i o n - as opposed to 1 ,2 -add i t i on - of a methyl group to a ,8-unsaturated - 42 -ketones. For example, r e a c t i o n of trans-pent-3-en-2-one 136 with e i t h e r methyl c o p p e r - t r i - n - b u t y l p h o s p h i n e 134 or l i t h i u m dimethylcuprate 135 afforded a product conta in ing > 99% of the 1 ,4-adduct , 4-methyl-pentan-2-one 137. Of the two complexes, l i t h i u m dimethylcuprate 135 was p a r t i c u l a r l y MeCuPBu 134 135 136 137 a t t r a c t i v e i n that i t could be convenient ly prepared simply by the a d d i t i o n o f two equiva lents of e therea l methyl l i t h i u m to a co ld ( 0 ° ) e therea l s l u r r y conta in ing one equiva lent of copper (I) i o d i d e . Thus, the s e l e c t i v i t y e x h i b i t e d by these organo-copper complexes upon r e a c t i o n with ketone 136 and other a ,B-unsaturated ketones, i n a d d i t i o n to the f a c i l e preparat ion of 135, suggested an obvious a p p l i c a b i l i t y to the eremophilene synthes i s . Thus, i t was found that r e a c t i o n of octalone 127 with an excess of e therea l l i t h i u m dimethylcuprate , at 0 ° and under n i t rogen for two hours , gave, upon a c i d h y d r o l y s i s , a product shown by g . I . e . to conta in 77% o f the des i red 73 -eremophi l - l l - en -3 -one 128. An a n a l y t i c a l sample, obtained by H H 127 128 - 43 -prepa r a t iv e g . l . c , a f forded spectroscopic data i n complete agreement with that requ ired by formulat ion 128. Of p a r t i c u l a r note i n the i . r . was the strong saturated carbonyl absorbance observed at 5.86 y and the absorbances due to the i sopropenyl double bond appearing at 6.10 and 11.27 y. The n . m . r . spectrum (Figure 3 ) gave a two-proton m u l t i p l e t at T 5.33, assigned to the C-12 v i n y l protons , a one-proton quartet at T 7.17 ( J ^ ^ = 6.7 Hz) due to the C-4 p r o t o n , and a poor ly reso lved t r i p l e t at x 8.29 r e a d i l y a t t r i b u t e d to the C-13 v i n y l methyl group. The C-14 and C-15 methyl groups af forded a doublet at x 9.11 ( J ^ ^ = 6.7 Hz) and a s i n g l e t at x 9.21, r e s p e c t i v e l y . Frequency-swept decoupl ing experiments confirmed the chemical s h i f t a s s ign-ments. Strong i r r a d i a t i o n at x 5.33 ef fected the co l lapse o f the x 8.29 t r i p l e t to a sharp s i n g l e t , thus confirming a l l y l i c coupl ing between the C-12 and C-13 protons . S i m i l a r l y , strong i r r a d i a t i o n at x 7.17 r e s u l t e d i n a p a r t i a l c o l l a p s e of the x 9.11 doublet to a poor ly reso lved t r i p l e t . Th i s was taken as evidence i n support of the above assignment o f the x 7.17 and x 9.11 s i g n a l s . Some mention o f the quenching procedure of the r e a c t i o n of octalone 127 with l i t h i u m dimethylcuprate 135 should be made. Subsequent to conjugate a d d i t i o n of a methyl group to a given a ,3-unsaturated ketone, an enolate anion i s formed which i s u l t i m a t e l y ketonized by protonat ion during the r e a c t i o n work-up procedure. The quenching procedure given by House e t . a l . r equ ired pouring the r e a c t i o n mixture in to v igorous ly s t i r r e d saturated aqueous ammonium c h l o r i d e . In p r e l i m i n a r y experiments, these workers found that the inverse procedure, a d d i t i o n of the ammonium c h l o r i d e s o l u t i o n to the r e a c t i o n mixture , led to a complex mixture containing both mono- and d i - a l k y l a t i o n product s . Keton iza t ion o f the 1 ,4 -add i t ion der ived enolate i s e v i d e n t l y f a s t e r than the a c i d d e s t r u c t i o n of the organo-copper spec ie s , - 45 -.hence, the sa turated ketone thus formed r a p i d l y undergoes fur ther a l k y l a t i o n •by 1 , 2 - a d d i t i o n o f the unreacted methyl copper spec ies . However, a p p l i c a -t i o n of the recommended ammonium c h l o r i d e quenching procedure i n our case gave a complex mixture of products . Subsequently i t was found that an increase i n the a c i d i t y o f the quenching medium was r e q u i r e d . Thus, slow a d d i t i o n o f the r e a c t i o n mixture to v i g o r o u s l y s t i r r e d 1 M aqueous hydrochlor a c i d af forded a cons iderably less complex product mixture conta in ing the d e s i r e d decalone 128 and only a small number of minor components. It might c o r r e c t l y be argued that the spectroscopic evidence g iven above would not prec lude assignment of an a - o r i e n t a t i o n to both the C-4 and C-5 methyl s u b s t i t u e n t s , r a t h e r than the 8 - o r i e n t a t i o n i n d i c a t e d i n s t r u c t u r e 128. An a - c o n f i g u r a t i o n at C-4 and C-5 would, of course , r e s u l t from an a- ra ther than B-attack o f the a l k y l a t i n g reagent on octalone 127• S t e r i c a l l y , t h i s appears less l i k e l y . However, the r e l a t i v e s tereochemistry i n d i c a t e d i n s t r u c t u r e 128 was confirmed by chemical c o r r e l a t i o n of t h i s compound with hydroxydihydroeremophilone 30, o f know absolute conf igur -a t i o n . S p e c i f i c a l l y , as descr ibed below, reduct ion o f decalone 128 led to an eremophilane, which was subsequently found to be s p e c t r o s c o p i c a l l y i d e n t i c a l with authent ic (+)-78-eremophilane 45, obtained from hydroxydihydro eremophilone _30_ by l i t e r a t u r e procedures (22). The r e a c t i o n of ( ± ) - e r e m o p h i l - l l - e n - 3 - o n e 128 with semicarbazide hydro-c h l o r i d e and sodium acetate i n r e f l u x i n g ethanol r e a d i l y af forded the corresponding semicarbazone 137, i n 65% y i e l d . The i . r . spectrum of an a n a l y t i c a l sample o f t h i s c r y s t a l l i n e mater ia l showed, i n a d d i t i o n to the i sopropenyl double bond absorbance at 11.20 y , strong carbonyl and N-H deformation absorbances at 5.95 and 6.40 y , r e s p e c t i v e l y . The n . m . r . spectrum of t h i s compound f u r t h e r confirmed s t r u c t u r a l assignment 137. The one- and two-proton broad mult ip le ts appearing at x 1.40 and x 4.24 were - 46 -r e a d i l y assigned to the secondary and primary amide hydrogen atoms, respec t -i v e l y . S igna l s due to the i sopropenyl group protons appeared as an 12 unresolved m u l t i p l e t at T 5.27 (-C =H2) and a poor ly reso lved t r i p l e t at 13 x 8.27 (-C H 3 ) . A three -proton s i n g l e t at T 9.24 was a t t r i b u t e d to the C-15 angular methyl group. F i n a l l y , a T . 9 .06 ( J ^ ^  = 6.8 Hz) doublet and a poor ly reso lved one-proton quartet centered at T 7.25 ( J ^ ^  = 6.8 Hz) were assigned to the methyl and t e r t i a r y hydrogen subst i tuents of C - 4 , r e s p e c t i v e l y . 128 NH2COHNN 137 45 138 Haung-Minlon reduc t ion (53) of the semicarbazone 137 (50) was accomplished upon treatment o f t h i s m a t e r i a l with excess hydrazine hydrate and base i n r e f l u x i n g d ie thylene g l y c o l . The r e a c t i o n c l e a n l y af forded ( t ) - eremophi l -11-ene 138 i n high y i e l d . The i . r . spectrum of an a n a l y t i c a l sample of o l e f i n 138, obtained by p r e p a r a t i v e g . l . c , exh ib i ted the expected o l e f i n i c s t r e t c h i n g and deformation absorbances at 6.08 and 11.28 u , r e s p e c t i v e l y . Both the carbonyl and the N-H absorbances p r e v i o u s l y observed i n the 5.5-6.5 y reg ion were now absent. The n . m . r . spectrum o f 138 showed an unresolved m u l t i p l e t at T 5.38, 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 three-- 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, character-istic 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 ^ 1 2 ( 1 3 ) = 6 H z^' 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). It is interesting that, as might reasonably be expected,. 