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A general synthetic route to monoterpenes and sesquiterpenes Hodgson, Gordon Lewis 1972

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A GENERAL SYNTHETIC ROUTE TO MONOTERPENES AND SESQUITERPENES BY GORDON L. HODGSON B.Sc. U n i v e r s i t y o f Washington, 1968 A THESIS SUBMITTED IN PARTIAL FULFILMENT OF THE REQUIREMENTS FOR THE DEGREE OF DOCTOR OF PHILOSOPHY i n the Department o f CHEMISTRY We accept t h i s t h e s i s as conforming to the requir e d standard THE UNIVERSITY OF BRITISH COLUMBIA September, 1972 In p r e s e n t i n g t h i s t h e s i s in p a r t i a l f u l f i l m e n t o f the requirements f o r an advanced degree at the U n i v e r s i t y of B r i t i s h Columbia, I agree that the 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 reference and study . I f u r t h e r agree t h a t p e r m i s s i o n fo r e x t e n s i v e copying o f t h i s t h e s i s f o r s c h o l a r l y purposes may be granted by the Head of my Department o r by h i s r e p r e s e n t a t i v e s . I t i s understood that copying or 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 ga in s h a l l not be a l lowed wi thout my w r i t t e n p e r m i s s i o n . Oepa rtment The U n i v e r s i t y o f B r i t i s h Columbia Vancouver 8, Canada Date ABSTRACT A b i o g e n e t i c hypothesis concerned with an a l t e r n a t i v e route to monoterpenes and sesquiterpenes bearing the bicyclo(2.2.1)heptane framework has l e d to a general s y n t h e t i c route to t h i s c l a s s o f com-pound. In p a r t i c u l a r , c o n s i d e r a t i o n of an oxygenated monocyclic cyclohexenyl s u b s t r a t e resembling dihydrocarvone enol phosphate as p o s s i b l e intermediate i n the biogenesis o f camphor has r e s u l t e d i n development o f an e f f i c i e n t l a b o r a t o r y s y n t h e s i s o f (±)-camphor 1_7 and r e l a t e d compounds i n c l u d i n g borneol 1_8, t r i c y c l e n e J9_ and camphene 20_. Extention of t h i s work i n the monoterpene f i e l d to the r e l a t e d sesquiterpenes provided s y n t h e t i c entry to (±)-campherenone 42, (±)-epicampherenone 47, (±)-<*-santalene 47, (±)-g-santalene 48 and (±)-epi-8-santalene 50. As a f u r t h e r s i m p l i f i c a t i o n o f the biogenesis o f sesquiterpenes, campherenone enol phosphate was considered a p o s s i b l precursor of such p o l y c y c l i c sesquiterpenes as copacamphor, ylango-camphor, longicamphor and s t r u c t u r a l l y r e l a t e d compounds. Laboratory analogy f o r t h i s b i o g e n e t i c r e l a t i o n s h i p was e s t a b l i s h e d i n the synthes i s o f (±)-copacamphor 52_, (±)-ylangocamphor S3_ and r e l a t e d compounds s t a r t i n g from campherenone. The success o f the s y n t h e t i c i n v e s t i g a t i o n s l e d to r e f i n e -ments i n the i n i t i a l b i o g e n e t i c p o s t u l a t e and n e c e s s i t a t e d the establishment o f the absolute c o n f i g u r a t i o n s o f various sesquiterpenes encompassed i n the p o s t u l a t e . (-)-Cryptomerion 99a was prepared s t a r t i n g from (-)-carvone 79a. A synthesis of (+)-epicampherenone 45a and (-)-campherenone 42b s t a r t i n g from (+)-camphor has allowed assignment o f absolute c o n f i g u r a t i o n to these compounds and to B-santalene and epi-B-santalene. Formal access to o p t i c a l l y a c t i v e copacamphor, ylangocamphor and r e l a t e d compounds i s i m p l i e d from the s y n t h e s i s o f (-)-campherenone. - i v -TABLE OF CONTENTS Page ABSTRACT i i TABLE OF CONTENTS ..... i v LIST OF FIGURES v ACKNOWLEDGEMENTS .: v i DEDICATION v i i INTRODUCTION 1 DISCUSSION 31 EXPERIMENTAL 133 BIBLIOGRAPHY 210 - V -LIST OF FIGURES Figure Page 1 N.M.R. Spectrum (100 M Hz) o f (±)-Campherenone 42^ 78 2 I n f r a r e d Spectrum o f (±)-Campherenone 42_ 79 3 N.M.R. Spectrum (100 M Hz) o f (±)-Epicampherenone 45 .. 80 4 In f r a r e d Spectrum o f (±)-Epicampherenone 45 81 5 N.M.R. Spectrum (100 M Hz) o f (±)-Copacamphor 52 95 6 I n f r a r e d Spectrum o f (±)-Copacamphor 52^  96 7 N.M.R. Spectrum (100 M Hz) o f (±)-Ylangocamphor 53 97 8 I n f r a r e d Spectrum o f (±)-Ylangocamphor 53_ 98 9 N.M.R. Specteum (100 M Hz) o f (±)-Sativene 60 104 10 I n f r a r e d Spectrum o f (±)-Sativene 60_ 105 11 N.M.R. Spectrum (100 M Hz) o f (+)-Epi - e-santalene 5Jte . 120 12 In f r a r e d Spectrum o f (+)-Epi-B-santalene 50a 121 13 N.M.R. Spectrum (100 M Hz) o f ( - ) - e-Santalene 48a 127 14 I n f r a r e d Spectrum o f ( - ) - e-Santalene 48a 128 - v i -ACKNOWLEDGEMENTS A t h e s i s o f t h i s type could not be w r i t t e n without extensive a s s i s t a n c e from s k i l l e d t e c h n i c i a n s and craftsmen, and I owe a great debt to the f i n e group o f people at U.B.C. who have helped i n t h i s f a s h i o n . The expert m i c r o a n a l y t i c a l work o f Mr. P. Borda i s g r a t e f u l l y acknowledged. To my c o l l a b o r a t o r s and f r i e n d s i n the department, and i n p a r t i c u l a r to Dr. John F a i r l i e , Dr. David MacSweeney and Dr. James F o r r e s t e r , who have c o n t r i b u t e d both i n s p i r a t i o n and many useful i d e a s , I express my thanks and best wishes. A s p e c i a l expression of g r a t i -tude i s due to Miss P h y l l i s Moore who has aided so g r e a t l y with her e x c e l l e n t t y p i n g a s s i s t a n c e . F i n a l l y I wish to acknowledge my research s u p e r v i s o r , Dr. Thomas Money, whose s t i m u l a t i n g ideas, words o f encouragement and warm genuine p e r s o n a l i t y have made my stay at U.B.C. a most i n t e r e s t i n g and enjoyable experience. - v i i -To my l o v i n g wife and daughter f o r t h e i r patience and encouragement during the p r e p a r a t i o n o f t h i s manuscript. INTRODUCTION Biogenetic-type s y n t h e t i c s t u d i e s o f f e r the organic chemist the opportunity to trespass the boundary between chemistry and b i o -chemistry and to pursue the wealth of chemical knowledge that remains to be revealed i n b i o l o g i c a l phenomena. Laboratory analogies f o r b i o -s y n t h e t i c processes not only lend support to b i o s y n t h e t i c p o s t u l a t e s and e s t a b l i s h g u i d e l i n e s f o r f u r t h e r b i o s y n t h e t i c i n v e s t i g a t i o n but, more important to the chemist, a l s o unveil new s y n t h e t i c methods and even new c l a s s e s o f r e a c t i o n s . A s i n g l e example from the f i l e s o f terpene chemistry should demonstrate t h i s p o i n t . The chemistry of 1 2 - 2 -1 ,5-dienes has developed l a r g e l y from model studies conducted i n search o f l a b o r a t o r y support f o r terpene b i o s y n t h e t i c p o s t u l a t e s . These model s t u d i e s have r e c e n t l y culminated i n useful routes to t o t a l s y n t h e s i s o f complex t r i t e r p e n e s such as malabaricanediol 2_. This e n t i r e complex o f r i n g systems was e s t a b l i s h e d in a one step b i o g e n e t i c - t y p e c y c l i z a -t i o n o f the a c y c l i c epoxy d i o l s u b s t r a t e 1_ (1). L a t e r i n t h i s t h e s i s i t w i l l be shown that an a l t e r n a t i v e hypothesis f o r the biogenesis o f monoterpenes and sesquiterpenes possessing the bicyclo(2.2.1 )heptane (bornane) skeleton has l e d to a general s y n t h e t i c route to numerous compounds o f t h i s type. Though b i o s y n t h e t i c s t u d i e s and b i o g e n e t i c - t y p e s y n t h e t i c s t u d i e s have been concerned with various metabolic pathways, the chemist has concentrated mainly on secondary m e t a b o l i t e s , l e a v i n g primary meta-b o l i t e s to the realm o f the biochemist. One such group o f secondary metabolites comprising an ever expanding l i s t o f i n t e r e s t i n g s t r u c t u r e s i s the terpene or i s o p r e n o i d compounds. As e a r l y as 1887 Wallach commented on t h i s group o f natural products i n d i c a t i n g t h a t they could be constructed by head to t a i l l i n k i n g o f isoprene 3_ u n i t s . L a t e r , more extensive s t r u c t u r a l s t u d i e s r e s u l t e d i n a restatement o f the o r i g i n a l hypothesis in the form o f the " b i o g e n e t i c isoprene r u l e " (2-4). In these papers Ruzicka p o s t u l a t e d t h a t n e a r l y a l l the s t r u c t u r a l l y d i v e r s e isoprenoids could be b i o -g e n e t i c a l l y accommodated by head to t a i l l i n k i n g o f two or more isoprene u n i t s forming key a c y c l i c intermediates which could then undergo various c y c l i z a t i o n s and m o d i f i c a t i o n s . - 3 -t a i l head " L i n k i n g o f two isoprene u n i t s would a f f o r d the C-10 s e r i e s o f is o p r e n o i d s known as the monoterpenes. Today i t i s f e l t that the key a c y c l i c i n t e r m e d i a t e ( s ) l e a d i n g to these compounds i s one or more o f three p o s s i b l e compounds; geranyl pyrophosphate ,^ neryl pyrophosphate 5_ or l i n a l y l pyrophosphate 6_. A l l three are formed i n nature by j o i n i n g isopentenyl pyrophosphate 1_ (the b i o l o g i c a l e q u i v a l e n t o f Ruzicka's isoprene u n i t ) with d i m e t h y l a l l y l pyrophosphate 8_, a rearrangement product o f 7_ (scheme I ) . A d d i t i o n o f another C-5 u n i t o f isopentenyl pyrophosphate 1_ to geranyl pyrophosphate ^ p r o d u c e s the C-15 a c y c l i c intermediate ( f a r n e s y l pyrophosphate, c i s 9 or trans 10) p o s t u l a t e d to be the precursor o f the sesquiterpenes. The various s t r u c t u r a l types of sesquiterpenes have been p o s t u l a t e d to a r i s e by c y c l i z a t i o n of e i t h e r c i s - f a r n e s y l pyrophosphate 9_ o r t r a n s - f a r n e s y l pyrophosphate 1_0 to one of s i x intermediate c a t i o n s , 1J_-16^ (scheme I I ) , followed by f u r t h e r transformations and e l a b o r a t i o n s (5,6). D e t a i l e d accounts o f the above b i o s y n t h e t i c p o s t u l a t e s f o r monoterpenes, sesquiterpenes, d i t e r p e n e s , t r i t e r p e n e s and s t e r o i d s have been presented elsewhere (3-11 and references t h e r e i n ) . Of a l l the vast number of known terpene compounds camphor 1_7 has enjoyed the longest and perhaps most c o l o r f u l record o f chemical - 4 " Scheme I: Bi o s y n t h e s i s o f C-10 and C-15 A c y c l i c Intermediates (OPP equals pyrophosphate) - 6 -e x p l o r a t i o n (12). Our i n t e r e s t i n terpenes bearing the camphane and r e l a t e d skeletons (e.g., camphor ]7_, borneol 18^ , t r i c y c l e n e 19 and camphene 20) developed from an i n i t i a l c u r i o u s i t y concerning the b i o -l o g i c a l formation o f the bicyclo(2.2.1)heptane nucleus which i s a common denominator o f these compounds. The general proposals f o r the b i o -genesis o f b i c y c l i c and t r i c y c l i c monoterpenes have not changed s i g n i f i c a n t l y from those i n i t i a l l y l a i d down by Ruzicka and co-workers ( c f . 3,4 and 11). C y c l i z a t i o n o f neryl phrophosphate 15 (or i t s counter-p a r t l i n a l y l pyrophosphate 6_, OPP equals pyrophosphate) a f f o r d s the mono-c y c l i c s u b s t r a t e 21_ where Z i s a c a t i o n o r an appropriate b i o l o g i c a l l e a v i n g group. There are strong i n d i c a t i o n s t h a t geranyl pyrophosphate 4 4 5 6 21 may serve as the acyclic p r e c u r s o r o f many monocyclic and b i c y c l i c monoterpenes (11). However the trans double bond o f t h i s s u b s t r a t e prohibits direct c y c l i z a t i o n t o 21_ and i t has been suggested t h a t 4_ i s transformed to ![ o r Monoterpenes possessing the bicyclo(2.2.1)heptane s k e l e t o n a r e postulated to be d e r i v e d from the monocyclic s u b s t r a t e 21_ by i n t e r -action of the i t - e l e c t r o n s o f the double bond with the Z group (Z equals + v cat ion , pyrophosphate, -^-Enz., e t c . ) to form c a t i o n 22 d i r e c t l y ( a n t i -Markovnikov c y c l i z a t i o n ) o r to form c a t i o n 23 i n i t i a l l y f o l lowed by Wagner—Meerwein rearrangement to 22. The n o n c l a s s i c a l v e r s i o n o f th is i n t e r a c t i o n i s shown i n 24_. Cation 22 can then l o s e a proton from C 6 to form t r i c y c l e n e 1_9 on the one hand o r l o s e a proton from the C 1 0 methyl with concomitant Wagner--Meerwein s h i f t a f f o r d i n g camphene 20. Simple h y d r a t i o n o f 22_ leads to borneol 18_ which then could be o x i d i z e d to camphor 17_. While such proposals are compeling from t h e i r schematic s i m p l i c i t y , Banthorpe, Charlwood, and F r a n c i s i n a recent and extensive review of monoterpene b i o s y n t h e s i s (11) emphasize the p a u c i t y o f meaning ful data p r e s e n t l y a v a i l a b l e from which to judge such hypotheses. One p o s s i b l e s i g n i f i c a n t r e s u l t from b i o s y n t h e t i c s t u d i e s was the incorpo-r a t i o n of ( J l t C ) = - t e r p i n e o l 25_ i n t o camphor 17 i n T. yulgare. However i t was not determined i f the i n c o r p o r a t i o n was s p e c i f i c and i t was a l s o shown that i n the same p l a n t system ( 1 1 +C)terpenen-4-ol 2 £ was l i k e w i s e i n c o r p o r a t e d and to the extent o f 0.5%. With s i g n i f i c a n t i n c o r p o r a t i o n s into monoterpenes u s u a l l y f a l l i n g i n the range o f 0.01 to 0.1% ( e x c l u d i n g methylcyclopentanoids where percentages are o f t e n higher) the - 9 -obvious c o n c l u s i o n to be drawn from these two r e s u l t s i s t h a t much remains to be d i s c l o s e d concerning the nature of the b i o l o g i c a l pre-c u r s o r o f the bornane s k e l e t o n . At the outset of our work, l a b o r a t o r y analogy f o r the b i o -genetic proposed c y c l i z a t i o n o f monocyclic substrates to b i c y c l o -(2.2.1)heptane systems was nonexistent. Despite c o n s i d e r a b l e e f f o r t s to e f f e c t c y c l i z a t i o n of monocyclic substrates such as 2J_where Z has been hydroxyl (13), orthophosphate and pyrophosphate (14,15,16), c h l o r i d e (17) and para-nitrobenzoate (17,18), d e t e c t a b l e amounts of b i c y c l i c m a t e r i a l s were not produced*. S i m i l a r l y no b i c y c l i c m a t e r i a l s were detected i n c y c l i z a t i o n attempts with a c y c l i c substrates such as 27, 28 or 29 with Z equal to hydroxyl (19), orthophosphate and pyro-phosphate (14,15,16), diphenyl phosphate (20), or para-nitrobenzoate (18); however, i n several cases c o n s i d e r a b l e amounts o f monocyclic m a t e r i a l s * E f f o r t s i n our l a b o r a t o r y to achieve c y c l i z a t i o n o f limonene (21, double bond between C 7 arid C 8) or «-terpineol (21_, Z equals OH) with various a c i d c a t a l y s t s ( f o r example: boron t r i f l u o r i d e , boron t r i -f l u o r i d e e t h e r a t e , s t a n n i c c h l o r i d e , s i l i c a gel or ion exchange r e s i n ) have f a i l e d to produce b i c y c l i c products. - 10 -were produced. In connection with t h e i r s o l v o l y s i s s t u d i e s on compounds such as 21_ (Z equals c h l o r i d e or p a r a - n i t r o b e n z o a t e ) , Wilcox and Chibber Z 21 27. 28 29 estimated that " p a r t i c i p a t i o n i n cyclohexenyl systems i s j u s t below the e n e r g e t i c t h r e s h o l d of o b s e r v a t i o n and that a c c e s s i b l e systems with appropriate s u b s t i t u e n t s can be expected to give p a r t i c i p a t i o n . " ( 1 7 ) S t r u c t u r a l a n a l y s i s o f terpenes bearing the camphane skeleton ( f o r example camphor V7 and borneol 18) l e d us to consider an oxygen f u n c t i o n (or the equivalent) at the C 2 p o s i t i o n of 21_ as an "appropriate s u b s t i t u e n t " capable of promoting c y c l i z a t i o n . Our reason f o r t h i s proposal was the common occurrence o f o x i d a t i o n at the analogous C 2 p o s i t i o n of terpenes based on the bicyclo(2.2.1)heptane framework. A p o s s i b l e model sub s t r a t e f o r the study of t h i s proposal might be 30 where Z could be the c a t i o n or an appropriate l e a v i n g group. We were aware however from c l a s s i c a l terpene chemistry t h a t one would r e q u i r e r e g i o s p e c i f i c enol (enolate) formation to e f f e c t t h i s c y c l i z a t i o n s i n c e c y c l i z a t i o n o f 30 (Z equals Br) i n the presence o f base leads e n t i r e l y to carone 31_ (21). S i m i l a r treatment of dihydrocryptomerion dihydro-bromide 32 i n our l a b o r a t o r y a f f o r d e d sesquicarones 33_ and 34_ with no i n d i c a t i o n of the a l t e r n a t i v e c y c l i z a t i o n to the bicyclo(2.2.1)heptane s k e l e t o n (22). S p e c i f i c e n d s ( e n c l a t e s ) are commonly generated i n the l a b o r -a t o r y by decomposition o f appro p r i a t e enol d e r i v a t i v e s (enol e s t e r s , enol e t h e r s , e t c . ) ( 2 3 ) . In Nature enol d e r i v a t i v e s are a l s o involved i n b i o -s y n t h e s i s . Phosphoenolpyruvate 35 appears at a key stage o f the s h i k i m i c a c i d pathway to aromatic compounds and condenses with erythrose-4-- 12 -phosphate 36_ to form 2-deoxy-D-arabino-heptulosonic acid-7-phosphate 37_. L a t e r i n t h i s same b i o s y n t h e t i c route s h i k i m i c a c i d 38_ i s converted to prephenic a c i d 40_ by c y c l i z a t i o n of enol ether 39_ (chorismic a c i d ) ( 2 4 ) . Enamines are a l s o p o s t u l a t e d as intermediates i n b i o s y n t h e s i s , f o r example, i n carbon-carbon bond formation r e a c t i o n s i n v o l v i n g thiamine pyrophos-phate (25). Combining the s y n t h e t i c q u a l i t i e s o f enol d e r i v a t i v e s and H0,C 35 CHO C0 9H -OH .OH CH 20P 36 H-H0-H' H-= 0 ( CH20H 37 - 13 -the b i o l o g i c a l precedent f o r such s t r u c t u r e s with our p r e v i o u s l y proposed s u b s t r a t e we a r r i v e d a t s t r u c t u r e 41_ (Z equals a c a t i o n or an a p p r o p r i a t e b i o l o g i c a l l e a v i n g group; X equals pyrophosphate). Thus the monocyclic s u b s t r a t e 41_ c o u l d undergo c y c l i z a t i o n d i r e c t l y to camphor ]7_ which c o u l d be reduced i n vivo to borneols 18a,b. Dehydration o f li8(a o r b) i n Nature c o u l d occur by analogy with the known processes i n the l a b o r a t o r y to produce t r i c y c l e n e 1_9 and camphene 20(12). The r e l a t i o n s h i p o f compounds 17-20 i s supported by the f a c t t h a t the f i v e apparently co-occur i n P i c e a rubens Sarg. (26). The c h i e f d i f f e r e n c e between t h i s proposal and e a r l i e r b i o g e n e t i c schemes i s the appointment o f camphor 17_ as the key intermediate o f the q u a r t e t o f compounds 17-20, a r e s u l t which f o l l o w s d i r e c t l y from the nature o f the proposed mono-c y c l i c p r e c u r s o r 41_. L a t e r i n t h i s t h e s i s i t w i l l be shown t h a t t h i s b i o g e n e t i c proposal forms the b a s i s o f b i o g e n e t i c - t y p e s y n t h e t i c s t u d i e s i n the monoterpene and sesquiterpene area. - 14 -The d i r e c t extension o f our b i o g e n e t i c proposals f o r b i -c y c l i c monoterpenes to the sesquiterpenes i s obvious i f one considers the s t r u c t u r a l r e l a t i o n s h i p s between camphor 1_7 and campherenone 42 or between borneol 1_8 and longiborneol 43_. C y c l i z a t i o n i n vivo o f a mono-c y c l i c s u b s t r a t e such as 44_ (Z equals c a t i c n , pyrophosphate, -^-Enz., e t c . ; X equals pyrophosphate) would lead to campherenone 42^ (27,28) and epicampherenone 45_ (29). In analogy with the scheme f o r camphor, - 15 -campherenone c o u l d be the precursor o f campherenols 46a,b (27,28), «-santa1ene 47 and B-santalene 48 (30). A s i m i l a r q u a r t e t o f compounds would emanate from epicampherenone 45 p r o v i d i n g epicampherenols 49a,b (2 9 ) , «-santalene 47 and epi-3-santalene 50 (30).* b R^OH, R2=H 50 * E p i - 3 - s a n t a l e n e could a l t e r n a t i v e l y be d e r i v e d from campherenone 42 through the intermediacy o f *-santalene 47. - 16 -A f u r t h e r extension o f t h i s proposal v/ould be the u t i l i z a t i o n of campherenone 42 as precursor of the p o l y c y c l i c sesquiterpenes. Thus, f o r example, enol phosphate 51_ (X = pyrophosphate) could be transformed i n t o copacamphor 52 (29), ylangocamphor 53 (29) or longicamphor 54 (29). Each o f the parent ketones (52-54) leads to sesquiterpene analogues o f borneol , camphene and t r i c y c l e n e and thus twelve p o l y c y c l i c sesquiterpene 54 skeletons can be d e r i v e d i n theory from campherenone 42 (scheme I I I ) . Copacamphor 52^  could provide copaborneols 55a,b (32,33), cyclocopa-camphene 5j[ (34) and copacamphene 57_ (29). From ylangocamphor 53_ one - 18 -obtains ylangoborneols 58a,b (29), c y c l o s a t i v e n e 59_ (35) and sativene 60 (36). Longicamphor 54 provides l o n g i b o r n e o l s 61a,b (37), l o n g i c y c l e n e 62 (38), and l o n g i f o l e n e 63 (30). The o v e r a l l s i m p l i c i t y of the above proposed b i o g e n e t i c scheme (39,40) i n v o l v i n g the generation o f numerous s k e l e t a l types by simple transformations o f analogous intermediates compare favourably with previous b i o g e n e t i c proposals. Previous p o s t u l a t e d routes to the santalenes and to campherenol and campherenone hinge on the formation o f c a t i o n 64_ (6,28). Transformations o f 64 ( e x a c t l y analogous to those mentioned f o r c a t i o n 22} lead to oc-santalene 47_, 3-santalene 48, campherenol 46a and campherenone 42_. 46a 42 I - 19 -More complex problems are encountered i n the previous postu-l a t e s f o r the biogenesis o f the copacamphane and ylangocamphane systems (6)(scheme IV). Cation 1_3 d e r i v e d from c i s - f a r n e s y l pyrophosphate 9_ must undergo 1,3-hydride t r a n s f e r to form c a t i o n 65_ which presumably upon c y c l i z a t i o n forms the c i s - d e c a l i n c a t i o n 66_. C y c l i z a t i o n o f 66_ a f f o r d s c a t i o n 67_ or 68_ depending on the r e l a t i v e stereochemistry o f the isopropyl group i n 66. As t r i c y c l i c analogues of 64_, c a t i o n s 67_ and 68 could l i k e w i s e be rearranged or o x i d i z e d to the various members of t h e i r q u a r t e t s . Cation 6£ could a l t e r n a t i v e l y be derived by a n t i -Markovnikov c y c l i z a t i o n of y-curcumene 69 to c a t i o n 70_ followed by 1,2-hydride t r a n s f e r ( 6 ) . In previous proposals a t h i r d route stem-ming from completely d i f f e r e n t intermediates i s r e q u i r e d to r a t i o n a l i z e the biogenesis o f the longicamphane quartet (6)(scheme V ) . A n t i -Markovnikov c y c l i z a t i o n o f c i s - f a r n e s y l pyrophosphate 9_ could lead to eleven membered c a t i o n 1_4. A 1,3-hydride s h i f t converts H_ to 71 which on c y c l i z a t i o n could lead to the c i s - f u s e d bicyclb(5.4.0)undecane i n t e r -mediate 12_. F u r t h e r c y c l i z a t i o n o f 72^ provides c a t i o n 73_ bearing the longicamphane s k e l e t o n . E l a b o r a t i o n o f 7_3 to the quartet members foll o w s the route p r e v i o u s l y o u t l i n e d f o r c a t i o n 64_. An a l t e r n a t i v e route to c a t i o n 72_ from y-curcumene 69_ v i a c a t i o n 74 has a l s o been suggested (6). The a b i l i t y o f enzyme systems to u t i l i z e common intermediates and e l a b o r a t e numerous v a r i a t i o n s on the same theme i s perhaps nowhere b e t t e r e x e m p l i f i e d than in the terpene f i e l d . In the t r i t e r p e n e s , f o r example, the l a n o s t e r o l skeleton i s e l a b o r a t e d i n a multitude o f v a r i a -t i o n s but holding to the same b a s i c s k e l e t a l theme. In t h i s context - 22 -the use o f common intermediates such as enol phosphates 44 and 51_ to produce numerous s k e l e t a l v a r i a t i o n s which are f u r t h e r e l a b o r a t e d by analogous transformations i s h i g h l y a t t r a c t i v e from a b i o s y n t h e t i c p e r s p e c t i v e . A survey o f the l i t e r a t u r e reveals t h a t many o f the members o f the various analogous quartets presented above have already been found i n nature. I f one allows f o r o p t i c a l isomerism, ten quartets i n a l l could t h e o r e t i c a l l y e x i s t , stemming from enantiomers o f campher-enone 42^ , epicampherenone 45, copacamphor 52^ , ylangocamphor 53_, and longicamphor 54_. In f a c t members, o f nearly every quartet are known and these are shown i n the f o l l o w i n g t a b l e s ( n a t u r a l l y o c c u r r i n g compounds i n d i c a t e d by **; see key to Tables I and II on page 27.) A n a l y s i s o f Tables I and II could s t i m u l a t e s t u d i e s i n several areas. F i r s t , one immediately n o t i c e s that several s t r u c t u r e s do not correspond to n a t u r a l l y o c c u r r i n g compounds. It seems h i g h l y p l a u s i b l e t h a t a thorough i n v e s t i g a t i o n of u n c h a r a c t e r i z e d f r a c t i o n s o f a p p r o p r i a t e e s s e n t i a l o i l s o r other sources of sesquiterpenes could reveal the "missing" members. The absolute c o n f i g u r a t i o n s of c o - o c c u r r i n g members of the various s t r u c t u r a l quartets i s of c r u c i a l importance as each member, according to our p o s t u l a t e , i s d e r i v e d through the correspond-ing camphor analogue and thus should belong to the same antipodal s e r i e s as the other quartet members. Such c o r r e l a t i o n s serve as a useful check on t h i s and previous b i o g e n e t i c hypotheses. Research i n each of the areas o u t l i n e d above i s already underway i n our l a b o r a t o r y . A t h i r d area o f i n v e s t i g a t i o n from our hypothesis would be b i o s y n t h e t i c s t u d i e s aimed at i d e n t i f y i n g or v e r i f y i n g p o s t u l a t e d intermediates between c i s - f a r n e s o l pyrophosphate and the quartet members. For example, the establishment of o x i d i z e d monocyclic precursors such - 23 -Table I: Terpenes S t r u c t u r a l l y Related to D-(+)-Camphor Monoterpenes Epicampherenone Epicampherenol «-Santalene Epi-3-santalene * (B,+)(22) * (B,+)(45) * (B,+)(22) * * ( I ) ( 3 0 ) , ( F ) ( 6 0 ) * * ( I ) ( 3 1 ) a-Santalol E p i - 3 - s a n t a l o l * (B,+)(46) Copacamphor Copaborneol Cyclocopacamphene Copacamphene * (E,-) * (E,-) * (E,+) * (E,+) * * ( J ) ( 3 4 ) 24 -Table I: (Cont'd.) Cyclocopacamphenol s * (C)(47) **(J)(47,48) C0,H Cyclocopacamphenic a c i d s * (C)(49) ** ( J ) ( 4 9 ) Ylangocamphor Ylangoborneol C y c l o s a t i v e n e * (C,+)(49) **(H)(35,42) Sativene * (C,+)(36) **(H)(42) Longicamphor * (C,+)(50,51) Longiborneol Longicyclene * (C,+)(50,51) * (C,+)(38) **(K)(37) **(H)(42),(L)(38) Longifolene' * (A,+)(52) **(H)(42),(L)(30) J u n i p e r o l acetate * (C,+)(53) **(M)(53) L o n g i f o l - 7 ( l 5)-en-* (C,+)(53) 5B-ol **(M)(53) Longifolan-3«,7«-* (C--H53) oxide **(M)(53) - 25 -Table I I : Terpenes S t r u c t u r a l l y Related to L-(-)-Camphor Monoterpenes '"'OH Camphor Borneol * (E,-) * (E,-) **(N)(26?),(0)(12) **(N)(26),(0)(12) T r i c y c l e n e **(H)(42),(N)(26) Camphene * (E,-) **(N)(26) Sesquiterpenes Campherenone * (B,-)(22) ?"OH Campherenol °=-Santalene * (B,+)(45) * * ( I ) ( 3 0 ) , ( F ) ( 6 0 ) HO <*-Santalol * (B,+)(46) * * ( I ) ( 3 0 ) CHO T r i c y c l oekaSctntal al * * ( I ) ( 5 4 ) B-Santalene * (B,-)(22) * * ( I ) ( 3 0 ) , ( F ) ( 6 0 ) H B- S a n t a l i c a c i d * * ( I ) ( 3 0 ) Epicampherenone Epicampherenol * (E.-) «-Santalene Epi-B-santalene * (E,-) - 26 -Table I I : (Cont'd.) Copacamphor * (B,+)(55) Copaborneol * (C,+)(32,33) * * ( P ) ( 3 2 , 3 3 ) Cyclocopacamphene Copacamphene * (B,-)(56) * (B,-)(56) Ylangocamphor Ylangoborneol C y c l o s a t i v e n e Sativene * (E,-) Longicamphor * (E,-) Longiborneol * (E,-) **(R)(57) Longicycl ene * (E,-) Longifolene * (E,-) **(R)(57) H0»i«v Culmorin * (C,-)(58) **(S)(59) - 27 -Key to Tables I and II * Absolute c o n f i g u r a t i o n assigned, p e r t i n e n t data i n d i c a t e d as f o l l o w s : (A,+) (26) j Reference \ \—: Rotational s i g n , 589 or 578 nm (may vary with solvent) ' Method o f a s s i g n i n g absolute c o n f i g u r a t i o n : A. X-ray c r y s t a l l o g r a p h y . B. T o t a l s y n t h e s i s . C. Chemical c o r r e l a t i o n to compound of known absolute c o n f i g u r a t i o n . D. ORD and/or CD. E. Enantiomer o f known absolute c o n f i g u r a t i o n . ** Natural product (F) (27) Reference * Source F. Cinnamomum camphora S i e b o l d (lauraceae) 6. Dryobalanops aromatica H. Abies magnifica A. Murray I. Santalum album Linn J . V e t i v e r i a z i z a n i o i d e s K. Cedrus deodar Loud. L. Pinus l o n g i f o l i a Roxb. M. Juniperus c o n f e r t a P a r i . N. Picea rubens Sarg. - 28 -0. BIumea balsamifera P. Pinus s y l v e s t r i s L. Q. Helminthosporium sativum R. Scapania undulata (L.) Dum. S. Fusarium culmorum (Link) T. Thuya o c c i d e n t a l i s - 29 -a s dihydrocryptomerion 75 or dihydrocarvone 7 £ or analogous compounds* 75 76 w i l l be a c r u c i a l t e s t o f the v a l i d i t y o f our hypothesis. Furthermore, sequence s t u d i e s to t e s t i n v i v o the i n t e r c o n v e r s i o n p a t t e r n s o f quartet members ( e . g . , camphor 17. -»• borneol 1J3 ->- t r i c y c l e n e 1_9 + camphene 20) are e x c i t i n g p o s s i b i l i t i e s . As a r e s u l t o f our s y n t h e t i c program we have developed s u i t a b l e s y n t h e t i c routes which can be adapted to the p r e p a r a t i o n o f r a d i o a c t i v e monocyclic and b i c y c l i c s u b s t r a t e s necessary f o r these b i o s y n t h e t i c s t u d i e s . F i n a l l y , c o n s i d e r a t i o n o f simple s t r u c t u r a l r e l a t i o n s between the members o f the q u a r t e t s , p a r t i c u l a r l y when viewed from our b i o g e n e t i c h y p o t h e s i s has s t i m u l a t e d an exceedingly f r u i t f u l s y n t h e t i c study o f p o l y c y c l i c monoterpenes and sesquiterpenes. The use o f enol d e r i v a t i v e s - 30 -to promote and d i r e c t c y c l i z a t i o n has been the b a s i s o f s y n t h e t i c entry to the s k e l e t a l systems of the m a j o r i t y o f the quartet members. Bond formation i n a sequence analogous to our b i o g e n e t i c p o s t u l a t e has proven to be an e f f i c i e n t route to the complex p o l y c y c l i c systems. Syntheses i n c o r p o r a t i n g the use o f s u i t a b l e o p t i c a l l y a c t i v e s t a r t i n g m a t e r i a l s have l e d to the establishment o f the absolute c o n f i g u r a t i o n s o f a number o f these sesquiterpenes while a t the same time e s t a b l i s h i n g a s y n t h e t i c route to o p t i c a l l y pure members o f the q u a r t e t s . T h i s s y n t h e t i c work surrounding our b i o g e n e t i c hypothesis w i l l be di s c u s s e d i n d e t a i l i n the remainder o f t h i s t h e s i s . DISCUSSION Prompted by an a l t e r n a t e b i o g e n e t i c scheme f o r the formation and i n t e r r e l a t i o n o f various monoterpenes bearing the b i c y c l o ( 2 . 2 . 1 ) -heptane s k e l e t o n , we sought l a b o r a t o r y support f o r our proposed t c y c l i z a t i o n o f intermediate 41 (Z equals c a t i o n , pyrophosphate, -^-Enz. e t c . ; X equals pyrophosphate). We a n t i c i p a t e d that by analogy with our b i o g e n e t i c scheme the d i r e c t s y n t h e s i s of camphor 1_7, from a C 2 oxygenated monocyclic precursor might be a f e a s i b l e l a b o r a t o r y route to members o f t h i s s k e l e t a l s e r i e s . The conversions o f camphor to the borneols 18a,b to t r i c y c l e n e 19_, and to camphene 20_ were known from c l a s s i c a l terpene chemistry (12) and thus the synthes i s o f camphor would c o n s t i t u t e a s y n t h e t i c entry to the e n t i r e quartet o f compounds. We were f u r t h e r encouraged along these l i n e s by the work o f F e l k i n and L i o n i n v o l v i n g the s o l v o l y t i c c y c l i z a t i o n o f enol ether 77 to 1-methylnorcamphor 78_ (61). While the y i e l d of t h i s r e a c t i o n was rat h e r low, t h i s c o n s t i t u t e d the f i r s t reported formation o f the bicyclo(2.2.1)heptane system by s o l v o l y t i c c y c l i z a t i o n o f a monocyclic cyclohexenyl s u b s t r a t e . Furthermore t h i s r e a c t i o n e s t a b l i s h e d the f e a s i b i l i t y and p o t e n t i a l usefulness o f enol d e r i v a t i v e s i n promoting and d i r e c t i n g c y c l i z a t i o n . We env i s i o n e d a t e r p e n o i d analogy to t h i s c y c l i z a t i o n proceeding through sub s t r a t e _4J_ where Z equals the carbonium ion and X i s a s u i t a b l e enol d e r i v a t i v e . Dihydrocarvone 76_ seemed to possess the necessary f u n c t i o n -a l i t i e s to t e s t our s y n t h e t i c proposals and i n a d d i t i o n , the compound was r e a d i l y a v a i l a b l e by red u c t i o n o f carvone 79_ with z i n c i n e t h a n o l i c potassium hydroxide (62). We chose, as the e n o l i c d e r i v a t i v e , enol acetate 80, p a r t i a l l y due to l i t e r a t u r e precedent (63) and p a r t i a l l y due to the greater s y n t h e t i c a c c e s s a b i l i t y o f enol e s t e r s as compared to enol ether d e r i v a t i v e s . Thus treatment of (-)-carvone 79a, (<*)£ -58.6°, - 33 -79 76 80 (Ac = CH 3C0-) with z i n c powder and potassium hydroxide i n 7:2 ethanol-water under r e f l u x with vigorous s t i r r i n g a f f o r d e d an 87% y i e l d o f (+)-dihydro-29 carvone, («) D +18.3°, as a 3:1 mixture o f epimers 76a and 76b [estimate based on the i n t e g r a l o f the epimeric C x methyl i n the nuclear magnetic resonance (n.m.r.) spectrum]. Considerable e f f o r t was made to improve the y i e l d i n t h i s r e a c t i o n (62) since dihydro-carvone became an important s u b s t r a t e f o r our l a t e r s y n t h e t i c work. Wallach's c o n d i t i o n s were reported to y i e l d 64 to 74% dihydrocarvone but i n our hands we found d i f f i c u l t y i n reproducing such y i e l d s . Wallach had reported i s o l a t i n g from t h i s r e a c t i o n a c r y s t a l l i n e s i d e produce of imperical formula C i 0 H i 5 0 (mp 148-149°) f o r which he proposed the molecular formula C I Q H I ^ ^ - ^ — C I Q H I ^ d e s c r i b i n g the m a t e r i a l as p o s s i b l y carvone p i n a c o l . In the i n t e r e s t o f improving our r e a c t i o n y i e l d we l i k e w i s e i s o l a t e d t h i s m aterial (mp 153-154°) and sought i t s i d e n t i t y s p e c t r o s c o p i c a l l y . Wallach's assignment o f molecular formula C20H30O2 was confirmed i n the mass spectrum by a molecular ion of m/e 302 which appeared as the base peak o f the spectrum. The dimeric type of s t r u c t u r e was a l s o supported by a monomer fragment ion of m/e 151 ( r e l a t i v e i n t e n s i t y 52.5). The - 34 -pinacol s t r u c t u r e was n e v e r t h e l e s s i n v a l i d a t e d by the i n f r a r e d spectrum which i n d i c a t e d no hydroxyl a b s o r p t i o n but i n s t e a d a strong carbonyl band a t 1705 cm" 1. The presence o f terminal double bond was a l s o i n d i c a t e d by absorptions a t 3090, 1650 and 892 cm" 1. The u l t r a v i o l e t spectrum confirmed the presence of s a t u r a t e d carbonyl (probably ketone) by an a b s o r p t i o n at 288 nm (e 90) and the l a r g e e x t i n c t i o n c o e f f i c i e n t suggested the presence o f two s i m i l a r ketones. The n.m.r. spectrum o f t h i s compound was found very s i m i l a r to t h a t o f dihydrocarvone with the exception t h a t most o f the peaks were doubled i n i n t e g r a l area. Thus a doublet a t 9 . 0 3 x(six protons, J = 6.5 Hz) i n d i c a t e d the presence o f two secondary methyls and s i g n a l s a t 8.22x ( m u l t i p l e t , s i x protons) and 5.18x ( m u l t i p l e t , f o u r protons) suggested two isopropenyl groups. Combination o f the f o r e g o i n g s p e c t r a l evidence with mechanistic arguments has l e d us t o a s s i g n s t r u c t u r e 82 to t h i s compound. M e c h a n i s t i c a l l y t h i s compound could be produced i n the r e a c t i o n by attack o f enolate anion 81_ (formed from the reduced m a t e r i a l , dihydrocarvone) i n Michael f a s h i o n on the enone system o f the s t a r t i n g m aterial 79a. ' As compound 82_ f r e q u e n t l y comprised from 5 to 10% ( i s o l a t e d ) o f the r e a c t i o n products, an attempt was made to a d j u s t r e a c t i o n c o ndi-t i o n s so as to d i s f a v o u r Michael a d d i t i o n . Indeed, very slow a d d i t i o n o f carvone to the v i g o r o u s l y s t i r r e d r e d u c t i o n medium, u t i l i z i n g a c o n s i d e r a b l y g r e a t e r ethanol to water r a t i o than d e s c r i b e d b y W a l l a c h , decreased the i s o l a b l e y i e l d o f 82_ to l e s s than 0.2% and correspond-i n g l y i ncreased the y i e l d o f dihydrocarvone to 87%. Other products from the r e a c t i o n i n c l u d e d phenolic m a t e r i a l s (ca. 1%, probably l a r g e l y c a r v a c r o l 83) and a resinous m a t e r i a l (ca. 9%) e x h i b i t i n g strong ketone - 35 -and hydroxyl absorptions i n the i n f r a r e d spectrum. We next turned our a t t e n t i o n to the preparation o f the enol acetate d e r i v a t i v e o f dihydrocarvone. Two o f the common methods o f a c i d c a t a l y z e d enol a c e t y l a t i o n [ a c e t i c a n h y d r i d e / p - t o l u e n e s u l f o n i c a c i d (64,65), and a c e t i c a n h y d r i d e / p e r c h l o r i c a c i d / c a r b o n t e t r a c h l o r i d e (66,67)] isomerized the a c i d l a b i l e terminal double bond o f 76 a,b. However, i t was found t h a t isopropenyl acetate with a c a t a l y t i c amount o f p - t o l u e n e s u l f o n i c a c i d (65,68) a f f o r d e d the d e s i r e d enol acetate 80a and the isomeric compound 84_ i n a 3:1 r a t i o r e s p e c t i v e l y . The stereochemical i n t e g r i t y o f the terminal double bond was apparent from both the i n f r a r e d spectrum (3090, 1645 and 892 cm" 1) and the n.m.r. - 36 -OAc + ix OAc 76a,b 80a 84 spectrum ( c a . 