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Stereoselective total synthesis of sesquiterpenoids; (-)-copacamphene and (-)-cyclocopacamphene Smillie, Robert Dean 1972

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STEREOSELECTIVE TOTAL SYNTHESIS OF SESQUITERPENOIDS: (-)-COPACAMPHENE AND (-)-CYCLOCOPACAMPHENE BY ROBERT DEAN SMILLIE B.Sc. (Hons.)» U n i v e r s i t y of B r i t i s h Columbia, 1966 M.Sc. U n i v e r s i t y of B r i t i s h Columbia, 1969 A THESIS SUBMITTED IN PARTIAL FULFILMENT OF THE REQUIREMENTS FOR THE DEGREE OF DOCTOR OF PHILOSOPHY i n the Department of CHEMISTRY We accept t h i s t h e s i s as conforming to the required standard THE UNIVERSITY OF BRITISH COLUMBIA January, 1972 In p r e s e n t i n g t h i s t h e s i s i n p a r t i a l f u l f i l m e n t o f t h e r e q u i r e m e n t s f o r an advanced degree a t t h e U n i v e r s i t y o f B r i t i s h Columbia, I agree t h a t 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 r e f e r e n c e and s t u d y . I f u r t h e r agree t h a t p e r m i s s i o n f o r e x t e n s i v e c o p y i n g o f t h i s t h e s i s f o r s c h o l a r l y p urposes may be g r a n t e d by the Head o f my Department o r by h i s r e p r e s e n t a t i v e s . I t i s u n d e r s t o o d t h a t c o p y i n g o r p u b l i c a t i o n o f t h i s t h e s i s f o r f i n a n c i a l g a i n s h a l l n o t be a l l o w e d w i t h o u t my w r i t t e n p e r m i s s i o n . Department o f C M ^ mSty. The U n i v e r s i t y o f B r i t i s h Columbia Vancouver 8, Canada ABSTRACT An e f f i c i e n t , 6-step syn t h e s i s of the (-)-diketone (122) from (-f)-carvomenthone (123) i s described. Conversion of 123 Into the corresponding n-butylthiomethylene d e r i v a t i v e (131), f o l l o w e d by a l k y l a t i o n of the l a t t e r w i t h e t h y l 2-iodopropionate and successive removal of the n-butythiomethylene b l o c k i n g group and e s t e r i f i c a t i o n of the r e s u l t i n g a c i d (134) , gave the keto e s t e r (135). Treatment of 135 w i t h sodium b i s ( t r i m e t h y l s i l y l ) a m i d e i n dimethoxyethane r e s u l t e d i n an e f f i c i e n t i n t r a m o l e c u l a r C l a i s e n condensation, a f f o r d i n g the (-)-diketone 122 i n 90% y i e l d . The stereochemistry of the (-)-diketone (122) was proven unambiguously i n the f o l l o w i n g way. Successive s u b j e c t i o n of the (+)-k e t o l (142), of known absolute stereochemistry, to hydrogenation, dehydration, condensation w i t h e t h y l formate, and o x i d a t i o n w i t h 2,3-dichloro-5,6-dicyanobenzoquinone, afforded the (+)-dienone aldehyde (153). Conjugate a d d i t i o n of l i t h i u m dimethylcuprate to 153, followed by trapping of the intermediate enolate anion w i t h a c e t y l c h l o r i d e gave the keto enol acetate (154). Ozonolysis of the l a t t e r , f ollowed by e s t e r i f i c a t i o n of the r e s u l t i n g a c i d (157) gave the (+)-keto e s t e r (138), which was c l e a r l y epimeric w i t h the p r e v i o u s l y prepared keto e s t e r (135). Intramolecular C l a i s e n condensation of 135 afforded the (+)-diketone (139), which was c l e a r l y d i f f e r e n t from the (-)-diketone (122). The (-)-diketone (122) was u t i l i z e d i n the s y n t h e s i s of (-)-copacamphene (23) and of (-)-cyclocopacamphene (24). Several methods f o r the conversion of the (-)-diketone (122) i n t o the (-)-keto o l e f i n - i i i -(125) were i n v e s t i g a t e d . The most e f f i c i e n t sequence found was as f o l l o w s . Reduction of 122 w i t h sodium borohydride gave the (-)-keto a l c o h o l (169) which was r e a d i l y converted i n t o the corresponding p_-tosylhydrazone (170). Treatment of the l a t t e r w i t h m e t h y l l i t h i u m , followed by Jones o x i d a t i o n afforded the (-)-keto o l e f i n (125) i n good y i e l d . Reaction of 125 w i t h methoxymethylenetriphenylphosphorane gave the isomeric o l e f i n i c enol ethers (172). Successive s u b j e c t i o n of the l a t t e r to a c i d h y d r o l y s i s and base-catalyzed e q u i l i b r a t i o n afforded the ( - ) - o l e f i n i c aldehyde (174). The l a t t e r was reacted w i t h methylenetriphenylphosphorane, and the r e s u l t i n g (+)-diene (175) was subjected to h y d r o b o r a t i o n - o x i d a t i o n , to produce the ( + ) - o l e f i n i c a l c o h o l (178) . Treatment of 178 w i t h p_-toluenesulf o n y l c h l o r i d e i n p y r i d i n e produced the corresponding p - t o s y l a t e (180), which underwent a h i g h - y i e l d i n g e l i m i n a t i v e c y c l i z a t i o n to a f f o r d (-)-copacamphene (23). Although a number of routes d i r e c t e d towards the s y n t h e s i s of (-)-cyclocopacamphene (24) were i n v e s t i g a t e d , the most e f f i c i e n t sequence employed the ( + ) - o l e f i n i c a l c o h o l (178) as s t a r t i n g m a t e r i a l . Oxidation of the l a t t e r w i t h C o l l i n s reagent afforded the ( - ) - o l e f i n i c aldehyde (194), which was r e a d i l y converted i n t o the corresponding p_-tosylhydrazone (210). P y r o l y s i s of the l i t h i u m s a l t of the l a t t e r produced the (+)-pyrazoline (213), which, upon p h o t o l y s i s i n ether, afforded (-)-cyclocopacamphene (24) i n 93% y i e l d . - i v -TABLE OF CONTENTS Page TITLE PAGE i ABSTRACT i i TABLE OF CONTENTS i v LIST OF FIGURES v ACKNOWLEDGEMENTS v i INTRODUCTION 1 1. General 1 2. Sesquiterpene B i o s y n t h e s i s 7 3. O r i g i n and S t r u c t u r a l E l u c i d a t i o n of Copacamphene and Cyclocopacamphene 16 4. A c i d Rearrangements 22 5. Other Sy n t h e t i c Approaches to "Copa-" and "Ylango-" type Sesquiterpenoids 28 DISCUSSION 38 1. General 38 2. Synthesis of the S u b s t i t u t e d B i c y c l o [ 3 . 2 . l ] o c t a d i o n e 122 45 3. Stereochemical Proof of Diketone 122 57 4. Synthesis of the S u b s t i t u t e d B i c y c l o [ 3 . 2 . l ] o c t e n o n e 125 75 5. Synthesis of (-)-Copacamphene (23) 88 6. Synthesis of (-)-Cyclocopacamphene (24) 107 EXPERIMENTAL 136 BIBLIOGRAPHY 179 - V -LIST OF FIGURES Figure Page 1 N.M.R. Spectrum of the Keto E s t e r (135) 53 2 N.M.R. Spectrum of the (-)-Diketone (122) 56 3 N.M.R. Spectrum of the (+)-Keto E s t e r (138) 67 4 N.M.R. Spectrum of the (+)-Diketone (139) 70 5 N.M.R. Spectrum of the (-)-Keto O l e f i n (125) 80 6 N.M.R. Spectrum of the (-)-Keto Aldehyde (174) 91 7 N.M.R. Spectrum of the (+)-Diene (175) 93 8 I n f r a r e d Spectrum of (-)-Copacamphene (23) 100 9 N.M.R. Spectrum of (-)-Copacamphene (23) 101 10 I n f r a r e d Spectrum of (+)-Sativene (26) 102 11 N.M.R. Spectrum of (+)-Sativene (26) 103 12 I n f r a r e d Spectrum of (-)-Isosativene (77) 104 13 N.M.R. Spectrum of (-)-Isosativene (77) 105 14 N.M.R. Spectrum of the (-)-Keto O l e f i n (190) I l l 15 N.M.R. Spectrum of the (-)-Keto O l e f i n (198) 118 16 N.M.R. Spectrum of the (+)-Pyrazoline (213) 130 17 I n f r a r e d Spectrum of (-)-Cyclocopacamphene (24) .... 132 18 N.M.R. Spectrum of (-)-Cyclocopacamphene (24) 133 19 I n f r a r e d Spectrum of (+)-Cyclosativene (27) 134 20 N.M.R. Spectrum of (+)-Cyclosativene (27) 135 - v i -ACKNOWLEDGEMENTS I would l i k e to express my s i n c e r e thanks to Dr. Edward P i e r s f o r h i s i n v a l u a b l e a d v i c e , guidance and e n l i g h t e n i n g d i s c u s s i o n s throughout the course of t h i s r e s e a r c h , and the p r e p a r a t i o n of t h i s manuscript. I would a l s o l i k e to thank Dr. Ronald W. B r i t t o n and Mr. Robert J . K e z i e r e , my co-workers i n t h i s r e s e a r c h , and a l l the members of Dr. P i e r s ' research group, f o r t h e i r h e l p f u l d i s c u s s i o n s and suggestions. The able t y p i n g of Miss Diane Johnson i s g r e a t l y appreciated. INTRODUCTION 1. General The terpenoids are a large family of natural products which have widespread d i s t r i b u t i o n i n the realm of nature. They are compounds which have structures that are normally based on head to t a i l 1 2 linkings of isoprene units (1) ' and usually contain two (mono-terpenoids), three (sesquiterpenoids), four (diterpenoids), f i v e (sesterterpenoids), s i x (triterpenoids) or eight (carotenoids) multiplets of the basic unit. However, during biogenesis of terpenoids, the linked isoprene units may rearrange to give a vast array of 2 d i f f e r e n t carbon skeletons. The sesquiterpenoids are a large group i n the terpenoid family which, are formed by the combination of three isoprene units. The virtuosity- of nature i n the construction of i n t r i c a t e molecules i s nowhere more evident than i n t h i s sesquiterpenoid group. Within t h i s t a i l head 1 - 2 -group can be found an e s p e c i a l l y concentrated and impressive display of synthetic expertise, with over f i f t y d i f f e r e n t sesquiterpenoid 3 s k e l e t a l types known to e x i s t i n nature. Sesquiterpenoids may occur as a c y c l i c , monocyclic, b i c y c l i c , t r i c y c l i c , or t e t r a c y c l i c hydrocarbons, alcohols, ketones, oxides or lactones. They have been known as constituents of the e s s e n t i a l o i l s , and have formed the basis for a wide range of exotic scents and perfumes for centuries. However, i t i s only i n comparatively recent times that the chemistry of these compounds has been investigated i n d e t a i l . One of the reasons for t h i s was that i n the e s s e n t i a l o i l s , sesquiterpenoids often occur as very complex mixtures which could not be resolved by the c l a s s i c a l methods that were a v a i l a b l e . The i s o l a t i o n of pure homogeneous compounds was quite d i f f i c u l t , and characterization of inseparable mixtures, which under the circumstances appeared homogeneous, led to inaccurate r e s u l t s and conclusions. With the development of new separation techniques such as g a s - l i q u i d chromatography and thin layer chromatography, and the introduction of modern spectroscopic methods such as nuclear magnetic resonance and o p t i c a l rotatory dispersion, the structure and stereochemistry of a large number of sesquiterpenes have been established. Three examples which i l l u s t r a t e t h i s great d i v e r s i t y of structure which can be found i n the sesquiterpenoids are the highly oxygenated 4 5 6 i l l u d i n - S (2), acorone (3) ' which contains a spirane carbon skeleton, and the a c y c l i c hydrocarbon farnesene (4).^ 3 -2 3 4 The s t r u c t u r e s of one i n t e r e s t i n g and s t r u c t u r a l l y r e l a t e d group of 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 sesquiterpenoids are i l l u s t r a t e d i n Chart 1. The sesquiterpenoids l i s t e d i n t h i s chart are arranged and drawn i n a manner which emphasizes t h e i r s t r u c t u r a l s i m i l a r i t i e s to p a r t i c u l a r monoterpenoids. A l s o , the s t r u c t u r a l s i m i l a r i t i e s among the sesquiterpenoids themselves i s c l e a r from an examination of Chart 1. For example, the sesquiterpenoids campherenone ( 8 ) , copacamphor (11), ylangocamphor (14), and longicamphor (17) a l l have the s t r u c t u r a l features of the monoterpenoid camphor (5) incorporated i n t o t h e i r s t r u c t u r e . In other words, these four sesquiterpenoids l i s t e d can be considered to be "isoprenologs" of the monoterpenoid camphor. S i m i l a r l y , sesquiterpenoids l i s t e d i n the other f i v e columns of Chart 1 can be considered to be s t r u c t u r a l " i s o p r e n o l o g s " of the monoterpenoids which head these columns. There are a l s o marked s t r u c t u r a l s i m i l a r i t i e s among the sesquiterpenoids i n a given row. For example, copacamphor (11) , copaborneol (12), and copaisoborneol (13) each contain a six-membered r i n g w i t h an a x i a l camphor borneol i s o b o r n e o l (-)-campherenone 8-10 f 11 (+)-copacamphor 11-13 rt r 14+ ylangocamphor (+)-longicamphor 14 LV -OHJ (-)-campherenol 8-10 L\-OHj 12* (+)-copaborneol 11-13 15 1 ylangoborneol .s \ I HO-,/ ! 18 (+)-longiborneol CHART 1 + + 14 HO 10 (+)-isocampherenol y HO 8-10 13 (+)-copaisoborneol 11-13 ~ - — / / ... HO 16 ylangoisoborneol \__ \ 19 (+ ) - l o n g i i s o b o r n e o l 14 - 5 -20 camphene 21 t r i c y c l e n e 22 a-pinene 23 _ t ^ v 1 1 , 1 2 , 1 5 - 1 7 .... . , 17,18 , . 1 9 - 2 1 (-)-copacamphene (+;-cyclocopacamphene (-)-a-copaene 26 (-)-satxvene / J 27 ,,x T ,. 24-26 . 27-30 (+;-cyclosatxvene (+)-a-ylangene 29_ (+)-longifolene 31-35 (+)-longicyclene 36 31 i i \ i • • 37,38 (+)-a-long i p mene CHART 1 ( c o n t ' d ) + + tf These compounds have been i s o l a t e d from n a t u r a l l y o c c u r r i n g sources, These compounds are as yet unknown. Absolute c o n f i g u r a t i o n s are depicted by these s t r u c t u r e s . - 6 -i s o p r o p y l group. The sesquiterpenoids ylangocamphor . (14), ylangoborneol (15) and ylangoisoborneol (16), as yet unknown compounds, have been added f o r the sake of completeness i n Chart 1. The names that are proposed f o r these terpenoids are based on t h e i r s t r u c t u r a l r e l a t i o n s h i p both to the corresponding monoterpenoids (camphor, b o r n e o l , i s o b o r n e o l , r e s p e c t i v e l y ) and to the sesquiterpene a-ylangene (28). Throughout t h i s t h e s i s , the groups of sesquiterpenoids under d i s c u s s i o n here w i l l be r e f e r r e d to as "copa-", "ylango-" and " l o n g i - " type sesquiterpenoids. Dealing w i t h each of these p r e f i x e s , the f i r s t , "copa", r e f e r s to sesquiterpenoids i n Chart 1 which possess a six-membered r i n g w i t h an a x i a l i s o p r o p y l group. The p r e f i x "copa" i s d e rived from copaene (25), which was the f i r s t sesquiterpene of 19 t h i s type to be i s o l a t e d (from A f r i c a n copaiba balsam o i l ) and named. "Ylango" r e f e r s to sesquiterpenoids i n Chart 1 which possess a s i x -membered r i n g w i t h an e q u a t o r i a l i s o p r o p y l group. In t h i s case, the p r e f i x "ylango" was derived from ylangene (28) ( i s o l a t e d from ylang-ylang o i l ) , which again was the f i r s t sesquiterpene of t h i s type to be 27 i s o l a t e d and named. F i n a l l y , the p r e f i x " l o n g i " r e f e r s to the group of sesquiterpenoids i n Chart 1 which have a seven-membered r i n g possessing gem-dimethyl groups. Longifolene (29) was the f i r s t sesquiterpene of t h i s type to be i s o l a t e d (from Pinus l o n g i f o l i a , R o x b . ) and 31 named, hence the p r e f i x " l o n g i " . The work described i n t h i s t h e s i s was concerned w i t h the s u c c e s s f u l I t i s assumed that the cyclohexane r i n g i s i n a c h a i r conformation. - 7 -attempt to synthesize (-)-copacamphene (23) and (-)-cyclocopacamphene (24). 2. Sesquiterpene Biosynthesis 1 2 39 I t i s generally believed ' ' that a l l sesquiterpenoids can be derived from the appropriate c y c l i z a t i o n of eit h e r trans-farnesyl 40 pyrophosphate (39) or c i s - f a r n e s y l pyrophosphate (40) followed by appropriate rearrangements, oxidations and reductions. The biosynthesis of farnesyl pyrophosphate from a c e t y l CoA (32) v i a the intermediacy of mevalonic acid (35) has been experimentally v e r i f i e d ^ ^ and i s outlined i n Chart 2. The successive condensation of three molecules of a c e t y l CoA (32) can occur i n two ways. A l i n e a r condensation (path A) leads to a str a i g h t chain product 33, generally considered to be the precursor of 1 groups of natural products such as the phenolic resins and the 44-46 acetogenins. The other mode of condensation (path B) leads to the formation of the branched 8-hydroxy -8-methyl g l u t a r y l CoA (34). Reduction of \34 with nicotinamide-adenine dinucleotide phosphate (NADPH) affords mevalonic acid (35), which upon phosphorylation with adenine 3 triphosphate (ATP) and subsequent decarboxylation, gives A -isopentenyl pyrophosphate (36). Isomerization of the terminal double bond of J36_ r e s u l t s i n the formation of d i m e t h y l a l l y l pyrophosphate (37), which upon condensation with \3j5_ gives geranyl pyrophosphate (38). Subsequent 3 condensation of geranyl pyrophosphate (38) with A -isopentenyl pyro-phosphate (36) affords trans- and c i s - f a r n e s y l pyrophosphates , 39 and 40, respectively. - 8 -CoA SCo A 32 NADPH OH HO^MD OH 35 ^ATP OPP OH HO 0" 34 SCoA -CO, "OPP path B 0 0 0 33 SCoA 0 SCoA I phenolic r e s i n s and acetogenins \—OPP 36 OPP 37 .OPP 39 OPP 40 38 -OPP OPP OPP CHART 2 - 10 -The next stage i n the b i o s y n t h e s i s of sesquiterpenes i s thought to be i n i t i a t e d by the i o n i z a t i o n of the a l l y l i c pyrophosphates (39 39 * and 40). The unstable cations formed could be n e u t r a l i z e d by e i t h e r the c e n t r a l or t e r m i n a l double bond, l e a d i n g to r e p r e s e n t a t i o n s such as c a t i o n s 41_ to 46_, as shown by Chart 3. The b i o s y n t h e s i s of the "copa-" and "ylango-" type sesquiterpenoids probably occurs v i a very c l o s e l y r e l a t e d pathways d i f f e r i n g only i n the c o n f i g u r a t i o n of the i s o p r o p y l group. So f o r convenience, only the "copa" s e r i e s w i l l be discussed i n d e t a i l . There are two d i s t i n c t l y d i f f e r e n t pathways which can be envisaged f o r the formation of the common in t e r m e d i a t e , c a t i o n 50. In the f i r s t of these, as shown i n Chart 4, c a t i o n 41_ could undergo successive deprotonation, r e p r o t o n a t i o n and f i n a l l y deprotonation to a f f o r d trxene Subsequent c y c l i z a t i o n of 47 would a f f o r d c a t i o n j+8 which could be deprotonated and reprotonated (a 1,2-hydride s h i f t ) to a f f o r d c a t i o n 50. In a second p o s s i b l e pathway, c a t i o n 4_3 could undergo a 1,3-hydride s h i f t to produce c a t i o n 49. Markownikoff c y c l i z a t i o n of the l a t t e r would form the same c a t i o n (50) as the previous pathway. Cation 51 The r e p r e s e n t a t i o n of a formal c a t i o n i n t h i s and subsequent d i s c u s s i o n s i s only a convenient symbolism, since the b i o g e n e t i c c y c l i z a t i o n s are undoubtedly e n z y m a t i c a l l y c o n t r o l l e d , and probably occur v i a p a r t i a l l y or f u l l y concerted processes. This might also be viewed as a 1,2-hydride s h i f t followed by deprotonation. I t should be emphasized that i n t h i s and subsequent treatments, the formalism of these mechanisms must be t r e a t e d w i t h c a u t i o n , as i n a l l cases, the t o t a l process probably takes place on an enzyme surface and i s probably concerted. - 11 -CHART 4 - 12 -- 13 -("ylango" s e r i e s ) could be formed i n an analogous manner to that of c a t i o n 50. In order to o b t a i n the "copa-"type sesquiterpenes from c a t i o n 50, i t has been proposed that the l a t t e r could c y c l i z e i n a Markownikoff or anti-Markownikoff f a s h i o n (Chart 5). The former mode of c y c l i z a t i o n (path A) would a f f o r d c a t i o n 52^, which could then deprotonate to produce a-copaene (25). Anti-Markownikoff c y c l i z a t i o n of c a t i o n _50 (path B, Chart 5) could l e a d to the formation of c a t i o n 53. I t can be seen that simple n e u t r a l i z a t i o n of c a t i o n _53_ w i t h water would a f f o r d copaborneol (12) . I t i s a l s o p o s s i b l e that t h i s c a t i o n (53) could undergo a 1,3-deprotonation step to form-cyclocopacamphene (24). A l t e r n a t i v e l y , a Wagner-Meerwein rearrangement of c a t i o n 5_3 could l e a d to c a t i o n 5_4 which could then undergo e i t h e r 1,2- or 1,3-deprctonation to a f f o r d •k copacamphene (23) or cyclocopacamphene (24), r e s p e c t i v e l y . In view of some i n t e r e s t i n g work by McMurry on the a c i d catalyzed conversion of copacamphene (23) to sativene (26) and c y c l o s a t i v e n e (27) i t i s i n t e r e s t i n g to speculate regarding the p o s s i b i l i t y of a conversion, (or an i n t e r c o n v e r s i o n ) of t h i s type being used by nature i n the b i o s y n t h e s i s of these compounds. McMurry's conversion of copacamphene to sativene w i l l be discussed l a t e r i n the I n t r o d u c t i o n . An a l t e r n a t i v e hypothesis f o r the b i o s y n t h e s i s of the "ylango-" and 48 "copa-"type sesquiterpenoids has r e c e n t l y been proposed. The b a s i c A The s t r u c t u r e s shown i n t h i s d i s c u s s i o n of b i o s y n t h e s i s do not n e c e s s a r i l y d e p i c t the absolute c o n f i g u r a t i o n , and there i s no attempt here to c o r r e l a t e the b i o s y n t h e s i s of these sesquiterpenes w i t h t h e i r absolute c o n f i g u r a t i o n . CHART 6 - 15 -- 16 -f e a t u r e of t h i s p o s t u l a t e i s that c e r t a i n b i c y c l i c and t r i c y c l i c sesquiterpenoids could be constructed by c y c l i z a t i o n of an appropriate enol phosphate. I t was envisaged t h a t c y c l i z a t i o n of dihydrocryptomerion enol phosphate (55) could be i n v o l v e d i n the b i o s y n t h e s i s of campherenone (8) (see Chart 6). The enol phosphate of campherenone (56) could then c y c l i z e i n each of three d i f f e r e n t ways, leading to the formation of copacamphor (11), ylangocamphor (14) or longicamphor (17). Reduction of the carbonyl f u n c t i o n of these compounds could produce the corresponding bprneol "isoprenologs" copaborneol (12), ylangoborneol (15) and l o n g i b o r n e o l (18). S o l v o l y s i s (or a r e l a t e d b i o g e n e t i c process) of these three borneol "isoprenologs" could produce the corresponding cations (53, 57 and 58) as i l l u s t r a t e d i n Chart 7. In a manner analogous to that discussed p r e v i o u s l y i n the b i o s y n t h e s i s of the "copa" s e r i e s , the t e t r a c y c l i c sesquiterpenes (24, 27, and 30) could be formed by deprotonation of cations 53_, 57_ and 5_8, r e s p e c t i v e l y . A Wagner-Meerwein rearrangement of these cations could lead to the formation of cations j54_, J59 and 60. Again, 1,3- or 1,2-deprotonation of these c a t i o n s would produce the t e t r a c y c l i c (24, \2_7 and 30) or t r i c y c l i c (23, 26 and 29) sesquiterpenes, r e s p e c t i v e l y . 3. O r i g i n and S t r u c t u r a l E l u c i d a t i o n of Copacamphene and Cyciocopacamphene This t h e s i s i s mainly concerned w i t h the t o t a l synthesis of copa-camphene (23) and of cyclocopacamphene (24). I t i s t h e r e f o r e p e r t i n e n t to discuss the o r i g i n of these compounds, and the work which l e d to the establishment of t h e i r s t r u c t u r e s and stereochemistry. - 17 -Copacamphene (23) , although not yet i s o l a t e d from a n a t u r a l source, 11 12 has been prepared by W e s t f e l t , ' by rearrangement of a d e r i v a t i v e of copaborneol (12). By analogy w i t h the e l i m i n a t i o n r e a c t i o n of 49 borneol and i s o b o r n e o l d e r i v a t i v e s ( c f . 6 -> 20), We s t f e l t reasoned that an e l i m i n a t i o n r e a c t i o n of copaborneol would produce copacamphene. On treatment w i t h p_-bromobenzenesulfonyl (b r o s y l ) c h l o r i d e i n p y r i d i n e at room temperature, copaborneol gave a c r y s t a l l i n e b r o s y l a t e (61). When a p y r i d i n e s o l u t i o n of the l a t t e r (61) was heated, a mixture of hydrocarbons was obtained, w i t h copacamphene (23) being the major product. The i n f r a r e d and nuclear magnetic resonance (n.m.r.) spe c t r a of 22 23 copacamphene were very s i m i l a r to those reported f o r sativene. ' - 18 -However, as W e s t f e l t r e p o r t e d , the hydrocarbons were not i d e n t i c a l , and d i f f e r e n t d i o l s were obtained from osmium t e t r o x i d e o x i d a t i o n . W e s t f e l t t h e r e f o r e concluded that the hydrocarbons were epimeric at the i s o p r o p y l p o s i t i o n , (see copacamphene (23) numbering). As f o r the absolute stereochemistry of copacamphene, W e s t f e l t 12 has synthesized (+)-copaborneol (12) from ( + ) - a - s a n t a l o l , a compound of known absolute c o n f i g u r a t i o n . " ^ This 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 of (+)-copaborneol (12) which i n turn 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 of (-)-copacamphene (23). I t i s perhaps p e r t i n e n t at t h i s p o i n t to discus s the s t r u c t u r a l e l u c i d a t i o n of (-)-sativene (26) s i n c e W e s t f e l t assigned the s t r u c t u r e and stereochemistry of copacamphene (23) mainly on the b a s i s of i t s s t r u c t u r a l s i m i l a r i t y t o sat i v e n e (26). (-)-Sativene (26) was f i r s t 22 i s o l a t e d by de Mayo and co-workers from Helminthosporium sativum. This hydrocarbon e x h i b i t e d a r o t a t i o n of -186° and i n f r a r e d absorptions at 3.27, 6.03 and 11.30 u, compatible w i t h an e x o c y c l i c methylene group. This i n t e r p r e t a t i o n was corroborated by the n.m.r. spectrum which e x h i b i t e d two one-proton s i g n a l s at x 5.28 and 5.60, which could r e a d i l y be assigned to the e x o c y c l i c methylene protons. A s i n g l e t at T 8.95 (3H) and a p a i r of doublets (6H, J % 5 Hz) at 9.10 and 9.13 suggested the presence of a t e r t i a r y and i s o p r o p y l methyl groups r e s p e c t i v e l y . A c r y s t a l l i n e d i o l d e r i v a t i v e of sat i v e n e was prepared by r e a c t i n g s a t i v e n e w i t h osmium t e t r o x i d e . This d i o l (62) showed no * 12 Although Kolbe-Haugwitz and W e s t f e l t were c o r r e c t i n t h e i r a s s i g n -ments regarding absolute stereochemistry, we found t h a t copacamphene of absolute c o n f i g u r a t i o n as shown i n 2J3 i s l e v o r o t a t o r y ([a]^-'- -159°, vi d e i n f r a ) and not d e x t r o r o t a t o r y ([a]n +28.9°) as reported. 11,12 N e i t h e r we nor Dr. W e s t f e l t ( p r i v a t e communication) have as yet been able to t r a c e the reason f o r t h i s discrepancy. absorption above 200 my i n the u l t r a v i o l e t , r e q u i r i n g the presence of but one double bond i n the o r i g i n a l hydrocarbon. Period a t e cleavage of J52 gave ketone 63 whose carbonyl absorption i n the i n f r a r e d (5.75 y) was c h a r a c t e r i s t i c of a saturated five-membered r i n g . De Mayo noted that the s p e c t r a l data was i n accord w i t h the proposed s t r u c t u r e , but 26 62 0 63 t h i s i n i t s e l f d i d not c o n s t i t u t e i r r e f u t a b l e proof of s t r u c t u r e . However, con c l u s i v e evidence was provided by the a c t u a l synthesis of (+)-sativene, as o u t l i n e d i n Sect i o n 5 of the I n t r o d u c t i o n (p. 31). C l o s e l y r e l a t e d to copacamphene (23) i s the t e t r a c y c l i c hydro-carbon (+)-cyclocopacamphene (24) which was obtained from the 18 reduction of the n a t u r a l l y o c c u r r i n g cyclocopacamphenic acids (64) by Yoshikoshi and co-workers. The epimeric mixture of the cyclocopacamphenic acids (64) were e s t e r i f i e d w i t h diazomethane, then reduced w i t h l i t h i u m aluminum hydride to a f f o r d the epimeric mixture of the corresponding a l c o h o l s (65). These a l c o h o l s were converted to t h e i r corresponding t o s y l a t e s by r e a c t i o n w i t h p - t o l u e n e s u l f o n y l c h l o r i d e , and the r e s u l t i n g * 18 Cyclocopacamphene apparently occurs n a t u r a l l y i n v e t i v e r o i l . The epimeric a l c o h o l s , cyclocopacamphenol and epicyclocamphenol (65) were subsequently i s o l a t e d from v e t i v e r o i l by Yoshikoshi and co-workers.51 - 20 -t o s y l a t e s were reacted again w i t h l i t h i u m aluminum hydride to produce (+)-cyclocopacamphene (24) 0 X , -OH OH \ 64 65 24 The i n f r a r e d and n.m.r. sp e c t r a of cyclocopacamphene were compared w i t h the corresponding s p e c t r a of c y c l o s a t i v e n e (27). The s p e c t r a of the two compounds were found to be q u i t e s i m i l a r , but not i d e n t i c a l . Therefore, i t was f e l t that cyclocopacamphene was a stereoisomer of c y c l o s a t i v e n e , and s p e c i f i c a l l y , that the two compounds were epimeric w i t h respect to the c o n f i g u r a t i o n of the i s o p r o p y l group. This s u p p o s i t i o n was confirmed by conversion of the epimeric cyclocopacamphenic acids (64) i n t o c y c l o s a t i v e n e (27) (Chart 8). Decarboxylative a c e t o x y l a t i o n of the epimeric acids (64) w i t h lead t e t r a -acetate produced the epimeric acetates (66). H y d r o l y s i s of the l a t t e r (66), followed by Jones o x i d a t i o n a f f o r d e d a s i n g l e a c e t y l d e r i v a t i v e , compound 67_. This compound was subjected to epimerizing c o n d i t i o n s (sodium methoxide i n methanol) and the corresponding epimeric a c e t y l compound (68) was i s o l a t e d . A W i t t i g r e a c t i o n w i t h methylenetriphenylphosphorane on compound 68 produced the d e s i r e d isopropenyl d e r i v a t i v e (69), which was then hydrogenated using t r i s ( t r i p h e n y l p h o s p h i n e ) - r h o d i u m c h l o r i d e as a c a t a l y s t , to o b t a i n (+)-cyclosativene (27). - 21 -0 27 69 68 CHART 8 Although i t has been suggested that (+)-cyclocopacamphene has 18 absolute stereochemistry as depicted i n 24_ t h i s point d i d not re c e i v e unambiguous v e r i f i c a t i o n u n t i l the completion of our synt h e s i s of (-)-cyclocopacamphene. The s t r u c t u r a l e l u c i d a t i o n of cyclocopacamphene (24) i s dependent on the c o r r e c t assignment of the c y c l o s a t i v e n e (27) s t r u c t u r e and stereochemistry. However, the s t r u c t u r a l e l u c i d a t i o n of c y c l o s a t i v e n e i n v o l v e d some of the i n t e r e s t i n g chemistry of these compounds and these features w i l l be discussed i n the next s e c t i o n of the I n t r o d u c t i o n . - 22 -4. Acid Rearrangements Longifolene (29) i s known to undergo some deep-seated rearrange-36 52~"5A ments i n the presence of acid. ' When treated with cupric acetate i n acetic acid at r e f l u x (+)-longifolene underwent isomerization to a mixture of racemic (or p a r t i a l l y racemic) hydrocarbons which contained longifolene (29), longicyclene (30) and iso l o n g i f o l e n e (70). - • • v — i 29 30 70 When the reaction was stopped a f t e r twenty-two hours, there was obtained 55% longifolene (29), 24% longicyclene (30) and 19% i s o l o n g i -folene (70). I f the isomerization was allowed to proceed for f i v e days, there was obtained 53% longifolene, 17% longicyclene and 30% i s o l o n g i -folene. When longicyclene (30) was treated under the same conditions 36 the same mixture of hydrocarbons was obtained. This i n fac t was one of the methods used i n the s t r u c t u r a l e l u c i d a t i o n of the n a t u r a l l y 36 occurring (-t-)-longicyclene (30) . A mechanistic pathway accounting for these r e s u l t s was o r i g i n a l l y proposed by Ourisson"^ '"^ and i s formulated f o r s i m p l i c i t y as proceeding through c l a s s i c a l carbonium ions (Chart 9). The exocyclic methylene group of 29_ could be protonated to produce cation 71. A 1,2- Wagner-Meerwein s h i f t would afford cation (-)-71 which i s the mirror image of CHART 9 - 24 -the o r i g i n a l c a t i o n ((+)-71), and would account f o r the f a c t that the products i n t h i s i s o m e r i z a t i o n were l a r g e l y racemized. A 1,2- or 1,3-deprotonation of cations (+)-71 and (-)-71 would produce the enantiomeric forms of l o n g i f o l e n e (29) and l o n g i c y c l e n e (30) r e s p e c t i v e l y . The formation of i s o l o n g i f o l e n e (70) i s p o s t u l a t e d to i n v o l v e a more deep seated s k e l e t a l change. Both enantiomeric forms of c a t i o n 71 would be i n v o l v e d , g i v i n g r i s e to racemic i s o l o n g i f o l e n e but only the rearrangement i n v o l v i n g c a t i o n (+)-71 i s shown d i a g r a m a t i c a l l y (Chart 9). A methyl m i g r a t i o n i n c a t i o n TL could lead to the formation of c a t i o n 72. M i g r a t i o n of the two carbon bridge of c a t i o n 7_2 would produce c a t i o n _73_. Ring c o n t r a c t i o n of 7_3 would a f f o r d c a t i o n 74_which could undergo a 1,2-hydride s h i f t to produce c a t i o n 75. A f u r t h e r 1,2-Wagner-Meerwein s h i f t i n the l a t t e r c a t i o n could produce c a t i o n 7_6_, which could undergo 1,2-deprotonation to a f f o r d i s o l o n g i -folene (70). Because of i t s s t r u c t u r a l s i m i l a r i t y to l o n g i f o l e n e , sativene (26) would be expected to e x h i b i t the same type of chemistry when trea t e d w i t h c u p r i c acetate and a c e t i c a c i d at r e f l u x . This i s indeed what v . -i . 