4 , 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 hydroxy-dihydroeremophilone 3_0 to (+)-73-eremophilane 45_. This reaction sequence 9 We are indebted to Dr. H. Ishii for a copy of the i. . spectrum of (+)-73-eremophilane. - 48 -has been p r e v i o u s l y reported (22) along with the c h a r a c t e r i z a t i o n of the com-pounds t h e r e i n . Thus hydroxydihydroderemophilone 3 0 ^ underwent a c e t y l a t i o n upon treatment with a c e t i c anhydride i n dry p y r i d i n e . A c r y s t a l l i n e product was i s o l a t e d from the r e a c t i o n mixture which, a f t e r r e c r y s t a l l i z a t i o n , exhib i ted a melt ing po int ( 6 8 - 7 1 ° ) and i . r . spectrum (3.42, 5.73, 5.80, 7 .70-8 .5 , 11.10 M) corresponding to that p r e v i o u s l y reported f o r hydroxydihydroeremophilone acetate 139. Subsequent treatment o f the keto acetate 139 with calc ium i n l i q u i d ammonia at - 3 3 ° (22), fol lowed by appropriate work-up afforded a crude o i l conta in ing the deacetoxylated product , (+) -78-eremophi l - l l -en-9-one 1 4 0 . ^ The very generous sample o f authent ic hydroxydihydroeremophilone obtained from Dr. L . H . Zalkow i s g r a t e f u l l y acknowledged. It i s per t inent to note here that the C-10 p o s i t i o n o f ketone 140 i s ep imer izab le , thus i n p r i n c i p l e enab l ing , under the condi t ions of t h i s r e a c t i o n , the formation o f decalone d e r i v a t i v e s conta in ing e i t h e r c i s - or t rans - fused A/B r i n g j u n c t i o n s . However, i t has been p r e v i o u s l y e s tab l i shed that the c i s - f u s e d A/B r i n g system of 7B-eremophi l - l l - en-9-one 140 i s thermodynamically favoured over the corresponding trans - fused system (22). t h i s i s predominantly due to the presence of the 7g- isopropenyl s u b s t i t u e n t . Thus upon c o n s i d e r a t i o n o f the t rans - fused stereoisomer, i t i s apparent that the c h a i r - c h a i r conformer 141a necess i ta tes a very s u b s t a n t i a l 1 , 3 - d i a x i a l 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 sopropenyl s u b s t i t u e n t . This 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 cha ir -boa 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 favoured, predominantly 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 subs t i tuent s . As both t rans - fused conformers 141a and 141b are obvious ly thermodynamically less s tab le than the c is -conformer 140b, c i s - 7 g - e r e m o p h i l - l l - e n - 9 - o n e 140 is the product formed under the a l k a l i n e condi t ions o f the above mentioned r e a c t i o n . - 49 -Repeated chromatography of this crude oil 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 , 1 4 Reduction of the C-9 carbonyl function of the thus obtained cis-dihydro-eremophilone 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 e s tab l i shed that the authent ic (+) -78-eremophi l - l l -ene 138 (derived from (+)30) and racemic 138 (der ived from (1)128, as descr ibed above) were i d e n t i c a l by r e f r a c t i v e index, i . r . , n . m . r . and g . l . c . r e t e n t i o n times on four d i f f e r e n t columns. Figure 4_ shows the comparison i . r . spectra of the "natura l" and "synthet ic" 7 8 - e r e m o p h i l - l l - e n e s . The f i n a l step i n the convers ion of n a t u r a l hydroxydihydroeremophilone 30 to (+)-7B-eremophilane was accomplished by c a t a l y t i c reduc t ion of (+)-e r e m o p h i l - l l - e n e 138 with hydrogen and plat inum oxide . An a n a l y t i c sample o f the authent ic (+)-7 8-eremophi lane , obtained by prepara t ive g . l . c , exh ib i ted 9 an i . r . spectrum i n accordance with that p r e v i o u s l y determined for (+)-45. Subsequent comparison of the thus obtained authent ic (+)-45_ with the corresponding racemic 7 8-eremophilane (derived from decalone 128, as descr ibed above) c l e a r l y e s tab l i shed that the two mater ia l s were i d e n t i c a l by r e f r a c -t i v e index, i . r . , n .m.r . . and g . l . c . r e t e n t i o n times on three d i f f e r e n t columns. F igure _5 shows the comparison i . r . spectra of the "natura l" and "synthet ic" 76-eremophilanes 45. The above c o r r e l a t i o n of the dextrorotatory and racemic compounds (+)-138_, (i)-l_38 and (+)-45, (-) -45 c o n c l u s i v e l y e s tab l i shed that the r e l a t i v e s tereochemistry o f ( i ) - 7B - e r e m o p h i l - l l - e n - 3 - o n e was c o r r e c t l y represented by s t r u c t u r e 128. Thus, the success fu l s t e r e o s e l e c t i v e conjugate a d d i t i o n of l i t h i u m dimethylcuprate 135 to octalone 127 c l e a r l y enabled a new and con-venient s y n t h e t i c entry in to the eremophilane c lass o f sesquiterpenes . With the stereochemistry of the c r u c i a l eremophilane d e r i v a t i v e 128 e s t a b l i s h e d , i t i s worthwhile to consider at t h i s point the nature o f the r e a c t i o n by which t h i s compound was synthes ized . Although the mechanism invo lved i n the r e a c t i o n of l i t h i u m dimethylcuprate 135 with ct ,g-unsaturated ketones i s as yet unes tab l i shed , an i n t e r e s t i n g hypothesis concerning - 53 -t h i s r e a c t i o n has been proposed by House and coworkers (51,54) and t h i s w i l l be o u t l i n e d below. I t has been suggested by these workers that the ether so luble l i t h i u m dimethylcuprate complex 155 ex i s t s i n r a p i d e q u i l i b r i u m with methyl l i t h i u m and methyl copper 142. The l a t t e r organometal l ic compound i s a ye l low, ether i n s o l u b l e , and apparent ly polymeric m a t e r i a l , which may be r e a d i l y prepared by r e a c t i n g equimolar amounts of methyl l i t h i u m and copper (I) i o d i d e i n dry ether (52). As depic ted i n equation (1) , the e q u i l i b r i u m con-centra t ions 'of both methyl l i t h i u m and the methyl copper species 142 are MeLi + (MeCu) n ——> Me 2Cu L i 142 155 normally extremely small i n that the e q u i l i b r i u m l i e s f a r to the r i g h t . The p o s i t i o n o f the e q u i l i b r i u m was evidenced by the observat ion that e therea l l i t h i u m dimethylcuprate e x h i b i t s a r e l a t i v e l y low r e a c t i v i t y ( r e l a t i v e to methyl l i th ium) toward carbonyl funct ions (51,54). Moreover, n . m . r . da ta , obtained from v a r i a b l e temperature s tudies o f the l i t h i u m dimethylcuprate system, has been reported (51) which supports both the existence and p o s i t i o n o f e q u i l i b r i u m (1). House has suggested that the a d d i t i o n o f l i t h i u m dimethylcuprate to an a ,g -unsaturated ketone proceeds v i a a one-e lec tron t r a n s f e r mechanism. The complete or p a r t i a l t r a n s f e r