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UBC Theses and Dissertations

Studies related to the (±)-aristolone and total synthesis of (±)-seychellene De Waal, William 1970

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STUDIES RELATED TO THE TOTAL SYNTHESIS OF (±)-ARISTOLONE AND TOTAL SYNTHESIS OF (+)-SEYCHELLENE BY WILLIAM DE WAAL B. S c , U n i v e r s i t y of B r i t i s h Columbia, 1966 A THESIS SUBMITTED IN PARTIAL FULFILMENT OF THE REQUIREMENTS FOR THE DEGREE OF 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 req u i r e d standard THE UNIVERSITY OF BRITISH COLUMBIA March, 1970 In presenting t h i s t h e s i s in p a r t i a l f u l f i l m e n t o f the requirements f o r an advanced degree at the U n i v e r s i t y of B r i t i s h Columbia, I agree that the L i b r a r y s h a l l make i t f r e e l y a v a i l a b l e f o r reference and study. I f u r t h e r agree tha permission f o r extensive copying of t h i s t h e s i s f o r s c h o l a r l y purposes may be granted by the Head of my Department or by h i s r e p r e s e n t a t i v e s . It i s understood that copying or p u b l i c a t i o n of t h i s t h e s i s f o r f i n a n c i a l gain s h a l l not be allowed without my w r i t t e n permission. W i l l i a m de Waal Department of Chemistry  The U n i v e r s i t y of B r i t i s h Columbia Vancouver 8, Canada Date March 26, 1970 ABSTRACT In the f i r s t p a r t of t h i s t h e s i s an 8-step synthesis of ( i ) - 4 -demethylaristolone 16_ i s described. This s y n t h e t i c sequence was eve n t u a l l y to provide the b a s i s f o r the t o t a l s y n t h e s i s of (±)-aristolone 11. A l k y l a t i o n of the known 2-methyl-6-n-butylthiomethylenecyclohexanone 77 with m e t h a l l y l c h l o r i d e gave, a f t e r removal of the b l o c k i n g group, ketone 79. Treatment of 79_ w i t h p_-toluenesulfonic a c i d i n r e f l u x i n g benzene y i e l d e d a mixture of o l e f i n i c ketones, 79_ and 80_. Reaction of 80_ with diethylcyanomethylphosphonate y i e l d e d a mixture of n i t r i l e s , 81 and 82, which upon base h y d r o l y s i s afforded i n good y i e l d , the 3,y-unsaturated c a r b o x y l i c a c i d 83^ as the s o l e product. The l a t t e r was converted i n t o the c r u c i a l diazoketone 86_ v i a the a c i d c h l o r i d e 84. Intramolecular c y c l i z a t i o n of 86_ i n the presence of c u p r i c s u l f a t e gave a mixture of (±)-4-demethylaristolone 16 and ( i ) - 5 - e p i - 4 - d e m e t h y l a r i s t o l o n e 88 i n a r a t i o of 2:1. Employing, i n each case, two successive B i r c h r e d u c t i o n s , compounds 16 and 88_ were converted i n t o decalones 90_ and 111, r e s p e c t i v e l y . An a l t e r n a t e synthesis of compound 90_ inv o l v e d the 1,4-conjugate a d d i t i o n of isopropenylmagnesium bromide to the known octalone 91, followed by c a t a l y t i c hydrogenation of the a d d i t i o n product 97. The compound obtained from t h i s sequence was i d e n t i c a l w i t h 90_ prepared from ( l ) - 4 -d e methylaristolone, thus e s t a b l i s h i n g the stereochemistry of the l a t t e r . That the p r e d i c t e d stereochemical outcome of the conjugate a d d i t i o n (to 91) was c o r r e c t , was shown as f o l l o w s . K e t a l i z a t i o n of 97 y i e l d e d compound 104, which was converted i n t o i t s more s t a b l e epimer 107, v i a keto k e t a l 106. The o l e f i n i c k e t a l 107 upon c a t a l y t i c hydrogenation followed by a c i d c a t a l y z e d h y d r o l y s i s y i e l d e d decalone 108. Since compound 108 was c l e a r l y d i f f e r e n t from decalone 111, prepared from (1)-5-epi-4-demethylaristolone 88, i t was e s t a b l i s h e d that the B i r c h r e d u c t i o n of the l a t t e r had y i e l d e d a product w i t h a c i s r i n g j u n c t i o n . In the second part of t h i s t h e s i s an e f f i c i e n t and very s t e r e o -s e l e c t i v e 16-step synthesis of ( i ) - s e y c h e l l e n e 1_3_ i s described. Conjugate a d d i t i o n of l i t h i u m dimethylcuprate to the known a,3-unsaturated ketone 142, followed by trapping of the intermediate enolat anion 150 w i t h a c e t y l c h l o r i d e , gave i n high y i e l d , the enol acetate 151. Epoxidation of the double bond of 151, and thermal rearrangement of the r e s u l t i n g crude product, gave the keto acetate 154. Reaction of 154 w i t h methylenetriphenylphosphorane y i e l d e d the o l e f i n i c acetate 156. Successive s u b j e c t i o n of 156 to hydrogenation [ t r i s ( t r i p h e n y l -phosphine)chlororhodium], base h y d r o l y s i s and S a r e t t o x i d a t i o n a f f o r d e d ketone 144. Reaction of ketone 144 with m e t h y l l i t h i u m gave the t e r t i a r y a l c o h o l 170 which upon dehydration with t h i o n y l c h l o r i d e i n p y r i d i n e afforded the o l e f i n 169. Hydroboration-oxidation of the l a t t e r gave a l c o h o l 173 which upon treatment with p_-toluenesulfonyl c h l o r i d e gave the t o s y l a t e 174 i n high y i e l d . Successive treatment of 174 w i t h p_-t o l u e n e s u l f o n i c a c i d i n methanol and w i t h chromium t r i o x i d e i n p y r i d i n e af f o r d e d the c r u c i a l keto t o s y l a t e 136. C y c l i z a t i o n of 136 i n the presence of m e t h y l s u l f i n y l carbanion y i e l d e d (+)-nor-seychellanone 117. Treatment of the l a t t e r w i t h methyl - i v -l i t h i u m f o l l owed by dehydration of the r e s u l t i n g a l c o h o l with t h i o n y l c h l o r i d e i n p y r i d i n e a f f o r d e d , i n high y i e l d , (+)-seychellene 13. The l a t t e r gave spe c t r a i d e n t i c a l w i t h those obtained from the n a t u r a l product. - V -TABLE OF CONTENTS P a § e TITLE PAGE i ABSTRACT • 1 1 TABLE OF CONTENTS v LIST OF FIGURES v i i ACKNOWLEDGEMENTS v i i i INTRODUCTION 1 I. General . 