5 . 2 5 x , two v i n y l p rotons) o f the enol a c e t a t e m i x t u r e . Pure samples of 80a and 84 were o b t a i n e d by p r e p a r a t i v e g a s - l i q u i d chromatography ( g . l . c . ) and were r e a d i l y d i s t i n g u i s h a b l e by t h e i r n . m . r . s p e c t r a . Thus enol a c e t a t e 80a e x h i b i t e d two v i n y l methyl s i g n a l s (8.51 and 8 .26x ) and no a d d i t i o n a l o l e f i n i c s i g n a l s to those mentioned above, w h i l e isomer 84_ showed one s i g n a l f o r v i n y l methyl ( 8 . 2 6 , th ree p ro tons ) and an o l e f i n i c proton (4 .86x) due to the enol a c e t a t e double bond. The use o f ( - ) - c a r v o n e 79a as s t a r t i n g m a t e r i a l no a f f o r d e d o p t i c a l l y a c t i v e 8 0 a , (<*) D + 8 1 . 1 ° , which i n view o f the method o f s y n t h e s i s must have the a b s o l u t e c o n f i g u r a t i o n shown. The c a t a l y s t chosen to t e s t the c y c l i z a t i o n was gaseous boron t r i f l u o r i d e . Among i t s many chemical and c a t a l y t i c p r o p e r t i e s , boron t r i f l u o r i d e i s known to promote C - a c y l a t i o n o f ketones i n the presence o f anhydr ides ( 2 3 ) , to decompose enol e s t e r s r e s u l t i n g aga in i n C - a c y l a t i o n ( 2 3 ) , to promote e l e c t r o p h i l i c s u b s t i t u t i o n , p a r t i c u l a r l y i n a romat ic sys tems, to s t a b i l i z e e n o l s as enol f l u o r o b o r a t e s ( 6 9 ) , and to f a c i l i t a t e the i n t e r a c t i o n o f enol e s t e r s w i t h double bonds ( 6 3 ) . In s p i t e o f t h i s generous endorsement of the c a p a b i l i t i e s of t h i s c a t a l y s t we were n e v e r t h e l e s s p l e a s a n t l y s u r p r i s e d when a 0.1% s o l u t i o n - 37 -o f enol acetate 80a i n methylene c h l o r i d e s a t u r a t e d with boron t r i -f l u o r i d e gas (10 minutes) y i e l d e d (±)-camphor 17 a,b i n 90% y i e l d as judged by g . l . c . (70). Higher concentrations o f 80a and other v a r i a -t i o n s i n r e a c t i o n c o n d i t i o n s r e s u l t e d i n lower y i e l d s o f camphor and corresponding i n c r e a s e i n the y i e l d o f carvenone 85 (71) X m,„ 234 nm — max (e 13,200)(methanol)H; v , a v 1670 and 880 cm" 1; ( C C l i J 8.95 (doublet, max • three protons, J = 6.5 Hz), 8.89 (doublet, s i x protons, J = 6.5 Hz and 4.27 ( s i n g l e t , one proton)) and other products. For example, a 0.7% s o l u t i o n of enol acetate 80a under the c y c l i z a t i o n c o n d i t i o n s a f f o r d e d a mixture of at l e a s t ten components as judged from g . l . c . a n a l y s i s i n c l u d i n g 10% camphor, 35% carvenone and 39% a compound t e n t a t i v e l y assigned s t r u c t u r e 86 cn the basis of the f o l l o w i n g s p e c t r a l c h a r a c t e r i s t i c s . The i n f r a r e d spectrum o f 85_ e x h i b i t e d a 85 86 - 38 -carbonyl absorption at 1745 cm"1 and a C -0 s t r e t c h a t 1210 cm"1 con-s i s t e n t with the presence o f an acetate f u n c t i o n . The n.m.r. spectrum ( C C U ) was well defined with a s i x proton doublet at 8 .97 T (J = 6.5 Hz) suggesting an isopropyl group; a broadened three proton s i n g l e t at 8.50x c o n s i s t e n t with a methyl group on an enol acetate double bond; a sharp three proton s i n g l e t at 7 .92T i n d i c a t i n g an acetate f u n c t i o n ; a one proton m u l t i p l e t a t 7.72x (methine proton); a four proton broadened s i n g l e t a t 7 .32T t y p i c a l o f a l l y l i c methylenes; and a one proton broadened s i n g l e t o l e f i n i c s i g n a l a t 4.65x. The a l t e r n a t i v e homoannular diene s t r u c t u r e 87_ was r u l e d out on the basis o f the u l t r a v i o l e t spectrum which e x h i b i t e d no absorption i n the 260-270 nm region [ * m a x c a l c u l a t e d f o r compound 87_ i s 273 nm, the value found f o r analogous compound 88_ i s 262 nm (acetate f u n c t i o n normally doesn't s h i f t p o s i t i o n of absorption band g r e a t l y ) (72) ] . 87 88 As the reagent grade methylene c h l o r i d e used contained about 0.01% water, we considered that the water content was a y i e l d d e t e r -mining f a c t o r i n the r e a c t i o n . Indeed, when the r e a c t i o n was run i n sc r u p u l o u s l y dry methylene c h l o r i d e , the r e s u l t was a n e g l i g i b l e y i e l d - 39 -o f camphor. The choice o f boron t r i f l u o r i d e gas as c a t a l y s t f o r t h i s r e a c t i o n proved f o r t u i t o u s as l a t e r attempts to e f f e c t c y c l i z a t i o n o f enol a c e t a t e 80a with o t h e r a c i d c a t a l y s t s (e.g., hydrogen c h l o r i d e , hydrogen f l u o r i d e , aluminum c h l o r i d e or boron t r i f l u o r i d e etherate) gave no d e t e c t a b l e amount o f camphor. Though pleased by the success o f the c y c l i z a t i o n , we were somewhat perplexed by the f a c t that from o p t i c a l l y a c t i v e enol acetate 80a we had obtained racemic camphor r a t h e r than the (+)-camphor 17a which we had a n t i c i p a t e d . A p l a u s i b l e s o l u t i o n to t h i s dilemma was the known racemization of camphor under a c i d i c c o n d i t i o n s (73). However, (+)-camphor proved c o n f i g u r a t i o n a l l y s t a b l e to our r e a c t i o n c o n d i t i o n s over prolonged periods o f exposure. One remaining p o s s i b i l i t y i s that d i s r u p t i o n o f the c h i r a l center at o f enol acetate 80a through double bond migration or hydride s h i f t occurs p r i o r to c y c l i z a t i o n . In the above d e s c r i p t i o n we have assumed t h a t formation of the enol a c e t a t e of dihydrocarvone was e s s e n t i a l i n d i r e c t i n g and promoting c y c l i z a t i o n . To provide some support f o r t h i s agrument, dihydrocarvone 76_ was subjected to r e a c t i o n c o n d i t i o n s i d e n t i c a l to those d e s c r i b e d above. The s t a r t i n g material 76^was consumed very r a p i d l y , but no t r a c e o f camphor was found among the r e a c t i o n products. Instead, a major product i n i t i a l l y was an unconjugated enone t e n t a -t i v e l y assigned s t r u c t u r e 89 on the basis o f s p e c t r a l evidence. The i n f r a r e d spectrum o f compound 8J3 showed a carbonyl a b s o r p t i o n at 1710 cm"1 while the n.m.r. spectrum ( C C l i J e x h i b i t e d a nine proton doublet at 8.96T (J = 6.5 Hz) f o r three secondary methyls, a broad s i n g l e t at 7.26T assigned to the. methylene group adjacent to the ketone - 40 -- f u n c t i o n and a l l y l i c t o the double bond i n 89 and a one proton o l e f i n i c s i g n a l a t 4.46x. When benzene was used as s o l v e n t the secondary methyl adjacent to the ketone f u n c t i o n o f 89 (9.01x, doublet, three protons, J = 5.0 Hz) appeared downfield from the i s o p r o p y l methyls (9.18x, doublet, s i x protons, J = 5.0 Hz). As the r e a c t i o n o f dihydrocarvone (BF3/CH 2C1 2) proceeded, the c o n c e n t r a t i o n o f carvenone 85_ increased a t the expense o f compound 89. Dihydrocarvone o f +10° r o t a t i o n a f f o r d e d • (+)-carvenone, («) i* + 6 7 ° . 76 89 85 Encouraged by the s u c c e s s f u l c y c l i z a t i o n o f enol a c e t a t e 80a, we next i n v e s t i g a t e d enol a c e t a t e 84 which we had p r e v i o u s l y obtained as a by-product i n the enol a c e t y l a t i o n o f dihydrocarvone. 28 Treatment o f 84_, («) D +90.5°, under analogous c o n d i t i o n s , however, f a i l e d to produce carone 3J_ and i n s t e a d y i e l d e d o nly carvenone 85_. One p o s s i b l e reason f o r the f a i l u r e o f enol acetate 84_ to y i e l d carone could be the i n s t a b i l i t y o f c e r t a i n s t r a i n e d small r i n g compounds to the r e a c t i o n c o n d i t i o n s . In other s t u d i e s i n our l a b o r a t o r y , aimed at preparing the bicyclo(3.1.1 )heptane r i n g system, we attempted c y c l i z a t i o n o f enol a c e t a t e 90 with the r e s u l t t h a t no nopinone 91_ was produced but r a t h e r enone 92_ appeared the major product. When we 93 94 - 42 -subjected nopinone 91_ to the c y c l i z a t i o n c o n d i t i o n s ( B F 3/CH 2C1 2) the r e s u l t was formation o f enone 92_. While these r e s u l t s do not o b l i g a t e the intermediate formation o f 91_ from enol acetate 90, they do a t t e s t to the i n s t a b i l i t y o f r i n g systems such as 91_ and p o s s i b l y 31_to our r e a c t i o n c o n d i t i o n s . I n t e r e s t i n g l y , another ketonic compound 94_, f o r m a l l y bearing a bicyclo(3.1.1.)heptane r i n g system, i s apparently s t a b l e to boron t r i f l u o r i d e . Stork and co-workers (74) have reported that treatment of c i s - d i m e t h y l o c t a l one 93_with boron t r i f l u o r i d e i n methylene c h l o r i d e a f f o r d s ketone 94_ i n 90% y i e l d . Our success i n the synthesis of camphor v i a monocyclic sub-s t r a t e 80a_ (95a; R = H, X = OAc) l e d us to c o n s i d e r e x t e n t i o n o f our s y n t h e t i c e f f o r t s to the sesquiterpene analogues o f camphor. Already i n the sesquiterpene f i e l d Corey and co-workers (63) had used enol acetate 97_ to e f f e c t c y c l i z a t i o n o f the noracorane s k e l e t o n 96 to the norcedrane skeleton 98^which was then elaborated to (±)-cedrol. Our i n t e r e s t s were mainly i n the preparation of sesquiterpene analogues o f camphor by extension of the c y c l i z a t i o n r e a c t i o n of mono-c y c l i c enol a c e t a t e s . The simplest known sesquiterpene analogue of camphor appeared to be campherenone 42 which was i s o l a t e d i n 1967 from the camphor t r e e [Cinnamomum camphora S i e b o l d (Lauraceae)] (27). Our b i o g e n e t i c scheme (repeated f o r convenience i n schemes VI and VII) de p i c t e d campherenone as d e r i v e d from a monocyclic precursor such as 95b_ where R i s a Y , Y - d i m e t h y l a l l y l s i d e chain and X equals pyrophosphate (OPP). Compound 95b i s simply the enol d e r i v a t i v e of dihy d r o c r y p t o -merion 75_, which can be regarded as the sesquiterpene analogue of dihydrocarvone 76. Dihydrocryptomerion i t s e l f i s not known i n nature 95a R=H b R=CH 2CH=C(CH 3) 2 - 45 -Scheme VII Copacamphor Ylangocamphor Longicamphor Copaborneols Ylangoborneols Longiborneols Cyclocopacamphene Cy c l o s a t i v e n e L o n g i c y c l i n e Copacamphene Sativene Longifolene - 46 -but cryptomeriori 99 occurs i n Cryptomeriori japonica D. Don. (75). Thus the s y n t h e s i s o f campherenone 42 appeared a l o g i c a l e xtension o f our s y n t h e t i c work i n the monoterpene area and we hoped to o b t a i n 42_ d i r e c t l y by c y c l i z a t i o n of dihydrocryptomerion enol a c e t a t e 95b (X equal to OAc). Moreover, we regarded campherenone as a key s y n t h e t i c intermediate i n the s y n t h e s i s o f the o t h e r " s e s q u i -camphanes" ( c f . b i o g e n e t i c p o s t u l a t e s , schemes VI and V I I ) . Thus, c y c l i z a t i o n o f an enol d e r i v a t i v e o f campherenone such as 51 c o u l d l e a d to copacamphor 52_, ylangocamphor 53_ and longicamphor 54_. Allow-ing f o r the p o s s i b l e rearrangement products o f campherenone, copa-camphor, ylangocamphor and longicamphor i t was apparent t h a t our s y n t h e t i c scheme, i f s u c c e s s f u l , could be an extremely u s e f u l , general s y n t h e t i c route to a l a r g e number o f p o l y c y c l i c sesquiterpenes. Much o f t h i s o r i g i n a l s y n t h e t i c scheme has s i n c e been achieved i n our l a b o r a t o r y though many o f the s y n t h e t i c intermediates which we o r i g i -n a l l y proposed were l a t e r a l t e r e d . Our s y n t h e t i c plans r e q u i r e d a f a c i l e route to d i h y d r o c r y p t o -merion 75_. Planning a s y n t h e s i s o f 75 presented no great problem as the compound had been p r e v i o u s l y s y n t h e s i z e d by two d i f f e r e n t m u l t i - s t e p routes by Vig and co-workers (76,77). The more d i r e c t o f the two previous s y n t h e t i c routes (77)(scheme VIII) employed e-ketosulfoxide 104 which was obtained by condensation of dimsyl sodium with a c e t a l e s t e r 103. E s t e r 103 was obtained v i a a lengthy s e r i e s o f r e a c t i o n s from 6-methylcyclohexenone 100_ as shown i n scheme VIII (78). A l k y l a t i o n o f 104 with l-bromo-3-methyl-2-buten y i e l d e d compound 105 which was reduced with aluminum/mercury amalgam to keto a c e t a l 106. A simple Scheme VIII - 47 -104 105 R=S0CH3 J07 106 R=H W i t t i g r e a c t i o n on 106 followed by h y d r o l y s i s of the a c e t a l group o f 107, a f f o r d e d 7_5 i n approximately 10% o v e r a l l y i e l d from 100. The route we chose i n i t i a l l y f o r the pre p a r a t i o n o f compound 75 u t i l i z e d the same intermediate keto a c e t a l 106 as Vig's scheme but we f e l t that a simple Grignard c o u p l i n g r e a c t i o n to give 106 d i r e c t l y from a c i d c h l o r i d e 111 would s i m p l i f y the r e a c t i o n sequence. While a c e t a l a c i d 110 could conceivably be prepared from Vig's a c e t a l e s t e r 103, we f e l t that a simpler route might be developed from dihydro-carvone 76 which was now r e a d i l y a v a i l a b l e to us. Indeed from t h i s - 48 -r e a c t i o n sequence we obtained 106 i n 38% o v e r a l l y i e l d from dihydro-carvone. Thus 76_ was converted i n high y i e l d to the known ethylene a c e t a l 108 (79,80) by treatment i n benzene with ethylene g l y c o l and a c a t a l y t i c amount o f o x a l i c a c i d . Use o f p-toluenesulphonic a c i d as p r e v i o u s l y d e s c r i b e d (79) to c a t a l y z e t h i s step l e d to double bond isomen'zation, evidenced by the gradual disappearance o f the 889 cm"1 a b s o r p t i o n i n the i n f r a r e d spectrum o f compound 108. Ozonolysis o f a c e t a l 108 followed by neutral r e d u c t i v e work-up with dimethyl sulphide (81) a f f o r d e d the s e l e c t i v e l y p r o t e c t e d keto a c e t a l 109 i n high y i e l d . The presence and p o s i t i o n of both the a c e t a l and ketone f u n c t i o n s were r e a d i l y apparent from the i n f r a r e d and n.m.r. s p e c t r a : v m Q x 1700, 1170 and 1090 cm"1; T(CC1 I + ) , 6.07 (four proton s i n g l e t , a c e t a l methylene 7.92 (sharp three proton s i n g l e t , methyl adjacent to ketone). Oxida-t i o n o f 109 with h y p o c h l o r i t e a f f o r d e d a modest y i e l d of c r y s t a l l i n e a c e t a l a c i d 110. Treatment o f 110 in dry benzene with o x a l y l c h l o r i d e provided a c i d c h l o r i d e 111 ( ^ m x 1790, 1165 and 1090 cm" 1) which was used without f u r t h e r p u r i f i c a t i o n . Inverse a d d i t i o n o f Grignard reagent 114, prepared from 2-methyl-5-bromo-2-pentene 113 [ a v a i l a b l e from c y c l o p r o p y l methyl ketone 112 ( 8 2 ) ] , to an ether s o l u t i o n o f 111 i n the presence of cuprous c h l o r i d e (83,84) a f f o r d e d keto a c e t a l 106 i n 77% y i e l d based on s t a r t i n g a c i d 110. Physical constants and s p e c t r a l data f o r compound 106 were i n agreement with those p r e v i o u s l y published (76,77). The transformation o f 106 t c dihydrocryptomerior. by treatment with methylenetriphenylphosphorane i n dimethyl s u l f o x i d e (85), followed by h y d r o l y s i s , proceeded smoothly i n 83% y i e l d . Enol a c e t y l a t i o n - 49 -76 108 R = CH 2 110 X = OH 109 R = 0 111 X = CI 106 R = 0 Zi 95b HI 107 R = CH2  I " R = CH 2CH = C ( C H 3 ) 2 - 50 -using isopropenyl acetate and p-toluenesulphonic a c i d followed by s e p a r a t i o n of the isomeric enol acetates 95b and 11_5 by p r e p a r a t i v e g . l . c . a f f o r d e d the d e s i r e d s u b s t r a t e 95b. I n f r a r e d absorptions at 1750, 1705, and 1210 cm"1 supported the presence o f the enol a c e t a t e f u n c t i o n (86) while other c h a r a c t e r i s t i c absorptions o f 95b occurred a t 3090, 1645 and 889 cm" 1 i n d i c a t i n g terminal o l e f i n . The n.m.r. spectrum evidenced three v i n y l methyl s i g n a l s a t 8.52, 8.40 and 8.33T, an a c e t a t e methyl at 7.95T, a terminal o l e f i n s i g n a l (two protons) a t 5.23T and a one proton o l e f i n i c s i g n a l at 4.92t. It would be appropriate to mention at t h i s p o i n t that sub-sequent to the development o f the above synthe s i s o f dihydrocrypto-merion, a f a r simpler route to t h i s compound was developed i n our l a b o r a t o r y . The background and p a r t i c u l a r s o f t h i s a l t e r n a t e route w i l l be given i n a l a t e r s e c t i o n i n connection with f u r t h e r enol a c e t a t e c y c l i z a t i o n s t u d i e s . S u f f i c e i t to say at t h i s p o i n t t h a t metalation o f dihydrocarvone a c e t a l 116 with n-butyl 1 ithiurn i n t e t r a -methylethylenediamine (TMEDA) followed by a l k y l a t i o n with l - c h l o r o - 3 -methyl-2-butene provided 117 which upon h y d r o l y s i s o f the a c e t a l f u n c t i o n y i e l d e d dihydrocryptomerion 75a at 88% o v e r a l l y i e l d . - 51 -With the a p p r o p r i a t e monocyclic s u b s t r a t e i n hand we attempted the proposed c y c l i z a t i o n o f enol acetate 95b_ to campherenone 42_ using boron t r i f l u o r i d e i n methylene c h l o r i d e . For t h i s r e a c t i o n to succeed the c y c l i z a t i o n must occur by s e l e c t i v e i n t e r a c t i o n o f the enol acetate f u n c t i o n with the terminal methylene double bond. The hope was held that the remaining t r i s u b s t i t u t e d double bond o f t h i s 1,5-diene system would remain i n e r t during the c y c l i z a t i o n . Treatment o f 95b under the p r e v i o u s l y described optimum r e a c t i o n c o n d i t i o n s a f f o r d e d a complex mixture of b i c y c l i c and t r i c y c l i c ketones with carbonyl absorptions at 1740, 1715 and 1680 cm" 1. The n.m.r. spectrum o f the crude mixture i n d i c a t e d no protons i n the proper r e g i o n f o r the t r i s u b s t i t u t e d double bond o f campherenone as described i n the published n.m.r. spectrum (27,28). Separation of the v o l a t i l e components of the mixture by p r e p a r a t i v e g . l . c . a f f o r d e d three major components A , B_ and C_ ( i n the order o f i n c r e a s i n g r e t e n t i o n times) none o f which e x h i b i t e d s p e c t r a l c h a r a c t e r i s t i c s corresponding to campherenone. Component A (25-30% o f the v o l a t i l e products) e x h i b i t e d i n f r a r e d absorptions at 1740 and 1410 cm"1 i n d i c a t i v e o f a s t r a i n e d f i v e membered r i n g ketone flanked by a methylene group. Bands a t 1375 and 1360 cm"1 suggested the presence of a sa t u r a t e d dimethyl group such as a gem-dimethyl or is o p r o p y l group. The n.m.r. spectrum ( C C l i J o f A was dominated by sharp high f i e l d methyl s i g n a l s and there were no o l e f i n i c s i g n a l s . A s i n g l e t a t 9.19x had a r e l a t i v e i n t e g r a l area o f three protons when compared to four sharp s i n g l e t s at 9.10, 9.05, 9.00 and 8.94T t o t a l i n g s i x protons. Though component A was homogenous by g . l . c . a n a l y s i s on several columns, s p e c t r a l evidence i n d i c a t e d t hat i t c o n s i s t e d o f a mixture o f disastereomers 119a and b - 52 -(scheme IX). Elemental a n a l y s i s and mass s p e c t r a l data are i n agree-ment with t h i s assignment. Component B_ (5%) was a s e m i s o l i d m a t e r i a l o f low melting p o i n t e x h i b i t i n g absorptions i n the i n f r a r e d a t 1715 and 1404 cm"i. The n.m.r. spectrum (CCl^) o f t h i s component showed a broadened doublet at 9.22T (three protons, J = 5 Hz, secondary methyl), two sharp s i n g l e t methyl s i g n a l s a t 9.07 and 9.03T and a very broad s i g n a l a t 8.55 T ( h a l f peak width 7 Hz) which contained s i x to seven protons. Component B_ i s s t a b l e to a c i d s such as boron t r i f l u o r i d e and o x a l i c a c i d and was a l s o s t a b l e to ozone i n s e v e r a l s o l v e n t s thus making the presence o f a t e t r a s u b s t i t u t e d double bond extremely u n l i k e l y . The above s p e c t r a l and chemical evidence combined with mass s p e c t r a l evidence f o r a mole-c u l a r ion o f m/e 220 suggests t h a t B_ may be a t r i c y c l i c compound. The presence o f a secondary methyl group suggests t h a t rearrangement may have occurred before c y c l i z a t i o n . The carbonyl a b s o r p t i o n (1715 cm" 1) i s a t lower frequency than expected f o r a ketone i n a s t r a i n e d f i v e membered r i n g and y e t the a b s o r p t i o n i s o f higher frequency than normally found f o r other s i x membered r i n g ketones i n t h i s s e r i e s o f compounds. The presence o f an e s t e r f u n c t i o n i s r u l e d out by the l a c k o f c h a r a c t e r i s t i c bands i n the 1200 cm" 1 region o f the i n f r a r e d spectrum as well as by o t h e r data. One type o f s t r u c t u r e which would seem to f i t much o f the data would be a bicyclo(2.2.2)octanone compound such as s t r u c t u r e 124a o r b which can be d e r i v e d on paper from enol acetate isomer 122_ by methyl m i g r a t i o n followed by c y c l i z a t i o n o f the c o r r e s -ponding double bond isomer 123. Present data however, make such a s t r u c t u r a l suggestion h i g h l y s p e c u l a t i v e . - 54 -Component C_ contained an enone f u n c t i o n a l i t y evidence by an a b s o r p t i o n i n the u l t r a v i o l e t spectrum a t 237 nm (e 15,000), by i n f r a -red a b s o r p t i o n s at 1670, 1625 and 880 cm"1 and by a low f i e l d o l e f i n i c a b s o r p t i o n a t 4.25T i n the n.m.r. spectrum ( C C 1 J . The n.m.r. spectrum a l s o i n d i c a t e d a s i x proton s i n g l e t at 9.03T (two overlapping t e r t i a r y methyl s i g n a l s ) and a three proton doublet at 8.93x (J = 6.5 Hz). The s p e c t r a l data above as well as the mass spectrum and elemental a n a l y s i s agree with s t r u c t u r e 121 t e n t a t i v e l y assigned f o r t h i s com-ponent. When enol a c e t a t e 95b was exposed to the c y c l i z a t i o n c o n d i t i o n s f o r very b r i e f p e r i o d s , a new component could be i s o l a t e d to which s t r u c t u r e 120 has been assigned on the basis o f s p e c t r a l data and by analogy with compound 86_ d e r i v e d from dihydrocarvone enol a c e t a t e 80a. As r e a c t i o n time was lengthened, compound 120 was depleted with a corresponding i n c r e a s e i n enone 121. I t may well be t h a t compound 120 i s thus the major precursor of the enone m a t e r i a l . A p o s s i b l e scheme accounting f o r components A (119a and b) and £ (121) i s shown above. The s t r u c t u r e s suggested f o r A and C_ are only t e n t a t i v e , although the evidence f o r these components i n view of the analogous r e a c t i o n s of dihydrocarvone enol acetate 80a seems q u i t e a t t r a c t i v e . C r y s t a l l i n e d e r i v a t i v e s of one o f the two disastereomers o f A (separated as t h e i r enol acetate d e r i v a t i v e s by p r e p a r a t i v e g . l . c . ) as well as of component B_ have been submitted f o r X-ray s t r u c t u r a l a n a l y s i s . One more recent piece o f data from our l a b o r a t o r y tends to support the s t r u c t u r e 119a,b assigned to component A: c y c l i z a t i o n (BF 3/CH 2C1 2) of enol acetate 125 (87), prepared from ketone 126 (87) (see reference (88)), a f f o r d s components A, B_ and C_ i n the r e l a t i v e - 55 -r a t i o s 5:3:1 r e s p e c t i v e l y (89). Though we were disappo i n t e d that the c y c l i z a t i o n of the enol a c e t a t e o f dihydrocryptomerion had f a i l e d to produce d e t e c t a b l e amounts o f campherenone, the presence o f component A (119a,b) among the r e a c t i o n products provided hope that the r e q u i s i t e c y c l i z a t i o n was i n f a c t o c c u r r i n g but that the presence of the a d d i t i o n a l double bond was a l t e r i n g the course o f the r e a c t i o n . At a l a t e r date when a s y n t h e t i c sample of campherenone was a v a i l a b l e from an a l t e r n a t e route, we d i s -covered t h a t campherenone i t s e l f i s not s t a b l e to treatment with boron t r i f l u o r i d e thus making the above r e s u l t s even l e s s s u r p r i s i n g . The obvious next approach to the p r e p a r a t i o n o f campherenone was to e l i m i n a t e the p o s s i b i l i t y of 1,5-diene i n t e r a c t i o n i n the s i d e chain of the c y c l i z a t i o n s u b s t r a t e . The a v a i l a b i l i t y o f keto a c e t a l 109 from our s y n t h e s i s o f dihydrocryptomerion l e d to the p r e p a r a t i o n o f a s e r i e s o f compounds possessing the basic s t r u c t u r e 127. Simple W i t t i g r e a c t i o n s on 109 provided compounds 127a-f or t h e i r precursors i n good y i e l d a l l o w i n g us to attempt the c y c l i z a t i o n o f t h e i r corresponding enol acetate d e r i v a t i v e s 128a-f. We f i r s t prepared 127a, the simple e t h y l i d e n e analogue of dihydrocarvone, to e s t a b l i s h that the t r i s u b s t i t u t e d double bond would p a r t i c i p a t e i n c y c l i z a t i o n i n the same manner as the terminal o l e f i n of dihydrocarvone enol a c e t a t e . Treatment of the corresponding enol a c e t a t e 128a under the c y c l i z a t i o n c o n d i t i o n s (BF 3/CH 2C1 2) provided the b i c y c l i c homocamphor compounds 129a,b i n good y i e l d : 56 109 127 128 a R = CH 3 b R = C0 2CH 3 c R = CH 2CH 2C0 2 C H 3 d R = C H 2CH 2CH 20CH 2C 6H 5 e R = CH 2CH 2Br f R = CH 2CH 2C1 OAc HCH: 129a 129b 128a - 57 -v m a x 1740 and 1410 cm" 1; (CC1 1 +) 9.15 (three proton s i n g l e t , C 1 0 methyls), 9.20 and 9.08 (two s i n g l e t s with combined i n t e g r a l of three protons, C 8 a n d C 9 methyls); T ( C 6 H 6 ) 9.44 and 9.39 (two s i n g l e t s with combined i n t e g r a l of three protons, C 8 and C g methyls) and 9.10 (three proton s i n g l e t , C 1 0 methyls).(90) However, p r e l i m i n a r y attempts to e f f e c t c y c l i z a t i o n with such substrates as 128b-e under analogous con-d i t i o n s f a i l e d to produce s u i t a b l e b i c y c l i c m a t e r i a l s f o r various reasons. In p a r t i c u l a r , compounds 128b and c f a i l e d to undergo c y c l i z a t i o n with our r e a c t i o n c o n d i t i o n s while compounds 128d and e apparently y i e l d e d some b i c y c l i c m a t e r i a l s but possessed f u n c t i o n a l groups which were l a b i l e under the c o n d i t i o n s o f r e a c t i o n and/or work-up thus l e a d i n g to complex mixtures o f products. Compound 128f appeared to be a reasonable a l t e r n a t i v e i n t e r -mediate f o r the s y n t h e s i s o f a s u i t a b l y f u n c t i o n a l i z e d b i c y c l i c precursor o f campherenone. The appropriate W i t t i g s a l t was prepared s t a r t i n g from commercially a v a i l a b l e 3-chloropropan-l-ol 130. Treatment of 130 with sodium i o d i d e i n acetone provided iodo a l c o h o l 131 i n high y i e l d . Pro-t e c t i o n of the hydroxyl f u n c t i o n as the tetrahydropyranyl (THP) ether 132 followed by d i r e c t r e a c t i o n with triphenylphosphine i n benzene a f f o r d e d the c r y s t a l l i n e phosphonium s a l t 133. Condensation of keto ac e t a l 109 with 133 i n the presence o f dimsyl sodium (85) a f f o r d e d 134. The use o f the y-tetrahydropyranyl phosphonium s a l t f o r t h i s step i n preference to other f u n c t i o n a l i z e d s a l t s avoided the i n t e r n a l i n t e r -a c t i o n s observed by others (91) and by ourselves with s a l t s such as 135 upon treatment with base. - 58 -- 59 -The next step i n the s y n t h e s i s r e q u i r e d s e l e c t i v e removal o f the THP p r o t e c t i v e group. This was achieved i n one step by treatment i n benzene with ethylene g l y c o l and o x a l i c a c i d . Hydroxy ac e t a l 136 was obtained i n 70% o v e r a l l y i e l d from keto acetal 109, and was con-verted i n 78% y i e l d to c h l o r o a c e t a l 137 by treatment with t r i - r v -octylphosphine and carbon t e t r a c h l o r i d e (92). Subsequent h y d r o l y s i s and enol a c e t y l a t i o n a f f o r d e d the d e s i r e d monocyclic s u b s t r a t e 128f. It would appear t h a t n o n s e l e c t i v e h y d r o l y s i s o f 134 to hydroxy ketone 138 followed by c h l o r i n a t i o n would provide a more d i r e c t i f not higher y i e l d i n g route to 127f. In p r a c t i c e , c o n s i s t e n t l y lower y i e l d s i n the c h l o r i n a t i o n step were obtained from 138 presumably due to attack at the ketone. It has been shown that triphenylphosphine 139 (R equals phenyl) r e a c t s with carbon t e t r a c h l o r i d e to form compounds 140 and 141 (93,94). Both 140 and 141 have been shown to react with cyclohexanone to form i n the case o f 140 dichloromethylene adduct 142, while 141 r e a c t s to form enyl choride 143 (95). However, when cyclohexanone i n c a r b o n t e t r a c h l o r i d e s o l u t i o n i s allowed to r e a c t with one mole o f t r i p h e n y l p h o s p h i n e , there i s formed 62% 143 and 3% 142. A mechanism has been proposed i n v o l v i n g compound 144 to account f o r the formation of greater than 50% enyl c h l o r i d e 143 (95). S i m i l a r r e a c t i o n s are probably o c c u r r i n g with t r i - n - o c t y l p h o s p h i n e 139 (R equals n - o c t y l ) and ketone 138. Concurrent with cur i n v e s t i g a t i o n s o f enol acetates 128a-f a new s y n t h e t i c route to dihydrocryptomerion 75 was developed i n our l a b o r a t o r y i n v o l v i n g a l k y l l i t h i u m species 145 (96). Though we had already by that time developed'a s a t i s f a c t o r y route to 128f (and to - 61 -V - 62 -campherenone f o r t h a t matter) the p o s s i b i l i t y o f g r e a t l y shortening t h a t route by d i r e c t a l k y l a t i o n o f 145 seemed h i g h l y a t t r a c t i v e and worthwhile i n v e s t i g a t i n g i n view o f the p o t e n t i a l usefulness o f the subsequent product, campherenone. Our i n t e r e s t i n t h i s r e a c t i o n was i n i t i a l l y s t imulated by a p r e l i m i n a r y paper presented by R. J . Crawford (97,98,99) concerning the metalation and a l k y l a t i o n o f limonene 146. Treatment o f limonene with the 1:1 complex o f n_-butyllithium and N,N,N',N'-tetramethylethylenediamine (TMEDA) s e l e c t i v e l y metalated the C i 0 p o s i t i o n forming the a l k y l l i t h i u m species i n d i c a t e d as s t r u c t u r e 147. I t was found t h a t 147 underwent many r e a c t i o n s t y p i c a l o f a l k y l l i t h i u m s i n c l u d i n g carbonation, oxygenation, c o u p l i n g r e a c t i o n s with a l k y l h a l i d e s , a d d i t i o n to carbonyl compounds and a d d i t i o n to epoxides form-ing d e r i v a t i v e s o f the general s t r u c t u r e 148. The r e a c t i o n o f 147 with 1-bromo-3-methyl-2-butene to a f f o r d a 4:1 mixture o f e-bisabolene 149 and isomer 150 was p a r t i c u l a r l y a t t r a c t i v e i n regard to our dihydro-cyptomerion work. A p o s s i b l e extension o f t h i s r e a c t i o n would be the metalation and a l k y l a t i o n o f dihydrocarvone a c e t a l 108 p r o v i d i n g a c e t a l diene 107 d i r e c t l y which upon h y d r o l y s i s would y i e l d dihydrocryptomerion i n three steps from dihydrocarvone. U n f o r t u n a t e l y 108 f a i l e d to undergo the d e s i r e d metalation as evidenced by the absence o f the c h a r a c t e r -i s t i c red c o l o r of the a l l y l i c a l k y l l i t h i u m species i n the r e a c t i o n mixture as well as by the lack o f a l k y l a t e d products a f t e r treatment with various a l k y l a t i n g agents. In f a c t treatment o f 108 with one e q u i v a l e n t o f the jv-butyllithium--TMEDA complex f o r 24 hours followed by the usual work-up and h y d r o l y s i s y i e l d e d dihydrocarvone 7_6 and a l e s s v o l a t i l e product i n approximately a 1:1 r a t i o as judged by g . l . c . - 63 -145 149 150 - 64 -a n a l y s i s . Heathcock and co-workers (100) had p r e v i o u s l y shown t h a t cyclohexanone ethylene a c e t a l 151 r e a c t s with t_-butyl 1 ithium or i s o -p r o p y l l i t h i u m c o n v e r t i n g 151 to t e r t i a r y a l c o h o l s 152 and 153 r e s p e c t i v e l y . The analogous r e a c t i o n with tv-butyllithium occurred to a small extent. The mechanism suggested f o r t h i s r e a c t i o n i s shown below. In keeping with t h i s mechanism acetal 154 was s t a b l e in the presence o f these a l k y l l i t h i u m reagents. We a n t i c i p a t e d that the 1:1 complex o f n_-butyllithium--TMEDA was a s u f f i c i e n t l y powerful metalating agent to cause analogous decom-p o s i t i o n of dihydrocarvone a c e t a l 108. The preparation o f the 1,3-dioxane 155 o f dihydrocarvone was a p o s s i b l e route to circumvent t h i s d i f f i c u l t y ; however, such a c e t a l s are notably d i f f i c u l t to prepare (e.g., a c e t a l 155 was prepared i n our l a b o r a t o r y i n only 35% y i e l d ) . Newman and Harper (101) found t h a t 2,2-dimethyl-l,3-propanediol reacted much more r a p i d l y with cyclohexanone than d i d ethylene g l y c o l while 1,3-propanediol reacted very slowly. We t h e r e f o r e attempted the analogous r e a c t i o n using 2,2-dimethyl-l,3-propanediol, o x a l i c a c i d and dihydrocarvone i n benzene at r e f l u x and obtained a high y i e l d of material e x h i b i t i n g no ketone absorption i n the i n f r a r e d but e x h i b i t i n g bands f o r terminal o l e f i n (3090, 1650 and 888 cm" 1) and f o r the a c e t a l f u n c t i o n (1150 and 1100 a n " 1 ) . The n.m.r. of t h i s product proved unexpectedly complex p a r t i c u l a r l y i n the regions o f the acetal methylenes (6-7 x) and o f the s a t u r a t e d methyls (above 8.8T ) . The complexity was f e l t to be p a r t i a l l y due to the presence o f two disasterecmers 116a and b and t h i s was confirmed by g . l . c . a n a l y s i s . Separation by g . l . c . provided samples o f 116a and 116b of" g r e a t e r than 90% p u r i t y . Compound 116a 155 116a 116b - 66 -with both i t s methyl and isopropenyl group e q u a t o r i a l i n the e n e r g e t i -c a l l y favored conformation was assumed to be the major product ( r e l a t i v e r e t e n t i o n time 21 minutes compared to 23.5 minutes f o r 116b). The n.m.r. spectrum ( C C l i J o f 116a was s t i l l complex i n the region o f the ac e t a l methylenes (6-7 T) p o s s i b l y i n d i c a t i n g slow conformational i n t e r -conversion o f the 5,5-dimethyldioxane r i n g (102). Sharp s i n g l e t s appeared at 8.88 and 9.33 x due to the gem-dimethyl group of the a c e t a l f u n c t i o n . Compound 116b on the other hand e x h i b i t e d a r a t h e r simple n.m.r. spectrum (CC1 4) with a broad f o u r proton s i n g l e t a t 6.63 x f o r the a c e t a l methylenes and two sharp s i n g l e t s a t 9.09 and 9.12 T due to the methyl groups o f the a c e t a l . A molecular model o f compound 116b does not reveal s i g n i f i c a n t d i f f e r e n c e i n s t e r i c i n t e r a c t i o n s f o r the various p o s s i b l e p r e f e r r e d conformations o f the a c e t a l r i n g (102) and thus r a p i d i n t e r c o n v e r s i o n s between these conformations may account f o r the s i m p l i c i t y of the n.m.r. spectrum. Thus ace t a l 116a,b was obtained i n 91% o v e r a l l y i e l d and metal-a t i o n was again attempted with t h i s new s u b s t r a t e . Reaction o f 116a,b with one e q u i v a l e n t o f the 1:1 n-butyl1ithium--TMEDA complex overnight produced a deep red s o l u t i o n of the metalated species represented by 145_ which, upon a l k y l a t i o n with l-chloro-3-methyl-2-butene and sub-sequent h y d r o l y s i s , provided dihydrocryptomerion i n 88% i s o l a t e d y i e l d based i n consumed ace t a l 116a,b. No evidence could be found f o r the a l l y l i c rearrangement product 156 analogous to 150 observed by Crawford e t . a l . Indeed r e p e t i t i o n o f Crawford's synthesis o f g-bisabolene, s u b s t i t u t i n g l-chloro-3-methyl-2-butene f o r the bromo analogue used by Crawford,1ikewise gave no t r a c e o f 150 (103). - 68 -The success