of an e l e c t r o n from the copper (I) atom of the ate-complex 155 to the a ,B -unsaturated carbonyl system 156 would lead to the formation o f an a n i o n - r a d i c a l 144 or a charge t r a n s f e r complex. Such e l ec t ron t r a n s f e r from the copper atom of 135 would l i k e l y be enhanced by the net negative charge o f the complex (52) . Subsequent t r a n s f e r of a methyl r a d i c a l from the t r a n s i e n t dimethyl copper (II) species 143 to the B-pos i t ion of anion-Q ) - 54 -L i + 0 ' •>-L i + (I)Cu-CH 3 < 136 135 143 142 r a d i c a l 144, or the co l lapse of the charge t r a n s f e r complex would y i e l d the a l k y l a t e d enolate 145 and methyl copper 142. Keton iza t ion 145 during work-up would then a f f o r d the f i n a l product , 137. Although i t remains to be experimental ly e s tab l i shed f o r the above a ,g-unsaturated ketone system, some support for House's pos tu la te i s der ived . from the e therea l r e a c t i o n o f l i t h i u m dimethylcuprate with fluorenone 146 (51). The e l e c t r o n sp in resonance ( e . s . r . ) .spectrum of t h i s green s o l u t i o n c l e a r l y i n d i c a t e d the presence o f the r e l a t i v e l y s table a n i o n - r a d i c a l 147. Moreover, u n l i k e the r e a c t i o n o f e therea l methylmagnesium bromide with 146 which f a i l e d to e x h i b i t an e . s . r . spectrum and simply led to 9 -methy l f luoreno l , the l i t h i u m dimethylcuprate r e a c t i o n afforded d i o l 148 as a s i g n i f i c a n t r e a c t i o n product . Thus the i m p l i c a t i o n was that d i o l 148 was formed v i a a coupl ing 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 generated by the organocopper reagent. As House has suggested, the a p p l i c a b i l i t y of these f ind ings to a d i s t i n c t l y d i f f e r e n t molecular system i s of course tenuous. However i t does i n d i c a t e that such i o n - r a d i c a l systems may be generated by l i t h i u m dimethylcuprate . - 55 -146 147 148 Assuming that the r e a c t i o n of l i t h i u m dimethylcuprate with a ,^-unsatur-ated ketones proceeds as descr ibed 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 of t h i s organocopper reagent to octalone 127 i s most probably due to s t e r i c f a c t o r s . Thus, approach o f the a l k y l a t i n g reagent from the a s i d e o f octalone 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 i n t e r a c t i o n 12 between the incoming reagent and the a x i a l C-4 , C-5 and C-7 hydrogens. 8-Approach on the other hand would be s i g n i f i c a n t l y less h indered . Complete 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 from a molecule of l i t h i u m d imethy l -cuprate s i t u a t e d on the r i n g A 3-face o f the oc ta lone , 127a, would a f ford the a n i o n - r a d i c a l or charge t r a n s f e r complex represented 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 to the C-9 p o s i t i o n o f 149, or c o l l a p s e o f the charge t r a n s f e r complex would g ive the enolate 150. Upon h y d r o l y s i s , 150 would y i e l d the a l l - c i s - d e c a l o n e 128a. The numbering employed here i s that of the A ' - oc ta l -2 -one system. - 56 -OLi 128a • 150 Conversion o f decalone 128 i n t o ( i ) - eremophi l -3 ,11-d iene 2_ was con-s idered to be most e f f i c i e n t l y accomplished by subjec t ing the tosylhydrazone d e r i v a t i v e of ketone 128 to the Bamford-Stevens r e a c t i o n (56) r a t h e r than to a sequence i n v o l v i n g metal hydr ide reduct ion of ketone 128 and subsequent dehydrat ion of the r e s u l t i n g a l c o h o l . Humber, Pinder and Wil l iams (17) r e c e n t l y reported that tosylhydrazone 151, upon heat ing with sodium ethylene g l y c o l a t e i n ethylene g l y c o l (Bamford-Stevens r e a c t i o n ) , c l e a n l y af forded an i s o m e r i c a l l y homogeneous product shown to be a-eudesmol 152. Thus, i t was suggested that a p p l i c a t i o n of the Bamford-Stevens r e a c t i o n i n - 57 -TsHNN' 152 the eremophilane case might enable the s p e c i f i c 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. 128 153 To t h i s end, decalone 128 was re f luxed with methanolic p - to luenesu lphony l -hydrazine thus y i e l d i n g the c r y s t a l l i n e tosylhydrazone 153. The i . r . spectrum o f t h i s compound e x h i b i t e d bands at 6.10, 6.25 and 6.92 u a t t r i b u t e d to the aromatic double bond s t r e t c h i n g v i b r a t i o n s . A strong absorbance at 8.58 y was assigned to the S=0 s t r e t c h i n g frequency. The c h a r a c t e r i s t i c 11.2 y i sopropenyl double bond absorbance was a l so present . The n . m . r . spectrum showed an A„B quartet centered at x 2.44 (J , ^ 8 Hz, (6,-6 ) ^  58 Hz) Z Z 3-D D 3. assigned to the four aromatic protons of the t o s y l moiety. The i sopropenyl group protons appeared as a three -proton poor ly reso lved t r i p l e t at x 8.32, due to the C-13 methyl group, and a two-proton unresolved m u l t i p l e t at x 5 .36, assigned to the C-12 v i n y l protons . A poor ly reso lved one-proton q u a r t e t , - 58 -a p p e a r i n g a t x 7.37 ( J . = 6.5 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 x 9.12 ( J = 6 . 5 Hz) were a t t r i b u t e d t o t h e hydrogen and m e t h y l s u b s t i t u e n t 4,14 o f C-4, r e s p e c t i v e l y . F i n a l l y , a s i n g l e t a t x 7.61 was a s s i g n e d t o t h e a r o m a t i c m e t h y l group and a s i n g l e t a t x 9.43 was a t t r i b u t e d t o t h e a n g u l a r m e t h y l group a t C-5. The c h e m i c a l s h i f t o f t h e l a t t e r m e t h y l group i s n o t e w o r t h y . The s i g n a l s a t t r i b u t e d t o t h e C-15 p r o t o n s i n t h e r e l a t e d k e t o n e 128 and s e m i c a r b a z o n e 137 appear a t x 9.21 and x 9.24, r e s p e c t i v e l y . The r e l a t i v e l y h i g h f i e l d x 9.43 m e t h y l group s i g n a l s u g g e s t s t h e o p e r a t i o n o f a d i a m a g n e t i c s h i e l d i n g e f f e c t (47) i n v o l v i n g t h e C-15 m e t h y l p r o t o n s and t h e TT e l e c t r o n system o f t h e t o s y l group. 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 i n t o (±)-eremophil-3,11-diene 2_ was t h e n e f f e c t e d by r e a c t i n g t h e h y d r a z o n e w i t h sodium e t h y l e n e g l y c o l a t e i n r e f l u x i n g e t h y l e n e g l y c o l f o r two h o u r s . A f t e r a p p r o p r i a t e work-up a p a l e y e l l o w l i q u i d was i s o l a t e d w h i c h was shown by g . l . c . a n a l y s i s t o c o n t a i n one m a j o r component ( c a . 90%) and s e v e r a l u n i d e n t i f i e d components o f s i g n i f i c a n t l y g r e a t e r r e t e n t i o n t i m e s . An a n a l y t i c a l sample o f t h e major component was i s o l a t e d by p r e p a r a t i v e g . l . c . T h i s compound e x h i b i t e d t h e e x p e c t e d o l e f i n i c a b s o r b a n c e s a t 6.11 and 11.28 y i n t h e i . r . s p e c t r u m , shown i n F i g u r e 6_. " • The n.m.r. sp e c t r u m o f compound _2 p r o v e d t o be p a r t i c u l a r l y i n f o r m a t i v e . As i n d i c a t e d i n F i g u r e 1_, t h e s p e c t r u m showed one- and 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 s a t x 4.70 and x 5.35 a t t r i b u t e d t o t h e C-3 and C-12 v i n y l p r o t o n s , r e s p e c t i v e l y . The two v i n y l m e t h y l group s i g n a l s appeared as a p o o r l y r e s o l v e d t r i p l e t a t x 8.30 ( J - 1 Hz) and an u n r e s o l v e d m u l t i p l e t a t x 8.40. The l a t t e r s i g n a l s were a s s i g n e d t o t h e C-13 and C-14 m e t h y l g r o u p s , r e s p e c t i v e l y . The s i g n a l s due t o t h e C-5 a n g u l a r m e t h y l group appeared as a s h a r p x 8.96 s i n g l e t . 