1 I I . The Biogenesis of Sesquiterpenes 5 PART 1: Studies Related to the T o t a l Synthesis of (±)-A r i s t o l o n e 12 INTRODUCTION 13 I. S t r u c t u r e and Stereochemistry of ( - ) - A r i s t o l o n e . . . 13 I I . Other S y n t h e t i c Approaches to A r i s t o l a n e - t y p e Sesquiterpenes 24 DISCUSSION 27 I. General Approach 27 I I . Synthesis of (t)-4-Demethylaristolone and (±)-5-epi-4-Demethylaristolone. 29 I I I . The Stereochemistry of (+)-4-Demethylaristolone and (i)-5-epi-4-Demethylaristolone 40 EXPERIMENTAL '52 PART 2: T o t a l Synthesis of ( i ) - S e y c h e l l e n e 73 INTRODUCTION 74 St r u c t u r e and Stereochemistry of (-)-Seychellene.. 74 - v i -Page DISCUSSION 80 I. General Approach 80 I I . S t e r e o s e l e c t i v e T o t a l Synthesis of (1)-Seychellene. 84 EXPERIMENTAL 119 BIBLIOGRAPHY 141 - v i i -LIST OF FIGURES Figure Page 1 N.M.R. Spectrum of Ca r b o x y l i c A c i d 83_ 33 2 N.M.R. Spectrum of (i)-4-Demethylaristolone 1_6 38 3 N.M.R. Spectrum of (±)-5-epi-4-Demethylaristolone 88. 39 4 N.M.R. Spectrum of Ketone 143 101 5 N.M.R. Spectrum of Keto Tosylate 136 114 6 N.M.R. Spectrum o f (±)-nor-Seychellanone 117 ........ 116 7 N.M.R. Spectrum of (+)-Seychellene 1_3 117 - v i i i -ACKNOWLEDGEMENT I wish to express my g r a t i t u d e to Dr. E. P i e r s f o r h i s constant encouragement and guidance during the course of my research. I t has been a rewarding experience to work under h i s d i r e c t i o n . My thanks and best wishes are extended to Ronald W. B r i t t o n whose c o l l a b o r a t i o n on many problems helped to s t i m u l a t e the necessary work. In a d d i t i o n , I wish to thank the other members of our research group f o r many worthwhile d i s c u s s i o n s . The able t y p i n g of t h i s t h e s i s by Miss Diane Johnson i s appreciated. The f i n a n c i a l support from the N a t i o n a l Research Council of Canada during my stu d i e s i s g r a t e f u l l y acknowledged. Above a l l , I wish to thank my wife f o r her patience and encouragement. INTRODUCTION I. General The terpenoids are a large group of n a t u r a l products which are predominantly produced i n p l a n t s (1). They are compounds whose s t r u c t u r e s are normally based on head to t a i l l i n k i n g of isoprene u n i t s 1_, and u s u a l l y contain 2, 3, 4, 5, 6, or 8 m u l t i p l e s of t h i s b a s i c s t r u c t u r e . Consequently, terpenoids are c l a s s i f i e d according to the number of such t a i l head 1 u n i t s contained i n t h e i r s k e l e t o n , as shown i n Chart 1. During the biogenesis of terpenoids the l i n k e d isoprene u n i t s may rearrange g i v i n g a vast array of d i f f e r e n t carbon skeletons (2). One large group of terpenoids are the sesquiterpenes (3) which are formed by the f u s i o n of three isoprene u n i t s . T h e i r s t r u c t u r e s (4) vary from the r a t h e r simple a c y c l i c system of f a r n e s o l 2_ to the complex t e t r a c y c l i c system of l o n g i c y c l e n e 3_ (5). The degree of oxygenation i n sesquiterpenoids can vary from hydrocarbons c o n t a i n i n g no oxygen (e.g. l o n g i c y c l e n e 3) to h i g h l y oxygenated systems l i k e - 2 -CHART 1: Types of Terpenoid Compounds Type Monoterpenes Sesquiterpenes Diterpenes Sesterterpenes Triterpenes Tetraterpenes Polyterpenes Number of isoprene units 2 3 4 5 6 n Occurrence or examples Terpentine o i l E s s e n t i a l o i l s Resin acids Phytol Vitamine A Squalene Steroids B i l e acids Carotenoids cis-Rubber i l l u d i n - S 4 ( 6 ) . CH.OH >* 2 Sesquiterpene hydrocarbons, and re l a t e d alcohols and ketones, as well as a few other functional types, have been commonly i s o l a t e d from es s e n t i a l o i l s . However, polyfunctional sesquiterpenes are seldom found i n es s e n t i a l o i l s because of t h e i r low v o l a t i l i t y . The very numerous sesquiterpenes present i n any one es s e n t i a l o i l and the s i m i l a r i t y i n physical properties, made separation of these compounds extremely d i f f i c u l t . Only recently with the advent of g a s - l i q u i d chroma-tography and absorption chromatography on s i l v e r nitrate-impregnated - 3 -absorbents, has the s e p a r a t i o n of these complex mixtures been s i m p l i f i e d . The s u b s t i t u t i o n of solvent e x t r a c t i o n of the p l a n t m a t e r i a l f o r steam d i s t i l l a t i o n as the e x t r a c t i n g process, has i n recent years been f r u i t f u l i n p r o v i d i n g a large v a r i e t y of poly-oxygenated sesquiterpenes. I t i s i n t e r e s t i n g to note that the sesquiterpenes d i f f e r from the higher terpenoids i n three ways. F i r s t l y , the d i v e r s i t y of carbon skeletons i n sesquiterpenes g r e a t l y exceeds that of a l l other c l a s s e s . Secondly, the d i v e r s i t y of compounds i s m u l t i p l i e d by stereochemical v a r i a t i o n s , the range of f u n c t i o n a l groups and by p o s i t i o n a l isomerism. T h i r d l y , with very few exceptions [e.g. a b s c i s i n ( 7 ) ] , sesquiterpenes are apparently useless i n l i v i n g t i s s u e . An i n t e r e s t i n g p a r a l l e l e x i s t s i n the s t r u c t u r e s of four c l a s s e s of sesquiterpenes. The eremophilane 5_ c l a s s may be derived b i o g e n e t i c a l l y from the eudesmane 6^  c l a s s , by m i g r a t i o n of a methyl group from p o s i t i o n 10 to p o s i t i o n 5. S i m i l a r l y , the a r i s t o l a n e 1_ c l a s s may be derived from the maaliane 8^  c l a s s . S p e c i f i c examples of these four c l a s s e s are eremophilane 9_ ( 8 ) , a-eudesmol 1_0_ ( 9 ) , a r i s t o l o n e 11_ (10), and m a a l i o l 12 (11). 