24-26 has been observed. 26 27 77 Treatment of sativene w i t h a c e t i c a c i d - c u p r i c acetate (two days at r e f l u x ) gave an e q u i l i b r i u m mixture which c o n s i s t e d of 7% s a t i v e n e 26 (26), 32% c y c l o s a t i v e n e (27) and 61% i s o s a t i v e n e (77). McMurry demonstrated that a true e q u i l i b r i u m d i d e x i s t between these is o m e r i c sesquiterpenes, s i n c e s u b j e c t i o n of samples of pure c y c l o s a t i v e n e or i s o s a t i v e n e to c u p r i c a c e t a t e - a c e t i c a c i d treatment produced the same e q u i l i b r i u m mixture of products. The f a c t that c y c l o s a t i v e n e could be converted to sativene was i n s t r u m e n t a l i n the s t r u c t u r a l e l u c i d a t i o n 24 25 of c y c l o s a t i v e n e , ' by analogy w i t h the s t r u c t u r a l e l u c i d a t i o n of 36 l o n g i c y c l e n e (30). 26 McMurry suggested the f o l l o w i n g mechanism f o r the a c i d - c a t a l y z e d e q u i l i b r i u m between 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 . - 26 -P r o t o n a t i o n of sativene (26) could lead to the formation of c a t i o n 5_9_ which could undergo 1 , 3-deprotonation to form c y c l o s a t i v e n e (27) . The c y c l o p r o p y l r i n g of c y c l o s a t i v e n e could then be opened by p r o t o n a t i o n i n e i t h e r of two d i r e c t i o n s to generate a new t e r t i a r y c a t i o n 7_8 or to regenerate c a t i o n 59. Deprotonation of c a t i o n 7_8 would give r i s e to i s o s a t i v e n e (77). There are both s i m i l a r i t i e s and d i f f e r e n c e s i n the a c i d c a t a l y z e d i s o m e r i z a t i o n of l o n g i f o l e n e and sativene. Each undergoes one unique type of transformation ( l e a d i n g to the two d i f f e r e n t i s o products) and one common type of transformation ( l e a d i n g to the two analogous t e t r a c y c l i c p r o d u c t s ) . One of the d i f f e r e n c e s i s that sativene does not undergo a deep-seated rearrangement analogous to the formation of i s o l o n g i f o l e n e (see Chart 9). I f such a rearrangement were to occur i n the sativene case, the analogous bridgehead c a t i o n 7j9_ would be formed. In 79, the c a t i o n i s contained i n a b i c y c l o [ 3 . 2 . l ] o c t a n e system w h i l e i n _72_, the c a t i o n i s i n the more f l e x i b l e b i c y c l o [ 4 . 2 . 1 ] -nonane system. Thus, McMurry"^ po s t u l a t e d that the consequent s t r a i n increases on moving to the s m a l l e r r i n g system, preventing t h i s - 27 -rearrangement from o c c u r r i n g . One f u r t h e r p o i n t of d i f f e r e n c e between the i s o m e r i z a t i o n of l o n g i f o l e n e and s a t i v e n e i s the carbonium i o n rearrangement ((+)-71 -* (-)-71, Chart 9) that accounts f o r the racemization i n the l o n g i f o l e n e s e r i e s . I f a rearrangement of t h i s type were to occur i n the sativene s e r i e s , i t would not lead to racemic s a t i v e n e , but to a compound which i s epimeric at the i s o p r o p y l group, namely copacamphene. However, t h i s product was never found i n the sativene i s o m e r i z a t i o n . This i s not s u r p r i s i n g , s i n c e the i s o p r o p y l group i n sativene has an e q u a t o r i a l o r i e n t a t i o n , w h i l e i n copacamphene the i s o p r o p y l group i s a x i a l to the six-membered r i n g . Therefore, s a t i v e n e , possessing the e q u a t o r i a l i s o p r o p y l group, would c l e a r l y be the thermodynamically more s t a b l e product and to demonstrate the existence of an i n t e r -conversion between sativene and i t s epimer (copacamphene), i t would be necessary to s t a r t w i t h the l a t t e r , and examine i t s rearrangement under a c i d c a t a l y s i s . When (-)-copacamphene (23) was t r e a t e d w i t h c u p r i c acetate i n r e f l u x i n g a c e t i c a c i d , rearrangement d i d indeed take p l a c e . "^ * ^ The products obtained were (+)-cyclosativene, sativene and i s o s a t i v e n e i n a r a t i o of 32:7:61 r e s p e c t i v e l y . The obvious conclusion"*"^ was that copacamphene. was being isomerized to s a t i v e n e , w i t h the l a t t e r compound undergoing f u r t h e r rearrangement as described p r e v i o u s l y (see p. 25) . I t i s assumed that the six-membered r i n g s i n sativene and copa-camphene are i n the c h a i r conformation. ** See the footnote on p. 18. - 28 -M e c h a n i s t i c a l l y , p r o t o n a t i o n of copacamphene, fo l l o w e d by Wagner-Meerwein rearrangement of the r e s u l t i n g c a t i o n (54) would lea d to the formation of c a t i o n 5j9. The l a t t e r i s s t r u c t u r a l l y i d e n t i c a l w i t h the c a t i o n which was p o s t u l a t e d as an intermediate i n the sativene rearrangement. 23 54 59 5. Other S y n t h e t i c Approaches to "Copa-" and "Ylango-"type  Sesquiterpenoids. 12 Recently, W e s t f e l t has reported the s y n t h e s i s of (+)-copa-borneol (12) i n conjunction w i t h the s t r u c t u r a l e l u c i d a t i o n of t h i s compound, w i t h the key s y n t h e t i c step i n v o l v i n g a s t e r e o s e l e c t i v e i n t r a m o l e c u l a r Michael c y c l i z a t i o n . The s t a r t i n g m a t e r i a l employed was (+)-ct-santalol (80) , (see Chart 10). When t h i s compound (80) was o x i d i z e d w i t h selenium d i o x i d e a mixture of s a n t a l a l s (81) was obtained. The c o n f i g u r a t i o n at the double bond had been p a r t i a l l y i n v e r t e d during the o x i d a t i o n , but t h i s stereochemical p o i n t was unimportant f o r the outcome of the s y n t h e s i s . S i l v e r oxide o x i d a t i o n of j31 produced the corresponding acids (82). This product was t r e a t e d w i t h formic a c i d , and since the c y c l o p r o p y l r i n g of 82_ could be - 2 9 -opened i n two d i f f e r e n t ways, a mixture of the syn ( 8 3 ) and a n t i ( 8 4 ) formates was obtained i n a r a t i o of 1 1 : 7 r e s p e c t i v e l y . H y d r o l y s i s of the formates ( 8 3 and 8 4 ) w i t h e t h a n o l i c sodium hydroxide, followed by Jones o x i d a t i o n of the r e s u l t i n g a l c o h o l s and F i s c h e r e s t e r i f i c a t i o n of the a l l y l i c a c i d s , generated the corresponding a n t i ( 8 5 ) and syn ( 8 6 ) keto e s t e r s , r e s p e c t i v e l y . When the mixture of saturated syn and a n t i keto e s t e r s was tr e a t e d w i t h potassium jt-butoxide i n dioxan at room temperature, the syn isomer ( 8 6 ) c y c l i z e d r a p i d l y to a f f o r d the keto e s t e r J37_, w h i l e the a n t i isomer ( 8 5 ) remained unchanged. Compound 8 7 was r e a d i l y separated from compound 85_ by column chromatography. The copacamphoric ester ( 8 7 ) was ster e o c h e m i c a l l y homogeneous w i t h respect to the o r i e n t a t i o n of the C ^Q side chain (see s t r u c t u r e 8_7 f o r numbering) , but epimeric w i t h respect to the secondary methyl group ( C - Q ) • Next, the carbomethoxy group (of 8 7 ) was transformed i n t o a methyl group. H y d r o l y s i s ( e t h a n o l i c sodium hydroxide) of the copacamphoric e s t e r ( 8 7 ) produced the corresponding a c i d , which was tre a t e d w i t h t h i o n y l c h l o r i d e i n benzene to a f f o r d the corresponding a c i d c h l o r i d e . The l a t t e r was reduced w i t h sodium borohydride i n J dioxan at room temperature to generate copacamphoric a l c o h o l 8 8 . This keto a l c o h o l ( 8 8 ) was then t r e a t e d w i t h methanesulfonyl c h l o r i d e i n p y r i d i n e to produce the corresponding methanesulfonate d e r i v a t i v e . L ithium aluminum hydride reduction of the l a t t e r a fforded copaisoborneol ( 1 3 ) , which was r e a d i l y o x i d i z e d by Jones reagent to give copacamphor ( 1 1 ) . Since the c o n f i g u r a t i o n of the hydroxyl group i n copaborneol ( 1 2 ) CHART 10 - 31 -i s the thermodynamically more favoured o r i e n t a t i o n , r e d u c t i o n of copa-camphor (11) w i t h sodium i n a l c o h o l y i e l d e d s y n t h e t i c (+)-copaborneol (12), i d e n t i c a l i n every respect to the n a t u r a l product. Since the l a t t e r compound (12) had p r e v i o u s l y been converted i n t o (-)-copa-camphene (23) Westfelt's s y n t h e s i s f o r m a l l y represented a t o t a l s y nthesis of t h i s sesquiterpene. 22 De Mayo reported the synt h e s i s of (+)-sativene as pa r t of the s t r u c t u r a l e l u c i d a t i o n of the n a t u r a l l y o c c u r r i n g (-)-sativene. 33-35 Longifolene (29) of known absolute stereochemistry, was reacted w i t h bromotrichloromethane"^ to give the trichlorobromo d e r i v a t i v e (89) (see Chart 11) v i a a w e l l documented f r e e - r a d i c a l transannular hydrogen t r a n s f e r . C o m p o u n d 89 was dehydrochlorinated to a f f o r d the chloroacetylene 90. Oxidation of the l a t t e r , followed by e s t e r i f i c a t i o n of the r e s u l t i n g a c i d produced the bromoester (91). On d i s t i l l a t i o n of t h i s compound from i r o n powder under reduced pressure (0.2 mm), o l e f i n i c e s t e r 92 was obtained i n 45% y i e l d . Hydrogenation of the double bond of 92_ produced e s t e r 93. Because of the convex nature of the six-membered r i n g , and the s t e r i c hinderance of the bridged system on the a-side of compound 9_2_, hydrogenation would be expected to take place from the B-side of the molecule, to produce the compound possessing an e q u a t o r i a l i s o p r o p y l group. The ester group of j93_ was then reduced w i t h l i t h i u m aluminum hydride to a f f o r d a l c o h o l 94. A c e t y l a t i o n of 5 8 the l a t t e r produced acetate 95_, which was pyrolyzed i n the vapour phase at 550° to give (+)-sativene (26). The l a t t e r was i d e n t i c a l w i t h the n a t u r a l (-)-sativene, except that i t s o p t i c a l r o t a t i o n was opposite i n s i g n . Since the absolute c o n f i g u r a t i o n of the s t a r t i n g m a t e r i a l - 32 -/ 29 89 Cl 90 94 95 CHART 11 - 33 -( ( + ) - l o n g i f o l e n e ) was known, t h i s synthesis e s t a b l i s h e d not only the stereochemistry, but a l s o the absolute c o n f i g u r a t i o n of n a t u r a l (-)-sativene. 23 McMurry has succeeded i n s y n t h e s i z i n g both (£)-sativene (26) and (±)-copacamphene ( 2 3 ) • 1 5 ' " ^ Dealing f i r s t w i t h the sativene s y n t h e s i s , McMurry's s t a r t i n g m a t e r i a l was the w e l l known Wieland-59 Miescher ketone (96). Under c a r e f u l l y c o n t r o l l e d c o n d i t i o n s , t h i s compound (96) was reacted w i t h ethylene g l y c o l using p_-toluenesulfonic a c i d as a c a t a l y s t . The saturated carbonyl (of 96) was s e l e c t i v e l y k e t a l i z e d , forming the keto k e t a l 97. C a t a l y t i c hydrogenation of 9_7 w i t h 10% palladium on cha r c o a l i n ethanol r e s u l t e d i n the formation of the c i s fused decalone (98) . Reaction of the decalone j98 w i t h i s o p r o p y l l i t h i u m i n r e f l u x i n g pentane generated a l c o h o l 99. Dehydration and d e k e t a l i z a t i o n of t h i s a l c o h o l - k e t a l was accomplished by s t i r r i n g compound 99_ overnight i n a two-phase system of hexane-50% aqueous s u l f u r i c a c i d , to a f f o r d the keto o l e f i n (100). - 34 -Treatment of 100 w i t h borane i n tetr a h y d r o f u r a n showed that t h i s reagent a f f e c t e d r e d u c t i o n of the carbonyl group f a s t e r than i t hydroborated the carbon-carbon double bond. Furthermore, attempts at p r o t e c t i n g the carbonyl group (of 10Q) by k e t a l i z a t i o n r e s u l t e d i n at l e a s t p a r t i a l m i g r a t i o n of the carbon-carbon double bond. However, the carbonyl was protected by forming the 2 , 4 - d i n i t r o p h e n y l -60 hydrazone (2,4-DNP) d e r i v a t i v e (101) and t h i s compound was reacted w i t h borane i n tetrahydrofuran. The r e s u l t i n g d i a l k y l b o r a n e i n t e r -mediate was o x i d i z e d w i t h b a s i c hydrogen peroxide to form the 2,4-DNP a l c o h o l (102). Removal of the 2,4-DNP p r o t e c t i n g group was r e a d i l y 61 accomplished by o z o n o l y s i s of 102 i n e t h y l acetate at -78°, and a f t e r r e d u c t i v e workup w i t h sodium b i s u l f i t e , keto a l c o h o l 103 was obtained. The keto a l c o h o l (103) was reacted w i t h p_-toluenesulfonyl ( t o s y l ) c h l o r i d e i n p y r i d i n e at room temperature f o r three days to form the corresponding keto t o s y l a t e (104). Intramolecular a l k y l a t i o n was accomplished by r e a c t i n g the keto t o s y l a t e (104) w i t h m e t h y l s u l f i n y l 6 2 carbanion i n dimethyl s u l f o x i d e at 60° f o r two hours to produce t r i c y c l i c ketone 63. Treatment of the l a t t e r (63) w i t h m e t h y l l i t h i u m followed by dehydration of the r e s u l t i n g t e r t i a r y a l c o h o l w i t h 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 y i e l d e d racemic sativene (26). McMurry, i n h i s synthesis of racemic copacamphene ( 2 3 ) u t i l i z e d as h i s s t a r t i n g m a t e r i a l an intermediate from the sativene s y n t h e s i s . Keto o l e f i n 100 was trea t e d w i t h m-chloroperbenzoic a c i d i n chloroform to give the 3-epoxide (105). On treatment w i t h e i t h e r m e t h y l s u l f i n y l - 35 -26 63 carbanion i n dimethyl s u l f o x i d e f o r two days at 65° or w i t h a r e f l u x i n g s o l u t i o n of potassium _t-butoxide i n jt-butanol f o r seven days, compound 105 underwent an i n t r a m o l e c u l a r epoxide opening to generate the t r i c y c l i c keto a l c o h o l (106). Dehydration was accomplished by s t i r r i n g the keto a l c o h o l 106 b r i e f l y i n a two phase hexane-50% aqueous s u l f u r i c a c i d system, to produce the t r i s u b s t i t u t e d o l e f i n (107) and the t e t r a s u b s t i t u t e d o l e f i n (108) i n a r a t i o of 7:3 r e s p e c t i v e l y . Hydrogenation of keto o l e f i n 107 over Adams c a t a l y s t i n a c e t i c a c i d gave t r i c y c l i c ketone 63_ (sativene s e r i e s ) as the only product. By analogy w i t h de Mayo's work on the s y n t h e s i s and s t r u c t u r a l 0 108 107 106 e l u c i d a t i o n of sativene (92 9J3; Chart 11) the hydrogenation would be expected to take place completely s t e r e o s e l e c t i v e l y from the l e s s hindered s i d e . Reduction of the carbonyl group of keto o l e f i n 107 w i t h l i t h i u m aluminum hydride i n ether gave o l e f i n i c a l c o h o l s 109 and 110 i n a r a t i o of 4:6 r e s p e c t i v e l y . However, the o l e f i n i c a l c o h o l 109 was formed as the major product when the r e d u c t i o n of compound 107 was c a r r i e d out w i t h l i t h i u m i n l i q u i d ammonia. Under these c o n d i t i o n s , a 6:4 r a t i o of 109 to 110 was obtained. The hydroxyl group of compound 109 i s i n c l o s e p r o x i m i t y to the double bond. This r e l a t i o n s h i p was important as hydrogenation was c a r r i e d out i n a non-polar solvent - 37 -(hexane) so that the c a t a l y s t (palladium on charcoal) might bond to the hydroxyl group and d e l i v e r hydrogen from the more hindered s i d e 63 of the carbon-carbon double bond. Although, i n p r a c t i c e , hydrogena-t i o n was slow, i t d i d reach completion a f t e r f i v e days. C o l l i n s 64 o x i d a t i o n of the hydrogenated a l c o h o l s gave a mixture of t r i c y c l i c ketones 111 and 63_ i n a r a t i o of 85:15 r e s p e c t i v e l y . Treatment of t h i s mixture (111 and 63) w i t h m e t h y l l i t h i u m f o l l o w e d by dehydration w i t h 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 a f f o r d e d (±)-copacamphene (23) and (+)-sativene (26) which could be separated by column chromatography on s i l v e r n i t r a t e impregnated s i l i c a g e l . DISCUSSION 1. General Because of the great d i v e r s i t y i n the number of pathways by which complex n a t u r a l products such as copacamphene, cyclocopacamphene and copaborneol could, i n theory, be constructed, some c o n s i d e r a t i o n of v a r i o u s s y n t h e t i c approaches to these sesquiterpenoids w i l l be discussed b r i e f l y . The t h e o r e t i c a l cleavage of a bond i n a p o l y c y c l i c s e s q u i -terpenoid would produce an intermediate which of t e n possesses a g r e a t l y s i m p l i f i e d s t r u c t u r e as compared w i t h the o r i g i n a l s t r u c t u r e of the n a t u r a l product i t s e l f . To regenerate the d e s i r e d p o l y c y c l i c s k e l e t o n , one would then have to c a r r y out the c y c l i z a t i o n of the a p p r o p r i a t e l y f u n c t i o n a l i z e d intermediate. This approach i s w e l l i l l u s t r a t e d by Corey and c o - w o r k e r s i n the s y n t h e s i s of l o n g i -folene (29). The t h e o r e t i c a l cleavage of the cg~C^Q bond i n l o n g i -folene (29) produced a s i m p l i f i e d s t r u c t u r e (112) as compared w i t h 29. The a p p r o p r i a t e l y f u n c t i o n a l i z e d intermediate (113) underwent an i n t r a m o l e c u l a r Michael c y c l i z a t i o n to produce the t r i c y c l i c diketone (114). - 39 -This same b a s i c approach was used by McMurry i n h i s synthesis 23 of (+)-sativene (26). The key step i n t h i s s y n t h e s i s i n v o l v e d the i n t r a m o l e c u l a r a l k y l a t i o n of an a p p r o p r i a t e l y f u n c t i o n a l i z e d intermediate, the b i c y c l i c keto t o s y l a t e (104), to a f f o r d the t r i c y c l i c ketone (63). 26 104 63 - 40 -Following t h i s general o u t l i n e , the t h e o r e t i c a l cleavage of se v e r a l carbon-carbon bonds i n copacamphene (23) were considered (see Chart 12). Cleavage of the C^-C^, C^-Cg and Cg-Cg bonds of copacamphene (23) (see numbering below) would lead to the h y p o t h e t i c a l intermediates 115, 116, and 117 r e s p e c t i v e l y . The a p p r o p r i a t e l y f u n c t i o n a l i z e d s y n t h e t i c intermediates that might be envisaged f o r the regeneration of the r e q u i r e d t r i c y c l i c carbon s k e l e t o n were 118, 119, and 120 r e s p e c t i v e l y . CHART 12 - 41 -Thus, i t was f e l t that the b i c y c l i c keto t o s y l a t e intermediates (118, 119 and 120) would undergo i n t r a m o l e c u l a r a l k y l a t i o n to a f f o r d the t r i c y c l i c ketone (111). Conversion of the carbonyl group of 111 to an e x o c y c l i c methylene group would then produce copacamphene (23). Apart from the obvious d i f f i c u l t i e s i n s y n t h e s i z i n g complex i n t e r -mediates such as 118, 119 and 120, i t was f e l t t hat t h i s whole s y n t h e t i c approach was too narrow i n scope, i n that only copacamphene could be synthesized v i a these schemes. What was d e s i r e d was an intermediate that could be u t i l i z e d not only f o r the synthesis of copacamphene (23) but a l s o f o r the s y n t h e s i s of cyclocopacamphene (24) and of copacamphor (11). Since (+)-copacamphor (11) had p r e v i o u s l y been converted ' i n t o both (+)-copaborneol (12) and (+)-copaisoborneol (13), the s y n t h e s i s of copacamphor would a l s o complete the t o t a l s ynthesis of these two sesquiterpenoids. - 42 -121 I n s p e c t i o n of the s t r u c t u r e s of the sesquiterpenoids i n question [copacamphene (23), cyclocopacamphene (24), and copacamphor (11)] revealed that these compounds could be considered to possess a b a s i c , common s u b s t i t u t e d b i c y c l o f 3 . 2 . 1 ] o c t a n e u n i t (121) , w i t h an a d d i t i o n a l two carbon u n i t attached i n various ways, to form the t r i c y c l i c skeletons of copacamphene (23) and copacamphor (11), or the t e t r a -c y c l i c s k eleton of cyclocopacamphene (24) . Therefore, the f u n c t i o n a l i z e d b i c y c l o [ 3 . 2 . l ] o c t a n e d e r i v a t i v e that we b e l i e v e d would be s y n t h e t i c a l l y u s e f u l was diketone 122. S y n t h e t i c a l l y , the diketone (122) could be considered as a c y c l o -hexane d e r i v a t i v e w i t h an added two carbon bridge. The j u d i c i o u s choice of a s t a r t i n g m a t e r i a l i s a c r i t i c a l step i n any s y n t h e t i c sequence, and i t was f e l t that the monoterpenoid (+)-carvomenthone (123) could be - 43 -u t i l i z e d as the re q u i r e d cyclohexane d e r i v a t i v e . This r e a d i l y a v a i l a b l e compound i s o p t i c a l l y a c t i v e and of known absolute c o n f i g u r a t i o n ^ and provides ten of the f i f t e e n carbons that are r e q u i r e d i n the synthe s i s of a sesquiterpenoid. A l k y l a t i o n of carvomenthone w i t h a s u i t a b l e a-halopropionate, and the subsequent c y c l i z a t i o n of the r e s u l t i n g product would, i f s u c c e s s f u l , produce the d e s i r e d diketone. Even though compound 122 possesses two saturated carbonyl groups, i t can r e a d i l y be seen that only the carbonyl group (see numbering above) would be capable of enolate formation. Therefore, s y n t h e t i c a l l y , i t would be p o s s i b l e to d i f f e r e n t i a t e between the two carbonyl groups. In t h i s manner, i t should be p o s s i b l e to introduce at Cg a two carbon u n i t w i t h an appropriate l e a v i n g group. Intramolecular a l k y l a t i o n of such a compound (124) would be expected to produce copacamphor (11). 122 124 11 - 44 -By conversion of diketone 122 i n t o the keto o l e f i n (125) , and subsequent i n t r o d u c t i o n of appropriate two carbon u n i t s at C O J i t o was f e l t that the syntheses of copacamphene and cyclocopacamphene could be accomplished. Thus, i t was f e l t that s o l v o l y t i c e l i m i n a t i v e c y c l i z a t i o n of a compound such as 126 could produce copacamphene (23), whereas i n t r a m o l e c u l a r a d d i t i o n to the carbon-carbon double bond of an o l e f i n i c carbenoid such as compound 127 could produce cyclocopacamphene (24). 24 127 23 - 45 -2. Synthesis of the Substituted Bicyclo[3.2.1]octadione 122 The f i r s t synthetic objective was the synthesis of the c r i t i c a l intermediate, diketone 122. As mentioned before, the s t a r t i n g material for the preparation of 122 was (-f-)-carvomenthone (123) . This material was prepared by c a t a l y t i c hydrogenation of commercially a v a i l a b l e (-)-carvone (128) i n ethanol over a Raney n i c k e l c a t a l y s t , followed by chromic acid oxidation of the r e s u l t i n g alcohol. The p o s s i b i l i t y of forming diketone 122 i n a one step reaction, involving a l k y l a t i o n of (+)-carvomenthone (123) with ethyl-2-bromo-propionate, followed by c y c l i z a t i o n i n s i t u of the r e s u l t i n g keto ester was quite a t t r a c t i v e . Once a l k y l a t i o n had taken place at of (+)-carvomenthone (123), the product could react with base to form the cyclohexanone enolate (129), which could then undergo an intramolecular Claisen condensation to produce the diketone (122). However, extensive experimentation ruled this p o s s i b i l i t y out, because the i n i t i a l a l k y l a t i o n was not taking place. Therefore, (+)-carvomenthone (123) was treated with e t h y l formate and sodium niethoxide i n dry benzene to produce the corresponding hydroxymethylene derivative (130) i n 83% y i e l d . Reaction of the l a t t e r (130) with n-butanethiol i n the presence of a c a t a l y t i c amount of p_-toluenesulfonic - 46 -a c i d i n benzene afforded the 2-n-butylthiomethylene d e r i v a t i v e (131) i n 83% y i e l d . A l k y l a t i o n of 131 w i t h e t h y l 2-bromopropionate i n j;-butyl a l c o h o l i n the presence of potassium _ t - b u t o x i d e ^ gave a mixture of products. G a s - l i q u i d chromatographic a n a l y s i s i n d i c a t e d that the product c o n s i s t e d of 50% s t a r t i n g m a t e r i a l (131), 25% of the d e s i r e d C - a l k y l a t e d product (132) and 25% of an undesired O-alkylated product (133). A n a l y t i c a l samples of both the carbon- and oxygen-alkylated products (132 and 133 r e s p e c t i v e l y ) were obtained by p r e p a r a t i v e g . l . c , and t h e i r s p e c t r a l data were i n accord w i t h t h e i r assigned s t r u c t u r e s . In the i n f r a r e d spectrum of 132, the e s t e r carbonyl and the unsaturated carbonyl absorptions appeared at 5.79 and 6.00 y r e s p e c t i v e l y . The O-alkylated product (133) e x h i b i t e d i n f r a r e d absorptions at 5.78 and 5.99 u, i n accord w i t h e s t e r carbonyl and e n o l i c carbon-carbon double bond absorptions, r e s p e c t i v e l y . The n.m.r. sp e c t r a of both of these products were very complex, as each product apparently possessed geometric isomers (with respect to the b l o c k i n g group) and stereo-isomers (with respect to the secondary methyl group adjacent to the est e r carbonyl group). Nevertheless, the most d i s t i n g u i s h i n g t r a i t between the n.m.r. spec t r a of the two products was the appearance of s i g n a l s due to v i n y l methyl groups at x 8.25 i n the O-alkylated product (133) and the absence of these peaks i n the C - a l k y l a t e d products (132). - 47 -133 132 131 These r e s u l t s were not acceptable, and led us to investigate t h i s a l k y l a t i o n reaction i n more d e t a i l . There are a number of variables that can be altered i n t h i s type of reaction, such as the structure of the a l k y l a t i n g reagent, the reaction solvent, the siz e and nature of the cation associated with the enolate anion, and the concen-68 t r a t i o n of the reactants i n so l u t i o n . A l k y l a t i o n on the carbon atom of an enolate anion can normally 68 be maximized by u t i l i z i n g a non-polar reaction solvent such as benzene, small cations (lithium and sodium) associated with the enolate anion, and f a i r l y high concentrations of reactants i n s o l u t i o n . However, applying these maximizing parameters to our p a r t i c u l a r a l k y l a t i o n increased the carbon/oxygen a l k y l a t i o n r a t i o only s l i g h t l y . - 48 -By modifying the a l k y l a t i n g reagent, s a t i s f a c t o r y r e s u l t s were obtained. Thus, use of ethyl 2-iodopropionate i n place of e t h y l 2-bromopropionate, and performing the a l k y l a t i o n i n t-butyl alcohol i n the presence of potassium t-butoxide, produced the carbon-alkylated product (132) i n 73% y i e l d . Two important features of t h i s reaction are i t s r e g i o s e l e c t i v i t y and i t s s t e r e o s e l e c t i v i t y . Dealing f i r s t with the former phenomenon, 6 8 v i r t u a l l y a l l recent studies have come to the same conclusion regarding the e f f e c t of the leaving group i n the a l k y l a t i n g agent on the carbon- vs oxygen-alkylation of enolate anions. For high C/0 a l k y l a t i o n r a t i o s the order of preference of leaving groups i s I ) Br y C l y TsO . These leaving groups are arranged i n an order of 69 decreasing "softness". The preference f o r C/0 a l k y l a t i o n may be r a t i o n a l i z e d on the basis of symbiosis, which i s the s p e c i a l s t a b i l i z a -t i o n associated with the combinations of "hard" acids with "hard" bases, or of " s o f t " acids with " s o f t " b a s e s . ^ These terms are q u a l i t a t i v e l y defined i n the following ways^: s o f t base-donor atom i s of high p o l a r i z a b i l i t y , low e l e c t r o n e g a t i v i t y , e a s i l y oxidized, and associated with empty low-lying o r b i t a l s ; hard base-donor atom i s of low p o l a r i z a b i l i t y , high e l e c t r o n e g a t i v i t y , hard to oxidize, and associated with empty o r b i t a l s of high energy and hence i n a c c e s s i b l e . If one considers the ambident anion of compound 131, the carbon centre (C ) should be a s o f t e r base than the oxygen centre. Furthermore, i n 6 the a l k y l a t i n g agents, the iodide i s a s o f t e r base than the bromide. Thus, i n e t h y l 2-iodopropionate, the carbon centre (C^) to which the iodide i s bonded would be a s o f t e r acid than the corresponding carbon centre (C^) of e t h y l 2-bromopropionate. Because of the s p e c i a l - 49 -s t a b i l i z a t i o n a s s o c i a t e d w i t h combination of s o f t acids w i t h s o f t bases, the combination of the s o f t e r a c i d (C^ of e t h y l 2-iodopropionate) w i t h the s o f t e r base (C^ of compound 131) would be the more e n e r g e t i c a l l y favourable a l k y l a t i o n . In any event, a l k y l a t i o n of compound 131 employing the e t h y l 2-halopropionate w i t h an i o d i d e l e a v i n g group, as opposed to a bromide l e a v i n g group, r e s u l t e d i n the product being completely C - a l k y l a t e d . The stereochemistry of a l k y l a t i o n of compound 131 to produce the a l k y l a t e d d e r i v a t i v e 132 i s the most c r i t i c a l step i n t h i s p a r t i c u l a r r e a c t i o n sequence which i s concerned w i t h the synth e s i s of diketone 122. The f a c t that t h i s a l k y l a t i o n was completely s t e r e o -s e l e c t i v e was not r e a d i l y evident from a s p e c t r a l a n a l y s i s of compound 132, i n that the geometric and stereoisomers of 132 made the s p e c t r a l i n t e r p r e t a t i o n of t h i s compound very d i f f i c u l t . However, removal of the b l o c k i n g group e l i m i n a t e d the geometric isomerism, and s p e c t r a l i n t e r p r e t a t i o n of the corresponding unblocked a l k y l a t e d products (vide i n f r a ) i n d i c a t e d that the a l k y l a t i o n was completely s t e r e o -s e l e c t i v e . That the stereochemistry of a l k y l a t i o n of compound 131 was indeed as i n d i c a t e d by s t r u c t u r e 132 was not confirmed u n t i l the proof of the stereochemistry of diketone 122 (vide i n f r a ) was c a r r i e d out. I f one considers the t r a n s i t i o n s t a t e i n t h i s a l k y l a t i o n (131 ->- 132) 72 to be r e a c t a n t - l i k e i n geometry, then the d i r e c t i o n of a l k y l a t i o n can be r e a d i l y r a t i o n a l i z e d . The ground s t a t e , " h a l f - c h a i r " conforma-t i o n s of 131 are i n d i c a t e d by s t r u c t u r e s 131a and 131b. - 50 -?