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 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 c o n f i r m e d t h e above c h e m i c a l s h i f t 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 sharp-ening 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). The fate of this intermediate normally -C=CH -CH-C=NNHTs I I H [-C-CH] -CH-C=N-N-Ts I I -"protic medium" -CH-C=N=N + Ts "aprotic medium" -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 - 64 -g i v i n g r i s e to decomposition predominantly v i a c a t i o n i c intermediates (diazonium cat ions and/or carbbnium ions) which are subsequently n e u t r a l i z e d upon r e a c t i o n with the s o l v e n t , Wagner-Meerwein rearrangement and/or proton loss (57). For s i m p l i c i t y , both pathways i n the above scheme are represented as terminat ing with o l e f i n format ion . In recent years cons iderable e f f o r t has been expended toward e l u c i d a t i n g the mechanist ic d e t a i l s of the Bamford-Stevens r e a c t i o n . S u f f i c e to say here that t h i s work has c l e a r l y demonstrated that the balance between the competit ive carbenoid and c a t i o n i c ' processes operat ive i n a given Bamford-Stevens r e a c t i o n i s a func t ion of both the proton donating a b i l i t y of the so lvent system (57) and the nature of the a l i p h a t i c or aromatic moiety of the tosylhydrazone d e r i v a t i v e (58,59). Thus, i n l i g h t o f the e x i s t i n g re l evant l i t e r a t u r e (17,57), the conversion of tosylhydrazone 153 i n t o eremophi l -3 ,11-diene 2_ under the r e a c t i o n c o n d i -t i ons c i t e d above most l i k e l y proceeded v i a a c a t i o n i c pathway, o l e f i n formation r e s u l t i n g due to a f a c i l e loss of the C-4 proton of 153. Comparison of a sample of the synthet i c ( ± ) - 7 g - e r e m o p h i 1 - 3 , 1 1 - d i e n e 2_ 13 with an authent ic sample of n a t u r a l eremophilene unambiguously e s tab l i shed that the two sesquiterpenes were not i d e n t i c a l . This was immediately apparent upon comparison i . r . spectra of these compounds; the i . r . spectra o f ( ± ) - 2 _ and n a t u r a l eremophilene are reproduced i n Figures 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 . spectra o f the two o l e f i n s , shown i n Figures 7_ and 9_, i n d i c a t e d marked d i f f e r e n c e s , p a r t i c u l a r l y i n the 8 to 9.5 tau r e g i o n . F i n a l l y , the 13 ' A sample o f authent ic eremophilene obtained from Dr. J . Krepinsky i s g r a t e f u l l y acknowledged; a copy of the n . m . r . and i . r . spectrum of t h i s compound was obtained from Dr. R . B . Bates, to whom gra t i tude i s a l so expressed. 14 The n . m . r . spectrum of authent ic eremophilene shown i n Figure 9 i s i n complete agreement with that r e c e n t l y reported for t h i s compound (9). Note that the C-14 methyl group doublet centered at 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. ' ' • - 65 -n a t u r a l and s y n t h e t i c eremophilenes exh ib i t ed n o n - i d e n t i c a l g . l . c . r e t e n t i o n times which f u r t h e r corroborated the above evidence. Subsequently, the a v a i l a b i l i t y of a sample of the r e c e n t l y i s o l a t e d eremoligenol _28_ ( 1 8 ) ^ enabled the correc t s t r u c t u r a l assignment o f eremo-p h i l e n e . Thus, dehydration o f eremoligenol 28_ with t h i o n y l chloride i n dry p y r i d i n e (18) a f forded a l i q u i d product which contained a mixture o f o l e f i n s . 28 3 Preparat ive g . l . c , . i s o l a t i o n afforded an a n a l y t i c a l sample o f the major isomer. This compound exh ib i t ed an i . r . spectrum (Figure 8^  ) which was found to be superimposable upon that of authent ic eremophilene. Moreover, the i d e n t i t y o f these substances was fur ther demonstrated by t h e i r i d e n t i c a l g . l . c . r e t e n t i o n times on three d i f f e r e n t columns. Hence, i t was c l e a r l y apparent the o r i g i n a l s t r u c t u r a l assignment f o r eremophilene requ ired r e v i s i o n to that represented by 3_. The very recent t o t a l synthesis of r a c i m i c 2_8 and 3_ by Coates and Shaw (10)*^ has confirmed the current s t r u c t u r a l and stereochemical assignments for eremoligenol and eremophilene. The synthesis of these compounds was The g i f t o f an authent ic eremoligenol sample from Dr . H. I s h i i i s g r a t e f u l l y acknowledged. ^ The author g r a t e f u l l y acknowledges a p r e p r i n t o f t h i s work forwarded by Professor Coates. - 66 -r e a l i z e d v i a the general s y n t h e t i c approach to the eremophilane sesquiterpenes p r e v i o u s l y developed by these workers i n the synthes is of A^ - a r i s t o l e n e 75. The s t a r t i n g m a t e r i a l i n the eremoligenol and eremophilene synthes is was the carbethoxy ketone 154, obtained as descr ibed i n the I n t r o d u c t i o n . Treatment o f the sodium s a l t of 154 with a c e t y l c h l o r i d e i n dimethoxyethane af forded the corresponding carbethoxy enol acetate 155. Reduction of the u n p u r i f i e d enol acetate 155 with l i t h i u m i n l i q u i d ammonia fol lowed by EtO treatment with ammonium c h l o r i d e gave the ester 157, i n 34% o v e r a l l y i e l d from 154. I t was suggested by Coates and Shaw that t h i s ra ther i n t e r e s t i n g r e a c t i o n l i k e l y proceed v i a an a ,3-unsaturated ester intermediate which upon f u r t h e r reduct ion would y i e l d the ester enolate anion 156. It was considered that the thermodynamically unfavourable B -or i en ta t ion o f the carbethoxy subst i tuent r e s u l t e d by way o f a k i n e t i c protonat ion o f anion 156 from the s t e r i c a l l y less hindered a -s ide o f the intermediate . Evidence i n support of the B-stereochemical assignment was der ived from the fac t t h a t , as i n d i c a t e d b e l o w , e s t e r 157a underwent e p i m e r i z a t i o n t o t h e c o r r e s -p o n d i n g a-epimer. A d i a m a g n e t i c s h i e l d i n g ' due t o t h e a x i a l c a r b e t h o x y group 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 o f a x 9.18 c h e m i c a l s h i f t f o r t h e a n g u l a r m e t h y l group. E q u i l i b r a t i o n t o t h e more s t a b l e e q u a t o r i a l 157a - 158 epimer 158 (presumably by base e p i m e r i z a t i o n ) was i n d i c a t e d by t h e absence o f t h i s s h i e l d i n g e f f e c t as r e f l e c t e d i n t h e appearance o f t h e c o r r e s p o n d i n g a n g u l a r m e t h y l group s i g n a l a t l o w e r f i e l d , x 9.05. Subsequent r e a c t i o n o f t h e e s t e r 157 w i t h e x c e s s m e t h y l l i t h i u m i n e t h e r gave