6 12 A r e c e n t l y i s o l a t e d sesquiterpene, seychellene (12,13), has been assigned the s t r u c t u r e and absolute stereochemistry as depicted i n 13. This o l e f i n i s probably r e l a t e d b i o g e n e t i c a l l y to p a t c h o u l i a l c o h o l 1_4_ (14), which i n t u r n has been proposed to be b i o g e n e t i c a l l y derived from bul n e s o l 1_5_ (3), a member of the large c l a s s of perhydroazulene sesquiterpenes, the guaiane c l a s s . 13 14 15 The work reported i n the f i r s t p art of t h i s t h e s i s was concerned with the s y n t h e s i s of (i ) - 4 - d e m e t h y l a r i s t o l o n e 1_6 (15), which was to provide the background f o r the synthesis of ( t ) - a r i s t o l o n e 11_ (16). In the second part of t h i s t h e s i s , work concerning the h i g h l y s t e r e o s e l e c t i v e synthesis of (±)-seychellene L3 (17) i s reported. 16 II. The Biogenesis of Sesquiterpenes The one feature that a l l sesquiterpenes appear to have i n common i s t h e i r b i o g e n e t i c o r i g i n . A l l sesquiterpenes can, t h e o r e t i c a l l y , be derived (3,18) from appropriate c y c l i z a t i o n of e i t h e r c i s - f a r n e s y l pyrophosphate 1_7 or t r a n s - f a r n e s y l pyrophosphate 18, followed by appropriate rearrangements, o x i d a t i o n s and re d u c t i o n s . These two compounds have been found to co-occur as t h e i r f r e e a l c o h o l s , f a r n e s o l and n e r o l i d o l (19). The intermediacy of mevalonic a c i d 1_9_ i n the biogenesis of f a r n e s y l pyrophosphate was po s t u l a t e d by Block and co-workers (20) and by Lynen and co-workers (21,22). These workers e l u c i d a t e d the s t r u c t u r e of t h i s precursor and i t s mode of b i o s y n t h e s i s . The proposed b i o -s y n t h e t i c pathway i s o u t l i n e d i n Chart 2. According to t h i s scheme, the terpenoid p r e c u r s o r , mevalonic a c i d , i s formed by nicotinamide-adenine d i n u c l e o t i d e phosphate (NADPH) r e d u c t i o n of g-hydroxy-(3-methyl g l u t a r y l CoA 20, which i t s e l f i s produced by the a d d i t i o n of a c e t i c a c i d to a c e t o a c e t i c a c i d a f t e r a c t i v a t i o n by coenzyme A. Mevalonic a c i d i s subsequently phosphorylated with adenine triphosphate (ATP) and decarboxylated to form isopentenyl pyrophosphate 21, which i s the s o - c a l l e d " a c t i v e " isoprene u n i t , and the tru e s t r u c t u r a l u n i t of a l l - 6 -CHART 2: The Biogenesis of Farnesyl Pyrophosphate 0 0 II 0 SCoA SCoA SCoA 0 ^-SCoA X OH NADPH OH C 0 2 H 0 ^ SCoA ATP OPP -CO, C0 2H C 0 2 H ^ OPP 20 19 - 7 -terpenoids. The t r a n s f o r m a t i o n of 21_ to d i m e t h y l a l l y l pyrophosphate 22_ i s e s s e n t i a l f o r f u r t h e r i n t e r l i n k a g e s of the terpene u n i t s . The l i n k a g e of these two u n i t s , head to t a i l , y i e l d s geranyl pyrophosphate 23. Subsequent a d d i t i o n of one more isopentenyl pyrophosphate u n i t y i e l d s f a r n e s y l pyrophosphate 18. According to Hendrickson (18) the biogenesis of sesquiterpenes i s i n i t i a t e d by the e l i m i n a t i o n of the a l l y l i c OPP group from e i t h e r c i s - 17 or t r a n s - f a r n e s y l pyrophosphate 1_8_. The unstable cations thus formed undergo c y c l i z a t i o n w i t h one of the double bonds (see Chart 3). The involvement of the c e n t r a l double bond i n these i n i t i a l c y c l i z a t i o n s i s p o s s i b l e only with c i s - f a r n e s y l pyrophosphate 1_7_. The r e s u l t i n g intermediate ca t i o n s can be s t a b i l i z e d e i t h e r by r e a c t i o n with the solvent or by the l i b e r a t i o n of a proton. The proposed biogenesis of ( - ) - a r i s t o l o n e 11_ (23) from t r a n s - f a r n e s y l pyrophosphate 18 v i a c a t i o n 24_ i s o u t l i n e d i n Chart 4. The c y c l i z a t i o n s i n d i c a t e d i n s t r u c t u r e 24_' would y i e l d an intermediate 25_ from which both m a a l i o l 12_ and a r i s t o l o n e 11_ could be d e r i v e d . H y droxylation of the t e r t i a r y carbonium ion would y i e l d m a a l i o l 12, w h i le a 1,2-hydride s h i f t g followed by a 1,2-methyl m i g r a t i o n and proton l o s s from C , as shown i n s t r u c t u r e 25, would a f f o r d 9 - a r i s t o l e n e 26_ (24). A l l y l i c o x i d a t i o n g of the l a t t e r (at C-) would give r i s e to a r i s t o l o n e 11. As i n the case of a r i s t o l o n e , (-)-seychellene L3_ can a l s o be thought to be b i o g e n e t i c a l l y derived from t r a n s - f a r n e s y l pyrophosphate v i a i o n 27, as o u t l i n e d i n Chart 5. According to Henrickson's scheme (18), an anti-Markownikoff c y c l i z a t i o n of c a t i o n 27* and n e u t r a l i z a t i o n - 11 -of the carbonium i on on the i s o p r o p y l group with water would y i e l d . i o n 28. Loss of a proton as shown i n 28_ would give b u l n e s o l 29_. A c i d -promoted transannular c y c l i z a t i o n of the l a t t e r as shown i n s t r u c t u r e 29 would a f f o r d i o n 30, from which both seychellene L3_ and p a t c h o u l i a l c o h o l 1_4_ could be d e r i v e d . The rearrangement shown by path "a" would y i e l d seychellene 13 while the one shown by path "b" would a f f o r d p a t c h o u l i a l c o h o l 14 (13). PART 1 Studies Related to the Total Synthesis of (±)-Aristolone INTRODUCTION I. S t r u c t u r e and Stereochemistry of ( - ) - A r i s t o l o n e The sesquiterpene ( - ) - a r i s t o l o n e was i n i t i a l l y i s o l a t e d from A r i s t o l a c h i a d e b i l i s Sieb. et_ Zucc. i n 1955 (25) and more r e c e n t l y from As arum canadense (26). The s t r u c t u r e determination of t h i s i n t e r e s t i n g n a t u r a l product was reported (27) some s i x years a f t e r the i n i t i a l i s o l a t i o n and, i n 1962, Buchi and co-workers (10), on the b a s i s of an i n d i r e c t c o r r e l a t i o n w i t h m a a l i o l (11,28) of known absolute c o n f i g u r a t i o n , 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 ( - ) - a r i s t o l o n e as depicted i n 11. 