o f t h i s a l k y l a t i o n l e d us to attempt the r e a c t i o n of 145 with other a l k y l a t i n g agents. Notably the r e a c t i o n o f 145 with 1,2 -dichloroethane (excess) seemed a p o s s i b l e d i r e c t route to ketone 160, the double bond isomer o f 127f. While some success was achieved with this a l k y l a t i o n on a small s c a l e , the r e s u l t s were not r e p r o d u c i b l e on a synthetically u s e f u l q u a n t i t y , the competing r e a c t i o n apparently being elimination o f hydrogen c h l o r i d e from the a l k y l a t i n g agent. A l k y l a t i o n with ethylene oxide proceeded much more smoothly to a f f o r d acetal alcohol 158 i n 91% o v e r a l l y i e l d ( c o n s i d e r a b l e s t a r t i n g material [ca. 48%] was recovered i n t h i s r e a c t i o n ) . Transformation o f 158 to the corresponding c h l o r o d e r i v a t i v e 159 (84% y i e l d ) and subsequent hydrolysis to c h l o r o ketone 160 (91% y i e l d ) were performed as i n the analogous s e r i e s from hydroxy a c e t a l 136. Enol a c e t y l a t i o n o f ketone 160 provided a 3:1 r a t i o o f isomeric enol acetates 161 and 162 which c o u l d be separated by p r e p a r a t i v e g . l . c . Treatment o f e i t h e r enol acetate 128f or 161 under the usual cyclization c o n d i t i o n s a f f o r d e d two major products i n the approximate ratio 3:2 as judged by g . l . c . a n a l y s i s ( r e l a t i v e r e t e n t i o n times 4.1 minutes and 6.0 minutes r e s p e c t i v e l y ) . Pure samples o f each could be ob t a i n e d e i t h e r by p r e p a r a t i v e g . l . c . o r f r a c t i o n a l d i s t i l l a t i o n . The more volatile major product (55 to 60%), a fragrant, c o l o r l e s s o i l with («)n = 0°, e x h i b i t e d absorptions i n the i n f r a r e d a t 1740 and 1410 cm indicative o f a five-membered r i n g ketone f l a n k e d by a methylene group and characteristic o f our various s y n t h e t i c camphor analogues. The n.m.r. spectrum of t h i s component e x h i b i t e d resonances [x ( C C l i J 9.11 (three proton s i n g l e t , t e r t i a r y methyl), 9.16 and 9.03 (two s i n g l e t s totalling three protons, d i s a s t e r e o m e r i c t e r t i a r y methyls), 6.55 and 70 -and 6.48 (two o v e r l a p p i n g t r i p l e t s t o t a l l i n g two protons, methylenes bearing c h l o r i n e atoms)], which are c o n s i s t e n t with a mixture o f disastereomers 163a and b. The above data combined with mass s p e c t r a l evidence f o r parent ions at m/e 214 ( r e l a t i v e i n t e n s i t y 97.3) and m/e 216 ( r e l a t i v e i n t e n s i t y 33.6), i n d i c a t e d t h a t the d e s i r e d c y c l i z a -t i o n to 163a,b had occurred. A d d i t i o n a l evidence f o r t h i s s t r u c t u r e was obtained by comparison o f the n.m.r. spectrum o f 163a,b with those o f camphor and methyl homocamphor 129a,b i n carbon t e t r a c h l o r i d e and i n benzene (see Table III) (104-106). Assuming that the C 8 and C 9 p o s i t i o n methyls have analogous p o s i t i o n s i n the n.m.r. sp e c t r a o f 163a,b and of camphor 17., and are s i m i l a r l y s h i f t e d when the s o l v e n t i s changed to benzene, the r a t i o o f product 163a to 163b was approxi-mately 5.8:4.2. The second main component (30-40%) i n the c y c l i z a t i o n product from 128f or 161 proved to possess an enone f u n c t i o n as evidenced by an u l t r a v i o l e t absorption at 234 nm (e 15,000) and by i n f r a r e d absorp-t i o n s a t 1670, 1210 and 883 cm" 1. The presence of an enone f u n c t i o n immediately suggested s t r u c t u r e 164 by analogy with the products obtained from enol acetates 80a and 95b. This s t r u c t u r e was f u r t h e r corroborated by the n.m.r. spectrum (CC1 4) T 8.91 (three proton doublet, J = 6.5 Hz, secondary methyl), 8.87 (three proton doublet, J = 6.5 Hz, secondary methyl), 6.52 (broadened t r i p l e t , two protons, J = 6 Hz, methylene bear-ing c h l o r i n e s u b s t i t u e n t ) and 4.30 (one proton s i n g l e t , proton on enone system) and by mass s p e c t r a l and elemental a n a l y s i s . One d i f f e r e n c e was noted between t h i s c y c l i z a t i o n and those d e s c r i b e d p r e v i o u s l y in t h a t the c y c l i z a t i o n o f dihydrocarvone enol TABLE I I I : N.M.R. Si g n a l s o f B i c y c l i c Analogues o f Camphor '10 Camphor Methyl Homocamphor 129a Methyl Homocamphor 129b Keto C h l o r i d e 163a Keto C h l o r i d e 163b CCli, C 6H 6 CClit C 6H 6 CC1 4 C 6 H 6 CC1 4 C 6 H 6 e c u C 6H 6 9.19 9.40 9.20 9.44 9.16 9.52 9.07 9.35 9.08 9.39 9.03 9.45 9.18 9.11 9.15 9.10 9.15 9.10 9.11 9.11 9.11 9.11 - 72 -a c e t a t e 80a, f o r example, r e q u i r e d l e s s than f i v e minutes ( i n f a c t i n one experiment the r e a c t i o n was shown to be complete i n t h i r t y seconds) while enol acetates 128f or 161 r e q u i r e d approximately one hour or more f o r t o t a l disappearance of enol acetate m a t e r i a l . The reason f o r t h i s longer r e a c t i o n time has not been i l l u c i d a t e d ; however, our previous experience with various f u n c t i o n a l groups preventing c y c l i z a -t i o n o r i n t e r a c t i n g during c y c l i z a t i o n suggests one p o s s i b l e area f o r f u r t h e r research. As noted e a r l i e r , the c y c l i z a t i o n o f the various enol acetates proceeded i n highest y i e l d when c a r r i e d out at approximately a one m i l l i g r a m per one m i l l i l i t e r c o n c e n t r a t i o n i n methylene c h l o r i d e . The high d i l u t i o n presented c e r t a i n p r a c t i c a l problems i n s c a l i n g up t h i s r e a c t i o n to produce useful s y n t h e t i c q u a n t i t i e s o f 163a,b. For example, a ten gram r e a c t i o n would r e q u i r e ten l i t e r s of s o l v e n t . I t was found, however, t h a t the r e a c t i o n could be performed by the a d d i t i o n o f several small p o r t i o n s o f substrate to a more moderate volume of s o l v e n t with the a d d i t i o n o f water between each p o r t i o n of s u b s t r a t e . The presence o f the p r e v i o u s l y added s u b s t r a t e (now p a r t i a l l y transformed to product) had no detrimental e f f e c t on the product r a t i o , while the a d d i t i o n o f water r e s t o r e d the water consumed during the r e a c t i o n o f the previous p o r t i o n of enol a c e t a t e . In t h i s manner f i v e grams o f s u b s t r a t e could be conveniently reacted i n 1.8 l i t e r s o f s o l v e n t and the methylene c h l o r i d e recovered d i r e c t l y from the r o t a r y evaporator a f t e r work-up could be used f o r f u r t h e r c y c l i z a t i o n s with no diminution c f y i e l d . The s e p a r a t i o n o f enol acetate isomers 161 and 162 by prepar-a t i v e g . l . c . or by d i s t i l l a t i o n proved tedious on a s y n t h e t i c s c a l e and - 73 -thus a mixture o f the two isomers was employed f o r l a r g e s c a l e c y c l i z a -t i o n s . Isomer 162 simply enhanced the amount o f enone 164_ which had to be separated from b i c y c l i c m a t e r i a l . Thus using the enol acetate mixture and the c y c l i z a t i o n procedure d e s c r i b e d above, b i c y c l i c ketones 163a,b were i s o l a t e d by f r a c t i o n a l d i s t i l l a t i o n from the r e a c t i o n mixture i n 46% y i e l d (based on enol acetate 161). At t h i s stage our o v e r a l l r e a c t i o n sequence from carvone 79_ to b i c y c l i c ketones 163a,b was h i g h l y e f f i c i e n t except a t the p o i n t o f the c y c l i z a t i o n of the enol acetate mixture. We were not bothered by the y i e l d o f the c y c l i z a t i o n i t s e l f (which d i d not improve under various changes i n r e a c t i o n c o n d i t i o n s ) f o r i n view o f our previous experience we were pleased t h a t c y c l i z a t i o n had proceeded i n 55 to 60% y i e l d (by g . l . c ) . The presence o f the o t h e r enol a c e t a t e isomer (approximately 25%) i n the r e a c t i o n however, presented problems i n t h a t i t g r e a t l y reduced our o v e r a l l y i e l d from ketone 160 and a t the same time i n c r e a s e d c o n s i d e r a b l y the q u a n t i t y o f enone 164 to be separated, a f t e r c y c l i z a t i o n , from the b i c y c l i c products. To circumvent t h i s annoyance with isomer 162 we again looked at a l t e r n a t e enol a c e t y l a t i o n c o n d i t i o n s . Our previous choice o f isopropenyl acetate and p_-toluenesulfon a c i d was r e q u i r e d to prevent double bond mig r a t i o n during the enol a c e t y l a t i o n step. A l i t e r a t u r e r e p o r t o f enol a c e t y l a t i o n using per-c h l o r i c a c i d and a c e t i c anhydride i n e t h y l acetate (107) looked promis-ing as the r e a c t i o n c o u l d be c a r r i e d out at room temperature and pro-ceeded very f a s t ( f i v e minutes). Indeed, on a ten m i l l i g r a m s c a l e ketone 160 was converted almost completely to enol acetates 161 and - 74 -and 162 i n the r e l a t i v e r a t i o 92:8 (based on g . l . c . ) with very l i t t l e double bond migration as judged by the n.m.r. i n t e g r a l o f the terminal o l e f i n s i g n a l (ca. 5.18 x) r e l a t i v e to t h e c h l o r o s u b s t i t u t e d methylene group (ca. 6.55 x). When the r e a c t i o n was s c a l e d up to a f e a s i b l e s i z e f o r p r e p a r a t i v e work, a g r e a t e r percentage o f double bond migration occurred and the volume o f reagent r e q u i r e d was ungainly. A f t e r con-s i d e r a b l e e f f o r t to optimize r e a c t i o n c o n d i t i o n s f o r our s u b s t r a t e , i t was found t h a t a d d i t i o n of 500 m i l l i l i t e r s o f reagent (anhydrous e t h y l acetate s o l u t i o n 1.06 molar i n a c e t i c anhydride and 0.23 molar i n p e r c h l o r i c acid) to 10 grams o f ketone i n 100 m i l l i l i t e r s o f anhydrous ethyl acetate (5.5 minutes) provided enol acetates 161a and 162a i n good y i e l d and i n the r e l a t i v e r a t i o o f 93:7 r e s p e c t i v e l y . Double bond i s o m e r i z a t i o n was found to have occurred to the extent o f 45% by n.m.r. a n a l y s i s , with isomer 128f accounting f o r roughly 18% o f the isomerized product. Since the b i c y c l i c products produced from e i t h e r enol acetate are racemic, and s i n c e double bond isomers 161 and 128f undergo c y c l i z a t i o n i n equal y i e l d , the stereochemical i n t e g r i t y of the terminal double bond i n 161a was not c r u c i a l . The y i e l d o f b i c y c l i c product from 161a was again 55-60% as judged by g . l . c . Transformation o f b i c y c l i c ketones 163a,b to campherenone and i t s C 7 epimer proceeded without c o m p l i c a t i o n . The mixture o f the two ketones was used as 163a and b proved extremely d i f f i c u l t to separate by d i s t i l l a t i o n and could not be r e s o l v e d by g . l . c . on a v a r i e t y o f columns. Treatment o f the mixture with ethylene g l y c o l and £-toluenesulfonic a c i d in benzene a f f o r d e d a c e t a l s 165a,b i n 95% y i e l d . Though a c e t a l s 165a and b were ^ r e a d i l y r e s o l v a b l e by g . l . c , i t was found to be more p r a c t i c a l to wait u n t i l a l a t e r stage o f the s y n t h e s i s - 75 -to perform t h i s s e p a r a t i o n . Treatment of c h l o r o a c e t a l s 165a,b with sodium i o d i d e i n dry acetone and i n the presence o f calcium carbonate a f f o r d e d iodo a c e t a l s 166a,b i n high y i e l d . As compounds' 166a,b proved s e n s i t i v e to aqueous work-up, a non-aqueous work-up was developed i n which the r e a c t i o n mixture was t r a n s f e r r e d d i r e c t l y under dry nitrogen i n t o dry pentane, p r e c i p i t a t i n g the i n o r g a n i c m a t e r i a l s . The pentane s o l u t i o n was then f i l t e r e d over c e l i t e and the r e s u l t i n g c o l o r l e s s s o l u t i o n concentrated and d i s t i l l e d a f f o r d i n g 166a,b i n 97% y i e l d . Once the s o l u t i o n of 166a,b had been f i l t e r e d over c e l i t e , i t no longer c o l o r i z e d upon exposure to the atmosphere. Iodo a c e t a l s 166a and b were r e a d i l y r e s o l v e d by g . l . c . on several columns but attempts to c o l l e c t samples o f e i t h e r compound by p r e p a r a t i v e g . l . c . l e d to con-s i d e r a b l e product degradation and thus the mixture was used i n the next step. The W i t t i g s a l t o f 166a,b, prepared by r e f l u x i n g with t r i -phenylphosphine i n dry benzene.was a c o l o r l e s s o i l . The s a l t , 167a,b, proved to be very hygroscopic and h i g h l y s e n s i t i v e to any moisture absorbed. Product 167a,b was a l s o very s o l u b l e i n organic solvents (such as benzene)which are normally used to e x t r a c t traces o f unreacted triphenylphosphine or s t a r t i n g h a l i d e from crude n o n - c r y s t a l l i n e phosphonium s a l t s . Circumventing a troublesome p u r i f i c a t i o n s t e p , phosphonium s a l t 167a,b was prepared from equimolar q u a n t i t i e s o f s t a r t i n g h a l i d e and triphenylphosphine and, a f t e r removal of benzene, the r e s u l t i n g product was used without f u r t h e r p u r i f i c a t i o n . Thin l a y e r chromatographic ( t . ' l . c . ) a n a l y s i s i n d i c a t e d no d e t e c t a b l e amount o f e i t h e r s t a r t i n g material o r ' t r i p h e n y l p h o s p h i n e in the crude product. - 77 -Generation of the y l i d e with dimsyl sodium and subsequent con-densation with acetone provided a c e t a l alkenes 168a,b i n 84% y i e l d from acetal iodide 166a ,b . H y d r o l y s i s o f the a c e t a l mixture provided a mixture of b i c y c l i c ketones e x h i b i t i n g s p e c t r a l p r o p e r t i e s c o n s i s t e n t with the assumption t h a t the mixture c o n s i s t e d o f campherenone 42_ and epicampherenone 45 i n the r a t i o 6:4 as judged by n.m.r. A n a l y s i s o f the mixture by g.l .c. on several d i f f e r e n t columns f a i l e d to separate the product into i t s two components. F o r t u n a t e l y the a c e t a l precursors of 42_ and 45, compounds 168a and b, were separated e a s i l y by pr e p a r a t i v e g.l .c. and two components were i s o l a t e d having r e l a t i v e r e t e n t i o n times of 42 minutes and 47 minutes. The component o f s h o r t e r r e t e n t i o n time was assigned s t r u c t u r e 168a on the b a s i s o f subsequent conversion to (±)-campherenone. Thus removal o f the ethylene a c e t a l from 168a (H +/acetone) provided (±)-campherenone 42_ e x h i b i t i n g s p e c t r a l p r o p e r t i e s ( i n f r a r e d , n.m.r., mass spectrum) (see Figu r e s 1 and 2) i n c l o s e agreement with published v a l u e s (27,28). U n f o r t u n a t e l y we were not able to ob t a i n an authentic sample o f (-)-campherenone 42a f o r d i r e c t comparison (27,28). Acetal 168b upon h y d r o l y s i s a f f o r d e d a product assigned s t r u c t u r e 45_ on the b a s i s o f the mode o f s y n t h e s i s and on s p e c t r a l characteristics (see Fi g u r e s 3 and 4 ) : v 1745, 1412 and 835 cm" 1; max T ( C C l i J 9.13 ( s i x proton s i n g l e t , C 8 and C 1 0 methyl), 8.38 and 8.32 (two broad s i n g l e t s t o t a l i n g s i x protons, and C 1 5 v i n y l methyls) and 4.89 (one proton m u l t i p l e t , o l e f i n i c s i g n a l ) . The n.m.r. s p e c t r a of (±)-campherenone and (±)-epicampherenone as compared to the c o r r e s -ponding spectrum o f camphor i n c a r b o n t e t r a c h l o r i d e and i n benzene are o o o 1 "In 78 -51 Ol o c CU i~ CU o I o N o o £= i~ +-> o CD Q . OO cu s-CD - 80 -U3 31 CU o c cu $-cu - C Q . e <o o •I— CL UJ +1 4-O zn. o o Z5 i-4-> o cu Q . co I - 82 -shown in T a b l e IV. Published values f o r natural (-)-campherenone are shown in p a r e n t h e s i s . F u r t h e r evidence f o r the s t r u c t u r e s o f both 42 and 45_ was o b t a i n e d by various chemical transformations d e s c r i b e d i n a l a t e r s e c t i o n . T h i s work c o n s t i t u t e d the f i r s t t o t a l s y n t h e s i s o f campherenone and provided independent c o n f i r m a t i o n o f the s t r u c t u r e but not the a b s o l u t e c o n f i g u r a t i o n assigned to t h i s compound (108). Campherenone occupies the key p o s i t i o n i n our proposed general s y n t h e t i c route to a group o f b i c y c l i c , t r i c y c l i c , and t e t r a -c y c l i c s e s q u i t e r p e n e s . Having developed an e f f i c i e n t route to campherenone and epicampherenone v i a monocyclic enol d e r i v a t i v e s , we now were ready to t e s t f u r t h e r aspects o f our s y n t h e t i c proposals. Our proposed b i o g e n e t i c scheme presented i n the i n t r o d u c t i o n i n d i c a t e d campherenone and perhaps epicampherenone as p o s s i b l e precursors o f the c o r r e s p o n d i n g iborneol analogues, campherenol and epicampherenol, as w e l l as o f t h e s a n t a l e n e s . Our s y n t h e t i c proposal s t a t e d t h a t an analogous r e l a t i o n s h i p might be e s t a b l i s h e d i n the l a b o r a t o r y . Indeed by simple t r a n s f o r m a t i o n s on campherenone 42 and 45 we have subsequently e s t a b l i s h e d a l t e r n a t e s y n t h e t i c routes to p-santalene 48, e p i - e -s a n t a l e n e 50_ and «-santalene 47 a l l i n good y i e l d . Campherenone 42_ on treatment with sodium/rnpropanol a f f o r d e d , a 7:1 m i x t u r e o f endo a l c o h o l 46a to exo isomer 46b. Isomer 46a has the n a t u r a l l y o c c u r r i n g endo hydroxyl stereochemistry found i n (-)-campherenol which co-occurs with (-)-campherenone (27,28). Reduction o f 42_with 1 i t h i u m trimethyoxyaluminohydride (109) a f f o r d e d isocampherenol 46b. The trimethoxy d e r i v a t i v e o f l i t h i u m aluminum h y d r i d e was chosen i n preference to the parent hydride i n an attempt Table IV: N.M.R. Si g n a l s o f B i c y c l i c Ketones * c8 C 9 C 1 2 , C l i * > C i 5 CC1 4 9.19 9.07 9.18 - -Camphor c6c6 9.40 9.35 9.11 - --- 9.03(9.04) 9.14(9.15) 4.95(4.97) 8.35(8.36),8.39(8.41) Campherenone c6c6 - 9.30(9.33) 9.07(9.10) 4.97(5.02) 8.35(8.38),8.48(8.51) ecu 9.13 - 9.13 4.89 8.32,8.38 Epicempherenone c6c6 9.35 - 9.06 4.83 8.28,8.41 * L i t e r a t u r e values (27,28) i n parentheses. - 85 -to a v o i d formation o f the endo alcohol 46a. Hikino et a l . found t h a t r e d u c t i o n o f campherenone with l i t h i u m aluminum hydride a f f o r d e d isocampherenol and some campherenol (28). Brown and Deck have shown t h a t reduction o f camphor with l i t h i u m aluminum hydride produces a 9:1 mixture o f exo to endo a l c o h o l s while reduction with the trimethoxy d e r i v a t i v e y i e l d s 99% isoborneol (109). The isocampherenol obtained by r e d u c t i o n o f 42 with l i t h i u m trimethoxyaluminohydride was shown to be one component by n.m.r. and g . l . c . a n a l y s i s . S i m i l a r treatment o f epicampherenone 45 a f f o r d e d the corresponding epicampherenols 49a and 49b. C o n s i d e r a t i o n o f the n.m.r. s p e c t r a o f the campherenols 46a and 46b and the epicampherenols 49a and 49b i n carbon t e t r a c h l o r i d e and i n p y r i d i n e (110) i n conjunction with the corresponding spectra of borneol and isoborneol (110-112) a f f i r m e d the s t r u c t u r a l assignments (see Table V). Proton assignments f o r the n.m.r. spectra of borneol and i s o -borneol have been p r e v i o u s l y worked out on the basis of comparison of s p e c t r a o f a l a r g e number o f d e r i v a t i v e s (112) as well as more r e c e n t l y by the use o f p y r i d i n e - i n d u c e d s o l v e n t s h i f t s (110) and s h i f t s produced by rare earth metal complexes (113). ( (±)-Isocampherenol 46b upon heating with p_-toluenesulfonyl c h l o r i d e i n p y r i d i n e provided (±)-3-santalene 48 (30,114) i n 80% over-a l l y i e l d (119). S i m i l a r l y , the treatment o f isoepicampherenol 49b under these r e a c t i o n c o n d i t i o n s provided (±)-epi-3-santalene (30,114). The i d e n t i t y o f s y n t h e t i c e- and epi-B-santalene was e s t a b l i s h e d by comparison o f g . l . c . c h a r a c t e r i s t i c s and s p e c t r a l data ( i n f r a r e d , n.m.r.) with a u t h e n t i c samples (--)-3-santalene and (+)-epi-B-santalene i s o l a t e d from sandalwood o i l (120) and with s y n t h e t i c samples obtained i n our Table V: N.M.R. S i g n a l s of B i c y c l i c A l cohols * c2 c8 C 9 C10 C12 Cli+»Ci 5 Borneol A ** CC1 4 6.08 -.22 9.14 -.01 9.14 -.01 9.17 -.13 - -Isoborneol A ecu 6.49 -.24 8.98 -.26 9.17 -.02 9.11 -.18 -Campherenol Li cci 4 6.00(6.03) -.35 - 9.11 -.05 9.17 -.19 4.94 8.34,8.41 Isocampherenol A ecu 6.46(6.49) -.33 - 9.18 -.08 9.12 -.24 4.92 8.36,8.39 Epicampherenol A ecu 6.06 -.33 9.13 -.06 - 9.18 -.21 4.92 8.33,8.40 Iso-epicampherenol A ecu 6.47 -.29 8.96 -.31 - 9.12 -.24 4.93 8.33,8.39 * L i t e r a t u r e values (27,28) i n parentheses. ** A = T p y r i d i n e - x C C U - 87 -l a b o r a t o r y by an a l t e r n a t i v e route d e s c r i b e d i n a l a t e r s e c t i o n (Figures 11-14). The t r i c y c l i c nucleus o f <=-santalene was generated i n analogy to the c l a s s i c a l conversion o f camphor to t r i c y c l e n e (121). A mixture of campherenone 42_ and epicampherenone 45_ was converted i n high y i e l d to the corresponding hydrazones L59 and 170. When a methanolic s o l u t i o n of hydrazones 169 and 170 was heated with mercuric oxide, (±)-°=-santalene 47 (30, 114) was obtained i n 65% o v e r a l l y i e l d . S y n t h e t i c ( + ) - o c-santalene e x h i b i t e d the same s p e c t r a l and g . l . c . c h a r a c t e r i s t i c s as a u t h e n t i c (+)-<*-santalene (120). The next o b j e c t i v e i n our s y n t h e t i c sequence was the achieve-ment of i n t r a m o l e c u l a r c y c l i z a t i o n o f campherenone, thereby c o n s t r u c t -ing the t r i c y c l i c systems represented by copacamphor 52,ylangocamphor 53 and longicamphor 54. W e s t f e l t and co-workers (33) in a previous study o f 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 o f copaborneol 55a achieved a p a r t i a l s y n t h e s i s of t h i s compound by i n t e r n a l Michael-type c y c l i z a t i o n o f unsaturated keto e s t e r 171 and subsequent t r a n s f o r m a t i o n to 55a. The c y c l i z a t i o n of 171, a compound der i v e d from the n a t u r a l l y o c c u r r i n g mixture o f oc- and g - s a n t a l o l s , i n d i c a t e d t h a t bond formation between C 3 and C 1 2 of the campherenone-type skeleton was indeed f e a s i b l e . In accord with our b i o g e n e t i c hypothesis we i n i t i a l l y considered a c y c l i z a t i o n o f campherenone 42_ i n v o l v i n g the i n t e r a c t i o n o f an enol d e r i v a t i v e such as an enol a c e t a t e , with the o l e f i n i c s i d e chain o f campherenone. In t h i s manner we hoped to generate perhaps a l l three skeletons 52_, 53_ and 54_ i n one r e a c t i o n . The p r e p a r a t i o n o f campherenone enol acetate 51_ (X equals - 89 -OAc) was based on the previous p r e p a r a t i o n o f camphor enol acetate 172. Warnhoff et a l . (122) had shown that treatment o f camphor under various a c i d c a t a l y z e d enol a c e t y l a t i o n c o n d i t i o n s y i e l d e d only s t a r t -ing m a t e r i a l . However the enol acetate could be prepared by generation o f the enolate anion with b u t y l ! i t h i u m followed by O - a l k y l a t i o n with a c e t i c anhydride. Following the procedure de s c r i b e d f o r camphor, campherenone was converted to enol acetate 51_ i n 84% y i e l d as judged by g . l . c . C y c l i z a t i o n of 51_ was attempted using the c o n d i t i o n s (BF 3/CH 2C1 2) p r e v i o u s l y employed i n o t h e r enol acetate c y c l i z a t i o n s . P r e l i m i n a r y a n a l y s i s ( g . l . c . on three d i f f e r e n t columns) i n d i c a t e d the presence o f components i n the mixture of r e t e n t i o n times corresponding to a u t h e n t i c samples o f copacamphor (123) and longicamphor (124) a l b i e t i n low y i e l d . Subsequent work has shown the r e a c t i o n to be of n e g l i -g i b l e s y n t h e t i c value, the major p o r t i o n of product being n o n - v o l a t i l e , p o s s i b l y polymeric m a t e r i a l . No attempt at f u r t h e r c h a r a c t e r i z a t i o n o f the r e a c t i o n products has y e t been made. An a l t e r n a t e route to the p o l y c y c l i c sesquiterpenes 52_, 5_3 and 54_ could i n v o l v e the c y c l i z a t i o n of a s u b s t r a t e such as 173 i n which X and Y equal any o f a number of p o s s i b l e d e r i v a t i v e s o f the double bond i n campherenone. In p r a c t i c e the epoxide (X,Y = - 0 - ) * * The choice o f an epoxide intermediate i s i n keeping with our d e s i r e to u t i l i z e s u b s trates o f p o s s i b l e b i o l o g i c a l analogy and s i g n i f i c a n c e . The importance of epoxides i n terpene b i o s y n t h e s i s (e.g., squalene epoxide) has been discussed elsewhere (125). - 90 -proved a convenient intermediate (126) and could be prepared from the parent ketone with m-chloroperbenzoic a c i d i n benzene a f f o r d i n g d i a s t e r e o m e r i c keto epoxides 173a,b i n good y i e l d . Treatment o f 173a,b with potassium 1>butoxide i n t>butanol a f f o r d e d t r i c y c l i c keto a l c o h o l s 174 and 175_ i n the r a t i o 45:55 ( r e l a t i v e r e t e n t i o n times 5.4 minutes and 6.5 minutes r e s p e c t i v e l y ) . A d i s t i n c t i o n between compounds 174 and 175 could t e n t a t i v e l y be made on the b a s i s o f t h e i r i n f r a r e d and n.m.r. s p e c t r a . A c a r b o n t e t r a c h l o r i d e s o l u t i o n o f compound 175 e x h i b i t e d two absorption bands i n the hydroxyl s t r e t c h region 3620 and 3440 cm" 1, the broad band o f lower energy i n d i c a t i n g hydrogen bonding. D i l u t i o n s t u d i e s on t h i s sample r e s u l t e d i n a r e l a t i v e i n c r e a s e i n i n t e n s i t y o f the 3620 cm"1 band and a corresponding decrease i n the 3440 cm"1 band. Isomeric keto alcohol 174 on the other hand e x h i b i t e d a strong hydrogen bonding band o f moderate width (3490 cm"1) which d i d not s i g n i f i c a n t l y vary i n i n t e n s i t y upon d i l u t i o n . T h i s s p e c t r a l behavior o f the hydroxyl f u n c t i o n o f 174 would be c o n s i s t e n t with i n t r a m o l e c u l a r hydrogen bonding between the hydroxyl group and the nearby ketone f u n c t i o n . Keto a l c o h o l 175 i s s t e r i c a l l y prevented from s i m i l a r i n t r a m o l e c u l a r hydrogen bonding and thus the hydroxyl band a t 3440 cm" 1, r e s u l t i n g from i n t e r m o l e c u l a r hydrogen bonding, decreases upon d i l u t i o n . The n.m.r. spectrum of 174 (CC1 4, 100 MHz) i n d i c a t e d two sharp methyl s i n g l e t s a t 9.10 and 9.08 T due to the Cio and C 9 methyls and two s i n g l e t s 8.95, 8.94 x ( t o t a l i n t e g r a l three protons) and a broadened s i n g l e t 8.76 x (three protons) due to the t e r t i a r y methyls bearing an alpha hydroxyl f u n c t i o n . A broad one proton s i n g l e t at 7.57 x can be assigned to the methine proton alpha to the ketone and a very broad absorption centered at 7.26 x ( h a l f peak width 42 H 173a - 92 -ca. 12 Hz) was shown to be the hydroxyl proton by exchange with deuterium oxide. The n.m.r. ( C C I 4 , 100 MHz) o f compound 175_ e x h i b i t e d two sharp methyl s i n g l e t s a t 9.12 and 9.07 T f o r the CIQ and C 9 methyls and two s l i g h t l y broadened methyl s i g n a l s at 8.87 and 8.80 T due to the t e r t i a r y methyls with adjacent hydroxyl f u n c t i o n . Two methine protons were d i s t i n g u i s h a b l e ; one appeared as a broad s i n g l e t (7.80x, h a l f peak width 4 Hz), while a hydroxyl proton with moderate broadening (half peak width ca. 2 Hz) appeared a t 7.43 T. The one proton s i g n a l at 7.80 T has t e n t a t i v e l y been assigned to the proton alpha to the ketone, which by i n s p e c t i o n o f models would be expected to be a s i n g l e t in a n a l o g y to the corresponding proton i n 174. The other methine s i g n a l (7.70 T.) c o u l d not be assigned with the d e s i r e d degree o f c e r t a i n t y but the low f i e l d p o s i t i o n o f t h i s s i g n a l would not agree with either o f the two remaining methines i n compound 174 and thus f a v o r s s t r u c t u r e 175. The s t r u c t u r a l assignment o f 175 was confirmed by subsequent conversion to copacamphor. Thus dehydration o f keto a l c o h o l 175 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 y i e l d e d a 7:3 mixture o f t r i c y c l i c alkenes 176 and 177 which were separated by p r e p a r a t i v e g . l . c . Other common reagents used in d e h y d r a t i o n o f a l c o h o l s ( f o r example phosphorus o x y c h l o r i d e / p y r i d i n e ; p_-toluensulfonyl c h l o r i d e / p y r i d i n e ; aluminum o x i d e / p y r i d i n e / h e a t ) showed no advantage i n product r a t i o . The two double bond isomers were r e a d i l y d i s t i n g u i s h e d by t h e i r n.m.r. s p e c t r a as 177 e x h i b i t e d no o l e f i n i c s i g n a l s but showed two v i n y l methyls at 8.37 and 8.28 T while 176 d i s p l a y e d a two proton m u l t i p l e t a t ca. 5.17 x and one v i n y l methyl - 94 -a t 8.28 x . Hydrogenation o f 176 using platinum oxide as the source o f c a t a l y s t provided (+)-copacamphor 52 whose g . l . c . and s p e c t r a l charac-t e r i s t i c s were i d e n t i c a l to those o f a u t h e n t i c (+)-copacamphor (32,33, 123) (see F i g u r e s 5 and 6). S i m i l a r dehydration o f 174 provided two isomeric alkenes i n the r a t i o 4:1. The minor product was shown to be i d e n t i c a l ( g . l . c , i n f r a r e d , n.m.r.) to 177 while the major component was assigned s t r u c t u r e 178 i n analogy to 176. Reduction o f 178 a f f o r d e d (±)-ylangocamphor 53_ [ v m a x 1730 cm" 1; n.m.r. (CDC1 3, 100 MHz), x 9.20 (three proton doublet, J = 6.5 Hz, i s o p r o p y l methyl), 9.11 and 9.10 (two s i n g l e t s , t e r t i a r y m ethyls), 9.03 (three proton d o u b l e t , J = 6.5 Hz, i s o p r o p y l methyl) and 7.76 (broad one proton s i n g l e t ) ] . Comparison o f our s p e c t r a (see Figu r e s 7 and 8) with those o f a sample o f (-)-ylangocamphor prepared by an a l t e r n a t e route (127) i n d i c a t e d t h a t the two compounds were i d e n t i c a l . Hydrogenation o f the t e t r a s u b s t i t u t e d double bond isomer 177 a f f o r d e d a 5:1 mixture o f ylangocamphor 53_ and copacamphor 52_. Both terminal alkenes 176 and 178 were isomerized to 177 upon treatment with palladium on carbon i n the presence o f hydrogen (128) thus f u r t h e r e s t a b l i s h i n g the isomeric r e l a t i o n s h i p o f the two s e r i e s o f compounds d e r i v e d from keto a l c o h o l s 174 and 175. No t r a c e o f the p o s s i b l e t h i r d s e r i e s o f products bearing the longicamphane s k e l e t o n was found a t any stage o f t h i s work d e s p i t e c a r e f u l search by g . l . c . and n.m.r. (129). The a v a i l a b i l i t y o f copacamphor and ylangocamphor opened the p o t e n t i a l route to two more sets o f rearrangement products. Copacamphor 52 alr e a d y had been converted to copaborneol 55a, isocopaborneol 55b 95 -cr, i -00 -I CO CM tr>| i . o x: o. <tt o Q . O O I •n o o o S-+-> o CD 00 cu s-— uo VVAVENUM3ER (CM') WAVENUMBER (CM ') Figure 6. I n f r a r e d Spectrum o f (t)-Copacamphor 52 i (Ti I - 97 CO CO s-o CL na a o cn c <a r — r— >-i +1 4 -O o o s-oo a: s-cn * i— Figure 8. I n f r a r e d Spectrum of (±)-Ylangocamphor 53 i CO - 99 -and copacamphene 5_7 by W e s t f e l t and co-workers (32,33). Cyclocopa-camphor* 56_ remains the only member o f t h i s quartet to be i n t e r r e l a t e d to copacamphor. Ylangocamphor and the ylangoborneols were not known p r e v i o u s l y but t h e i r p o t e n t i a l rearrangement products, sativene 60 and c y c l o s a t i v e n e 59_ are n a t u r a l l y o c c u r r i n g m a t e r i a l s (35,36,42) and have been synthesized from other routes (36,130,131). McMurry has shown t h a t i n the presence o f copper(II) acetate and a c e t i c a c i d , sativene 60 e x i s t s i n e q u i l i b r i u m with c y c l o s a t i v e n e 59 and i s o s a t i v e n e 179 (131, c f . 