an a l c o h o l i c p r o d u c t shown t o be i d e n t i c a l ( i . r . , n.m.r.) w i t h a sample o f a u t h e n t i c e r e m o l i g e n o l 28• 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 c h l o r i d e i n d r y p y r i d i n e gave, a f t e r g . l . c . p u r i f i c a t i o n , 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 were i n d i s t i n g u i s h a b l e from 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_. Thus 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 (7) f o r e r e m o p h i l e n e has been shown t o be i n c o r r e c t . M o r e o v e r , i t has been demonstra-t e d h e r e i n t h a t e r e m o p h i l e n e i s r e l a t e d t o e r e m o l i g e n o l by d e h y d r a t i o n and as s u c h , t h e 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 o f e r e m o p h i l e n e i s 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_. The s y n t h e s i s o f (±)-eremophil-3,ll-diene 2_ d e s c r i b e d i n t h i s t h e s i s has c o n c o m m i t e n t l y e s t a b l i s h e d a r e m a r k a b l y s t e r e o -s e l e c t i v e s y n t h e t i c e n t r y i n t o t h e e r e m o p h i l a n e c l a s s o f s e s q u i t e r p e n o i d s . - 68 -The g e n e r a l i t y o f the above conjugate a d d i t i o n approach to the eremophilane sesquiterpenes i s c u r r e n t l y being i n v e s t i g a t e d i n t h i s l a b o r a t o r y . I t i s worthwhile to note here that l i t h i u m dimethylcuprate i s a reagent which o f f e r s a cons i d e r a b l e s y n t h e t i c 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 of 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 copper-ate complex, as w e l l as a number of other l i t h i u m d i a l k y l - and d i v i n y l c u p r a t e complexes (e.g., the d i e t h y l - , d i - n - b u t y l - , d i p h e n y l - , and d i - l - p r o p e n y l c u p r a t e analogues) have r e c e n t l y been s u c c e s s f u l l y prepared and employed i n a number of other 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 r e a c t i o n s (63). There can be l i t t l e doubt that these organo-copper reagents 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 to the f i e l d o f n a t u r a l products s y n t h e s i s i n p a r t i c u l a r , and c e r t a i n l y to s y n t h e t i c organic chemistry i n ge n e r a l . EXPERIMENTAL Except where otherwise d e t a i l e d , the r e a c t i o n products were i s o l a t e d by repeated e x t r a c t i o n with the so lvent s p e c i f i e d , the combined extracts were then consecut ive ly washed and d r i e d with the reagents i n d i c a t e d i n the parentheses , concentrated i n i t i a l l y at water a s p i r a t o r pressure and f i n a l l y at vacuum pump pressure (1-10 mm). A l l melt ing points were determined on a K o f l e r b lock and are uncorrected . U l t r a v i o l e t spec tra were recorded i n methanol on a Cary 14 record ing spectrophotometer. Infrared spectra ( i . r . ) were recorded on a Perkin-Elmer Infracord model 137 spectrophotometer or a Perkin-Elmer model 421 Grat ing spectrophotometer, a l l comparison i . r . spectra were obtained us ing the l a t t e r instrument. Nuclear magnetic resonance ( n . m . r . ) spec tra were determined i n deuter iochloroform ( te tramethyls i lane as i n t e r n a l standard) and recorded on a JEOLCO C-60-H spectrometer, a V a r i a n A-60 or V a r i a n HA-100 spectrometer. S igna l p o s i t i o n s are given i n the T i e r s x sca le with m u l t i p l i c i t y and proton assignment i n parentheses . G a s - l i q u i d chromatography ( g . l . c . ) was c a r r i e d out with an Aerograph Autoprep, model 700, us ing helium as a c a r r i e r gas at a flow rate of 80-85 ml min .The fo l lowing 1/4" x 10' columns were employed using 60/80 mesh Chromsorb W. as an i n e r t packing support: A , 20% SE30; B, 20% Apiezon-J C, 20% FFAP; D, 10% FFAP; E , 15% QF-1; F , 20% Carbowax. The g . l . c . columns are noted, with column temperature, i n parentheses. Microanalyses were performed by Mr. P. Borda, M i c r o a n a l y t i c a l Laboratory , U n i v e r s i t y of - 70 -B r i t i s h Columbia, Vancouver. 3-Isopropenylcyclohexanone 130 The procedure employed was e s s e n t i a l l y that of House, Latham and S l a t e r (46). A s o l u t i o n of i sopropenyl magnesium bromide (from 12.7 g (0.53 mole) o f magnesium t u r n i n g s , 87.4 g (0.74 mole) o f 2-bromopropene i n 70 ml o f dry te trahydrofuran (THF)), under n i t r o g e n , was d i l u t e d with 350 ml o f dry THF then cooled to 0 ° . 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) o f anhydrous CuCl fol lowed by the dropwise a d d i t i o n of 24.2 g (0.25 mole) of 2- cyclohexenone i n 150 ml of THF over 20 min. The r e a c t i o n mixture was s t i r r e d at 0 ° f o r 2 h r , then poured i n t o a s t i r r e d aqueous s o l u t i o n of ammonium chloride-ammonium hydroxide (pH 8) at 0 ° . T h e . r e a c t i o n product was i s o l a t e d with ether ( d i l . NH^OH, water, b r i n e ) . D i s t i l l a t i o n of the r e s u l t i n g o i l gave 24.54 g (70.5%) of e s s e n t i a l l y g . l . c . pure (column A , 1 5 0 ° ) 3 - i s o p r o p e n y l -cyclohexanone 130, b . p . 6 8 - 7 2 ° (7.5mm) ( l i t . 4 6 8 0 . 5 - 8 4 ° (8mm)), n ^ 6 , 0 1.4749 ( l i t . 4 6 1.4743-1.47.49). Infrared ( f i l m ) , A 5.85, 6.12, 11.20 u; n . m . r . , x 5.22 (unresolved m u l t i p l e t , =CH 2 ) , 7.62 (broad m u l t i p l e t , a - C H 2 ) , 8.24 ( s i n g l e t , - C H 3 ) . 3- Isopropenylcyclohexanone hydroxymethylene 131 The procedure employed i s s i m i l a r to that given by Sorm e t . a l . (60). To a s t i r r e d s l u r r y conta in ing 31.6 g (0.58 mole) of sodium methoxide i n 160 ml of dry benzene was added a s o l u t i o n of 43.3 g (0.58 mole) of e thy l formate i n 160 ml of dry benzene. The system was then cooled e x t e r n a l l y with i c e to c a . 0 ° then a s o l u t i o n o f 26.4 g (0.20 mole) of 3 - i s o p r o p e n y l -cyclohexanone 130 i n 160 ml of dry benzene was added dropwise over 20 min. The r e a c t i o n mixture was p laced under n i t r o g e n , the system allowed to come gradua l ly to 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 yel low - 71 -c o l l o i d a l system was added 500 ml of water; a f t e r s t i r r i n g w e l l i t was ex trac ted severa l times with 7% aqueous sodium hydroxide . The combined a l k a l i n e extracts were a c i d i f i e d (pH 3) with 12 M h y d r o c h l o r i c a c i d , cooled and the product i s o l a t e d with ether (water, br ine ) a f f o r d i n g 27.58 g of red-brown o i l . D i s t i l l a t i o n gave 20.65 g (75%) of the hydroxymethylene 131 as a pale yel low o i l , b . p . 6 0 - 7 6 ° (0.03 mm), 1 0 1 - 1 0 2 ° (4 mm), n * 9 - 3 1.5198. U l t r a v i o l e t , X 283 my; i . r . ( f i l m ) , X 6.02, 6.22 (broad), 11.15 y; HI 3.X III 3.X T163t n . m . r . , T 8.26 ( s i n g l e t , -CHg) , 5.25 (unresolved m u l t i p l e t , =CH2), 7.7 ' (broad m u l t i p l e t , a - l ^ ) , 1.4 ( s i n g l e t , -CHO), -4 .0 (very broad m u l t i p l e t , =CH0H). 