11 The gross s t r u c t u r e of a r i s t o l o n e , determined by Furukawa and co-workers (27), was based upon spectroscopic data from a r i s t o l o n e 11 and from a number of chemical degradation products, and upon comparison of a key degradation product with s y n t h e t i c 3-isopropyl-5-hydroxy-o_-t o l u i c a c i d . - 14 -The molecular formula f o r a r i s t o l o n e ( C ^ ^ ^ O ) i n d i c a t e d 5 degrees of u n s a t u r a t i o n , two of which could be accounted f o r by the presence of a carbonyl (as i n d i c a t e d by i n f r a r e d ) and by the presence of a double bond (as i n d i c a t e d by c a t a l y t i c hydrogenation). Therefore, the carbon s k e l e t o n had to be t r i c y c l i c . Moreover, the u l t r a v i o l e t and i n f r a r e d s p e c t r a of a r i s t o l o n e 11_ suggested the presence of an a,B-unsaturated ketone. The hydrogenation product, d i h y d r o a r i s t o l o n e 31, s t i l l e x h i b i t e d a strong u l t r a v i o l e t absorption at 213 my and an i n f r a r e d absorption at 5.92 y , which suggested that the ketone was a l s o conjugated to a c y c l o p r o p y l r i n g . Thus the ketone was conjugated on one side by a double bond and on the other side by a c y c l o p r o p y l r i n g . Dehydrogenation of a r i s t o l o n e w i t h selenium afforded 5-methyl-2-naphthol 32, while deoxyaristolone 26_ (from Wolff-Kischner r e d u c t i o n of 11) and a r i s t o l o l 3_3_ (from l i t h i u m aluminum hydride r e d u c t i o n of 11) gave, upon s i m i l a r dehydrogenation, 1-methylnaphthalene 34. This evidence allowed the assignment of the f o l l o w i n g as two p o s s i b l e p a r t i a l s t r u c t u r e s : Permanganate o x i d a t i o n of a r i s t o l o n e 11_ and deoxyaristolone 26_ gave a r i s t o i c a c i d 35 , C ^ ^ H ^ Q O ^ , which upon treatment with mineral a c i d afforded a p h e n o l i c c a r b o x y l i c a c i d , C. H 0 . The l a t t e r , by the - 15 -determination of C-methyl groups and by means of absorption s p e c t r a , was assumed to be a m-hydroxybenzoic a c i d d e r i v a t i v e possessing one methyl and one i s o p r o p y l group. Based on t h i s assumption, 3 - i s o p r o p y l -5-hydroxy-o-toluic a c i d 36_ was synthesised from 2 - i s o p r o p y l - 4 - n i t r o -toluene, and was found to be i d e n t i c a l to the above degradation product. During the a c i d h y d r o l y s i s of a r i s t o i c a c i d 55, the l i b e r a t i o n of a C^-monocarboxylic a c i d was presumed. The presence of t h i s fragment as c r o t o n i c a c i d 37 was confirmed. Thus the gross s t r u c t u r e of a r i s t o i c a c i d 31 36 - 16 -and a r i s t o l o n e were p o s t u l a t e d t o be as depicted i n 35_ and 11. While Buchi and co-workers (10) were i n v e s t i g a t i n g the c o n f i g u r a -t i o n of (+)-calarene''" 38_ the gross s t r u c t u r e of a r i s t o l o n e was proposed (27). The c o r r e l a t i o n of these two compounds, as o u t l i n e d below, made p o s s i b l e the assignment of the absolute c o n f i g u r a t i o n of ( - ) - a r i s t o l o n e 11 when that of (+)-1(10)-aristolene 38 had been determined. 38 I t should be noted t h a t some confusion e x i s t e d about the p u r i t y of calarene 38, i s o l a t e d by F. Sorm e_t_.al_. (29) and by G. Buchi et . a l . (10). This confusion, however, was c l a r i f i e d by Sorm (24), who, by gas l i q u i d chromatographic a n a l y s i s , discovered that calarene i s o l a t e d from sweet-flag o i l was contaminated w i t h approximately 20% of the A^'iO i s o m e r , while Buchi's calarene from spikenard o i l was pure. Sorm a l s o proposed that calarene and 3-gurgunene (which were shown to be i d e n t i c a l ) should be named 1 ( 1 0 ) - a r i s t o l e n e and that the A 9>!0 isomer should be named 9 - a r i s t o l e n e . This convention, t h e r e f o r e w i l l subsequently be followed i n t h i s t h e s i s . - 17 -The key step i n the stereochemical proof i n v o l v e d the formic a c i d rearrangement of 1 ( 1 0 ) - a r i s t o l e n e 38, which gave the conjugated diene 39. The same diene was formed by formic a c i d rearrangement of m a a l i o l 12 (11), whose absolute c o n f i g u r a t i o n was known. Thus the absolute c o n f i g u r a t i o n at Cp of 1 ( 1 0 ) - a r i s t o l e n e 38_was determined. The assignment of the stereochemistry of the c y c l o p r o p y l r i n g was a l s o based on a rearrangement r e a c t i o n . Treatment of 1 ( 1 0 ) - a r i s t o l e n e 38 w i t h N-bromoacetamide y i e l d e d the bromohydrin £0 which was reduced with Raney-nickel c a t a l y s t to the t e r t i a r y a l c o h o l 41_. Treatment of t h i s a l c o h o l with t h i o n y l c h l o r i d e and p y r i d i n e gave the unconjugated diene 42. This diene was a l s o i s o l a t e d from a mixture of three compounds which r e s u l t e d from the successive treatment of e p i - m a a l i o l 43 .with t h i o n y l c h l o r i d e i n ether and with hot c o l l i d i n e . Since the opening of the c y c l o p r o p y l r i n g occurs, i n each case, with r e t e n t i o n of c o n f i g u r a t i o n at C , the stereochemistry of the c y c l o p r o p y l r i n g i n 38 was e s t a b l i s h e d OH 12 - 18 -as being g . I t should be noted that t h i s experiment d i d not a l l o w the 4 assignment of c o n f i g u r a t i o n about C , since the asymmetry about t h i s center was destroyed during the rearrangement of e p i - m a a l i o l 43. 