35,42) (see scheme X). While one might have a n t i c i p a t e d that a s i m i l a r e q u i l i b r i u m would i n t e r r e l a t e copacamphene 5_7 with c y c l o -copacamphene 56_, McMurry i n f a c t obtained upon treatment o f copa-camphene under the e q u i l i b r a t i n g c o n d i t i o n s the i d e n t i c a l e q u i l i b r i u m mixture of s a t i v e n e , c y c l o s a t i v e n e and i s o s a t i v e n e as obtained from sativene i t s e l f (126b, 132). Presumably the copacamphene skeleton i n t e r -converts with the more s t a b l e s a t i v e n e skeleton ( e q u a t o r i a l i s o p r o p y l group) through the pathway depicted i n scheme X. For the purpose o f our work we d e s i r e d to complete the transformations of copacamphor by attempting the s y n t h e s i s of c y c l o -copacamphor v i a hydrazone 180 i n analogy to our work i n the santalene s e r i e s . S i m i l a r l y we hoped to e s t a b l i s h the analogous r e l a t i o n s h i p s among ylangocamphor, sativene and c y c l o s a t i v e n e ( v i a 181). Work on these various transformations i s now i n progress i n our l a b o r a t o r y . Thus f a r we have been s u c c e s s f u l i n c o n v e r t i n g ylangocamphor i n t o * This compound i s known both,in nature (34) and through synthesis (56). - 100 -60 - 102 -s a t i v e n e . Treatment o f ylangocamphor 53_ with l i t h i u m aluminum hydride i n ether a f f o r d e d isoylangoborneol 58b: v , 3500 and 1095 cm" 1; J J max T ( C C 1 I J , 9.21 (three proton s i n g l e t , t e r t i a r y methyl), 9.16 (three proton s i n g l e t , t e r t i a r y methyl), 9.08 ( s i x proton doublet, J = 7 Hz) and 6.28 (one proton doublet, J = 7k Hz, methine on carbon bearing hydroxyl f u n c t i o n ) . The s p l i t t i n g p a t t e r n and the c o u p l i n g constant f o r the endo methine proton on the carbon bearing the hydroxyl f u n c t i o n i s i n agreement with the assigned s t r u c t u r e (58). Treatment o f 58b under the usual rearrangement c o n d i t i o n s ( p _ - t o l u e n e s u l f o n y l c h l o r i d e / - 103 -p y r i d i n e ) y i e l d e d o n l y recovered s t a r t i n g m a t e r i a l . In view o f the s t e r i c bulk surrounding the hydroxyl f u n c t i o n o f 58b we considered employing a l e s s s t e r i c a l l y hindered e s t e r i f y i n g agent. Thus when isoylangoborneol was heated with m e t h a n e s u l f o n y l c h l o r i d e i n p y r i d i n e , (+)-sativene was obtained e x h i b i t i n g s p e c t r a l c h a r a c t e r i s t i c s ( i n f r a -r e d , n.m.r.) i n agreement with p u b l i s h e d values (36) (see F i g u r e s 9 and 10). Encouraged by the s u c c e s s f u l achievement o f much o f our i n i t i a l s y n t h e t i c g o a l , we turned our a t t e n t i o n to the more r e f i n e d p o i n t s o f our b i o s y n t h e t i c hypothesis. In p a r t i c u l a r , we were con-cerned with the absolute c o n f i g u r a t i o n s o f several o f the n a t u r a l l y o c c u r r i n g members i n c l u d e d w i t h i n the scope o f our s y n t h e t i c and b i o g e n e t i c schemes (see pages 44, 45 ). We f i r s t c o nsidered the monocyclic substrates which, as we mentioned e a r l i e r , i n the case o f campherenone could p o s s i b l y be dihydrocryptomerion 75 a l o g i c a l r e l a t i v e to the known sesquiterpene cryptomerion 99_ found i n Cryptomerion  j a p o n i c a D. Don (75). The absolute c o n f i g u r a t i o n o f cryptomerion had not been assigned p r e v i o u s l y and p r i o r m u l t i - s t a g e syntheses were o f the racemic form o f the compound (76,77). We f e l t t h a t s i n c e (-)-campherenone had been a s c r i b e d the (+)-camphor c o n f i g u r a t i o n as i n 42a (27,28) i t would be s i g n i f i c a n t to know i f (-)-cryptomerion had the r e l a t e d (-)-carvone c o n f i g u r a t i o n and thus we sought a s t e r e s p e c i f i c route to cryptomerion from (-)-carvone 79a. In the p r e v i o u s l y mentioned work o f Crawford et a l . (97,99) concerning the m e t a l a t i o n o f limonene, i t was shown t h a t a l k y l l i t h i u m 147 r e t a i n e d i t s o p t i c a l p u r i t y i n a l l i t s various r e a c t i o n s . Our I- H -L un - 107 -previous success with metalation o f dihydrocarvone a c e t a l 116 with the 1:1 butyl 1ithium--TMEDA complex l e d us to prepare carvone a c e t a l 182 on from (-)-carvone [(«) - 58.6°)] by r e a c t i o n with 2,2-dimethyl-l ,3-propanediol and o x a l i c a c i d i n benzene i n a Dean-Stark apparatus. The r e a c t i o n was followed by g . l . c . and the r a t i o o f a c e t a l to s t a r t i n g material approached 1:2 r e s p e c t i v e l y a f t e r four days and d i d not change s i g n i f i c a n t l y t h e r e a f t e r . A d d i t i o n o f molecular seives to the s i d e arm o f the Dean-Stark water tr a p as well as other measures f a i l e d to s h i f t the e q u i l i b r i u m f u r t h e r towards product. F o r t u n a t e l y i s o l a t i o n 30 of 182 was simple s i n c e the a c e t a l was a s o l i d [mp 82-82.5°, («) D -71.8°] which e a s i l y c r y s t a l l i z e d from a c o l d dry pentane s o l u t i o n o f the r e a c t i o n product l e a v i n g l a r g e l y s t a r t i n g material i n s o l u t i o n . Treatment o f carvone ac e t a l 182 with one e q u i v a l e n t o f the 1:1 b u t y l -1ithium--TMEDA complex r a p i d l y formed a deep red c o l o r e d s o l u t i o n which p r e c i p i t a t e d a red viscous mass a f t e r one hour standing at room temperature. As i t was not p o s s i b l e to a l k y l a t e the a l k y l l i t h i u m species i n the form produced, the s o l v e n t (hexane from the b u t y l l i t h i u m ) was removed under reduced pressure and t e t r a h y d r o f u r a n was added and immediately upon s o l u t i o n the r e a c t i o n mixture was cooled to -78° and t r e a t e d with l-chloro-3-methyl-2-butene. In c o n t r a s t to the r e a c t i o n o f dihydrocarvone ac e t a l 116 no a l k y l a t e d material was recovered but only s t a r t i n g acetal 182. R e p e t i t i o n o f the above procedure using two equivalents o f the metalating agent a f f o r d e d a f t e r h y d r o l y s i s and d i s t i l l a t i o n a recovery o f about one t h i r d o f the s t a r t i n g (-)-carvone, 31 («) p -58.2°, a low y i e l d o f monoalkylated material and the remainder as l e s s v o l a t i l e products. - 108 -The monoalkylated material c o n s i s t e d o f two products r e l a t i v e r e t e n t i o n times 4.5 minutes and 5.4 minutes i n the approximate r a t i o 1:4 r e s p e c t i v e l y . I s o l a t i o n by p r e p a r a t i v e g . l . c . o f the major mono-a l k y l a t e d product and comparison o f s p e c t r a l c h a r a c t e r i s t i c s ( u l t r a -29 v i o l e t , i n f r a r e d , n.m.r.) and s p e c i f i c r o t a t i o n [(«) D -39.3°] e s t a b l i s h e d the i d e n t i t y o f the product with natural (-)-cryptomerion («) p -38° (75) which now can be assigned s t r u c t u r e 99a. The minor component o f the mixture was assigned s t r u c t u r e 183 on the basis o f the f o l l o w i n g s p e c t r a l c h a r a c t e r i s t i c s : X a v 234 nm (e 7,230); ; . . max vmax 3 1 0 0 ' 1 6 7 5 ' 8 9 2 a n d 8 3 0 c m " 1 ; n- m- r- ( C C I I J . T 8.42 and 8.40 (two v i n y l methyl s i n g l e t s , i s o p r o p y l i d e n e group), 8.23 ( m u l t i p l e t , v i n y l methyl), 5.23 (two proton m u l t i p l e t , terminal o l e f i n ) , 4.98 ( m u l t i p l e t , o l e f i n i c p r o t o n ) , and 3.43 ( m u l t i p l e t , o l e f i n i c proton on beta-carbon o f enone). The a l l y l i c rearrangement product 184 analogous to compound 150 obtained by Crawford et a l . (97,99) from the a l k y l a t i o n o f limonene was not found among the r e a c t i o n products, again a t t e s t i n g to the absence o f a l l y l i c rearrangement i n l-ch1oro-3-methyl-2-butene. Vig and co-workers had p r e v i o u s l y reported the conversion o f dihydrocryptomerion 75 to cryptomerion 9 £ through the intermediacy o f the bromo ketone. Using phenyltrimethylammoniumtribromide (PTT) (134) as the brominating reagent and e f f e c t i n g dehydrobromination by r e f l u x i n g the crude bromide i n p y r i d i n e , the o v e r a l l conversion v/as report e d to proceed i n 92% y i e l d (76). Though we had e s t a b l i s h e d the absolute c o n f i g u r a t i o n o f (-)-cryptomerion through the a l k y l a t i o n o f a c e t a l 182, our i n t e r e s t i n f u r t h e r transformations on t h i s com-pound prompted us to repeat Vig's conversion using the more r e a d i l y - 109 -a v a i l a b l e o p t i c a l l y a c t i v e dihydrocryptomerion 75a from our previous 29 study o f metalated ac e t a l 145. In t h i s way (-)-cryptomerion [ ( o c ) Q -37°] was obtained i n good y i e l d . While the above s y n t h e s i s o f (-)-cryptomerion was in progress, 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 o f (+)-delobanone 185, i s o l a t e d from Lindera t r i l o b a S i e b , et Zucc. Blume, was p u b l i s h e d , based on s p e c t r a l and chemical evidence (135). In the process o f s t r u c t u r e i l l u c i d a t i o n (+)-delobanone was dehydrated to (+)-crypto-23 merion [(«) n +21.4°] assigned s t r u c t u r e 99b which i s i n accord with - no -our work e s t a b l i s h i n g 99a as (-)-cryptomerion. Delobanone would be an e q u a l l y s u i t a b l e monocyclic precursor of campherenone i n terms o f our b i o s y n t h e t i c proposal and thus both antipodal forms o f the proposed monocyclic su b s t r a t e occur i n nature. During our work with cryptomerion we n o t i c e d that a sample l e f t standing on the bench several days showed s i g n i f i c a n t changes i n the i n f r a r e d spectrum. In p a r t i c u l a r , a new absorbance i n the carbonyl region (1735 cm" 1) appeared at the expense of the 1670 cm"1 a b s o r p t i o n . We were aware of e a r l i e r work i n v o l v i n g the p h o t o c y c l i z a t i o n o f carvone 79 to carvonecamphor 186 (136-139) and o f i s o p i p e r i t e n o n e 187 to compound 188 (140,141). In view o f the analogy among the s t r u c t u r e s o f cryptomerion, 79 and 187, we considered t h a t s i m i l a r photo-tr a n s f o r m a t i o n might be o c c u r r i n g with cryptomerion. Indeed, when (-)-cryptomerion 99a, (°0 p -39°, was photolyzed three days i n ethanol s o l u t i o n using an o r d i n a r y sunlamp with a f i l t e r which e s s e n t i a l l y e l i m i n a t e d l i g h t o f wave length s h o r t e r than 340 nm ( c f . reference 138), two compounds were present i n the p h o t o l y s i s mixture i n the r e l a t i v e r a t i o of 73:27 with r e l a t i v e r e t e n t i o n times 3.9 minutes and 5.4 minutes r e s p e c t i v e l y . The component o f g r e a t e r r e t e n t i o n time was i s o l a t e d by p r e p a r a t i v e g . l . c . and shown to be s t a r t i n g material 99a. The major component ( r e t e n t i o n time 3.9 minutes) proved unstable to the pre-p a r a t i v e g . l . c . c o n d i t i o n s (SE-30, 240°) though a pure sample [ ( a ) -41°] was obtained by column chromatography and e x h i b i t e d the f o l l o w i n g s p e c t r a l c h a r a c t e r i s t i c s : v , v 1735, 1410, and 835 cm l\ max T( C C1 4) 8.93 (sharp methyl s i n g l e t ) , 8.40 and 8.32 (two v i n y l methyls) and 4.96 ( o l e f i n i c proton). The replacement of the enone carbonyl by - 112 -a s t r a i n e d s a t u r a t e d carbonyl (1735 cm" 1) was h i g h l y i n d i c a t i v e t h a t c y c l i z a t i o n had occurred. The f a c t that the t r i s u b s t i t u t e d double bond remained i n t a c t was evidenced by the n.m.r. absorptions f o r v i n y l methyls and the o l e f i n i c proton. The above s p e c t r a l evidence plus the analogy with s i m i l a r p h o t o c y c l i z a t i o n s a l l p o i n t to s t r u c t u r e 189 and t h i s assignment was f u r t h e r corroborated by high r e s o l u t i o n mass s p e c t r a l a n a l y s i s . We propose the name (-)-photocryptomerion f o r t h i s photoproduct and note t h a t i t s formation i s analogous to the conversion o f carvone 79_ to carvonecamphor 186. At the o u t s e t o f our work the absolute c o n f i g u r a t i o n o f (-)-campherenone 42_ and (-)-campherenol 46_ had been proposed on the ba s i s o f o p t i c a l r o t a t o r y d i s p e r s i o n and c i r c u l a r d i c h r o i s m s t u d i e s u s i n g (+)-camphor as a model. The c o n f i g u r a t i o n o f campherenone and thus o f 46_ (which had been converted to 42_), was s t a t e d to be the same as (+)-camphor (see s t r u c t u r e s 42a and 46a) on the grounds o f s i m i l a r p o s i t i v e Cotton e f f e c t s . T h i s c o n f i g u r a t i o n a l assignment was p a r t i -c u l a r l y d i s c o n c e r t i n g to us from the standpoint t h a t (+)-(°0-santalene or 47a [(«) D +11.1°], known by t o t a l s y n t h e s i s to have the absolute 26 c o n f i g u r a t i o n shown [(«) D +18.4°] (44), was i d e n t i f i e d i n the same pl a n t system i n which campherenone occurs (60). Our b i o s y n t h e t i c p o s t u l a t e and indeed a l l previous p o s t u l a t e s (see f o r example references 6 and 28) were d i r e c t l y c o n t r a d i c t e d by t h i s f i n d i n g , as campherenone and the santalenes were presumably d e r i v e d from a common intermediate. Therefore i n order to place our proposals on a c r e d i b l e f o o t i n g i t became necessary to r e i n v e s t i g a t e the absolute c o n f i g u r a t i o n o f campherenone. At the same time we were i n t e r e s t e d i n e s t a b l i s h i n g the - 114 -absolute c o n f i g u r a t i o n s o f n a t u r a l 3-santalene and epi-3-santalene which had not p r e v i o u s l y been assigned on a r i g o r o u s b a s i s . W e s t f e l t e t a l . had p r e v i o u s l y prepared keto e s t e r 171 i n apparently good o p t i c a l p u r i t y from a s t a r t i n g mixture o f «-,3- and (presumably) e p i - 3 - s a n t a l o l s through f o r m o l y s i s o f the corresponding «,B — u n s a t u r a t e d e s t e r s 190, 191 and 192 7 (33). A f t e r h y d r o l y s i s and o x i d a t i o n , keto e s t e r s 171 and 193 were obtained (the presence ' " o f 193 i n the r e a c t i o n mixture was given as evidence f o r e p i - p - s a n t a l o l 194 i n the o r i g i n a l s a n t a l o l m i x t u r e ) . One might expect t h a t f o r m o l y s i s o f the corresponding hydrocarbon o=-santalene 47a would provide a pos-s i b l e route to o p t i c a l l y a c t i v e ketone 42b with absolute c o n f i g u r a t i o n known from t h a t o f (+)-o=-santalene (45). U n f o r t u n a t e l y W e s t f e l t ' s f o r m o l y s i s c o n d i t i o n s , when a p p l i e d to a mixture o f <*-,3 and epi-3-santalene ( r e l a t i v e r a t i o 4.3:1.0:3.0 r e s p e c t i v e l y ) , a f f o r d e d one major product (71% by g . l . c . ) which was not the d e s i r e d f o r m o l y s i s product. The absence o f a carbonyl absorption i n the i n f r a r e d spectrum i n d i c a t e d t h a t the d e s i r e d formate e s t e r ( s ) had not been formed. The appearance o f a new a b s o r p t i o n band a t 797 cm" 1, r e p l a c i n g the absorption bands due to the t r i s u b s t i t u t e d double bonds, the terminal o l e f i n s and the cyclopropane r i n g protons o f the s t a r t i n g hydrocarbon mixture (ca. 800 to 900 cm" 1) suggested t h a t double bond i n t e r a c t i o n had occur-red. The n.m.r. spectrum ( C C U ) confirmed t h i s assumption showing only one o l e f i n i c p r o t o n , a well d e f i n e d t r i p l e t a t 4.68 T (J = 2 Hz), which was coupled to an i s o l a t e d a l l y l i c methylene group (7.97 x , two proton doublet, sharp, J = 2 Hz), a s i x hydrogen s i n g l e t at 9.05 x and a s i x hydrogen doublet (J = 7 Hz) a t 8.96 x , i n d i c a t e d the presence o f f o u r s a t u r a t e d methyl groups. S t r u c t u r e s 195, 196 and 197 a l l appear to - 116 -be i n reasonable agreement with s p e c t r a l evidence and no c l e a r d i s -t i n c t i o n among the three has y e t been made. An a l t e r n a t e s y n t h e t i c route to o p t i c a l l y a c t i v e campherenone 42 and epicampherenone 45_ was s t i m u l a t e d by a r e c e n t l y reported s y n t h e s i s (117) o f epi- e-santalene 50_ and ^-santalene 47 i n which i o d i d e s 198 and 199 r e s p e c t i v e l y were coupled with the n i c k e l ( I ) complex from 1-bromo-3-methyl-2-butene i n d i c a t e d by s t r u c t u r e 200. No data v/as given as to the o p t i c a l a c t i v i t y o f e i t h e r product so produced. We f e l t that an analogous r e a c t i o n with i o d i d e 201 might give access to o p t i c a l l y pure epicampherenone which i n turn could be transformed i n t o e p i - e - s a n t a l e n e . The same r e a c t i o n on the d i s a s t e r e o m e r i c i o d i d e 202 would provide a route to campherenone and subsequently B-santalene. In f a c t , both the c o u p l i n g r e a c t i o n s and the subsequent transformations proved s u c c e s f u l . The known bromo a c e t a l 206 (142) was chosen as the source o f i o d i d e 201. Thus commerically a v a i l a b l e (+)-3-bromocamphor 203 was converted to 3,9-dibromocamphor 204 by treatment with c h l o r o s u l f o n i c a c i d and bromine (45). Reduction with z i n c and hydrogen bromide y i e l d e d (+)-9-bromocamphor 205 (45). This sequence o f r e a c t i o n s has p r e v i o u s l y been shown to t r a n s p i r e with f u l l r e t e n t i o n of absolute c o n f i g -u r a t i o n , w hile i n c o n t r a s t , 9-bromination o f camphor i t s e l f a f f o r d s p a r t i a l l y racemized 9-bromocamphor (143,144). Treatment o f 205 with ethylene g l y c o l and p_-toluenesul f o n i c a c i d i n benzene provided bromo ac e t a l 206 (142). Reaction of 206 with sodium i o d i d e i n acetone a f f o r d e d only 12% o f the d e s i r e d i o d i d e 201 a f t e r four days r e f l u x i n g . A much more e f f i c i e n t conversion ( 83%) to the i o d i d e was obtained when 206 was heated with sodium i o d i d e i n dimethyl s u l f o x i d e (145). - 118 -H i e n i c k e l complex r e q u i r e d f o r the c o u p l i n g r e a c t i o n with 201 had been prepared p r e v i o u s l y by Corey et a l . (117) through a procedure i n v o l v i n g low temperature r e c r y s t a l l i z a t i o n o f the a i r and heat s e n s i t i v e n i c k e l compound. Sato and co-workers (146) r e c e n t l y r e p o r t e d s a t i s f a c t o r y p r e p a r a t i o n and use o f the complex with e l i m i n a t i o n o f t h i s d i f f i c u l t r e c r y s t a l l i z a t i o n step and we chose t h i s modified r o u t e . Thus a c e t a l i o d i d e 201 was t r e a t e d with e i g h t e q u i v a l e n t s o f the n i c k e l complex a t 50° o v e r n i g h t a f f o r d i n g epicampherenone a c e t a l 168b and some o f the corresponding ketone 45a i n good y i e l d . The keto i o d i d e d e r i v e d from 201 r e q u i r e d c o n s i d e r a b l y longer r e a c t i o n time than i o d i d e 20"!. The need f o r a l a r g e excess o f the complex was probably due to decomposition o f the t h e r m a l l y s e n s i t i v e reagent. However, at lower temperatures [e.g., 22° as d e s c r i b e d by Corey e t a l . (117)] the r e a c t i o n f a i l e d to proceed. P u r i f i c a t i o n by p r e p a r a t i v e g . l . c . provided (+)-epicampherenone 45a [ ( a ) n +84.6°] i d e n t i c a l ( i n f r a r e d , n.m.r., g . l . c . ) e x c e p t i n r o t a t i o n with our p r e v i o u s l y synthesized (±)-epi-campherenone (108). The c i r c u l a r d i c h r o i s m spectrum o f 45a e x h i b i t e d a s t r o n g p o s i t i v e cotton e f f e c t a t 298 nm [ ( e ) = 4.2 X 101*] and a s t r o n g e r n e g a t i v e curve a t higher energy [ ( e ) ^ = ~2-2 x I O 4 ] . The s t r o n g p o s i t i v e c o t t o n e f f e c t a t the n -- ir* t r a n s i t i o n i s i n accord w i t h (+)-camphor and apparently with a l a r g e number o f known 9 - p o s i t i o n s u b s t i t u t e d (+)-camphor d e r i v a t i v e s (147). Reduction o f (+)-epicampherenone with l i t h i u m trimethoxy-alumi no h y d r i d e a f f o r d e d (+)-isoepicampherenol which was t r e a t e d with t o s y l c h l o r i d e i n p y r i d i n e at 95° o v e r n i g h t y i e l d e d (+)-epi-B-santalene, («) p +26.9° , (see Figures 11 and 12) i n agreement with the natural on isomer, («) Z +23.3°, i s o l a t e d i n our l a b o r a t o r y from Mysore o i l (120). cn U -- 122 -Thus (+)-epi-g~santalene has the absolute c o n f i g u r a t i o n shown i n 50a and i s c o n f i g u r a t i o n a l l y r e l a t e d to (+)-cc-santalene 47a by formal cleavage of the bond between carbon atoms a and b of the cyclopropane r i n g i n 47a. The p r e p a r a t i o n of o p t i c a l l y a c t i v e campherenone r e q u i r e d p r e p a r a t i o n o f intermediate a c e t a l i o d i d e 202 and the route chosen to t h i s compound was based on two previous s y n t h e t i c endeavours. Corey et a l . (145) had prepared lactone 212 by rearrangement of the hydroxy a c i d 211 derived from 9-bromocamphor, however, no data on o p t i c a l a c t i v i t y was given. Rodig et a l . (148) had prepared (±)-lactone 212 by another route and subsequently transformed i t i n t o (±)-keto i o d i d e 216. We f e l t t h a t combination of the two routes could produce the d e s i r e d o p t i c a l l y a c t i v e keto i o d i d e 216 i f the formation of lactone 212 proceeded with f u l l r e t e n t i o n of c o n f i g u r a t i o n . A c e t o l y s i s of 9-bromocamphor 205 a f f o r d e d (+)-9-acetoxycamphor 208 which was hydrolyzed to (+)-9-hydroxycamphor 20£ (149,145). Oxida-t i o n o f 209 by the procedure of Corey et a l . (145) provided (+)-trans-i s o k e t o p i n i c a c i d 2^0 («) j j 2 +1.4° [ l i t . («) 2 7 +3.2° (150)]. Reduction with sodium borohydride and l a c t o n i z a t i o n i n r e f l u x i n g t r i f l u o r o a c e t i c a c i d - s u l f u r i c a c i d (145) provided lactone 21_2 with mp 199-200°, 30 (oc) D -60.7°, which disagrees with material prepared by another route [mp 191°; (oc) J 7 -117.9°] s t a r t i n g from t e r e s a n t a l o l (151). Lactone 212 was converted to c r y s t a l l i n e d i o l 213 by r e d u c t i o n with l i t h i u m aluminum hydride f o l l o w i n g the procedure of Rodig (148). S e l e c t i v e monotosylation with one mole of p_-toluenesulfonyl c h l o r i d e (-10°) followed by o x i d a t i o n of the crude product 214_ (144,148) a f f o r d e d - 124 -k e t o t c s y l a t e 21_5 as an o i l which c r y s t a l l i z e d a f t e r standing two weeks a t -10°. Treatment of 21_5 with sodium i o d i d e i n dimethyl s u l f o x i d e a f f o r d e d (-)-8-iodocamphor 21_6, mp 40-41°, (°0 3 2 -92.1° [ l i t . (±) mp 40-42° (148)]. F i n a l l y , treatment o f keto i o d i d e 21_6 with ethylene g l y c o l and p_-toluenesulfonic a c i d a f f o r d e d the d e s i r e d a c e t a l 202 i n good y i e l d . Hydrogenolysis of keto i o d i d e 216 with palladium on carbon provided (-)-camphor, («0 3 2- 44.8° [ l i t . («) 1 6 - 4 3 . 6 ° (152)]. Reaction of a c e t a l i o d i d e * 20_2 with the n i c k e l complex 200, as p r e v i o u s l y d e s c r i b e d , a f f o r d e d campherenone ac e t a l which was p u r i f i e d 33 by d i s t i l l a t i o n and hydrolyzed, p r o v i d i n g (-)-campherenone, («) p -33.6° [ l i t . («) p -33.0° (27,28)]. The c i r c u l a r d ichroism spectrum of our product ([©] -370) d i d not agree with the published value [ [ e ] ^ + 600 (28)J f o r (-)-campherenone. This anomally between our data and t h a t of the natural campherenone makes assignment of absolute c o n f i g u r a -t i o n to the natural product impossible at present. I t would appear t h a t the p h y s i c a l constants f o r the natural m a t e r i a l need r e i n v e s t i g a -t i o n and we are c u r r e n t l y attempting to obtain a sample of natural campherenone f o r t h i s purpose. Reduction of (-)-campherenone with l i t h i u m trimethoxyalumino-hydride a f f o r d e d (+)-isocampherenol (+)-46b which upon heating with * Attempts to transform 216 d i r e c t l y to campherenone by r e a c t i o n with 200 under analogous c o n d i t i o n s l e d to consumption of 216 but pro-d u c t i o n of no d e t e c t a b l e amount of campherenone. (+)- 46b 48a - 126 -p_-toluenesulfonyl c h l o r i d e i n pyridene provided ( - ) - B - s a n t a l e n e , 33 (.«) D - 112°, i d e n t i c a l i n s p e c t r a l data (see Figures 13 and 14) and 28 s i g n o f r o t a t i o n with natural e-santalene [(<*) D -102°] i s o l a t e d from Mysore sandlewood o i l (120). The absolute c o n f i g u r a t i o n of (-)-B-santalene must be as shown i n 48a thus r e l a t i n g ( - ) - B - s a n t a l e n e with (+ ) -oc-.- Santalene 47a through formal cleavage between carbon atoms a and c i n 47a. g-Santalene of undetermined s p e c i f i c r o t a t i o n has been reported to co-occur with (+)-<*-santalene i n the same p l a n t species i n which "(-)-campherenone" i s found (60). T h i s m a t e r i a l i s probably (-)-3-santalene i n agreement with our b i o s y n t h e t i c p o s t u l a t e . Establishment of the absolute c o n f i g u r a t i o n of campherenone, epicampherenone and the corresponding 3- and epi-3-santalenes f o r m a l l y concluded the i n i t i a l goals o f t h i s s y n t h e t i c i n v e s t i g a t i o n i n t o p o s s i b l e b i o g e n e t i c routes to monoterpenes and sesquiterpenes bearing the bicyclo(2.2.1)heptane framework. We have demonstrated the s y n t h e t i c u t i l i t y o f enol d e r i v a t i v e s i n d i r e c t i n g and promoting c y c l i z a t i o n of monocyclic cyclohexenyl substrates to f u n c t i o n a l i z e d camphor d e r i v a t i v e s . Furthermore, t h i s work e s t a b l i s h e d the f e a s i b i l i t y of preparing many p o l y c y c l i c sesquiterpenes u t i l i z i n g campherenone as a key intermediate or synthon. F i n a l l y , having shown the chemical f e a s i b i l i t y of our b i o -g e n e t i c p o s t u l a t e , we have used our p o s t u l a t e to p r e d i c t the absolute stereochemical r e l a t i o n s h i p s of various sesquiterpene f a m i l i e s or "q u a r t e t s " r e s u l t i n g i n our current r e i n v e s t i g a t i o n of the absolute c o n f i g u r a t i o n s o f c e r t a i n known sesquiterpenes. While our o r i g i n a l goals f o r t h i s p r o j e c t have been achieved, the p o t e n t i a l s of our s y n t h e t i c approach have by no means been exhausted. In f a c t , as our work progressed i t became apparent t h a t a much broader, - 129 -much more g e n e r a l s y n t h e t i c and p o s s i b l y b i o g e n e t i c r e l a t i o n s h i p l a y b e f o r e us and t h a t we had only tapped one p o r t i o n o f the p o t e n t i a l r e s o u r c e s . The u t i l i z a t i o n o f campherenone as a key intermediate i n th e p r e p a r a t i o n o f more complex p o l y c y c l i c skeletons has proven to be a p a r t i c u l a r l y rewarding approach. An extension of t h i s approach would be the i n t r a m o l e c u l a r c y c l i z a t i o n o f s u b s t r a t e 217 which should be r e a d i l y o b t a i n a b l e from campherenone. I f s u c c e s s f u l , t h i s c y c l i z a -t i o n would gen e r a t e the longicamphane skeleton p r o v i d i n g a simple r o u t e t o longicamphor 54_, l o n g i b o r n e o l s 61a,b , l o n g i c y c l e n e 62 and l o n g i f o l e n e 63. Ox i d a t i o n o f longicamphor i n analogy to the known o x i d a t i o n o f camphor (12) might open a route to culmorin 218 (58). S i m i l a r o x i d a t i v e f u n c t i o n a l i z a t i o n o f ylangocamphor 53 f o l l o w e d by rearrangement to the s a t i v e n e - l i k e skeleton 219 could p r o v i d e a s u i t a b l e s u b s t r a t e f o r cleavage to helminthosporal 220 i n analogy w i t h the proposed b i o s y n t h e s i s (153). B a e y e r - V i l l i g e r oxida-t i v e c l e a v a g e o f the copacamphor s k e l e t o n to 221 would generate the b a s i c s k e l e t o n o f the l a r g e group o f picrotoxane sesquiterpenes i n c l u d i n g a l k a l o i d s such as dendrobine 222 and h i g h l y oxygenated s e s q u i t e r p e n e s such as t u t i n 223. B i o s y n t h e t i c p o s t u l a t e s (6,154) and l a b e l l i n g s t u d i e s (155-158) have i m p l i c a t e d an analogous cleavage i n c the b i o s y n t h e s i s o f both 222 and 223 and the recent s p e c i f i c incorpo-r a t i o n o f t h e t r i t i u m l a b e l l e d copaborneol 58* i n t o 223 (159) confirms t h i s r o u t e . The s y n t h e s i s o f o p t i c a l l y a c t i v e campherenone now makes p o s s i b l e the s y n t h e s i s o f o p t i c a l l y a c t i v e members (both antipodes) o f the copacamphor and ylangocamphor s e r i e s . I f the s y n t h e s i s of l o n g i -camphor i s a c h i e v e d from a campherenone d e r i v a t i v e , then i t may be - 130 -220 - 131 -p o s s i b l e to prepare every member of both antipodal quartets f o r camphere-none 42_, epicampherenone 45_, copacamphor 52_, ylangocamphor 53_ and longicamphor 54 s t a r t i n g from e i t h e r (+)- or (-)- campherenone. A f u r t h e r extension o f t h i s work would be the m o d i f i c a t i o n of our c y c l i z a t i o n r e a c t i o n so as to allow the formation of compounds bearing the bicyclo(3.1.1)heptane s k e l e t o n . We have p r e v i o u s l y generated the bicyclo(4.1.0)heptane ( f o r example 33 and 34_) and the b i c y c l o ( 2 . 2 . 1 ) -heptane r i n g systems using s u i t a b l e enol (enolate) d e r i v a t i v e s . C y c l i z a -t i o n of a s u b s t r a t e such as 224, i s o p i p e r i t e n o n e enol d e r i v a t i v e , to verbenone 225_ (12) or a s i m i l a r c y c l i z a t i o n of 226 to compound 2Z7 (160) would complete the p o s s i b l e modes of c y c l i z a t i o n of cyclohexenyl sub-s t r a t e s and provide a new route to a h i g h l y i n t e r e s t i n g group of mono-terpenes and sesquiterpenes. Whether or not f u t u r e i n v e s t i g a t i o n s prove our b i o g e n e t i c p o s t u l a t e to be c o r r e c t , the success of our s y n t h e t i c s t u d i e s a t t e s t s to the r i c h n e s s of chemical information that awaits d i s c o v e r y through c o n s i d e r a t i o n and experimental a p p l i c a t i o n of p o s s i b l e b i o s y n t h e t i c processes to the s y n t h e s i s of natural products. Through b i o g e n e t i c patterned s y n t h e t i c s t u d i e s such as these we can perhaps unlock some o f the f a s c i n a t i n g s e c r e t s surrounding enzyme mediated r e a c t i o n s and thus g r e a t l y broaden our s y n t h e s i s c a p a b i l i t i e s i n the l a b o r a t o r y . EXPERIMENTAL Unless otherwise noted the f o l l o w i n g are implied. Melting p o i n t s , which were determined on a K o f l e r apparatus, and b o i l i n g points are uncorrected. G a s - l i q u i d chromatography ( g . l . c . ) was c a r r i e d out on e i t h e r a Varian Aerograph, model 90-P, or an Aerograph Autoprep, model 700. The f o l l o w i n g columns were employed: Column Length " S t a t i o n a r y Phase Support Mesh A 10 f t . x 1/4 i n . 3% SE 30 Varoport 30 100/120 B " 5% QF 1 Chromosorb W 60/80 C " 10% FFAP D " 10% Carbowax E " 20% DEGS F 10 f t . x 3/8 i n . 30% FFAP G 20 f t . x 3/8 i n . 30% SE 30 " 45/60 H " 30% QF 1 C a r r i e r gas (helium) flow-rate f o r 1/4 i n columns was 60 ml/min. and f o r 3/8 i n columns was 170 ml/min. O p t i c a l r o t a t i o n s were measured with e i t h e r a Perkin-Elmer model 141 polarimeter o r a Rudolph po l a r i m e t e r . C i r c u l a r d i c h r o i s m spectra were recorded on a JASC0 J-20 spectro-polarimeter. U l t r a v i o l e t spectra were recorded on a Unicam model - 134 -S.P. 800 spectrophotometer i n methanol s o l u t i o n . Routine i n f r a r e d s p e c t r a were recorded on a Perkin-Elmer I n f r a c o r d model 137 spectro-photometer; comparison s p e c t r a were recorded on Perkin-Elmer model 21 o r model 457 spectrophotometer. The 60 MHz n u c l e a r magnetic resonance (n.m.r.) spectra were recorded on Varian A s s o c i a t e s model A-60 or model T-60 while 100 MHz spectra were recorded on Varian A s s o c i a t e s model HA-100 or model XL-100. Signal p o s i t i o n s are given i n the T i e r s tau s c a l e with t e t r a m e t h y l s i l a n e as an i n t e r n a l r e ference. Signal m u l t i -p l i c i t y and i n t e g r a t e d area as well as proton assignments are i n d i c a t e d i n parentheses. Mass spectra were recorded on an A t l a s model CH-4 or on an AEI model MS-9 mass spectrometer. High r e s o l u t i o n mass sp e c t r a were determined on the AEI model MS-9 instrument. 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 o f B r i t i s h Columbia, Vancouver. Solvents employed were o f e i t h e r Reagent grade or C e r t i f i e d grade. The term "petroleum ether" w i l l r e f e r to the low b o i l i n g f r a c t i o n o f C e r t i f i e d grade petroleum d i s t i l l a t e (bp ca. 30-60°). Dry solvents or reagents, where i n d i c a t e d , were prepared as f o l l o w s : benzene, e t h e r , pentane or petroleum ether by storage over sodium followed by d i s t i l -l a t i o n ; acetone, dimethylformamide or d i m e t h y l s u l f o x i d e by storage over molecular seives type 4A; p y r i d i n e by storage over potassium hydroxide p e l l e t s ; and t e t r a h y d r o f u r a n by d i s t i l l a t i o n from l i t h i u m aluminum hydride. A d d i t i o n a l p u r i f i c a t i o n of d i m e t h y l s u l f i d e was e f f e c t e d by d i s t i l l a t i o n and of t h i o n y l c h l o r i d e by d i s t i l l a t i o n from t r i p h e n y l phosphite. - 135 -Prepa r a t i o n o f Dihydrocarvone 76a,b To a 3 l i t e r three neck f l a s k f i t t e d with dropping funnel and r e f l u x condenser was added 250 g (3.83 mole) z i n c powder, 100 g (1.78 mole) potassium hydroxide, 1000 ml 95% ethanol and 400 ml water. The mixture was heated to r e f l u x with vigorous s t i r r i n g and 203 g (1.35 mole) 1-carvone [ A l d r i c h , («) p° -58.6° (c 4.78, CHC1 3)] d i s s o l v e d i n 400 ml 95% ethanol was added dropwise over a p e r i o d o f 6 hours. Reflux was continued f o r 1 hour a t which t i m e r t h e r e d u c t i o n was determined complete as judged by the disappearance o f the absorp-t i o n a t 234 nm i n the u l t r a v i o l e t spectrum o f an a l i q u o t . A f t e r c o o l i n g and f i l t e r i n g through a Buchner f u n n e l , the s o l v e n t was removed under reduced pressure and the residue was e x t r a c t e d with three 250 ml por t i o n s o f petroleum ether. The orga n i c l a y e r s were washed f i r s t with water, then with d i l u t e a c e t i c a c i d u n t i l the aqueous l a y e r t e s t e d neutral to wide range pH t e s t paper, and f i n a l l y again with water. Drying over anhydrous sodium s u l f a t e followed by s o l v e n t removal and d i s t i l l a t i o n a f f o r d e d 178 g (87%) dihydrocarvone 76a,b as a mixture o f epimers at C i i n the r a t i o 1:3 ci s - 1 , 4 to trans-1,4 as judged by n.m.r.: bp 80° (6 mm) [ l i t . bp 100-104° (17mm)(161)]; homogeneous by g . l . c . ?9 (column A, 150°); (°0 p +18.3° (c 10.4, CHC1 3) [ i n another preparation using Wallach's procedure (62) the dihydrocarvone e x h i b i t e d a r o t a t i o n o f +12° i n d i c a t i n g a d i f f e r e n t r a t i o o f the epimers]; u l t r a v i o l e t , X 284 nm (e 30); i n f r a r e d ( n e a t ) , v 3100, 1710, 1650 and 892 cm""1; max max n.m.r. (CC1 4), T 9.04 and 8.99 (two doublets, r e l a t i v e area 76:24 r e s p e c t i v e l y , 3H, J = 6.0 Hz and 6.5 Hz r e s p e c t i v e l y , epimeric secondary methyls), 8.27 ( m u l t i p l e t , 3H,.vinyl methyl), and 5.29 ( m u l t i p l e t , 2H =CH 2). - 136 -I s o l a t i o n o f Michael A d d i t i o n Product 82 The residue remaining from d i s t i l l a t i o n o f dihydrocarvone 76_ i n the above r e a c t i o n was t r i t u r a t e d with petroleum ether and s t o r e d at -10°. F i l t r a t i o n and r e c r y s t a l l i z a t i o n o f the crude product from petroleum ether-methylene c h l o r i d e (80:1) provided 0.37 g (< 0.2%) o f c o l o r l e s s c r y s t a l s [other preparations f o l l o w i n g Wallach's procedure (62) produced from 5 to 10% of t h i s m a t e r i a l ] : mp 153-154° [ l i t . mp 148-149° ( 6 2 ) ] ; u l t r a v i o l e t (95% e t h a n o l ) , X a v 288 nm ( e 90); i n f r a -max red (KBr), v m a x 3090, 1705, 1650 and 892 cm" 1; n.m.r. (CDC1 3), T9.03 (doublet, 6H, J = 6.5 Hz, secondary methyls), 8.22 ( m u l t i p l e t , 6H, v i n y l methyls) and 5.18 ( m u l t i p l e t , 4H, two =CH2 groups); mass spectrum, m/e ( r e l a t i v e i n t e n s i t y ) , 302 (100, M +), 259 (81.2), 151 (52.5), 109 (36.9), 97 (25.0) and 55 (30.0). Preparation of Enol Acetates 80a and 84 Dihydrocarvone (6.00 g, 0.039 mole) was heated with 15 ml isopropenyl acetate and 100 mg p_-toluenesulfonic a c i d monohydrate 30 hours with slow d i s t i l l a t i o n o f the acetone generated. The r e a c t i o n mixture was c o o l e d , d i l u t e d with petroleum ether, washed with saturated sodium bicarbonate, with water and twice with s a t u r a t e d sodium c h l o r i d e and then d r i e d over anhydrous sodium s u l f a t e . Solvent removal under reduced pressure followed by d i s t i l l a t i o n y i e l d e d 7.20 g (94%) o f a mixture of enol acetates 8J_and 80a: bp 41-44° (0.02 mm); two com-ponents by g . l . c . a n a l y s i s (column A, 140°) i n the r a t i o 29:71 f o r - 137 -compounds 84 and 80a r e s p e c t i v e l y ( r e l a t i v e r e t e n t i o n times 3.0 minutes and 3.7 minutes r e s p e c t i v e l y ) . (In another p r e p a r a t i o n the r a t i o o f compounds 84_ and 80a was 1:4.) Pure samples of 84_ and 80a were obtained by p r e p a r a t i v e g . l . c . (column G, 175°) followed by evaporative d i s t i l -l a t i o n . Enol acetate 84_ e x h i b i t e d the f o l l o w i n g c h a r a c t e r i s t i c s : («) p 8 +90.5° (c 2.56, CHC1 3); i n f r a r e d ( n e a t ) , v m a x 3090, 1745, 1680, 1645, 1210 and 890 cm" 1; n.m.r. (CC 1 4 ) , T 9.04 (doublet, 3H, J = 6.5 Hz, secondary methyl), 8.26 ( m u l t i p l e t , 3H, v i n y l methyl), 7.93 ( s i n g l e t , sharp, 3H, acetate methyl), 5.23 ( m u l t i p l e t , 2H, =CH2 ) and 4.86 ( m u l t i -p l e t , 1H, o l e f i n i c proton); mass spectrum, m/e ( r e l a t i v e i n t e n s i t y ) , 194 (5.5, M +), 152 (90.4), 137 (79.4), 109 (35.2), 95 (35.8), 43 (100) and 41 (51.5). Enol acetate 80a showed the f o l l o w i n g c h a r a c t e r i s t i c s : p E po np- 1.4757; («) J ° +81.1° (c 2.46 CHC1 3)(another p r e p a r a t i o n gave a +77° r o t a t i o n ) ; i n f r a r e d ( n e a t ) , v m 3 V 3090, 1745, 1705, 1645, 1210 and max 888 cm" 1; n.m.r. (C C1 4), T 8.51 ( s i n g l e t , broad 3H, methyl on enol acetate double bond), 8.26 ( m u l t i p l e t , 3H, v i n y l methyl), 7.95 ( s i n g l e t , sharp, 3H, acetate methyl) and 5.26 ( m u l t i p l e t , 2H, =CH 2); mass spectrum, m/e ( r e l a t i v e i n t e n s i t y ) , 194 (5.1, M +), 152 (67.0), 109 (100), 84 (37.3), 43 (72.9), and 41 (51.7). C y c l i z a t i o n o f Enol Acetate 80a po A s o l u t i o n o f 203 mg (1.04m mole) enol acetate 80a, («) ~J +77°, i n 200 mis methylene c h l o r i d e (Baker reagent grade, 0.012% water) was - 138 -s a t u r a t e d with boron t r i f l u o r i d e gas by r a p i d bubbling o f the gas i n t o the v i g o r o u s l y s t i r r e d enol acetate s o l u t i o n . A f t e r 10 minutes the r e a c t i o n was quenched by shaking with 50 ml saturated sodium bicarbonate and the organic phase was washed twice with water and d r i e d over anhydrous sodium s u l f a t e . Solvent removal a f f o r d e d a f a i n t l y yellow residue which became c r y s t a l l i n e when cooled to -10°. Sublimation (50°, 14mm) a f f o r d e d 103 mg (64%) (±)-camphor 17_: («) 2 3 0° (c 1.96, 95% EtOH); u l t r a v i o l e t , x 3 v 288 nm (e 36); i n f r a r e d ( C C K ) , v 1740, max max 1422 and 1050 cm" 1, e n t i r e spectrum superimposable on spectrum o f a u t h e n t i c (±)-camphor; n.m.r. (C C l t J T9.17 ( s i n g l e t , 3H, C 8 t e r t i a r y methyl), 9.15 ( s i n g l e t , 3H, C 1 0 t e r t i a r y methyl) and 9.04 ( s i n g l e t , 3H, C 9 t e r t i a r y methyl); (C 6H 6) T 9.41 ( s i n g l e t , 3H, C 8 t e r t i a r y methyl), 9.37 ( s i n g l e t , 3H, C 9 t e r t i a r y methyl) and 9.10 ( s i n g l e t , 3H, C 1 0 t e r t i a r y methyl), e n t i r e spectrum i n both s o l v e n t systems superimposable on spectrum o f a u t h e n t i c (±)-camphor. In other c y c l i z a t i o n s higher y i e l d s were obtained by pre-s a t u r a t i o n of the s o l v e n t with boron t r i f l u o r i d e . Thus to 50 mis of methylene c h l o r i d e s a t u r a t e d with boron t r i f l u o r i d e gas was added a s o l u t i o n o f 100 mg (0.51 m mole) enol acetate 80a i n 50 ml methylene c h l o r i d e in p o r t i o n s over a period o f 4 minutes and the r e a c t i o n was continued 10 minutes. Uork-up as above a f f o r d e d a c o l o r l e s s product which was estimated to be 90% camphor by g . l . c . a n a l y s i s (column F, 170°). Higher concentrations o f 80a l e d to reduced y i e l d s of camphor. Thus 335 mg (1.7 m mole) 80a in 50 ml methylene c h l o r i d e was t r e a t e d 1 hour with boron t r i f l u o r i d e gas followed by the usual work-up a f f o r d -- 139 -ing 300 mg crude product. The product c o n s i s t e d o f at l e a s t ten components by g . l . c . a n a l y s i s and the three major components were i s o l a t e d by p r e p a r a t i v e g . l . c . (column F, 170°) having r e t e n t i o n times o f 10, 25 and 29 minutes. The component o f r e t e n t i o n time 10 minutes (10%) was i d e n t i f i e d as camphor 17_ by i n f r a r e d and n.m.r. sp e c t r a and by i t s mass spectrum (M +, m/e 150) as compared to the corresponding s p e c t r a o f a u t h e n t i c (±)-camphor. Component 85 (carvenone) o f r e t e n t i o n time 25 minutes (35%) e x h i b i t e d the f o l l o w i n g data: u l t r a v i o l e t , X 234 nm (e 13,200); 3 max v ' i n f r a r e d ( n e a t ) , v a v 1670, 1210 and 880 cm" 1; n.m.r. ( C C 1 J 8.95 (doublet, max 3H, J = 6.5 Hz, v i n y l methyl), 8.89 (doublet, 6H, J = 6.5 Hz, two secondary methyls) and 4.27 ( s i n g l e t , IH, o l e f i n i c proton).