=CHSnBu 1 — l - > • 131a 131b ( 1 3 ) 71 In conformer 131a there e x i s t s a s i z a b l e A s t r a i n a s s o c i a t e d w i t h the e x o c y c l i c carbon-carbon double bond of the b l o c k i n g group and the i s o p r o p y l group. A c c o r d i n g l y , 131b would be the p r e f e r r e d conformation i n that t h i s conformer would undoubtedly be of 72 lower energy than conformer 131a. I f , as suggested by House, the geometry of t r a n s i t i o n s t a t e s i n a l k y l a t i o n s of enolate anions are r e a c t a n t - l i k e , then i t i s reasonable to suggest that the r e l a t i v e s t a b i l i t i e s of v a r i o u s ground s t a t e conformations w i l l be r e f l e c t e d i n the r e l a t i v e s t a b i l i t i e s of the corresponding t r a n s i t i o n s t a t e s . Therefore, i n the a l k y l a t i o n of compound 131, the t r a n s i t i o n s t a t e f o r a l k y l a t i o n should resemble conformer 131b r a t h e r than conformer 131a. In t h i s p a r t i c u l a r conformer (131b) there are two s t e r i c f a c t o r s which could i n f l u e n c e the d i r e c t i o n of a l k y l a t i o n . The i s o p r o p y l group and the pseudoaxial hydrogen (a- to the v i n y l methyl) s t e r i c a l l y hinder the approach to the a l k y l a t i n g agent from the g-side (see 131b) of the molecule. Therefore because of these o v e r r i d i n g s t e r i c f a c t o r s _ For s t e r e o e l e c t r o n i c reasons, the enolate anion must at t a c k the ^ a l k y l a t i n g agent perpendicular to the plane of the enolate anion. - 51 -the 2-n-butylthiomethylene d e r i v a t i v e 131 would be expected to a l k y l a t e on the a-side of 131b and produce, s t e r e o s e l e c t i v e l y , the corresponding a l k y l a t e d d e r i v a t i v e 132. Treatment of the a l k y l a t e d n-butylthiomethylene d e r i v a t i v e (132) 67 w i t h potassium hydroxide i n r e f l u x i n g aqueous d i e t h y l e n e g l y c o l r e s u l t e d i n the removal of the blocking group and i n the h y d r o l y s i s of the e t h y l e s t e r f u n c t i o n a l i t y , a f f o r d i n g keto a c i d 134. E s t e r i f i c a t i o n of the l a t t e r w i t h an e t h e r e a l s o l u t i o n of diazomethane produced the keto e s t e r (135) i n 85% y i e l d from compound 132. Because of the epimerizable nature of secondary methyl groups adjacent to the carbomethoxy f u n c t i o n a l i t y , the keto e s t e r (135) was obtained as an epimeric mixture of diastereomers. No attempt was made to separate these epimers, since i t was a n t i c i p a t e d that t h i s stereochemical ambiguity would be res o l v e d when the m a t e r i a l was c y c l i z e d . An a n a l y t i c a l sample of the keto e s t e r (135) e x h i b i t e d s p e c t r a l data i n complete accord w i t h the assigned s t r u c t u r e . A c c o r d i n g l y , absorptions at 5.77 and 5.89 u i n the i n f r a r e d spectrum were a t t r i b u t e d to the e s t e r and ketone absorptions r e s p e c t i v e l y . The epimeric mixture (approximately 1:1 r a t i o ) was most evident from the - 52 -n.m.r. spectrum (Figure 1). The protons of the methyl groups of the e s t e r f u n c t i o n a l i t y appeared as s i n g l e t s at x 6.34 and 6.36. The protons adjacent to the e s t e r carbonyl groups were present as quartets at T 7.00 (J = 7.5 Hz) and 7.13 (J = 7.0 Hz). Two s i n g l e t s at x 8.76 and 8.87 were assigned to the t e r t i a r y methyl groups whereas the t h r e e -proton doublets at x 8.84 (J = 7.5 Hz) and 8.89 (J = 7.0 Hz) were designated as the secondary methyl groups adjacent to the e s t e r carbonyl groups. F i n a l l y , the protons of the i s o p r o p y l methyl groups appeared as a doublet (J = 6.0 Hz) at x 9.09. A c y c l i z a t i o n s i m i l a r to the type that we d e s i r e d (keto e s t e r 135 74 diketone 122) had been reported by Roberts and co-workers i n the synthesis of ( i ) - c u l m o r i n . By r e a c t i n g keto e s t e r 136 w i t h sodium 136 137 hydride i n dimethoxyethane f o r seventeen hours at 75°, and quenching the r e a c t i o n w i t h aqueous a c e t i c a c i d , these workers were able to o b t a i n dione 137 i n 67% y i e l d . I t should be noted, however, that w h i l e the c y c l i z a t i o n c a r r i e d out by Roberts and co-workers produced a s u b s t i t u t e d b icyclo[4.2.l]nonadione system, our s y n t h e t i c work n e c c e s s i t a t e d a c y c l i z a t i o n that would produce a s u b s t i t u t e d b i c y c l o [ 3 . 2 . l ] o c t a d i o n e system. - 54 -When the procedure of Roberts was applied to keto ester 135, the desired diketone was obtained, but only i n very poor y i e l d . When sodium hydride i s used as a base, the enolate i s formed r e l a t i v e l y slowly, because the base i s only s l i g h t l y soluble i n the solvent. Thus, when the enolate i s formed, there would also be present a considerable quantity of the keto ester (135) which had not enolized, s e t t i n g up the p o s s i b i l i t y of intermolecular condensation. This could explain the fact that u n i d e n t i f i e d very h i g h - b o i l i n g products were also obtained from t h i s p a r t i c u l a r reaction. In view of the fact that sodium hydride was unsatisfactory i n e f f e c t i n g the desired intramolecular condensation, i t was decided to investigate the use of other bases. It was found that sodium bis(trimethylsilyl)amide^"* was a very u s e f u l base for several reasons. It i s a white c r y s t a l l i n e material that i s very stable and e a s i l y handled, although somewhat hygroscopic. I t i s a strong base and quite soluble i n most organic solvents. By r e f l u x i n g the keto ester (135) with sodium b i s ( t r i m e t h y l s i l y l ) a m i d e i n dimethoxyethane for one hour, followed by quenching the reaction mixture with aqueous a c e t i c acid, the desired (-)-diketone (122) was obtained i n 90% y i e l d , as a white c r y s t a l l i n e s o l i d . 135 122 This c r y s t a l l i n e material 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 which were i n complete agreement w i t h the proposed s t r u c t u r e 122. The i n f r a r e d absorptions at 5.66 and 5.79 y are c h a r a c t e r i s t i c of the 74 carbonyl absorptions of t h i s type of b i c y c l i c dione. Furthermore, the n.m.r. spectrum (Figure 2) e x h i b i t e d a one-proton broadened doublet at T 7.08 ( J = 4.8 Hz) which was designated as the bridgehead proton (C^H). A one-proton quartet of doublets at x 7.66 was a t t r i b u t e d to proton (J =7.0 Hz, J = 1.5 Hz), w i t h the secondary methyl appearing as a doublet ( J = 7.0 Hz) at x 8.75. These assignments were confirmed by a frequency-swept decoupling experiment i n which the 0^ proton was i r r a d i a t e d causing the s i g n a l at x 7.08 to appear as a clean doublet ( J = 4.8 Hz), and the doublet at x 8.75 to c o l l a p s e to a s i n g l e t . The three-proton s i n g l e t at x 8.90 and the three-proton doublets (J=6.0Hz)at x 9.00 and 9.10 were assigned as the t e r t i a r y methyl group and the i s o p r o p y l methyl groups r e s p e c t i v e l y . There are two stereochemical features of the (-)-diketone (122) which warranted f u r t h e r i n v e s t i g a t i o n . These are the stereochemistry at C-j and at of 122. The former stereochemical po i n t r e f e r s to the o r i e n t a t i o n of the secondary methyl group at C^. With regard to the l a t t e r (C^), i t should be noted that the f a c t o r s which a f f e c t the stereochemical outcome of the a l k y l a t i o n of cyclohexanone d e r i v a t i v e s 72 are not w e l l understood i n d e t a i l . Therefore, i t was r a t h e r d i f f i c u l t to p r e d i c t a p r i o r i , and w i t h complete c e r t a i n t y , the stereochemistry of the a l k y l a t i o n (131 ->• 132) . Thus, i t became necessary to o b t a i n unambiguous proof concerning t h i s p o i n t . I t was subsequently proved that t h i s a l k y l a t i o n produced a product i n which the i s o p r o p y l and propionate groups were i n a trans r e l a t i o n s h i p . - 57 -3. Stereochemical Proof of Diketone 122 I t was f e l t the e a s i e s t and s y n t h e t i c a l l y most s a t i s f y i n g method of e s t a b l i s h i n g the stereochemistry would be the unambiguous synthesis of a compound which possessed i s o p r o p y l and propionate groups i n a c i s r e l a t i o n s h i p to each other. These stereochemical features are present i n the keto e s t e r (138). The l a t t e r could i n t u r n be c y c l i z e d to produce the s u b s t i t u t e d b i c y c l o [ 3 . 2 . l ] o c t a d i o n e (139). 138 139 I t was f e l t t hat these compounds (138 and 139) would have great s y n t h e t i c u t i l i t y . The synt h e s i s of 138 would r e s o l v e the st e r e o -chemistry at of diketone 122 (and the corresponding a l k y l a t e d cyclohexane d e r i v a t i v e s 132 and 135). A l s o , the synthesis of diketone 139 would provide a p o t e n t i a l l y u s e f u l s y n t h e t i c intermediate to the "ylango"-type sesquiterpenoids. That i s , the l a t t e r n a t u r a l products could be obtained from diketone 139 i n a manner analogous to that o u t l i n e d f o r the conversion of diketone 122 to the "copa"-type sesquiterpenoids (see page 44). The s t a r t i n g m a t e r i a l chosen f o r t h i s unambiguous synthesis of diketone 139 was, as before, (-)-carvone (128). B i r c h r e d u c t i o n of (-)-128 w i t h sodium i n l i q u i d ammonia i n the presence of e t h a n o l , - 58 -followed by chromic a c i d o x i d a t i o n of the r e s u l t i n g a l c o h o l gave, i n 76 80% y i e l d , (+)-dihydrocarvone (140). I t was found that t h i s method was s u p e r i o r to the w e l l known red u c t i o n of (-)-carvone w i t h z i n c and sodium hydroxide i n e t h a n o l , ^ e s p e c i a l l y i n large s c a l e r e a c t i o n s . Condensation of (+)-dihydrocarvone (140) w i t h l - d i e t h y l a m i n o - 3 -pentanone methiodide (141) i n the presence of a sodium amide afforded mainly the (+)-ketol (142), accompanied by an epimeric mixture of 78 (-)-7-epi-a-cyperone (143) and (+)-q-cyperone (144). 144 143 142 - 59 -The (+)-ketol (142) was separated from the epimeric cyperones by f r a c t i o n a l c r y s t a l l i z a t i o n . R e c r y s t a l l i z a t i o n of the k e t o l , which 7 8 i s of known absolute c o n f i g u r a t i o n , a f f o r d e d a c o l o u r l e s s c r y s t a l l i n e m a t e r i a l which 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 i n complete agreement 78 w i t h s t r u c t u r e 142 and w i t h the data reported i n the l i t e r a t u r e f o r t h i s compound. A c c o r d i n g l y , the i n f r a r e d spectrum showed a hydroxyl absorption at 2.96 u, a saturated carbonyl absorption at 5.92 u, and isopropenyl double bond absorptions at 6.14 and 11.28 u. The n.m.r. spectrum e x h i b i t e d an unresolved m u l t i p l e t at T 5.35 corresponding to the e x o c y c l i c methylene group protons, and the v i n y l methyl group appeared as a doublet (J = 1.0 Hz) at x 8.33. The s i n g l e t at x 8.77 was assigned to the t e r t i a r y methyl group, whereas the doublet (J = 6,5 Hz) at x 8.97 was a t t r i b u t e d to the protons of the secondary methyl group. Hydrogenation of the (+)-ketol (142) i n ethanol w i t h 10% palladium on charcoal as a c a t a l y s t a f f o r d e d the c r y s t a l l i n e (+)-dihydro k e t o l (145). Of p a r t i c u l a r note i n the i n f r a r e d spectrum of t h i s m a t e r i a l was the absence of any o l e f i n i c double bond absorptions. Consistent w i t h t h i s , there were no o l e f i n i c protons evident i n the n.m.r. spectrum of 145. However, a s i x - p r o t o n doublet ( J = 6.0 Hz) at x 9.16 could be a t t r i b u t e d to the newly created i s o p r o p y l group. The t e r t i a r y methyl group (a s i n g l e t at x 8.75) and secondary methyl group (a doublet at x 8.94, J = 7.0 Hz) were a l s o evident. Condensation of the more r e a d i l y a v a i l a b l e (+)-carvomenthone (123) w i t h l-diethylamino-3-pentanone methiodide (141), i n a manner analogous - 60 -to that reported f o r (+)-dihydrocarvone, d i d produce mainly the (-f-)-dihydro k e t o l (145), accompanied by the i s o p r o p y l analogs of compounds 143 and 144. However, p u r i f i c a t i o n of t h i s m a t e r i a l was more d i f f i c u l t than the corresponding p u r i f i c a t i o n of (+)-ketol 142 owing to the f a c t that the (+)-dihydro k e t o l (145) d i d not c r y s t a l l i z e out of the condensation mixture. Thus, extensive column chromatography had to be used i n order to o b t a i n the (+)-ketol 145 i n a pure form. The (-t-)-dihydro k e t o l (145) was dehydrated to the corresponding (-)-unsaturated ketone (146) by treatment of the former w i t h r e f l u x i n g a l c o h o l i c potassium hydroxide. The s p e c t r a l p r o p e r t i e s of the product were i n agreement w i t h s t r u c t u r e 146. Of p a r t i c u l a r pertinence were the u l t r a v i o l e t spectrum (A 250 mu, e = 15,800) and i n f r a r e d max ' spectrum (A 6.05 u ) , which c l e a r l y i n d i c a t e d the presence of the max J Y a,3-unsaturated carbonyl group. In the n.m.r. spectrum, the v i n y l methyl group appeared as a doublet (J = 1.7 Hz) at T 8.23. The t e r t i a r y methyl group ( s i n g l e t at x 8.74) and the i s o p r o p y l group (doublet at x 9.09, J = 6.0 Hz) were a l s o r e a d i l y evident. The u t i l i t y of compound 146 i n the stereochemical!^ unambiguous synthesis of dione 139 i s now more obvious. Although compound 146 i s b i c y c l i c , the saturated r i n g contains an i s o p r o p y l group and a t e r t i a r y - 61 -methyl group (at asymmetric centres and C ^ Q r e s p e c t i v e l y , see s t r u c t u r e 146 f o r numbering ) of known absolute stereochemistry. Furthermore, the carbon-carbon double bond (of 146) could presumably be converted to a carbonyl group (at C , . ) by o z o n o l y s i s . In order to o b t a i n a compound such as keto e s t e r 138 i n which the i s o p r o p y l and propionate groups were i n a c i s o r i e n t a t i o n to each other, a methyl group would have to be introduced at of 146, and a l s o o x i d a t i v e cleavage of the C „ - C „ and C . - C , . would be r e q u i r e d . 146 138 The obvious means of i n t r o d u c i n g a methyl group at of 146 would be f i r s t to subject t h i s compound to 2,3-dichloro-5,6-dicyanobenzoquinone 79 (DDQ) o x i d a t i o n i n order to o b t a i n the cross-conjugated dienone (147). The l a t t e r (147)could undergo conjugate methylation to produce the a l k y l a t e d product 148. 146 147 148 I t i s now general p r a c t i c e to number eudesmane-type sesquiterpenoids according to the s t e r o i d numbering system, as i n d i c a t e d by formula 146. - 62 -However, i n our l a b o r a t o r y , the DDQ o x i d a t i o n of epi-a-cyperone (143) to the corresponding cross-conjugated dienone (149) was found 80 to be a very poor y i e l d i n g process. I t was subsequently shown that by i n t r o d u c i n g a hydroxymethylene group at the C 2 p o s i t i o n of compound 143, and then performing the DDQ o x i d a t i o n , a good y i e l d of the corresponding cross-conjugated dienone aldehyde (151) could be obtained 80 HOHC 14% y i e l d 68% y i e l d o v e r a l l 150 151 A c c o r d i n g l y , condensation of (^-dihydro-epi-a-cyperone (146) w i t h e t h y l formate i n the presence of sodium methoxide i n dry benzene afforded the (-)-2-hydroxymethylene d e r i v a t i v e (152)in 96% y i e l d . This c r y s t a l l i n e m a t e r i a l e x h i b i t e d the expected s p e c t r a l p r o p e r t i e s . Of p a r t i c u l a r i n t e r e s t was the u l t r a v i o l e t spectrum (A 260 and 311 mu), max c h a r a c t e r i s t i c a l l y s h i f t i n g (A 256 and 358 mu) by the a d d i t i o n of J ° max J sodium hydroxide. In the n.m.r. spectrum, s i g n a l s at T-4.17 and 2.61 i n d i c a t e d the presence of the hydroxymethylene protons. Dehydrogenation of the (-)-hydroxymethylene d e r i v a t i v e (152) w i t h - 63 -DDQ i n dioxan f o r ten minutes afforded the (+)-2-formyl c r o s s -conjugated dienone (153), i n 78% y i e l d , as a pale y e l l o w c r y s t a l l i n e m a t e r i a l . Again, the s p e c t r a l data were i n complete agreement w i t h the s t r u c t u r a l assignment of 153. Of note was the appearance i n the n.m.r. spectrum of the aldehydic proton as a s i n g l e t at T 1.20. A l s o present was a s i n g l e t at T 2.45 corresponding to the v i n y l proton. Other assignable s i g n a l s were s i m i l a r i n chemical s h i f t and m u l t i p l i c i t y to that of compound 146. 146. 152 153 The i n t r o d u c t i o n of the secondary methyl group at was 81 82 accomplished by the conjugate a d d i t i o n of l i t h i u m dimethylcuprate ' to the cross-conjugated dienone system of compound 153. This reagent was chosen f o r the conjugate a d d i t i o n since i t had been shown to be of greater general u t i l i t y than the copper-catalyzed methylmagnesium 83 h a l i d e reagents. In p a r t i c u l a r , the l i t h i u m dimethylcuprate reagent 81 gives v i r t u a l l y no 1,2-addition products and a f f o r d s higher y i e l d s of 84 the d e s i r e d product than the Grignard reagents. When there are two conjugate a d d i t i o n s i t e s , (as i n compound 153) t h i s reagent w i l l a l k y l a t e i n a r e g i o s e l e c t i v e manner, g i v i n g s u b s t i t u t i o n only at the l e s s hindered p o s i t i o n . Furthermore, t h i s reagent u s u a l l y reacts i n a - 64 -s t e r e o s e l e c t i v e manner, a feature that was not e s s e n t i a l i n t h i s sequence, but i s always s y n t h e t i c a l l y p l e a s i n g . Since the conjugate a d d i t i o n of the dimethylcuprate reagent to the cross-conjugated dienone system of 153 would generate a s p e c i f i c enolate anion, i t was thought to be d e s i r a b l e to trap t h i s enolate 85 anion w i t h a c e t y l c h l o r i d e . I t was expected that the r e s u l t i n g enol acetate would be of greater s y n t h e t i c u t i l i t y than the corresponding hydroxymethylene d e r i v a t i v e which would be obtained by quenching the enolate anion w i t h a proton source. The l i t h i u m dimethylcuprate a d d i t i o n to compound 153 was c a r r i e d out at 0° and the r e a c t i o n mixture was quenched w i t h an excess of a c e t y l c h l o r i d e . In order to ensure b a s i c work-up c o n d i t i o n s , the quenched s o l u t i o n was immediately poured i n t o a r a p i d l y s t i r r e d i c e -ammonium hydroxide s o l u t i o n , and the organic p o r t i o n was q u i c k l y separated. The enol acetate (154) thus obtained was somewhat unstable and the crude product was used d i r e c t l y i n the next r e a c t i o n . However, an a n a l y t i c a l sample was obtained by p r e p a r a t i v e g . l . c . and the s p e c t r a l data i n d i c a t e d that the r e a c t i o n had been completely r e g i o s e l e c t i v e and s t e r e o s e l e c t i v e . In the i n f r a r e d spectrum, absorptions at 5.66 and 5.99 u were c h a r a c t e r i s t i c of an enol acetate a b s o r p t i o n , w h i l e the unsaturated carbonyl group and the o l e f i n i c double bond absorptions were recorded at 5.99 and 6.21 u r e s p e c t i v e l y . That the d e s i r e d conjugate a d d i t i o n had taken place was q u i t e evident from the n.m.r. spectrum. In a d d i t i o n to the s i g n a l s of the v i n y l methyl group (a broad s i n g l e t at x 8.14), the t e r t i a r y methyl group (a s i n g l e t at x 8.83), and the i s o p r o p y l methyl groups (poorly r e s o l v e d m u l t i p l e t s at x 9.07), - 65 -the v i n y l proton appeared as a s i n g l e t at x 1.80, the a c e t y l methyl group appeared as a s i n g l e t at x 7.77 and the newly introduced secondary methyl group was evident as a doublet (J = 7.0 Hz) at x 8.97. It i s perhaps pertinent to deal b r i e f l y with the stereochemistry assigned to compound 154. I t has been proposed that i n 1,4-conjugate addition reactions of the type employed to produce compound 154, the a l k y l a t i n g agent must attach the 3 _carbon of the a,3-unsaturated ketone 86 i n a manner perpendicular to the fr-electron system. Attack on t h i s s i t e may occur from the a-side or the S-side of the molecule. In the p a r t i c u l a r reaction under discussion, a-attack i s not favoured due to the s i g n i f i c a n t s t e r i c i n t e r a c t i o n s of the approaching a l k y l a t i n g reagent with the t e r t i a r y methyl group. On the other hand, 6-approach would be s i g n i f i c a n t l y less hindered and a l k y l a t i o n would thus be expected to occur from the side making the secondary methyl group 8-oriented. That the conjugated addition of l i t h i u m dimethylcuprate to dienones of t h i s type 0-54) proceeds to give the corresponding trans-v i c i n a l methyl groups has clear l i t e r a t u r e precedent. This i s well i l l u s t r a t e d by the conjugate addition of l i t h i u m dimethylcuprate to dienone 155, to a f f o r d octalone 156 which possesses t r a n s - v i c i n a l methyl groups. 155 156 - 66 -Ozonolysis of the enol acetate (154) i n e t h y l acetate at -78°, followed by an o x i d a t i v e workup (aqueous sodium hydroxide and hydrogen 88 peroxide at 90° f o r approximately one hour) afforded the keto a c i d 157. This m a t e r i a l was e s t e r i f i e d by treatment w i t h e t h e r e a l d i a z o -methane to produce the (+)-keto e s t e r (138) i n 45% y i e l d from the c r o s s -conjugated dienone (153). 153 154 157 138 The s p e c t r a l data of the (+)-keto e s t e r (138) were i n complete accord w i t h the assigned s t r u c t u r e . A c c o r d i n g l y , the i n f r a r e d spectrum showed e s t e r carbonyl and ketone carbonyl absorptions at 5.76 and 5.85 y r e s p e c t i v e l y . The n.m.r. spectrum (Figure 3) revealed a s i n g l e t at T 6.34 i n accord w i t h the protons of the methyl e s t e r f u n c t i o n a l i t y . The proton adjacent to the e s t e r carbonyl group appeared as a quartet (J = 7.2 Hz) at T 6.93, and the secondary methyl group appeared as a doublet (J = 7.2 Hz) at T 9.04. The s i n g l e t at T 9.01 and the doublets (J = 6.0 Hz) at x 9.09 and 9.10 accounted f o r the t e r t i a r y and i s o p r o p y l methyl groups, r e s p e c t i v e l y . D i r e c t comparison of the i n f r a r e d spectrum of keto e s t e r s 135 and 138 was not p r a c t i c a l i n that the former was an epimeric mixture of diastereomers whereas the l a t t e r was completely homogeneous. - 68 -However, as mentioned p r e v i o u s l y , the n.m.r. spectrum of 135 revealed a d i s t i n c t set of s i g n a l s f o r each of the two diastereomers and i t was r e l a t i v e l y easy to show that the n.m.r. spectrum of the (+)-keto e s t e r (138) was q u i t e d i f f e r e n t from that of e i t h e r of the keto e s t e r epimers (135). Thus, as j u s t d e s c r i b e d , the (+)-keto e s t e r 138, w i t h the i s o p r o p y l group and propionate group i n a t r a n s - r e l a t i o n s h i p , had been synthesized unambiguously. Since t h i s compound (138) was d i f f e r e n t from e i t h e r of the epimers of keto e s t e r (135), t h i s c l e a r l y e s t a b l i s h e d that the r e l a t i o n s h i p between the i s o p r o p y l group and propionate group of compound 135 was c i s , and provided i r r e f u t a b l e proof f o r the s t e r e o -chemistry of the a l k y l a t e d cyclohexanone d e r i v a t i v e s 132, 134 and 135. The d i f f e r e n c e between the keto e s t e r s 135 and 138 was f u r t h e r confirmed by t h e i r d i f f e r e n t chemical behaviour. When 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 of 138 was attempted, employing the same r e a c t i o n c o n d i t i o n s that were used i n the p r e p a r a t i o n of diketone 122, the d e s i r e d diketone 139 was obtained, but i n very low y i e l d . However, by changing the solvent and r e a c t i o n c o n d i t i o n s , b e t t e r r e s u l t s were obtained. A s o l u t i o n of the (+)-keto e s t e r (138) i n dry benzene was added over a period of one hour to a r e f l u x i n g s o l u t i o n - 69 -of sodium b i s ( t r i m e t h y l s i l y l ) a m i d e i n benzene, and the r e a c t i o n mixture was then r e f l u x e d f o r an a d d i t i o n a l one and one-half hours. The r e a c t i o n mixture was quenched w i t h aqueous a c e t i c a c i d i n the usual manner to a f f o r d the (+)-diketone (139_) i n 60% y i e l d . The s p e c t r a l p r o p e r t i e s of the c r y s t a l l i n e (+)-diketone (139) were i n complete accord w i t h the assigned s t r u c t u r e , and were s i m i l a r t o , but not i d e n t i c a l w i t h ^ those of i t s epimer, the (-)-diketone (122). In the i n f r a r e d spectrum of compound 139, the carbonyl absorptions 74 appeared at 5.66 and 5.80 p. In the n.m.r. spectrum (Figure 4) a one-proton m u l t i p l e t at x 7.10 was assigned to the bridgehead proton (CH) , whereas the one-proton quartet of doublets (x 7.71, J = 7.3 Hz, Jn u T T = 1.5 Hz) was a t t r i b u t e d to the proton at C,. The C,-n.—C^ H / secondary methyl group appeared as a doublet (J = 7.3 Hz) at x 8.83. The s i n g l e t at x 8.90 and the doublets ( J = 6.3 Hz) at x 9.02 and 9.15 were designated as the t e r t i a r y and i s o p r o p y l methyl groups r e s p e c t i v e l y . The most d i s t i n g u i s h i n g property between diketones 122 and 139 however, was the r o t a t i o n (diketone 139, [a] D + 100°; diketone 122, [ a ] D -56°). The s u c c e s s f u l synthesis of the (+)-diketone (139) , besides cor r o b o r a t i n g the conclusions p r e v i o u s l y o u t l i n e d regarding the stereochemistry of the keto e s t e r 135, als o provided a p o t e n t i a l l y u s e f u l s y n t h e t i c intermediate f o r the "ylango-"type sesquiterpenoids. Although, as j u s t o u t l i n e d , the stereochemistry at of diketone 122 had been e s t a b l i s h e d c o n c l u s i v e l y , the stereochemistry of the secondary methyl group at s t i l l remained unresolved. In t h i s connection, i t i s p e r t i n e n t to p o i n t out that the diketone 137 which - 71 -Roberts and co-workers u t i l i z e d i n t h e i r s y n t h e s i s of culmorin had been assigned the stereochemistry as depicted by 137. Their study of a 158 137 molecular model of the bicyclo[4.2.l]nonane system revealed that approach of any reagent to the five-membered r i n g should be s t r o n g l y d i r e c t e d to the face opposite the four-carbon b r i d g e , due to s t e r i c i n t e r f e r e n c e by the l a t t e r . A c c o r d i n g l y , diketone 137 was envisaged to a r i s e v i a s t e r e o s e l e c t i v e k i n e t i c a l l y c o n t r o l l e d p r o t o n a t i o n of enolate 158 from the side opposite the four-carbon bridge. Even though our r i n g system was a b i c y c l o [ 3 . 2 . 