43 42 The assignment of the stereochemistry of the methyl group was based on a t h e o r e t i c a l r a t i o n a l i z a t i o n concerning the r e s u l t s of the f o l l o w i n g r e a c t i o n s : - 19 -Ketone 44 was prepared from 1 ( 1 0 ) - a r i s t o l e n e 38_ by chromium t r i o x i d o x i d a t i o n of i t s hydroboration product. Treatment of ketone 44 w i t h base a f f e c t e d e p i m e r i z a t i o n at C^, and q u a n t i t a t i v e l y y i e l d e d ketone 45 wi t h the trans r i n g j u n c t i o n . The assignment of the r i n g j u n c t i o n s was supported by o p t i c a l r o t a t o r y d i s p e r s i o n data. Ketone 44_ e x h i b i t e d a strong p o s i t i v e Cotton e f f e c t curve, while i t s epimer 45 e x h i b i t e d a weak negative Cotton e f f e c t curve. Since the stereochemistry of the r i n g j u n c t i o n s of ketones 44_ and 45 was now e s t a b l i s h e d , i t was p o s s i b l e to assign the stereochemistry of the r i n g j u n c t i o n of ketone 46, the a c i d - c a t a l y z e d rearrangement product formed from both 44_ and 4_5_. C a t a l y t i c hydrogenation of 46 furnis h e d 47, which was converted to the t h i o k e t a l 4_8_. The l a t t e r was d e s u l f u r i z e d w i t h Raney n i c k e l to a f f o r d the saturated hydrocarbon 49. An a l t e r n a t e synthesis of 49_ i n v o l v e d Wolff-Kischner r e d u c t i o n of 45, of e s t a b l i s h e d stereochemistry,to a f f o r d the t r i c y c l i c hydrocarbon 50, followed by 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 the l a t t e r to compound 51. C a t a l y t i c r e d u c t i o n of compound 5J_ gave the decalone 49, which was i d e n t i c a l w i t h the sample synthesized from 46_. Thus the stereochemistry about C^, C^, and C 1^ i n ketone 46_ was e s t a b l i s h e d . The proof of stereochemistry about C^ r e s t s on the f a c t that only one product was obtained from the a c i d i s o m e r i z a t i o n of ketones 44 and 45_. A r a t i o n a l i z a t i o n of these r e s u l t s can be obtained from a d e t a i l e d examination of e q u i l i b r i a A and B as represented conformational i n Chart 6 and 7 r e s p e c t i v e l y . Let us f i r s t consider e q u i l i b r i u m A. As can be seen from Chart 6, the conformational e q u i l i b r i u m between 52a - 20 -45 50 51 and 52b i s expected to be i n favor of conformer 52b, sin c e a 1,3-d i a x i a l — ^ -C=0 i n t e r a c t i o n i s much l a r g e r i n energy than a 3-methyl ketone i n t e r a c t i o n . Therefore to determine which compound i s favored i n the c o n f i g u r a t i o n a l e q u i l i b r i u m 46^ 7-" 52, only conformations 46 and 52b need to be considered. In t h i s e q u i l i b r i u m , compound 46_ should be g r e a t l y favored (see Chart 6 ) . This i s mainly due to the severe 1 , 3 - d i a x i a l isopropenyl-methyl i n t e r a c t i o n which i s present i n 52b but absent i n 46. Let us next consider e q u i l i b r i u m B. As i n d i c a t e d i n Chart 7, the energy d i f f e r e n c e between conformers 54a and 54b i s probably s m a l l , - 21 -since the sum of the 1 , 3 - d i a x i a l isopropenyl-methylene i n t e r a c t i o n and the 1 , 3 - d i a x i a l isopropenyl-carbonyl i n t e r a c t i o n i n 54a i s probably clo s e i n magnitude to the sum of the two 1 , 3 - d i a x i a l methyl-methylene i n t e r a c t i o n s i n 54b. Thus to determine which compound should be favored i n the c o n f i g u r a t i o n a l e q u i l i b r i u m 53_ ^> 54, one can consider the probable energy d i f f e r e n c e between 5_3 and e i t h e r 54a or 54b. As again i n d i c a t e d i n Chart 7, the d i f f e r e n c e i n energy between 53_ and 54b i s probably q u i t e s m a l l , and thus, i n e q u i l i b r i u m B, a mixture of two compounds would be expected. Therefore, s i n c e Buchi and co-workers (10) obtained only one isomer from the a c i d - c a t a l y z e d rearrangement of ketones 44 and 45, they concluded that the C^ methyl group i n 1 ( 1 0 ) - a r i s t o l e n e 38 must have an a - o r i e n t a t i o n . E q u i l i b r i u m A 53 54 22 -CHART 6: Equilibrium A; a-C. Methyl 46 4-syn-axial CH^-H 1-skew CH -CH 3-syn a x i a l — ^ -H 1-3-methyl ketone = 52a AE 52b-52a 4-syn-axial CH^-H 1-skew CH 3-CH 3 1-syn-axial — ^ -H 1 - 1 , 3 - d i a x i a l — ^ — ^ C ^ 1 - 1 , 3 - d i a x i a l — ^ - C=0 ( 1 - 1 , 3 - d i a x i a l — ( - C=0) • (1-3-methyl ketone) 3-syn-axial ' C^-H l-'syn-axial CH^-H 1-skew CH 3-CH 3 1-skew — ^ -CH 1-1, 3 - d i a x i a l— { -CH3 1-3-methyl ketone 52b AE 52b-46 (2-syn-axial CH3-H) + (1-1,3-diaxial —(x -CH ) - (2-syn-axial — H ) 2 Since no energy values have been assigned to inte r a c t i o n s involving isopropenyl groups only q u a l i t a t i v e estimates of energy differences can be made. - 23 -CHART 7: E q u i l i b r i u m B; g-C M e t h y l 53 5 - s y n - a x i a l CH^-H 2 - s y n - a x i a l — ( ^ -H 1 - 1 , 3 - d i a x i a l — ^ -CH, 1-3-methyl k e t o n e "mm 54a AE 54a-54b 54b 3 - s y n - a x i a l CH^-H 1 - s y n - a x i a l — ^ 1-skew CH_-CH„ 3 3 / \ 1 - 1 , 3 - d i a x i a l — ^ - / C H 2 1 - 1 , 3 - d i a x i a l — ^ " C = 0 1-3-methyl k e t o n e (1-skew CH 3-CH 3) + ( l - l , 3 - d i a x i a l - { - ^ C H 2 ) + ( 1 - 1 , 3 - d i a x i a l - ^ - C=0) ( 2 - 1 , 3 - d i a x i a l CH 3 ( l - s k e w - ( N - C H 3 ) > 2 ) 2 - s y n - a x i a l CH -H \ 1- s y n - a x i a l CH -H / ^ 2- 1 , 3 - d i a x i a l CH 3- CH, 1 - s k e w — ^ -CH, 1-3-methyl k e t o n e 1 - s y n - a x i a l -H AE r., = ( 2 - 1 , 3 - d i a x i a l CH_- C H J - ( 2 - s y n - a x i a l CH_-H) 54b-53 3 / 2 ' 3 ( 1 - 1 , 3 - d i a x i a l - ^ -CH ) Thus, t h e e x p e r i m e n t s d e s c r i b e d above d e t e r m i n e d t h e a b s o l u t e c o n f i g u r a t i o n o f ( + ) - 1 ( 1 0 ) - a r i s t o l e n e 38 and ( - ) - a r i s t o l o n e 11 s i n c e t h e s e had been c o r r e l a t e d . - 24 -I I . Other S y n t h e t i c Approaches to A r i s t o l a n e - t y p e Sesquiterpenes A f t e r the t o t a l synthesis of (±)-4-demethylaristolone 1_6 (15) and of (±)-aristolone 