(162a,b, 163). Component 86 with r e t e n t i o n time 29 minutes (39%) showed the f o l l o w i n g s p e c t r a l data: u l t r a v i o l e t , end a b s o r p t i o n ; i n f r a r e d ( n e a t ) , v _ 1745, 1210, 840 and 805 cm" 1; n.m.r. ( C C 1 J T 8.97 (doublet, 6H, max J = 6.5 Hz, secondary methyls), 8.50 ( s i n g l e t , broad, 3H, v i n y l methyl), 7.92 ( s i n g l e t , 3H S a c e t a t e methyl), 7.72 ( m u l t i p l e t , IH, methine proton), 7.32 ( s i n g l e t , broad, 4H, two a l l y l i c methylene groups) and 4.65 ( s i n g l e t , IH, o l e f i n i c proton). Employment of s c r u p u l o u s l y dry methylene c h l o r i d e ( d i s t i l l e d from phosphorus pentoxide) i n the c y c l i z a t i o n o f enol acetate 80a l e d to a mixture o f products c o n t a i n i n g only a t r a c e amount of camphor as judged by g . l . c . a n a l y s i s . Attempted Racemization o f (+)-Camphor (+)-Camphor, (<*) n +46.4°, commercial grade was used without - 140 -f u r t h e r p u r i f i c a t i o n . A s o l u t i o n o f 152 mg (+)-camphor i n 150 ml methylene c h l o r i d e was s a t u r a t e d with boron t r i f l u o r i d e gas, stoppered and allowed to stand 4 hours at room temperature. The mixture was washed with saturated sodium bicarbonate and two times with 1 water and then d r i e d over anhydrous sodium s u l f a t e . Solvent removal followed by two sublimations (50°, 0.15 mm) a f f o r d e d (+)-camphor (-) 2 5 +43.6° (c 1.52, 95% EtOH) [ l i t . («) 2 0 +44.3° (95% Et0H)(164)]. Another sample o f (+)-camphor (200 mg i n 200 ml methylene c h l o r i d e ) was t r e a t e d as above except that the p e r i o d o f exposure to boron t r i f l u o r i d e was extended to 66 hours. Two sublimations a f f o r d e d (+)-camphor («) 2 5 +43.4° (c 5.23, 95% EtOH). Treatment of Dihydrocarvone With Boron T r i f l u o r i d e OA Dihydrocarvone 76a,b (100 mg, 0.66 m mole) [(«) J +12° (c 2.70, 95% EtOH)] i n 50 ml methylene c h l o r i d e was added over 3.5 minutes to 50 ml o f v i g o r o u s l y s t i r r e d methylene c h l o r i d e s a t u r a t e d with boron t r i f l u o r i d e gas. A f t e r 10 minutes s t i r r i n g the s o l u t i o n was washed with s a t u r a t e d sodium bicarbonate and twice with water and d r i e d over anhydrous sodium s u l f a t e . G.l.c. a n a l y s i s (column F, 170°) i n d i c a t e d t hat the product c o n s i s t e d of three major components with r e l a t i v e r e t e n t i o n times o f 13, 20 and 25 minutes. Component 89_ o f r e t e n t i o n time 13 minutes e x h i b i t e d the f o l l o w i n g s p e c t r a l data: u l t r a v i o l e t , end a b s o r p t i o n ; i n f r a r e d ( n e a t ) , v 1710 and 805 cm"1; n.m.r. ( C C l J , x 8.96 (doublet, 9H, J = 6.5 Hz, - 141 -three secondary methyls), 7.26 ( s i n g l e t , broad, 2H, a l l y l i c methylene adjacent to ketone) and 4.46 ( s i n g l e t , broad, 1H, o l e f i n i c p r o t o n ) ; ( C 6 H 6 ) , x 9.18 (doublet, 6H, J = 5Hz, two secondary methyls) and 9.01 (doublet, 3H, J = 5 Hz, secondary methyl). The component o f r e t e n t i o n time 20 minutes d i d not appear pure on s p e c t r a l a n a l y s i s but was assigned a t e n t a t i v e s t r u c t u r e c o r r e s -ponding to a double bond isomer of dihydrocarvone (with an i s o p r o p y l i d e n e group) based on the f o l l o w i n g evidence: i n f r a r e d ( n e a t ) , v a v 1705 cm" 1; max n.m.r. (CC1 H) 8.97 (doublet, 3H, J = 6 Hz, secondary methyl) and 8.32 ( s i n g l e t , broad, 6H, v i n y l methyls). Component 85 o f r e t e n t i o n time 25 minutes e x h i b i t e d s p e c t r a l p r o p e r t i e s ( u l t r a v i o l e t , i n f r a r e d , n.m.r.) i n agreement with those found f o r carvenone 85 produced i n the c y c l i z a t i o n o f enol acetate 80a 24 and was shown to have a p o s i t i v e s p e c i f i c r o t a t i o n : (°=) ^  +67° (c 2.94, 95% EtOH). Attempted C y c l i z a t i o n o f Enol Acetate 84 Enol acetate 84 (19 mg, 0.098 m mole) i n 9 ml methylene c h l o r i d e was added at room temperature to 10 ml of methylene chl o r i d e , s a t u r a t e d with boron t r i f l u o r i d e gas, with s t i r r i n g . A slow stream o f the gas was maintained through the s o l u t i o n f o r 10 minutes. The s o l u t i o n was washed with 5 ml sa t u r a t e d sodium bicarbonate and twice with water and then d r i e d over anhydrous sodium s u l f a t e . Solvent removal a f f o r d e d a nearly pure material (93% by g . l . c ; column F, 170°, r e t e n t i o n time 25 minutes), e x h i b i t i n g s p e c t r a l c h a r a c t e r i s t i c s ( u l t r a v i o l e t , i n f r a r e d ) i n agreement - 142 -with those found f o r carvenone 85 i s o l a t e d i n the c y c l i z a t i o n o f enol a c e t a t e 80a. Preparation of Dihydrocarvone Ethylene Acetal 108 A mixture o f 15.0 g (0.986 mole), dihydrocarvone 76a,b, 25 ml ethylene g l y c o l and 500 mg o x a l i c a c i d i n 300 ml benzene was heated to r e f l u x temperature i n a Dean-Stark apparatus and r e f l u x e d 20 hours using " D r i e r i t e " i n the s i d e arm to a i d i n water removal. The r e a c t i o n mixture was cooled, the s o l v e n t removed under reduced pressure and the residue was e x t r a c t e d with petroleum ether. Washing o f the e x t r a c t with s a t u r a t e d sodium bicarbonate and saturated sodium c h l o r i d e s o l u t i o n f o llowed by d r y i n g over sodium s u l f a t e and s o l v e n t removal provided a c o l o r l e s s o i l . D i s t i l l a t i o n y i e l d e d 18.8 g (97%) a c e t a l 108: bp 52° (0.25 mm); n 2 5 1.4749; («) 2 4 -7.5° (c 10.2, CHC1 3) [ l i t . bp 69-71° (1.0 mm; n 2 2 1.4737; («) 2 4 -6.1° (c 3.3, CHC1 3)(79)]; i n f r a r e d ( n e a t ) , v m a v 3100, 1650, 1170, 1090 and 889 cm' 1; n.m.r. ( C C 1 J , x 9.18 (doublet, If lO A broad, 3H, J = 5.5 Hz, secondary methyl), 8.30 ( m u l t i p l e t , 3H, v i n y l methyl), 6.15 and 6.12 (two s i n g l e t s , 4H, -0CH 2CH 20-) and 5.33 ( s i n g l e t , broad, 2H, =CH 2). (162a, 79) Preparation o f Keto Acetal 109 A s o l u t i o n o f 15.0 g (0.076 mole) of dihydrocarvone a c e t a l 108 i n 400 ml methanol cooled i n a dry i c e -- acetone bath was t r e a t e d with a stream of ozone i n t r a i n e d i n oxygen u n t i l the blue c o l o r o f ozone - 143 -i n s o l u t i o n p e r s i s t e d . Excess ozone was removed by bubbling n i t r o g e n i n t o the s o l u t i o n (-70°) u n t i l the s o l u t i o n became c o l o r l e s s . Reductive v/ork-up was e f f e c t e d by a d d i t i o n o f 15 ml (0.13 mole) o f dimethyl-s u l f i d e to the s o l u t i o n , s t i l l maintained a t low temperature, f o l l o w e d by slow warming to room temperature o v e r n i g h t . Excess dimethyl s u l f i d e was removed by bubbling n i t r o g e n through the s o l u t i o n ( i n fume hood). The s o l v e n t was removed under reduced pressure and the residue d i l u t e d w i t h petroleum e t h e r , washed with water and s a t u r a t e d sodium c h l o r i d e s o l u t i o n and d r i e d over anhydrous sodium s u l f a t e . S olvent removal and vacuum d i s t i l l a t i o n a f f o r d e d 14.7 g (97%) keto-acetal 109 as a c o l o r -l e s s o i l : bp 78° (0.2 mm); n 2 5 1.4708; (*) 2 4 -18.0° (c 12.5, CHC1 3); u l t r a v i o l e t , A m w 280 nm (e 34); i n f r a r e d ( n e a t ) , v m a v 1710, 1170 and ma x max 1090 cm" 1; n.m.r. ( C C l i J , T 9.18 (doublet, 3H, J = 6 Hz, secondary methyl), 7.92 ( s i n g l e t , sharp, 3H, methyl adjacent ketone) and 6.07 ( s i n g l e t , broad 4H, -0CH 2CH 20-); mass spectrum, m/e ( r e l a t i v e i n t e n s i t y ) , 198 (3.6, M +), 155 (100), 113 (27.2), 99 (16.8), 55 (13.2) and 43 (19.8). Anal. C alcd. f o r C n H 1 8 0 3 : C, 66.64; H, 9.15. Found: C, 66.74; H, 9.27. -< P r e p a r a t i o n o f A c e t a l A c i d HQ. A s o l u t i o n o f potassium h y p o c h l o r i t e was prepared (165) by d i s s o l v i n g 30.0 g c a l c i u m h y p o c h l o r i t e ( F i s h e r C e r t i f i e d , 72.7% a v a i l -a b le c h l o r i n e ) i n 120 ml warm water and adding a s o l u t i o n o f 21.0 g potassium carbonate and 6.00 g potassium hydroxide i n 60 ml warm water to form a s l u r r y o f calcium carbonate p r e c i p i t a t e i n the sodium hypo-- 144 -c h l o r i t e s o l u t i o n . S u c t i o n f i l t r a t i o n followed by washing of the f i l t e r pad with 25 ml water and combining o f f i l t r a t e s provided a c l e a r pale green s o l u t i o n o f the oxidant. Keto acetal 109 (12.0 g, 6.06 mole) was added to the v i g o r o u s l y s t i r r e d h y p o c h l o r i t e s o l u t i o n at such a ra t e as to maintain the r e a c t i o n temperature between 55 and 60°. S t i r r i n g was continued f o r 3 hours a t room temperature a f t e r which time the excess sodium h y p o c h l o r i t e was destroyed by a d d i t i o n o f a 20% s o l u t i o n o f sodium m e t a b i s u l f i t e u n t i l the aqueous r e a c t i o n mixture no longer c o l o r i z e d s t a r c h and potassium i o d i d e t e s t paper (ca. 20 ml). A f t e r washing with petroleum ether and c o o l i n g to 5° i n an i c e bath, the s o l u t i o n o f crude a c i d s a l t was a c i d i f i e ' d to pH 5 by dropwise a d d i t i o n o f 12 N h y d r o c h l o r i c a c i d . The p r e c i p i t a t e d a c i d was f i l t e r e d c o l d y i e l d i n g 6.97 g o f white s o l i d . R e c r y s t a l l i z a t i o n from 9:1 petroleum e t h e r - e t h e r y i e l d e d 6.29 g (52%) o f the d e s i r e d product 110, mp 71-74°. An a n a l y t i c a l sample r e c r y s t a l 1 i z e d from petroleum ether e x h i b i t e d the f o l l o w i n g : mp 73-75.5°; (cc) 2 5 _ 3 1 > 1 o ( c 9 A 3 i C H C l 3 ) . u l t r a v i o l e t , X m a x 212 nm (e 75); i n f r a r e d ( C C 1 H ) , v m a x 3300-3000 (shoulder) and 2650, 1700, 1170 and 1090 cm" 1; n.m.r. ( C C l i J , T 9.08 (doublet, broad, 3H, J = 6 Hz, secondary methyl), 6.05 ( s i n g l e t , 4H, -0CH 2CH 20-) and -1.09 ( s i n g l e t , broad, 1H, -C0 2H); mass spectrum, m/e ( r e l a t i v e i n t e n s i t y ) , 200 (22.1, M +), 155 (100), 113 (77.4), 69 (36.8), 55 (47.9) and 41 (62.9). Anal. Calcd. f o r C^H^O^: C, 59.98; H, 8.05. Found: C, 60.16; H, 7.92. - 145 -Preparation o f 2-Methyl-5-bromo-2-pentene Magnesium turn i n g s (5.00 g, 0.206 mole, f r e s h l y ground with mortar and p e s t l e ) were covered with 15 ml anhydrous ether and t r e a t e d with 29.2 g (0.206 mole) methyl i o d i d e i n 60 ml anhydrous ether at s u f f i c i e n t r a t e to maintain r e f l u x (ca. 30 min). Reflux was continued f o r 30 minutes a f t e r completion o f the a d d i t i o n . To the r e s u l t i n g Grignard s o l u t i o n was added with vigorous s t i r r i n g a s o l u t i o n o f 15.0 g (0.178 mole) c y c l o p r o p y l methyl ketone 112 in 90 ml anhydrous ether maintaining r e f l u x temperature by the r a t e of a d d i t i o n (ca. 30 min). The r e s u l t i n g s l u r r y was r e f l u x e d f o r an a d d i t i o n a l 1 hour period a f t e r which time the excess Grignard reagent was destroyed by the a d d i t i o n o f s a t u r a t e d ammonium c h l o r i d e s o l u t i o n . The product was decanted and e x t r a c t e d with ether while the remaining s o l i d was d i s s o l v e d i n water by the a d d i t i o n of 6N h y d r o c h l o r i c a c i d and was e x t r a c t e d with ether. Combined ether e x t r a c t s were washed with s a t u r a t e d sodium c h l o r i d e and d r i e d over anhydrous sodium s u l f a t e . Solvent removal provided the crude dimethyl c y c l o p r o p y l c a r b i n o l which was used without f u r t h e r p u r i f i c a t i o n : i n f r a r e d ( n e a t ) , v m a x 3400, 3100, 1150, 845 and 825 cm"1. The e n t i r e product was cooled in an i c e bath and t r e a t e d over a p e r i o d o f 2 minutes with 60 ml o f 48% hydrobromic a c i d ( c h i l l e d i n an i c e bath) i n 10 ml p o r t i o n s with vigorous shaking and frequent c o o l i n g i n i c e . The o r g a n i c l a y e r was separated and the aqueous phase e x t r a c t e d with petroleum ether. The combined org a n i c l a y e r s were washed with s a t u r a t e d sodium c h l o r i d e , saturated sodium bicarbonate and three times with sat u r a t e d sodium c h l o r i d e and then d r i e d over anhydrous sodium s u l f a t e . S olvent removal under reduced pressure followed by vacuum d i s t i l l a t i o n - 146 -a f f o r d e d 18.0 g (62% based on s t a r t i n g ketone) o f bromide 113: bp 58-60° (25 mm) [ l i t . bp 84-85° (84 mm)(82)]; homogeneous by g . l . c . a n a l y s i s (column A, 125°); i n f r a r e d ( n e a t ) , v m 3 V 835 cm"1 and no max a b s o r p t i o n f o r hydroxyl; n.m.r. ( C C l i J , 8.36 and 8.30 (two s i n g l e t s , broad, 6H, v i n y l methyls), 7.49 ( q u a r t e t , broad, 2H, J = 7 Hz, ^C=CHCH 2), 6.73 ( t r i p l e t , 2H, J = 7 Hz, -CH 2Br) and 4.89 ( m u l t i p l e t , IH, o l e f i n i c p r o ton). Preparation o f Keto Acetal 1Q6_ Acetal a c i d 110_ (6.00 g, 0.0300 mole) i n 10 ml benzene at r e f l u x temperature (dry n i t r o g e n atmosphere) was t r e a t e d with 6.00 ml 0.070 mole) o x a l y l c h l o r i d e and r e f l u x e d 30 minutes. Excess o x a l y l c h l o r i d e was removed on the r o t a r y evaporator (with " D r i e r i t e " guard tube to prevent entrance of moisture) by a d d i t i o n and evaporation o f small p o r t i o n s of dry benzene and f i n a l l y one p o r t i o n o f anhydrous ether. The crude a c i d c h l o r i d e 111 was used without f u r t h e r p u r i f i c a -t i o n : i n f r a r e d ( n e a t ) , v 1790, 1170 and 1090 cm"1 (no absorption f o r max v r hydroxyl). The Grignard reagent 114 o f 2-methyl-5-bromo-2-pentene was prepared by dropwise a d d i t i o n of 5.87 g (0.036 mole) o f the bromide 113 i n 40 ml anhydrous ether to 900 mg (0.037 mole) magnesium tu r n i n g s covered with 20 ml anhydrous ether maintained at r e f l u x temperature with a dry n i t r o g e n atmosphere. Refluxing was continued 1 hour a f t e r completion o f a d d i t i o n and the r e a c t i o n mixture was cooled and t r a n s -f e r r e d under nitrogen to a dropping f u n n e l . Crude a c i d c h l o r i d e 111 - 147 -prepared above (0.03 mole) i n 25 ml anhydrous e t h e r was t r e a t e d i n the presence o f 200 mg cuprous c h l o r i d e (0-5°, dry n i t r o g e n atmosphere, v i g o r o u s s t i r r i n g ) with the Grignard s o l u t i o n dropwise over 1 hour. The r e s u l t i n g s l u r r y was allowed to s t i r o v e r n i g h t a t room temperature. Aqueous b i c a r b o n a t e was added to hydrolyze remaining a c i d c h l o r i d e and the e n t i r e m i x t u r e , aqueous and o r g a n i c , was f i l t e r e d through a Buchner f u n n e l . F o l l o w i n g s e p a r a t i o n o f the o r g a n i c phase, the aqueous l a y e r ' was f u r t h e r e x t r a c t e d with ether and the combined org a n i c phases were washed w i t h water and d r i e d over anhydrous sodium s u l f a t e f o r 1 hour. S o l v e n t removal y i e l d e d 7.70 g crude product which was immediately d i s t i l l e d under reduced pressure p r o v i d i n g 6.15 g (77% based on s t a r t -i n g a c i d ) keto a c e t a l 106: bp 103-104° (0.03 mm); n p° 1.4852 [ l i t . bp 180 - 1 8 5 ° (7 mm); n jj0 1.4682 ( 7 7 ) ] ; (°=) 2 5 -13.9° (c 10.6 CHC1 3); u l t r a v i o l e t , i „ 285 nm ( E 58); i n f r a r e d ( n e a t ) , v 1705, 1170, 1090 max max and 835 cm" 1; n.m.r. ( C C 1 4 ) , T 9.18 (doub l e t , broad, 3H, J = 6 Hz, secondary m e t h y l ) , 8.35 ( m u l t i p l e t , broad 6H, v i n y l m ethyls), 6.09 ( s i n g l e t , 4 H , -0CH 2CH 20-) and 4.98 ( m u l t i p l e t , 1H, o l e f i n i c p roton); mass spectrum, m/e ( r e l a t i v e i n t e n s i t y ) , 266 (42.8, M +), 155 (97.4), 69 ( 8 4 . 2 ) , 55 (100), 43 (92.3), and 42 (81.3). (162a, 77) c A n a l . C a l c d . f o r C 1 6 H 2 6 0 3 : C, 72.14; H, 9.84. Found: C, 72.18; H, 9.93. P r e p a r a t i o n o f Dihydrocryptomerion Ethylene A c e t a l 107_ Sodium hydride (0.806 g, 50% o i l d i s p e r s i o n , 0.0168 mole) i n a flame d r i e d f l a s k (dry n i t r o g e n atmosphere) was washed with a small - 148 -p o r t i o n o f anhydrous ether and then heated with 5 ml dry dimethyl -s u l f o x i d e in a 70° o i l bath u n t i l l i b e r a t i o n o f hydrogen ceased: The r e s u l t i n g s o l u t i o n o f dimsyl sodium was cooled i n an i c e bath and 6.00 g (0.0168 mole) methyltriphenylphosphonium bromide i n 10 ml dimethyl-s u l f o x i d e was added slowly a f t e r which the l i g h t y e l low s o l u t i o n o f y l i d e was allowed to warm to room temperature. Keto a c e t a l 106 (3.01 g, 0.0113 mole) i n 10 ml dry t e t r a h y d r o f u r a n was added a f t e r the y l i d e had s t i r r e d 5 minutes at room temperature and the r e s u l t i n g l i g h t brown s o l u t i o n was s t i r r e d 24 hours. The r e a c t i o n mixture was e x t r a c t e d with three 70 ml portions o f petroleum e t h e r , washing each with dimethyl-s u l f o x i d e , twice with water and f i n a l l y with saturated sodium c h l o r i d e s o l u t i o n . The dimethyl s u l f o x i d e l a y e r s were combined, d i l u t e d with water and e x t r a c t e d with a f u r t h e r 70 ml p o r t i o n of petroleum e t h e r , washing as before, and the combined organic phases were d r i e d over sodium s u l f a t e . Concentration followed by column chromatography over 20 g o f alumina, e l u t i n g with petroleum ether, provided 2.45 g (82%) o f a c e t a l diene 107: homogeneous by g . l . c . a n a l y s i s (column A, 200°); i n f r a r e d ( n e a t ) , v a w 3090, 1645, 1170, 1090, 890 and 830 cm" 1; n.m.r. max ( C C 1 J , T 9.17 (doublet, broad, 3H, J = 6 Hz, secondary methyl), 8.38 and 8.32 ( s i n g l e t s , o v e r l a p p i n g , 6H, v i n y l methyls), 4.10 ( s i n g l e t , 4H, -0CH 2CH 20-), 5.33 ( s i n g l e t , broad, 2H, =CH2) and 4.94 ( m u l t i p l e t , IH, o l e f i n i c proton). (162a, 77) Preparation o f Dihydrocryptomerion 75. Acetal diene 107 prepared i n the manner d e s c r i b e d above but - 149 -from 2.66 g(0.0T00 mole) o f keto a c e t a l 106 was hydrolyzed d i r e c t l y i n 100 ml acetone with 3 ml 6N h y d r o c h l o r i c a c i d added and the r e a c t i o n was quenched a f t e r 4 hours by the a d d i t i o n o f s a t u r a t e d bicarbonate s o l u t i o n and subsequent e v a p o r a t i o n o f s o l v e n t . The r e s i d u e was taken up i n petroleum e t h e r , washed with water and d r i e d over sodium s u l f a t e . C oncentration provided 2.14 g crude ketone which was d i s t i l l e d under reduced pressure p r o v i d i n g 1.82 g (83% from keto a c e t a l 106) dihydro- ' cryptomerion: bp 80-82° (0.04 mm) [ l i t . bp 135-138° (5 mm)(77)]; i n f r a r e d ( n e a t ) , v „ 3100, 1710, 1650, 892 and 835 cm" 1; n.m.r. ( C C 1 4 ) , max T 9.02 and 8.97 (two d o u b l e t s , 3H, J = 6.0 Hz and 6.5 Hz r e s p e c t i v e l y , epimeric secondary methyls), 8.38 and 8.32 (two s i n g l e t s , broad, 6H, v i n y l methyls), 5.23 ( s i n g l e t , broad, 2H, =CH 2) and 4.96 ( m u l t i p l e t , broad, 1H, o l e f i n i c p r o t o n ) . (162a, 77) Preparation o f Dihydrocryptomerion Enol Acetate 95b_ Dihydrocryptomerion 75_ (1.2g, 5.5m mole) and p_-toluenesulfonic a c i d monohydrate (60 mg) i n 20 ml isopropenyl acetate were heated 24 hours with slow d i s t i l l a t i o n o f v o l a t i l e m a t e r i a l s . A f t e r washing with s a t u r a t e d sodium bicarbonate and d r y i n g over anhydrous sodium s u l f a t e , the crude product was chromatographed over 35 g aluminum oxide a f f o r d -ing 1.3 g o f a mixture o f enol a c e t a t e s 115 and 95b. Pure samples o f 115 and 95b were obtained by p r e p a r a t i v e g . l . c . (column G, 250°) r e l a t i v e r e t e n t i o n times 58 minutes and 66 minutes r e s p e c t i v e l y ( r a t i o 1:3) followed by e v a p o r a t i v e d i s t i l l a t i o n . - 150 -Compound 115 was i d e n t i f i e d by the f o l l o w i n g c h a r a c t e r i s t i c s : i n f r a r e d ( n e a t ) , v m a x 3090, 1750, 1680, 1645, 1210, 895 and 830 cm" 1; n.m.r. (CC 1 4 ) , T 9.03 (doublet, 3H, J = 7 Hz, secondary methyl), 8.39 and 8.33 (two broadened s i n g l e t s , 6H, v i n y l methyls), 7.92 ( s i n g l e t , 3H, acetate methyl), 5.17 ( m u l t i p l e t , 2H, =CH2) and 4.87 ( m u l t i p l e t , 2H, o l e f i n i c p r o t o n s ) ; mass spectrum m/e ( r e l a t i v e i n t e n s i t y ) , 262 (0.6, M +), 220 (96.9), 151 (99.9), 109 (61.4), 107 (6.13) and 69 (100). Compound 95b showed the f o l l o w i n g : i n f r a r e d ( n e a t ) , v m a x 3100, 1750, 1715, 1645, 1210, 890 and 830 cm" 1; n.m.r. ( C C l J , T 9.18 ( s i n g l e t , broad, 3H, methyl on enol acetate double bond), 8.41 and 8.34 (two broadened s i n g l e t s , 6H, v i n y l methyls), 7.96 ( s i n g l e t , 3H, acetate methyl), 5.23 ( m u l t i p l e t , 2H, =CH2) and 4.92 ( m u l t i p l e t , 1H, o l e f i n i c proton); mass spectrum, m/e ( r e l a t i v e i n t e n s i t y ) , 262 (20.1, M +), 220 (100), 202 (68.8), 151 (70.7), 135 (65.0) and 109 (69.4). Anal. Calcd. f o r C 1 7 H 2 6 0 2 : C, 77.81; H, 9.98. Found: C, 78.00; H, 10.11. C y c l i z a t i o n o f Dihydrocryptomerion Enol Acetate 95b (89) To 1500 ml wet methylene c h l o r i d e saturated with boron t r i -f l u o r i d e gas was added a s o l u t i o n o f 5.4g (0.02 mole) enol acetate 95b i n 500 ml methylene c h l o r i d e over a perio d o f 30 minutes ( r e a c t i o n was vi g o r o u s l y s t i r r e d and a slow stream o f boron t r i f l u o r i d e was maintained). A f t e r two hours s t i r r i n g the r e a c t i o n mixture was n e u t r a l i z e d with saturated sodium bicarbonate, washed twice with water and d r i e d over anhydrous sodium s u l f a t e . Solvent removal a f f o r d e d 4.4g crude product which was chromatographed over s i l i c a gel and d i s t i l l e d . G.l.c. a n a l y s i s (column B, 155°) i n d i c a t e d that the d i s t i l l a t e contained three main com-- 151 -ponents A, B_ and C_ with r e t e n t i o n times o f 3.8, 5.6 and 7.5 minutes r e s p e c t i v e l y . Separation by p r e p a r a t i v e g . l . c . (column G, 240°) a f f o r d e d pure samples o f the three major components. Component A (119a,b) (25-30%) e x h i b i t e d the f o l l o w i n g s p e c t r a l c h a r a c t e r i s t i c s : i n f r a r e d ( n e a t ) , v a v 1740 and 1410 cm" 1; n.m.r. ( C C 1 J , max T 9.19 ( s i n g l e t , 3H, t e r t i a r y methyl), 9.10, 9.05, 9.00 and 8.94 (four s i n g l e t s , 6H, diastereomeric t e r t i a r y methyls); mass spectrum, m/e ( r e l a t i v e i n t e n s i t y ) , 220 (22.5), 105 (68.4), 77 (100), 69 (31.6), 53 (34.9) and 43 (34.6). Component B_ (5%) showed the ensuing data: i n f r a r e d ( n e a t ) , vmax 1 7 1 5 a n d 1 4 0 4 c m _ 1 ' n-m-r- ( C C"U)> T 9- 2 2 (doublet, broad, 3H, J = 5 Hz, secondary methyl), 9.07 ( s i n g l e t , 3H, t e r t i a r y methyl), 9.03 ( s i n g l e t , 3H, t e r t i a r y methyl) and 8.55 (broad s i n g l e t , 6 or 7 H, h a l f peak with 7 Hz); mass spectrum, m/e ( r e l a t i v e i n t e n s i t y ) , 220 (22.5), 111 (68.9), 110 (100), 109 (94.1), 69 (81.3) and 43 (67.3). Component C (121 ) (40-45%) was i d e n t i f i e d by the f o l l o w i n g data: u l t r a v i o l e t , \ v 237.nm (e 15,000); i n f r a r e d ( n e a t ) , v max max 1670, 1625, 1210 and 880 cm" 1; n.m.r. ( C C I J . T 9.03 ( s i n g l e t , 6H, t e r t i a r y methyls), 8.93 (doublet, 3H, J = 6.5 Hz, secondary methyl) and 4.25 ( s i n g l e t , IH, o l e f i n i c p r o t o n ) ; mass spectrum, m/e ( r e l a t i v e i n t e n s i t y ) , 220 (64.6, M +), 178 (59.8), 163 (66.6), 95 (93.5), 79 (58.0) and 41 (100). Anal. Calcd. f o r C 1 5H 2 1 +0: C, 81.76; H, 10.98. Found: C, 81.85; H, 10.93. - 152 -Preparation o f Dihydrocarvone Acetal 116a,b (+)-Dihydrocarvone [120 g, 0.79 mole; («) p 9 +18.3 (CHC1 3)] was r e f l u x e d with a mixture o f 90.0 g (0.86 mole) 2,2-dimethyl-l,3-propanediol and 3.0 g o x a l i c a c i d i n 150 ml benzene i n a Dean-Stark apparatus f o r 4 days. G.l.c. a n a l y s i s (column A, 160°) o f the r e a c t i o n mixture i n d i c a t e d 93% product and 7% s t a r t i n g m a t e r i a l . Longer r e a c t i o n time f a i l e d to s i g n i f i c a n t l y improve the y i e l d o f product. The r e a c t i o n mixture was washed with s a t u r a t e d sodium bicarbonate and twice with saturated sodium c h l o r i d e and d r i e d over anhydrous sodium s u l f a t e . Solvent removal and d i s t i l l a t i o n a f f o r d e d 155 g pure 116a,b (82%) and 22 g o f a material c o n t a i n i n g s t a r t i n g ketone. Retreatment of the lower f r a c t i o n and d i s t i l l a t i o n provided 16 g 116a,b or an o v e r a l l y i e l d o f 91%: bp 50° (0.025 mm); n 2 0 1.4748; («) 2 4 -9.4 (c 10.3, CHC1 3); i n f r a r e d ( n e a t ) , v a 3100, 1650, 1150, 1100 and 888 cm"1. max Anal. Calcd. f o r C 1 5 H 2 5 0 2 : C, 75.58; H, 10.99. Found: C, 75.58; H, 11.15. The n.m.r. o f compound 116a,b was very complex and a n a l y s i s by g . l . c . (column E, 100°) i n d i c a t e d two components o f r e l a t i v e reten-t i o n times 70 and 79 minutes i n the r a t i o 3:1 r e s p e c t i v e l y . Samples o f each component were c o l l e c t e d using the a n a l y s i s c o n d i t i o n s above. The component o f r e t e n t i o n time 70 minutes (g r e a t e r than 90% pure by 25 n.m.r. a n a l y s i s ) was assigned s t r u c t u r e 116a: («) D -20° (c 4.05, CHC1 3); n.m.r. (CC1 [ +)(100M Hz) x 9.33 ( s i n g l e t , 3H, t e r t i a r y methyl), 9.05 ( m u l t i p l e t , 3H, secondary methyl);, 8.88 ( s i n g l e t , 3H, t e r t i a r y methyl), 8.33 ( m u l t i p l e t , 3H, v i n y l methyl), 7.32 ( m u l t i p l e t , IH, major co u p l i n g j = 13 Hz), 6.79 ( m u l t i p l e t , 2H, major co u p l i n g 0 = 11 Hz, - 153 -a c e t a l methylenes), 6.46 and 6.30 (two doublet,s 2H, J = 11 Hz, a c e t a l methylenes) and 5.38 ( m u l t i p l e t , 2H, -CH ); mass spectrum, m/e ( r e l a t i v e i n t e n s i t y ) 238 (24.7, M +), 155 (69.2), 95 (69.4), 69 (100), 56 (85.3), 55 (89.2), 43 (83.9), 41 (83.3). The component o f 79 minutes r e t e n t i o n time 116b ( g r e a t e r than p c 90% pure by n.m.r. a n a l y s i s ) e x h i b i t e d the f o l l o w i n g : (<*) ^ + 23° (c 0.90, CHC1 3); n.m.r. (CC1 4)(100M Hz) T 9.12 ( s i n g l e t , 3H, t e r t i a r y methyl), 9.10 (doublet, 3H, J = 7 Hz, secondary methyl), 9.09 ( s i n g l e t , 3H, t e r t i a r y methyl), 8.31 ( m u l t i p l e t , 3H, v i n y l methyl), 6.63 ( m u l t i p l e t , 4H, h a l f peak width 4 Hz, a c e t a l methylenes) and 5.37 ( m u l t i p l e t , 2H, =CH 2); mass spectrum, m/e ( r e l a t i v e i n t e n s i t y ) , 238 (3.4, M +), 181 (53.5), 155 (50.4), 69 (100), 55 (51.6) and 41 (67.5). A l t e r n a t i v e Synthesis o f Dihydrocryptomerion 7_5_ (96) A s o l u t i o n o f j v b u t y l l i t h i u m — T M E D A (tetramethylethylene-diamine) as the 1:1 complex was prepared by slow a d d i t i o n o f 15 mis (0.1 mole) TMEDA to 43 mis (0.1 mole) o f 2.35 molar jx-butyll ithium i n hexane with s t i r r i n g under a dry n i t r o g e n atmosphere. To the r e s u l t a n t yellow s o l u t i o n was added 19.5 g (0.082 mole) o f the 2,2-dimethyl-l,3-dioxane o f dihydrocarvone(116a,b) and the s o l u t i o n was s t i r r e d under nitrogen 18 hours. The deep red s o l u t i o n thus formed was cooled to -50° and t r e a t e d slowly with 10.5 g (0.1 mole) l-chloro-3-methyl-2-butene. A f t e r warming to room temperature, water was added c a u t i o u s l y and the mixture was e x t r a c t e d with ether and washed with 3N HC1. Removal o f the ac e t a l f u n c t i o n (3N HCl/acetone) followed by d i s t i l l a t i o n - 154 -af f o r d e d 5 g recovered dihydrocarvone (40%) and 9.5 g (88% based on consumed s t a r t i n g m a t e r i a l ) o f dihydrocryptomerion, bp 100-103° (0.04 mm), which was i d e n t i c a l ( g . l . c , i n f r a r e d , n.m.r.) to aut h e n t i c di hydro-. cryptomerion 75_ prepared from our previous route. Preparation o f Compounds 128a-e (90) Dimsyl sodium (85) was prepared i n the usual way (see pre-p a r a t i o n o f 107) and the appropriate phosphonium s a l t was added at 0° followed by a d d i t i o n o f keto a c e t a l 109 at room temperature. The W i t t i g products were hydrolyzed with 6N HC1 in acetone and enol a c e t y l a t i o n was performed with i s o p r o p e n y l a c e t a t e and £-toluenesulfonic a c i d . Thus from 109 and ethyltriphenylphosphonium bromide was obtained a f t e r h y d r o l y s i s ketone 127a (67%): bp 54° (0.15 mm), i n f r a r e d ( n e a t ) , v „ a w 1705 and max 815 cm" 1; n.m.r. ( C C V ) , T 9.03 and 8.98 (two doublets, 3H, J = 6 Hz, secondary methyl), 8.37 ( s i n g l e t , 6H, v i n y l methyls) and 4.84 ( m u l t i p l e t , 1H, o l e f i n i c proton). Enol a c e t y l a t i o n followed by sepa r a t i o n o f the isomers by p r e p a r a t i v e g . l . c . a f f o r d e d enol acetate 128a: i n f r a r e d ( n e a t ) , v 1750, 1705, 1210, 845 and 810 cm' 1; n.m.r. ( C C 1 4 ) , T 8.45 and 8.37 (broad, 6H, v i n y l methyls) and 4.83 ( m u l t i p l e t , 1H, o l e f i n i c proton). Condensation o f 109 with trimethylphosphonoacetate i n the presence of sodium hydride i n dimethoxyethane followed by h y d r o l y s i s y i e l d e d keto e s t e r 127b: i n f r a r e d ( n e a t ) , v- 1710, 1640, 1210 and m a x 860 cm" 1; n.m.r. (C C 1 4 ) , T 9.02 (doublet, 3H, J = 6 Hz, secondary methyl), 7.83 ( m u l t i p l e t , 3H, v i n y l methyl), 6.33 ( s i n g l e t , 3H, 0CH 3) and 4.33 - 155 -( m u l t i p l e t , IH, o l e f i n i c proton). Enol a c e t y l a t i o n provided mainly enol acetate 128a: i n f r a r e d ( n e a t ) , v a v 1750, 1720, 1640, 1210 and max 860 cm" 1; n.m.r. ( C C l i J , T 8.47 ( s i n g l e t , 3H, methyl on enol acetate double bond), 7.90 ( s i n g l e t , 3H, acetate methyl), 7.82 ( m u l t i p l e t , 3H, v i n y l methyl), 6.00 ( s i n g l e t , 3H, 0CH 3) and 4.28 ( m u l t i p l e t , IH, o l e -f i n i c proton). Compound 128c was prepared by condensation o f 109 with the W i t t i g s a l t prepared by heating 4 - c h l o r o b u t y r i c a c i d with t r i p h e n y l -phosphine (150°, 24 hours). A mixture o f the s a l t and 109 i n 1:1 d i m e t h y l s u l f o x i d e - t e t r a h y d r o f u r a n with excess sodium hydride was s t i r r e d 24 hours at room temperature under n i t r o g e n . Careful a c i d i f i c a t i o n to pH 6 and e x t r a c t i o n provided the crude a c i d which was e s t e r i f i e d with diazomethane, hydrolyzed, and d i s t i l l e d a f f o r d i n g 172c: bp 100° (0.06 mm); i n f r a r e d ( n e a t ) , v 1735, 1705, 1200 and 850 cm"i; v / \ i m a x n.m.r. ( C C l ^ ) , T 9.03 (doublet, 3H, J = 6 Hz, secondary methyl), 8.33 ( m u l t i p l e t , 3H, v i n y l methyl), 7.7 ( m u l t i p l e t , 3H, isomeric v i n y l methyls), 6.40 ( s i n g l e t , 3H, 0CH 3) and 4.92 ( m u l t i p l e t , IH, o l e f i n i c proton). Enol a c e t y l a t i o n followed by p r e p a r a t i v e g . l . c . provided 128c: i n f r a r e d ( n e a t ) , v a w 1750, 1220 and 850 cm" 1; n.m.r. ( C C 1 J , T 8.49 ( s i n g l e t , max 3H, methyl on enol acetate double bond), 8.37 ( s i n g l e t , 3H,.vinyl methyl), 7.93 ( s i n g l e t , 3H, acetate methyl), 6.40 ( s i n g l e t , 3H, 0CH 3) and 4.97 ( m u l t i p l e t , IH, o l e f i n i c proton). Compound 128ri was prepared by condensation o f 109 under the above s t a t e d W i t t i g c o n d i t i o n s with (4-benzyloxybutyl)triphenyl-phosphonium i o d i d e followed by the usual removal o f the ace t a l f u n c t i o n and enol a c e t y l a t i o n . The W i t t i g , s a l t (166) was prepared s t a r t i n g from 1,4-butanediol which was reacted with one e q u i v a l e n t o f sodium metal i n - 156 -m-xylene at 120°, followed by one e q u i v a l e n t o f benzyl c h l o r i d e . C h l o r i n a t i o n o f the 4-benzyloxybutanol. with t h i o n y l c h l o r i d e i n the presence of dimethyl a n i l i n e (167) followed by r e a c t i o n with sodium i o d i d e i n acetone a f f o r d e d l-iodo-4-benzyloxybutane i n good y i e l d . R e f l u x i n g the i o d i d e with triphenylphosphine in benzene y i e l d e d the d e s i r e d s a l t . Compound 127d, the W i t t i g product a f t e r h y d r o l y s i s , e x h i b i t e d the f o l l o w i n g data: i n f r a r e d ( n e a t ) , v 3040, 1705, 1500, 3 v 1 max 1100, 740 and 700 cm" 1; n.m.r. ( C C l J , x 9.08 (doublet, 3H, J = 6 Hz, secondary methyl), 8.38 ( m u l t i p l e t , 3H, v i n y l methyl), 6.65 ( t r i p l e t , 2H, J = 6 Hz, CH 3CH 20-), 5.60 ( s i n g l e t , 2H, benzyl methylenes), 4.92 ( m u l t i p l e t , IH, o l e f i n i c proton) and 2.75 ( s i n g l e t , 5H, - C 6 H 5 ) . Enol a c e t y l a t i o n provided l a r g e l y 128d: i n f r a r e d ( n e a t ) , v m a x 3040, 1750, 1710, 1500, 1210, 1100, 740 and 700 cm"1. Compound 128e was prepared s t a r t i n g from hydroxy ac e t a l 136 whose preparation i s d e s c r i b e d subsequently. Treatment o f 136 with carbontetrabromide and tri-n_-octylphosphine i n ether (92), followed by chromatography over s i l i c a a f f o r d e d keto bromide 127e d i r e c t l y : i n f r a -red ( n e a t ) , v m a x 1705 and 850 cm" ; n.m.r. ( C C l J , T 9.02 (doublet, 3H, J = 6 Hz, secondary methyl), 8.30 ( s i n g l e t , 3H, v i n y l methyl), 6.80 ( m u l t i p l e t , 2H, CH 2Br) and 4.90 ( m u l t i p l e t , IH, o l e f i n i c proton). Enol a c e t y l a t i o n and column chromatrography a f f o r d e d n e a r l y pure 128e: i n f r a r e d ( n e a t ) , v _ 1750, 1710, 1210 and 815 cm" 1; n.m.r. ( C C l J , max T 8.50 ( s i n g l e t , 3H, methyl on enol a c e t a t e double bond), 8.35 ( m u l t i -p l e t 3H, v i n y l methyl), 7.95 ( s i n g l e t , 3H, acetate methyl), 6.73 ( m u l t i p l e t , 2H, CH 2Br) and 4,90 ( m u l t i p l e t , IH, o l e f i n i c proton). - 157 -Preparation o f Methyl Home-camphors 129a,b (90) Enol acetate 128a (250 mg, 1.2m mole) i n 125 ml methylene c h l o r i d e was added to wet methylene c h l o r i d e (125 ml) p r e s a t u r a t e d with boron t r i f l u o r i d e gas and s t i r r e d 5 minutes followed by the usual work-up. Separation by p r e p a r a t i v e g . l . c . a f f o r d e d two main components with r a t i o 5.3:1.0. The minor (and l e s s v o l a t i l e ) component was apparently a mixture o f double bond isomers of s t a r t i n g ketone 127a. The major component (a semi s o l i d m a t e r i a l ) e x h i b i t e d the f o l l o w i n g data: i n f r a r e d (neat), v m a x 1740 and 1410 cm" 1; n.m.r. (CC1 4),x 9.15 ( s i n g l e t , 3H, t e r t i a r y methyls), 9.20 and 9.08 (two s i n g l e t s , 3H, d i a s t e r e o m e r i c t e r t i a r y methyls); (C 6H 6) x 9.44 and 9.39 (two s i n g l e t s , 3H, d i a s t e r e o m e r i c t e r t i a r y methyls) and 9.10 ( s i n g l e t , 3H, t e r t i a r y methyls). Attempted C y c l i z a t i o n o f Enol Acetates 1?8h-e Enol acetates 128b-e were t r e a t e d under the p r e v i o u s l y d e s c r i b e d c y c l i z a t i o n c o n d i t i o n s . Compound 128b slowly hydrolyzed to a mixture o f keto e s t e r 127b and the corresponding keto a c i d as judged by the i n f r a r e d spectrum. Compound 128c was slowly hydrolyzed and isomerized to various double bond isomers of keto e s t e r 127c as judged by g . l . c , u l t r a v i o l e t , i n f r a r e d and n.m.r. s p e c t r a l a n a l y s i s . Compound 128d a f f o r d e d a mixture of components as judged by g . l . c , t h i n l a y e r chromatography ( t . l . c ) , and the i n f r a r e d spectrum. Column chromatography over aluminum oxide a f f o r d e d two main f r a c t i o n s - 158 -(both complex mixtures) o f which the l e s s p o l a r f r a c t i o n was shown to have l o s t the benzyl p r o t e c t i n g group (absence o f absorption at 3040, 1500, 740 and 700 cm" 1). Compound 128e y i e l d e d a product with an absorption at 1730 cm"1 i n the i n f r a r e d spectrum and no o l e f i n i c s i g n a l s i n the n.m.r. spectrum. However, the product darkened r a p i d l y on standing and chromatography over s i l i c a gel f a i l e d to provide any i d e n t i f i a b l e product. Preparation o f 3-Iodopropan-1-oi 131 3-Chloropropan-l-ol (30.0 g, 0.317 mole) i n 500 ml acetone was t r e a t e d with sodium i o d i d e (100 g, 0.667 mole) and the s o l u t i o n was r e f l u x e d i n an atmosphere of n i t r o g e n f o r 48 hours. Concentration followed by d i l u t i o n o f the residue with e t h e r , washing f i r s t with a d i l u t e s o l u t i o n o f m e t a b i s u l f i t e and then with water and d r y i n g over anhydrous sodium s u l f a t e , y i e l d e d , a f t e r c o n c e n t r a t i o n , 57.6 g crude i o d i d e . D i s t i l l a t i o n under reduced pressure provided 55.2 g (93%) o f the d e s i r e d compound 131_: bp 97-99° (15 mm); n 2 5 1.5520 [ l i t . bp 88° (4 mm); n 7. 