1 ] o c t a n e , i t was f e l t that the s t e r i c e f f e c t of the three-carbon bridge should be s i m i l a r to that of the four-carbon b r i d g e , so that s t e r e o s e l e c t i v e k i n e t i c p r o t o n a t i o n of enolate 159 should r e s u l t i n the formation of diketone 122. However, diketone 122 was a l s o found to be the thermo-dynamically more s t a b l e diketone. That i s , when diketone 122 was subjected to e p i m e r i z i n g c o n d i t i o n s (potassium carbonate i n aqueous dioxan at room temperature) the diketone was recovered unchanged. That these c o n d i t i o n s were s u f f i c i e n t l y strong to e f f e c t e p i m e r i z a t i o n of the diketone was v e r i f i e d by changing the solvent from water to deuterium oxide i n the above r e a c t i o n . In t h i s case, deuterium was incorporated - 72 -at C 7, as shown by n.m.r. 159 122 Because the product from p r o t o n a t i o n of the enolate anion 159 i s the thermodynamically more s t a b l e product and not s o l e l y the product of k i n e t i c c o n t r o l , the argument f o r s t e r e o s e l e c t i v e k i n e t i c p r o t o n a t i o n as a stereochemical proof was not v a l i d . Therefore a chemical proof regarding t h i s p o i n t was sought and the stereochemistry at C 7 of compound 122 was e s t a b l i s h e d c o n c l u s i v e l y by the f o l l o w i n g r e a c t i o n sequence. The (-)-diketone (122) was t r e a t e d w i t h sodium b i s ( t r i m e t h y l s i l y l ) -amide i n benzene at room temperature and the r e s u l t i n g s o l u t i o n was quenched w i t h a c e t y l c h l o r i d e to a f f o r d the corresponding keto enol acetate (160). Hydrogenation of the l a t t e r w i t h Adams c a t a l y s t i n ethanol produced the keto acetate (161). I t i s apparent from the study of a molecular model of 160, that hydrogenation should occur only from the l e a s t hindered exo s i d e of the double bond, that i s , the side ax</ay from the three-carbon bridge. Reduction of compound 161 w i t h l i t h i u m aluminum hydride a f f o r d e d the c r y s t a l l i n e d i o l 162. Again, the approach of the reducing agent to the ketone carbonyl group of compound 161 would be expected to take place from the l e a s t hindered s i d e , producing the hydroxyl group at Cft w i t h stereochemistry as - 73 -i n d i c a t e d by s t r u c t u r e 162. When the (-)-diketone (122) was subjected to re d u c t i o n w i t h e i t h e r sodium borohydride or l i t h i u m aluminum hydride the same 89 c r y s t a l l i n e d i o l (162) was obtained. 162 Since the c o n f i g u r a t i o n at of the keto acetate (161) was almost c e r t a i n l y as shown (hydrogenation of 160 from the l e s s hindered side) and si n c e the nonepimerizable reductions of compound 161 and of the diketone 122 produced the same d i o l (162), t h e r e f o r e the stereochemistry at of the diketone 122 was as i n d i c a t e d by s t r u c t u r e 122. The n.m.r. spec t r a of compounds 161 and 162 served to confirm the assigned s t r u c t u r e s . The proton at Cg i n both compounds appeared as a p a i r of doublets. That the hydrogenation (160 ->• 161) had indeed - 74 -90 taken place i n a c i s manner from the l e s s hindered exo s i d e of the double bond i n compound 160 was confirmed by the observed coupling constants, J and J _ . Thus, molecular models i n d i c a t e d 5 6 6 7 that the d i h e d r a l angle between the protons i n and of compounds 161 and 162 was n e a r l y 0°, and, i n agreement w i t h the Karplus equation, the observed coupling constants, J„ was 10.5 Hz i n each case. L,rl— t._n o 7 S i m i l a r l y , in each of compounds 161 and 162, J was found to be C,_n—C,H 5 6 approximately 7.5 Hz. Again, t h i s was i n agreement w i t h the Karplus 90 equation, since the d i h e d r a l angle between the protons on C,. and Cg was, on the b a s i s of molecular models, approximately 15-25°. Moreover, copaisoborneol (13) has a s i m i l a r d i h e d r a l angle between protons at C^ and C^Q (see below f o r numbering) and the reported coupling constant 11 u u w a s 8*0 Hz. On the other hand, the proton at C i r i i n copaborneol (12) appeared as a broad s i n g l e t , because the d i h e d r a l angle between protons at C^ and i n t h i s compound i s approximately 90°. 13 12 The intermediate (-)-diketone (122) was s u c c e s s f u l l y u t i l i z e d i n the synthesis of (+)-copacamphor (11) (-)-copacamphene (23) and 13 (-)-cyclocopacamphene (24). The synt h e s i s of (+)-copacamphor which was c a r r i e d out i n a manner s i m i l a r to the scheme o u t l i n e d on page 43 f See the footnote on page 41. - 75 -w i l l not be discussed i n t h i s t h e s i s , as i t represents a p o r t i o n of the Ph.D. t h e s i s of my co-worker R.J. K e z i e r e . 4. Synthesis of the S u b s t i t u t e d Bicyclo[3.2.l]octenone 125 For the s y n t h e s i s of (-)-copacamphene and of (-)-cyclocopacamphene (as o u t l i n e d on page 44) i t was necessary to introduce an o l e f i n i c double bond (A^'^) i n t o the diketone (122). As i n d i c a t e d p r e v i o u s l y , i t was planned to use the carbonyl group at as a "handle" i n accomplishing t h i s transformation (diketone 122 •> keto o l e f i n 125). A number of d i f f e r e n t s y n t h e t i c routes f o r o b t a i n i n g the keto o l e f i n (125) were i n v e s t i g a t e d . Each of these w i l l be discussed i n t u r n . 91 In 1969, F e t i z o n and co-workers reported that the r e d u c t i o n of enol d i e t h y l phosphates w i t h sodium or l i t h i u m i n l i q u i d ammonia gave the corresponding o l e f i n . These enol phosphates were prepared from the corresponding ketones by f i r s t making the a-bromoketones, and then r e a c t i n g the l a t t e r w i t h t r i e t h y l p h o s p h i t e . The r e d u c t i o n was c a r r i e d out by adding a s o l u t i o n of the enol phosphate i n t e t r a h y d r o f u r a n and tj-butyl a l c o h o l to a s o l u t i o n of l i t h i u m or sodium i n l i q u i d ammonia. S h o r t l y a f t e r t h i s communication by Fetizon and co-workers, I r e l a n d 92 and P f i s t e r reported an a l t e r n a t i v e method f o r the s y n t h e s i s and reduction of enol d i e t h y l phosphates. This synthesis i n v o l v e d r e a c t i n g an enolate anion of a ketone w i t h d i e t h y l phosphorochlorodate (163), w h i l e the r e d u c t i o n i n v o l v e d use of l i t h i u m i n ethylamine-_t-butyl 92 a l c o h o l . One of the exampled c i t e d by I r e l a n d and P f i s t e r i s given below. - 77 -A c c o r d i n g l y , diketone 122 was t r e a t e d w i t h sodium b i s ( t r i m e t h y l s i l y l ) -amide i n t e t r a h y d r o f u r a n to generate the d e s i r e d enolate (159). The l a t t e r was quenched w i t h d i e t h y l phosphorochlorodate (163) i n p y r i d i n e to a f f o r d the (-)-keto enol phosphate (164) i n 94% y i e l d . The i n f r a r e d absorptions of compound 164 at 5.69 and 5.96 u c l e a r l y showed the presence of the carbonyl and e n o l i c double bond r e s p e c t i v e l y . In the n.m.r. spectrum the protons of the ethoxy groups e x h i b i t e d i n When the r e a c t i o n mixture i n v o l v e d i n the c y c l i z a t i o n of the keto e s t e r (135) to the diketone (122) was quenched d i r e c t l y w i t h d i e t h y l phosphorochlorodate (163) i n s t e a d of w i t h aqueous a c e t i c a c i d , the (-)-keto enol phosphate (164) was a l s o formed, but i n lower y i e l d . - 78 -a d d i t i o n to the cou p l i n g normally found i n e t h y l groups, coupling due to the presence of the phosphorus atom. Thus the methylene protons (of the ethoxy groups) appeared as a p a i r of quartets (J = 7.0 Hz, J u ^ = 1.0 Hz) at x 4.82, and the methyl protons (of the ethoxy groups) n—r appeared as a p a i r of t r i p l e t s ( J = 7.0 Hz, J u = 1.0 Hz) at x 8.63. The protons of the v i n y l methyl group a l s o e x h i b i t e d long range coupling w i t h the phosphorus atom, and appeared as a p a i r of doublets (J = 1.0 Hz, J = 2.2 Hz) at x 8.30. These phosphorus-proton coupling H—r assignments were v e r i f i e d i n a heteronuclear frequency swept decoupling experiment by i r r a d i a t i n g the phosphorus atom. The c o l l a p s e of the s i g n a l s a t t r i b u t e d to the ethoxy groups to the normal t r i p l e t and quartet ( J = 7.0 Hz) f o r the methyl and methylene protons r e s p e c t i v e l y was observed, as w e l l as the c o l l a p s e of the protons of the v i n y l methyl group to a doublet ( J = 1.0 Hz). The t e r t i a r y methyl group ( s i n g l e t at x 8.98) and the i s o p r o p y l group (doublet at x 9.08, J = 6.3 Hz) were also evident i n the n.m.r. spectrum of compound 164. Reduction of compound 164 w i t h l i t h i u m i n ethylamine-_t-butyl a l c o h o l gave a mixture of products. The r e a c t i o n was st u d i e d i n considerable d e t a i l and the e f f e c t of v a r y i n g s e v e r a l d i f f e r e n t r e a c t i o n parameters (reactant c o n c e n t r a t i o n , r e a c t i o n temperature, proton source, r e a c t i o n time and method of quenching) were i n v e s t i g a t e d . However, the maximum y i e l d of the de s i r e d keto o l e f i n (125) that was obtained was 26%. Moreover, the product was contaminated w i t h the a l c o h o l i c o l e f i n (165), a saturated ketone (166) and u n i d e n t i f i e d high b o i l i n g m a t e r i a l . The o l e f i n i c a l c o h o l (165) was r e a d i l y o x i d i z e d to the d e s i r e d product, but the only method that was found f o r separating - 79 -122 166 165 the keto o l e f i n from the unwanted r e d u c t i o n products was p r e p a r a t i v e g . l . c . The (-)-keto p l e f i n (125) obtained i n t h i s f a s h i o n gave a n a l y t i c a l and s p e c t r a l data which was i n complete agreement w i t h the assigned s t r u c t u r e . In the i n f r a r e d spectrum, absorptions at 3.29 y and 6.13 y i n d i c a t e d the presence of an o l e f i n i c double bond, whereas the carbonyl absorption appeared at 5.71 y. The v i n y l and a l l y l i c protons were now evident i n the n.m.r. spectrum (Figure 5 ) , and appeared as unresolved m u l t i p l e t s at x 4.13 and 7.17 r e s p e c t i v e l y . Also of i n t e r e s t was the appearance of the v i n y l methyl group as a p a i r of doublets at x 8.25 ( J ^ „ _ = 1.0 Hz, J _ = 1.6 Hz). These 5 13 6 13 coupling constants were assigned a f t e r i r r a d i a t i n g the v i n y l proton (x 4.13) and the a l l y l i c proton (x 7.17) i n separate frequency-swept - 81 -decoupling experiments and observing the c o l l a p s e of the p a i r of doublets to a doublet i n each case, w i t h coupling constants of 1.0 Hz and 1.6 Hz r e s p e c t i v e l y . The t e r t i a r y methyl group ( s i n g l e t at x 9.00) and the i s o p r o p y l group (doublets at x 9.00 and 9.09, J = 6.0 Hz) were als o evident i n the n.m.r. spectrum of 125. Since the l i t h i u m - e t h y l a m i n e - ^ - b u t y l a l c o h o l r e d u c t i o n of the (-)-keto enol phosphate (164) proved to be a very temperamental r e a c t i o n , gave only poor y i e l d s of the d e s i r e d product (125) , and n e c e s s i t a t e d the use of rather tedious methods f o r product p u r i f i c a t i o n , a l t e r n a t i v e routes f o r the conversion of diketone 122 to keto o l e f i n 125 were i n v e s t i g a t e d . Another method f o r the conversion of ketones to o l e f i n s i s the 93 Bamford-Stevens r e a c t i o n . In g e n e r a l , t h i s r e a c t i o n i n v o l v e s the r e a c t i o n of p_-tosylhydrazones of aldehydes and ketones w i t h bases to y i e l d the corresponding s a l t s of the p_-tosylhydrazone d e r i v a t i v e s . The l a t t e r can be heated to give intermediate diazo compounds, which can decompose i n s i t u by carbenic mechanisms i f a p r o t i c s o l v e n t s are used, or by c a t i o n i c processes i f a p r o t i c media i s used. In each case, the corresponding o l e f i n s are normally generated. The (-)-diketone (122) was reacted w i t h p_-toluenesulfonylhydrazide 94 i n methanol i n the presence of hydrogen c h l o r i d e to produce the corresponding p_-tosylhydrazone (167). Although the crude product (167) was normally used d i r e c t l y i i n the Bamford-Stevens r e a c t i o n s , an a n a l y t i c a l sample was obtained a f t e r p u r i f i c a t i o n by column chromato-graphy and r e c r y s t a l l i z a t i o n . The c r y s t a l l i n e p_-tosylhydrazone (167) thus obtained e x h i b i t e d s p e c t r a l data i n complete accord w i t h the - 82 -assigned s t r u c t u r e . In the i n f r a r e d spectrum, the carbonyl absorption appeared at 5.73 y, w h i l e the carbon-nitrogen double bond, and the aromatic double bonds appeared at 6.05 and 6.25 y r e s p e c t i v e l y . The n.m.r. spectrum of compound 167 d i s p l a y e d two doublets ( J = 9.0 Hz) at x 2.18 and x 2.72 a t t r i b u t e d to the aromatic protons, and a s i n g l e t (x 7.50) a t t r i b u t e d to the aromatic methyl group. The secondary methyl group appeared as a doublet ( J = 7.0 Hz) at x 8.82, while the t e r t i a r y methyl group ( s i n g l e t at x 9.05) and the i s o p r o p y l group (doublets at x 9.02 and 9.19, J = 6.0 Hz) were a l s o r e a d i l y evident i n t h i s spectrum. The s p e c t r a l data obtained from compound 167 does not, however, provide c o n c l u s i v e evidence f o r the r e g i o s e l e c t i v i t y of the p_-tosylhydrazone formation. That i s , i f the p_-toluenesulfonylhydrazide had reacted p r e f e r e n t i a l l y at the Cg carbonyl group of diketone 122, i n s t e a d of at the Cg carbonyl group, the expected s p e c t r a l p r o p e r t i e s of the corresponding product would be very s i m i l a r to those of compound 167. However, t h e o r e t i c a l c o n s i d e r a t i o n s (vide i n f r a ) , as w e l l as the f a c t that the (-)-keto o l e f i n (125) was the major product formed from the Bamford-Stevens r e a c t i o n of compound 167, confirmed the f a c t that the r e a c t i o n i n v o l v e d i n tosylhydrazone formation was indeed l a r g e l y r e g i o s e l e c t i v e . In the attempted conversion of the p_-tosylhydrazone (167) i n t o the keto o l e f i n (125), i t was found t h a t the Bamford-Stevens r e a c t i o n under p r o t i c c o n d i t i o n s was only m a r g i n a l l y s u c c e s s f u l . Thus, when compound 167 was pyrolyzed i n the presence of sodium ethylene g l y c o l a t e at temperatures of 190-200°, keto o l e f i n 125 was the major product formed, as determined by g a s - l i q u i d chromatographic a n a l y s i s , but i t was - 83 -produced i n only poor y i e l d s (15-20%) and was accompanied by a l a r g e number of minor components. U t i l i z a t i o n of the Bamford-Stevens r e a c t i o n under a p r o t i c c o n d i t i o n s proved to be more s u c c e s s f u l . The p_-tosylhydrazone (167) was reacted w i t h sodium b i s ( t r i m e t h y l s i l y l ) a m i d e i n dry tetr a h y d r o f u r a n to form the corresponding sodium s a l t (168). Although decomposition of 168 could be e f f e c t e d by heating the dry s a l t , higher y i e l d s of the d e s i r e d keto o l e f i n were obtained by adding approximately 10% (by weight) of high b o i l i n g n u j o l to the r e a c t i o n mixture. This presumably, allowed f o r more uniform heating of the s a l t (168). The r e a c t i o n mixture was heated slowly to a temperature of 125° under reduced pressure (water a s p i r a t o r , 10-20 mm). When the r e a c t i o n mixture had reached t h i s temperature, d i r e c t d i s t i l l a t i o n of the product was accomplished by a p p l i c a t i o n of a vacuum pump (0.3 mm) to the r e a c t i o n system. 122 6-many minor + components + 167 168 125 Unfortunately the (-)-keto o l e f i n (125) was formed i n only approximately 40% y i e l d , and was contaminated w i t h a l a r g e number of minor components as determined by g a s - l i q u i d chromatographic a n a l y s i s . A f t e r c a r e f u l d i s t i l l a t i o n of the crude product under reduced pressure, - 84 -followed by column chromatography of the d i s t i l l a t e , the (-)-keto o l e f i n (125) s t i l l had to be p u r i f i e d by p r e p a r a t i v e g . l . c . Therefore, t h i s method of converting the (-)-diketone (122) i n t o the (-)-keto o l e f i n (125) a l s o proved to be q u i t e tedious and i n e f f i c i e n t . Another method of generating an o l e f i n from a tosylhydrazone 95 96 i n v o l v e s r e a c t i n g the l a t t e r w i t h an a l k y l l i t h i u m reagent. ' Consider-in g p_-tosylhydrazone (167), t h i s r e a c t i o n would not be s y n t h e t i c a l l y u s e f u l , i n that the a l k y l l i t h i u m i n a l l p r o b a b i l i t y , would a l s o a t t a c k the Cg carbonyl group of 167. However, i t was hoped that t h i s problem could be avoided by the s e l e c t i v e r e d u c t i o n of the C 0 carbonyl group of the o diketone 122. A c c o r d i n g l y , when the (-)-diketone (122) was reacted w i t h one equivalent of hydride (from sodium borohydride) i n ethanol at i c e temperature f o r f i f t e e n minutes, the Cg carbonyl group was p r e f e r e n t i a l l y reduced. The r e a c t i o n was completely r e g i o s e l e c t i v e and s t e r e o s e l e c t i v e , and a f f o r d e d the (-)-keto a l c o h o l (169) i n 89% y i e l d . A a n a l y t i c a l sample of t h i s m a t e r i a l e x h i b i t e d s p e c t r a l data i n complete accord w i t h the assigned s t r u c t u r e . Hydroxyl and carbonyl group absorptions (2.93 and 5.80 u r e s p e c t i v e l y ) h i g h l i g h t e d the i n f r a r e d spectrum. The r e g i o s e l e c t i v i t y and s t e r e o s e l e c t i v i t y of the borohydride r e d u c t i o n was evident from a n a l y s i s of the n.m.r. spectrum of compound 169. The proton adjacent to the hydroxyl group appeared as a doublet (J = 5.5 Hz) at T 6 . 1 2 - Had p r e f e r e n t i a l r e d u c t i o n of the C^ carbonyl group occurred a p a i r of doublets (coupling from C^H and C 7H) would have r e s u l t e d f o r the proton adjacent to the hydroxyl group. Stereochemically, hydride - 85 -attack on the C Q carbonyl (of 122) would be expected to take place on o the side opposite the bulky i s o p r o p y l group. That t h i s was indeed the case was confirmed by the C CH-C 0H coupling constant (5.5 Hz) which was _> o 90 i n good agreement w i t h that p r e d i c t e d by the Karplus equation (5.0-6.0 Hz) f o r a d i h e d r a l angle between 30-40°. I t i s i n t e r e s t i n g to note that the borohydride r e d u c t i o n of the diketone 122 r e g i o s e l e c t i v e l y produced the keto a l c o h o l 169 ( r e a c t i o n at Cg), w h i l e r e a c t i o n of the diketone 122 w i t h p_-toluenesulfonylhydrazide r e g i o s e l e c t i v e l y afforded the p_-tosylhydrazone (167) ( r e a c t i o n at C^). Although the reasons behind these r e g i o s e l e c t i v e r e a c t i o n s are not immediately obvious, i t i s tempting to speculate that the angle s t r a i n 2 (C -CQ-C,- angle l e s s than 120°) associated w i t h the sp centre at C 0 1 O J o makes t h i s carbonyl group more e l e c t r o p h i l i c than the C^ carbonyl group. 2 3 Transformation of the Cg carbon from an sp centre to an sp centre would r e l i e v e t h i s angle s t r a i n and t h i s would thus e x p l a i n why attack of sodium borohydride on the diketone 122 was completely r e g i o s e l e c t i v e . I f one accepts t h a t , due to angle s t r a i n , the Cg carbonyl group of compound 122 i s more e l e c t r o p h i l i c than the C^ carbonyl group, then p_-toluenesulfonylhydrazide would a l s o be expected to p r e f e r e n t i a l l y a t t a c k the Cg carbonyl group. However, a f t e r the i n i t i a l n u c l e o p h i l i c 3 attack generates an sp centre (at Cg) , p_-tosylhydrazone formation 2 requ i r e s the e l i m i n a t i o n of water, which would regenerate an sp centre. I t can be r e a d i l y seen from the above argument that t h i s t r a n s f o r m a t i o n 3 2 (sp -> sp ) would be e n e r g e t i c a l l y unfavourable. This would not be the case w i t h the C^ carbonyl group (of 122). Even though t h i s carbonyl - 86 -group might be l e s s e l e c t r o p h i l i c than the C 0 carbonyl group, once o p_-toluenesulfonylhydrazide does at t a c k the p o s i t i o n , the r e s u l t i n g a-hydroxy amine would r e a d i l y l o s e water to form the corresponding p_-tosylhydrazone. Therefore the o v e r a l l r e a c t i o n i n t h i s case i s thermodynamically c o n t r o l l e d and one can e x p l a i n the observed r e g i o -s e l e c t i v i t y on t h i s b a s i s . The (-)-keto a l c o h o l (169) was reacted w i t h p_-toluenesulfonylhydrazide i n methanol i n the presence of an a c i d c a t a l y s t to a f f o r d the corresponding a l c o h o l i c p_-tosylhydrazone (170) i n 98% y i e l d . This crude product (170) was reacted i n dry t e t r a h y d r o -furan w i t h e i g h t equivalents of e t h e r e a l m e t h y l l i t h i u m at i c e tempera-97 t u r e . A f t e r quenching the r e a c t i o n mixture w i t h water, followed by appropriate workup, the ( - ) - o l e f i n i c a l c o h o l (171) was obtained i n 88% y i e l d . I t was e s s e n t i a l that t e t r a h y d r o f u r a n was used as the solvent r a t h e r than the more normally used e t h y l e t h e r , i n that l i t h i u m s a l t s of p o l y c y c l i c hydroxy compounds are s o l u b l e i n the former solven t . The i n f r a r e d spectrum of the ( - ) - o l e f i n i c a l c o h o l (171) e x h i b i t e d a hydroxyl absorption at 2.94 u and o l e f i n i c absorptions at 3.28 and 6.17 u . Of p a r t i c u l a r i n t e r e s t i n the n.m.r. spectrum of compound 171 was the presence of the o l e f i n i c proton (a broad s i n g l e t at x 4.60) and the v i n y l methyl group (a p a i r of doublets at x 8.38, w i t h the coupling constants being i d e n t i c a l w i t h those of the v i n y l methyl group of the (-)-keto o l e f i n (125), (p. 79 ). The other assignable s i g n a l s were s i m i l a r i n chemical s h i f t and m u l t i p l i c i t y to those of the (-)-keto o l e f i n (125). - 87 -125 171 The o x i d a t i o n of the ( - ) - o l e f i n i c a l c o h o l (171) was accomplished 64 98 99 w i t h e i t h e r C o l l i n s reagent ' of w i t h Jones reagent. Both methods produced good y i e l d s (approximately 90% i n each case) of the d e s i r e d keto o l e f i n 125 but the Jones o x i d a t i o n was p r e f e r r e d as i t was more e a s i l y a p p l i e d to l a r g e r s c a l e r e a c t i o n s . The (-)-keto o l e f i n (125) thus obtained was i d e n t i c a l i n every respect w i t h the m a t e r i a l prepared p r e v i o u s l y . Even though t h i s conversion of the (-)-diketone (122) to the (-)-keto o l e f i n (125) i n v o l v e d more s y n t h e t i c steps than e i t h e r of the two p r e v i o u s l y described methods, i t was by f a r the best, not only from the poi n t of view of e f f i c i e n c y (69% o v e r a l l y i e l d of 125 from 122) but a l s o from the p o i n t of view of product p u r i t y . - 88 -That i s , i n t h i s l a t t e r conversion, the f i n a l product (125) was obtained completely pure, and no l a b o r i o u s s e p a r a t i o n of products was r e q u i r e d . 5. Synthesis of (-)-Copacamphene (23) Having achieved an e f f i c i e n t s y n t h e s i s of the b i c y c l i c keto o l e f i n (125), the remaining s y n t h e t i c transformations necessary f o r the sy n t h e s i s of (-)-copacamphene and (-)-cyclocopacamphene i n v o l v e d the extension of the carbonyl group i n t o a f u n c t i o n a l i z e d two carbon s i d e c h a i n , f o l l o w e d by appropriate r i n g c l o s u r e r e a c t i o n s . The carbonyl group of compound 125 was to be used as a "handle" f o r the i n t r o d u c t i o n of the s i d e chain. To avoid stereochemical problems at Cg, i t was f e l t t hat i t would be more advantageous to introduce the s i d e chain i n two stages. The f i r s t stage would i n v o l v e the s y n t h e s i s of a compound c o n t a i n i n g a formyl group at C 0. Since o there would be a l a r g e 1 , 3 - d i a x i a l i n t e r a c t i o n between an a x i a l s u b s t i t u e n t at Cg and the i s o p r o p y l group at C^, s u b j e c t i n g such a compound to e p i m e r i z i n g c o n d i t i o n s would then a f f o r d the product w i t h the d e s i r e d e q u a t o r i a l o r i e n t a t i o n of the formyl group. The second stage of developing ;the two carbon s i d e chain would be to use t h i s formyl group again as a "handle" f o r the i n t r o d u c t i o n of the second carbon u n i t . The (-)-keto o l e f i n (125) was reacted with' methoxymethylenetriphenyl-62 phosphorane i n dimethyl s u l f o x i d e at 50° f o r one and one-half hours. This produced a diastereomeric mixture of the corresponding o l e f i n i c - 89 -enol ethers (172) i n 71% y i e l d . In accordance w i t h the assigned s t r u c t u r e , 172 e x h i b i t e d an u l t r a v i o l e t absorption at 208 my (e = 8,030) and an i n f r a r e d absorption at 5.88 y. Both of the absorptions are c h a r a c t e r i s t i c of an enol ether f u n c t i o n a l i t y . In the n.m.r. spectrum, the v i n y l protons of the two isomeric compounds e x h i b i t e d the same chemical s h i f t and appeared as a s i n g l e t at T 4.43. However, the f a c t that the product d i d indeed c o n s i s t of a mixture of two isomeric compounds was c l e a r l y shown by the presence of two s i n g l e t s (x 6.51 and 6.54) due to two d i f f e r e n t -0 -CH^ groups. From the i n t e g r a t e d area of these two peaks i t was estimated that the two isomers were present i n the mixture i n a r a t i o of approximately 3:2. H y d r o l y s i s of the mixture of o l e f i n i c enol ethers (172) w i t h 35% p e r c h l o r i c a c i d i n ether at room temperature"*"*^ afforded an epimeric mixture of o l e f i n i c aldehydes (173 and 174). Presumably, the presence of 173 i n t h i s mixture was due to k i n e t i c p r o t o n a t i o n of the correspond-i n g intermediate e n o l , or of the o r i g i n a l enol ether 172. Obviously, the h y d r o l y s i s c o n d i t i o n s d i d not e f f e c t complete e p i m e r i z a t i o n of compound 173 to the more s t a b l e epimer (17A). G.l.c. and n.m.r. a n a l y s i s of the h y d r o l y s i s product i n d i c a t e d that the two o l e f i n i c aldehydes (173 and 174) were present i n a r a t i o of approximately 1:1. 125 172 173 174 - 90 -As mentioned p r e v i o u s l y , i n o l e f i n i c aldehyde 173, there e x i s t s a 1 , 3 - d i a x i a l i n t e r a c t i o n between the formyl group and the i s o p r o p y l group, making t h i s compound thermodynamically l e s s s t a b l e than the epimeric o l e f i n i c aldehyde (174). Because of t h i s r a t h e r s i z a b l e i n t e r a c t i o n , when the aldehydes (173 and 174)were subjected to e p i m e r i z i n g conditions (potassium carbonate i n aqueous ethanol) o l e f i n i c aldehyde 173 was completely converted i n t o the epimeric o l e f i n i c aldehyde 174, and the l a t t e r was obtained i n 86% y i e l d from the enol ethers (172). The ( - ) - o l e f i n i c aldehyde (174) was obtained as a c o l o u r l e s s o i l , and i t e x h i b i t e d a n a l y t i c a l and s p e c t r a l p r o p e r t i e s i n accord w i t h the -f assigned s t r u c t u r e . O l e f i n i c (3.30 and 6.08 u) and aldehydic (3.67 and 5.83 u) absorptions were evident i n the i n f r a r e d spectrum. In the n.m.r. spectrum of compound 174 (Figure 6 ) , the aldehydic proton appeared as a doublet ( J = 4.2 Hz) at x 0.40. The v i n y l proton appeared as a broad s i n g l e t at T 4.56, and the a l l y l i c proton appeared as an unresolved m u l t i p l e t at x 7.53. The proton adjacent to the formyl group, C„H, was o evident as a doublet ( J = 4.2 Hz) at x 7.80. This m u l t i p l i c i t y i s as a n t i c i p a t e d , i n that the d i h e d r a l angle between C CH and C 0H i s close j o to 90°, so that no coupling between these two protons was expected. The v i n y l methyl group c h a r a c t e r i s t i c a l l y appeared as a p a i r of doublets (x 8.38, J = 1.6 Hz, J „ „ „ • „ = 1.0 Hz), w h i l e the t e r t i a r y 6 14 5 14 methyl group (x 8.97) and i s o p r o p y l methyl groups (doublets, x 9.08 and 9.16, J = 6.2 Hz) were a l s o c l e a r l y d i s t i n g u i s h a b l e . I n t r o d u c t i o n of the second carbon u n i t i n t o the s i d e chain could again be accomplished i n s e v e r a l d i f f e r e n t ways, depending on the f u n c t i o n a l i t y d e s i r e d i n the s i d e chain. For the copacamphene s y n t h e s i s , - 92 -we chose to convert the formyl group of compound 174 i n t o a t e r m i n a l o l e f i n i c double bond. Reaction of ( - ) - o l e f i n i c aldehyde (174) w i t h methylenetriphenyl-6 2 phosphorane, again f o l l o w i n g Corey's procedure f o r the W i t t i g r e a c t i o n , afforded the (+)-diene (175) i n 83% y i e l d . The n.m.r. spectrum of the (+)-diene (175) (Figure 7) was p a r t i c u l a r l y i n t e r e s t i n g . The C^ proton (x 4.22), experiencing coupling w i t h the Cg proton ( J = 9.0 Hz) as w e l l as c i s ( J = 10.0 Hz) and trans ( J = 17.5 Hz) coupling w i t h the t e r m i n a l o l e f i n i c protons at C^Q, appeared as an e i g h t - l i n e s i g n a l . The C^^ protons each appeared as a p a i r of doublets as a r e s u l t of geminal coupling ( J = 2.5 Hz) and coupling w i t h the proton on C^. The Cg proton appeared as a doublet (J = 9.0 Hz) at x 7.83. The other assignable s i g n a l s were s i m i l a r i n chemical s h i f t and m u l t i p l i c i t y to the corresponding resonances of the ( - ) - o l e f i n i c aldehyde (174) . In accord w i t h the o u t l i n e f o r the planned synthesis of copacamphene (page 44 ), i t was necessary at t h i s stage of the s y n t h e s i s to s e l e c t i v e l y f u n c t i o n a l i z e the t e r m i n a l o l e f i n i c double bond of the (+)-diene (175). Conversion of t h i s t e r m i n a l double bond i n t o a primary a l c o h o l f u n c t i o n a l i t y , followed by t o s y l a t i o n of the hydroxyl - 94 -group, would produce an o l e f i n i c t o s y l a t e a p p r o p r i a t e l y f u n c t i o n a l i z e d f o r e l i m i n a t i v e c y c l i z a t i o n . Brown and Z w e i f e l ^ ^ " have shown that the s e l e c t i v e hydroboration of the l e s s hindered of two double bonds i n a diene can r e a d i l y be c a r r i e d out by the use of a hindered hydroborating agent, such as disiamylborane (Sia2BH). For example, treatment of limonene (176) w i t h disiamylborane, followed by o x i d a t i o n of the intermediate t r i a l k y l -borane w i t h a l k a l i n e hydrogen peroxide, afforded the primary a l c o h o l 177 i n very good y i e l d . 