1 9 l - M e t h y l - 7 B - i s o p r o p e n y l - A ' -oc ta l -2 -one 127 The procedure employed was s i m i l a r to that given by Banerjee , Chatterjee and Bhattacharya (49). To a s t i r r e d s o l u t i o n of 15.9 g (0.10 mole) o f commercial 1-diethylamino-3-pentanone i n 70 ml o f dry benzene under n i t rogen at 0° was added dropwise 14.6 g (0.10 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 . The r e a c t i o n mixture was s t i r r e d f o r 3 hr at 0 ° then stored i n a r e f r i g e r a t o r overnight . A f t e r evaporat ing the benzene and excess methyl i o d i d e , the r e s u l t i n g v i scous c o l o r l e s s methiodide s a l t was d i s s o l v e d i n 40 ml of methanol for subsequent use i n the Robinson anne la t ion r e a c t i o n . The above methanolic methiodide s o l u t i o n was added dropwise over 20 min to a s t i r r e d s o l u t i o n of 2.41 g (44.7 mmoles) o f sodium methoxide and ' ' 11.70 g (70.4 mmoles) o f 3-isopropenylcyclohexanone hydroxymethylene 131 i n 60 ml of methanol. The r e a c t i o n mixture was s t i r r e d under n i t rogen at room temperature f o r 26 hr then poured i n t o a co ld saturated aqueous ammonium s u l f a t e 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 with h y d r o c h l o r i c a c i d . The r e s u l t i n g c o l l o i d a l system was thoroughly extracted with e ther; the combined extracts y i e l d e d 16.12 g o f crude product a f ter concentra t ion . Deformylat ion was e f fec ted by s t i r r i n g the concentrate i n 630 ml o f 2% aqueous sodium hydroxide for 1 hr at room temperature under n i t r o g e n . The 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 (pH 6) and the product i s o l a t e d with ether (water, br ine ) g i v i n g 14.52 g of yel low o i l . The i . r . spectrum of t h i s m a t e r i a l exh ib i t ed a s i g n i f i c a n t l y stronger saturated (5.86 y) than unsaturated (6.02 y) carbonyl absorbance. Thus, r i n g c losure was completed by r e f l u x i n g the crude product i n a s o l u t i o n of 0.5 g o f sodium methoxide i n 125 ml o f dry methanol for 5-6 hr at which time the unsaturated carbonyl absorbance o f a c i d quenched a l i q u o t s of the r e a c t i o n mixture had a t ta ined a maximum i n t e n s i t y ( s t a r t i n g m a t e r i a l p r e s e n t ) . The methanol was evaporated, 50 ml of water added, the system a c i d i f i e d (pH 5) with h y d r o c h l o r i c a c i d and the crude product i s o l a t e d with ether (water, b r i n e ) . F r a c t i o n a l d i s t i l l a -t i o n gave 10.56 g of pale yel low l i q u i d i n four f r a c t i o n s : (I) 0.59 g , 7 3 . 8 0 ° (5mm); (II) 2.25 g, 1 1 0 - 1 2 8 ° (0 .3mm); (III) 6.55 g, 1 2 7 - 1 3 1 ° (0 .3mm); (IV) 1.17 g, 1 3 2 - 1 7 8 ° (0.3 mm). F r a c t i o n (I) was shown to be i d e n t i c a l to 3- isopropenylcyclohexanone 130 ( i . r . , g . l . c ) . Frac t ions IT , III and IV contained 92, 94 and 95% r e s p e c t i v e l y of octalone 127 as determined by g . l . c . (column B, 2 3 0 ° ) . The octalone y i e l d , based on the hydroxymethylene d e r i v a t i v e 131 was thus 64%. A n a l y t i c a l samples of octalone 127 were obtained v i a h y d r o l y s i s o f i t s oxime 159 and by prepara t ive g . l . c . (column B, 2 3 0 ° ) , b . p . 1 2 7 - 1 3 1 ° (0.3 mm), n £ 3 . 5 1.5320. U l t r a v i o l e t , X 249.5 my J J r . ' D max (e = 14,600); i . r . ( f i l m ) ; X 6.00, 6.20, 11.25, 11.82 y; n . m . r . , T 5.26 (unresolved m u l t i p l e t , =CH2) > 8.22 (poorly reso lved q u a r t e t , -CH3, J - 1.2 and 1.8 Hz, h o m o a l l y l i c coupl ing (47)) , 8.25 ( t r i p l e t , i sopropenyl - C H ^ , J = 1.2 Hz, a l l y l i c coupl ing (47)). The chemical s h i f t s assigned to the v i n y l i c methyl groups were e s t a b l i s h e d by a decoupling experiment i n which the o l e f i n i c protons o f the i sopropenyl group (T 5.26) were s t rong ly i r r a d i a t e d thus e f f e c t i n g c o l l a p s e of the x 8.25 t r i p l e t to a sharp s i n g l e t , while the T 8.22 quarte t remained unaf fec ted . A n a l . C a l c d . for C 1 4 H 2 0 O : C , 82.30; H , 9.87. Found: C , 82.43; H , 10.03. 1 9 1-Methyl- 7 - i s o p r o p e n y l -A ' - oc ta l -2 -one oxime 159 To an aqueous s o l u t i o n o f 0.170 g (2.45 mmoles) o f hydroxylamine hydro-c h l o r i d e and 0.333 g (2.95 mmoles) o f sodium acetate t r i h y d r a t e was added 0.500 g (2.45 mmoles) o f the a,8-unsaturated ketone 127. Methanol was added u n t i l a c l e a r s o l u t i o n was obta ined . The r e a c t i o n mixture was then s t i r r e d overnight at room temperature y i e l d i n g , a f t e r f i l t r a t i o n and d r y i n g , 0.370 g (69%) o f c o l o r l e s s c r y s t a l s . R e c r y s t a l l i z a t i o n from methanol af forded an a n a l y t i c a l sample, m.p. 1 6 3 - 1 6 5 ° . U l t r a v i o l e t , ^ m a x 243 my; i . r . ( C H C l j ) , X 2.82, 3.10, 3.44, 6.08, 10.50, 11.18 y; n . m . r . , x 8.15, 8.26 ( s i n g l e t s , in 3.x v i n y l i c C H 3 groups) , 5.30 ( s i n g l e t , =CH 2 ) , 1.63 (broadened s i n g l e t , =N0H). A n a l . C a l c d . f o r C 1 4 H 2 1 0 N : C , 76.66; H, 9.65; N, 6.39. Found: C , 76.84; H, 9.55; N, 6.21. 1 9 1 -Methy l -7 - i sopropeny l-A ' - oc ta l -2 -one 127 from i t s oxime 159 H y d r o l y s i s o f the oxime 159 to the a ,8-unsaturated ketone 127 was 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 g o f the oxime, 0.46 g o f o x a l i c a c i d and 2.7 ml of 37% aqueous formaldehyde d i s s o l v e d i n 9 ml o f methanol, 4 ml of water and 5 ml of 8 0 - 1 0 0 ° petroleum e ther . The product was i s o l a t e d with ether (water, b r i n e ) . Reduced pressure d i s t i l l a t i o n gave a small a n a l y t i c a l sample o f pure octalone 127, the data for which i s given above. ( i ) - 7 8 - E r e m o p h i l - l l - e n - 3 - o n e 128 The procedure employed i s s i m i l a r to that of House, Respess and Whitesides (51). - 74 -To a s t i r r e d s l u r r y conta in ing 6.02 g (31.3 mmoles) o f copper (I) i od ide i n 120 ml of anhydrous ether at 0° and under N 2 , was added 39.4 ml o f 1.59 M (62.6 mmoles) o f e therea l methyl l i t h i u m by i n j e c t i o n from a dry 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 , s l i g h t l y tan coloured s o l u t i o n conta in ing the l i t h i u m dimethyl copper reagent was s t i r r e d f o r 5 min with c o o l i n g , then a s o l u t i o n conta in ing 2.00 g (10.4 mmoles) o f octalone 127 i n 80 ml of anhydrous ether was added dropwise over 15 min. The r e a c t i o n mixture was s t i r r e d at 0° f o r an a d d i t i o n a l 1.75 hr then s lowly added to 800 ml of 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 . The r e a c t i o n product was i s o l a t e d with ether (water, br ine) g i v i n g 2.185 g o f a pale yel low l i q u i d which was found by g . l . c . (column C, 2 1 5 ° ) to conta in 77% decalone 128 ( y i e l d ca . 80%) i n a d d i t i o n to 5% s t a r t i n g mater ia l and severa l u n i d e n t i f i e d components. An a n a l y t i c a l sample was obtained by preparat ive 19 2n n g . l . c . (column C , 2 1 5 ° ) , b . p . 