1.5585 (168)]; i n f r a r e d ( n e a t ) , v 3350 and 1040 cm" 1; u max n.m.r. ( C C l j J , x 7.93 (pentet, 2H, J = 6, -CH 2-), 6.67 ( t r i p l e t , -2H, J = 6 Hz, -CH 2I), 6.29 ( t r i p l e t , 2H, J = 6 Hz, -CH20H) and 5.97 ( s i n g l e t , 1H, -CH 20H). Preparation of Phosphonium S a l t 133 The hydroxyl f u n c t i o n o f 3-iodopropan-l-ol 131 was f i r s t - 159 -p r o t e c t e d as the t e t r a h y d r o p y r a n y l e t h e r by t reatment o f 37 .2 g (0 .200 mole) o f the i o d i d e w i th 50 ml d ihydropyran and one drop 12 N hydro -c h l o r i c a c i d a t room temperature o v e r n i g h t . Excess d ihydropyran was removed under reduced pressure and the heat s e n s i t i v e iodo e t h e r was used w i thout f u r t h e r p u r i f i c a t i o n . T r ipheny lphosph ine (53 .0 g , 0.202 mole) was d i s s o l v e d i n 200 ml sodium d r i e d benzene and 20 ml were d i s -t i l l e d . To t h i s s o l u t i o n was added the crude i o d i d e a long w i t h 50 ml dry benzene and 10 ml more benzene were d i s t i l l e d . R e f l u x i n g f o r 85 hours f o l l o w e d by c o o l i n g , f i l t e r i n g , washing w i t h dry benzene, and s u c t i o n d r y i n g p rov ided the crude phosphonium s a l t . Vacuum d r y i n g i n a d e s i c c a t o r over phosphorus pentox ide (8 h o u r s , c a . 1 mm) y i e l d e d 98 .2 g o f 133 (92%), mp 162-164°. P r e p a r a t i o n o f A c e t a l A l c o h o l 136 A s o l u t i o n o f d imsyl sodium anion was prepared by washing 8 . 0 0 g (0 .167 mole) sodium hydr ide (50% o i l d i s p e r s i o n ) tw ice w i t h dry benzene and then heat ing w i t h 50 ml d i m e t h y l s u l f o x i d e i n a dry n i t r o g e n atmosphere (70° o i l bath) u n t i l e v o l u t i o n o f hydrogen ceased . C o o l i n g the an ion i n an i c e bath and adding 8 8 . 0 g (0 .165 mole) o f phosphonium s a l t 133 ( i n 150 ml warm d i m e t h y l s u l f o x i d e ) produced a deep red s o l u t i o n o f the y l i d e phosphorane. A f t e r the y l i d e had s t i r r e d a t room temper-a t u r e 10 m i n u t e s , keto a c e t a l 109 (25 .0 g , 0 .126 mole) was added and the mix ture s t i r r e d 43 hours a t room temperature . Work-up was e f f e c t e d by s e v e r a l e x t r a c t i o n s w i t h petro leum e t h e r washing each e x t r a c t w i t h d i m e t h y l s u l f o x i d e and then water . The e x t r a c t s were concent ra ted and - 160 -d r i e d by sequential a d d i t i o n and evaporation o f several p o r t i o n s o f benzene. The crude product (ca. 50 g) e x h i b i t e d peaks at 1160, 1080, and 835 cm"1 i n the i n f r a r e d spectrum and no hydroxyl or carbonyl a b s o r p t i o n . Without f u r t h e r p u r i f i c a t i o n s e l e c t i v e removal o f the tetrahydropyranyl p r o t e c t i n g group was performed by t r e a t i n g the crude W i t t i g product with 106 ml ethylene g l y c o l , 1 g o x a l i c a c i d , and 200 ml benzene a t r e f l u x over the weekend i n a Dean-Stark apparatus. The cooled r e a c t i o n mixture was washed with saturated sodium bicarbonate s o l u t i o n and water and then concentrated. D i s t i l l a t i o n at reduced pressure provided 17.3 g (57%) o f pure a c e t a l alcohol 136. Retreatment o f the i n v o l a t i l e residue under the hy d r o l y s i s , c o n d i t i o n s above followed by d i s t i l l a t i o n a f f o r d e d 4.0 g more or a t o t a l o f 70% of compound 136: bp 100-102° (0.02 mm); («) 2 4 +20.4° (c 10.9, CHC1 3); i n f r a r e d ( n e a t ) , vmax 3 4 5 0 s 1 1 6 5 ' 1 0 8 0 a n d 8 3 5 c m " 1 ' n- m- r- ( c c l t ) > T 9- 1 8 (doublet, 3H, J = 5.5 Hz, secondary methyl), 8.41 (doublet, 3H, J = 1.5 Hz, v i n y l methyl), 7.00 ( s i n g l e t , IH, CH 20H), 6.52 ( t r i p l e t , 2H, J = 7 Hz, CHj>0H), 6.11 ( s i n g l e t , 4H, -0CH 2CH 20-), and 4.95 ( t r i p l e t , broad, IH, J = 7 Hz, o l e f i n i c p roton); mass spectrum, m/e ( r e l a t i v e i n t e n s i t y ) , 240 (65.3,M +), 183 (100, 113 (100), 87 (72.6), 86 (62.1), and 41 (81.0). Anal. Calcd. f o r CmH 2 i+0 3: C, 69.96; H, 10.07. Found: C. 70.15; H, 9.90. Preparation o f Acetal C h l o r i d e 137 A s o l u t i o n o f ace t a l a l c o h o l }36_ (21.5 g, 0.0892 mole) i n 150 ml c a r b o n t e t r a c h l o r i d e ( d r i e d over calcium c h l o r i d e ) was t r e a t e d dropwise with 37.0 g (0.0997 mole) tri-n_-octylphosphine. The m i l d l y - 161 -exothermic r e a c t i o n was moderated during the a d d i t i o n with a c o l d water bath and r a p i d s t i r r i n g . S t i r r i n g was continued 1 hour at room temper-ature a f t e r which the s o l v e n t was removed under reduced pressure. D i s t i l l a t i o n a t o i l pump pressure a f f o r d e d 17.8 g (78%) o f a c e t a l c h l o r i d e 137; bp 109-111° (0.02 mm); n 2 0 1.4960; («) 2 4 +17.8° (c 10.8, CHC1 3); i n f r a r e d ( n e a t ) , v m g x 1168, 1090 and 835 cm"1 with no absorption f o r hydroxyl; n.m.r. (CC1 H), x 9.18 (doublet, 3H, J = 5.5 Hz, secondary methyl), 8.38 ( m u l t i p l e t , 3H, v i n y l methyl), 7.48 ( m u l t i p l e t , 2H, C=CH-CHj> ), 6.57 ( t r i p l e t , 2H, J = 7 Hz, CH 2C1), 6.10 ( s i n g l e t , 2H, -0CH 2CH 20-) and 4.92 ( s e x t e t , 1H, J = 7 and J = 1.5 Hz, o l e f i n i c p r o t o n ) ; mass spectrum, m/e ( r e l a t i v e i n t e n s i t y ) , 260 (25.7,M ), 258 (63.2,M ), 203 (86.2), 202 (54.0), 201 (100), 113 (76.4) and 86 (62.6). Anal. Calcd. f o r C l H H 2 3 0 2 C l : C, 64.98; H, 8.96; CI, 13.70. Found: C, 64.82; H, 8.83; CI, 13.56. Preparation o f Keto C h l o r i d e 127f Ac e t a l c h l o r i d e 137_ (12.0 g, 0.463 mole), d i s s o l v e d i n 125 ml acetone, was t r e a t e d with 50 drops 6N h y d r o c h l o r i c a c i d and s t i r r e d overnight. The r e a c t i o n was quenched with 15 ml saturated bicarbonate and most o f the v o l a t i l e m a t e r i a l s were removed on the r o t a r y evaporator. The residue was washed with water and then r e t r e a t e d under the h y d r o l y s i s c o n d i t i o n s above. Quenching with bicarbonate and c o n c e n t r a t i o n followed by aqueous washing and d r y i n g over anhydrous magnesium s u l f a t e y i e l d e d 10.0 g crude produce from which was d i s t i l l e d 8.48 g (85%) keto c h l o r i d e 127f; bp 80-85° (0.02 mm); i n f r a r e d ( n e a t ) , v 1710, 1660, 850 and - 162 -835 cm" 1; n.m.r. ( C C l ^ ) , x 8.97 (doublet, 3H, J = 6 Hz, methyl on enol acetate double bond), 8.23 (doublet, 3H, J = 1.5 Hz, v i n y l methyl), 6.51 ( t r i p l e t , 2H, J = 7 Hz, -CH 2C1) and 4.86 ( m u l t i p l e t , IH, o l e f i n i c proton). Preparation o f Enol Acetate 128f Keto c h l o r i d e 127f (8.90 g, 0.414 mole) was t r e a t e d with isopropenyl acetate (15 ml) and p_-toluenesulphonic a c i d monohydrate (100 mg) f o r 48 hours under slow d i s t i l l a t i o n c o n d i t i o n s (head temperature 50-70°). The r e a c t i o n mixture was cooled to room temperature, d i l u t e d with petroleum e t h e r , washed with saturated bicarbonate and then water, and d r i e d over anhydrous sodium s u l f a t e . Solvent removal provided a crude mixture which was d i s t i l l e d at reduced pressure y i e l d i n g 9.61 g (90%) of a mixture o f isomeric enol a c e t a t e s : bp 89-92° (0.02 mm); two main components by g . l . c . a n a l y s i s (column A, 175°) i n the r a t i o 5.5:1.0 f o r compounds 128f and i t s isomer r e s p e c t i v e l y ( r e l a t i v e r e t e n t i o n times 5.1 and 4.2 minutes r e s p e c t i v e l y ) . A pure sample of compound 128f was obtained by pr e p a r a t i v e g . l . c . (column G, 225°): i n f r a r e d ( n e a t ) , vmax 1 7 5 0 ' 1 7 1 0 ' 1 2 1 0 a n d 8 5 0 cm~1' n - m - r - ( C C 1 J > T 8- 5 0 ( s i n g l e t , 3H, methyl on enol acetate double bond), 8.34 (doublet, 3H, J = 1.5 Hz, v i n y l methyl), 7.95 ( s i n g l e t , 3H, acetate methyl), 6.58 ( t r i p l e t , 2H, J = 7 Hz, -CH 2C1) and 4.87 ( m u l t i p l e t , IH, o l e f i n i c proton). - 163 -Preparation o f Acetal Alcohol 158 To 135 ml (0.322 mole) n-butyl 1 ithium (2.38 molar i n hexane) i n a dry nitrogen atmosphere was added with c o o l i n g 48.0 ml (0.414 mole) tetramethylethylenediamine followed by 75.7 g (0.317 mole) dihydrocarvone ac e t a l (2,2-dimethyl-l,3-dioxane)116a,b. The r e a c t i o n was allowed to stand under a s t a t i c atmosphere of n i t r o g e n at room temperature 32 hours during which time a deep red c o l o r developed. The s o l u t i o n o f anion was allowed to r e a c t with ethylene oxide by passing the gas i n a c a r r i e r stream o f n i t r o g e n r a p i d l y i n t o the i c e bath cooled s o l u t i o n u n t i l the red anion c o l o r disappeared. The a d d i t i o n o f ethylene oxide r e q u i r e d ca. 15 minutes and the r e s u l t i n g y e l l o w s o l u t i o n was purged o f remain-ing t r a c e s of ethylene oxide by continued bubbling o f nitrogen accompanied by warming o f the s o l u t i o n to 40°. Crushed i c e was added c a r e f u l l y u n t i l a l l the i n i t i a l l y formed i n o r g a n i c p r e c i p i t a t e r e d i s s o l v e d . The organic phase was separated and washed twice with water and then n e u t r a l i z e d by s e q u e n t i a l adding and shaking with d i l u t e sodium b i s u l f a t e u n t i l the aqueous phase t e s t e d neutral to pH t e s t paper. A l l aqueous washes were r e - e x t r a c t e d with petroleum e t h e r and n e u t r a l i z e d as above. A f t e r dry-ing over anhydrous sodium s u l f a t e the combined organic e x t r a c t s were concentrated and d i s t i l l e d under reduced pressure to provide 35.2 g (48%) recovered s t a r t i n g material and 42.6 g (48%; 91% based on consumed s t a r t -ing m a t e r i a l ) o f acetal a l c o h o l 158 as a c o l o r l e s s viscous l i q u i d : bp 120° (0.02 mm); n p° 1.4901 ; (<*) 2 4 -16.5° (c 6.05 CHC1 3); i n f r a r e d ( n e a t ) ; v 3420, 1645, 1148, 1098 and 890 cm" 1; n.m.r. (CC1 4),T9.0 ( m u l t i p l e t , 9H, methyl s i g n a l s ) , 8.22 (broad, 1H, CH20H_), 6.5 ( m u l t i p l e t , 6H, methylenes adjacent oxygen) and 5.27 ( s i n g l e t , 2H, =CH 2); mass spectrum, m/e ( r e l a t i v e i n t e n s i t y ) , 282 (16.6, M +), 225 (41.9), 155 (73,2), - 164 -69 (100), 55 (36.5) and 41 (43.4). Anal. Calcd. f o r C 1 7H3o0 3: C, 72.30; H, 10.71. Found: C, 72.00; H, 10.55. Preparation o f Acetal C h l o r i d e 159 Acetal alcohol 158 (81.3 g, 0.288 mole) i n s o l u t i o n with 50 ml s p e c t r a l grade c a r b o n t e t r a c h l o r i d e was t r e a t e d with t r i - n -octylphosphine (113 g, 0.305 mole) by c a r e f u l a d d i t i o n with vigorous s t i r r i n g and c o o l i n g o f the exothermic r e a c t i o n i n an i c e bath. When the a d d i t i o n was completed, the r e a c t i o n was s t i r r e d 1 hour at room temperature and then the so l v e n t was removed under reduced pressure. D i s t i l l a t i o n under reduced pressure provided the crude a c e t a l c h l o r i d e [ d i s t i l l e d u n t i l temperature o f d i s t i l l a t e reached 165° (0.07 mm)] which was r e d i s t i l l e d to a f f o r d 72.2 g (84%) a c e t a l c h l o r i d e 159: bp 110-112° (0.07 mm); n 2 0 1.4910; («) 2 5 -10.6° (c 10.7, CHC1 3); i n f r a r e d ( n e a t ) , vmax 1 1 4 5 ' 1 0 9 8 a n d 8 9 2 c m " 1 ; n - m - r - ( C C " U ) » T 9 - ° ( m u l t i p l e t , 9H, methyl s i g n a l s ) , 6.5 ( m u l t i p l e t , 6H, CH2C1 and ac e t a l methylenes), 5.21 ( m u l t i p l e t , 2H, =CH 2); mass spectrum, m/e ( r e l a t i v e i n t e n s i t y ) , 302 (9.4, M +), 300 (26.0, M +), 265 (43.1), 243 (69.9), 155 (100), 69 (60.2) and 55 (48.8). Anal. Calcd. f o r C 1 7 H 2 9 0 2 C 1 : C, 67.87; H, 9.72; C l , 11.78. Found: C, 68.16; H, 9.72; C l , 11.61. Preparation o f Keto C h l o r i d e 160. Chloro-acetal 1_5_9_ (55.2 g, 0.184 mole) d i s s o l v e d i n 1400 ml - 165 -acetone was t r e a t e d with 5 ml 6N h y d r o c h l o r i c a c i d at room temperature and allowed to stand 16 hours. The r e a c t i o n was quenched by the a d d i t i o n o f 50 ml s a t u r a t e d aqueous bicarbonate. Solvent was removed under reduced pressure and the r e s i d u e was washed with water and s a t u r a t e d sodium c h l o r i d e r e - e x t r a c t i n g each wash with ether and d r y i n g the com-bined organic l a y e r s over anhydrous sodium sulphate. Solvent removal a f f o r d e d the crude c h l o r i d e (51.7 g). D i s t i l l a t i o n under reduced pres-sure y i e l d e d ( a f t e r a f o r r u n of the 2,2-dimethyl-1,3-propanediol a c e t a l o f acetone) 36.0 g (91%) ketone c h l o r i d e 1_60: bp 82° (0.03 mm Hg); («) p 4 +6.9° (c 2.31, CHC1 3); n 2 0 1.4946; u l t r a v i o l e t , A m a x 284 nm (e 32); i n f r a r e d ( f i l m ) , v a v 1710, 1645, 895 and 730 cm" 1; n.m.r. (CC1 H), max T 9.05 and 8.98 (two doublets, 3H, J = 7 and 6 Hz r e s p e c t i v e l y , secondary methyl), 6.08 ( t r i p l e t , 2H, J = 6 Hz, CH 2C1) and 5.15 ( m u l t i p l e t , 2H, =CH 2); mass spectrum, m/e ( r e l a t i v e i n t e n s i t y ) , 216 (19.2, M +), 214 (86.0, M +), 137 (90.0), 109 (86.6), 95 (86.6), 81 (96.6), 68 (86.6) and 55 (100). Anal. Calcd. f o r C i 2 H i 9 0 CI: C, 67.12; H, 8.92; CI, 16.51. Found: C, 67.05; H, 9.03; CI, 16.32. Preparation o f Enol Acetate 161 Slow d i s t i l l a t i o n o f a mixture o f 30.7 g (0.143 mole) o f keto c h l o r i d e 160, 76 ml isopropenyl a c e t a t e and 500 mg p_-toluenesulphonic a c i d monohydrate 4 days with a d d i t i o n o f more isopropenyl acetate as needed (head temperature maintained at 50-60°) e f f e c t e d t o t a l conversion o f the ketone i n t o enol acetate as judged by g . l . c . a n a l y s i s . The r e a c t i o n was c o o l e d , d i l u t e d with petroleum ether and washed with - 166 -sat u r a t e d sodium bicarbonate, water and saturated sodium c h l o r i d e . A f t e r d r y i n g over anhydrous sodium s u l f a t e , the s o l v e n t was removed and the residue was d i s t i l l e d under reduced pressure through a 12 cm Vigreaux column a f f o r d i n g q u a n t i t a t i v e l y a mixture o f chloro enol acetates 1_62_ and 161 i n the r a t i o 28:72 as judged by g . l . c . a n a l y s i s (column A, 175°, r e t e n t i o n times 4.2 and 5.2 minutes r e s p e c t i v e l y ) . A f r a c t i o n o f pure enol acetate 161 could be obtained by c o l l e c t i o n o f the f i n a l f r a c t i o n (3-4 g) of the d i s t i l l a t e followed by r e d i s t i l l a t i o n . Pure enol acetate 161 showed the f o l l o w i n g c h a r a c t e r i s t i c s : bp 95° (0.03 mm); n 2 0 1.4948; («) 2 5 +56.2 (c 10.6, CHC1 3); i n f r a r e d ( n e a t ) , v a w 3100, 1745, 1710, 1645, 1210 and 895 cm" 1; n.m.r. ( C C K ) , T 8.50 max ( s i n g l e t , 3H, v i n y l methyl), 7.93 ( s i n g l e t , 3H, acetate methyl), 6.51 ( t r i p l e t , 2H, J = 6 Hz) and 5.17 ( m u l t i p l e t , 2H, o l e f i n i c p r o t o n s ) ; mass spectrum, m/e ( r e l a t i v e i n t e n s i t y ) , 258 (5.5, M ), 256 (11.4, M ), 211 (67.7), 132.5 (59.9), 104 (68.9) and 89 (100). Anal. Calcd. f o r C ^ H z ^ C l : C, 65.49; H, 8.24; C l , 13.81. Found: C, 65.37; H, 8.39; C l , 13.55. C y c l i z a t i o n of Enol Acetates 128f and 161 C y c l i z a t i o n c o n d i t i o n s and r e s u l t s were i d e n t i c a l f o r both enol acetates 128f and 161. The r e a c t i o n was co n v e n i e n t l y run on a 5 g s c a l e as f o l l o w s : a 2 l i t e r three neck f l a s k was f i t t e d with two a d d i t i o n funnels (one 250 ml funnel and another smaller f u n n e l ) , a gas i n l e t tube (extending n e a r l y to the bottom of the f l a s k ) and a magnetic s t i r r i n g d evice. A s o l u t i o n o f 5.00 g (0.0195 mole) enol acetate i n - 167 -1000 ml methylene c h l o r i d e was added i n 200 ml p o r t i o n s at 20 minute i n t e r v a l s (through the l a r g e a d d i t i o n funnel) to a v i g o r o u s l y s t i r r e d mixture of 800 ml methylene c h l o r i d e and 2 ml water (mixture was pre-s a t u r a t e d with boron t r i f l u o r i d e gas and a moderate flow of the gas was maintained throughout a d d i t i o n p r o c e s s ) . Water was added i n 2 ml p o r t i o n s 5 min immediately p r i o r to each a d d i t i o n of enol acetate (small a d d i t i o n f u n n e l ; a l l a d d i t i o n s made under 5 l b s nitrogen p r e s s u r e ) . With a d d i t i o n s complete the r e a c t i o n was allowed to s t i r 2 hours. The r e a c t i o n mixture was t r a n s f e r r e d to a 2 l i t e r separatory funnel and a lower l a y e r dark yellow i n c o l o r was d i s c a r d e d . Shaking 5 minutes with 100 ml water produced a c l e a r , c o l o r l e s s organic phase which was n e u t r a l -i z e d with d i l u t e sodium bicarbonate, shaking u n t i l the aqueous phase t e s t e d neutral to pH t e s t paper. Further washing with 100 ml water and 100 ml s a t u r a t e d sodium c h l o r i d e followed by drying over anhydrous sodium s u l f a t e and s o l v e n t removal a f f o r d e d a n e a r l y c o l o r l e s s o i l ( s o l v e n t recovered i n t h i s step could be used i n next run without f u r t h e r p u r i f i -c a t i o n with no diminution o f y i e l d ) . F i l t r a t i o n over 5 g o f c e l i t e (petroleum ether) and s o l v e n t removal a f f o r d e d 3.91-4.06 g (94-97% recovery) o f a c o l o r l e s s o i l . A n a l y s i s by g . l . c . (column A, 160°) i n d i c a t e d the presence o f 55-60% b i c y c l i c c h l o r o ketones 163a,b and 35-40% chloro enone 1_64_ ( r e t e n t i o n times 4.6 and 6.5 minutes r e s p e c t i v e l y ) . Two minor components ( r e t e n t i o n times 3.1 and 3.6 minutes) were present to the extent o f ca. 2% and 4% r e s p e c t i v e l y . The d i f f i c u l t y e n t a i l e d i n s e p a r a t i n g isomeric enol acetates 161 and 162 l e d to the use of the mixture of isomers i n the c y c l i z a t i o n step. Thus from 23.0 g enol acetates 1_61_ and 162_ ( r a t i o 76:24 respec-- 168 -t i v e l y ) , t r e a t e d i n p o r t i o n s under the c o n d i t i o n s d e s c r i b e d above, was obtained 18.4 g o f c o l o r l e s s o i l shown by g . l . c . a n a l y s i s to c o n s i s t o f 43% b i c y c l i c ketones 163a,b and 48% enone 162. D i s t i l l a t i o n twice under reduced pressure with r e f r a c t i o n a t i o n o f the higher and lower b o i l i n g f r a c t i o n s provided 6.68 g b i c y c l i c c h l o r o ketones 163a,b (46% based on enol acetate 161), 7.03 g enone 164 and 800 mg o f the minor v o l a t i l e components p r e v i o u s l y mentioned. Component 163a,b, bp 64-65° (0.03 mm), was g r e a t e r than 95% pure by g . l . c . a n a l y s i s (163a and 163b d i d not r e s o l v e on columns A, B, C or D) c o n t a i n i n g l e s s than 1% 164 and ca. 4% o f the more v o l a t i l e minor components: («) 2 5 0° (c 10.0, CHC1 3); n 2 0 1.4980; u l t r a v i o l e t , A m a w 285 nm (e 44); i n f r a r e d ( n e a t ) , v „ 1740 and 1410 cm" 1; n.m.r. max max ( C C 1 J , T 9.11 ( s i n g l e t , 3H, t e r t i a r y methyl), 9.16 and 9.03 (two s i n g l e t s , 3H, d i a s t e r e o m e r i c t e r t i a r y methyls), 6.55 and 6.48 (two o v e r l a p p i n g t r i p l e t s , 2H, J = 6 Hz, CH 2C1); ( C 6 H 6 ) , T 9.52 and 9.45 (two s i n g l e t s , 3H, d i a s t e r e o m e r i c t e r t i a r y methyls), 9.12 ( s i n g l e t , 3H, t e r t i a r y methyl), 7.04 and 6.92 (two o v e r l a p p i n g t r i p l e t s , 2H, J = 7 Hz, CH 2C1); mass spectrum, m/e ( r e l a t i v e i n t e n s i t y ) , 216 (33.6, M +), 214 (97.3, M +), 157 (92.6), 109 (100), 81 (93.3) and 69 (85.2). Component 164 e x h i b i t e d the f o l l o w i n g c h a r a c t e r i s t i c s : bp 76° (0.05 mm); n 2 0 1.5032; («) 2 5 +0.2° (c 10.0, CHC1 3); u l t r a -v i o l e t , A m a„ 234 (e 15,000), 339 (e 58); i n f r a r e d ( neat), v , 1670, max max 1210 and 883 cm" 1; n.m.r. (CCl, T),T 8.91 (doublet, 3H, J = 6.5 Hz, secondary methyl), 8.87 (doublet, 3H, J = 6.5 Hz, secondary methyl), 6.52 ( t r i p l e t , broad, 2H, J = 6 Hz, CH 2C1) and 4.30 ( s i n g l e t , IH, o l e f i n i c p roton); mass spectrum, m/e ( r e l a t i v e i n t e n s i t y ) , 216 (33.0, - 169 -M +), 214 (73.5, M +), 172 (63.0), 137 (45.9), 109 (65.3), 96 (100) and 95 (67.0). An a l . Calcd. f o r C i 2 H 1 9 0 C l : C, 67.12; H, 8.92; C l , 16.51. Found: C, 67.40; H, 8.83; C l . 16.31. Samples of the two minor components r e t e n t i o n times 3.1 and 4.6 minutes from the c y c l i z a t i o n o f 161 were i s o l a t e d by p r e p a r a t i v e g . l . c . The component of r e t e n t i o n times 3.1 minutes showed the f o l l o w -i n g : u l t r a v i o l e t , 299 ( e 48), i n f r a r e d ( n e a t ) , v m a x 1760 cm" 1; n.m.r. ( C C l J , 8.96 ( s i n g l e t , 3H, t e r t i a r y methyl), 8.77 ( s i n g l e t , 3H, t e r t i a r y methyl), 7.37 ( s i n g l e t , 2H) and 6.54 ( m u l t i p l e t , 2H, CH 2C1). The minor component of r e t e n t i o n time 4.6 minutes was c h a r a c t e r i z e d by the f o l l o w i n g data: i n f r a r e d (neat), v 1760 cm" 1; • max n.m.r. (CC1 4), T 8.96 ( s i n g l e t , 3H, t e r t i a r y methyl), 8.78 ( s i n g l e t , 3H, t e r t i a r y methyl), 7.51 and 7.37 (two s i n g l e t s , 2H) and 6.53 ( m u l t i -p l e t , 2H, CH 2C1). A l t e r n a t i v e Enol A c e t y l a t i o n of Keto C h l o r i d e 161 Keto c h l o r i d e 161 could be con v e n i e n t l y enol a c e t y l a t e d i n 10 g q u a n t i t i e s by the f o l l o w i n g procedure: a 10.0 g qu a n t i t y of ketone d i s -solved i n 100 ml anhydrous ethyl acetate was tr e a t e d a t room temperature f o r 5.5 minutes (vigorous s t i r r i n g ) with 500 ml of a reagent comprised of an ethyl acetate s o l u t i o n 1.06 M i n a c e t i c anhydride and 0.023 M i n p e r c h l o r i c a c i d (prepared by adding 50 .0 ml a c e t i c anhydride and 1.0 ml 70% p e r c h l o r i c a c i d to 300 ml anhydrous ethyl acetate and making the volume up to 500 ml with anhydrous ethyl a c e t a t e ) . S o l i d sodium b i -carbonate (10.0 g) was added to the auburn s o l u t i o n with vigorous s t i r r i n g . - 170 -When the mixture had s t i r r e d 5 minutes producing a n e a r l y c o l o r l e s s s o l u -t i o n , the s o l v e n t was removed on a r o t a r y evaporator (room temperature) and the excess a c e t i c anhydride was removed with an o i l pump (40°, 1 mm). The crude enol acetate was taken up i n petroleum ether, washed with c o l d saturated sodium bicarbonate and d r i e d over anhydrous sodium s u l f a t e . When 70.0 g (0.326 mole) keto c h l o r i d e 161 was t r e a t e d as above i n 10 g batches and the r e s u l t i n g product d i s t i l l e d there was obtained 49.6 g (59%) of enol acetates 161a and 162a, bp 94-96° (0.05 mm) and 21.8 g of m a t e r i a l c o n t a i n i n g 31% ketone. Retreatment o f the ketone c o n t a i n i n g f r a c t i o n and d i s t i l l a t i o n a f f o r d e d a f u r t h e r 17.5 g enol acetate mixture or an o v e r a l l y i e l d o f 80%. A n a l y s i s by g . l . c . (column A, 160°) i n d i c a t e d t h a t enol acetates 161a and 162a (greater than 97% p u r i t y , ca. 2% ketone) were i n the r a t i o 93:7 r e s p e c t i v e l y . A n a l y s i s by n.m.r. demonstrated t h a t i s o m e r i z a t i o n of the terminal o l e f i n had occurred to the extent of 45%. Treatment of t h i s enol acetate mixture under the same c y c l i z a t i o n c o n d i t i o n s as described f o r 161 a f f o r d e d b i c y c l i c ketones 163a,b i n 55 to 60% y i e l d as judged by g . l . c . a n a l y s i s (column A, 160°). Preparation of B i c y c l i c Chloro A c e t a l s 165a,b B i c y c l i c c h l o r o ketones 163a,b (6.50 g, 0.0303 mole) were t r e a t e d with 17 ml ethylene g l y c o l , 600 mg p_-toluenesulfonic a c i d monohydrate and 30 ml benzene at r e f l u x i n a Dean-Stark apparatus f o r 4 days. The cooled r e a c t i o n mixture was washed with saturated sodium b i -carbonate, water, and saturated sodium c h l o r i d e . A f t e r drying over anhydrous sodium s u l f a t e , the s o l v e n t was removed and the r e s i d u e d i s -t i l l e d under reduced pressure y i e l d i n g 7.43 g (95%) b i c y c l i c c h l o r o a c e t a l s 165a,b: bp 73° (0.04 mm); n 2 0 1.5010; (<*) 2 b 0° (c 10.4, CHC1 3); - 171 -i n f r a r e d ( n e a t ) , v m a x 1120 and 1044 cm" 1; n.m.r. (CC1 H), x 9.23 ( s i n g l e t , 3H, t e r t i a r y methyl), 9.16 and 9.00 ( s i n g l e t s , 3H, dia s t e r e o m e r i c t e r t i a r y methyls), 6.57 and 6.53 (overlapping t r i p l e t s , 2H, J = 6 Hz, CH 2C1) and 6.23 ( m u l t i p l e t , 4H, -0CH 2CH 20-); mass spectrum, m/e ( r e l a t i v e i n t e n s i t y ) , 260 (41.3, M +), 258 55.5, M +), 69 (79.2), 55 (93.0), 43 (100) and 42 (90.4). Anal. Calcd. f o r C 1 4 H 2 3 0 2 C 1 : C, 64.97; H, 8.96; CI, 13.70. Found: C, 65.03; H, 8.79; CI, 13.50. Preparation o f Iodo A c e t a l s 166a,b B i c y c l i c c h l o r o a c e t a l s 165a,b (5.15 g, 0.0199 mole), sodium io d i d e (7.50 g, 0.050 mole) and 700 mg anhydrous calcium carbonate i n 10 ml dry acetone were r e f l u x e d i n a dry nitrogen atmosphere 48 hours. A f t e r c o o l i n g , the r e a c t i o n mixture was t r a n s f e r r e d under nitrogen i n t o 100 ml dry pentane p r e c i p i t a t i n g the i n o r g a n i c m a t e r i a l s . The s o l u t i o n was immediately f i l t e r e d over 10 g o f c e l i t e (oven d r i e d , 100° overnight) e l u t i n g with another 100 ml of dry pentane. D i s t i l l a t i o n a f f o r d e d 6.75 g (97%) iodo a c e t a l s 166a,b: bp 89-90° (0.02 mm); n 2 0 1.5409; («) 2 5 0° (c 2.09, CHC1 3); i n f r a r e d ( n e a t ) , v m a v 1116 and 1045 cm" 1; n.m.r. (CC1 4), x 9.22 ( s i n g l e t , 3H, t e r t i a r y methyl); 9.15 and 8.98 (two s i n g l e t s , 3H, diastereomeric t e r t i a r y methyls); 6.84 ( t r i p l e t , 2H, J = 6 Hz, CH 2I) and 6.20 ( m u l t i p l e t , 4H, -0CH 2CH 20-); mass spectrum, m/e ( r e l a t i v e i n t e n s i t y ) , 350 (10.0, M +), 223 (81.8), 125 (34.7), 113 (30.6), 95 (100) and 87 (32.7). - 172 -Anal. Calcd. f o r C i i ^ O ^ I : C, 48.05; H, 6.61; I, 36.26. Found: C, 48.00; H, 6.52; I, 36.10. Preparation of Campherenone and Epicampherenone Ethylene A c e t a l s  168a and 168b Triphenylphosphine (4.60 g, 0.0176 mole) was d i s s o l v e d i n 10 ml dry benzene and 2 ml of the benzene were slowly d i s t i l l e d to remove f i n a l t r a c e s o f water. Acetal iodides 166a,b (6.00 g, 0.0171 mole) was added along with 2 ml more benzene and the s o l u t i o n was r e f l u x e d under nitr o g e n 38 hours. The s o l v e n t was removed and the s a l t , a viscous o i l , was used without f u r t h e r p u r i f i c a t i o n . Dimsyl sodium was prepared as f o l l o w s : sodium hydride (0.864 g, 50% o i l d i s p e r s i o n , 0.018 mole) was washed twice with dry pentane and heated under nitr o g e n with 5 ml dry d i m e t h y l s u l f o x i d e in a 65-75° bath u n t i l e v o l u t i o n o f hydrogen ceased (ca. 45 minutes). The r e a c t i o n mixture was c h i l l e d i n an i c e bath and the crude W i t t i g s a l t prepared above ( d i s s o l v e d i n 5 ml dry dimethyl sul foxide) v/as added dropwise at a r a t e s u f f i c i e n t to prevent f r e e z i n g o f the d i m e t h y l s u l f o x i d e from the r e a c t i o n mixture. The deep red y l i d e s o l u t i o n was allowed to warm to room temperature and to stand 5 minutes a f t e r which time 1.50 ml (0.0203 mole) dry acetone was added. The r e a c t i o n was allowed to s t i r over the weekend (70 hours) and then was e x t r a c t e d with three 70 ml p o r t i o n s o f petroleum e t h e r , washing each e x t r a c t in turn with dimethyl-s u l f o x i d e , water, and saturated b r i n e . The combined c o l o r l e s s e x t r a c t s were d r i e d over anhydrous sodium sulphate and, a f t e r s o lvent removal - 173 -under reduced pressure, the mixture o f a c e t a l alkenes was vacuum d i s -t i l l e d y i e l d i n g 3.83 g (84%) o f a mixture o f the a c e t a l s o f campherenone and epicampherenone: bp 75-76° (0.03 mm Hg). Separation by p r e p a r a t i v e g . l . c . (column A, 240°) a f f o r d e d two components o f r e t e n t i o n times 42 and 47 minutes which were f u r t h e r p u r i f i e d by evaporative d i s t i l l a t i o n . The component o f r e t e n t i o n time 42 minutes, 168a, showed the f o l l o w i n g c h a r a c t e r i s t i c s : n 2 0 1.4956; («) 2 5 0° (c 1.31, CHC1 3); i n f r a r e d ( n e a t ) , vmax 1 1 2 0 a n d 1 0 5 0 c m _ 1 ; n-m-r* (CCM> T 9- 2 3 ( s i n g l e t , 3H, t e r t i a r y methyl), 9.13 ( s i n g l e t , 3H, t e r t i a r y methyl), 8.40 and 8.33 (two s i n g l e t s , 6H, v i n y l methyls), 6.22 ( m u l t i p l e t , 4H, -0CH 2CH 20-) and 4.90 ( m u l t i p l e t , IH, o l e f i n i c p roton); mass spectrum, m/e ( r e l a t i v e i n t e n s i t y ) , 264 (59.7, M +), 125 (100), 95 (81.6), 87 (61.4), 69 (75.7), and 41 (74.0). Anal. Calcd. f o r C 1 7 H 2 8 0 2 : C, 77.22; H, 10.67. Found: C, 76.96; H, 10.63. The component of r e t e n t i o n time 47 minutes, 168b, e x h i b i t e d the f o l l o w i n g : n 2 0 1.4965; («) 2 5 0° (c 1.03, CHC1 3); i n f r a r e d ( n e a t ) , v a u 1115 and 1045 cm" 1; n.m.r. (CC1 4), T 9.23 ( s i n g l e t , 3H, t e r t i a r y max methyl), 8.97 ( s i n g l e t , 3H, t e r t i a r y methyl), 8.40 and 8.33 (two s i n g l e t s , 6H, v i n y l methyls), 6.22 ( m u l t i p l e t , 4H, -0CH 2CH 20-) and 4.92 ( m u l t i p l e t , IH, o l e f i n i c p roton); mass spectrum, m/e ( r e l a t i v e i n t e n s i t y ) , 264 (9.7, M +), 109 (35.5), 95 (100), 69 (51.6), 55 (32.2) and 41 (64.5). Anal. Calcd. f o r C 1 7 H 2 8 0 2 : C, 77.22; H, 10.67. Found: C, 76.99; H, 10.86. - 174 -Preparation of (±)-Campherenone 42. Ethylene a c e t a l 168a (491 mg, 1.86 m mole) i n 50 ml acetone was t r e a t e d with 10 drops of 6N h y d r o c h l o r i c a c i d and allowed to stand 24 hours. Saturated sodium bicarbonate was added (ca. 2 ml) and the s o l v e n t was removed on a r o t a r y evaporator. The residue was d i l u t e d with petroleum ether and washed with saturated sodium c h l o r i d e . A f t e r drying over anhydrous sodium s u l f a t e , the s o l v e n t was removed and the crude ketone d i s t i l l e d a f f o r d i n g 404 mg (99%) (±)-campherenone 42_. The p u r i t y o f the campherenone at t h i s stage was dependent on the care taken e a r l i e r i n the f r a c t i o n a t i o n o f keto c h l o r i d e s 163a,b from the more v o l a t i l e minor components of the c y c l i z a t i o n mixtures (as these m a t e r i a l s were c a r r i e d through and i s o l a t e d with the ketal 168a during p r e p a r a t i v e g . l . c ) . T y p i c a l l y , a small percentage of impurity was d e t e c t a b l e by g . l . c . (column B, 175°) with r e t e n t i o n time 2.0 minutes compared to 2.8 minutes f o r campherenone 42_. A pure sample o f campher-enone obtained by p r e p a r a t i v e g . l . c . (column G, 220°) followed by evaporative d i s t i l l a t i o n (60° o i l bath, 0.05 mm), e x h i b i t e d the f o l l o w -e r ing c h a r a c t e r i s t i c s : n p 1.4888; («) D 0° (c 1.02, CHC1 3); i n f r a r e d ( n e a t ) , v m a x 1738, 1415 and 830 cm" 1; n.m.r. (CC1 4), T 9.14 ( s i n g l e t , 3H, t e r t i a r y methyl), 9.03 ( s i n g l e t , 3H, t e r t i a r y methyl), 8.39 and 8.35 ( two broad overlapping s i g n a l s , 6H, v i n y l methyls) and 4.95 ( m u l t i p l e t , 1H, o l e f i n i c p r o t o n ) ; ( C 6 H 6 ) , T 9.30 ( s i n g l e t , 3H, t e r t i a r y methyl), 9.07 ( s i n g l e t , 3H, t e r t i a r y methyl), 8.48 and 8.35 (two broad s i n g l e t s , 6H, v i n y l methyls) and 4.97 ( m u l t i p l e t , 1H, o l e f i n i c proton); mass spectrum,m/e ( r e l a t i v e i n t e n s i t y ) 220 (82.2, M +), 135 (44.6), 109 - 175 -(93.8), 95 (46.4), 81 (33.9), 69 (99.0), 55 (47.2), and 41 (100). (162a,b,c, 27,28) Anal. Calcd. f o r C i 5 H 2 t f 0 : C, 81.76; H, 10.98. Found: C, 82.00; H, 10.83. Preparation o f (±)-Epicampherenone 45 Removal o f the a c e t a l f u n c t i o n o f 168b (934 mg, 3.54m mole) under i d e n t i c a l c o n d i t i o n s to those described f o r a c e t a l 168a a f f o r d e d a f t e r d i s t i l l a t i o n 746 mg (96%) epicampherenone: bp (bath temperature) 69° (0.05 mm); n ^ 1.4887; homogeneous by g . l . c . a n a l y s i s (column B, Of) 175°, r e t e n t i o n time 2.8 minutes); («) ^ u 0° (c 2.81, CHC1 3); i n f r a r e d ( n e a t ) , v m a v 1738, 1415 and 835 cm" 1; n.m.r. (CC'k), T 9.13 ( s i n g l e t , max 6H, t e r t i a r y methyls), 8.38 and 8.32 (two broad s i g n a l s , 6H, v i n y l methyls) and 4.89 ( m u l t i p l e t , IH, o l e f i n i c p r o t o n ) ; ( C 6 H 6 ) , T 9.35 ( s i n g l e t , 3H, t e r t i a r y methyl), 9.06 ( s i n g l e t , 3H, t e r t i a r y methyl), 8.41 and 8.28 (two broad s i n g l e t s , 3H, v i n y l methyls) and 4.83 ( m u l t i -p l e t , IH, o l e f i n i c p roton); mass spectrum, m/e ( r e l a t i v e i n t e n s i t y ) , 220 (46.4, M +), 135 (45.5), 109 (100), 95 (92.7), 81 (52.7), 69 (98.3), 67 (46.4) and 41 (87.3). Anal. Calcd. f o r C 1 5H 2 1 t0: C, 81.76; H, 10.98. Found: C, 82.00; H, 10.94. - 176 -Preparation o f (±)-Camphereno1 Ma. (169) Campherenone 42_ (35 mg, 0.16 mole) was d i s s o l v e d i n 12 ml n_-propanol and sodium metal (0.6 g, excess) was added i n small p i e c e s . The mixture was r e f l u x e d 2 hours, the s o l v e n t was removed under reduced pressure and the residue was d i l u t e d with water and e x t r a c t e d with ether. The i s o l a t e d product (a 7:1 mixture of campherenol and i s o -campherenol) a f t e r d rying and s o l v e n t removal (35 mg, >95%) e x h i b i t e d the f o l l o w i n g data: i n f r a r e d ( n e a t ) , v cm"1 3400 and 835 cm" 1; n.m.r. 3 \ /> m a x ( C C 1 J , x 9.17 ( s i n g l e t , 3H, t e r t i a r y methyl), 9.11 ( s i n g l e t , 3H, t e r t i a r y methyl), 8.41 and 8.34 (two broad s i n g l e t s , 6H, v i n y l methyls), 6.46 ( t r i p l e t ) and 6.00 (broadened doublet, J = 10 Hz) ( r e l a t i v e i n t e g r a l areas 1:7 r e s p e c t i v e l y , -CH0H, l a r g e l y endo a l c o h o l ) and 4.94 ( m u l t i p l e t , IH, o l e f i n i c p roton); (C 5H 5N), T 9.06 ( s i n g l e t , 3H, t e r t i a r y methyl), 8.98 ( s i n g l e t , 3H, t e r t i a r y methyl), 6.13 and 5.65 ( r e l a t i v e i n t e g r a l areas 1:7 r e s p e c t i v e l y , -CH0H). (162a,b; 27,28) Preparation o f (±)-Isocampherenol 46b and (±)-g-Santalene 48 (169) Campherenone 42_ (100 mg, 0.45m mole) was s t i r r e d overnight (under nitrogen atmosphere) with 4 equ i v a l e n t s o f l i t h i u m trimethoxy-aluminohydride (109) i n te t r a h y d r o f u r a n . A d d i t i o n o f water and e x t r a c t i o n with ether followed by solvent, removal and chromatography over 5 g of s i l i c a gel a f f o r d e d 96 mg (95%) (±)~isocarnpherenol: homogeneous by g . l . c . a n a l y s i s (column A, 160°); i n f r a r e d ( n e a t ) , v m,„ 3400 and 835 cm" 1; max n.m.r. (CC'U), T 9.18 (singlet.^ 3H, t e r t i a r y methyl), 9.12 ( s i n g l e t , 3H, - 177 -t e r t i a r y methyl), 8.39 and 8.36 (two doublets, 6H, J = 1.5 Hz and J = 2 Hz r e s p e c t i v e l y , v i n y l methyls), 6.46 ( t r i p l e t , 1H, J = 6 Hz, -CHOH, exo alcohol) and 4.92 ( m u l t i p l e t , 1H, o l e f i n i c proton); (C 5H 5N), x 9.10 ( s i n g l e t , 3H, t e r t i a r y methyl), 8.88 ( s i n g l e t , 3H, t e r t i a r y methyl) and 6.13 ( m u l t i p l e t , 1H, -CHOH). Treatment o f 45 mg (0.02m mole) isocampherenol 46b with 100 mg p_-toluenesulfonyl c h l o r i d e i n 4 ml dry p y r i d i n e at 95° f o r 22 hours e f f e c t e d smooth dehydration and rearrangement. 