176 177 Disiamylborane was prepared by adding a s o l u t i o n of the tet r a h y d r o -furan-borine complex to 2-methyl-2-butene i n tetrahydrofuran (1:2.2 molar r a t i o r e s p e c t i v e l y ) at i c e temperature. I t was d e s i r a b l e to use an excess of the butene to insure that there would be no excess tetrahydrofuran-borine complex present. This procedure would create no undue problems s i n c e the butene undergoes r a p i d hydroboration to the di a l k y l b o r a n e stage, but f u r t h e r r e a c t i o n to the t r i a l k y l b o r a n e stage i s r e l a t i v e l y slow. Subjection of the (+)-diene (175) to hydroboration w i t h A This i s the common name f o r bis-3-methyl-2-butylborane. - 95 -disiamylborane i n t e t r a h y d r o f u r a n , followed by decomposition of the intermediate t r i a l k y l b o r a n e w i t h a l k a l i n e hydrogen peroxide a f f o r d e d the d e s i r e d ( + ) - o l e f i n i c a l c o h o l (178) i n 91% y i e l d . An a n a l y t i c a l sample of t h i s m a t e r i a l was obtained by p r e p a r a t i v e g . l . c . and e x h i b i t e d s p e c t r a l data i n complete accord w i t h the assigned s t r u c t u r e . Most notable i n the n.m.r. spectrum of compound 178 was the absence of the ter m i n a l o l e f i n protons and the appearance of protons adjacent to the hydroxyl group as a m u l t i p l e t at x 6.38. The a l l y l i c proton appeared as an unresolved m u l t i p l e t at x 7.63, wh i l e the p a i r of doublets (x 8.44, u n TJ = 1-6 Hz, J =1.0 Hz) r e a d i l y accounted f o r the o l o i> l o v i n y l methyl group. The t e r t i a r y methyl group (x 9.10) and the i s o p r o p y l methyl groups (doublets at x 9.04 and 9.14, J = 6.0 Hz) were a l s o evident i n the n.m.r. spectrum of compound 178. Care had to be taken to avoid exposure of the ( + ) - o l e f i n i c a l c o h o l (178) to a c i d , since even t r a c e amounts of a c i d caused the c y c l i z a t i o n of t h i s m a t e r i a l to the c y c l i c ether (179). An a n a l y t i c a l sample of t h i s ether 179 was obtained by p r e p a r a t i v e g . l . c . and e x h i b i t e d the expected s p e c t r a l p r o p e r t i e s . Of p a r t i c u l a r note i n the i n f r a r e d spectrum was the absence of the absorptions due to the hydroxyl group and o l e f i n i c double bond. The n.m.r spectrum e x h i b i t e d a two-proton m u l t i p l e t at x 6.30 corresponding to the protons adjacent to the oxygen atom. The t e r t i a r y methyl groups were evident as s i n g l e t s at x 8.94 and 9.11 while the i s o p r o p y l methyl groups appeared as doublets (J = 6.0 Hz) at x 9.14 and 9.16. - 96 -175 178 Treatment of the ( + ) - o l e f i n i c a l c o h o l (178) w i t h p_-toluenesulfonyl c h l o r i d e i n p y r i d i n e at room temperature gave the o l e f i n i c t o s y l a t e (180) which, presumably l a r g e l y due to the p r o x i m i t y of the t o s y l a t e f u n c t i o n a l i t y and the o l e f i n i c double bond, e x h i b i t e d a high propensity towards e l i m i n a t i v e c y c l i z a t i o n . Thus merely a l l o w i n g the t o s y l a t e (180) to stand at room temperature gave, a f t e r f i l t r a t i o n of the r e s u l t a n t m a t e r i a l through a s i l i c a g e l column, a 90% y i e l d (from the o l e f i n i c a l c o h o l 178) of a mixture c o n s i s t i n g l a r g e l y of (-)-copa-camphene (23), accompanied by two other hydrocarbons. The l a t t e r comprised approximately 3% and 4% of the mixture, as determined by g a s - l i q u i d chromatographic a n a l y s i s . Pure s y n t h e t i c (-)-copacamphene (23) was r e a d i l y obtained from t h i s mixture by chromatography of the l a t t e r over s i l v e r n i t r a t e 21 * impregnated s i l i c a g e l and e x h i b i t e d [ a j ^ -159 . The i n f r a r e d spectrum (Figure 8) showed absorptions at 3.26, 6.03 and 11.42 p , due to the e x o c y c l i c methylene group. The l a t t e r was a l s o c l e a r l y evident i n the n.m.r. spectrum (Figure 9). Thus, the two o l e f i n i c protons appeared as See the footnote on p. 18. s i n g l e t s at x 5.21 and 5.49. Furthermore, the broad s i g n a l at x 7.54 could r e a d i l y be assigned to the a l l y l i c proton. F i n a l l y , the s i n g l e t at x 9.00 and the doublet ( J = 6.0 Hz) at x 9.10 were r e a d i l y a t t r i b u t e d to the t e r t i a r y methyl group and i s o p r o p y l methyl groups, r e s p e c t i v e l y . The (-)-copacamphene thus prepared e x h i b i t e d g . l . c . r e t e n t i o n times and i n f r a r e d spectrum i d e n t i c a l w i t h that of (±)-copacamphene. 178 180 23 In order to f u l l y determine what the two i m p u r i t i e s i n t h i s r e a c t i o n were, we f e l t i t was necessary to o b t a i n samples of some of the compounds of the sativene s e r i e s , i n p a r t i c u l a r 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 . These were r e a d i l y obtained by r e a c t i n g (-)-copa-47 camphene w i t h c u p r i c acetate i n r e f l u x i n g a c e t i c a c i d f o r four days (see p. 27 )- The r a t i o of products, as determined by g a s - l i q u i d 47 chromatographic a n a l y s i s , was i d e n t i c a l w i t h that reported by McMurry : 31% (+)-cyclosativene (27); 7% (+)-sativene (26) ; and 62% (-)-is o s a t i v e n e (77). Vie are yery g r a t e f u l to Profess o r J.E. McMurry f o r a s m a l l sample of t h i s compound. - 98 -23 27 26 77 P u r i f i c a t i o n of t h i s mixture by a combination of column chromato-graphy on s i l v e r n i t r a t e impregnated s i l i c a g e l and p r e p a r a t i v e g . l . c . allowed the i s o l a t i o n of a l l three compounds. Thus (+)-cyclosativene (27) 25 o* e x h i b i t e d [a]^ +63 as w e l l as absorptions at 3.28, 11.62 and 11.87 p i n the i n f r a r e d spectrum (Figure 19), the l a t t e r being c h a r a c t e r i s t i c 102 of the t r i c y c l e n e - t y p e s t r u c t u r e . In the n.m.r. spectrum (Figure 20), the t e r t i a r y methyl groups appeared as sharp s i n g l e t s at T 9.02 and 9.24, w h i l e the i s o p r o p y l methyl groups were evident as doublets (J = 6.0 Hz) at T 9.09 and 9.13. The c y c l o p r o p y l protons appeared at x 9.22 ( s i n g l e t ) and 9.33 (doublet, J = 5.5 Hz). This s p e c t r a l 18 24 47 data was i n good agreement w i t h that reported i n the l i t e r a t u r e ' ' f o r (+)-cyclosativene. (+)-Sativene (26) e x h i b i t e d a r o t a t i o n of +174° ( l i t 22 +191 ± 3°) as w e l l as i n f r a r e d absorptions (Figure 10) at 3.26, 6.04 and The o r i g i n a l r o t a t i o n f o r (+)-cyclosativene reported by Zavarin was + 9 4 . 1 ° . Our r o t a t i o n i s more i n l i n e w i t h that reported by Y o s h i k o s h i (+67.8)18 and McMurry ( + 6 1 ° ) . 4 7 The discrepancy i s p o s s i b l y accounted f o r i n p a r t by the e r r o r s associated i n working w i t h a very small amount of t h i s somewhat v o l a t i l e hydrocarbon. - 99 -11.45 u, which are c h a r a c t e r i s t i c of an e x o c y c l i c methylene group. In the n.m.r. spectrum (Figure 11), the o l e f i n i c protons of the e x o c y c l i c methylene group were c l e a r l y evident as s i n g l e t s at x 5.26 and 5.58. The a l l y l i c proton appeared as a broad s i g n a l at x 7.39, wh i l e a s i n g l e t at x 8.96 and doublets ( J = 6.0 Hz) at x 9.10 and 9.13 accounted f o r the protons of the t e r t i a r y methyl group and i s o p r o p y l methyl groups, r e s p e c t i v e l y . The s p e c t r a l data was i n good agreement w i t h that 22 23 reported i n the l i t e r a t u r e ' f o r (+)-sativene. The major product from the a c e t i c a c i d - c u p r i c acetate rearrangement of (-)-copacamphene was (-)-isosativene (77). The l a t t e r e x h i b i t e d the c h a r a c t e r i s t i c absorptions of an e x o c y c l i c methylene group (3.27, 6.06 and 11.42 u) i n the i n f r a r e d spectrum (Figure 12). In the n.m.r. spectrum (Figure 13), the e x o c y c l i c methylene protons ( s i n g l e t s at x 5.23 and 5.52), the a l l y l i c proton (broad s i g n a l at x 7.39), the t e r t i a r y methyl group ( s i n g l e t at x 9.03) and the i s o p r o p y l methyl groups (doublet at x 9.12, J = 6.0 Hz) were c l e a r l y evident. This s p e c t r a l data was i n good agreement w i t h that reported i n the - >+. _ 24-26 •  , v . l i t e r a t u r e f o r (-) - i s o s a t i v e n e . Even though copacamphene, sativene and i s o s a t i v e n e are s t r u c t u r a l l y very s i m i l a r , i t was r e l a t i v e l y easy to d i s t i n g u i s h between these three compounds on the b a s i s of t h e i r i n f r a r e d and n.m.r. sp e c t r a (Figures 8-13). I t i s appropriate now to r e t u r n to the d i s c u s s i o n regarding the i d e n t i t y of the two hydrocarbon i m p u r i t i e s formed during the e l i m i n a t i v e c y c l i z a t i o n of the o l e f i n i c t o s y l a t e 180 to (-)-copacamphene. A sm a l l 6 7 8 9T Figure 9. N.M.R. Spectrum of (-)-Copacamphene (23). Figure 10. I n f r a r e d Spectrum of (+)-Sativene (26). Figure 12. I n f r a r e d Spectrum of (-)-Isosativene (77). - 105 -- 106 -sample of each of the two i m p u r i t i e s was obtained by p r e p a r a t i v e g . l . c . These compounds were i d e n t i f i e d as (+)-cyclosativene (27) and (-)-isosativene (77) by a d i r e c t comparison ( g . l . c . r e t e n t i o n times and i n f r a r e d spectra) w i t h authentic samples of the two sesquiterpenes. These i m p u r i t i e s were thought to a r i s e from exposure of the i n i t i a l l y formed copacamphene to a c i d i c c o n d i t i o n s . That i s , when the e l i m i n a t i v e c y c l i z a t i o n of the o l e f i n i c tosylate(180)was c a r r i e d out by a l l o w i n g the l a t t e r compound to stand at room temperature, p_-toluene-s u l f o n i c a c i d was produced, thus exposing the i n i t i a l l y formed (-)-copacamphene to a c i d i c c o n d i t i o n s . This could then cause the p a r t i a l rearrangement of t h e - f i r s t - f o r m e d product [(-)-copacamphene] to the two i m p u r i t i e s , (+)-cyclosativene and ( - ) - i s o s a t i v e n e . We were i n t e r e s t e d i n t e s t i n g the v a l i d i t y of t h i s argument by determining whether or not s m a l l amounts of p_-toluenesulfonic a c i d would cause rearrangement of (-)-copacamphene. A c c o r d i n g l y , (-)-copa-camphene was reacted w i t h a 10 mM s o l u t i o n of p_-toluenesulf o n i c a c i d i n benzene f o r one hour at room temperature. Complete rearrangement of the s t a r t i n g m a t e r i a l was observed, w i t h the formation of the same e q u i l i b r i u m mixture of compounds [(+)-cyclosativene (32%), (+)-sativene (7%) and (-)-isosativene (61%)] that occurred w i t h the a c e t i c a c i d - c u p r i c acetate rearrangement. The three products were i s o l a t e d by p r e p a r a t i v e g . l . c . and i n each case, the s t r u c t u r e was confirmed by d i r e c t comparison ( g . l . c . r e t e n t i o n times, i n f r a r e d and n.m.r. spectra) w i t h an auth e n t i c sample. In order to avoid, as much as p o s s i b l e , the formation of the s i d e products during the synthesis of (-)-copacamphene, the procedure - 107 -in v o l v e d i n the e l i m i n a t i v e c y c l i z a t i o n of the o l e f i n i c t o s y l a t e 180 was modified. That i s , i n order to avoid prolonged exposure of the i n i t i a l l y formed (-)-copacamphene to a c i d , the crude o l e f i n i c t o s y l a t e (180) was a p p l i e d to the top of a s i l i c a g e l column, and the r e s u l t i n g column was e l u t e d w i t h pentane. From the e l u a n t , could be i s o l a t e d i n high y i e l d , (-)-copacamphene which was now contaminated w i t h only very s m a l l amounts 1-2%) of (+)-cyclosativene and (- ) - i s o s a t i v e n e . 6. Synthesis of (-)-Cyclocopacamphene (24) Of the number of p o s s i b l e routes which might be employed i n the synthe s i s of cyclocopacamphene, we f i r s t " chose a r e a c t i o n sequence i n v o l v i n g an 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 of an o l e f i n i c diazoketone. This appeared to be a p o t e n t i a l l y e f f i c i e n t method f o r the synth e s i s of the t e t r a c y c l i c r i n g system. The use of o l e f i n i c diazoketones i n 103 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 s was already w e l l documented, and some s u c c e s s f u l syntheses i n our l a b o r a t o r y had been based upon t h i s type of reaction'. For example, t h i s i s w e l l i l l u s t r a t e d by the synth e s i s of ( i ) - a r i s t o l o n e ( 1 8 4 ) F o r m a t i o n of the sodium s a l t of a c i d 181 followed by r e a c t i o n of the s a l t w i t h o x a l y l c h l o r i d e produced the a c i d c h l o r i d e (182). Reaction of the l a t t e r w i t h e t h e r e a l diazomethane afforded the o l e f i n i c diazoketone (183). Intramolecular c y c l i z a t i o n r e s u l t e d when 183 was r e f l u x e d i n cyclohexane i n the presence of cup r i c s u l f a t e . (±)-Aristolone (184) and (±)-6,7-epi-aristolone (185) were formed i n a r a t i o of 2:1 r e s p e c t i v e l y . - 108 -For the pr o j e c t e d s y n t h e s i s of (-)-cyclocopacamphene (24), the o l e f i n i c a c i d (186), would be req u i r e d . Obviously t h i s compound could r e a d i l y be obtained by o x i d a t i o n of the p r e v i o u s l y prepared ( - ) - o l e f i n i c aldehyde (174). Following a r e a c t i o n sequence s i m i l a r to that described f o r the synthesis of a r i s t o l o n e , the o l e f i n i c a c i d (186) would be converted to the corresponding o l e f i n i c diazoketone (187) , and c y c l i z a t i o n of the l a t t e r would produce cyclocopacamphenone (188) . Wolff-Kishner r e d u c t i o n (or the equivalent) of compound 188 would then a f f o r d cyclocopacamphene (24). - 109 -24 188 The o l e f i n i c a c i d (186) was r e a d i l y prepared by a "wet" Sar e t t o x i d a t i o n p r o c e d u r e . T h u s , treatment of 174 w i t h chromium t r i o x i d e i n pyridine-water a f f o r d e d , i n 80% y i e l d , the (-)-keto a c i d (186). This c r y s t a l l i n e m a t e r i a l e x h i b i t e d the expected s p e c t r a l p r o p e r t i e s . Most notably, the ac i d proton appeared at x 0.18 as a broad s i g n a l i n the n.m.r. spectrum, w i t h the v i n y l proton appearing at x 4.55 as a broad s i n g l e t . A one-proton m u l t i p l e t at x 7.19 accounted f o r the a l l y l i c proton, w h i l e the v i n y l methyl group was evident as a p a i r of doublets (J„ „ u = 1.0 Hz, J _ „ n = 1.6 Hz) at x 8.40. The L. _ H—L.,., H C,ri—L - . , r i 5 14 6 14 t e r t i a r y methyl group and the i s o p r o p y l methyl groups were c l e a r l y evident i n the n.m.r. spectrum of compound 186 as a s i n g l e t (x 8.89) and two doublets (x 9.07 and 9.11, J = 6.0 Hz) r e s p e c t i v e l y . - 110 -The sodium s a l t of the ( - ) - o l e f i n i c a c i d (186) was t r e a t e d w i t h o x a l y l c h l o r i d e i n anhydrous ether at i c e temperature, to a f f o r d the corresponding o l e f i n i c a c i d c h l o r i d e (189) (X 5.52 y ) . The l a t t e r max was reacted immediately w i t h a l a r g e excess of dry e t h e r e a l d i a z o -methane. The progress of the r e a c t i o n was monitored by i n f r a r e d , and although weak absorptions due to the diazoketone were noted (X 4.70, max 6.04 y ) , an i n f r a r e d absorption at 5.73 y grew i n i n t e n s i t y as the a c i d c h l o r i d e absorption (^ m a x 5.52 y) disappeared. A f t e r 2.5 hours at 0°, the a c i d c h l o r i d e (189) had completely reacted, as judged by the absence of the corresponding absorptions i n the i n f r a r e d . Even though the diazoketone (187) was b e l i e v e d to be only a very minor component i n the r e a c t i o n mixture (as judged by the appropriate weak absorptions i n the i n f r a r e d ) the carbenoid a d d i t i o n r e a c t i o n was attempted. A c c o r d i n g l y , a s o l u t i o n of the crude mixture of r e a c t i o n 103 products i n cyclohexane was r e f l u x e d i n the presence of c u p r i c s u l f a t e f o r one hour. The crude product thus obtained c o n s i s t e d mainly of the (-)-keto o l e f i n (190), accompanied by a number of minor products. P r e p a r a t i v e g . l . c . allowed the i s o l a t i o n of compound 190 i n approximately 60% y i e l d from the ( - ) - o l e f i n i c a c i d (186). The a n a l y t i c a l and s p e c t r a l data e x h i b i t e d by t h i s compound were i n complete-accord w i t h the assigned s t r u c t u r e . In the i n f r a r e d spectrum, the five-membered r i n g carbonyl group appeared c h a r a c t e r i s t i c a l l y at 5.73 y, w h i l e the t e r m i n a l o l e f i n absorptions were evident at 3.26, 6.01 and 11.38 y. In the n.m.r. spectrum of the keto o l e f i n (190) (Figure 14), the s i g n a l s due to the v i n y l protons appeared as s i n g l e t s at T 5.03 and 5.27. The s i g n a l s due to the a l l y l i c proton (an unresolved m u l t i p l e t at T 7.13), - 112 -the t e r t i a r y methyl group (a s i n g l e t at T 8.99) and the i s o p r o p y l methyl groups (a doublet at x 9.12, J = 6.0 Hz) were a l s o apparent i n t h i s spectrum. As a f u r t h e r v e r i f i c a t i o n of the s t r u c t u r e , the (-)-keto o l e f i n (190) was subjected to the Huang-Minion modified Wolff-Kishner reduction"*"^ producing (-)-copacamphene (23) i n 58% y i e l d . The l a t t e r was i d e n t i f i e d by d i r e c t comparison ( g . l . c . r e t e n t i o n times, i n f r a r e d and n.m.r. spectra) w i t h authentic m a t e r i a l . 189 190 23 One of the minor components (approximately 5%) that was al s o i s o l a t e d by p r e p a r a t i v e g . l . c . from the c u p r i c s u l f a t e catalyzed c y c l i z a t i o n r e a c t i o n was b e l i e v e d to be cyclocopacamphenone (188). The g . l . c . r e t e n t i o n time of t h i s m a t e r i a l (188) was s i m i l a r to that of the (-)-keto o l e f i n (190). Although l a c k of s u f f i c i e n t m a t e r i a l precluded the f u l l c h a r a c t e r i z a t i o n of compound 188, the s p e c t r a l p r o p e r t i e s that were obtained were i n good agreement w i t h the proposed s t r u c t u r e . In the i n f r a r e d spectrum, the carbonyl group absorption appeared at 5.73 u, w h i l e the absorptions at 11.42 and 12.03 u were 102 c h a r a c t e r i s t i c of a t r i c y c l e n e - t y p e nucleus. The t e r t i a r y methyl groups appeared as sharp s i n g l e t s (x 8.82 and 9.08) i n the n.m.r. - 113 -spectrum of 188, w h i l e the i s o p r o p y l methyl groups were evident as doublets ( J = 6.0 Hz) at T 9.12 and 9.15. I t i s appropriate to comment b r i e f l y regarding the p o s s i b l e mechanism i n v o l v e d i n the formation of the (-)-keto o l e f i n (190). Attack of diazomethane on the carbonyl group of the a c i d c h l o r i d e (189), w i t h subsequent e x p u l s i o n of a c h l o r i d e i o n , would leave the p o s i t i v e l y charged species 191. A b s t r a c t i o n of a proton from the p o s i t i o n a to the carbonyl group (path A) would produce the n e u t r a l diazoketone (187) . However, because of the p r o x i m i t y of the o l e f i n i c double bond and the e l e c t r o p h i l i c carbon (a to the carbonyl and diazo groups) compound 191 could undergo an i n t r a m o l e c u l a r e l i m i n a t i v e c y c l i z a t i o n (path B) to produce the (-)-keto o l e f i n (190). A l s o produced would be hydrogen c h l o r i d e which, presumably, would be r a p i d l y destroyed by excess diazomethane. - 114 -When the r e a c t i o n mixture that was obtained from the treatment of the a c i d c h l o r i d e (189) w i t h diazomethane was reacted w i t h p_-toluene-s u l f o n i c a c i d i n benzene, the i n f r a r e d absorptions corresponding to the diazoketone (187) disappeared almost immediately. The crude product thus obtained again c o n s i s t e d mainly of the (-)-keto o l e f i n (190), as determined by g a s - l i q u i d chromatographic a n a l y s i s and lacked the t e t r a c y c l i c compound 188. Presumably, the diazoketone (187) was protonated, and the r e s u l t i n g charged species 191 underwent 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 to produce the (-)-keto o l e f i n (190). In support of the above c o n c l u s i o n , i t should be noted the a c i d -c a t a l y z e d 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 of o l e f i n i c diazoketones was r e c e n t l y reported by Erman and S t o n e . T h u s , these workers found, f o r example, that the o l e f i n i c diazoketone (192), when t r e a t e d w i t h a c a t a l y t i c amount of a Lewis a c i d (boron t r i f l u o r i d e e t h e r a t e ) , c y c l i z e d to the corresponding b i c y c l i c system (193) . C0CHN2 192 193 Although the work j u s t described r e s u l t e d i n an i n t e r e s t i n g a l t e r n a t i v e s y n t h e s i s of (-)-copacamphene, the sequence was c l e a r l y u n s a t i s f a c t o r y f o r the synthesis of (-)-cyclocopacamphene. Therefore, a l t e r n a t i v e routes were considered. One p o s s i b i l i t y which was - 115 -i n v e s t i g a t e d , f o r example, i n v o l v e d the proposed conversion of the ( - ) - o l e f i n i c aldehyde (174) i n t o the next higher homolog, the o l e f i n i c aldehyde (194). Subsequent a c i d c a t a l y z e d c y c l i z a t i o n of the l a t t e r would presumably a f f o r d the o l e f i n i c a l c o h o l (195), p o s s i b l y a p o t e n t i a l l y u s e f u l i n t e r m e d i a t e f o r the s y n t h e s i s of (-)-cyclocopacamphene. 174 194 195 Recently, Herz and co-workers reported a s y n t h e s i s of methyl t r a c h y l o -banate (see below)' i n which the key s y n t h e t i c step i n v o l v e d the formation of the cyclopropane r i n g by r e d u c t i o n of the o l e f i n i c mesylate w i t h sodium borohydride. I t was thus f e l t that a s i m i l a r r e d u c t i o n of the mesylate corresponding to the o l e f i n i c a l c o h o l (195) could r e s u l t i n the formation of (-)-cyclocopacamphene. - 116 -Reaction of the ( - ) - o l e f i n i c aldehyde (174) w i t h methoxymethylene-6 2 triphenylphosphorane i n dimethyl s u l f o x i d e a f f o r d e d , i n 55% y i e l d , a mixture of the cis-and t r a n s - o l e f i n i c e n o l ethers (196 and 197) i n a 1:6 r a t i o , r e s p e c t i v e l y , as determined by g a s - l i q u i d chromatographic a n a l y s i s . An a n a l y t i c a l sample of the t r a n s - o l e f i n i c enol ether (197) was obtained by p r e p a r a t i v e g . l . c , and 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 i n complete accord w i t h the assigned s t r u c t u r e . In the n.m.r. spectrum, the doublet (J = 15 Hz) at T 3.62 was assigned to the C^Q proton (see compound 197 f o r numbering), w h i l e the p a i r of doublets(J=15Hz,J=10Hz) at T 5.23 was a t t r i b u t e d to the C Q proton. The other v i n y l proton y appeared at T 4.64 as a broad s i n g l e t , w h i l e the protons of the methoxy group were evident as a sharp s i n g l e t at x 6.54. The v i n y l methyl group appeared as a p a i r of doublets (Jn u = 1.0 Hz, 5 16 3n a n u = Hz) at x 8.38, w h i l e the t e r t i a r y methyl group (a s i n g l e t \>, rl— r il 6 16 at x 9.16) and the i s o p r o p y l methyl groups (doublets at x 9.08 and 9.14 J = 6.0 Hz) were a l s o r e a d i l y evident i n the n.m.r. spectrum of 197. When the mixture of enol ethers (196 and 197) was subjected to h y d r o l y s i s w i t h 35% p e r c h l o r i c a c i d i n ether at room temperature,"'"^^ the corresponding o l e f i n i c aldehyde 194 was not obtained. Rather, the r e s u l t a n t product was the t r i c y c l i c o l e f i n i c a l c o h o l 195, undoubtedly formed by an a c i d c a t a l y z e d i n t e r n a l P r i n s r e a c t i o n of the intermediate o l e f i n i c aldehyde 194. The o l e f i n i c a l c o h o l was somewhat unstable, and f o r t h i s reason, i t was not f u l l y c h a r a c t e r i z e d . However, the s p e c t r a l data that was obtained was i n complete agreement w i t h the assigned s t r u c t u r e . In the i n f r a r e d spectrum, the hydroxyl absorption - 117 -appeared at 2.96 y, w h i l e the absorptions at 3.25, 6.03 and 11.38 y were c h a r a c t e r i s t i c of an e x o c y c l i c methylene group. N.m.r. evidence i n d i c a t e d that t h i s m a t e r i a l was an epimeric mixture of d i a s t e r i o m e r s , presumably w i t h respect to the centre (Cg) bea r i n g the hy d r o x y l group. The v i n y l protons were evident as a broad s i n g l e t (width at h a l f -height =7.0 Hz) at T 5.05, w h i l e the proton adjacent to the hydroxyl group appeared as m u l t i p l e t at T 5.94. Because of the epimeric nature of t h i s m a t e r i a l , the other s i g n a l s were d i f f i c u l t to assign. Due to the f a c t that the o l e f i n i c a l c o h o l (195) c o n s i s t e d of a mixture of epimeric compounds and somewhat unstable, t h i s m a t e r i a l 98 was subjected d i r e c t l y to C o l l i n s o x i d a t i o n . I t was f e l t that the (-)-keto o l e f i n (198) thus dotained would a l s o be a p o t e n t i a l l y u s e f u l intermediate (vide i n f r a ) f o r the synthesis of (-)-cyclocopacamphene. An a n a l y t i c a l sample of compound 198 was obtained by p r e p a r a t i v e g . l . c , and e x h i b i t e d the expected s p e c t r a l p r o p e r t i e s . In the i n f r a r e d spectrum, the carbonyl group absorption was evident at 5.69 y, w h i l e the t e r m i n a l methylene group absorptions appeared at 3.25, 6.03 and 11.28 y. In the n.m.r. spectrum (Figure 15) the s i g n a l s corresponding to the o l e f i n i c protons appeared as t r i p l e t s ( J = 0.8 Hz) at x 4.82 and 5.18. The a l l y l i c proton appeared as a broad s i n g l e t at x 7.04, w h i l e the three-proton s i n g l e t at x 8.90, and the s i x - p r o t o n doublet ( J = 6.3 Hz) at 9.07 accounted f o r the presence of the t e r t i a r y methyl group and i s o p r o p y l methyl groups r e s p e c t i v e l y . 25.00 Figure 15. N.M.R. Spectrum of the (-)-Keto O l e f i n (198). - 119 -198 195 194 Due to the f a c t that the o v e r a l l y i e l d of the above r e a c t i o n sequence was q u i t e poor (10-15% from 174 198) , other means of s y n t h e s i z i n g the (-)-keto o l e f i n (198) were i n v e s t i g a t e d . In p a r t i c u l a r , i t was decided to o x i d i z e the p r e v i o u s l y prepared ( + ) - o l e f i n i c a l c o h o l (178) under b a s i c or n e u t r a l c o n d i t i o n s , and then to c y c l i z e the r e s u l t a n t o l e f i n i c aldehyde (194) under c a r e f u l l y c o n t r o l l e d c o n d i t i o n s . 