123.5-124.5 (0.03mm), 1.5041. Infrared ( f i l m ) , \ 5.86, 6.10, 6.93, 10.59, 11.27 p; n . m . r . , . x 5.33 (unresolved IH3-X m u l t i p l e t , =CH 2 ) , 7.17 (quartet , - C 4 H , 1 4 = 6.7 H z ) , 8.29 (poorly reso lved t r i p l e t , - C 1 3 H 3 ) , 9.11 (doublet , - C 1 4 H 3 , J J 4 4 = 6.7 H z ) , 9.21 ( s i n g l e t , - C ^ H j ) . The coupl ing assignments were confirmed by two frequency-swept decoupl ing experiments. The o l e f i n i c protons at T 5.33 were i r r a d i a t e d e f f e c t i n g the co l lapse of the x 8.29 t r i p l e t to a sharp s i n g l e t . S i m i l a r l y , strong i r r a d i a t i o n of the x 7.17 quartet r e s u l t i n g i n a p a r t i a l c o l l a p s e of the x 9.11 doublet to a poor ly reso lved t r i p l e t , which was taken as evidence o f coupl ing between the C-4 and C-14 protons . A n a l . C a l c d . f or C 1 5 H 2 4 0 : C , 81.76; H , 10.98. Found: C , 81.61; H , 10.71. (1)-78-Eremophil-ll-en-3-one tosylhydrazone 153 The procedure employed i s s i m i l a r to that given by D j e r a s s i e t . a l . (61). To a s o l u t i o n conta in ing 2.00 g (7.36 mmoles]'"'7 o f decalone 128 and severa l drops of a c e t y l c h l o r i d e i n 16 ml o f methanol was added 1.680 g (9.08 mmoles) o f p - t o l u e n e s u l f o n y l h y d r a z i d e . The system was p laced under n i t r o g e n , r e f l u x e d f o r 40 min, allowed to cool to room temperature and f i n -a l l y t o 0 ° . The ye l l owi sh c r y s t a l s (1.977 g) thus af forded were separated by f i l t r a t i o n . R e c r y s t a l l i z a t i o n from methanol gave 1.656 g (58%) o f c o l o r l e s s needles , m.p. 1 5 9 - 1 6 1 ° . Infrared (CHC1 3 ) , Xffiax 6.10, 6.25, 6.92, 8.58, 11.2 y; n . m . r . , T 9.43 ( s i n g l e t , - C 1 5 H 3 ) , 9.12 (doublet; - C 1 4 H 3 , 13 ^ = 6.5 H z ) , 8.32 (poorly reso lved t r i p l e t , -C H 3 ) , 7.61 ( s i n g l e t , aromatic CH^), 7.37 (poorly reso lved q u a r t e t , - C ^ H , ^ = 6.5 H z ) , 5.36 12 (unresolved m u l t i p l e t , =C H 2 ) , 2.44 (A2B2 q u a r t e t , four aromatic protons , J , ^8 Hz, (6,-6 ) ^ 58 Hz) . ab v b a A n a l . C a l c d . f or C 2 2 H 3 2 0 2 N 2 S : C ' 6 8 t 0 0 ' ti> 8 - 3 0 ' H , 7.21; S, 8.25. Found: C , 68.22; H , 8.41; N, 7.41; S, 8.11. ( ± } - 7 6 - E r e m o p h i l - l l - e n - 3 - o n e semicarbazone 137 Water was added dropwise to a s o l u t i o n o f 5.00 g o f decalone 128 i n 50 ml absolute ethanol u n t i l a s l i g h t permanent c loudiness was e s t a b l i s h e d . A few drops of ethanol were added to j u s t c l e a r the s o l u t i o n and 5.00 g o f semicarbazide hydroch lor ide and 7.50 g of sodium acetate were added. The system was r e f l u x e d for 30 min then cooled to room temperature and the c r y s t a l s thus formed were separated 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 semicarbazone 137. R e c r y s t a l l i z a t i o n from ethanol gave, a f t er vacuum d r y i n g , 18 3.205 g. (64.8%) o f c o l o r l e s s p l a t e s , m.p. 1 9 1 . 5 - 1 9 4 . 5 ° . Infrared (CHC1 3 ) , X 5.95, 6.40, 6.92, 11.20 y; n . m . r . , T 1.40 (broad m u l t i p l e t , =N-NH), ni3.x 4.24 (broad m u l t i p l e t , - C 0 N H 2 ) , 5.27 (unresolved m u l t i p l e t , = C 1 2 H 2 ) , 7.25 17 S t a r t i n g m a t e r i a l 81% decalone 18 S t a r t i n g m a t e r i a l v/as 82% decalone - 76 -(poorly resolved quartet, -C4H), J ... ^  6.8 Hz), 8.27 (poorly resolved 4 , 1 4 triplet, -C13H3), 9.06 (doublet, -C14H3, J 4 u ^ 6.8 Hz), 9.24 (singlet, -C15H3). Anal. Calcd. for C^H^ON • C, 69.27; H, 9.81; N, 15.15. Found: C, l o 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. The system was placed under nitrogen then refluxed for 2 hr. 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 identi-fied. An analytical sample of (i)-eremophil-3,11-diene 2_ was collected by 19 preparative g.l.c. (column D, 170°), b.p. 85-88° (bath temp.) (0.4 mm) 20 n D u 1.5052. Infrared (film), X 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, =C12H2), 8.30 (triplet, -C13H3), 8.40 (multiplet, -C14H3), 8.96 (singlet, -C^H3). 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 of the C-3 v i n y l proton at T 4.70 e f fec ted a s u b s t a n t i a l sharpen-ing o f the T 8.40 m u l t i p l e t . This r e s u l t , and the observed sharpening of 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 of x 8.40 c l e a r l y demonstrated a l l y l i c coupl ing between the C-3 and C^14 protons o f s t r u c t u r e 2. A n a l . C a l c d . f o r C 1 5 H 2 4 : C , 88.16; H , 11.84. Found: C , 88.36; H, 11.98 (+)-78-Eremophil-11-ene 138 from semicarbazone 137 For an analogous procedure see Church, Ire land and Shr idar (50). A s t i r r e d s o l u t i o n conta in ing 2.00 g (7.5 mmoles) of semicarbazone 137, 1.8.2 ml ' (32 .2 mmoles) of 85% hydrazine hydrate , 1.87 (30.9 mmoles) of potassium hydroxide i n 20 ml d ie thy lene g l y c o l was gradua l ly heated to 1 6 0 - 1 6 5 ° and thus maintained for 21 h r . As t h i n - l a y e r chromatography ( t . l . c . ) i n d i c a t e d l i t t l e or no product formation the temperature was increased to 1 9 0 - 1 9 5 ° and thus re f luxed f o r 24 h r . The r e a c t i o n mixture was then cooled to room temperature then poured in to 100 ml of water. The product , i s o l a t e d with ether (water, br ine ) was a yel low o i l (1.466 g) which was shown by g . l . c . (column D, 1 4 0 ° ) to be 97% o l e f i n 138_ (91% y i e l d ) . These condi t ions were employed i n c o l l e c t i n g an a n a l y t i c a l sample which was found to be i d e n t i c a l (n^, i . r . , n . m . r . , g . l . c . r e t e n t i o n times on columns A , 1 8 0 ° ; B, 1 8 0 ° ; C , 1 6 8 ° ; E , 1 2 0 ° ) with a sample o f authent ic (+) -78-eremophi l - l l -ene 138 der ived from (+)-hydroxydihydroeremophilone 30, as d e t a i l e d below. A n a l . C a l c d . f or C l r H 0 , : C, 87.30; H, 12.70. Found: C , 87.02; H , 12.79 I D lb ( t ) -7B-Eremophilane 45 . A s o l u t i o n conta in ing 648 mg (3.15 mmoles) o f ( t )-eremophil-11-ene 138 and 0.70 g of plat inum oxide i n 25 ml o f ethanol was s t i r r e d at room temp-erature under hydrogen overnight . The r e a c t i o n mixture was f i l t e r e d and concentrated y i e l d i n g 596 mg of a c o l o r l e s s o i l shown by g . l . c . (column D, - 78 -1 3 5 ° ) to be 95% ( ± ) - 7 B - e r e m o p h i l a n e 45_. An a n a l y t i c a l sample was c o l l e c t e d 23 6 by prepara t ive g . l . c . (column D, 1 3 5 ° ) , n Q ' 1.4820. Infrared ( f i l m ) , A " 3 .4 , 6.90, 6.82, 7.30, 7.22, 10.00, 10.81 u; n . m . r . , T 9.15 (doublet , IT13.X - C 1 2 H 3 and - C 1 3 H 3 > Jn 1 2 ^ 3 j = 6 H z ) , 9.16 ( s i n g l e t , - C 1 5 H 3 ) , 9.28 (doublet , 14 - C H 3 , ^ = 6.5 Hz) . This m a t e r i a l was found to be i d e n t i c a l ( n Q , i . r . , n . m . r . , and g . l . c . r e t e n t i o n time on columns A , 1 5 8 ° ; C , 1 5 8 ° ; E , 1 2 0 ° ) , with authent ic (+)-73-eremophilane 45_ der ived from hydroxydihydroeremophilone 30, as d e t a i l e d below. A n a l . C a l c d . for C 1 5 H 2 g : C , 86.46; H, 13.54. Found: C , 86.34; H , 13.26. (+)-Hydroxydihydroeremophilone Acetate 139 The procedure fol lowed i s that of D j e r a s s i , Mauli and Zalkow (22). A s o l u t i o n of 1.000 g (4.68 mmoles) of hydroxydihydroeremophilone 30, 4.25 ml o f a c e t i c anhydride d i s s o l v e d i n 8.5 ml of dry p y r i d i n e was s tored i n a r e f r i g e r a t o r f o r 2 days. The r e a c t i o n mixture was then poured in to 15 ml o f water and the product i s o l a t e d with chloroform (1.2 M h y d r o c h l o r i c a c i d , d i l u t e sodium b icarbonate , water, br ine) g i v i n g 1.188 g o f o i l which c r y s t a l l i z e d on standing at 0 ° . R e c r y s t a l l i z a t i o n from methanol gave 416 mg of the keto acetate 139 as c o l o r l e s s p l a t e s , m.p. 6 8 - 7 1 ° . In frared (CHC1 3 ) , A -3 .42, 5.73, 5.80, 7 .90-8 .5 , 11.10 u. An a d d i t i o n a l 658 mg of the max • crude keto acetate was recovered from the mother l i q u o r ( y i e l d ca . 