1_1_ (16) had been achieved i n our l a b o r a t o r y , an a l t e r n a t e synthesis of ( i ) - a r i s t o l o n e 11 and a t o t a l synthesis of ( t ) - l ( 1 0 ) -a r i s t o l e n e 3^8_ were published by G. Ourisson, et_.al_. (30) and by R.M. Coates, et .al_. (31) 5 r e s p e c t i v e l y . Both of these l a t t e r syntheses u t i l i z e d p y r a z o l i n e s to form the r e q u i r e d cyclopropane r i n g . The f i r s t step i n Ourisson's synthesis of ( 1 ) - a r i s t o l o n e i n v o l v e d a Robinson a n n e l a t i o n of 2,3-dimethylcyclohexanone 55_.with methyl v i n y l ketone, y i e l d i n g a mixture of two ajg-unsaturated ketones 56_ i n a r a t i o of 2:3. B i r c h r e d u c t i o n of t h i s mixture gave the two t r a n s -decalones 57, which upon t r e a-tment with bromine i n a c e t i c a c i d gave the bromoketones 58a and 58b. From t h i s mixture i t was p o s s i b l e to c r y s t a l l i z e the d e s i r e d epimer 58b, whose s t r u c t u r e was i n d i c a t e d by i t s subsequent conversion to a r i s t o l o n e . Dehydrobromination of 58b i n hexamethylphosphoramide at 120°, y i e l d e d the dimethyl octalone 5_9_. A d d i t i o n of diazo-2-propane to the double bond gave the p y r a z o l i n e 60_ which upon i r r a d i a t i o n with u l t r a v i o l e t l i g h t f u r n i s h e d t r a n s - d i h y d r o a r i s t o l o n e 61. This ketone was converted by The f i r s t step i n the synthesis of (±)-1 ( 1 0 ) - a r i s t o l e n e _38_ (31) was a Robinson a n n e l a t i o n of the p y r r o l i d i n e enamine of 2-methylcyclo-hexane-1,3-dione 63_ w i t h pent-3-en-2-one i n formamide to y i e l d a 1:1 mixture of epimeric diones 64_ (32). This mixture was converted i n t o a mixture of octalones, 65a and 65b, v i a the corresponding monothioketals, which were d e s u l f u r i z e d by treatment with Raney n i c k e l . The d e s i r e d - 26 -isomer, 65b, with c i s methyl groups was separated from the mixture by f r a c t i o n a l d i s t i l l a t i o n through a spinning band column. Reaction of 65b with sodium hydride and d i e t h y l carbonate a f f o r d e d the expected g-ketoester 66_ which e x i s t e d as a mixture of keto and enol tautomers. Upon treatment w i t h methyl l i t h i u m i n ether, 66^ gave r i s e to the k e t o l 67_ which, without p u r i f i c a t i o n was dehydrated with hydro-c h l o r i c a c i d i n methanol to the is o p r o p y l i d e n e d e r i v a t i v e 68. The p y r a z o l i n e 69, formed from the r e a c t i o n of 68_ with one equivalent of hydrazine i n eth a n o l , was decomposed over powdered potassium hydroxide at 240-255° to a f f o r d compound 38_ which was shown to e x h i b i t s p e c t r a i d e n t i c a l w i t h those of a u t h e n t i c ( + ) - 1 ( 1 0 ) - a r i s t o l e n e . 68 69 DISCUSSION I. General Approach In any c o n s i d e r a t i o n of p o s s i b l e approaches to the t o t a l synthesis of (±)-aristolone 11, i t i s obvious that the most d i f f i c u l t and complex pa r t of the synthesis would i n v o l v e the c o n s t r u c t i o n of r i n g B, c o n t a i n i n g the o l e f i n i c double bond and the gem d i m e t h y l c y c l o p r o p y l moiety conjugated to the carbonyl. Of the number of p o s s i b l e routes which might be employed i n the c o n s t r u c t i o n of these f u n c t i o n a l i t i e s , we chose the scheme which can be i l l u s t r a t e d , i n general terms, by the h y p o t h e t i c a l conversion of 70_ t o 71_. This conversion, 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, appeared at f i r s t s i g h t 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 synthesis of the r e q u i r e d s u b s t i t u t e d bicyclo[4.1.0]-heptanone system. 11 28 -Since the f i r s t r eport of 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 by G. Stork and J . F i c i n i (33) i n 1961 there have been a number of reports concerned with t h i s type of r e a c t i o n and with i t s a p p l i c a t i o n to organic synthesis (34). In a systematic study o f a c y c l i c o l e f i n i c diazoketones, M.M. Fawzi and C.D. Gutsche (35) c l e a r l y demonstrated that the p r o x i m i t y of the o l e f i n i c center and the diazo-a l k y l center i s an important f a c t o r i n determining the success o f the r e a c t i o n . I t was found that the y i e l d of c y c l o p r o p y l ketones i n the f o l l o w i n g general r e a c t i o n increased from 3% when n = 4, to 37% when n = 3, and to 59% when n = 2. Doering e t - a l . (34a) a l s o s t u d i e d the CH, 0 II CH(CH_) CCHN„ 2 n 2 | 2'n C=0 c y c l i z a t i o n s of a number of o l e f i n i c diazoketones, and reported y i e l d s of c y c l o p r o p y l ketones v a r y i n g from 30-65%. Probably because o f the more complex s t r u c t u r e s s t u d i e d , as compared w i t h those s t u d i e d by Fawzi and Gutsche (35), no c l e a r trends could be observed. F i n a l l y , the s y n t h e s i s of (+)-2-carone 72_ (36) i n approximately 50% from the diazoketone 7_3 was of p a r t i c u l a r i n t e r e s t because of the obvious s t r u c t u r a l s i m i l a r i t y of the former to a r i s t o l o n e 11. 