98 U t i l i z i n g the modified C o l l i n s o x i d a t i o n procedure, the (+)-o l e f i n i c a l c o h o l (178) was converted i n t o the ( - ) - o l e f i n i c aldehyde (194) i n 91% y i e l d . The a n a l y t i c a l and s p e c t r a l data of t h i s m a t e r i a l was i n complete accord w i t h the assigned s t r u c t u r e . In the i n f r a r e d spectrum of compound 194, the aldehydic absorptions appeared at 3.68 and - 120 -5.80 u, w h i l e the o l e f i n i c double bond absorptions appeared at 3.29 and 5.96 u. The aldehydic proton appeared as a t r i p l e t ( J = 2.5 Hz) at x 0.20 i n the n.m.r. spectrum. The v i n y l proton appeared as a broad s i n g l e t at x 4.60, w h i l e the v i n y l methyl group appeared at i 8.42 as a p a i r of doublets (J = 1.0 Hz, J C.H—C. ,-H 6 15 =1.6 Hz). The i s o p r o p y l methyl groups were evident as doublets ( J = 6.5 Hz) at T 9.07 and 9.13, w h i l e the t e r t i a r y methyl group was evident as a s i n g l e t at x 9.10. The i n t r a m o l e c u l a r P r i n s r e a c t i o n was accomplished by r e a c t i n g the ( - ) - o l e f i n i c aldehyde (194) w i t h a 0.05 mM s o l u t i o n of p_-toluene-s u l f o n i c a c i d i n benzene at room temperature f o r t h i r t y minutes. The r e a c t i o n mixture was then quenched by a d d i t i o n of p y r i d i n e . The crude 98 c y c l i z a t i o n product was immediately o x i d i z e d w i t h C o l l i n s reagent to produce a mixture of the (-)-keto o l e f i n (198) and the s t a r t i n g m a t e r i a l Q-94) i n a r a t i o of 5:2 r e s p e c t i v e l y . The (-)-keto o l e f i n (198) p u r i f i e d by p r e p a r a t i v e g.1.c. , was obtained i n 65% y i e l d (based on unrecovered o l e f i n i c aldehyde 194). Considerable e f f o r t was expended i n an attempt to f i n d optimum r e a c t i o n conditions f o r the i n t e r n a l P r i n s r e a c t i o n . I t was found that the use of r e a c t i o n times longer than t h i r t y minutes, or of more concentrated s o l u t i o n s of p_-toluenesulfonic a c i d , produced, a f t e r C o l l i n s o x i d a t i o n of the crude product, p r i m a r i l y the des i r e d keto o l e f i n (198) but i n much lower y i e l d . Use of sh o r t e r r e a c t i o n times r e s u l t e d i n the i s o l a t i o n of considerable amounts of s t a r t i n g m a t e r i a l (194). As a f u r t h e r v e r i f i c a t i o n of the s t r u c t u r e of the (-)-keto o l e f i n 106 (198), t h i s m a t e r i a l was subjected to the Huang-Minion m o d i f i c a t i o n of the Wolff-Kishner r e d u c t i o n . The r e a c t i o n produced, i n poor y i e l d - 121 -(25%), two hydrocarbon i n a r a t i o of 4:1, as determined by g a s - l i q u i d chromatographic a n a l y s i s . These compounds were separated by column chromatography on s i l v e r n i t r a t e impregnated s i l i c a g e l and the major component was i d e n t i f i e d as (-)-copacamphene by d i r e c t comparison ( g . l . c . r e t e n t i o n times, i n f r a r e d and n.m.r. spectra) w i t h a u t h e n t i c m a t e r i a l . The minor component was i d e n t i f i e d as (-)-cyclocopacamphene 21 (24), and e x h i b i t e d [ a } D -42°. The i n f r a r e d spectrum (Figure 17) showed absorptions at 3.29, 11.60, 11.80, and 12.10 y which are c h a r a c t e r i s t i c 102 of the t r i c y c l e n e - t y p e s k e l e t o n . In the n.m.r. spectrum (Figure 18), the t e r t i a r y methyl groups appeared as s i n g l e t s at T 8.99 and 9.26, while the i s o p r o p y l methyl groups were evident as doublets ( J = 6.5 Hz) at T 9.10 and 9.13. Two broad s i g n a l s at x 9.32 and 9.37 could be a t t r i b u t e d to the presence of the c y c l o p r o p y l protons. The i n f r a r e d and n.m.r. sp e c t r a of t h i s m a t e r i a l were i d e n t i c a l w i t h those of 18 authentic (+)-cyclocopacamphene (24). F. Kido, Ph.D. T h e s i s , Tohoku U n i v e r s i t y , Sendai, Japan (1970). We are g r a t e f u l to Dr. Kido f o r h i s help i n c a r r y i n g out t h i s comparison. - 122 -The formation of (-)-cyclocopacamphene (24) i n the Huang-Minion red u c t i o n of the (-)-keto o l e f i n (198) was somewhat s u r p r i s i n g . S p e c u l a t i v e l y , the former compound could be thought to a r i s e v i a one or both of two d i f f e r e n t pathways i n v o l v i n g decomposition of the intermediate hydrazone (199). F i r s t l y , a b s t r a c t i o n by base of one of the amine protons of compound 199, followed by normal p r o t o n a t i o n of the r e s u l t i n g intermediate on C Q (path A ) , would produce the t r i c y c l i c o azo intermediate (200). A b s t r a c t i o n of a second proton from the n i t r o g e n atom of 200, followed by concomitant e l i m i n a t i o n of n i t r o g e n , closure of the cyclopropane r i n g and p r o t o n a t i o n of the t e r m i n a l carbon of the e x o c y c l i c methylene group, would produce the t e t r a c y c l i c s t r u c t u r e of cyclocopacamphene (24). Another p o s s i b l e mechanism to account f o r the formation of compound 24^  (path B) would simply i n v o l v e r e v e r s a l of the order of the two steps obtained above. Thus, proton a b s t r a c t i o n from compound 199, followed by concomitant r i n g c l o s u r e and p r o t o n a t i o n at C^Q, would produce the t e t r a c y c l i c azo compound (201). A b s t r a c t i o n of the second amine proton, followed by e l i m i n a t i o n of n i t r o g e n and normal protonation of the r e s u l t i n g carbanion would - 123 -also account f o r the production of (-)-cyclocopacamphene (24). Although the work j u s t described represented a t o t a l s y n t h e s i s of (-)-cyclocopacamphene, an a l t e r n a t e , more e f f i c i e n t r e a c t i o n sequence was sought. There are s e v e r a l examples i n the l i t e r a t u r e of r e a c t i o n s i n v o l v i n g the c y c l i z a t i o n of camphor or camphor-like substances i n t o j . • • , • 109,110 compounds con t a i n i n g cyclopropane r i n g s . These r e a c t i o n s were of p a r t i c u l a r i n t e r e s t , since the hydrogenated form of the (-)-keto o l e f i n (198), ketone 202, has incorporated i n t o i t the same s t r u c t u r a l u n i t ( s u b s t i t u t e d bicyclo[2.2.l]heptanone system) present i n camphor (5). - 124 -202 5 When camphor tosylhydrazone (.203) was reacted w i t h more than one equivalent of base i n an a p r o t i c s o l v e n t , t r i c y c l e n e (21) was the 109 only product formed, i n y i e l d s of between 90-95%. The intermediate diazocamphane (204) loses n i t r o g e n to give a carbene or carbenoid intermediate which undergoes an i n t r a m o l e c u l a r carbon-hydrogen i n s e r t i o n r e a c t i o n . In t h e i r t o t a l s y n t h e s i s of a-santalene, Corey and co-workers u t i l i z e d another procedure f o r the formation of a cyclopropane r i n g . The bromocamphor (205) was converted i n t o the corresponding hydrazone (206), and the l a t t e r was o x i d i z e d w i t h mercuric oxide i n methanol to produce bromotricyclene (207). Presumably, an intermediate carbenoid was a l s o i n v o l v e d i n t h i s r e a c t i o n . - 125 -0 Br / Br 205 206 207 Hydrogenation of the (-)-keto o l e f i n (198) i n ethanol over 5% palladium on charcoal a f f o r d e d the ( - ) - t r i c y c l i c ketone (202). The stereochemistry at the newly created asymmetric centre (C^Q) w a s of some importance. That i s , i f one wishes to achieve cyclopropane r i n g formation by i n s e r t i o n of a carbene (generated at C 0) i n t o the C. -H bond, o l u then the l a t t e r bond would have to be endo to the bicyclo[2.2.l]heptanone system present i n compound 202. In other words, hydrogenation of compound 198 would have to a f f o r d compound 202 w i t h stereochemistry at C^Q as shown. A study of a molecular model of the (-)-keto o l e f i n (198) revealed that hydrogenation of t h i s compound should indeed occur i n the des i r e d sense and one could be reasonably c e r t a i n that the hydrogenation product possessed the de s i r e d stereochemistry. The s p e c t r a l p r o p e r t i e s of the hydrogenated product (202) were i n complete accord w i t h the assigned s t r u c t u r e . The carbonyl group absorption appeared at 5.73 y i n the i n f r a r e d spectrum. Of p a r t i c u l a r i n t e r e s t i n the n.m.r. spectrum was the absence of any s i g n a l s corresponding to the v i n y l protons, and the appearance of a doublet (J = 7.0 Hz) at x 9.19 which was a t t r i b u t e d to the newly created secondary methyl group. - 126 -The t e r t i a r y methyl group (a s i n g l e t at T 9.08) and the i s o p r o p y l methyl groups (a doublet at x 9.11, J = 6.3 Hz) were a l s o c l e a r l y evident i n the n.m.r. spectrum of compound 202. 198 202 Reaction of the ( - ) - t r i c y c l i c ketone (202) w i t h p_-toluenesulfonyl-hydrazide i n r e f l u x i n g methanol i n the presence of an a c i d c a t a l y s t afforded the corresponding p_-tosylhydrazone (208) . The l a t t e r was converted i n t o the corresponding carbene intermediate i n two d i f f e r e n t ways. F i r s t l y , compound 208 was added to a suspension of sodium hydride i n diglyme, and a f t e r formation of the 2_-tosylhydrazone s a l t , the r e a c t i o n mixture was heated at 140° f o r one hour. In the second procedure, one equivalent of n - b u t y l l i t h i u m i n hexane was added to a s o l u t i o n of compound 208 i n tetrahydrofuran. The s o l v e n t s were removed under reduced pressure, and the remaining dry tosylhydrazone s a l t was pyrolyzed i n the absence of a s o l v e n t . In each case, gas-l i q u i d chromatographic a n a l y s i s of the product i n d i c a t e d that approximately only 10% of (-)-cyclocopacamphene was formed. Furthermore, the major product (approximately 65%) was the ( + ) - t r i c y c l i c o l e f i n (209). Also present were a number of minor u n i d e n t i f i e d hydrocarbons. - 127 -202 \ NNTs 208 24 209 In each case, (-)-cyclocopacamphene (24) was i s o l a t e d by preparative g . l . c . and i d e n t i f i e d by d i r e c t comparison ( g . l . c . retention time and i n f r a r e d spectrum) with the authentic material. The ( + ) - t r i c y c l i c o l e f i n (209) was also i s o l a t e d by preparative g . l . c . and exhibited s p e c t r a l properties i n accord with the assigned structure. The o l e f i n i c double bond absorptions appeared at 3.26, 6.03 and 13.90 y i n the i n f r a r e d spectrum. In the n.m.r. spectrum of 209, the v i n y l protons appeared as an overlapped p a i r of doublets at x 3.80. The isopropyl methyl groups appeared as doublets (J = 6.0 Hz) at x 9.16 and 9.17, while the sharp s i n g l e t of the t e r t i a r y methyl group (x 9.28) and the doublet (J = 7.0 Hz) of the secondary methyl group (x 9.30) were also c l e a r l y evident. In a rel a t e d attempt at the synthesis of (-)-cyclocopacamphene, the hydrazone of the ketone 202 was prepared. When th i s hydrazone was reacted with yellow mercuric oxide i n r e f l u x i n g methanol, (-)-cyclocopacamphene was obtained i n approximately 30% y i e l d , although the t r i c y c l i c o l e f i n (209) was again the major product (55%) - 128 -of the r e a c t i o n . These attempts to prepare (-)-cyclocopacamphene v i a a carbene i n s e r t i o n r e a c t i o n were not persued f u r t h e r because, w h i l e t h i s research was i n progress, another more e f f i c i e n t s y n t h e t i c route to (-)-cyclocopacamphene was developed. The s y n t h e t i c route which f i n a l l y r e s u l t e d i n an e f f i c i e n t s y n t h e s i s of (-)-cyclocopacamphene was o r i g i n a l l y based on a proposed i n t r a m o l e c u l a r a d d i t i o n of a carbenoid to a carbon-carbon double bond. Thus, i t was planned to convert the p r e v i o u s l y prepared ( - ) - o l e f i n i c aldehyde (194) i n t o the corresponding p_-tosylhydrazone (210) . P y r o l y s i s of the l i t h i u m s a l t (211) of the l a t t e r would, h o p e f u l l y , product the corresponding diazo compound (212) which would, presumably, be a d i r e c t precursor of the required c a r b e n o i d - o l e f i n (127). I n t r a -molecular a d d i t i o n of the l a t t e r would then produce (-)-cyclocopa-camphene (24) . - 129 -P r e p a r a t i o n of the p_-tosylhydrazone 210 was r e a d i l y accomplished by r e a c t i n g the ( - ) - o l e f i n i c aldehyde Q-94) w i t h p_-toluenesulfonyl-hydrazide i n r e f l u x i n g benzene f o r f i v e minutes. Compound 210 was unstable, so i t was reacted immediately w i t h one equivalent of n - b u t y l -l i t h i u m to form the corresponding s a l t (211). P y r o l y s i s (120-140°) of compound 211 under reduced pressure (0.25 mm) w i t h d i r e c t d i s t i l l a t i o n of the product a f f o r d e d , not the diazo compound (212), or cyclocopa-camphene, but the (+)-pyrazoline (213) i n 81% y i e l d from 194. Obviously, the (+)-pyrazoline (213) was formed by a f a c i l e i n t r a m o l e c u l a r 1,3-d i p o l a r c y c l o a d d i t i o n of the intermediate diazoalkene (212). The f a c i l i t y w i t h which t h i s r e a c t i o n took place was presumably a f u n c t i o n of the p r o x i m i t y of the two r e a c t i n g f u n c t i o n a l groups and of the 111 f a i r l y s t r a i n e d nature of the o l e f i n i c double bond. The (+)-p y r a z o l i n e (213) e x h i b i t e d the expected s p e c t r a l p r o p e r t i e s w i t h c h a r a c t e r i s t i c p y r a z o l i n e absorptions at 334 my (e = 232) i n the u l t r a v i o l e t spectrum, and at 6.45 y i n the i n f r a r e d spectrum. The r e g i o s e l e c t i v i t y of the r e a c t i o n (212 -> 213) was demonstrated by the n.m.r. spectrum (Figure 16) of compound 213. Thus, the one-proton m u l t i p l e t at x 5.11 was.assigned to the proton adjacent to the 112 -N=N-moeity. Furthermore, the t e r t i a r y methyl groups ( s i n g l e t s at x 8.42 and 9.18) and the i s o p r o p y l methyl groups (a doublet at x 9.14, J = 6.0 Hz) were r e a d i l y d i s t i n g u i s h a b l e . The (+)-pyrazoline (213) was i r r a d i a t e d i n ether at room temperature f o r approximately one hour, using a Rayonet r e a c t o r equipped w i t h o 3500 A lamps and a pyrex f i l t e r . Removal of the s o l v e n t , and reduced I-1 1 1 1 1 1 1 1 ; 1 ' ' ' ' ' ' ' ' ' I ' ' ' ' I I 5 6 7 Figure 16. N.M.R. Spectrum of the (+)-Pyrazoline (213). - 131 -pressure d i s t i l l a t i o n of the r e s u l t i n g o i l afforded pure ( ^ - c y c l o c o p a -camphene (24) i n 93% y i e l d . This m a t e r i a l was i d e n t i c a l [ g . l . c . r e t e n t i o n times, s p e c i f i c r o t a t i o n , i n f r a r e d and n.m.r. sp e c t r a (Figures 17 and 18)] w i t h the (-)cyclocopacamphene prepared p r e v i o u s l y . Thus, i n c o n c l u s i o n , the s t r u c t u r e and absolute stereochemistry of (-)-copacamphene and of (-)-cyclocopacamphene have been f u l l y corroborated by the described s t e r e o s e l e c t i v e s y n t h e s i s of these compounds. Figure 17. I n f r a r e d Spectrum of (-)-Cyclocopacamphene (24). Figure 19. I n f r a r e d Spectrum of (+)-Cyclosativene (27). EXPERIMENTAL General M e l t i n g p o i n t s , which were determined on a K o f l e r b l o c k , and b o i l i n g p o i n t s are uncorrected. O p t i c a l r o t a t i o n s were obtained at the sodium D l i n e , using a Rudolph P o l a r i m e t e r , model 219, a Bendix ETL-NPL Automatic P o l a r i m e t e r Type 143A, or Perkin-Elmer Model 141 Automatic P o l a r i m e t e r . U l t r a v i o l e t s p e c t r a were, unless otherwise noted, measured i n methanol s o l u t i o n on e i t h e r a Cary, model 14, or a Unicam, model SP 800, spectrophotometer. 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 or a Perkin-Elmer Model 710 spectrophotometer while comparison s p e c t r a were recorded on a Perkin-Elmer spectrophotometer, model 457. N.m.r. sp e c t r a were, unless otherwise noted, recorded i n deuterochloroform s o l u t i o n on Varian Associates spectrometers models A-60, T-60 and/or HA-100, XL-100. Line p o s i t i o n s are given i n the T i e r s x s c a l e , w i t h t e t r a m e t h y l s i l a n e as i n t e r n a l standard; the m u l t i p l i c i t y , i n t e g r a t e d peak areas and proton assignments are i n d i c a t e d i n parentheses. Gas-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 an Aerograph Autoprep model 700 or a V a r i a n Aerograph, model 90-P. The f o l l o w i n g columns C10 f t x 1/4 i n , unless otherwise noted) were employed, w i t h the i n e r t supporting m a t e r i a l being, i n each case, 60/80 mesh Chromosorb W (unless otherwise noted): column A (5 f t x 1/4 i n ) , - 137 -20% SE 30; column B, 20% SE 30; column C (20ft x 3/8 i n ) , 30% SE 30; column D, 20% Apiezon J ; column E (10 f t x 3/8 i n ) , 8% FFAP (60/80 mesh Chromosorb G); column F, 8% FFAP (60/80 mesh Chromosorb G); column G (10 f t X 3/8 i n ) 30% Apiezon J . The s p e c i f i c column used, along w i t h the column temperature and c a r r i e r gas (helium) f l o w - r a t e ( i n ml/min), are i n d i c a t e d i n parentheses. Microanalyses were performed by Mr. P. Borda, M i c r o a n a l y t i c a l Laboratory, U n i v e r s i t y of B r i t i s h Columbia, Vancouver. High r e s o l u t i o n mass spec t r a were recorded on a AEI type MS-9 mass spectrometer. Pr e p a r a t i o n of the Hydroxymethylene D e r i v a t i v e (130) To an i c e - c o o l e d , s t i r r e d suspension of powdered sodium methoxide (81.5 g, 1.51 moles) i n 300 ml of dry benzene, kept under an atmosphere of dry n i t r o g e n , was added a s o l u t i o n of 77.2 g (.502 mole) of (-)-carvomethone (123) i n 300 ml of dry benzene. The r e s u l t i n g mixture was s t i r r e d f o r 10 min, and then a s o l u t i o n of 112 g (1.51 moles) of e t h y l formate i n 60 ml of dry benzene was added. The mixture was warmed to room temperature and allowed to s t i r overnight. Water was added, the mixture was thoroughly shaken and the l a y e r s were separated. The organic l a y e r was e x t r a c t e d w i t h two p o r t i o n s of 10% aqueous sodium hydroxide. The combined aqueous l a y e r and a l k a l i n e e x t r a c t s were cooled, a c i d i f i e d w i t h concentrated h y d r o c h l o r i c a c i d and thoroughly e x t r a c t e d w i t h ether. The combined e t h e r e a l e x t r a c t s were washed w i t h water and h r i n e , and d r i e d over anhydrous magnesium s u l f a t e . Removal of s o l v e n t , followed by d i s t i l l a t i o n of the r e s i d u a l o i l under - 138 -reduced pressure, gave 75.3 g (83%) of the hydroxymethylene d e r i v a t i v e (130) (mixture of epimers) as a pale yellow o i l , b.p. 89-93° at 1.0 mm; n j 1 1.4936; u l t r a v i o l e t , \ 291 my Ce = 6,570), A N a ° H a d d e d 317 my D ' ' max M ' ' max v (e = 17,000); i n f r a r e d ( f i l m ) , \ 5.78, 5.88, 6.14, 6.32, 6.88, 7.35 y. ni3x Preparation of the 2-n-Butylthiomethylene Derivative (131) A s o l u t i o n of the hydroxymethylene d e r i v a t i v e (130) (62.0 g , .341 mole), n-butanethiol (36.8 g, .408 mole), and p_-toluenesulfonic acid (40 mg) i n 400 ml of dry benzene was refluxed i n a nitrogen atmosphere under a Dean Stark water separator overnight, at which time 6 ml of water had been c o l l e c t e d . The cooled s o l u t i o n was washed with saturated aqueous sodium bicarbonate, then with water, and f i n a l l y dried over anhydrous magnesium s u l f a t e . Removal of the solvent gave an o i l , which, upon d i s t i l l a t i o n under reduced pressure, afforded 72.1 g (83%) of the n-butylthiomethylene d e r i v a t i v e (131) (mixture of 21 epimers), b.p. 120-126° at 0.2 mm; n^ 1.5252; u l t r a v i o l e t , X D max 302 my ( e = 11,700); i n f r a r e d ( f i l m ) , X 6.00, 6.51, 6.89, 8.58, in 3.x 12.51 y. Anal. Calcd. for C-^H^OS: C, 70.82; H, 10.30; S, 12.58. Found: C, 70.57; H, 10.42; S, 12.40. Preparation of the Alkylated n-Butylthiomethylene Derivative (132) The n-butylthiomethylene d e r i v a t i v e (131) (101.6 g, 0.40 mole) was added to U of dry _t-butanol containing 46.0 g (0.46 mole) of potassium _t-butoxide and the r e s u l t i n g s o l u t i o n was s t i r r e d at room temperature f o r 10 min and then cooled to 0°. Ethyl 2-iodiopropionate - 139 -[prepared from r e a c t i o n of 181.9 g (1.0 moles) of e t h y l 2-bromopropionate and 165 g (1.1 moles) of sodium i o d i d e i n 1 £ of acetone, followed by appropriate workup] was added s l o w l y , and the r e a c t i o n mixture was s t i r r e d at room temperature under an atmosphere of dry n i t r o g e n overnight. Most of the solvent was removed under reduced pressure and the residue was d i l u t e d w i t h water. The r e s u l t i n g mixture was ext r a c t e d w i t h e t h e r , and the organic l a y e r was washed w i t h water and b r i n e , and d r i e d over anhydrous magnesium s u l f a t e . Removal of the solvent gave an o i l , which upon d i s t i l l a t i o n under reduced pressure, afforded 103.2 g (73%) of the de s i r e d a l k y l a t e d product (132) (mixture of epimers), b.p. 172-180° at 0.8 mm; 1.5181; u l t r a v i o l e t , X r D max 301 mp (e = 10,300); i n f r a r e d ( f i l m ) , X 5.79, 6.00, 6.51, 6.88, in 3.x 8.50 u. Anal. Calcd. f o r C o„H_.0 oS: C, 67.76; H, 9.67; S, 9.03. Found: 20 34 3 C, 67.74; H, 9.49; S, 9.00. Pre p a r a t i o n of Keto E s t e r (135) To a s o l u t i o n of the a l k y l a t e d n-butylthiomethylene d e r i v a t i v e (132) (103 g) i n 450 ml of diethylene g l y c o l was added 450 ml of 25% aqueous potassium hydroxide 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 under n i t r o g e n f o r 22 h. The r e a c t i o n mixture was cooled and a c i d i f i e d w i t h concentrated h y d r o c h l o r i c a c i d and then thoroughly e x t r a c t e d w i t h ether. The e t h e r e a l l a y e r was d r i e d over anhydrous magnesium s u l f a t e and then concentrated. The crude a c i d (134) thus obtained was reacted w i t h excess e t h e r e a l diazomethane, then the excess diazomethane was destroyed by the a d d i t i o n of a c e t i c a c i d . The e t h e r e a l - 140 -l a y e r was washed w i t h water, a 10% sodium carbonate s o l u t i o n and b r i n e , then d r i e d over anhydrous magnesium s u l f a t e . Removal of the solvent followed by d i s t i l l a t i o n of the r e s i d u a l o i l gave 61.2 g (85%) of the de s i r e d keto e s t e r (135) (epimeric mixture of diastereomers), b.p. 120-126° at 0.2 mm; n ^ 1 1.4722; i n f r a r e d ( f i l m ) , A 5.77, 5.89, D max 6.87, 8.38 u ; n.m.r., T 6.34, 6.36 ( s i n g l e t s , 3H, methyl e s t e r protons) 7.00, 7.13 ( q u a r t e t s , IH, protons adjacent to the e s t e r carbonyls, JT 7 00 = 7 ' 5 H z ' J T 7 13 = 7"° H z ^ ' 8 " 7 6 ' 8 , 8 7 ( s i n g l e t s , 3H, t e r t i a r y m ethyls), 8.84, 8.89 (doublets, 3H, secondary methyls, J 7 T8.84 " H Z ' T8 89 " 7 , 0 Hz^-' 9 , 0 9 ( d o u b l e t > 6 H » i s o p r o p y l methyls, J = 6.0 Hz). Anal. Calcd. f o r C^H^O.^: C, 69.96; H, 10.07. Found: C, 69.84; H, 9.90. Pr e p a r a t i o n of Sodium B i s ( t r i m e t h y l s i l y l ) a m i d e To a s o l u t i o n of 89.0 g (.553 mole) of 1,1,1,3,3,3-hexamethyl-d i s i l a z a n e i n 200 ml of dry benzene was added 20.0 g (.513 mole) of sodium amide. The mixture was r e f l u x e d f o r 4 h at which time the e v o l u t i o n of ammonia had ceased. The hot s o l u t i o n was f i l t e r e d through c e l i t e , then the solvent and the excess hexamethyldisilazane were removed under water a s p i r a t o r pressure. The r e s u l t i n g c r y s t a l l i n e m a t e r i a l was r e c r y s t a l l i z e d from dry benzene, and the l a s t traces of the solvent were removed by p l a c i n g the c r y s t a l s under vacuum overnight, to a f f o r d 57.5 g (57%) of the de s i r e d sodium b i s ( t r i m e t h y l s i l y l ) a m i d e . - 141 -Pre p a r a t i o n of the (-)-Diketone '. (122) To a s o l u t i o n of 80.6 g (0.44 mole) of sodium b i s ( t r i m e t h y l s i l y l ) -amide i n 900 ml of dry dimethoxyethane was added a s o l u t i o n of 48.0 g (0.20 mole) of the keto e s t e r (135) i n 100 ml of dry dimethoxyethane, and the r e s u l t i n g mixture was r e f l u x e d under an atmosphere of dry ni t r o g e n f o r 1.0 h. The r e a c t i o n was then cooled, and quenched by pouring the cooled r e a c t i o n mixture i n t o a r a p i d l y s t i r r e d s o l u t i o n of 27.0 g (0.45 mole) of g l a c i a l a c e t i c a c i d i n 300 ml of i c e water. The r e a c t i o n mixture was concentrated, and the residue was d i s s o l v e d i n ether. The e t h e r e a l l a y e r was washed w i t h water, a 10% sodium bicarbonate s o l u t i o n , and b r i n e , and then d r i e d over anhydrous magnesium s u l f a t e . Removal of the solvent afforded a c r y s t a l l i n e m a t e r i a l which was r e c r y s t a l l i z e d from petroleum ether (b.p. 60-110°) to y i e l d 37.4 g (90%) of the d e s i r e d diketone (122), m.p. 76-77°; [a]^° -56° (c, 4.0 i n CHC1 ); i n f r a r e d (CHC1,), A 5.66, 5.79, 6.88, 8.46 u; •J J IT13.X n.m.r., x 7.08 (broadened doublet, IH, bridgehead proton, J = 4.8 Hz), 7.66 (quartet of doublets, C ?H, J c H _ c R = 7.0 Hz, J c R _ c = 1.5 Hz), 8.75 (doublet, 3H, secondary methyl, J = 7.0 Hz), 8.90 ( s i n g l e t , 3H, t e r t i a r y methyl), 9.00, 9.10 (doublets, 6H, i s o p r o p y l methyls, J = 6.3 Hz). Anal. Calcd. f o r C^H^O^ C, 74.96; H, 9.68. Found: C, 74.80; H, 9.75. Mol. Wt. Calcd. f o r C 1 3 H 2 0 ° 2 : 2 0 8 - 1 4 6 - Found (high r e s o l u t i o n mass spectrometry): 208.143. - 142 -P r e p a r a t i o n of (+)-Dihydrocarvone (140) To approximately 2 £ of l i q u i d ammonia was added 35 g (5.00 moles) of l i t h i u m metal, and the r e s u l t i n g blue s o l u t i o n was s t i r r e d f o r 30 min. A s o l u t i o n of (-)-carvone (128) (150 g, 1.00 moles) i n 250 ml of anhydrous ether was added over a period of one hour, and the r e s u l t i n g s o l u t i o n was s t i r r e d f o r an a d d i t i o n a l hour. A f t e r the r e a c t i o n had been quenched w i t h 150 ml of methanol, the ammonia was allowed to evaporate and the r e s i d u a l m a t e r i a l was d i l u t e d w i t h water. The aqueous l a y e r was saturated w i t h s a l t and thoroughly e x t r a c t e d w i t h ether. The combined e x t r a c t s were d r i e d over anhydrous magnesium s u l f a t e . Removal of the solvent under reduced pressure afforded 132 g of the crude a l c o h o l . 99 Standard chromic a c i d s o l u t i o n was added to a s o l u t i o n of the crude a l c o h o l (132 g) i n 750 ml of acetone at 0° u n t i l an orange colour p e r s i s t e d . Isopropyl a l c o h o l was added to destroy the excess o x i d i z i n g reagent and the s o l u t i o n was evaporated under reduced pressure. The r e s i d u a l m a t e r i a l was d i l u t e d w i t h water and then ex t r a c t e d thoroughly w i t h ether. The e t h e r e a l e x t r a c t s were d r i e d over anhydrous magnesium s u l f a t e and the ether was removed at a s p i r a t o r pressure. D i s t i l l a t i o n of the r e s i d u a l o i l gave 116 g (78%) of (+)-dihydrocarvone (140) as a c o l o u r l e s s o i l , b.p. 67-68° at 2.0 mm, l i t . 7 7 b.p. 100-104° at 12.0mm; i n f r a r e d ( f i l m ) , A 5.85, 6.10, max 11.20 u; n.m.r., T 5.30 (unresolved m u l t i p l e t , 2H, v i n y l p r o t o n s ) , 8.26 ( s i n g l e t , 3H, v i n y l methyl), 8.95 (doublet, 3H, secondary methyl, J = 6.5 Hz). - 143 -Pr e p a r a t i o n of the (+)-Ketol(142) To a s o l u t i o n of (+)-dihydrocarvone (140) (100 g, 0.657 mole) i n 1 l of anhydrous ether was added sodium amide (29 g, 0.725 mole). To t h i s mixture was added s l o w l y a s o l u t i o n of l-diethylamino-3-pentanone methiodide (141) (206 g, 0.690 mole), [prepared by r e a c t i o n of l-diethylamino-3-pentanone (110 g, 0.690 mole) w i t h methyl i o d i d e (96 g, 0.690 mole)] i n 200 ml of dry p y r i d i n e . The r e a c t i o n mixture was s t i r r e d at 0° f o r 6 h and then r e f l u x e d f o r 6 h. Water was then added and the r e s u l t i n g mixture was ext r a c t e d w i t h ether. The combined ether e x t r a c t s were washed w i t h water and b r i n e , then d r i e d over anhydrous magnesium s u l f a t e . Removal of the s o l v e n t , afforded a ye l l o w o i l which was subjected to f r a c t i o n a l d i s t i l l a t i o n under reduced pressure. The i n i t i a l f r a c t i o n s (22 g, b.p. 75-110° at .8 mm) c o n s i s t e d mainly of the s t a r t i n g m a t e r i a l , (+)-dihydrocarvone (140). The l a t e r f r a c t i o n s (98 g, b.p. 144-174° at 0.8 mm) con s i s t e d of an o i l which s o l i d i f i e d on standing. R e c r y s t a l l i z a t i o n of the above s o l i d i f i e d m a t e r i a l from hexane gaye 42.3 g of the pure k e t o l (142) (52% based on unrecovered (+)-dihydrocarvone) m.p. 108°, l i t . 7 8 m.p. 106°; i n f r a r e d (CHC1-), X 3 max 2.96, 5.92, 6.14, 11.28 u; n.m.r., x 5.35 ( m u l t i p l e t , 2H, v i n y l p r o t o n s ) , 8.33 (doublet, 3H, v i n y l methyl, J = 1.0 Hz), 8.77 ( s i n g l e t , 3H, t e r t i a r y methyl), 8.97 (doublet, 3H, secondary methyl, J = 6.5 Hz). Pre p a r a t i o n of the (+)-Ketol (145) The k e t o l (142) (42.0 g) i n 250 ml of ethanol was hydrogenated over 4.0 g of 10% palladium on charcoal at room temperature u n t i l the - 144 -uptake of hydrogen was complete (approximately 1 h). Removal of c a t a l y s t and solvent y i e l d e d the (+)-ketol (145) (41.6 g) as c o l o u r l e s s 78 20 c r y s t a l s , m.p. 65°, l i t . m.p. 64-65°; [ a ] ^ +49.4° (c, 1.5 i n MeOH); i n f r a r e d (CHC1J, A 2.85, 5.87, 6.90, 9.65 y; n.m.r., x 7.10 (quartet , IH, C^H, J = 7.0 Hz), 8.75 ( s i n g l e t , 3H, t e r t i a r y methyl), 8.94 (doublet, 3H, secondary methyl, J = 7.0 Hz), 9.16 (doublet, 6H, i s o p r o p y l methyls, J = 6.0 Hz). Anal. Calcd. f o r C 1 5 H 2 6 0 2 : C ' 7 5 - 5 8 5 H> 10.99. Found: C, 75.40; H, 10.83. Pr e p a r a t i o n of (-)-ll,12-Dihydro-7-epi-a-cyperone (146) The (+)-ketol (145) (41.0 g) was d i s s o l v e d i n 425 ml of 10% e t h a n o l i c potassium hydroxide and the r e s u l t i n g s o l u t i o n was heated under r e f l u x i n an atmosphere of n i t r o g e n f o r 10 h. The cooled s o l u t i o n was d i l u t e d w i t h water and n e u t r a l i z e d w i t h concentrated h y d r o c h l o r i c a c i d . The r e s u l t i n g mixture was ext r a c t e d w i t h petroleum ether (b.p. 30-60°). The organic e x t r a c t s were d r i e d over anhydrous magnesium s u l f a t e . Removal of the s o l v e n t , followed by d i s t i l l a t i o n of the r e s i d u a l o i l under reduced pressure afforded 32.9 g (87%) of the desi r e d octalone (146), b.p. 114-120° at 0.5 mm; n ^ 3 1.5178, l i t . 