3-Santalene was i s o l a t e d by d i l u t i o n with water and e x t r a c t i o n with pentane, washing with 6N h y d r o c h l o r i c a c i d , saturated sodium bicarbonate and water and drying over anhydrous sodium s u l f a t e . S olvent removal and chromatography over s i l i c a g e l , e l u t i n g with petroleum e t h e r , a f f o r d e d 32 mg (80%) 3-santalene: homogeneous by g . l . c . a n a l y s i s (column A, 110°) with i d e n t i c a l r e t e n t i o n time to authentic (-)-3-santalene (120) ( r e l a t i v e r e t e n t i o n times of 3-santalene and epi-3-santalene at t h i s temperature are 17 minutes and 16 minutes r e s p e c t i v e l y ) ; i n f r a r e d ( n e a t ) , v m a v 3060, 1655, 878 and max 830 cm" 1; n.m.r. (CC1 4), x 8.97 ( s i n g l e t , 3H, t e r t i a r y methyl), 8.42 and 8.35 (two broadened s i n g l e t s , 6H, v i n y l methyls), 7.36 ( s i n g l e t , broad, 1H, a l l y l i c methine), 5.57 and 5.31 (two s i n g l e t s , 2H = CH 2) and 4.96 ( m u l t i p l e t , 1H, o l e f i n i c proton). (162a,b; 31) Preparation by (±)-Epicampherenol 49a (169) Epicampherenol was prepared from epicampherenone 45 i n d i r e c t analogy to the preparation o f campherenol 46a, using 0.7 g sodium metal i n jvpropanol to reduce 40 mg (0.18m mole) o f epicampherenone. E p i -- 178 -campherenol (as a 3:2 mixture with isoepicampherenol) e x h i b i t e d the f o l l o w i n g : i n f r a r e d ( n e a t ) , v 3400 and 825 cm" 1; n.m.r. ( C C I L ) , max x 9.18 ( s i n g l e t , 3H, t e r t i a r y methyl), 9.13 ( s i n g l e t , 3H, t e r t i a r y methyl), 8.40 and 8.33 (two broadened s i n g l e t s , 6H, v i n y l methyls), 6.47 ( t r i p l e t ) and 6.06 (broadened doublet, J = 10 Hz) ( r e l a t i v e i n t e g r a l area 2:3 r e s p e c t i v e l y , -CH0H, predominantly endo a l c o h o l ) and 4.92 ( m u l t i p l e t , IH, o l e f i n i c proton); ( C 5 H 5 N ) , T 9.07 ( s i n g l e t , 3H, t e r t i a r y methyl), 8.97 ( s i n g l e t , 3H, t e r t i a r y methyl), 6.18 and 5.73 ( r e l a t i v e i n t e g r a l areas 2:3 r e s p e c t i v e l y , -CH0H). Preparation of (±)-Isoepicampherenol 49b. and (±)-Epi-£-Santalene 50 (169) The transformation o f epicampherenone i n t o 49b and 50 was performed in d i r e c t analogy to the s i m i l a r transformations o f camphere-none 42_ i n t o 46b and 48. Thus reduction of epi campherenone with l i t h i u m , trimethoxyaluminohydride i n t e t r a h y d r o f u r a n a f f o r d e d isoepicampherenol 49b: homogeneous by g . l . c . a n a l y s i s (column A, 175°); i n f r a r e d ( n e a t ) , vmax 3 4 4 0 a n d 8 3 8 c m" 1 ; n-ni-r- ( C C"U)> T 9- 1 2 ( s i n g l e t , 3H, t e r t i a r y methyl), 8.96 ( s i n g l e t , 3H, t e r t i a r y methyl), 8.39 and 8.33 (two broadened s i n g l e t s , 6H, v i n y l methyls), 6.47 ( t r i p l e t , IH, J = 5 Hz, -CH0H, exo_ a l c o h o l ) and 4.93 ( m u l t i p l e t , IH, o l e f i n i c p roton); (C 5H 5N), T 8.88 ( s i n g l e t , 3H, t e r t i a r y methyl), 8.65 ( s i n g l e t , 3H, t e r t i a r y methyl) and 6.18 ( t r i p l e t , IH, J = 5 Hz, -CH0H). Treatment o f isoepicampherenol 49b under the same c o n d i t i o n s employed with isocampherenol 46b ( p _ - t o l u e n e s u l f o n y l c h l o r i d e / p y r i d i n e / A ) a f f o r d e d (±)-epi-g-santalene: homogeneous with i d e n t i c a l r e t e n t i o n time - 179 -to authentic (+)-epi-6-santalene (120) by g . l . c . a n a l y s i s (column A, 110°); infrared ( n e a t ) , v 3060, 1655, 878 and 835 cm" 1; n.m.r. (C C 1 4 ) , II lot A T 9.00 (singlet, 3H, t e r t i a r y methyl), 8.40 and 8.35 (two broadened singlets, 6H, v i n y l m ethyls), 7.35 ( s i n g l e t , broad, 1H, a l l y l i c methine), 5.57 and 5.34 (two s i n g l e t s , 2H, -CH 2) and 4.93 ( m u l t i p l e t , 1H, o l e -finic proton). (162a,b; 31) Preparation of ( ± ) - c c - S a n t a l e n e 42 (169) A mixture (ca. 1:1) o f campherenone 42_ and epicampherenone 4J5 (35 mg, 0.16m mole) was r e f l u x e d i n a s o l u t i o n o f 60 mg o f hydrazine 0.1 ml acetic a c i d and 2 ml absolute ethanol f o r 4 hours. The s o l v e n t was removed and the residue was d i l u t e d with water and e x t r a c t e d with e t h e r , washing with s a t u r a t e d sodium bicarbonate and water and dr y i n g over anhydrous sodium s u l f a t e . The crude hydrazone obtained a f t e r solvent removal was t r e a t e d i n 3 ml dry methanol with 100 mg o f red mercuric oxide at r e f l u x f o r 16 hours. The s o l u t i o n was f i l t e r e d , rinsing the solid with pentane, and the f i l t r a t e was evaporated l e a v -ing the crude «-santalene which was d i l u t e d with pentane, washed with water and dried over anhydrous sodium s u l f a t e . Solvent removal a f f o r d e d 30 mgs of material which was 35% =-santalene and 65% s t a r t i n g material by g. l .c. analysis. Chromatography over s i l i c a gel a f f o r d e d 10 mg (±)-oc-santalene (31%) and 18 mg s t a r t i n g ketone (51%) o r an o v e r a l l yield of 64% «-santalene (based on consumed s t a r t i n g m a t e r i a l ) : homo-geneous by g.l.c. a n a l y s i s (column A, 110°) with r e t e n t i o n time i d e n t i -cal to authentic (+)-«-santalene (120); i n f r a r e d ( n e a t ) , v m a v 3080, - 180 -855 and 840 cm" 1; n.m.r. ( C C 1 J , T 9.17 ( s i n g l e t , 3H, t e r t i a r y methyl), 8.99 ( s i n g l e t , 3H, t e r t i a r y methyl), 8.41 and 8.34 (two broadened s i n g l e t s , 6H, v i n y l methyls) and 4.92 ( m u l t i p l e t , 3H, o l e f i n i c proton). Preparation o f Campherenone Enol Acetate 51 (X = OAc) Campherenone 42_ (120 mgs, 0.55m mole) i n 2 mis dry t e t r a -hydrofuran was t r e a t e d at room temperature with 0.275 ml (0.65m mole) of n_-butyl 1 ithium (2.38 M s o l u t i o n i n hexane) 15 minutes. The enolate anion thus generated was cooled to -50° and t r e a t e d with 0.107 ml (1.1m mole) a c e t i c anhydride ( f r e s h l y opened b o t t l e ) . A f t e r 15 minutes the r e a c t i o n was allowed to warm slowly to room temperature and a f t e r 15 minutes at room temperature the excess a c e t i c anhydide was destroyed by s t i r r i n g 15 minutes with s a t u r a t e d sodium bicarbonate. D i l u t i o n with petroleum ether and washing with water and saturated sodium c h l o r i d e a f f o r d e d , a f t e r d r y i n g and s o l v e n t removal, 148 mg o f material (theo-r e t i c a l , 144 mg) which was 85% enol acetate 5J_ as judged by g . l . c . a n a l y s i s (column A, 175°, r e t e n t i o n time 3.4 minutes as compared to 2.8 minutes f o r campherenone 42): i n f r a r e d ( n e a t ) , v a 1755, 1205, — max 835 and 810 cm" 1; n.m.r. (CC1 4), T 9.24 ( s i n g l e t , 3H, t e r t i a r y methyl), 9.10 ( s i n g l e t , 3H, t e r t i a r y methyl), 8.44 and 8.36 (two broadened s i n g l e t s , 6H, v i n y l methyls), 7.90 ( s i n g l e t , 3H, acetate methyl), 7.57 ( t r i p l e t , 1H, J = 1.5 Hz, a l l y l i c methine), 4.93 ( m u l t i p l e t , 1H, o l e f i n i c proton) and 4.85 (doublet, 1H, proton on enol acetate double bond). - 181 -C y c l i z a t i o n Attempts With Enol Acetate 5J_ Campherenone enol acetate 51_ was t r e a t e d under the p r e v i o u s l y s t a t e d optimum c y c l i z a t i o n c o n d i t i o n s (BF3 / C H 2 C I 2/.l% enol a c e t a t e by volumn). G.l.c. a n a l y s i s (columns A, C, D; 160°) i n d i c a t e d only a very small percentage o f v o l a t i l e products. Peaks were present on a l l three g . l . c . t r a c e s which corresponded to auth e n t i c longicamphor 54_ and copacamphor 52_ (123,124). A n a l y s i s on column B (160°) however, f a i l e d to i n d i c a t e s i m i l a r correspondence. In view o f the l a r g e per-centage o f i n v o l a t i l e material encountered i n t h i s r e a c t i o n (even when the r e a c t i o n was performed at a con c e n t r a t i o n o f 100 mg i n 1500 mis) other means were sought to obt a i n c y c l i z a t i o n o f campherenone. [Other a c i d s used to attempt t h i s c y c l i z a t i o n , e.g., s t a n n i c c h l o r i d e , boron-t r i f l u o r i d e e t h e r a t e , p e r c h l o r i c a c i d , h y d r o c h l o r i c a c i d , s i l i c a gel or phosphate b u f f e r (pH 7) l e d to p a r t i a l o r complete regeneration o f s t a r t i n g ketone.] Preparation and C y c l i z a t i o n o f Campherenone Epoxides 173a,b Campherenone 42_ (500 mg, 2.27m mole) i n 5 ml dry benzene (cooled i n i c e bath) was t r e a t e d with 480 mg (2.36m mole) 85% m-chloro-perbenzene a c i d i n 15 ml dry benzene over a pe r i o d o f 1 hour and the r e a c t i o n was s t i r r e d an a d d i t i o n a l 2 hours. The r e a c t i o n mixture was washed with s a t u r a t e d sodium bicarbonate and j u s t enough sodium b i s u l f i t e to give a negative starch-potassium i o d i d e t e s t f o r the aqueous bicarbonate phase. Washing with water and saturated sodium c h l o r i d e - 182 -followed by d r y i n g (anhydrous sodium s u l f a t e ) and s o l v e n t removal y i e l d e d 508 mg (95%) o f the mixture o f epoxides 173a,b which was g r e a t e r than 85% pure as judged by g . l . c . (column A, 160°): i n f r a r e d ( n e a t ) , v m g x 1240, 870 and 800 cm" 1. The crude epoxide (495 mg) was added d i r e c t l y to a s o l u t i o n o f potassium t^-butoxide [prepared by r e f l u x i n g a mixture o f 390 mg (10m mole) potassium metal and 8 ml dry t>butanol u n t i l a l l the metal had reacted] and r e f l u x e d 36 hours under a dry n i t r o g e n atmosphere. The r e a c t i o n mixture was poured i n t o water and e x t r a c t e d with several p o r t i o n s o f petroleum e t h e r , washing with water and s a t u r a t e d sodium c h l o r i d e . A f t e r d rying over anhydrous sodium s u l f a t e , s o l v e n t removal a f f o r d e d 488 mg (99% recovery) o f crude c y c l i c products (174 and 175). G.l.c. a n a l y s i s i n d i c a t e d two main components i n the approximate r a t i o 45:55 with r e t e n t i o n times 5.4 and 6.6 minutes r e s p e c t i v e l y (column A, 175°). Separation by p r e p a r a t i v e g . l . c . (column G, 230°) a f f o r d e d pure samples o f each component ( r e t e n t i o n times 53 and 60 minutes). Alcohol 174 ( r e t e n t i o n time 53 minutes) e x h i b i t e d the f o l l o w -i n g : i n f r a r e d ( C C 1 4 ) , v m a v 3620 (weak), 3490 ( s t r o n g ) , 1734 (weak) and 1728 cm"1 ( s t r o n g ) ( r e l a t i v e strengths o f bands at 3620 and 3490 cm"1 d i d not change upon d i l u t i o n from 0.08 M to 0.01 M s o l u t i o n s ) ; n.m.r. (CCU) 0°° M Hz), T 9.10 ( s i n g l e t , 3H, t e r t i a r y methyl), 9.08 ( s i n g l e t , 3H, t e r t i a r y methyl), 8.S5 and 8.94 (two overlapping s i n g l e t s , 3H, O - C - C H 3 ) , 8.76 ( s i n g l e t , 3H, 0-C-CH 3), 7.57 ( s i n g l e t , broad, 1H, methine alpha to ketone) and 7.26 (broad, 1H, h a l f peak width 12 Hz, -C-0H); mass spectrum, m/e ( r e l a t i v e i n t e n s i t y ) , 236 (11.6, M +), 178 (60.5), 163 (54.2), 95 (100), 51 (60.0) and 41 (81.5). - 183 -Mole. Wt. Calcd. f o r C 1 5 H 2 i t 0 2 : 236.1775. Found (high r e s o l u t i o n mass spectrometry): 236.1782. Alcohol 175 ( r e t e n t i o n time 60 minutes) showed data as f o l l o w s : i n f r a r e d ( C C l J , v 3620, 3440 and 1740 cm"1 ( d i l u t i o n v 4 max v from 0.064 M to 0.01 M increased the i n t e n s i t y of the band at 3620 r e l a t i v e to the 3440 cm"1 a b s o r p t i o n ) ; n.m.r. (CC1 4) (100 M Hz), x 9.12 ( s i n g l e t , 3H, t e r t i a r y methyl), 9.07 ( s i n g l e t , 3H, t e r t i a r y methyl), 8.87 ( s i n g l e t , broad, 3H, 0-C-CH 3), 8.80 ( s i n g l e t , broad, 3H, O-C-CH3), 7.80 ( s i n g l e t , broad, IH, methine), 7.70 (doublet, broad, IH, methine) and 7.43 ( s i n g l e t , broad, IH, h a l f peak width 2 Hz, -C-0H); mass spectrum, m/e ( r e l a t i v e i n t e n s i t y ) , 236 (13.6, M +), 95 (52.9), 93 (39.9), 59 (100), 51 (35.6) and 41 (44.8). Mole. Wt. Calcd. f o r C 1 5 H 2 J ) 2 : 236.1775. Found (high r e s o l u t i o n mass spectrometry): 236.1793. Preparation of Alkenes ]7j6_ and IZZ. Alcohol 175 (44 mg, 0.19m mole) i n 1 ml dry p y r i d i n e was t r e a t e d with 0.050 ml t h i o n y l c h l o r i d e f o r 30 minutes. The mixture was d i l u t e d with petroleum e t h e r and washed with water (three p o r t i o n s ) and saturated sodium c h l o r i d e and d r i e d over anhydrous sodium s u l f a t e . Solvent removal on a r o t a r y evaporator and f i n a l removal o f p y r i d i n e traces at 0.03 mm a f f o r d e d 37 mg (91%) of a 7:3 mixture o f keto alkenes 176 and 177 as judged by g . l . c . a n a l y s i s (column B, 150°, r e l a t i v e - 184 -times 9.0 and 11.5 minutes). P r e p a r a t i v e g . l . c . (column B, 150°) a f f o r d e d pure samples o f each component. Component 176 e x h i b i t e d the f o l l o w i n g : i n f r a r e d ( n e a t ) , vmax 3 1 0 0 ' 1 7 4 0 ' 1 6 5 0 a n d 8 9 0 c m _ 1 ' n-m- r- (CCM> T 9- 1 2 ( s i n g l e t , 3H, t e r t i a r y methyl), 9.08 ( s i n g l e t , 3H, t e r t i a r y methyl), 8.27 ( s i n g l e t , 3H, v i n y l methyl) and 5.15 ( m u l t i p l e t , 2H, =CH 2); mass spectrum, m/e ( r e l a t i v e i n t e n s i t y ) , 218 (51.5, M +), 95 (99.5), 79 (48.6), 69 (60.6), 55 (48.1), 43 (89.4) and 41 (100). Component 177 showed: i n f r a r e d ( n e a t ) , v 1740 cm" 1; x max n.m.r. ( C C 1 J , T 9.07 ( s i n g l e t , 6H, t e r t i a r y methyls), 8.37 and 8.28 (two s i n g l e t s , 6H, v i n y l methyls) and 7.06 ( s i n g l e t , 1H, a l l y l i c methine). Preparation of (±)-Copacamphor 52. Hydrogenation o f 176 using platinum oxide as the source o f c a t a l y s t with e t h y l a c e t a t e - a c e t i c a c i d (19:1) as s o l v e n t and an external sodium borohydride source o f hydrogen a f f o r d e d (±)-copa-camphor. A sample p u r i f i e d by p r e p a r a t i v e g . l . c . (column H, 220°) followed by evaporative d i s t i l l a t i o n e x h i b i t e d the f o l l o w i n g data: pc n^ 1.4898; homogeneous by g . l . c . a n a l y s i s with i d e n t i c a l r e t e n t i o n times ( c o - i n j e c t i o n ) to authentic (+)-copacamphor (123) on four columns (A, 150°; B, 150°, C, 150°, D, 175°); i n f r a r e d ( n e a t ) , v , v 1735 cm" 1; ma x n.m.r. (CDC1 3), x 9.11 (doublet, 3H, J = 6.5 Hz, secondary methyl), 9.10 ( s i n g l e t , 3H, t e r t i a r y methyl), 9.09 (doublet, 3H, J = 6.5 Hz, secondary methyl), 9.06 ( s i n g l e t , 3H, t e r t i a r y methyl) and 7.84 ( m u l t i -p l e t , 1H, methine alpha to ketone); mass spectrum, m/e ( r e l a t i v e - 185 -i n t e n s i t y ) , 220 (82.2, M +), 149 (36.6), 135 (40.5), 124 (100), 95 (55.5) and 41 (42.8). Anal. Calcd. f o r C 1 5H 2 1 +0: C, 81.76; H, 10.98. Found: C, 81.64; H, 11.07. Preparation o f Keto Alkenes IZ8. and 17_7 Keto alcohol 174 (39 mg, 0.17m mole) was dehydrated under analogous c o n d i t i o n s to those employed f o r 175 (1 ml p y r i d i n e , 0.050 ml t h i o n y l c h l o r i d e , 30 minutes). Work-up provided 26 mgs (72%) o f a 5:1 mixture o f 178 and 177, r e l a t i v e r e t e n t i o n times 9.0 and 11.5 minutes r e s p e c t i v e l y (column B, 150°). P r e p a r a t i v e g . l . c . (column B, 150°) provided pure samples of the two components and 177 e x h i b i t e d i d e n t i c a l c h a r a c t e r i s t i c s ( g . l . c , i n f r a r e d , n.m.r.) to those o f 177 i s o l a t e d i n the dehydration o f alcohol 175. Keto alkene 178 was c h a r a c t e r i z e d by the f o l l o w i n g data: i n f r a r e d ( n e a t ) , v m a x 3100, 1740, 1650 and 890 cm" 1; n.m.r. (CC1 U), T 9.12 ( s i n g l e t , 3H, t e r t i a r y methyl), 9.08 ( s i n g l e t , 3H, t e r t i a r y methyl), 8.26 ( s i n g l e t , 3H, v i n y l methyl) and 5.23 ( s i n g l e t , broad, 2H, =CH 2); mass spectrum, m/e ( r e l a t i v e i n t e n s i t y ) , 218 (96.5, M +), 124 (40.0), 123 (49.4), 107 (47.1), 95 (100) and 55 (37.4). Preparation o f (±)-Ylangocamphor 5.3. Hydrogenation of keto alkene 178 under analogous c o n d i t i o n s to those used i n the preparation o f copacamphor 52_ a f f o r d e d (±)-ylango-- 186 -camphor: n ^ 1.4909; homogeneous by g . l . c . a n a l y s i s on f o u r columns (A, 150°; B, 150°; C, 150°; D, 150°); i n f r a r e d ( n e a t ) , v m a v 1730 cm" 1; max n.m.r. (CDC1 3), x 9.20 (doublet, 3H, J = 6.5 Hz, secondary methyl), 9.11 ( s i n g l e t , 3H, t e r t i a r y methyl), 9.10 ( s i n g l e t , 3H, t e r t i a r y methyl), 9.03 (doublet, 3H, J = 6.5 Hz, secondary methyl) and 7.77 ( s i n g l e t , broad, IH, methine alpha to ketone); mass spectrum, m/e ( r e l a t i v e i n t e n s i t y ) , 220 (100, M +), 124 (73.1), 110 (72.3), 95 (69.8), 93 (62.5) and 41 (78.0). (162a,b; 127) Anal. Calcd. f o r C ^ r ^ O : C, 81.-6; H, 10.98. Found: C, 81.90; H, 10.84. Hydrogenation of Keto Alkene 1ZZ T e t r a s u b s t i t u t e d o l e f i n 177 was hydrogenated i n g l a c i a l a c e t i c a c i d over platinum oxide as the source o f c a t a l y s t (24 hours, atmospheric pressure) a f f o r d i n g a 5:1 mixture o f ylangocamphor 53 and copacamphor 52_ as judged by g . l . c . a n a l y s i s (column B, 150°, r e l a t i v e r e t e n t i o n times 6.5 and 8.5 minutes r e s p e c t i v e l y ) . I n f r a r e d and n.m.r. spectra were i n accord with t h i s assignment. Isomerization o f Alkenes 176 and 178 to 177 Treatment o f e i t h e r 176 or 178 (separate or as the mixture) f o r 1 hour ( e t h y l a cetate as s o l v e n t ) with palladium on carbon i n the presence o f hydrogen a f f o r d e d one component by g . l . c . a n a l y s i s (column B, 150°) with i n f r a r e d and n.m.r. sp e c t r a i d e n t i c a l to t e t r a s u b s t i t u t e d keto- al kene 177. - 187 -Large Scale Preparation o f Copacamphor 5JL and Ylangocamphor 53. For l a r g e s c a l e preparations o f 52_ and 53_ i t was found more convenient to employ a mixture o f campherenone 42_ and epicampherenone 45 as s t a r t i n g material. Epoxidation of 4.80 g o f a 1:1 mixture o f 42_ and 45 as p r e v i o u s l y d e s c r i b e d followed by c y c l i z a t i o n i n potassium t>butoxide (prepared from 4 g potassium metal and 100 ml dry t_-butanol) a f f o r d e d 4.99 g crude product. Dehydration with t h i o n y l c h l o r i d e i n p y r i d i n e followed by d i s t i l l a t i o n a f f o r d e d 2.03 g of mixed keto alkenes (epicampherenone epoxide y i e l d s an a l l y l i c a l c o h o l , r e s u l t i n g from epoxide opening i n the r e a c t i o n medium, and t h i s a l c o h o l i s e a s i l y removed i n the d i s t i l l a t i o n s t e p ) . Hydrogenation over 700 mg platinum oxide (9:1 ethyl a c e t a t e - a c e t i c a c i d ) a f f o r d e d q u a n t i t a t i v e l y a mixture of copacamphor and ylangocamphor (ca. 84% o v e r a l l based on campherenone) in the approximate r a t i o 45:55 r e s p e c t i v e l y . P r e p a r a t i v e g . l . c . (column H, 220°) followed by evaporative d i s t i l l a t i o n a f f o r d e d pure copa-camphor 52_ and ylangocamphor 53. Preparation of (±)-Sativene 60 Ylangocamphor 45_ (200 mg, 0.91m mole) was t r e a t e d with 35 mg (0.92 mole) l i t h i u m aluminum hydride i n dry t e t r a h y d r o f u r a n overnight. Careful a d d i t i o n o f water followed by ether e x t r a c t i o n (washing with water and s a t u r a t e d sodium c h l o r i d e ) , d r ying (anhydrous sodium s u l f a t e ) and s o l v e n t removal a f f o r d e d the crude alcohol which was chromato-graphed over 5 g s i l i c a gel y i e l d i n g 180 rngs (89%) an o i l which c r y s t a l -- 188 -1i z e d on standing overnight.mp 41-42°. The s o l u b i l i t y of compound 58b (isoylangoborneol) made r e c r y s t a l l i z a t i o n very d i f f i c u l t : i n f r a r e d ( n e a t ) , v 3500 and 1095 cm" 1; n.m.r. (C C 1 4 ) , T 9.21 ( s i n g l e t , 3H, Hid A t e r t i a r y methyl), 9.16 ( s i n g l e t , 3H, t e r t i a r y methyl), 9.08 (doublet, 1H, J = 7.5 Hz, -CHOH, exo a l c o h o l ) ; (C 5H 5N), T 9.13 ( s i n g l e t , 3H, t e r t i a r y methyl), 8.94 ( s i n g l e t , 3H, t e r t i a r y methyl), 8.94 (doublet, 6H, secondary methyls) and 5.97 ( m u l t i p l e t , 1H, -CHOH). Treatment of 150 mg (0.68m mole) o f 58Jb wi th 0.10 ml (1.3m mole) methanesulfonylchloride i n 1 ml dry p y r i d i n e (105°) overnight followed by the usual work-up (see p r e p a r a t i o n o f (±)-$-santalene) a f f o r d e d a f t e r column chromatography, 73 mg (53%) ( t ) - s a t i v e n e 60. D i s t i l l a t i o n provided 60 mg pure compound: bp (bath temperature) 60° (1 mm); i n f r a r e d ( n e a t ) , v m,„ 3080, 1660 and 875 cm" 1; n.m.r. ma x (CC1 4), T 9.15 (doublet, 3H, J = 3.5 Hz, secondary methyl), 9.09 (doublet, 3H, J = 3.5 Hz, secondary methyl), 8.98 ( s i n g l e t , 3H, t e r t i a r y methyl), 7.40 ( s i n g l e t , broad, 1H, a l l y l i c methine), 5.59 and 5.27 (two s i n g l e t s , 2H, -CH 2); mass spectrum, m/e ( r e l a t i v e i n t e n s i t y ) , 204 (52.3, M +), 161 (57.5), 108 (100), 105 (41.8), 91 (43.8), and 41 (44.4). (160a,b; 36) Preparation of Acetal 182. A s o l u t i o n of 25.0 g (0.167 mole) (-)-carvone [(«) 3 0 -58.6° (c 4.78, CHC1 3)], 20 g 2,2-dimethyl-1,3-dioxane and 250 mg o x a l i c a c i d i n 350 ml benzene was r e f l u x e d 5 days in a Dean-Stark apparatus with molecular s e i v e s added to the s i d e arm t r a p to a i d i n water removal. - 189 -G.l.c. analysis (column A, 160°) indicated roughly 30% conversion to acetal and the ratio of product to starting material did not change significantly with longer reaction time. The cooled reaction mixture was washed with saturated sodium bicarbonate and saturated sodium chloride and dried over anhydrous sodium sulfate. Solvent removal followed by solution in dry pentane and storage at -10° afforded four batches of crystals totalling 12.8 g (32%, mp 80.5-82.5°). From the mother liquor was obtained a near quantitative recovery of carvone and ketal by distillation of the carvone (16.5 g, 66%; bp 48°, 0.3 mm) and recrystallization of the residue. A recrystallized sample of the acetal 182 gave the following data: mp 82-82.5°; («) 3 0 -71.8° (c 10.26, CHC13); infrared (mull), v m a x 3100, 1650, 1125, 1105, 1070 and 890 cm"1; n.m.r. (CCliJ, x 9.25 (singlet, 3H, tertiary methyl), 8.77 (singlet, 3H, tertiary methyl), 8.23 (multiplet, 3H, vinyl methyl), 7.67 (multi-plet, IH, major coupling J = 12 Hz, methine), 6.75 (multiplet, 2H, major coupling J = 11.5 Hz, acetal methylenes), 6.32 (quartet, 2H, J = 11.5 Hz and J = 3.5 Hz) acetal methylenes), 5.28 (singlet, broad, 2H, =CH2) and 4.52 (multiplet, IH, olefinic proton); mass spectrum, m/e (relative intensity), 236 (4.4, M+), 168 (100), 109 (18.9), 82 (76.3), 69 (35.4) and 41 (25.8). Anal. Calcd. for C15H21+02: C, 76.23; H, 10.24. Found: C, 76.06; H, 10.31. Preparation of (-)-Cryptomerion 99a. (-)-Carvone acetal 182_ (6.00 g, 0.0254 mole) in 20 ml dry - 190 -pentane was t r e a t e d at 0° with 22 ml (0.052 mole) n_-butyl! ithium (2.38 M i n hexane) followed by 7.7 ml (6.0 g, 0.051 mole) TMEDA ( d r i e d over molecular s e i v e s ) and the r e a c t i o n stood overnight in a dry n i t r o g e n atmosphere. The s o l v e n t was pumped o f f from the dark red residue which had formed and, a f t e r an atmosphere o f dry n i t r o g e n had been r e s t o r e d , 20 ml o f dry t e t r a h y d r o f u r a n was added with r a p i d s w i r l i n g to e f f e c t s o l u t i o n . Immediately upon s o l u t i o n the r e a c t i o n mixture was cooled to -70° and 3.0 ml (2.8 g, 0.027 mole) l - c h l o r o - 3 -methyl-2-butene was added dropwise. Slow warming to room temperature and the usual work-up (see preparation of 117) followed by h y d r o l y s i s (150 ml acetone, 1 ml 6N h y d r o c h l o r i c acid) and d i s t i l l a t i o n a f f o r d e d 1.20 g (32%) recovered (-)-carvone, (cc) 3 1 -58.2° (c 5.43, CHC1 3), followed by 728 mg o f two monoalkylated products (91% pure by g . l . c . a n a l y s i s , t h e r e f o r e 19% y i e l d o f monoalkylated material based on consumed carvone a c e t a l ) . The two products were i n the r a t i o 1:4 by g . l . c . a n a l y s i s (column A, 175°, r e t e n t i o n times 4.5 and 5.4 minutes r e s p e c t i v e l y ) . Pure samples were i s o l a t e d by p r e p a r a t i v e g . l . c . (column G, 240°) followed by evaporative d i s t i l l a t i o n . The minor product 183 e x h i b i t e d the f o l l o w i n g : u l t r a v i o l e t , 234 nm ( £ 7230); i n f r a r e d ( n e a t ) , v _ 3100, 1675, 892 and 830 cm" 1; max max n.m.r. ( C C ! 4 ) , x 8.42 and 8.40 (two s i n g l e t s , broad 6H, v i n y l methyls), 8.23 ( m u l t i p l e t , 3H, v i n y l methyl), 5.23 ( m u l t i p l e t , 2H, =CH 2), 4.98 ( m u l t i p l e t , 1H, o l e f i n i c p r o t o n ) , and 3.43 ( m u l t i p l e t , 1H, o l e f i n i c proton). The major component, r e t e n t i o n time 5.4 minutes, was i d e n t i -f i e d as (-)-cryptomerion 99a on* the basis o f the f o l l o w i n g evidence: - 191 -n n 1.5058; H l 9 -39.3° (c 1.45, CHC1 3); u l t r a v i o l e t (EtOH), X av u u ma x 235 and 317 nm (e 8800 and 43) [ l i t . n p 6 1.5050; ( « ) D -38° (c 1.45 chloroform); \ (EtOH), 236 and 304 nm (e 9600 and 110) ( 7 5 ) ] ; i n f r a -red ( n e a t ) , v m a x 3100, 1680, 1645, 897 and 825 cm" 1; n.m.r. ( C C l i J , T 8.38 ( s i n g l e t , 3H, v i n y l methyl), 8.30 ( m u l t i p l e t , 6H, v i n y l methyls), 5.18 ( s i n g l e t , 2H, =CH 2), 4.93 ( m u l t i p l e t , IH, o l e f i n i c proton) and 3.38 ( m u l t i p l e t , IH, o l e f i n i c p roton); mass spectrum, m/e ( r e l a t i v e i n t e n s i t y ) , 218 (10.9, M +), 148 (33.2), 135 (27.6), 109 (49.5), 69 (100) and 41 (85.2). (162a,b; 75) Anal. Calcd. f o r C 1 5 H 2 2 0 : C, 82.51; H, 10.16. Found: C, 82.77; H, 10.07. A l t e r n a t i v e Preparation o f (-)-Cryptomerion 99a (169) To 250 mg (1.1m mole) dihydrocryptomerion 75a (prepared by a l k y l a t i o n o f dihydrocarvone acetal 116a,b) i n 6 ml t e t r a h y d r o f u r a n was added 600 mg phenyltrimethylammonium tribromide (134). Reaction appeared instantaneous as judged by the disappearance o f c o l o r from the reagent. Saturated sodium bicarbonate was added and s t i r r e d 10 minutes a f t e r which time the crude bromo ketone was recovered by ether e x t r a c t i o n , washing with s a t u r a t e d sodium c h l o r i d e and d r y i n g over anhydrous sodium s u l f a t e . A f t e r solvent removal, the crude product was d i s s o l v e d i n 5 ml p y r i d i n e and r e f l u x e d 40 minutes. The cooled r e a c t i o n mixture was e x t r a c t e d with e t h e r , washing with d i l u t e h y d r o c h l o r i c a c i d , s a t u r a t e d sodium bicarbonate and water. A f t e r d r y i n g (anhydrous sodium s u l f a t e ) and s o l v e n t removal, chromatography - 192 -over s i l i c a gel provided 180 mg (72%) of (-)-cryptomerion 99a. A 29 d i s t i l l e d sample e x h i b i t e d s p e c i f i c r o t a t i o n [(<*) ^ -37° (c 2.65, CHC1 3)] and s p e c t r a l data ( i n f r a r e d , n.m.r.) i n agreement with (-)-cryptomerion obtained by a l k y l a t i o n o f carvone a c e t a l 182. P h o t o l y s i s of (-)-Cryptomerion 99a (-)-Cryptomerion 99a (250 mg, 1.10m mole) i n 250 ml 95% ethanol (degassed with nitrogen) was photolyzed i n a pyrex vessel 74 hours with the r a d i a t i o n from a Westinghouse 275 Watt sun lamp passed through a 20 mm Corning No. 7380 f i l t e r (transmittence approaches zero at wavelengths s h o r t e r than 340 nm). E s s e n t i a l l y one product was formed i n the p h o t o l y s i s . The r a t i o of s t a r t i n g material to photo-product was t e s t e d a t i n t e r v a l s by g . l . c . as i n d i c a t e d below (column A, 175°, r e t e n t i o n times 3.9 and 5.4 minutes f o r photoproduct and s t a r t -ing material r e s p e c t i v e l y ) . Time (hr) % S t a r t i n g M a t e r i a l % Product 11 93 7 31 68 32 50 50 50 74 27 73 Longer periods of i r r a d i a t i o n f a i l e d to improve the r a t i o of photo-product to s t a r t i n g m a t e r i a l . P reparative g . l . c . (column G, 240°) allowed recovery o f s t a r t i n g material which was i d e n t i c a l ( i n f r a r e d spectrum, g . l . c . r e t e n t i o n time) with our s y n t h e t i c (-)-cryptomerion. - 193 -Attempts to i s o l a t e the p h o t o l y s i s product under i d e n t i c a l g . l . c . c o n d i t i o n s l e d to degradation as i n d i c a t e d by the appearance o f a new product (30%) i n the a n a l y t i c a l g . l . c . t r a c e of the i s o l a t e d photo-product (column A, 175°, r e t e n t i o n time 4.5 minutes). Column chromato-graphy o f the p h o t o l y s i s mixture over s i l i c a gel and over aluminum oxide allowed i s o l a t i o n o f a pure sample o f the photoproduct, photo-PR cryptomerion 189: ( = ) jj° -41° (c 1.5, CHC1 3); u l t r a v i o l e t , absence o f strong absorbance i n the 235 nm r e g i o n ; i n f r a r e d (neat),v 1735,1410 max and 835 cm" 1; n.m.r. ( C C 1 J , T 8.93 ( s i n g l e t , 3H, t e r t i a r y methyl), 8.40 and 8,32 (two s i n g l e t s , broad, 6H, v i n y l methyls) and 4.96 ( m u l t i -p l e t , 1H, o l e f i n i c p r o t o n ) ; mass spectrum, m/e ( r e l a t i v e i n t e n s i t y ) , 218 (53.6, M +), 151 (42.5), 110 (42.2), 108 (41.1), 92 (42.8) and 70 (100). Mole. Wt. Calcd. f o r C 1 5 H 2 2 0 : 218.1670. Found (high r e s o l u t i o n mass spectrometry): 218.1662. Formolysis of Natural g-, and Epi-g-Santalene A mixture of the n a t u r a l l y o c c u r r i n g santalenes (3.10 g; i n the r e l a t i v e r a t i o 4.3:1.0:3.0 f o r <*-, g- and epi-g-santalene respec-t i v e l y ) i n 10 ml formic a c i d (> 98%) was s t i r r e d at 50° f o r 44 hours. Work-up (washing twice with s a t u r a t e d sodium c h l o r i d e , saturated bicarbonate, and again with s a t u r a t e d sodium c h l o r i d e followed by d r y i n g over anhydrous sodium s u l f a t e and s o l v e n t removal) and sub-sequent d i s t i l l a t i o n a f f o r d e d one major product i n good y i e l d (71% by g . l . c . ) which showed the f o l l o w i n g : i n f r a r e d ( n e a t ) , v 797 cm" 1; - 194 -n.m.r. (CC1 4), T 9.05 ( s i n g l e t , 6H, t e r t i a r y methyls). 8.96 (doublet, 6H, J = 7 Hz, secondary methyls), 7.97 (doublet, 2H, J = 2Hz, a l l y l i c methylenes) and 4.68 ( t r i p l e t , 1H, J = 2 Hz, o l e f i n i c proton). Preparation of (+)-3,9-Dibromocamphor 204. Following the procedure o f Corey et a l . (45), 120 ml c h l o r o -s u l f o n i c a c i d , cooled in an i c e bath, was t r e a t e d with 36 ml (112 g, 0.70 mole) bromine followed by 150 g (0.65 mole) o f (+)-3-bromocamphor [ ( * ) Q 5 +134° (c 14.6, CHC1 3)] i n one p o r t i o n . A f t e r approximately 1 hour s t i r r i n g , the exothermic r e a c t i o n r e q u i r e d c o o l i n g with a water bath to moderate the r e a c t i o n temperature. Rapid e v o l u t i o n o f hydrogen bromide was observed throughout the r e a c t i o n . A f t e r 4 hours the r e a c t i o n mixture was poured i n t o 500 cc crushed i c e and a d d i t i o n a l i c e was added with s t i r r i n g u n t i l the product became granular. Excess bromine was destroyed with sodium b i s u l f i t e and the product was f i l t e r e d and washed (500 ml water, 200 ml 5% sodium hydroxide and 400 ml water). A f t e r p r e s s i n g dry, the crude product was d i s s o l v e d i n methylene c h l o r i d e and d r i e d over anhydrous sodium s u l f a t e . The s o l u t i o n was d i l u t e d with methanol and the s o l v e n t removed under vacuum u n t i l c r y s t a l s formed. The s o l u t i o n was allowed to stand at 25° and than at 0°. F i l t r a t i o n a f f o r d e d 107 g (53%) mp 151-155° (majority melting 145-156°) [ l i t . mp 152-156° (45)]. Concentration of the mother l i q u o r y i e l d e d another 54 g which was d i f f i c u l t to p u r i f y through f u t h e r r e c r y s t a l l i z a t i o n s . A sample o f the i n i t i a l crop of c r y s t a l s was r e c r y s t a l l i z e d from methanol 33 and e x h i b i t e d the f o l l o w i n g c h a r a c t e r i s t i c s : mp 156-158.5°, («) n +136° - 195 -(c 10.01, C H C l 3 ) [ l i t . («) D + 98.8° (c 4.0, CHC1 3)(170)]; u l t r a v i o l e t , xm a v 3 0 5 n m ( £ 2 3 ° ) i i n f r a r e d (KBr), v a v 1745 cm" 1, n.m.r. (CDC1 3), i n a x max x 8.95 ( s i n g l e t , 3H, t e r t i a r y methyl), 8.89 (doublet, 3H, J = 1.5 Hz, t e r t i a r y methyl), 6.34 (doublet o f m u l t i p l e t s ) and 6.71 (doublet) (ABX p a t t e r n , 2H, J f t B = 10 Hz, u* A X = 1.5 Hz, J * B X = 0 Hz, CH 2Br) and 5.42 (doublet, IH, J = 5 Hz, -CHBr); mass spectrum, m/e ( r e l a t i v e i n t e n s i t y ) , 312 (15.7, M +), 310 (29.5, M +), 308 (16.9, M +), 232 (65.6), 230 (66.2), 204 (62.6), 202 (66.9), 122 (84.4), 81 (81.4), 69 (73.5) and 41 (100). (162a,b; 144) Preparation of (+)-9-Bromocamphor 20JL Reduction o f (+)-3,9-dibromocamphor was achieved as p r e v i o u s l y described (45) by treatment o f 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 100 g (0.322 mole) o f the dibromide i n 400 ml methylene c h l o r i d e with 70 g (1.1 mole) z i n c powder and a slow stream o f hydrogen bromide bubbled i n t o the r e a c t i o n mixture. A f t e r 4 hours the mixture was f i l t e r e d , washed with water, saturated sodium bicarbonate and s a t u r a t e d sodium c h l o r i d e , and d r i e d over anhydrous sodium s u l f a t e . Removal o f s o l v e n t and r e c r y s t a l 1 i z a t i o n from petroleum ether a f f o r d e d 63.5 g (85%) o f (+)-9-bromocamphor, mp 93-94.5°. One f u r t h e r r e c r y s t a l l i z a t i o n provided a pure sample: mp 95-95.5° (cc) 3 2 + 110° (c 0.934, absolute e t h a n o l ) ; u l t r a v i o l e t , X m a v 290 nm ( e 64) [ l i t . mp 93-95° (45); (<*) 2 3 +109° max u (c 0.93, 95% ethanol)(144); \ v (ethanol) 291 nm ( e 63)(147)]; ma x i n f r a r e d (KBr), v m a x 1740 and 1418 cm" 1; n.m.r. (CDC1 3), T9.02 ( s i n g l e t , 3H, t e r t i a r y methyl), 8.99 (doublet, 3H, J = 1 Hz, t e r t i a r y methyl), - 196 -6.76 (doublet) and 6.41 (doublet o f m u l t i p l e t s ) ( A B X p a t t e r n , 2H, J ^ B = 10 Hz, = 1 Hz, Jgj, = 0 Hz, CH 2Br); mass spectrum, m/e ( r e l a t i v e i n t e n s i t y ) , 232 (17.5, M +), 230 (17.5, M +), 109 (53.7), 108 (57.0), 107 (75.9), 81 (100) and 41 (53.2). (162a,b; 144) Preparation of 9-Bromocamphor Ethylene A c e t a l 20j6 (+)-9-Bromocamphor (5.00 g, 0.0216 mol) i n benzene was t r e a t e d with 8 ml ethylene g l y c o l and 500 mg p_-toluenesulfonic a c i d a t r e f l u x i n a Dean-Stark water separator f o r 36 hours. The r e a c t i o n mixture was cooled, washed with s a t u r a t e d sodium bicarbonate and saturated sodium c h l o r i d e and d r i e d over anhydrous sodium s u l f a t e . Solvent removal followed by vacuum d i s t i l l a t i o n a f f o r d e d , a f t e r a forerun o f 740 mg of the a c e t a l c o n t a i n i n g t r a c e o f ketone, 4.68 g (79%) 206: bp 64-65° (0.06 mm); n 2 5 1.5208; («) 2 4 +1.2 (c 7.46, CHC1 3); i n f r a -red ( n e a t ) , v 1120 cm" 1; n.m.r. ( C C l J , T 9.20 ( s i n g l e t , 3H, t e r t i a r y methyl), 8.83 (doublet, 3H, J = 1.5 Hz, t e r t i a r y methyl), 6.90 (doublet) and 6.47 (doublet o f quartets)(ABX p a t t e r n , 2H, J f t B = 10.5 Hz, J A X = 1.5 Hz, J B X = 0 Hz, CH 2Br) and 6.20 ( m u l t i p l e t , 4H, -0CH 2CH 20-); mass spectrum, m/e ( r e l a t i v e i n t e n s i t y ) , 276 (1.3, M +), 274 (1.3, M +), 195 (100), 109 (44.2), 95 (37.7), 87 (56.8) and 41 (21.4). (162b; 142) Preparation of 9-Iodocamphor Ethylene Acetal 201 A s o l u t i o n o f bromo ace t a l 206 (4.40 g, 0.016 mole) i n 40 ml dry d i m e t h y l s u l f o x i d e was t r e a t e d with 15 g (0.10 mole) sodium i o d i d e - 197 -( d r i e d over phorphorus pentoxide, 1mm, 24 hours) i n the presence o f 5 g anhydrous calcium carbonate at 110° f o r three days (dry n i t r o g e n atmos-phere). The cooled r e a c t i o n mixture was d i l u t e d with sodium bicarbonate s o l u t i o n and e x t r a c t e d with three 100 ml p o r t i o n s o f petroleum e t h e r , washing each with saturated sodium bicarbonate and s a t u r a t e d sodium c h l o r i d e and d r y i n g over anhydrous sodium s u l f a t e . A n a l y s i s by g . l . c . i n d i c a t e d two components i n the approximate r a t i o 1:4 (column A, 175°, r e t e n t i o n times4.2 and 6.3 minutes r e s p e c t i v e l y ) corresponding to s t a r t i n g material and iodo a c e t a l 201. D i s t i l l a t i o n twice a f f o r d e d 1.48 g mixed s t a r t i n g material and 201 followed by 2.83 g (55%) a c e t a l 201 or an o v e r a l l y i e l d o f greater than 83%. Pure iodo a c e t a l 201 was c h a r a c t e r i z e d as f o l l o w s : bp 75° (0.05 mm); n ^ 1.5502; (*) ^ -2.2° (c 5.00, CHC1 3); i n f r a r e d ( n e a t ) , v 1120 cm" 1; n.m.r. ( C C 1 J , x 9.19 II Id A ( s i n g l e t , 3H, t e r t i a r y methyl), 8.85 (doublet, 3H, J = 1.5 Hz, t e r t i a r y methyl), 7.08 (doublet) and 6.62 (doublet o f quartets)(ABX p a t t e r n , 2H, J A B = 9.5 Hz, J M = 1.5 Hz, J g x = 0 Hz, -CH 2I) and 6.11 ( m u l t i p l e t , 4H, -0CH 2CH 20-); mass spectrum, m/e ( r e l a t i v e i n t e n s i t y ) , 195 (85.0, M + - I ) , 109 (100), 87 (95.9), 67 (78.1) and 41 (90.4). Anal. Calcd. f o r C 1 2 H 1 9 0 2 I : C, 44.73; H, 5.94; I, 39.39. Found: C, 44.90; H, 6.03; I, 39.21. Preparation o f (+)-Epicamphorenone 45a To 20 ml dry benzene was added 6 ml (7.9 g, 45m mole) n i c k e l carbonyl (fume hood)(171) and 3 ml (3.8 g, 25m mole) 1-bromo-3-methyl-2-butene and the r e a c t i o n was s t i r r e d 2.5 hours at 50° under an atmos-- 198 -phere o f dry nit r o g e n . Solvent was removed under vacuum and 20 ml o f dry dimethylformamide was added. When a l l the red-brown s o l i d was d i s s o l v e d , 1.50 g (4.7m mole) acetal i o d i d e 201 i n 5 ml dry dimethyl-formamide was added and the r e a c t i o n s t i r r e d 14 hours at 55-60° (n i t r o g e n atmosphere). G.l.c. a n a l y s i s o f an a l i q u o t i n d i c a t e d only p a r t i a l r e a c t i o n and thus more o f the n i c k e l complex (prepared e x t e r -n a l l y from 12.5m mole o f l-bromo-3-methyl-2-butene) was added and the r e a c t i o n continued 48 hours at 55-60°. The r e a c t i o n mixture was poured i n t o d i m e t h y l s u l f o x i d e and e x t r a c t e d with several p o r t i o n s o f petroleum et h e r , washing with water and satura t e d sodium c h l o r i d e and dr y i n g (anhydrous sodium s u l f a t e ) . Solvent removal and d i s t i l l a t i o n followed by column chromatography over s i l i c a gel a f f o r d e d 468 mg o f material which was l a r g e l y epicampherenone (before chromatography epicamphere-none and epicampherenone ac e t a l were present i n the r a t i o o f 3:7). Estimated y i e l d o f coupled product was ca. 40-45%. Pure (+)-epicamphere-none, obtained by pr e p a r a t i v e g . l . c . (column G, 240°), followed by 27 evaporative d i s t i l l a t i o n , e x h i b i t e d the f o l l o w i n g : (°0 D +84.4° (c 4.88, CHC1 3); [ 0 ] ^3 " 2- 2 * 1 Q l + (c 0.0027, CH3CN) [0] £93 + 1 - 4 x 1C )1+ (c 0.054, CH 3CN); i d e n t i c a l i n g . l . c . and s p e c t r a l c h a r a c t e r i s t i c s ( i n f r a r e d , n.m.r.) with (±)-epicampherenone p r e v i o u s l y synthesized. Preparation o f (+)-Epi-B-Santalene 5J2a. (+)-Epicampherenone (150 mg, 0.68m mole) was reduced (as p r e v i o u s l y d e s c r i b e d f o r the racemic m a t e r i a l ) with l i t h i u m trimeth-oxyaluminohydride i n tetrahydrofuran a f f o r d i n g , a f t e r chromatography over 5 g s i l i c a g e l , 140 mg (93%) isoepicampherenol (+)-49b: - 199 -(°0 p +7.0° (c 5.10, CHC1 3); g . l . c . a n a l y s i s and s p e c t r a l c h a r a c t e r -i s t i c s ( i n f r a r e d and n.m.r.) were i n f u l l agreement with p r e v i o u s l y synthesized (±)-isoepicampherenol. The e n t i r e sample o f ( + ) - i s o e p i -campherenol was t r e a t e d with 500 mg p_-toluenesulfonyl c h l o r i d e i n 1 ml p y r i d i n e and the mixture heated 19 hours a t 90-92°. I s o l a t i o n as p r e v i o u s l y d e s c r i b e d followed by p r e p a r a t i v e g . l . c . (column G, 160°) and evaporative d i s t i l l a t i o n a f f o r d e d pure (+)-epi - e-santalene: pq («) p +26.9° (c 2.6, CHC1 3) [a sample o f natural (+)-epi-3-santalene i s o l a t e d i n our l a b o r a t o r y from sandalwood o i l (120) e x h i b i t e d : pq ( « ) - Q +23.3° (c 4.12, CHCla)]; i n f r a r e d and n.m.r. sp e c t r a were i n f u l l agreement with racemic material p r e v i o u s l y prepared; mass spectrum, m/e ( r e l a t i v e i n t e n s i t y ) , 204 (9.6, M +), 122 (55.9), 94 (100), 93 (24.3), 79 (19.2) and 41 (39.0). Preparation of (+)-9-Acetoxycamphor 208 In accordance with the procedure of Guha and Bhattacharyya, 60.0 g (0.260 mole) (+)-9-bromocamphor and 120 g (1.2 mole) anhydrous potassium acetate were d i s s o l v e d i n 115 ml a c e t i c a c i d with heating and the r e s u l t i n g s o l u t i o n was r e f l u x e d (175-185° o i l bath) 48 hours. The hot r e a c t i o n mixture was poured i n t o c o l d water, n e u t r a l i z e d by c a r e f u l a d d i t i o n of s o l i d sodium bicarbonate and e x t r a c t e d with four 350 ml portions of e t h e r , washing each p o r t i o n twice with water. The s o l v e n t was removed and the r e s i d u e was taken up i n petroleum ether and d r i e d over anhydrous sodium s u l f a t e . Evaporation of s o l v e n t y i e l d e d 54 g crude acetate which was d i s t i l l e d a f f o r d i n g 52.0 g (95%) - 200 -(+)-9-acetoxycamphor 208: bp 70° (0.05 mm)[lit. bp 123°, 5 mm (149)]; n 2 5 1.4760; («)p° +53.2° (c 0.881, CHC1 3); u l t r a v i o l e t , * m a x 288 nm (e 3 4 ) [ l i t . X m a v (ethanol) 289 nm (e 40)(147)]; i n f r a r e d ( n e a t ) , v max max 1745 and 1230 cm" 1; n.m.r. (CDC1 3), T 9.05 ( s i n g l e t , 3H, t e r t i a r y methyl), 9.01 ( s i n g l e t , 3H, t e r t i a r y methyl), 7.89 ( s i n g l e t , 3H, a c e t a t e methyl), 6.02 and 5.82 (AB q u a r t e t , 2H, J = 11.5 Hz, CH 2-0-); mass spectrum, m/e, 210 (M +), 122, 108, 107, 95, 93 and 43. (162a,b; 144) Preparation of (+)-9-Hydroxycamphor 209 This compound was prepared f o l l o w i n g the procedure o f Corey et a l . (145). A s o l u t i o n of 50 g (0.89 mole) potassium hydroxide i n 400 ml 95% ethanol was heated to r e f l u x temperature and 52.0 g (0.247 mole) (+)-9-acetoxycamphor i n 100 ml 95% ethanol was added. A f t e r r e f l u x with vigorous s t i r r i n g f o r 1 hour the s o l v e n t was evaporated under reduced pressure u n t i l c r y s t a l s formed. The residue was d i l u t e d with water and saturated sodium c h l o r i d e and e x t r a c t e d with ether, washing twice with saturated sodium c h l o r i d e and d r y i n g over anhydrous sodium s u l f a t e . Solvent removal a f f o r d e d crude c r y s t a l l i n e 208 which was r i n s e d with small p o r t i o n s of petroleum ether u n t i l c o l o r l e s s (44.5 g). R e c r y s t a l l i z a t i o n from 1:5 petroleum ether-ether provided 38.0 g (91%) of the hydroxy camphor (mp 237-239°). One f u r t h e r r e c r y s t a l l i z a t i o n a f f o r d e d a pure sample e x h i b i t i n g the f o l l o w i n g c h a r a c t e r i s t i c s : mp 237-239°; («) 3 2 +61.2° (c 0.873, absolute e t h a n o l ) ; u l t r a v i o l e t , X m a x 290 (E 3 3 ) [ l i t . mp 238-240° (145); 243.5-244° (144); («) 2 3 +63.1° (c 0.87, 95% ethanol)(144); x a v (ethanol) 290 ( e 34)(147)]; i n f r a r e d max - 201 -( K B r ) > v m a v 3 5 2 0 > 1 7 3 0 » 1 4 1 5 a n d ! 