90%). (+)-73-Eremophil- l l -en-9 -one 140 The procedure fol lowed i s that o f D j e r a s s i , Maul i and Zalkow (22). 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 7.45 g of calc ium metal i n 185 ml o f l i q u i d ammonia at - 3 3 ° was added dropwise over 25 min a s o l u t i o n of 765 mg (3.02 mmoles) o f keto acetate 139 i n 15 ml of dry to luene . The r e a c t i o n mixture was thus s t i r r e d for a fur ther 10 min then 7.45 ml of bromobenzene - 79 -was added dropwise (exothermic) fol lowed by the c a r e f u l a d d i t i o n of 36 ml o f water. The ammonia was then evaporated and the product i s o l a t e d with chloroform (0.6 M h y d r o c h l o r i c a c i d , water, br ine ) g i v i n g 706 mg o f yel low o i l . The crude eremophi l - l l - en -9 -one thus obtained was found to be s i g n i f -i c a n t l y contaminated with an u n i d e n t i f i e d aromatic i m p u r i t y , as i n d i c a t e d by t . l . c . and i . r . Successive column chromatography (Woehlm n e u t r a l a lumina, a c t i v i t y I) subsequently af forded 84 mg o f the d e s i r e d ketone 140 which was s l i g h t l y contaminated and 129 mg o f prec ious g . l . c . pure (column E , * 2 0 5 ° ) (+) -eremophi l - l l - en-9-one 140. Infrared ( f i l m ) , > m 3 .45, 5.86, 6.08, 11.20 vi n . m . r . , T 9.23 (doublet , - C 1 4 H 3 , 3^ = 5.9 H z ) , 8.97 15 13 ( s i n g l e t , - C H^) , '8.27 (unresolved t r i p l e t , -C H^) , 5.26 (unresolved 12 m u l t i p l e t , =C H 2 ) . (+) -7B-Eremophi l - l l - ene 138 from (+)-7g-eremophi l - l l -en-9-one 140 A s o l u t i o n conta in ing 190 mg o f (+)-eremophil-11-en-9-one i n 2.0 ml of 85% hydrazine hydrate , 0.75 g of potassium hydroxide i n 10 ml of d ie thy lene g l y c o l was r e f l u x e d for 2 h r , then the excess hydrazine was d i s t i l l e d o f f s lowly by d r a i n i n g the water condenser and a l lowing the temperature to gradua l ly increase to 2 0 5 - 2 1 5 ° . The system was then re f luxed at t h i s temperature f o r 8 h r . A f t e r c o o l i n g , the r e a c t i o n mixture was d i l u t e d with 20 ml of water and the product i s o l a t e d with ether (water, b r i n e ) . The c o l o r l e s s l i q u i d (145 mg) thus obtained was shown by g . l . c . (column D, 1 4 0 ° ) to conta in 65% of the des i red o l e f i n 138 ( y i e l d c a . 53%). An a n a l y t i c a l sample was obtained by preparat ive g . l . c . (column D, 1 4 0 ° ) , n j 3 ' 6 1.4933. Infrared ( f i l m ) , X 3 .4 , 6.08, 6.90, 7.28, 7.23, 11.28 uj D max ' ' ' 12 n . m . r . , T 5.36 (unresolved m u l t i p l e t , =C H 2 ) , 8.30 (poorly reso lved t r i p l e t , - C 1 3 H 3 ) , 9.16 ( s i n g l e t , - C 1 5 H 3 ) , 9.26 (doublet , - C 1 4 H 3 , 3^ u = 6.6 H z ) . - 80 -(+)-78-Eremophi lane 45_ A s o l u t i o n conta in ing 94 mg o f (+) -7g-eremophi l - l l -ene 138 and 94 mg o f p lat inum oxide i n 4 ml o f absolute ethanol was s t i r r e d at room tempera-ture overnight under hydrogen. 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 concentrated y i e l d i n g 80 mg o f c o l o r l e s s o i l which was shown by g . l . c . (column F , 1 4 0 ° ) to conta in 78% of (+)-78-eremophilane 45_ ( y i e l d c a . 64%). An a n a l y t i c a l sample was c o l l e c t e d by preparat ive g . l . c . (column F , 1 4 0 ° ) , n P ' 6 1.4820. Infrared ( f i l m ) , X 3 .4 , 6.90, 6.82, 7.30, 7.22, 10.00, D max ' 10.81 y; n . m . r . , T 9.15 (doublet , - C 1 2 H 3 and - C U H 3 , J n 1 2 ( - 1 3 ) = 6 H z ) , 9.16 ( s i n g l e t , - C 1 5 H 3 ) , 9.28 (doublet , - C 1 4 H 3 , 3^ u = 6.5 Hz) . Eremophilene _3 from eremoligenol 28_ The procedure employed i s that o f I s h i i , Tozyo and Minato (18). To a s o l u t i o n o f 44.1 mg (0.198 mmole of eremoligenol 28_ i n 0.5 ml o f dry p y r i d i n e at 0° was added 0.05 ml o f t h i o n y l c h l o r i d e . A f t e r several minutes at 0 ° the r e a c t i o n mixture was allowed to come to room temperature and thus react for 1 h r . It was then quenched i n severa l m i l l i t e r s of i ce -water and the product i s o l a t e d with ether (2 N s u l f u r i c a c i d , d i l u t e sodium b icarbonate , water, br ine ) y i e l d i n g 34.4 mg of yel low o i l . An a n a l y t i c a l sample, c o l l e c t e d by g . l . c . (column B, 1 8 0 ° ) , exh ib i ted an i n f r a r e d spectrum i d e n t i c a l to that o f na tura l eremophilene. ( l ) - 7 8 - E r e m o p h i l - l l - e n - 3 - o n e 128 by copper (II) acetate ca ta lyzed Grignard a d d i t i o n To a s t i r r e d e therea l s o l u t i o n of methylmagnesium iodide (from 71.4 mg (2.94 mmoles)' o f magnesium t u r n i n g s , 0.19 ml (3.04 mmoles) of methyl iod ide i n 3.2 ml o f anhydrous ether) at - 1 0 ° under N 2 was added a s o l u t i o n conta in ing 48.8 mg (0.245 mmole) of copper (II) acetate monohydrate, 200 mg (0.980 mmole) of octalone 127 i n 4.8 "ml of dry te trahydrofuran - 81 -dropwise over 30 min. The co ld bath was then removed and the yel low c o l l o i d a l r e a c t i o n mixture allowed to come to room temperature and thus remain over 4 h r . A f t e r r e f l u x i n g f o r 1.5 hr the r e s u l t i n g grey hetero-geneous system was poured slowly in to v igorous ly s t i r r e d 1.2 M h y d r o c h l o r i c a c i d . The product was i s o l a t e d with ether ( d i l u t e sodium b icarbonate , water, br ine ) g i v i n g 190 mg o f orange o i l . This m a t e r i a l exh ib i t ed a strong saturated carbonyl (5.85 u) and weak unsaturated carbonyl (6.00) absorbance and was subsequently shown by g . l . c . (column D, 1 8 0 ° ) to con-t a i n 25% of the des ired decalone 128 (peak enhancement), 12% s t a r t i n g m a t e r i a l i n a d d i t i o n to at l eas t 14 other components. An a n a l y t i c a l sample of decalone 128 was i s o l a t e d from t h i s r e a c t i o n mixture by preparat ive g . l . c . (column D, 1 6 0 ° ) and exh ib i t ed an i n f r a r e d spectrum superimposable upon that o f authent ic ( i ) - 7 8 - e r e m o p h i l - l l - e n - 3 - o n e . It should be noted that the product compositions obtained from a number o f such reac t ions v a r i e d somewhat i r r e p r o d u c i b l y i n complexity and percent 1,4-adduct (10 to^25%). - 82 -BIBLIOGRAPHY 1. 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For a number of recently reported synthetic applications involving copper-ate complexes see: CM. Whitesides, J. San Filippo, J r . , CP. Casey, and E.J. Panek. J. Am. Chem. Soc. 89, 5302 (1967); E.J. Corey and G.H. Posner. J. Am. Chem. Soc. 89, 3911 (1967); E.J. Corey and G.H. Posner. Ibid. 90, 5615 (1968); E.J. Corey, J.A. Katzenellenbogen, N.W. Gilman, S.A. Roman, B.W.. Erickson. Ibid. 90, 5618 (1968); M. Pesaro, G. Bozzato and P. Schudel. Chem. Comm. 1152 (1968). J.A. Marshall and H. Roebke. J. Org. Chem. 33, 840 (1968). 

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