7 8 20 20 n 1.5190; [a]ti -170° (c, 1.3 i n MeOH); u l t r a v i o l e t , A 250 mu D max (e = 15,800); i n f r a r e d ( f i l m ) , A 6.01, 6.22, 6.90, 8.36, 9.85 y; IH3.X n.m.r., x 8.23 (doublet, 3H, v i n y l methyl, J = 1.7 Hz), 8.74 ( s i n g l e t , 3H, t e r t i a r y methyl), 9.08 (doublet, 6H, i s o p r o p y l methyls, J = 6.0 Hz). Anal. Calcd. f o r C^H^O: C, 81.76; H, 10.98. Found: C, 81.59; H, 10.97. - 145 -P r e p a r a t i o n of (-)-2-Hydroxymethylene-ll,12-dihydro-7-epi-a-cyperone (152) To an i c e - c o o l e d , s t i r r e d suspension of powdered sodium methoxide (10.8 g, 0.20 mole) i n 60 ml of dry benzene, kept under an atmosphere of dry n i t r o g e n , was added a s o l u t i o n of 14.5 g (.0659 mole) of the (-)-octalone (146) i n 120 ml of dry benzene. The r e s u l t i n g mixture was s t i r r e d f o r 10 min, and then a s o l u t i o n of 14.8 g (0.20 mole) of e t h y l formate i n 60 ml of dry benzene was added. The mixture was warmed to room temperature and allowed to s t i r f o r 4 days. Water was added, the mixture was thoroughly shaken, and the l a y e r s separated. The organic l a y e r was e x t r a c t e d w i t h two p o r t i o n s of 10% aqueous sodium hydroxide. The combined aqueous l a y e r and a l k a l i n e e x t r a c t s were cooled, a c i d i f i e d w i t h concentrated h y d r o c h l o r i c a c i d and thoroughly e x t r a c t e d w i t h ether. The combined e t h e r e a l e x t r a c t s were washed w i t h water and d r i e d over anhydrous magnesium s u l f a t e . Removal of the s o l v e n t , followed by d i s t i l l a t i o n of the r e s i d u a l o i l under reduced pressure, gave 15.7 g (96%) of the (-)-hydroxymethylene d e r i v a t i v e (152) as a pale y e l l o w o i l , w h i c h then solidified,m.p.45-48°; 20 [ a ] " -16.4 (c, 1.3 i n MeOH); u l t r a v i o l e t , X 260 my (e 9,350), 311 my D max (e 4,760); A N a 0 H a d d e d 256 my (e = 9,620), 358 my (e = 8,620); max i n f r a r e d (CHC1J, \ 6.12, 6.40, 6.88, 8.25 y; n.m.r., x -4.17 •J max (broad s i g n a l , IH, =CH0H), 2.61 ( s i n g l e t , IH, =CH0H, width at h a l f -height = 7.0 Hz), 8.14 (doublet, 3H, v i n y l methyl, J = 1.6 Hz), 8.93 ( s i n g l e t , 3H, t e r t i a r y methyl), 9.07 (doublet, 6H, i s o p r o p y l methyls, J = 6.0 Hz). Anal. Calcd. f o r C.,H o /0 o: C, 77.38; H, 9.74. Found: C, 77.20; 16 24 2 H, 9.64. - 146 -Pr e p a r a t i o n of the (+)-Dienone Aldehyde (153) A s o l u t i o n of 15.6 g (62.9 mmoles) of the hydroxymethylene d e r i v a t i v e (152) and 15.3 g (67.3 mmoles) of 2,3-dichloro-5,6-dicyano-benzoquinone i n 500 ml of dry dioxan was s t i r r e d f o r 10 min under a dry n i t r o g e n atmosphere. This s o l u t i o n was then f i l t e r e d through a s i n t e r e d g l a ss f u n n e l , and the solvent was removed under reduced pressure. The r e s u l t i n g o i l was taken i n t o ether and washed w i t h a 1% s o l u t i o n of sodium hydroxide, and water, then d r i e d over anhydrous magnesium s u l f a t e . The solvent was removed, and the r e s u l t i n g y e l l o w o i l was d i s t i l l e d (b.p. 143° at 0.23 mm). The d i s t i l l a t e s o l i d i f e d on standing and was r e c r y s t a l l i z e d from hexane-ether to a f f o r d 12.0 g (78%) of the des i r e d dienone aldehyde (153), m.p. 54°; [a]^ +139° (c, 1.0 i n MeOH); u l t r a v i o l e t , \ 262 mu (e = 11,600); i n f r a r e d max ^ (CHC1 3), A m a x 3.67, 5.88, 6.07, 6.14, 6.24, 6.88, 8.03, 12.11 u; n.m.r., x -1.20 ( s i n g l e t , IH, aldehydic p r o t o n ) , 2.45 ( s i n g l e t , IH, v i n y l p roton), 8.00 (doublet, 3H, v i n y l methyl, J = 1.0 Hz), 8.63 ( s i n g l e t , 3H, t e r t i a r y methyl), 9.03, 9.17 (doublets, 6H, i s o p r o p y l methyls, J = 6.0 Hz). Anal. Calcd. f o r C.,H o o0 •. C, 78.01; H, 9.00. Found: C, 78.12; lb IL 2. H, 8.95. Pr e p a r a t i o n of the (+)-Keto E s t e r (138) To a s t i r r e d suspension of cuprous i o d i d e (2.8 g, 20.0 mmoles) i n 90 ml of anhydrous ether at 0° and under an atmosphere of dry n i t r o g e n , was added 18.5 ml of 2.16 M e t h e r e a l m e t h y l l i t h i u m . A small - 147 -amount of cuprous i o d i d e was added u n t i l a n o t i c e a b l e amount of y e l l o w p r e c i p i t a t e was c l e a r l y v i s i b l e , thus ensuring that no excess m e t h y l l i t h i u m was present. To the r e s u l t i n g l i t h i u m dimethylcuprate s o l u t i o n was added a s o l u t i o n of the (+)-dienone aldehyde (153) (2.46 g, 10.0 mmoles) i n 90 ml of anhydrous ether, over a p e r i o d of 10 min. The r e a c t i o n was s t i r r e d at 0° f o r an a d d i t i o n a l 2 h. A s o l u t i o n of a c e t y l c h l o r i d e (1.57 g, 20.0 mmoles) i n 40 ml of anhydrous ether was added over a p e r i o d of 5 min. The r e s u l t i n g s o l u t i o n was poured i n t o a r a p i d l y s t i r r e d -mixture of concentrated ammonium hydroxide and crushed i c e , i n a r a t i o of approximately 1:2. The ether l a y e r was q u i c k l y separated from the aqueous l a y e r and washed w i t h water and sa t u r a t e d b r i n e , d r i e d over anhydrous magnesium s u l f a t e and concentrated. This m a t e r i a l was somewhat unstable, and 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 next r e a c t i o n . However, an a n a l y t i c a l sample of the keto acetate (154) was obtained by p r e p a r a t i v e g . l . c . (column A, 210°, 90) and e x h i b i t e d i n f r a r e d ( f i l m ) , X 5.66, 5.99, 6.21, 7.33, 8.42, 8.77 u; max ' ' ' H n.m.r., x 1.80 ( s i n g l e t , IH, v i n y l p r o t o n ) , 7.77 ( s i n g l e t , 3H, acetate methyl), 8.14 (broad s i n g l e t , 3H, v i n y l methyl), 8.83 ( s i n g l e t , 3H, t e r t i a r y methyl), 8.97 (doublet, 3H, secondary methyl, J = 7.0 Hz), 9.07 (poorly r e s o l v e d m u l t i p l e t s , 6H, i s o p r o p y l methyls). A s o l u t i o n of the crude keto acetate (154) (2.5 g) i n 80 ml of e t h y l acetate was cooled to -78° by means of a dry ice-acetone bath. Ozone was bubbled through the s o l u t i o n u n t i l a permanent blue colour p e r s i s t e d , and then continued f o r an a d d i t i o n a l 20 min. The s o l u t i o n was allowed to warm to room temperature, and then concentrated, w i t h the l a s t traces of solvent being removed by vacuum pump. To the crude - 148 -o z i n i d e was added 80 ml of 5% NaOH, and the r e a c t i o n mixture was s t i r r e d at room temperature. To t h i s mixture was added 16.5 ml of 30% hydrogen peroxide, i n 1 ml p o r t i o n s over the p e r i o d of 1 h. During t h i s hour, the r e a c t i o n was heated to 90°, and then maintained at t h i s temperature f o r an a d d i t i o n a l hour. The r e a c t i o n was then cooled, n e u t r a l i z e d w i t h concentrated 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 thoroughly w i t h ether. The e t h e r e a l l a y e r was d r i e d over anhydrous magnesium s u l f a t e , and concentrated. The crude a c i d (157) thus obtained was t r e a t e d w i t h excess e t h e r e a l diazomethane, then the excess diazomethane was destroyed by the a d d i t i o n of a c e t i c a c i d . The e t h e r e a l l a y e r was washed w i t h water, 10% sodium bicarbonate s o l u t i o n and b r i n e , then d r i e d over anhydrous magnesium s u l f a t e . Removal of the s o lvent and d i s t i l l a t i o n of the r e s i d u a l o i l , gave 1.09 g (45% from the dienone aldehyde) of the d e s i r e d keto e s t e r (138), b.p. 120° at 0.15 mm; n 2 2 1.4744; I a ] 2 2 +147° ( c , 1.4 i n CHC1 3); i n f r a r e d ( f i l m ) , x 5.76, 5.85, 6.89, 8.47 u ; n.m.r., T 6.34 ( s i n g l e t , 3H, methyl in 3.x e s t e r p r o t o n s ) , 6.93 (quartet, IH, proton adjacent to the carbonyl e s t e r , J = 7.2 Hz), 9.01 ( s i n g l e t , 3H, t e r t i a r y methyl), 9.04 (doublet, 3H, secondary methyl, J = 7.2 Hz), 9.09, 9.10 (doublets, 6H, i s o p r o p y l methyls, J = 6.0 Hz). Anal. Calcd. f o r C H^O^ C, 69.96; H, 10.07. Found: C, 69.86; H, 9.97. P r e p a r a t i o n of the (+)-Diketone (139) To a r e f l u x i n g s o l u t i o n of 8.97 g (49.0 mmoles) of sodium b i s -( t r i m e t h y l s i l y l ) a m i d e i n 165 ml of dry benzene under an atmosphere of - 149 -dry n i t r o g e n gas was added, over a p e r i o d of 1 h, a s o l u t i o n of 3.36 g (14.0 mmoles) of the (+)-keto e s t e r (138) i n 30 ml of dry benzene. The r e a c t i o n mixture was r e f l u x e d f o r an a d d i t i o n a l hour, then cooled to i c e temperature and quenched by pouring t h i s cooled s o l u t i o n i n t o a r a p i d l y s t i r r e d s o l u t i o n of 10 ml of a c e t i c a c i d and 30 ml of water. The organic l a y e r was washed w i t h water, a saturated sodium carbonate s o l u t i o n , and b r i n e , then d r i e d over anhydrous magnesium s u l f a t e . Removal of the solvent afforded a c r y s t a l l i n e m a t e r i a l which, was r e c r y s t a l l i z e d from pentane to y i e l d 1.75 g (60%) of the 90 d e s i r e d diketone (139), m.p. 77-78°; Ia]p +100° (c, 2.8 i n CHC1 3); i n f r a r e d (CHC1 ) , \ 5.66, 5.80, 6.87, 8.50, 9.95 u ; n.m.r., x 7.10 C m u l t i p l e t , IH, GVH) , 7.71 Cquartet of doublets, C..H, J„ „ „ „ = 7.3 Hz, JC H-C H = 1 , 5 H z ^ ' 8 , 3 8 (doublet, 3H, secondary methyl, J = 7.3 Hz), 8.90 ( s i n g l e t , 3H, t e r t i a r y methyl),9.02,9.15(doublets,6H,isopropyl methyls,J=6.3Hz) , Anal. Calcd. f o r C ^ H ^ O ^ C, 74.96; H, 9.68. Found: C, 74.65; H, 9.48. P r e p a r a t i o n of the (-)-Keto Enol Phosphate (164) To a s o l u t i o n of 6.6 g (36 mmoles) of sodium b i s ( t r i m e t h y l s i l y l ) -amide i n 90 ml of dry tetrahydrofuran was added a s o l u t i o n of 5.0 g (24 mmoles) of the (-)-diketone (122) i n 10 ml of dry tetrahydrofuran. The r e a c t i o n mixture was s t i r r e d at room temperature under an atmosphere of dry n i t r o g e n f o r 20 min, then quenched by the a d d i t i o n of a s o l u t i o n of 10.7 g (62 mmoles) of d i e t h y l phosphorochlorodate (163) d i s s o l v e d i n 30 ml of dry p y r i d i n e . A f t e r s t i r r i n g at room temperature f o r 30 min, the r e a c t i o n mixture was concentrated under - 150 -water a s p i r a t o r pressure. The r e s i d u a l m a t e r i a l was d i l u t e d w i t h water then thoroughly e x t r a c t e d w i t h ether. The combined e t h e r e a l e x t r a c t s were washed w i t h water and sa t u r a t e d b r i n e , then d r i e d over anhydrous magnesium s u l f a t e . Removal of the s o l v e n t , followed by d i s t i l l a t i o n of the r e s i d u a l o i l under reduced pressure afforded 7.8 g (94%) of 21 the d e s i r e d keto e n o l phosphate (164), b.p. 135-145° at 0.25 mm; n Q 1.4722; [ a ] 2 5 -5.8° (c, 1.4 i n CHC1J; i n f r a r e d ( f i l m ) , A 5.69, D 3 max 5.96, 7.87, 9.14, 9.77, 10.42, 11.42, 12.01 y ; n.m.r., x 4.82 ( p a i r of q u a r t e t s , 4H, -0CH„CH„, J = 7.0 Hz, J„ _ = 1.0 Hz), 8.30 ( p a i r of —J. J ri—r doublets, 3H, v i n y l methyl, J „ _ = 1.0 Hz, J „ = 2.2 Hz), 8.63 (-.(.H—C^ -j" n — r ( p a i r of t r i p l e t s , 6H, -O-CH-CH,, J = 7.0 Hz, J „ _ = 1.0 Hz), 8.98 Z j H—r ( s i n g l e t , 3H, t e r t i a r y methyl), 9.08 (doublet, 6H, i s o p r o p y l methyls, J = 6.3 Hz). Anal. Calcd. f o r C 1 ?H 0,-P: C, 59.29; H, 8,49. Found: C, 59.18; H, 8.45. P r e p a r a t i o n of the (-)-Keto A l c o h o l (169) A , s o l u t i o n of the (-)-diketone (122) (14.0 g, 67.3 mmoles) i n 170 ml of ethanol was cooled to 0° and a s o l u t i o n of 825 mg (21.8 mmoles) of sodium borohydride d i s s o l v e d i n 30 ml of ethanol was added. The s o l u t i o n was s t i r r e d at 0° f o r 15 min and then the excess hydride was destroyed by a d d i t i o n of 4.4 g (74.0 mmoles) of a c e t i c a c i d . The r e a c t i o n mixture was concentrated under reduced pressure then the residue was d i l u t e d w i t h water, and thoroughly e x t r a c t e d w i t h ether. The combined e t h e r e a l e x t r a c t s were washed w i t h a saturated sodium carbonate s o l u t i o n and b r i n e , and then d r i e d over anhydrous magnesium - 151 -s u l f a t e . Removal of the so l v e n t f o l l o w e d by d i s t i l l a t i o n of the r e s i d u a l o i l under reduced pressure afforded 12.5 g (89%) of the 2 5 d e s i r e d keto a l c o h o l (169), b.p. 125-130° at 0.4 mm; n D 1.4916; [a]?.5 -69° (c, 1.0 i n CHC1 ); i n f r a r e d ( f i l m ) , A 2.93, 5.80, 6.85, 9.00, 9.10 u ; n.m.r., T 6.12 (doublet, IH, C DH, J = 5.5 Hz), 7.30 o ( m u l t i p l e t , IH, C^E) , 8.92 (doublet, 3H, secondary methyl, J = 7.0 Hz), 8.97 ( s i n g l e t , 3H, t e r t i a r y methyl), 9.02, 9.13 (doublets, 6H, i s o p r o p y l methyls, J = 6.5 Hz). Anal. Calcd. f o r C ^ H ^ O ^ C, 74.24; H, 10.54. Found: C, 74.12; H, 10.50. Preparation of the ( - ) - O l e f i n i c A l c o h o l (171) A mixture of the (-)-keto a l c o h o l (169) (12.0 g, 57.2 mmoles), p_-toluenesulfonylhydrazide (11.7 g, 62.8 mmoles) and 9.0 ml of methanol were heated and s t i r r e d u n t i l a homogeneous s o l u t i o n was obtained. Then 300 u£ of a c e t y l c h l o r i d e was added to the s o l u t i o n , and the r e a c t i o n mixture was s t i r r e d under an atmosphere of dry n i t r o g e n at 90-100° f o r 3 h. The r e a c t i o n was d i l u t e d w i t h water and thoroughly e x t r a c t e d w i t h ether. The combined e t h e r a l e x t r a c t s were washed w i t h a 10% s o l u t i o n of sodium bicarbonate, then w i t h b r i n e , and f i n a l l y d r i e d over anhydrous magnesium s u l f a t e . Removal of the solvent under reduced pressure y i e l d e d 2.1.2 g (98%) of the p_-tosylhydrazone a l c o h o l (170) as a viscous yellow o i l [ i n f r a r e d ( f i l m ) , A 2.76, 2.98, 3.01, TT13.X 6.03, 6.25, 8.55 u]. This m a t e r i a l was used without f u r t h e r p u r i f i c a t i o n . To an i c e - c o o l e d s o l u t i o n of the p_-tosylhydrazone a l c o h o l (170) (21.2 g, 56.2 mmoles) d i s s o l v e d i n 1100 ml of dry tetrahydrofuran was added 214 ml of 2.1 M e t h e r e a l m e t h y l l i t h i u m over a p e r i o d of 30 min. - 152 -The r e a c t i o n was allowed to warm to room temperature and was s t i r r e d under an atmosphere of dry n i t r o g e n f o r an a d d i t i o n a l 3 h. The s o l u t i o n was then cooled to 0°, and the excess m e t h y l l i t h i u m was destroyed by the c a r e f u l a d d i t i o n of water. The r e a c t i o n mixture was concentrated, then the residue was d i l u t e d w i t h water and thoroughly e x t r a c t e d w i t h ether. The combined e t h e r a l e x t r a c t s were washed w i t h b r i n e and d r i e d over anhydrous magnesium s u l f a t e . Removal of the solvent followed by d i s t i l l a t i o n of the r e s i d u a l o i l under reduced pressure afforded 9.57 g (88%) of the de s i r e d o l e f i n i c a l c o h o l (171) as a c o l o u r l e s s o i l , b.p. 80° at 0.25 mm; n^ 5 1.4898; [ct]^ 5 -61° (c, 0.7 i n CHC13) ; i n f r a r e d ( f i l m ) , A 2.94, 3.28, 6.17, 6.90, 9.18, 9.38, 12.43 u; n.m.r., T 4.60 (broad max ' ' s i n g l e t , IH, v i n y l p r o t o n ) , 5.57 ( s i n g l e t , IH, hydroxyl p r o t o n ) , 6.36 (doublet, IH, C gH, J = 5.5 Hz), 7.34 ( m u l t i p l e t , IH, a l l y l i c p r o t o n ) , 8.38 ( p a i r of doublets, 3H, v i n y l methyl, J = 1.6 Hz, J = Lrti—„rt L._ri—C,, ~ n 6 13 5 13 1.0 Hz), 9.10 ( s i n g l e t , 3H, t e r t i a r y methyl), 9.03, 9.13 (doublets, 6H, i s o p r o p y l methyls, J = 6.5 Hz). Anal. Calcd. f o r C 1 3 H 2 2 0 : C> 8 0 - 3 5 ; H> H-41. Found: C, 80.16; H, 11.27. Pr e p a r a t i o n of the (-)-Keto O l e f i n (125) (a) from lith i u m - e t h y l a m i n e reduction of the (-)-keto enol phosphate (164) A s o l u t i o n of 1.38 g (200 mmoles) of l i t h i u m metal i n approximately 70 ml of dry ethylamine was s t i r r e d a t room temperature f o r 20 min. To t h i s s o l u t i o n was added dropwise over a p e r i o d of 10 min a s o l u t i o n of the (-)-keto enol phosphate (164) (3.43 g, 10.0 mmoles), and t - b u t y l - 153 -a l c o h o l (1.48 g, 20.0 mmoles) i n 10 ml of dry ether and then the r e a c t i o n was allowed to proceed f o r an a d d i t i o n a l 5 min. The s o l u t i o n was f i l t e r e d through a small glass wool plug to remove the excess l i t h i u m , and the f i l t r a t e was added to a r a p i d l y s t i r r e d ether-water mixture. The s o l u t i o n was e x t r a c t e d twice w i t h e t h e r , then the combined e t h e r e a l e x t r a c t s were washed w i t h water and b r i n e , and d r i e d over anhydrous magnesium s u l f a t e . The ether was removed at a s p i r a t o r pressure and the crude product was d i s t i l l e d under reduced pressure (b.p. 65-75° at 0.5 mm) to a f f o r d 900 mg of a yellow o i l . G a s - l i q u i d chromatographic a n a l y s i s (column B, 170°, 95) of the d i s t i l l e d product i n d i c a t e d that i t c o n s i s t e d of a mixture of approximately 50% of the keto o l e f i n (125), 20% of the corresponding a l c o h o l i c o l e f i n (165) , 10% of the saturated ketone (166) and s e v e r a l minor, u n i d e n t i f i e d components. 99 Standard chromic a c i d s o l u t i o n was added to a s o l u t i o n of the d i s t i l l e d r e duction product (900 mg) i n acetone (25 ml) at 0° u n t i l the orange colour p e r s i s t e d . I s o p r o p y l a l c o h o l was added to destroy the excess o x i d i z i n g reagent, and the s o l u t i o n was evaporated under reduced pressure. The r e s i d u a l m a t e r i a l was d i l u t e d w i t h water and thoroughly e x t r a c t e d w i t h ether. The combined e t h e r e a l e x t r a c t s were d r i e d over anhydrous magnesium s u l f a t e and the ether was removed at a s p i r a t o r pressure. P u r i f i c a t i o n of the keto o l e f i n was achieved by pr e p a r a t i v e g . l . c . (column C, 230°, 200). The (-)-keto o l e f i n (125) 23 thus obtained (500 mg, 26%) was a c o l o u r l e s s o i l and e x h i b i t e d n D 1.4789; [a]!! 3 -29° (c, 1.3 i n CHC1 ) ; i n f r a r e d ( f i l m ) , X 3.29, 5.71, JJ O IT13.X 6.13, 9.44, 12.22 p ; n.m.r., T 4.13 (unresolved m u l t i p l e t , IH, v i n y l p r o t o n ) , 7.17 (unresolved m u l t i p l e t , IH, a l l y l i c p r o t o n ) , 8.25 ( p a i r - 154 -of doublets, 3H, v i n y l methyl, J C 6H-C 1 3H = 1.6 Hz, J = 1.0 Hz), 9.00 ( s i n g l e t , 3H, t e r t i a r y methyl), 9.00, 9.09 (doublets, 6H, i s o p r o p y l methyls, J = 6.0 Hz). Anal. Calcd. f o r C^H^O: C, 81.20; H, 10.48. Found: C, 81.30; H, 10.59. (b) from the Bamf ord-Stevens r e a c t i o n of the p_-tosylhydrazone (167) A mixture of the (-)-diketone (122) (11.6 g, 56.0 mmoles), p_-toluenesulfonylhydrazide (13.0 g, 70.0 mmoles) and 10 ml of methanol was heated and s t i r r e d under an atmosphere of dry n i t r o g e n u n t i l a homogeneous s o l u t i o n was obtained. Then 100 u£ a c e t y l c h l o r i d e was added to the s o l u t i o n and the r e a c t i o n mixture was s t i r r e d at room temperature f o r 3 h. The methanol was removed under reduced pressure, and the residue was d i l u t e d w i t h water and thoroughly e x t r a c t e d w i t h ether. The e t h e r e a l e x t r a c t s were washed w i t h a 10% s o l u t i o n of sodium bicarbonate and b r i n e , and d r i e d over anhydrous magnesium s u l f a t e . Removal of the solvent under reduced pressure y i e l d e d 21.1 g (100%) of the p_-tosylhydrazone (167). In general, t h i s m a t e r i a l was used f o r the next r e a c t i o n without f u r t h e r p u r i f i c a t i o n . However an a n a l y t i c a l sample was obtained by r e c r y s t a l l i z a t i o n of compound (167) and e x h i b i t e d m.p. 77-80°; i n f r a r e d (CHC1J, X 2.84, 3.12, 5.73, 6.05, 3 max 6.25, 8.59 u; n.m.r., x 2.18, 2.72 (doublets, 4H, aromatic protons, J = 9.0Hz), 7.50 ( s i n g l e t , 3H, aromatic methyl), 8.82 (doublet, 3H, secondary methyl, J = 7.0 Hz), 9.05 ( s i n g l e t , 3H, t e r t i a r y methyl), 9.02, 9.19 (doublets, 6H, i s o p r o p y l methyls, J = 6.0 Hz). To a s o l u t i o n of the p-tosylhydrazone (167) (21.1 g, 56.0 mmoles) - 155 -d i s s o l v e d i n 150 ml of dry t e t r a h y d r o f u r a n was added a s o l u t i o n of 10.7 g (58.7 mmoles) of sodium b i s ( t r i m e t h y l s i l y l ) a m i d e and 2.2 ml of high b o i l i n g n u j o l (> 210° at 0.2 mm) d i s s o l v e d i n 50 ml of dry t e t r a -hydrof uran, and the r e a c t i o n was s t i r r e d under an atmosphere of dry n i t r o g e n f o r 1 h. The r e a c t i o n mixture was then concentrated under reduced pressure. The remaining mixture of n u j o l and the sodium s a l t of the p_-tosylhydrazone was heated slowly to 125° under reduced pressure (water a s p i r a t o r , 10-20 mm) at which temperature decomposition of the s a l t was observed to take place. At t h i s temperature, d i r e c t d i s t i l l a t i o n of the product was accomplished by a p p l i c a t i o n of a vacuum pump (0.3 mm) to the r e a c t i o n system. The product thus obtained was r e d i s t i l l e d (75-80° at 0.5 mm) and those d i s t i l l a t i o n f r a c t i o n s c o n taining s i g n i f i c a n t amounts of keto o l e f i n ( g a s - l i q u i d chromatographic a n a l y s i s , column B, 170°, 95) were chromatographed on s i l i c a g e l . E l u t i o n w i t h 10:1 petroleum ether (b.p. 30-60°)-ether affo r d e d f r a c t i o n s c o n t a i n i n g s i g n i f i c a n t amounts of keto o l e f i n ( g a s - l i q u i d chromatographic a n a l y s i s , column B, 170°, 95). These f r a c t i o n s were then subjected to p r e p a r a t i v e g . l . c . (column C, 230°, 150) and (4.0 g, 38%) of the pure (-)-keto o l e f i n (125) was obtained i n t h i s manner. This m a t e r i a l was i d e n t i c a l ( g . l . c . r e t e n t i o n time, i n f r a r e d and n.m.r. spectra) w i t h the keto o l e f i n prepared p r e v i o u s l y . (c) from Jones o x i d a t i o n of ( - ) - o l e f i n i c a l c o h o l (171) 99 Standard chromic a c i d s o l u t i o n was added to a s o l u t i o n of the ( - ) - o l e f i n i c a l c o h o l (171) (1.94 g, 10 mmoles) i n acetone (50 ml) at 0°, u n t i l the orange colour p e r s i s t e d . I s o p r o p y l a l c o h o l was added - 156 -to destroy the excess o x i d i z i n g agent, and the s o l u t i o n was evaporated under reduced pressure. The r e s i d u a l m a t e r i a l was d i l u t e d w i t h water and thoroughly e x t r a c t e d w i t h ether. The combined e t h e r e a l e x t r a c t s were washed w i t h b r i n e and d r i e d over anhydrous magnesium s u l f a t e . Removal of the s o l v e n t , followed by d i s t i l l a t i o n of the r e s i d u a l o i l under reduced pressure (b.p. 70° at 0.5 mm) a f f o r d e d 1.71 g (89%) of the (-)-keto o l e f i n (125). This m a t e r i a l was i d e n t i c a l ( g . l . c . r e t e n t i o n time, i n f r a r e d and n.m.r. spectra) w i t h the (-)-keto o l e f i n (125) prepared p r e v i o u s l y . P r e p a r a t i o n of the O l e f i n i c Enol Ethers (172) A s t i r r e d suspension of sodium hydride (200 mg, 8.35 mmoles) i n dry dimethyl s u l f o x i d e (9 ml) was slowly heated, under an atmosphere of dry n i t r o g e n , to 75° and kept at t h i s temperature u n t i l f r o t h i n g had ceased (approximately 30 min). The s o l u t i o n was cooled to room temperature and a s o l u t i o n of methoxymethyltriphenylphosphonium c h l o r i d e (3.07 g, 10 mmoles) i n 12 ml of dry dimethyl s u l f o x i d e was added. The r e s u l t i n g s o l u t i o n was s t i r r e d f o r 10 min, and then a s o l u t i o n of the (-)-keto o l e f i n (125) (320 mg, 1.67 mmoles) i n 9 ml of dimethyl s u l f o x i d e was added. The r e a c t i o n mixture was heated at 40-50° f o r 1.5 h, then cooled, d i l u t e d w i t h water and thoroughly e x t r a c t e d w i t h petroleum ether (b.p. 30-60°). The combined e x t r a c t s were washed twice w i t h water, once w i t h saturated b r i n e and then d r i e d over anhydrous magnesium s u l f a t e . Removal of the s o l v e n t , followed by c a r e f u l hot box d i s t i l l a t i o n of the r e s i d u a l o i l under reduced pressure y i e l d e d 262 mg (71%) of the o l e f i n i c enol ethers (172) as a c o l o u r l e s s - 157 -21 o i l , b.p. 76° at 0.5 mm; n^ 1.4927; u l t r a v i o l e t , X 208 mu (e = D max 8,030); i n f r a r e d ( f i l m ) , A 3.30, 5.88, 6.90, 8.09, 8.23, 8.99 u; nicix n.m.r., x 4.43 ( s i n g l e t , 2H, v i n y l p r o t o n s ) , 6.51, 6.54 ( s i n g l e t s , 3H, -0CH3) , 7.23 (broad s i n g l e t , IR, c y i ) . A n a l . Calcd. f o r C 1 c H o / 0 : C, 81.76; H, 10.98. Found: C, 82.00; 15 24 H, 11.11. Mol. Wt. Calcd. f o r C^H^O: 220.183. Found (high r e s o l u t i o n mass spectrometry): 220.183. Pr e p a r a t i o n of the ( - ) - O l e f i n i c Aldehyde (174) To a s o l u t i o n of 10 ml of 35% p e r c h l o r i c a c i d d i s s o l v e d i n 45 ml of ether was added 250 mg of the o l e f i n i c enol ethers (172) i n 5 ml of ether. The r e a c t i o n mixture was s t i r r e d f o r 1 h at room temperature, and then n e u t r a l i z e d by the slow a d d i t i o n of s o l i d sodium carbonate to the s t i r r e d s o l u t i o n . The e t h e r e a l l a y e r was then concentrated, and the residue was d i s s o l v e d i n 5 ml of methanol and added to a s t i r r e d s o l u t i o n of 0.5 g potassium carbonate d i s s o l v e d i n 2.5 ml water and 25 ml of methanol. The r e s u l t i n g s o l u t i o n was s t i r r e d f o r 2 h and then concentrated. The residue was d i l u t e d w i t h water, then thoroughly e x t r a c t e d w i t h ether. The combined e t h e r e a l e x t r a c t s were washed w i t h b r i n e , and d r i e d over anhydrous magnesium s u l f a t e . Removal of the s o l v e n t , followed by d i s t i l l a t i o n of the r e s i d u a l o i l under reduced pressure y i e l d e d 202 mg (86%) of the ( - ) - o l e f i n i c aldehyde (174) as a 21 22 co l o u r l e s s o i l , b.p. 105° at .3 mm (bath temperature); n^ 1.4931; -20° (c, 1.7 i n CHC1 ); i n f r a r e d ( f i l m ) , X 3.30, 3.67, 5.83, 6.08, o nicix 6.90, 7.24, 12.38; n.m.r., x 0.40 (doublet, IH, aldehydic proton, - 158 -J = 4.2 Hz), 4.56 (broad s i n g l e t , IH, v i n y l proton, width at h a l f - h e i g h t = 6.0 Hz), 7.53 (unresolved m u l t i p l e t , IH, a l l y l i c p r o t o n ) , 7.80 (doublet, IH, C gH, J = 4.2 Hz), 8.38 ( p a i r of doublets, 3H, v i n y l methyl, JC H-C H = 1 , 6 H z ' JC H-C H = 1 , 0 H z ) ' 8 , 9 7 ( s i nS l e t» 3 H> t e r t i a r y 6 14 5 14 methyl), 9.08, 9.16 (doublets, 6H, i s o p r o p y l methyls, J = 6.2 Hz). Mol. Wt. Calcd. f o r C^^^O: 206.167. Found (high r e s o l u t i o n mass spectrometry): 206.166. P r e p a r a t i o n of the (+)-Diene (175) A s t i r r e d suspension of sodium hydride (540 mg, 22.5 mmoles) i n dry dimethyl s u l f o x i d e (27 ml) was heated s l o w l y , under an atmosphere of dry n i t r o g e n , to 75° and kept at t h i s temperature u n t i l the f r o t h i n g had ceased (approximately 45 min). The s o l u t i o n was cooled to room temperature and a s o l u t i o n of methyltriphenylphosphonium bromide (9.65 g, 27.0 mmoles) i n 36 ml of dimethyl s u l f o x i d e was added. The s o l u t i o n was s t i r r e d f o r 10 min and then a s o l u t i o n of the ( - ) - o l e f i n i c aldehyde (174) (900 mg, 4.5 mmoles) i n 27 ml of dimethyl s u l f o x i d e was added. The r e a c t i o n mixture was heated at 40-50° f o r 1 h, then cooled, d i l u t e d w i t h water and thoroughly e x t r a c t e d w i t h petroleum ether (b.p. 30-60°). The combined petroleum ether e x t r a c t s were washed twice w i t h water, once w i t h saturated b r i n e and then d r i e d over anhydrous magnesium s u l f a t e . Removal of the s o l v e n t , followed by d i s t i l l a t i o n of the r e s i d u a l o i l under reduced pressure afforded 740 mg (83%) of the d e s i r e d diene (175), b.p. 90° at 0.30 mm (bath temperature); n j 6 1.4820; [ a ] 2 1 +4.3° (c, 1.5 i n CHC1J; i n f r a r e d ( f i l m ) , X 3.30, D D 3 max ' - 159 -6.10, 6.90, 10.03, 11.04, 11.87, 12.41 u; n.m.r., x 4.22 (doublet of a doublet of a doublet, IH, C gH, J c R _ c R = 9.0 Hz, J c R _ c R 8 9 9 10 trans 17.5 Hz, Jn „ _ „ = 10.0 Hz), 4.67 (broad s i n g l e t j IH, C,H, width 9 10 C I S at h a l f - h e i g h t = 4.0 Hz), 5.07 ( p a i r of doublets, IH, C 1 QH rans J = 2.5 Hz, J =17.5 Hz), 5.16 ( p a i r of doublets, 10 10 9 10 trans 1 H> C 1 0 H c i s > JC i nH-C i nH = 2 ' 5 H Z ' JC QH-C i nH . = 1 0 ' ° H z ) - 7 ^ ( s o l v e d 10 10 9 10 c i s m u l t i p l e t , IH, C_H), 7.83 (doublet, IH, C.H, J = 9.0 Hz), 8.42 D O ( p a i r of doublets, 3H, v i n y l methyl, J c H _ c R = 1.6 Hz, J R _ c R= 6 15 5 15 1.0 Hz), 9.07, 9.15 (doublets, 6H, i s o p r o p y l methyls, J = 6.5 Hz), 9.16 ( s i n g l e t , 3H, t e r t i a r y methyl). Anal. Calcd. f o r C. cH n /: C, 88.16; H, 11.84. Found: C, 88.08; 15 24 H, 12.00. Mol. Wt. Calcd. f o r C^H^^: 204.188. Found (high r e s o l u t i o n mass spectrometry): 204.188. Prep a r a t i o n of the ( + ) - O l e f i n i c A l c o h o l (178) To a s o l u t i o n of 630 mg (9.0 mmoles) of 2-methyl-2-butene i n 6 ml of dry tetrahydrofuran at 0° and under an atmosphere of dry n i t r o g e n was added 1.37 ml of 3.4 M borane i n tetrahydrofuran. A f t e r t h i s s o l u t i o n had been s t i r r e d f o r 30 min at 0°, a s o l u t i o n of 306 mg (1.5 mmoles) of the (+)-diene (175) i n 6 ml of tet r a h y d r o f u r a n was added, and the r e a c t i o n mixture was then s t i r r e d at room temperature f o r 1.5 h. The r e a c t i o n mixture was again cooled to i c e temperature, and 2 ml of 3 N NaOH was added s l o w l y , followed by a d d i t i o n of 2 ml of 30% hydrogen peroxide. The r e a c t i o n mixture was warmed to room - 160 -temperature and s t i r r e d f o r 1 h, then concentrated. The r e s u l t i n g m a t e r i a l was d i l u t e d w i t h water then thoroughly e x t r a c t e d w i t h ether. Then combined ether e x t r a c t s were washed w i t h a saturated b r i n e s o l u t i o n , and d r i e d over anhydrous magnesium s u l f a t e . Removal of the s o l v e n t , followed by d i s t i l l a t i o n of the r e s i d u a l m a t e r i a l under reduced pressure [b.p. 120° at 0.2 mm (bath temperature)] afforded 300 mg (91%) of the d e s i r e d o l e f i n i c a l c o h o l (178) as a c o l o u r l e s s o i l . An a n a l y t i c a l sample was obtained by pr e p a r a t i v e g . l . c . (column B, 210°, 100) and e x h i b i t e d n j 4 1.4936; [ a ] 2 0 +8.5° ( c , 5.6 i n CHC1 3) ; i n f r a r e d ( f i l m ) , A 3.05, 3.31, 6.09, 6.90, 7.26, 9.50 y; n.m.r., max f 4.68 (broad s i n g l e t , IH, v i n y l proton, width at h a l f - h e i g h t = 4.2 Hz), 6.38 ( m u l t i p l e t , 2H, protons adjacent to the h y d r o x y l ) , 7.63 (unresolved m u l t i p l e t , IH, a l l y l i c p r oton), 8.44 ( p a i r of doublets, 3H, v i n y l methyl, Jn „ _ =1.6 Hz, Jn « _ „ = 1.0 Hz), 9.08, 9.14 (doublets, 6H, i s o p r o p y l methyls, J = 6.0 Hz), 9.10 ( s i n g l e t , 3H, t e r t i a r y methyl). Anal. Calcd. f o r C^H^O: C, 81.02; H, 11.79. Found: C, 80.78; H, 11.78. Mol. Wt. Calcd. f o r C^H^O: 222.198. Found (high r e s o l u t i o n mass spectrometry): 222.198. Pr e p a r a t i o n of the (+) - C y c l i c Ether (179) A s o l u t i o n of the ( + ) - o l e f i n i c a l c o h o l (178) (50 mg) and p_-toluene-s u l f o n i c a c i d (10 mg) i n 25 ml of dry benzene was s t i r r e d under n i t r o g e n f o r 5 h. The s o l u t i o n was then washed w i t h saturated aqueous sodium bicarbonate and b r i n e , and d r i e d over anhydrous magnesium s u l f a t e . The organic l a y e r was concentrated and d i s t i l l e d under reduced pressure. G a s - l i q u i d chromatographic a n a l y s i s (column D, 210°, 95) of the - 161 -r e s u l t a n t o i l i n d i c a t e d that the major product was the ( + ) - c y c l i c ether (179) accompanied by a small amount (^  5%) of s t a r t i n g m a t e r i a l (178) and s e v e r a l u n i d e n t i f i e d components. An a n a l y t i c a l sample of compound 179 was obtained by p r e p a r a t i v e g . l . c . (column D, 210°, 95) and e x h i b i t e d n D 1.4908; [a]* +13.5° (c, 1.1 i n CHC1 3); i n f r a r e d ( f i l m ) , X 6.89, 9.22, 9.42 u; n.m.r, x 6.30 ( m u l t i p l e t , 2H, protons in 3.x adjacent to the oxygen), 8.94, 9.11 ( s i n g l e t s , 6H, t e r t i a r y m e t h yls), 9.14, 9.16 (doublets, 6H, i s o p r o p y l methyls, J = 6.0 Hz). Mol. Wt. Calcd. f o r C^H^O: 222.198. Found (high r e s o l u t i o n mass spectrometry): 222.198. P r e p a r a t i o n of (+)-Cyclosativene (27) , (+)-Sativene (26) , and ( ^ - I s o -sativene (77) (a) from the a c e t i c a c i d - c u p r i c acetate rearrangement of (-)-copacamphene (23) A s o l u t i o n of 102 mg (0.50 mmole) of (-)-copacamphene and 25 mg (.125 mmole) of c u p r i c acetate i n 5 ml of g l a c i a l a c e t i c a c i d was r e f l u x e d f o r 4 days. The s o l u t i o n was cooled and d i l u t e d w i t h water, then thoroughly e x t r a c t e d w i t h petroleum ether (b.p. 30-60°). The combined petroleum ether e x t r a c t s were washed w i t h water, 10% sodium bicarbonate s o l u t i o n , and d r i e d over anhydrous magnesium s u l f a t e . The m a t e r i a l obtained a f t e r removal of the sol v e n t was chromatographed on 5 g of 10% s i l v e r n i t r a t e impregnated s i l i c a g e l . E l u t i o n w i t h 10 ml of pentane produced 25 mg of (+)-cyclosativene (27), 25 b.p. 80° at .25 mm (bath temperature); [ a ] D +63° (c, 1.1 i n CHC1 3), - 162 -l i t . 1 8 [a]^° +67.8°(c, 1.15 i n CHC1 ) ; i n f r a r e d ( f i l m ) , A 3.28, 6.88, JJ j TU3.X 7.21, 7.29, 11.62, 11.87, 12.05, 12.19 y; n.m.r., x 9.02, 9.24 ( s i n g l e t s , 6H, t e r t i a r y m e t h y l s ) , 9.09, 9.13 ( d o u b l e t s , 6H, J = 6.0 H z ) , 9.22 ( s i n g l e t , I H , c y c l o p r o p y l p r o t o n ) , 9 . 