0 2 5 cm"1; n.m.r. (CDC1 3), T 9.02 max ( s i n g l e t , 6H, t e r t i a r y methyls), 7.98 ( s i n g l e t , overlapping a m u l t i p l e t , IH, CH 20H), 6.48 and 6.27 (AB q u a r t e t , 2H, J = 11 Hz, CHj,0H); mass spectrum, m/e ( r e l a t i v e i n t e n s i t y ) , 168 (29.8, M +), 137 (31.8), 109 (30.2), 108 (63.7), 95 (100) and 41 (36.8). (162a,b; 144) Preparation of ( + ) - t r a n s - I s o k e t o p i n i c Acid 2 1 0 The o x i d a t i o n of (+)-9-hydroxycamphor was performed i n accordance with the procedure of Corey e t a l . ( 1 4 5 ) . To a s o l u t i o n of 8 6 g ( 0 . 8 6 mole) chromium t r i o x i d e and 1 4 6 g ( 0 . 8 6 mole) manganous s u l f a t e monohydrate i n 2 2 0 ml water was added slowly 26 ml (ca. 0 . 4 8 mole) concentrated s u l f u r i c a c i d followed by the a d d i t i o n with vigorous s t i r r i n g of 3 6 . 2 g ( 0 . 2 1 5 mole) (+)-9-hydroxycamphor i n 6 0 0 ml water over a perio d of 1 . 5 hours. The r e a c t i o n mixture was s t i r r e d 8 hours at 2 5 ° and 8 hours more a t 6 5 ° . A f t e r c o o l i n g and d i l u t i n g with saturated sodium c h l o r i d e s o l u t i o n , the a c i d was removed by e x t r a c t i o n with f o u r 2 5 0 ml p o r t i o n s of ether, washing each e x t r a c t with saturated sodium c h l o r i d e . P u r i f i c a t i o n of the a c i d by e x t r a c t i o n with 2 N aqueous sodium hydroxide followed by a c i d i f i c a t i o n with 6 N hydro-c h l o r i c a c i d and r e - e x t r a c t i o n with three 2 5 0 ml p o r t i o n s of ether a f f o r d e d a f t e r s o l v e n t removal 3 4 . 3 g of n e a r l y pure a c i d . R e c r y s t a l -l i z a t i o n from acetone y i e l d e d 3 0 . 8 g ( 7 9 % ) of 2 1 £ mp 2 5 5 - 2 5 7 ° . One fu r t h e r r e c r y s t a l l i z a t i o n a f f o r d e d a pure sample: mp 2 5 6 - 2 5 7 ° ; ( < x ) 3 2 + 1 . 4 ° (c 0 . 8 9 9 , absolute ethanol ) [ l i t . mp 2 4 8 - 2 5 1 ° ( 1 4 5 ) , - 202 -257-258° (144); («)£' +3.2 (c 5.0, absolute ethanol (150); [ « ] " +5.9° (c 0.90, 95% e t h a n o l ) ( 1 4 4 ) ] ; u l t r a v i o l e t , x 214 nm (shoulder, e 7 3 ) , max 288 nm ( e 30); i n f r a r e d (KBr), v v 3100, 1730, 1705 ( s h o u l d e r ) , 1405 max and 1220 cm" 1; n.m.r. (CDC1 3), x 8.79 ( s i n g l e t , 3H, t e r t i a r y methyl), 8.74 ( s i n g l e t , 3H, t e r t i a r y methyl) and -0.97 ( s i n g l e t , broad, 1H, C00H); mass spectrum, m/e ( r e l a t i v e i n t e n s i t y ) , 182 (12.4, M +), 108 (42.9), 95 (72.6), 93 (49.1), 69 (78.2), 43 (100) and 41 (91.0). (162a,b; 144) Preparation of Lactone 212a Lactone 212a was prepared a f t e r the procedure of Corey e t a l . (145). ( + ) - T r a n s - i s o k e t o p i n i c a c i d 2]_0 (9.10 g, 0.050 mole) was d i s -solved i n 250 ml methanol and n e u t r a l i z e d with 10% methanolic potassium hydroxide u n t i l j u s t a l k a l i n e to phenolphthalein. Sodium borohydride (20 g, 0.53 mole) was added i n one p o r t i o n and the r e a c t i o n was s t i r r e d a t room temperature 12 hours using a cold water bath as needed to moderate the r e a c t i o n . The s o l v e n t was removed under reduced pressure and the residue taken up i n water, a c i d i f i e d with 6 N h y d r o c h l o r i c a c i d , and e x t r a c t e d f o u r times with ether, washing each e x t r a c t with saturated sodium c h l o r i d e . The ether e x t r a c t s were evaporated and the residue was taken up i n methylene c h l o r i d e and d r i e d over anhydrous sodium s u l f a t e . Removal of s o l v e n t a f f o r d e d 9.39 g (9.2 g t h e o r e t i c a l y i e l d ) of the crude hydroxy a c i d 211: n.m.r. (CDC1 3), x 8.73 ( s i n g l e t , 3H, t e r t i a r y methyl), 8.59 ( s i n g l e t , 3H, t e r t i a r y methyl), 6.40 ( t r i p l e t s J = 6 Hz) and 6.03 ( m u l t i p l e t ) ( t o t a l of 1H, epimeric -CHOH) and 3.56 ( s i n g l e t , broad, 2H -CHOHi and -C00H_). The crude hydroxy a c i d (a mixture - 203 -of the exo and endo a l c o h o l s i n the r a t i o 6:4 i s judged by the r e l a t i v e i n t e g r a l areas o f the protons a t 6.40 and 6.03 T r e s p e c t i v e l y i n the n.m.r. spectrum) was used without f u r t h e r p u r i f i c a t i o n i n the l a c t o n i -z a t i o n step. Thus 9.39 g of 21J_ was d i s s o l v e d i n a s o l u t i o n of 100 ml t r i f l u o r o a c e t i c a c i d to which 20 ml concentrated s u l f u r i c a c i d had been added and the s o l u t i o n was r e f l u x e d 2.5 hours. Approximately 80% of the t r i f l u o r o a c e t i c a c i d was recovered by d i s t i l l a t i o n from the r e a c t i o n vessel and the remaining r e a c t i o n mixture was d i l u t e d with ether, washed s u c c e s s i v e l y with two port i o n s of saturated sodium c h l o r i d e , sat u r a t e d sodium bicarbonate ( u n t i l n e u t r a l ) and again with saturated sodium c h l o r i d e and the ether p o r t i o n was d r i e d over anhydrous sodium s u l f a t e . Solvent removal followed by sublimation (110°, 0.05 mm) and r e c r y s t a l l i z a t i o n from petroleum ether a f f o r d e d 6.18 g (74% from t r a n s -i s o k e t o p i n i c a c i d 210) mp 198-200°. One f u r t h e r sublimation a f f o r d e d m a t e r i a l e x h i b i t i n g the f o l l o w i n g : mp 199-200°; H 3 0 -60.7° (c 2.22, absolute ethanol) [ l i t . mp 190-196° (145), 191° (151); [-]J7 -117.9°]; i n f r a r e d (KBr), v m , v 1770 and 1070 cm" 1; n.m.r. (CDC1 3), x 8.93 ( s i n g l e t , II lu A 3H, t e r t i a r y methyl), 8.89 ( s i n g l e t , 3H, t e r t i a r y methyl) and 5.73 (doublet, IH, J = 3 Hz, -CH0—); mass spectrum, m/e ( r e l a t i v e i n t e n s i t y ) , 166 (34.2, M +), 138 (64.7), 95 (75.8), 94 (100), 79 (19.7) and 41 (22.3). (162a,b; 148) Preparation of Diol 21J3 Lactone 212a (16.6 g , 0.10 mole) d i s s o l v e d i n 40 ml anhydrous ether was added dropwise to a s t i r r e d mixture of 4 g (0.11 mole) l i t h i u m - 204 -aluminum hydride i n 100 ml anhydrous ether and the r e s u l t i n g mixture was s t i r r e d o v ernight [ c f . reference (148)]. The mixture was r e f l u x e d f o r 1 hour and the excess hydride decomposed by dropwise a d d i t i o n of water. E x t r a c t i o n with ether (three p o r t i o n s ) , followed by washing with water and saturated sodium c h l o r i d e and drying over anhydrous sodium s u l f a t e , a f f o r d e d a f t e r s o l v e n t removal 15.3 g crude d i o l . Sublimation a f f o r d e d 15.1 g (94) mp ca. 275°. R e c r y s t a l l i z a t i o n from ethyl acetate and petroleum ether (bp 60-80°) y i e l d e d 13.6 g of m a t e r i a l (mp unchanged). A small sample was f u r t h e r p u r i f i e d by r e c r y s t a l l i z a t i o n from e t h y l acetate and e x h i b i t e d the f o l l o w i n g c h a r a c t e r i s t i c s : mp ca. 275° [ l i t . mp 273-275° (148)]; ( « ) 3 2 +22.4 (c 2,03, CHC1 3); i n f r a r e d (KBr), v m a x 3380 (broad) and 1010 (broad cm" 1; n.m.r. (CDC1 3), T 9.08 ( s i n g l e t , 3H, t e r t i a r y methyl), 9.03 ( s i n g l e t , 3H, t e r t i a r y methyl), 6.68 ( s i n g l e t , 2H, C0H and 6.3 (overlapping m u l t i p l e t s , 3H, -CH^OH and -CH0H); mass spectrum, m/e ( r e l a t i v e i n t e n s i t y ) , 152 (8.9, M +-H 20), 108 (100), 95 (91.1), 94 (40.5), 93 (38.0) and 41 (55.7). (162a,b,c; 148) Preparation of 8-Iodocamphor 216 The p r e p a r a t i o n o f 8-iodocamphor was accomplished d i r e c t from d i o l 213 without p u r i f i c a t i o n o f intermediates. A s o l u t i o n of 8-hydroxy-isoborneol 21_3 (13.6 g, 0.080 mole) in 40 ml dry p y r i d i n e (under a dry n i t r o g e n atmosphere) was cooled to ca. -10° (ice/acetone bath) and a s o l u t i o n of 15.3 g (0.030 mole) p_-to1uenesulfonylchloride i n 40 ml dry p y r i d i n e was added at a moderate rate with vigorous s t i r r i n g of the d i o l . A f t e r s t i r r i n g 4 hours at 0 to-10°, the r e a c t i o n mixture was allowed to - 205 -stand 18 hours at -10°. T h i s crude s o l u t i o n of crude 8-tosyloxyisoborneol 214_ was used d i r e c t l y without i s o l a t i o n . Oxidation o f 214 was achieved by a d d i t i o n o f the crude monotosylate/pyridine s o l u t i o n to a c o l d s l u r r y o f 24 g chromic anhydride i n 175 ml dry p y r i d i n e followed by s t i r r i n g 7 hours a t room temperature under a nitrogen atmosphere. The r e a c t i o n mixture was e x t r a c t e d with three p o r t i o n s o f ether washing each with water, 6 N h y d r o c h l o r i c a c i d and s a t u r a t e d sodium c h l o r i d e . The com-bined e x t r a c t s were d r i e d over anhydrous sodium s u l f a t e , s o l v e n t was removed and f u r t h e r d r ying was e f f e c t e d by a d d i t i o n and removal under vacuum o f several p o r t i o n s of dry benzene p r o v i d i n g crude 8-tosyloxy-camphor 215: l a r g e l y one component on g . l . c . a n a l y s i s (column A, 225°, r e t e n t i o n time 26 minutes). A sample s t o r e d at -10° two weeks s o l i d i f i e d a f f o r d i n g c r y s t a l l i n e material o f mp ca. 75° but i t was found more con-venient to perform the next step o f the s y n t h e s i s on the crude t o s y l a t e . Crude keto t o s y l a t e 215 was t r e a t e d with 60 g sodium i o d i d e ( d r i e d over phosphorus pentoxide at 1 mm 24 hours) i n 200 ml dry d i m e t h y l s u l f o x i d e at 110° (dry nitrogen atmosphere) f o r 84 hours. A f t e r c o o l i n g and d i l u t i n g with water, the product was e x t r a c t e d with four 150 ml portions o f petroleum ether, washing each e x t r a c t with d i l u t e sodium metabi-s u l f i t e s o l u t i o n and s a t u r a t e d sodium c h l o r i d e and d r y i n g the combined e x t r a c t s over anhydrous sodium s u l f a t e . Solvent removal and c r y s t a l l i z a -t i o n from c o l d petroleum ether a f f o r d e d 5.8 g (26%) 8-iodocamphor 216, mp 39-41°. A r e c r y s t a l l i z e d sample e x h i b i t e d the f o l l o w i n g c h a r a c t e r -i s t i c s : the mp 40-41° [ l i t . (±) mp 40-42°]; ( a ) 3 2 -92.1° (c 1.14, CHC1 3); u l t r a v i o l e t , \ v 256 nm (e 580); i n f r a r e d (KBr), v 1740 and max max 1415 cm" 1; n.m.r. (CDC1 3), T 9.05 ( s i n g l e t , 3H, t e r t i a r y methyl), 8.86 - 206 -( s i n g l e t , 3H, t e r t i a r y methyl), and 7.02 ( s i n g l e t , 2H, C H 2 I ) ; mass spectrum, m/e ( r e l a t i v e i n t e n s i t y ) , 278 (71.1 , M +), 151 (49.5), 109 (94.5), 107 (100), 81 (94.8), 55 (74.2) and 41 (75.2). (162a,b,c; 148) Preparation of Acetal Iodide 202 A mixture o f 8-iodo-camphor 21_6 (4.50 g, 0.0162 mole), 10 ml ethylene g l y c o l , 500 mg p_-toluenesulfonic a c i d and 50 ml benzene was r e f l u x e d 18 hours i n a Dean-Stark apparatus. A f t e r c o o l i n g to room temperature, the r e a c t i o n mixture was washed with s a t u r a t e d sodium b i -carbonate and saturated sodium c h l o r i d e and d r i e d over anhydrous sodium s u l f a t e . Solvent removal and d i s t i l l a t i o n under reduced pressure a f f o r d e d f i r s t 530 mg (ca. 10%) o f 202 c o n t a i n i n g l e s s than 10% s t a r t i n g ketone followed by the main f r a c t i o n of 4.51 g (86%) pure a c e t a l i o d i d e pc 202: bp 76° (0.03 mm); n ^ 1.5480; homogeneous by g . l . c . a n a l y s i s (column A, 175°); («) -37.3° (c 5.12, CHC1 3); i n f r a r e d ( n e a t ) , v a u max 1120 cm"1; n.m.r. (CC1 H), x 9.21 ( s i n g l e t , 3H, t e r t i a r y methyl), 8.96 (doublet, 3H, J = 2 Hz, t e r t i a r y methyl), 7.67 (doublet) and 6.00 (doublet o f m u l t i p l e t s ) (ABX p a t t e r n , 2H, J A B = 10.5 Hz, J A X = 2 Hz, J g x = 0 Hz, -CH 2I) and 6.20 ( m u l t i p l e t , 4H, -0CH 2CH 20-); mass spectrum, m/e ( r e l a t i v e i n t e n s i t y ) , 195 (82.5, M +-I), 109 (95.0), 87 (100), 67 (60.0), 43 (50.0) and 41 (57.5). Anal. Calcd. f o r C 1 2 H i 9 0 2 I : C, 44.73; H, 5.94; I, 39.39. Found: C, 44.71; H, 6.12; I, 39.24. - 207 -Preparation o f (-)-Camphor Hydrogenolysis o f 8-iodo-camphor 216 was performed according to the procedure o f Rodig et a l . (148). A s o l u t i o n o f 175 mg (0.63m mole) 8-iodo-camphor i n 20 ml o f ethanol was mixed with a s l u r r y o f 500 mg 10% palladium on charcoal i n 2 ml o f water c o n t a i n i n g 45 mg potassium hydroxide. Hydrogenation of the mixture f o r 12 hours under 40 psi of hydrogen (Parr apparatus) followed by f i l t r a t i o n over c e l i t e , aqueous washing and s o l v e n t removal a f f o r d e d crude c r y s t a l l i n g camphor. Two sublimations (60°, 15 mm) a f f o r d e d 78 mg (82%) (-)-camphor: mp (cc) 3 2 - 4 4 . 8 ° (c 1.82 absolute ethanol) [ l i t . mp 178°; («) D 6 -43.6 ( e t h a n o l ) ( 1 6 4 ) ] ; i n f r a r e d and n.m.r. spectra are i n agreement with a u t h e n t i c (±)-camphor. Preparation of (-)-Campherenone 42b A s o l u t i o n o f 20 ml dry benzene and 6.5 ml n i c k e l carbonyl (171) was t r e a t e d with 3.5 ml 1-bromo-3-methyl-2-butene (4.5 g, 30m mole) in a dry nitr o g e n atmosphere and the r e a c t i o n was s t i r r e d 2.5 hours at 50°. A f t e r c o o l i n g and removal of s o l v e n t under vacuum, 20 ml dry dimethylformamide was added and the mixture s t i r r e d u n t i l a l l of the red s o l i d had d i s s o l v e d . Acetal i o d i d e 202 (2.00 g 6.22m mole) was added i n 10 ml dry dimethylformamide and the r e a c t i o n was s t i r r e d 36 hours at 55-65° under dry n i t r o g e n . The cooled r e a c t i o n mixture was poured i n t o 20 ml d i m e t h y l s u l f o x i d e and e x t r a c t e d 4 times with petroleum et h e r , washing with water and satu r a t e d sodium c h l o r i d e . Drying over anhydrous sodium s u l f a t e and s o l v e n t removal a f f o r d e d 3.22 g crude - 208 -product. D i s t i l l a t i o n a f f o r d e d 1.51 g (92%) of campherenone ethylene a c e t a l bp 74° (0.06 mm), which was greater than 95% pure by g . l . c . a n a l y s i s (column A, 175°). A middle f r a c t i o n o f the d i s t i l l a t e was c o l l e c t e d and shown by g . l . c . (column A, 150°) to c o n t a i n no d e t e c t -able t r a c e of impurity: («) 3 2 +14.5° (c 4.98, CHC1 3); i n f r a r e d and n.m.r. spectra i n complete agreement with spectra of the (±)-camphere-none a c e t a l p r e v i o u s l y synthesized. H y d r o l y s i s o f the pure f r a c t i o n (H +/acetone) and evaporative d i s t i l l a t i o n provided pure (-)-campherenone 42b: bp (bath temperature) 60° 0.1 mm; («) 3 3 -33.6° (c 10.0, CHC1 3); [0] 294 "370 (0.11 g/100 ml or 0.0050 M, methanol) [ l i t . («) -33.0 (c 10.0, CHC1 3); [0] m g g +600 (c 0.1097, methanol) ( 2 8 ) ] ; i n f r a r e d and n.m.r. spectra i n complete agreement with p r e v i o u s l y synthesized (+)-campherenone. Preparation o f (-)-g-Santalene Reduction of (-)-campherenone with l i t h i u m trimethoxyalumino-hydride (as p r e v i o u s l y described f o r (±)-campherenone) a f f o r d e d , a f t e r 32 chromatography over s i l i c a , (+)-isocampherenol: [«] +25° (c 2.60, CHC1 3) [ l i t . («) D +15.3 (c 2.6, CHC1 3) ( 2 8 ) ] ; s p e c t r a l data ( i n f r a r e d , n.m.r.) i n accord with p r e v i o u s l y synthesized racemic m a t e r i a l . T r e a t -ment o f 86 mg (0.39m mole) with 120 mg (0.64m mole) p_-toluenesulfonyl c h l o r i d e i n 1 ml p y r i d i n e 18 hours at 95° under n i t r o g e n , followed by the p r e v i o u s l y described work-up, a f f o r d e d crude (-)-g-santalene which was chromatographed f i r s t over 5 g s i l i c a gel and then over 5 g aluminum oxide (Woelm grade I) with petroleum ether e l u t i o n y i e l d i n g 55 mg (69%) - 209 -8-santalene. Evaporative d i s t i l l a t i o n a f f o r d e d pure (-)-B-santalene: bp (bath temperature) 60° (1 mm); («) 3 3 -112° (c 4.19, CHC1 3) [A sample o f natural (-)-B-santalene i s o l a t e d i n our l a b o r a t o r y from sandalwood o i l (120) e x h i b i t e d : («) 2 8 -102° (c 5.01, CHC1 3).]; s p e c t r a l data (n.m.r., i n f r a r e d ) were i n accord with p r e v i o u s l y synthe-s i z e d (±)-8-santalene as well with the natural m a t e r i a l . BIBLIOGRAPHY 1. K.B. Sharpless, J . Am. Chem. S o c , 92, 6999 (1970). 2. See references (7 and 8) f o r h i s t o r i c a l background. 3. L. Ruzicka, E x p e r i e n t i a , 9, 357 (1953). 4. L. Ruzicka, Proc. Chem. S o c , 341 (1959). 5. J.B. Hendrickson, Tetrahedron, 7_, 82 (1959). 6. W. Parker, J.S. Roberts and R. Ramage, Quart. Rev., 2J_, 331 (1967) 7. H.J. Nicholas i n "Biogenesis of Natural Compounds," Ed., P. B e r n f e l d , Pergamon Press L t d . , London, 1963, p. 641-691. 8. J.H. Richards and J.B. Hendrickson, "The Bios y n t h e s i s of S t e r o i d s , Terpenes and Acetogenins," W.A. Benjamin, New York, N.Y., 1964. 9. R.B. Cla y t o n , Quart. Rev., 19_, 168, 201 (1965). 10. "Terpenoids i n P l a n t s , " J.B. Pridham, Ed., Academic Press, London and New York, 1967. 11. D.V. Banthorpe, B.V. Charlwood, and M.J.O. F r a n c i s , Chem. Rev., 72, 115 (1972). 12. J.L. Simonsen, "The Terpenes," Vol.11, Cambridge U n i v e r s i t y Press, Cambridge, England, 1949. 13. C F . Wilcox, M.F. Wilcox and S.S. Chibber, J . Org. Chem., 27_, 2286 (1962). 14. W. R i t t e r s d o r f , Angew. Chem., Internat. Edn., 4, 4444 (1965). 15. F. Cramer and W. R i t t e r s d o r f , Tetrahedron, 23, 3015 (1967). 16. P. Valenzuela and 0. C o r i , Tetrahedron L e t t e r s , 3089 (1967). - 211 -17. C R . Wilcox and S.S. Chibber, J . Org. Chem., 27, 2332 (1962). 18. S. Wi n s t e i n , G. Val Kanas and C F . Wilcox, J . Am. Chem. S o c , 94, 2286 (1972). 19. W. Stephan, J . Prakt. Chem., 58, 109 (1898). 20. R.C Haley, J.A. M i l l e r and J.C.S. Wood, J . Chem. S o c (C), 264 (1969). 21. A. von Baeyer, Ber., 27, 1919 (1894). 22. G.L. Hodgson, D.F. MacSweeney and T. Money, to be p u b l i s h e d . 23. H.O. House, "Modern S y n t h e t i c Reactions," 2nd Ed.,' W.A. Benjamin Inc., New York, N. Y., 1971. 24. D.H.G. Crout i n "Topics i n C a r b o c y c l i c Chemistry," V o l . I, e d i t e d by D. L l o y d , Logos Press, London, 1969. 25. E.E. Conn and P.K. Stumpf, "O u t l i n e s of Biochemistry," 2nd Ed., John Wiley and Sons Inc., New York, N.Y., 1966. 26. E. von R u b l o f f , Phytochem., 5_, 331 (1966). 27. H. H i k i n o , N. Suzuki and T. Takemoto, Tetrahedron L e t t e r s , 5069 (1967). 28. H. H i k i n o , N. Suzuki and T. Takemoto, Chem. Pharm. B u l l , (Tokyo), 19., 87 (1971). 29. T h i s compound has not y e t been found i n nature but i s known through s y n t h e s i s . 30. O.L. Simonsen and D.H.R. Barton, "The Terpenes," V o l . I l l , Cambridge U n i v e r s i t y Press, Cambridge, England, 1952. 31. E.J. Corey, R. Hartmann and P.A. Vatakencherry, J . Am. Chem. Soc., 84, 2611 (1962). 32. M. Kolbe and C W e s t f e l t , A c t a . Chem. Scand., 2J_, 585 (1967). 33. M. Kolbe-Hangwitz and L. W e s t f e l t , Acta. Chem. Scand., 24, 1623 (1970). 34. N.H. Andersen, Tetrahedron L e t t e r s , 4651 (1970). 35. L. Smedman, E. Z a v a r i n , Tetrahedron L e t t e r s , 3833 (1968). 36. P. deMayo, R.E. W i l l i a m s , J . Am. Chem. S o c , 87, 3275 (1965). 37. G. Ourisson, S. M u n a r a l l i and C. Ehret, " I n t e r n a t i o n a l Tables of S e l e c t e d Constants," V o l . 15_, Data R e l a t i v e to Sesquiterpenoids. Pergamon Press, New York, N.Y., 1960. - 212 -38. U.R. Nayak and S. Dev, Tetrahedron L e t t e r s , 243 (1963). 39. (a) J.C. F a i r l i e , G.L. Hodgson and T. Money, as presented before the J o i n t Conference of the Chemical I n s t i t u t e o f Canada and the American Chemical S o c i e t y , Toronto, Canada, May, 1970. (b) J.C. F a i r l i e , G.L. Hodgson and T. Money, as presented before the Northwest Regional Conference of the American Chemical S o c i e t y , S e a t t l e , Washington, J u l y , 1970. 40. T. Money, "Biogenetic-Type Synthesis of Terpenes," Progress i n Organic Chemistry, V o l . 8, i n press. 41. F.H. A l l e n and D. Rogers, J . Chem. Soc. (B), 632 (1971). 42. L.A. Smedman, E. Zava r i n and R. T e r a n i s h i , Photochem., 1457 (1969). 43. V. P r e l o g , Helv. Chim. Acta, 36 , 308 (1953). 44. A.C. Shaw, Can. J . Chem., 31_, 277 (1953). 45. E.J. Corey, S.W. Chow and R.A. S c h e r r e r , J . Am. Chem. S o c , 79, 5773 (1957). 46. R.G. Lewis, D.H. Gustafson and W.F. Erman, Tetrahedron L e t t e r s , 401 (1967). 47. A. Homma, M. Kato, M. Wu and A. Y o s h i l c o s h i , Tetrahedron L e t t e r s , 231 (1970). 48. N.H. Andersen, Tetrahedron L e t t e r s , 1755 (1970). 49. F. Kido, R. Sakuma, H. Uda and A. Yo s h i k o s h i , Tetrahedron L e t t e r s , 3169 (1969). 50. P. Naffa and G. Ourisson, Chem. Ind., 917 (1953). 51. G. Ourisson, Chem. Ind., 918 (1953). 52. R.H. M o f f e t t and D. Rogers, Chem. Ind., 916 (1953). 53. K. Doi and T. Shibuya, Phytochem., V[_, 1174 (1972). 54. H.C. Kretschmar, Z.S. Barneis and W.F. Erman, Tetrahedron L e t t e r s , 37 (1970). 55. E. P i e r s , R.W. B r i t t o n , R.J. Kezieve and R.O. S m i l l i e , Can. J . Chem., 49, 2620 (1971). 56. E. P i e r s , R.W. B r i t t o n . R.J. Keziere and R.D. S m i l l i e , Can. J .  Chem., 49, 2623 (1971). 1 - 213 -57. S. Huneck and E. K l e i n , Phytochem., 6, 383 (1967). 58. D.H.R. Barton and N.H. Werstiuk, J . Chem. S o c , (C), 148 (1968). 59. J.N. Ashley, B.C. Hobbs and J . R a i s t r i c k , Biochem. J . , 31, 385 (1937). ~" 60. S. Hayashi, N. Hayashi, K. Yano, M. Okans and T. Matsuura, B u l l . Chem. Soc., Japan, 4T_, 234 (1968). 61. H. F e l k i n and C. L i o n , Chem. Comm., 60 (1968); Tetrahedron, 27, 1403 (1971). ~ 62. 0. Wallach, Ann., 275, 377 (1894). 63. E.J. Corey, N.N. G i r o t r a and C T . Mathew, J . Amer. Chem. Soc., 9J_, 1557 (1969). 64. CW. M a r s h a l l , T.H. Kritchevsky, S. Lieberman and T.F. G a l l a g h e r , J . Amer. Chem. S o c , 70_, 1837 (1948). 65. H.O. House and H.W. Thompson, J . Org. Chem., 26_, 3729 (1961) and references t h e r e i n . 66. D.H.R. Barton, R.M. Evans, J . C Hamlet, P.G. Jones and T. Walker, J . Chem. S o c , 747 (1954). 67. H.O. House and B.M. T r o s t , J . Org. Chem., 30_, 2502 (1965) and references t h e r e i n . 68. R.B. Moffet and D.I. Weisblat, J . Amer. Chem. S o c , 74, 2183 (1952). 69. J.M. Townsend and T.A. Spencer, Tetrahedron L e t t e r s , 137 (1971). 70. J.C. F a i r l i e , G.L. Hodgson and T. Money, Chem. Comm., 1196 (1969). 71. J.L. Simonsen, "The Terpenes," V o l . I, Cambridge U n i v e r s i t y Press, Cambridge, England, 1949. 72. A.I. S c o t t , " I n t e r p r e t a t i o n of the U l t r a v i o l e t Spectra of Natural Products," Pergamon, London, 1964. 73. A.M.T. Finch and W.R. Vaughan, J . Amer. Chem. S o c , 9J_, 1416 (1969). 74. G. Stork and P.A. Gri e c o , Tetrahedron L e t t e r s , 1807 (1971). 75. S. Nagahama, B u l l . Chem. S o c Japan, 37_, 1029 (1964). 76. O.P. V i g , J.C. Kapoor, J . Puri and S.D. Sharma, Indian J . Chem., 6, 60 (1968). 77. O.P. V i g , J.M. Sehgal, M.M. Mahajan and S.D. Sharma, J . Indian Chern. S o c , 46, 887 (1969). - 214 -78. O.P. V i g , Zhur. Obshchei Khim., 31, 669 (1961); Chem. Abs., 55, 22358 (1961T ~~ ~ 79. A.R. Pinder and R.A. W i l l i a m s , J . Chem. S o c , 2773 (1963). 80. O.P. V i g , A.L. Khurana and K.L. Matta, J . Indian Chem. Soc., 45, 615 (1968). 81. J . J . Pappas, W.P. Keaveney, E. Gancher and M. Berger, Tetrahedron  L e t t e r s , 4273 (1966). 82. M. J u l i a , S. J u l i a and R. Guegan, B u l l . Soc. Chim. France, 1072 (1960). 83. A. Manjarrez and A. Guzman, J . Org. Chem., 31_, 348 (1966). 84. J.A. MacPhee and J.E. Dubois, Tetrahedron L e t t e r s , 467 (1972) and references t h e r e i n . 85. R. Greenwald, M. Chaykousky and E.J. Covey, J . Org. Chem., 28, 1128 (1963). 86. H.O. House and V. Kramar, J . Org. Chem., 28, 3362 (1963). 87. Sp e c t r a l data ( i n f r a r e d , n.m.r. and mass spectrum) and elemental a n a l y s i s are i n accord with t h i s s t r u c t u r e . 88. Ketone 126 was the major v o l a t i l e product produced from a b r i e f treatment of dihydrocryptomerion 75a with boron t r i f l u o r i d e i n methylene c h l o r i d e . 89. Parts o f the work i n v o l v i n g dihydrocryptomerion enol acetate 95b and r e l a t e d compounds were c a r r i e d out by Dr. D.F. MacSweeney. 90. The work i n v o l v i n g the p r e p a r a t i o n of homocamphor compounds 129a,b as well as compounds 128b,c i s l a r g e l y a c c r e d i t e d to Dr. J.C. F a i r l i e . 91. A Maercker i n "Organic Reactions," V o l . 14, John Wiley and Sons Inc., New York, N.Y., 1956, p. 270-490. 92. J . Hooz and S.S.H. G i l a n i , Canad. J . Chem., 46, 86 (1968). 93. R. Rabinowitz and R. Marcus, J . Amer. Chem. S o c , 84, 1312 (1962). 94. F. Ramirez, N.B. Desai and N. McKelvie, J . Amer. Chem. Soc., 84, 1746 (1962). 95. N.S. Isaacs and D. K i r k p a t r i c k , J.C.S. Chem. Comm., 443 (1972). 96. We are g r a t e f u l to Mr. R* Bradshaw f o r h i s developmental work on the synthes i s of dihydrocryptomerion. - 215 -97. R.J. Crawford, W.F. Erman and C. D. Broaddus ( P r o c t o r & Gamble Co.), as presented before the J o i n t Conference of the Chemical I n s t i t u t e o f Canada and the American Chemical S o c i e t y , Toronto, Canada, May 24-29, 1970. 98. We are g r a t e f u l to Dr. Crawford f o r k i n d l y supplying experimental d e t a i l s o f the me t a l a t i o n and a l k y l a t i o n o f limonene p r i o r to p u b l i c a t i o n . 99. R.J. Crawford, W.F. Erman and C D . Broaddus, J . Amer. Chem. Soc., 94, 4298 (1972). 100. C H . Heathcock, J.E. E l l i s and R.A. Badger, J . H e t e r o c y c l i c Chem., 6, 139, 1969. 101. M.S. Newman and R.J. Harper, J . Amer. Chem. S o c , 80, 6350 (1958). 102. G.M. K e l l i e and F.G. R i d d e l ! 9 J . Chem. S o c Perkin I I , 252 (1972), and r e f e r e n c e s t h e r e i n . 103. T. Money, unpublished r e s u l t s . 104. J.D. Connolly and R. McCrindle, Chem. and Ind., 379 (1965). 105. J.D. Connolly and R. McCrindle, J . Chem. S o c , (C), 1613 (1966). 106. E.M. Engler and P. L a s z l o , J . Amer. Chem. S o c , 93, 1317 (1971). 107. B.E. Edwards and P.N. Rao, J . Org. Chem., 3J_, 324 (1966). 108. G.L. Hodgson, D.F. MacSweeney and T. Money, Chem. Comm., 766 (1971). 109. H.C. Brown and H.R. Deck, J . Amer. Chem. S o c , 87, 5620 (1965). 110. P.V. Demarco, E. Farkas, D. Doddnell, B.L. M y l a r i and E. Wenkert, J . Amer. Chem. S o c , 90, 5480 (1968). 111. T . J . F l a u t t and W.F. Erman, J . Amer. Chem. S o c , 85, 3212 (1962). 112. K. T o r i , Y. Hamashima and A. Takamizawa, Chem. Pharm. B u l l , 12, 924 (1964). 113. P.V. Demarco, T.K. E l z e y , R.B. Lewis and E, Wenkert, J . Amer. Chem. S o c , 92, 5734 (1970). 114. S y n t h e t i c routes to p-santalene (31,115,116), epi-3-santalene (31,115,117) and «- Santalene (44,117,118) have p r e v i o u s l y been r e p o r t e d . 115. G. B r i e g e r , Tetrahedron L e t t e r s , 1949 (1963). - 216 -116. J . Wolinsky, R.L. Marhenke and R. Lau, S y n t h e t i c Comm., 165 (1972). 117. E.J. Corey and M.F. Semmelhack, J . Amer. Chem. Soc., 89, 2755 (1967). 118. S.Y. Kamat, K.K. Chakravarti and S.C. Bhattacharyya, Tetrahedron, 23, 4487 (1967). 119. The conversion o f natural campherenone to e-santalene has r e c e n t l y been described (28). 120. We are g r a t e f u l to F r i t z s c h e , Dodge and O l c o t t , Inc., New York, and Norda E s s e n t i a l O i l and Chemical Co., Inc., New York, f o r generous samples o f Mysore sandalwood o i l . 121. H. Meerwein and K. van Emster, Ber., 53, 1815 (1920); c f . reference (117). 122. G.C. J o s h i , W.D. Chambers and E.W. Warnhoff, Tetrahedron L e t t e r s , 3613 (1967). 123. We are g r a t e f u l to Pr o f e s s o r E. P i e r s o f t h i s department f o r pr o v i d i n g us with an aut h e n t i c sample and s p e c t r a l c h a r a c t e r i s t i c s o f copacamphor: c f . reference (55). 124. We are g r a t e f u l to Pr o f e s s o r D.H.R. Barton f o r an aut h e n t i c sample o f culmorin diketone d i t h i o k e t a l the precursor o f (-)-longicamphor: c f . r e f erence (58). 125. E.E. van Tamelan, Accounts Chem. Res., _1_, 111 (1968). 126. For another example o f i n t r a m o l e c u l a r a l k y l a t i o n o f a ketone i n v o l v i n g an epoxide see the t o t a l s ynthesis o f copacamphene: (a) J.E. McMurry, Tetrahedron L e t t e r s , 3731 (1970); (b) J . Org. Chem., 36, 2826 (1971). 127. We are g r a t e f u l to Pr o f e s s o r E. Pie r s o f t h i s department f o r pro-v i d i n g us with s p e c t r a l c h a r a c t e r i s t i c s o f ylangocamphor (prepared by an a l t e r n a t e route) p r i o r to p u b l i c a t i o n . 128. H.C. Brown and C A . Brown, Tetrahedron, Suppl. 8, Part I, 149 (1966). 129. A p r e l i m i n a r y account o f the transformations o f campherenone to the santalenes and to copacamphor and ylangocamphor has been p u b l i s h e d : G.L. Hodgson, D.F. MacSweeney and T. Money, Tetrahedron L e t t e r s , i n press. 130. J.E. McMurry, J . Amer. Chem. Soc., 90, 6821 (1968). 131. J.E. McMurry, Tetrahedron L e t t e r s , 55 (1969). 132. J.E. McMurry, Tetrahedron L e t t e r s , 3735 (1970). - 217 -133. R. D. S m i l l i e , Ph.D. T h e s i s , U n i v e r s i t y o f B r i t i s h Columbia, 1972. 134. A. Marquet and J . Jacques, B u l l . Chem. Soc. France, 94 (1962). 135. K. Takeda, K. Sakurawi and H. I s h i i , Tetrahedron, 27, 6049 (1971). 136. G. Ciamician and P. S i l b e r , Ber., 41_, 1928 (1908). 137. G. Biichi and I.M. Goldman, J . Amer. Chem. Soc., 7£, 4741 (1957). 138. J . Meinwald and R.A. Schneider, J . Amer. Chem. Soc. , 87, 5218 (1965). 139. T. Gibson and W.F. Erman, J . Org. Chem., 31_, 3028 (1966). 140. W.F. Erman, J . Amer. Chem. Soc., 89, 3828 (1967). 141. W.F. Erman and T.W. Gibson, Tetrahedron, 2_5, 2493 (1969). 142. K.M. Baker and B.R. Davis, Tetrahedron, 24, 1655, 1663 (1968). 143. H. N i s h i m i t s u , M. Nishikawa and H. Hagiwara, Proc. Japan Acad., 27, 285 (1951); Chem. Abs t r . , 46, 6112 (1952^ 144. W.L. Meyer, A.P. Lobo and R.N. McCarty, J . Org. Chem., 32, 1754 (1967). 145. E.J. Corey, M. Ohno, S.W. Chow and R.A. Sch e r r e r , J . Amer. Chem. Soc., 81_, 6305 (1959). 146. K. Sato, S. Inoue, S. Ota and Y. F u j i t a , J . Org. Chem., 37, 462 (1972). 147. M.T. Hughes and J . Hudec, Chem. Comm., 805 (1971). 148. O.R. Rodig and R.J. Sysko, J . Org. Chem., 36, 2324 (1971 ). 149. P.C. Guha and S.C. Bhattacharyya, J . Indian Chem. Soc., 21, 271 (1944); Chem. Abs t r . , 40, 5036 (1946). 150. Y. Asahina and M. I s h i d a t e , Ber., 66, 1673 (1933); 68, 947 (1935). 151. Y. Asahina, M. I s h i d a t e and T. Momose, Ber., 68, 559 (1935). 152. "Handbook o f Chemistry and Physics," 52nd E d i t i o n , Ed., R.C. Weast, The Chemical Rubber Co., Clevel a n d , Ohio. 153. P. de Mayo, R. Robinson, E.Y. Spencer and R.W. White, E x p e r i e n t i a , 18, 359 (1962). 154. A.D. Cross, Quart. Rev. (London), 14_, 317 (1960). - 218 -155. M. Yamazaki, M. Matsuo and K. A v a i , Chem. Pharm. B u l l . (Tokyo), 1_4, 1058 (1966). 156. O.E. Edwards, J.L. Douglas and B. Mootoo, Can. J . Chem., 48, 2517 (1970). 157. M. B i o l l a z and D. A r i g o n i , Chem. Comm., 633 (1969). 158. (a) A. C o r b e l l a , P. G a r i b o l d i , G. Jommi and C. S c o l a s t i c o , Chem. Comm., 634 (1969). (b) A. C o r b e l l a , P. G a r i b o l d i and G. Jommi, J.C.S. Chem. Comm., 600 (1972). 159. K.W. T u r n b u l l , W. A c k l i n , D. A r i g o n i , A. C o r b e l l a , P. G a r i b o l d i and G. Jommi, J.C.S. Chem. Comm., 598 (1972). 160. V.H. Kapadia, B.A. Nagasampagi, V.G. Naik and S. Dev, Tetrahedron  L e t t e r s , 1933 (1963). 161. M. Yoshida, Chem. Pharm. B u l l . (Tokyo), 3, 215 (1955). 162. T h i s compound e x h i b i t e d s p e c t r a l c h a r a c t e r i s t i c s i n accord with p r e v i o u s l y r e p o r t e d s p ectra or s p e c t r a l data i n the reference c i t e d : a. I n f r a r e d b. N.M.R. c. Mass spectrum 163. W.G. Dauben, G.W. Sh a f f e r and N.D. Vietmeyer, J . Org. Chem.. 33, 4060 (1968). 164. "Handbook o f Chemistry and Physics," 52nd E d i t i o n , Ed., R.C. Weast, The Chemical Rubber Co., C l e v e l a n d , Ohio. 165. M.S. Newman and H.L. Holmes, Org. Syn. C o l l . V o l . , 2_, 428 (1943). 166. We are g r a t e f u l to Dr. J.R. Cannon f o r experimental d e t a i l s con-cerning the preparation o f (4-benzyloxybutyl)triphenyl-phosphonium i o d i d e . 167. T.D. P e r r i n e , J . Org. Chem. , 18_, 1356 (1953). 168. B e i l s t e i n , Suppl. I, Vol. I, p. 182. 169. The preparation o f compounds 46a, 47, 48, 49a, and 50_ was done i n c o l l a b o r a t i o n with Dr. D.F. MacSweeney as was the a l t e r n a t i v e p r e p a r a t i o n o f (-)-cryptomerion 99a. 170. F.S. Kipping and W.J. Pope, J . Chem. Soc., 67_, 371 (1895). 171. Extreme caution must be used i n handling t h i s t o x i c and spontane-ously inflammable compound. 

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