0 CHN, 73 72 - 29 -With t h i s l i t e r a t u r e precedent we f e l t that the synthesis of ( t ) - a r i s t o l o n e 11 v i a an appropriate diazoketone was an a t t r a c t i v e and p o t e n t i a l l y e f f i c i e n t route. However, before attempting to synthesize ( i ) - a r i s t o l o n e , we f e l t i t would be advantageous to t e s t the c r u c i a l diazoketone c y c l i z a t i o n . Hence, we set out to synthesize a diazoketone of the type 7_4_. This s y n t h e s i s , leading to (±)-4-demethylaristolone 16, would i n v o l v e fewer stereochemical problems than the synthesis of a diazoketone with c i s - v i e - m e t h y l groups. I I . Syntheses of (+)-4-Demethylaristolone and (±)-5-epi-4-Demethyl-a r i s t o l o n e The s t a r t i n g m a t e r i a l chosen f o r the synthesis of the c r u c i a l diazoketone of the type 74 was 2-methylcyclohexanone 75_ si n c e i t could be elaborated at the 2 p o s i t i o n by way of an a l k y l a t i o n . Furthermore, the carbonyl group could subsequently be used as a "handle" f o r the i n t r o d u c t i o n o f the re q u i r e d diazoketone-containing side chain. D i r e c t a l k y l a t i o n of 2-methylcyclohexanone 76_ was not considered si n c e t h i s would undoubtedly r e s u l t i n the formation of a mixture of s t r u c t u r a l l y isomeric products (37) . A p a r t i a l s o l u t i o n to the problem of o b t a i n i n g isomers from the d i r e c t a l k y l a t i o n of 7jS was achieved by House and co-workers (38) i n t h e i r work on the a l k y l a t i o n of enolate 74 16 - 30 -anions which r e t a i n e d t h e i r s t r u c t u r a l i n t e g r i t y . I n t r o d u c t i o n of a b l o c k i n g group at the 6 p o s i t i o n would, however, circumnavigate t h i s problem completely. The b l o c k i n g group chosen f o r t h i s a l k y l a t i o n was the n-butylthiomethylene b l o c k i n g group (39), s i n c e i t i s e a s i l y formed, does not d e a c t i v a t e the ketone towards a l k y l a t i o n (see re f e r e n c 40), and a f t e r a l k y l a t i o n i s e a s i l y removed from the molecule. Conversion of 2-methylcyclohexanone 75_ to i t s hydroxymethylene d e r i v a t i v e 76_ was accomplished i n 91% y i e l d by r e a c t i o n of the former with e t h y l formate i n the presence of powdered sodium methoxide i n dry benzene (41) . The blocked ketone 77_ was prepared i n 86% y i e l d by r e a c t i o n of compound 76_ with n-butanethiol i n benzene i n the presence of a c a t a l y t i c amount of p_-toluenesulfonic a c i d (39) . A l k y l a t i o n of 2-methyl-6-n-butylthiomethylenecyclohexanone 77_ with m e t h a l l y l c h l o r i d e i n t - b u t y l a l c o h o l i n the presence of potassium t-butoxide gave,after removal (39) of the b l o c k i n g group from the product 7_8_ by treatment of the l a t t e r w i t h aqueous potassium hydroxide i n ethylene g l y c o l , a 56% o v e r a l l y i e l d of 2-methyl-2-methallylcyclohexanone 79. Conversion of the l a t t e r i n t o the d e s i r e d 2-methyl-2-methylpropenylcycl hexanone 80 r e q u i r e d i s o m e r i z a t i o n of the o l e f i n i c double bond from the t e r m i n a l p o s i t i o n to the more h i g h l y s u b s t i t u t e d i n t e r n a l p o s i t i o n . Although a number of d i f f e r e n t methods were attempted i n order to c a r r y out t h i s t r a n s f o r m a t i o n , i t was e v e n t u a l l y found that simple 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 was the most convenient. Thus, treatment of the m e t h a l l y l compound 79^ with p_-toluenesulfonic a c i d i n r e f l u x i n g benzene f o r three days produced, i n 77% y i e l d , a mixture of compounds which, by g a s - l i q u i d chromatographic a n a l y s i s , was shown to c o n s i s t of approximately 80% of the d e s i r e d isomerized ketone 80, 17% of the s t a r t i n g m a t e r i a l 79, and 3% of an u n i d e n t i f i e d component. C a r e f u l f r a c t i o n a t i o n of t h i s mixture through a spinning band column allowed the i s o l a t i o n of n e a r l y pure d e s i r e d ketone 80_. The f a c t that simple double bond i s o m e r i z a t i o n had taken place was shown c l e a r l y by the nuclear magnetic resonance (n.m.r.) spe c t r a of compounds 79 and 80. Thus, although the s t a r t i n g m a t e r i a l 79_ e x h i b i t e d s i g n a l s f o r two o l e f i n i c protons (x 5.18 and x.5.33) and one v i n y l methyl group (x 8.33), the product 80_ showed s i g n a l s f o r one o l e f i n i c proton (x 4.74) and two v i n y l methyl groups (x 8.31 and x 8.57). In order to o b t a i n , from ketone 80, the diazoketone r e q u i r e d to t e s t the f e a s i b i l i t y of the proposed 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 , the reaction of 80 w i t h a W i t t i g reagent was considered. Instead of using the more normal phosphorane-type reagent a modified W i t t i g reagent of the phosphonate-type was employed (42) . This choice was made because i t had been shown that the phosphonate-type W i t t i g reagents r e a c t at a much greater r a t e w i t h hindered ketones than do the phosphorane-type reagents. Moreover, i s o l a t i o n of the d e s i r e d W i t t i g product i s much e a s i e r i n the former case, s i n c e the use of phosphoranes i n the W i t t i g r e a c t i o n r e s u l t s i n the formation of triphenylphosphine oxide which i s o f t e n d i f f i c u l t to separate from the d e s i r e d o l e f i n i c compound (43). The r e a c t i o n of ketone 80 w i t h t r i e t h y l phosphonoacetate (42) proved very s l u g g i s h , and even a f t e r prolonged r e a c t i o n times at elevated temperatures, none of the d e s i r e d product could be i s o l a t e d . However, use of the s t e r i c a l l y l e s s demanding reagent (44), d i e t h y l - 32 -cyanomethylphosphonate, proved s u c c e s s f u l . Thus, r e a c t i o n of the cyclohexanone 80_ w i t h t h i s reagent i n the presence of m e t h y l s u l f i n y l carbanion i n dimethyl s u l f o x i d e (45) at 100° f o r 15 h gave, i n 95% y i e l d , a mixture of the a,3-unsaturated n i t r i l e 81 and the 3,y-unsaturated n i t r i l e 82, i n a r a t i o of approximately 4:1, r e s p e c t i v e l y . An a n a l y t i c a l sample of the major isomer 81, obtained by p r e p a r a t i v e g a s - l i q u i d chromatography ( g . l . c ) , showed an u l t r a v i o l e t absorption at 219 mp. Furthermore, the n.m.r. spectrum showed a one-proton s i n g l e t at x 4.75 (C=CHCN), thus c l e a r l y e s t a b l i s h i n g that the major product was indeed the a ,3-unsaturated isomer. The n.m.r. spectrum of the mixture of products showed a broad s i g n a l at x 4.05 due to the y - v i n y l hydrogen of the minor, 3,y-unsaturated isomer. H y d r o l y s i s of the mixture of n i t r i l e s 81_ and 8_2 w i t h potassium hydroxide i n water-ethanol produced, i n good y i e l d , the 3,y-unsaturated a c i d 85_ as the s o l e product. The f a c t that the double bond had now completely isomerized i n t o the 3,Y-position was c l e a r l y shown by the s p e c t r a l data. The a c i d 83_ e x h i b i t e d no strong absorption i n the u l t r a -v i o l e t spectrum and. i n the n.m.r. spectrum.