3 3 ( d o u b l e t , I H , c y c l o p r o p y l p r o t o n , J = 5.5 H z ) . M o l . Wt. C a l c d . f o r C H ^ : 204.188. Found ( h i g h r e s o l u t i o n mass s p e c t r o m e t r y ) : 204.188. F u r t h e r e l u t i o n o f t h e column w i t h e t h e r a f f o r d e d a m i x t u r e o f ( + ) - s a t i v e n e and ( - ) - i s o s a t i v e n e . These compounds were s e p a r a t e d by p r e p a r a t i v e g . l . c . (column E, 145°, 1 20). The m i n o r component, (+)-s a t i v e n e (26) (4 mg, 4 % ) , e x h i b i t e d [ a ] 2 4 +174° ( c , 0.3 i n CHC1 3); l i t . 2 2 [a] + 191°; i n f r a r e d ( f i l m ) , A 3.26, 6.04, 7.22, 7.30, JJ TTlciX 11.45 y; n.m.r., x 5.26, 5.58 ( s i n g l e t s , 2H, v i n y l p r o t o n s ) , 7.39 (broad s i g n a l , I H , a l l y l i c p r o t o n ) , 8.96 ( s i n g l e t , 3H, t e r t i a r y m e t h y l ) , 9.10, 9.13 ( d o u b l e t s , 6H, i s o p r o p y l m e t h y l s , J = 6.0 H z ) . M o l . Wt. C a l c d . f o r C-^H^: 204.188. Found ( h i g h r e s o l u t i o n mass s p e c t r o m e t r y ) : 204.188. The major component i s o l a t e d by p r e p a r a t i v e g . l . c . was ( - ) - i s o -24 s a t i v e n e (77) (45 mg, 44%) and e x h i b i t e d [ a ] D -23° ( c , 0.9 i n CHC1 3); i n f r a r e d ( f i l m ) , A 3.27, 6.06, 6.85, 7.23, 7.42, 11.42 y; n.m.r., max ' ' ' x 5.23, 5.52 ( s i n g l e t s , 2H, v i n y l p r o t o n s ) , 7.39 ( b r o a d s i g n a l , I H , a l l y l i c p r o t o n ) , 9.03 ( s i n g l e t , 3H, t e r t i a r y m e t h y l ) , 9.12 ( d o u b l e t , 6H, i s o p r o p y l m e t h y l s , J = 6.0 H z ) . M o l . Wt. C a l c d . f o r C ^ H ^ : 204.188. Found ( h i g h r e s o l u t i o n mass s p e c t r o m e t r y ) : 204.187. - 163 -(b) from the p_-toluenesulf onic a c i d rearrangement of (^-copa-camphene (23). To 20 ml of a 10 mM s o l u t i o n of p_-toluenesulfonic a c i d i n dry benzene was added a s o l u t i o n of 100 mg of (-)-copacamphene i n 1 ml of dry benzene. The r e a c t i o n mixture was s t i r r e d under an atmosphere of dry n i t r o g e n at room temperature f o r 1 h, then washed w i t h a 10% sodium bicarbonate s o l u t i o n , and b r i n e . The organic l a y e r was d r i e d over anhydrous magnesium s u l f a t e , and then concentrated, to a f f o r d 85 mg of a c o l o u r l e s s o i l . G a s - l i q u i d chromatographic a n a l y s i s (column F, 135°, 90) i n d i c a t e d that t h i s o i l c o n s i s t e d of approximately 32% (+)-cyclosativene (27) , 7% (+)-sativene (26) and 61% (-)-isosativene (77). These three products 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 E, 145°, 120) and i n each case, the s t r u c t u r e was confirmed by d i r e c t comparison ( g . l . c . r e t e n t i o n time, i n f r a r e d and n.m.r. spectra) w i t h an authentic sample. Pr e p a r a t i o n of the ( - ) - O l e f i n i c A c i d (186) A s o l u t i o n of 206 mg (10.0 mmoles) of the ( - ) - o l e f i n i c aldehyde (174) i n 1.5 ml of p y r i d i n e was added to the S a r e t t reagent prepared from 1.2 g of chromium t r i o x i d e and 12 ml of p y r i d i n e ; then 5 drops of water was added, and the dark mixture was s t i r r e d f o r 18 h at room 105 temperature. The r e a c t i o n mixture was then d i l u t e d w i t h water, and e x t r a c t e d w i t h ether. The combined e t h e r e a l e x t r a c t s were washed f i r s t w i t h water and then w i t h a d i l u t e h y d r o c h l o r i c a c i d s o l u t i o n . The organic l a y e r was e x t r a c t e d w i t h 10% aqueous sodium hydroxide. The - 164 -a l k a l i n e e x t r a c t s were cooled, a c i d i f i e d w i t h 6 N h y d r o c h l o r i c a c i d and thoroughly e x t r a c t e d w i t h ether. The combined e t h e r e a l e x t r a c t s were washed w i t h water, and d r i e d over anhydrous magnesium s u l f a t e . Removal of the solvent a f f o r d e d 174 mg (82%) of the c r y s t a l l i n e ( - ) - o l e f i n i c a c i d (186), m.p. 138-139.5°; [ a ] 2 6 -16.7° (c, 1.2 i n CHC1 3); i n f r a r e d (CHC1_), X 5.87 y; n.m.r., T 0.18 (very broad s i g n a l , IH, a c i d p r o t o n ) , 4.55 (broad s i n g l e t , IH, v i n y l proton, width at h a l f - h e i g h t = 6.0 Hz), 7.19 (unresolved m u l t i p l e t , IH, a l l y l i c p r o t o n ) , 7.50 ( s i n g l e t , IH, C QH), 8.40 ( p a i r of doublets, 3H, v i n y l methyl, J _ „ „ = 1.6 Hz, o CH— C _ , ri 6 14 JC H-C H = 1 , 0 H z ^ ' 8 ' 8 9 ( s i nS l e t> 3 H> t e r t i a r y methyl), 9.07, 9.11 5 14 (doublets, 6H, i s o p r o p y l methyls, J = 6.0 Hz). Anal. Calcd. f o r C 1 4 H 2 2 0 2 : C ' 7 5 - 6 3 ? H> 9 - 9 7 - F° und: C, 75.33; H, 9.98. P r e p a r a t i o n of (-)-Keto O l e f i n (190) The ( - ) - o l e f i n i c c a r b o x y l i c a c i d (186) (111 mg, 0.5 mmole) was d i s s o l v e d i n aqueous sodium hydroxide (.55 mmole), the water was evaporated under reduced pressure, and the residue was d r i e d i n a vacuum oven at 70°. A s t i r r e d suspension of the r e s u l t i n g dry sodium s a l t i n 10 ml of anhydrous ether containing 20 y £ of dry p y r i d i n e was cooled to 0° and 640 mg (5.0 mmoles) of o x a l y l c h l o r i d e was added. The r e a c t i o n mixture was s t i r r e d at 0° f o r 15 min under an atmosphere of dry n i t r o g e n , then f i l t e r e d , and concentrated under reduced pressure (vacuum pump). The s o l u t i o n was kept at 0° during t h i s process. The crude a c i d c h l o r i d e (189) [ i n f r a r e d ( f i l m ) , X 5.52 y ] thus obtained max was d i s s o l v e d i n 15 ml of anhydrous ether and the r e s u l t i n g s o l u t i o n - 165 -was added to excess a l c o h o l - f r e e e t h e r e a l diazomethane which had been d r i e d over potassium hydroxide. This r e a c t i o n mixture was s t i r r e d at 0° f o r 2.5 h, then the excess diazomethane and solvent was removed under reduced pressure. The r e s u l t i n g crude r e a c t i o n mixture [ i n f r a r e d ( f i l m ) , ^max 5*73 u (strong), 4.70, 6.04 u (weak)] was d i s s o l v e d i n 15 ml of dry cyclohexane, and c u p r i c s u l f a t e (400 mg) was added. The r e s u l t i n g suspension was r e f l u x e d , w i t h s t i r r i n g , f o r 3 h. The cooled r e a c t i o n mixture was f i l t e r e d , and the f i l t r a t e was washed w i t h s a t u r a t e d aqueous sodium bicarbonate, water, and b r i n e , and then d r i e d over anhydrous magnesium s u l f a t e . Removal of the s o l v e n t , followed by d i s t i l l a t i o n of the r e s i d u a l m a t e r i a l under reduced pressure, y i e l d e d 66 mg (60%) of a c o l o u r l e s s o i l , b.p. 115° at 0.25 mm (bath temperature). This m a t e r i a l was shown by g a s - l i q u i d chromatographic a n a l y s i s (column D, 200°, 95) to c o n s i s t mainly ( ' v 80%) of the keto o l e f i n (190). In a d d i t i o n , the t e t r a c y c l i c ketone (188) (^  5%) and a number of minor u n i d e n t i f i e d compounds were a l s o present. Compounds 188 and 190 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°, 200). The t e t r a c y c l i c ketone 188, thus obtained,exhibited i n f r a r e d ( f i l m ) , A max 3.27, 5.73, 11.42, 12.03 u; n.m.r., x 8.82, 9.08 ( s i n g l e t s , 6H, t e r t i a r y methyls), 9.12, 9.15 (doublets, 6H, i s o p r o p y l methyls, J = 6.0 Hz). 24 The (-)-keto o l e f i n (190) thus obtained, e x h i b i t e d n D 1.5036; [ a ] 2 6 -100° (c, 1.0 i n CHC1 ); i n f r a r e d ( f i l m ) , A 3.26, 5.73, 6.01, 6.84, 8.55, 11.38 u; n.m.r., x 5.03, 5.27 ( s i n g l e t s , 2H, v i n y l p r o t o n s ) , 7.13 (unresolved m u l t i p l e t , IH, a l l y l i c p r o t o n ) , 8.99 ( s i n g l e t , 3H, t e r t i a r y methyl), 9.12 (doublet, 6H, i s o p r o p y l methyls, J = 6.0 Hz). - 166 -Mol. Wt. Calcd. f o r C 1 5 H 2 2 0 : 218.167. Found (high r e s o l u t i o n mass spectrometry): 218.165. The attempted diazoketone formation r e a c t i o n was repeated employing a r e a c t i o n procedure i d e n t i c a l w i t h t h a t j u s t described. The crude product obtained by r e a c t i o n of the a c i d c h l o r i d e (189) w i t h diazomethane [ i n f r a r e d ( f i l m ) , X 5.73 u ( s t r o n g ) , A.70, 6.04 u max (weak)] was d i s s o l v e d i n approximately 1 ml of dry benzene, and added to 25 ml of a 5.0 mM s o l u t i o n of p_-toluenesulfonic a c i d i n benzene. The r e a c t i o n mixture was s t i r r e d f o r 30 min at room temperature under an atmosphere of dry n i t r o g e n . The s o l u t i o n was then washed w i t h saturated aqueous sodium bicarbonate, water and b r i n e , and then d r i e d over anhydrous magnesium s u l f a t e . Removal of the s o l v e n t , followed by d i s t i l l a t i o n of the reduced m a t e r i a l under reduced pressure y i e l d e d 65 mg (60%) of a c o l o u r l e s s o i l . The major product (^  80%) was the (-)-keto o l e f i n (190), w i t h no t r a c e of the t e t r a c y c l i c ketone 188 being present as determined by g a s - l i q u i d chromatographic a n a l y s i s (column D, 200°, 95). The (-)-keto o l e f i n (190) was obtained by p r e p a r a t i v e g . l . c . (column G, 240°, 200) and was i d e n t i c a l ( g . l . c . r e t e n t i o n time, i n f r a r e d and n.m.r. spectra) to the m a t e r i a l prepared p r e v i o u s l y . P r e p a r a t i o n of the ( - ) - O l e f i n i c Aldehyde (194) To a s o l u t i o n of 286 mg (3.6 mmoles) of dry p y r i d i n e d i s s o l v e d i n 4.0 ml of dry methylene c h l o r i d e was added 180 mg (1.8 mmoles) of dry chromium t r i o x i d e . The r e a c t i o n was s t i r r e d under an atmosphere of dry n i t r o g e n at room temperature f o r 15 min, during which time the - 167 98 dark red colour of the chromium . t r i o x i d e - p y r i d i n e complex developed. To t h i s mixture was added a s o l u t i o n of 64 mg (.301 mmole) of the ( + ) - o l e f i n i c a l c o h o l (178) d i s s o l v e d i n .5 ml of methylene c h l o r i d e . The r e a c t i o n was allowed to proceed f o r 15 min, then approximately 10 ml of ether was added, and the organic l a y e r was washed w i t h a saturated sodium carbonate s o l u t i o n . A f t e r the organic l a y e r had been washed w i t h water and d r i e d over anhydrous magnesium s u l f a t e , the solvent was removed, and the remaining o i l was d i s t i l l e d under reduced pressure to y i e l d 58 mg (91%) of the d e s i r e d o l e f i n i c aldehyde (194) as a c o l o u r l e s s o i l , b.p. 85° at 0.25 mm (bath temperature); n^ 1.4906; [ a ] D -39° (c, 1.6 i n CHC1 ); i n f r a r e d ( f i l m ) , A 3.29, 3.68, 5.80, 5.96, 6.86, j max 7.22 u; n.m.r., x 0.20 ( t r i p l e t , IH, aldehydic proton, J = 2.5 Hz), 4.60 ( s i n g l e t , IH, v i n y l p r o t o n ) , 8.42 ( p a i r of doublets, 3H, v i n y l methyl, J„ „ _ „ = 1.6 Hz, J _ „ _ = 1.0 Hz), 9.07, 9.13 (doublets, 6 15 5 15 6H, i s o p r o p y l methyls, J = 6.5 Hz), 9.10 ( s i n g l e t , 3H, t e r t i a r y methyl). Anal. Calcd. f o r C^H^O: C, 81.76; H, 10.98. Found: C, 81.45; H, 10.98. Prep a r a t i o n of (-)-Copacamphene (23) (a) from the ( + ) - o l e f i n i c a l c o h o l (178) To a s o l u t i o n of 200 mg (.902 mmole) of the ( + ) - o l e f i n i c a l c o h o l (178) i n 4 ml of dry p y r i d i n e was added a s o l u t i o n of 342 mg (1.80 mmoles) of p_-toluenesulfonyl c h l o r i d e i n 1 ml of dry p y r i d i n e . The r e a c t i o n mixture was s t i r r e d under an atmosphere of dry n i t r o g e n f o r 2.5 h. The s o l u t i o n was then d i l u t e d w i t h hexane and the organic l a y e r was washed f i r s t w i t h a sodium bicarbonate s o l u t i o n , and then - 168 -water and b r i n e , and d r i e d over anhydrous magnesium s u l f a t e . The solvent was removed f i r s t at a s p i r a t o r pressure, and f i n a l l y the l a s t traces of p y r i d i n e were removed by a p p l i c a t i o n of a vacuum pump. The r e s i d u a l o i l was t r a n s f e r r e d to the top of a s i l i c a g e l column (5.0 g) and the column was e l u t e d w i t h approximately 50 ml of pentane. Removal of the solvent from the e l u a n t , f o l l o w e d by reduced pressure d i s t i l l a t i o n of the r e s i d u a l o i l (80° at 0.25 mm, bath temperature) aff o r d e d 164 mg (89%) of a c o l o u r l e s s o i l . G a s - l i q u i d chromatographic a n a l y s i s (column F, 135°, 85) of t h i s m a t e r i a l i n d i c a t e d that i t c o n s i s t e d of a major component (98%) accompanied by two minor components ( i n a r a t i o of approximately 1:1) that comprised 1-2% of the t o t a l mixture. F i n a l p u r i f i c a t i o n was e f f e c t e d by column chromatography on 10% s i l v e r n i t r a t e impregnated s i l i c a g e l . E l u t i o n w i t h 25:1 pentane-ether afforded pure (-)-copacamphene (23) , [ c t ] 2 1 -159° (c, 2.2 i n CHC13) ; i n f r a r e d ( f i l m ) , X 3.26, 6.03, 7.20, 7.30, 11.42 y; n.m.r., T 5.21, max ' ' 5.49 ( s i n g l e t s , 2H, v i n y l p r o t o n s ) , 7.54 (broad s i g n a l , IH, a l l y l i c p r o t o n ) , 9.00 ( s i n g l e t , 3H, t e r t i a r y methyl), 9.10 (doublet, 6H, i s o p r o p y l methyls, J = 6.0 Hz). This m a t e r i a l was found to be i d e n t i c a l ( g . l . c . r e t e n t i o n time, i n f r a r e d ) w i t h authentic (1")-copa-camphene (23) (see the footnote on page 9 7 ) . Mol. Wt. Calcd. f o r C ^ H ^ : 204.188. Found (high r e s o l u t i o n mass spectrometry): 204.188. The minor components were c o l l e c t e d by pr e p a r a t i v e g . l . c . (column E, 145°, 120) and were i d e n t i f i e d as (+)-cyclosativene (27) and ( - ) - i s o -sativene (77) by d i r e c t comparison, i n each case, ( g . l . c . r e t e n t i o n times, i n f r a r e d spectra) w i t h an authe n t i c sample. - 169 -(b) from r e d u c t i o n of the (-)-keto o l e f i n (190) A s o l u t i o n of 50 mg of the (-)-keto o l e f i n (190) i n 2.0 ml of ethylene g l y c o l c o n t a i n i n g 0.1 ml of 85% hydrazine hydrate and 100 mg of potassium hydroxide was r e f l u x e d f o r 2 h. The r e f l u x condensor was removed and replaced by a d i s t i l l a t i o n head and the temperature of the r e a c t i o n mixture was slowly r a i s e d to 200° and maintained at t h i s temperature f o r 3 h. The d i s t i l l a t e was c o l l e c t e d i n a dry i c e -acetone cooled r e c e i v e r and combined w i t h the cooled r e a c t i o n mixture. This s o l u t i o n was d i l u t e d w i t h water and thoroughly e x t r a c t e d w i t h petroleum ether (b.p. 30-60°). The combined petroleum ether e x t r a c t s were washed w i t h water and b r i n e and d r i e d over anhydrous magnesium s u l f a t e . The d r i e d petroleum ether e x t r a c t s were f i l t e r e d through 2 g of s i l i c a g e l , and the column was f u r t h e r e l u t e d w i t h petroleum ether. Removal of the solvent followed by d i s t i l l a t i o n of the r e s i d u a l o i l produced 27 mg (58%) (-)-copacamphene (23). This m a t e r i a l was i d e n t i c a l ( g . l . c . r e t e n t i o n time, s p e c i f i c r o t a t i o n , i n f r a r e d and n.m.r. spectra) w i t h the (-)-copacamphene prepared p r e v i o u s l y . P r e p a r a t i o n of the O l e f i n i c Enol Ethers (196 and 197) The procedure u t i l i z e d was s i m i l a r to that employed f o r the pre p a r a t i o n of the o l e f i n i c enol ethers (172) (see p. 156 ). The crude product was d i s t i l l e d under reduced pressure [100° at 0.25 mm, (bath temperature)] to a f f o r d a c o l o u r l e s s o i l (55% from o l e f i n i c aldehyde 174). G a s - l i q u i d chromatographic a n a l y s i s (column B, 200°, 100) i n d i c a t e d that t h i s m a t e r i a l c o n s i s t e d of a mixture of the c i s - and t r a n s - o l e f i n i c enol ethers, i n a r a t i o of approximately 1:6, r e s p e c t i v e l y . - 170 -An a n a l y t i c a l sample of each of the cis-(196) and trans-(197) products was obtained by preparative g . l . c . (column B, 200°, 100). The c i s -o l e f i n i c enol ether (196) exhibited i n f r a r e d ( f i l m ) , \ 3.28, 5.97, LT13.X 6.88, 8.30, 8.82 y. The t r a n s - o l e f i n i c enol ether (197) exhibited n 2 5 1.4926; [ a ] 2 5 -22° (c, 0.6 i n CHC13) ; i n f r a r e d ( f i l m ) , A m a x 3.27, 6.08, 6.90, 8.29, 8.76 y; n.m.r., T 3.62 (doublet, IH, C^H, J = 15.0 Hz), 4.64 (broad s i n g l e t , IH, C,H) , 5.23 (pair of doublets, IH, o C H, J = 10.0 Hz, J = 15.0 Hz), 6.54 ( s i n g l e t , 3H, 9 CgH-CgH C 9H-C 1 QH -0CH„), 8.38 (pair of doublets, 3H, v i n y l methyl, J„ v n „ = 1.6 Hz, J C n — C . , r i 6 16 J = 1.0 Hz), 9.08, 9.14 (doublets, 6H, isopropyl methyls, L._H— L, rti 5 16 J = 6.0 Hz), 9.16 ( s i n g l e t , 3H, t e r t i a r y methyl). Mol. Wt. Calcd. for C^H^O: 234.198. Found (high r e s o l u t i o n mass spectrometry): 234.198. Preparation of the (-)-Keto O l e f i n (198) (a) from the o l e f i n i c enol ethers.(196 and 197) To a s o l u t i o n of 10 ml of 35% p e r c h l o r i c acid dissolved i n 40 ml of ether was added 200 mg of the mixture of o l e f i n i c enol ethers (196 and 197)in 5 ml of ether. The reaction mixture was s t i r r e d at room temperature f o r 1 h, then n e u t r a l i z e d by the slow addition of sodium carbonate to the s t i r r e d s o l u t i o n . The ethereal layer was separated, then dried over anhydrous magnesium s u l f a t e and concentrated. The r e s i d u a l o i l (^ 90 mg) was i d e n t i f i e d as an epimeric mixture of the o l e f i n i c alcohols (195), i n f r a r e d ( f i l m ) , A 2.96, 3.25, 6.03, TllclX 11.38 y; n.m.r., x 5.05 (broad s i n g l e t , 2H, o l e f i n i c protons, width at half-height = 7.0 Hz), 5.94 (multiplet, IH, proton adjacent to the hydroxyl). - 171 -To a s o l u t i o n of 400 mg (5.05 mmoles) of dry p y r i d i n e d i s s o l v e d i n 5.5 ml of dry methylene c h l o r i d e was added 253 mg (2.53 mmoles) of dry chromium t r i o x i d e . The r e a c t i o n mixture was s t i r r e d at room temperature under an atmosphere of dry n i t r o g e n f o r 15 min. To t h i s mixture was added a s o l u t i o n of 90 mg (.422 mmole) of the crude o l e f i n i c a l c o h o l (195) d i s s o l v e d i n 0.5 ml of methylene c h l o r i d e . The r e a c t i o n was allowed to proceed f o r 15 min, then 15 ml of ether was added to the r e a c t i o n mixture, and the organic l a y e r was washed w i t h a saturated sodium carbonate s o l u t i o n . A f t e r the organic l a y e r had been washed w i t h water, and d r i e d over anhydrous magnesium s u l f a t e , the solvent was removed and the r e s i d u a l m a t e r i a l was d i s t i l l e d under reduced pressure. The d e s i r e d keto o l e f i n (198) was separated from a number of minor components by means of p r e p a r a t i v e g . l . c . (column E, 220°, 120). Compound 198 thus obtained (43 mg, 23% y i e l d from 196 23 and 197) e x h i b i t e d b.p. 110° at 0.2 mm (bath temperature); n D 1.5120; [ a ] 2 2 -183° (c, 1.2 i n CHC1_); i n f r a r e d ( f i l m ) , X 3.25, 5.69, 6.03, v j max 6.82, 8.81, 11.28 y ; n.m.r., T 4.82, 5.18 ( t r i p l e t s , 2H, o l e f i n i c protons, J <= 0.8 Hz), 7.04 (broad s i n g l e t , IH, a l l y l i c proton, width at h a l f - h e i g h t = 4.0 Hz), 8.90 ( s i n g l e t , 3H, t e r t i a r y m e t h y l ), 9.07 (doublet, 6H, i s o p r o p y l methyls, J = 6.3 Hz). Anal. Calcd. f o r C^H 0: C, 82.51; H, 10.16. Found: C, 82.19; H, 10.38. (b) from the ( - ) - o l e f i n i c aldehyde (194) To 20 ml of a 0.05 mM s o l u t i o n of p_-toluenesulfonic a c i d i n dry benzene was added 110 mg (0.5 mmole) of the ( - ) - o l e f i n i c aldehyde (194), - 172 -and the r e a c t i o n mixture was s t i r r e d at room temperature f o r 30 min. The r e a c t i o n was then quenched by adding 1 ml of dry p y r i d i n e , and the solvent was removed under reduced pressure. The r e s i d u a l m a t e r i a l was d i s s o l v e d i n 1 ml of dry methylene c h l o r i d e and the r e s u l t i n g 98 s o l u t i o n was added to a pre-formed s o l u t i o n of C o l l i n reagent [360 mg (3.6 mmoles) of chromium t r i o x i d e , 572 mg (7.2 mmoles) of p y r i d i n e i n 8 ml of methylene c h l o r i d e ] . The r e a c t i o n mixture was s t i r r e d f o r 15 min, then approximately 20 ml of ether was added. The organic l a y e r was then washed w i t h a saturated sodium carbonate s o l u t i o n , water, saturated b r i n e , and then d r i e d over anhydrous magnesium s u l f a t e . The organic l a y e r was then concentrated and the r e s i d u a l m a t e r i a l was d i s t i l l e d under reduced pressure. G a s - l i q u i d chromatographic a n a l y s i s (column B, 200°, 100) of the d i s t i l l a t e i n d i c a t e d that i t c o n s i s t e d of a mixture of the (-)-keto o l e f i n (198) and the ( - ) - o l e f i n i c aldehyde (194) i n a r a t i o of approximately 5:2. Separation of t h i s mixture was e f f e c t e d by p r e p a r a t i v e g . l . c . (column E, 220°, 120) to y i e l d 58 mg 165% based on recovered s t a r t i n g m a t e r i a l (194) , 12 mg.] of the ( - ) - o l e f i n i c ketone (194) . This m a t e r i a l was i d e n t i c a l ( g . l . c . r e t e n t i o n time, i n f r a r e d and n.m.r. spectra) w i t h the (-)-keto o l e f i n (198) prepared as described p r e v i o u s l y . P r e p a r a t i o n of the (-)-Ketone (202) The (-)-keto o l e f i n (198) (58 mg) i n 10 ml of ethanol was hydrogenated over 29 mg of 5% palladium on charcoal at room temperature overnight. Removal of the c a t a l y s t and solvent y i e l d e d 55 mg of the (-)-ketone (202) as a c o l o u r l e s s o i l , b.p. 110° at .2 mm (bath - 173 -temperature), n D 1.4968; [ a ] D -53.5° (c, 0.9 i n CHC1 3); i n f r a r e d ( f i l m ) , X 5.73, 6.81, 8.62 y; n.m.r., x 9.08 ( s i n g l e t , 3H, t e r t i a r y in 3.x methyl), 9.11 (doublet, 6H, i s o p r o p y l methyls, J = 6.3 Hz), 9.19 (doublet, 3H, secondary methyl, J = 7.0 Hz). Anal. Calcd. f o r C 1 c H o / 0 : C, 81.76; H, 10.98. Found: C, 81.47; 15 24 H, 11.07. Pr e p a r a t i o n of the (+)-Pyrazoline (213) In a 5 ml f l a s k equipped w i t h a Dean Stark water separator there was placed 58 mg (0.263 mmoles) of the ( - ) - o l e f i n i c aldehyde (194) and 49 mg (0.263 mmole) of p_-toluenesulfonylhydrazide i n 2.5 ml of dry benzene. The r e a c t i o n mixture was r e f l u x e d i n an atmosphere of dry n i t r o g e n f o r 5 min. The solvent was then removed, and replaced w i t h 2.5 ml of dry tetrahydrofuran. To t h i s s t i r r e d s o l u t i o n was added 0.131 ml of 2 M n - b u t y l l i t h i u m i n hexane. A f t e r 30 min, the solvent was removed, and the r e s i d u a l l i t h i u m s a l t of the p_-tosyl-hydrazone was heated s l o w l y under reduced pressure (.25 mm). Between the temperatures of 120° and 140°, 50 mg of the (+)-pyrazoline (213) 24 (81% y i e l d from the aldehyde) was c o l l e c t e d as a c o l o u r l e s s o i l , n^ 22 I . 5042; [a] +95° (c, 1.0 i n CHCl,); u l t r a v i o l e t , X 334 my (e = JJ Jj TU3.X 232); i n f r a r e d ( f i l m ) , X 6.45, 6.87, 7.26, 8.91 y; n.m.r., x 5.11 max ( m u l t i p l e t , IH, proton adjacent to the -N=N- moiety), 8.42, 9.18 ( s i n g l e t s , 6H, t e r t i a r y methyls), 9.14 (doublet, 6H, i s o p r o p y l methyls, J = 6.0 Hz). The i n s t a b i l i t y of t h i s m a t e r i a l precluded s a t i s f a c t o r y elemental a n a l y s i s . - 174 -Pre p a r a t i o n of (-)-Cyclocopacamphene (24) (a) from r e d u c t i o n of the (-)-keto o l e f i n (198) The Huang-Minion modified Wolff Kishner r e d u c t i o n of the (-)-keto o l e f i n (198) was c a r r i e d out under c o n d i t i o n s very s i m i l a r to those employed f o r the conversion of the (-)-keto o l e f i n (190) to (-)-copacamphene (23) (see p. 169). The crude product obtained from r e a c t i o n of 218 mg of the (-)-keto o l e f i n (198) was 50 mg (25%) of a c o l o u r l e s s o i l , which was composed of two components i n a r a t i o of 4:1, as determined by g a s - l i q u i d chromatographic a n a l y s i s (column F, 140°, 85). This m a t e r i a l was chromatographed on 3.5 g of 10% s i l v e r n i t r a t e impregnated s i l i c a g e l . E l u t i o n w i t h 10 ml of pentane gave 10 mg of pure (-)-cyclocopa-21 camphene, b.p. 80° at 0.25 mm (bath temperature); [ a l ^ -42° (c, 1.1 i n CRC1J; i n f r a r e d ( f i l m ) , X 3.29, 6.85, 7.21, 11.60, 11.80, 12.10 y; 3 max ' n.m.r., x 8.99, 9.26 ( s i n g l e t s , 6H, t e r t i a r y m e t h yls), 9.10, 9.13 (doublets, 6H, i s o p r o p y l methyls, J = 6.5 Hz), 9.32, 9.37 (broad s i g n a l s , 2H, c y c l o p r o p y l protons). The i n f r a r e d and n.m.r. sp e c t r a of t h i s m a t e r i a l were i d e n t i c a l w i t h those of authentic (+)-cyclocopa-camphene (24) (see the footnote on page 121). Anal. Calcd. f o r C ^ H ^ : C, 88.14; H, 11.84. Found: C, 88.35; H, 11.90. E l u t i o n w i t h 10 ml of ether afforded 38 mg of (-)-copacamphene which was i d e n t i c a l w i t h the m a t e r i a l prepared p r e v i o u s l y . - 175 -(b) from the p_-tosylhydrazone (208) of the (-)-ketone (202) To a s o l u t i o n of the (-)-ketone (202) (50 mg,.228 mmole) and p_-toluenesulfonylhydrazide (47 mg, .250 mmole) i n 3 ml of methanol was added 10 pft a c e t y l c h l o r i d e , and the r e a c t i o n mixture was r e f l u x e d f o r 2 h. The methanol was then removed under reduced pressure, and the residue was d i l u t e d w i t h water, and then thoroughly e x t r a c t e d w i t h ether. The e t h e r e a l e x t r a c t s were washed w i t h a 10% s o l u t i o n of sodium bicarbonate, w i t h b r i n e , and then d r i e d over anhydrous magnesium s u l f a t e . Removal of the solvent under reduced pressure y i e l d e d 64 mg C97%) of the p-tosylhydrazone (208), i n f r a r e d (CHC1,), A 2.87, j TTlciX 6.05, 6.25, 8.63 p. This m a t e r i a l was used without f u r t h e r p u r i f i c a t i o n . To a s o l u t i o n of 30 mg (.104 mmole) of the p_-tosylhydrazone (208) i n 2 ml of dry diglyme was added 7 mg (.310 mmole) of sodium hydride, and the r e a c t i o n mixture was s t i r r e d under an atmosphere of dry ni t r o g e n u n t i l the e v o l u t i o n of hydrogen had ceased (approximately 5 min). The r e a c t i o n mixture was heated to 140° f o r 1 h, then cooled and d i l u t e d w i t h water. The r e a c t i o n mixture was thoroughly e x t r a c t e d w i t h petroleum ether (b.p. 30-60°) and the combined petroleum ether e x t r a c t s were d r i e d over anhydrous magnesium s u l f a t e . This organic l a y e r was then f i l t e r e d through 3 g of s i l i c a g e l , and the solvent was removed under reduced pressure. G a s - l i q u i d chromatographic a n a l y s i s (column F, 140°, 85) of the r e s i d u a l o i l (16 mg) i n d i c a t e d that (-)-cyclocopacamphene (24) comprised only 10% of the mixture. This m a t e r i a l (24) was i d e n t i f i e d by d i r e c t comparison ( g . l . c . r e t e n t i o n time and i n f r a r e d spectrum) w i t h an authentic sample. The major component (65%), obtained by p r e p a r a t i v e g . l . c . (column E, 140°,120), - 176 -24 was i d e n t i f i e d as the t r i c y c l i c o l e f i n (209) and e x h i b i t e d [ a ] D +9.3° (c, 0.4 i n CHC1-); i n f r a r e d ( f i l m ) , X 3.26, 6.03, 6.89, 13.90 u; 3 max n.m.r., x 3.80 (overlapped p a i r of doublets, 2H, o l e f i n i c p r o t o n s ) , 9.16, 9.17 (doublets, 6H, i s o p r o p y l methyls, J = 6.0 Hz), 9.28 ( s i n g l e t , 3H, t e r t i a r y methyl), 9.30 (doublet, 3H, secondary methyl, J = 7.0 Hz). Mol. Wt. Calcd. f o r C ^ H ^ : 204.188. Found (high r e s o l u t i o n mass spectrometry): 204.188. To a s o l u t i o n of 30 mg (.104 mmole) of p-tosylhydrazone (208) i n 2 ml of dry tetrahydrofuran was added 76 u£ of 2 M n - b u t y l l i t h i u m i n hexane. The r e a c t i o n mixture was allowed to stand f o r 15 min, and then the solvent was removed, and the residue was heated s l o w l y under reduced pressure (0.3 mm). Between temperatures of 120° and 140°, 15 mg of a c o l o u r l e s s o i l was c o l l e c t e d . G a s - l i q u i d chromatographic a n a l y s i s (column F, 135°, 85) of t h i s o i l revealed that (-)-cyclocopacamphene (24) again only comprised 10% of the mixture, w h i l e the ( + ) - t r i c y c l i c o l e f i n (209) accounted f o r 65%. These products were i s o l a t e d by pre p a r a t i v e g . l . c . (column E, 145°, 120) and were i d e n t i f i e d i n each case by d i r e c t comparison ( g . l . c . r e t e n t i o n time and i n f r a r e d spectra) w i t h the authe n t i c samples. (c) from hydrazone of the (-)-ketone (202) A s o l u t i o n of 30 mg (.136 mmole) of the (-)-ketone (202) , 48 u£ of 95% hydrazine, 9 u£ of g l a c i a l a c e t i c a c i d and 1.0 ml of ethanol was r e f l u x e d f o r 4 h. The r e a c t i o n mixture was then cooled and the ethanol was removed under reduced pressure. The residue was d i l u t e d w i t h - 177 -water, and the r e s u l t a n t mixture was thoroughly e x t r a c t e d w i t h ether. The combined e t h e r e a l e x t r a c t s were washed w i t h a 10% s o l u t i o n of sodium bicarbonate, w i t h b r i n e , and then d r i e d over anhydrous magnesium s u l f a t e . Removal of the ether at a s p i r a t o r pressure gave the crude hydrazone [ i n f r a r e d ( f i l m ) , \ 3.01, 6.14, 6.88 u] which was max used without f u r t h e r p u r i f i c a t i o n . To a s o l u t i o n of the crude hydrazone (32 mg) i n 1 ml of methanol was added 100 mg of y e l l o w mercuric oxide, and the r e a c t i o n mixture was r e f l u x e d overnight. The r e a c t i o n mixture was then cooled and d i l u t e d w i t h petroleum ether (b.p. 30-60°) and f i l t e r e d through c e l i t e . The r e s u l t i n g f i l t r a t e was concentrated, and the residue was d i s s o l v e d i n petroleum ether (b.p. 30-60°) and f i l t e r e d through 3 g of s i l i c a g e l . The solvent was again removed under reduced pressure to a f f o r d 18 mg (65%) of a c o l o u r l e s s o i l . G a s - l i q u i d chromatographic a n a l y s i s (column F, 135°, 85) of the r e a c t i o n product i n d i c a t e d that (-)-cyclocopacamphene (24) comprised 30% of the mixture, while the major product (55%) was again the ( + ) - t r i c y c l i c o l e f i n (209). These products 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 E, 140°, 120) and were i d e n t i f i e d , i n each case, by d i r e c t comparison ( g . l . c . r e t e n t i o n time and i n f r a r e d spectra) w i t h authentic samples. (d) from the (+)-pyrazoline (213) A s o l u t i o n of 35 mg of the (+)-pyrazoline (213) i n 35 ml of dry o ether was i r r a d i a t e d i n a Rayonet Reactor, using 3500 A lamps and a pyrex f i l t e r , f o r 1 h. 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