(see f i g u r e 1) e x h i b i t e d ' the expected s i g n a l s due to the angular methyl group and the methylpropenyl side c h a i n , a two-proton m u l t i p l e t at x 7.09 (-C^COOH) and a one-proton " t r i p l e t " at x 4.38 due to the y - v i n y l hydrogen. Although i t i s w e l l known that e q u i l i b r a t i o n of a , 3 - and 3,y-unsaturated c a r b o x y l i c acids occurs i n the presence of base (46), i t i s of i n t e r e s t t o note that i n the present case the e q u i l i b r i u m l i e s completely on the s i d e of the - 35 -g,y-unsaturated isomer. One of the major f a c t o r s c o n t r i b u t i n g to fl 31 t h i s phenomenon may w e l l be the A ' s t r a i n (47) which would be ass o c i a t e d w i t h the e x o c y c l i c double bond i n the a,g-unsaturated isomer, as shown i n conformations A and B. Presumably t h i s i s more severe than the A ' s t r a i n (47) which i s i n h e r e n t l y present i n the g,y-unsaturated compound (C_ and D) . Treatment of the sodium s a l t of the c a r b o x y l i c a c i d 83_ with o x a l y l c h l o r i d e i n benzene at room temperature gave the a c i d c h l o r i d e 84 (34). The l a t t e r was q u i t e unstable and.readily c y c l i z e d to the cro s s -conjugated dienone 85_ (14). In f a c t , when the a c i d c h l o r i d e was allowed to stand at room temperature, or i f i t was gently warmed, a n e a r l y q u a n t i t a t i v e y i e l d of the'""'&i"endhe 85_ was obtained. Therefore, even though - 36 -s p e c i a l precautions were taken during the i s o l a t i o n o f the crude a c i d c h l o r i d e and even though the l a t t e r was reacted immediately with excess diazomethane, the r e s u l t i n g crude diazoketone 86_ contained a considerable q u a n t i t y of the b i c y c l i c dienone 85. Since no s e p a r a t i o n of t h i s mixture was a f f e c t e d at t h i s stage, compound 8_5_ was e v e n t u a l l y i s o l a t e d along with the demethylaristolones (vide i n f r a ) . I t i s important to note that the n.m.r. spectrum of the crude diazoketone c l e a r l y showed by i t s one-proton, broad m u l t i p l e t at x 4.41 and i t s two-proton m u l t i p l e t at x 7.07 that the o l e f i n i c bond of t h i s compound had remained i n the g , y - p o s i t i o n with respect to the carbonyl group. Had the double bond migrated i n t o conjugation with the c a r b o n y l , the proposed 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 would have been rendered extremely u n l i k e l y . Thus, a molecular model of compound 86_ revealed that the diazoketone moiety could be brought i n t o c l o s e p r o x i m i t y to the double bond of the methylpropenyl s i d e c h a i n , and c y c l i z a t i o n o f t t h i s compound th e r e f o r e appeared q u i t e l i k e l y . However, i t can r e a d i l y be seen that i n the case of the a,g-unsaturated ketone 87, with the diazoketone moiety 3 trans to the s u b s t i t u t e d p o s i t i o n of the cyclohexane r i n g , 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 i n v o l v i n g the diazoketone moiety and the methylpropenyl double bond would be impossible. COCHN^ I 3 The geometric isomer of 87 with the c i s double bond would not be expected to form because of the severe non-bonded i n t e r a c t i o n between the diazoketone moiety and the methyl group or the methylpropenyl group on the cyclohexane r i n g . - 37 -The crude diazoketone 86_ was heated w i t h anhydrous c u p r i c s u l f a t e i n r e f l u x i n g cyclohexane (35) f o r 2 h, at which time the i n f r a r e d band at 4.80 p had disappeared. A n a l y s i s of the crude r e a c t i o n mixture by g . l . c . showed that i t contained, i n a d d i t i o n to a number of minor components, three major products, the cross-conjugated dienone 85, ( i ) - 4 - d e m e t h y l a r i s t o l o n e 1_6 and (+)-'5-epi-4-demethylaristolone 88, i n a r a t i o of approximately 2:2:1, r e s p e c t i v e l y . Treatment of t h i s mixture with sodium hydroxide i n hot aqueous ethanol f o r 10 minutes removed the minor components and gave a n e u t r a l product c o n t a i n i n g only the three compounds 85, 16 and 88_. P u r i f i c a t i o n of t h i s l a t t e r mixture by means of successive column chromatography on alumina and p r e p a r a t i v e g . l . c . allowed i s o l a t i o n of a l l three compounds. The f a c t that the c r u c i a l c y c l i z a t i o n had indeed taken place was c l e a r l y shown by the s p e c t r a l data of the two c y c l i z a t i o n products ljS and 88^ . The major c y c l i z a t i o n product, (-)-4-demethylaristolone 16_, gave an u l t r a v i o l e t maximum at 235 mp and a strong carbonyl absorption at 6.10 p i n the i n f r a r e d . The n.m.r. spectrum (see f i g u r e . 2 ) of compound 16 e x h i b i t e d a broad s i n g l e t at T 4.32, due to the o l e f i n i c proton, and three sharp s i n g l e t s at x 8.70, 8.77 and 8.83 due to the three t e r t i a r y methyl groups. The minor c y c l i z a t i o n product (±)-5-epi-4-demethylaristolone 88^ was shown to be isomeric w i t h 1_6_ by means of a high r e s o l u t i o n mass spectrometric measurement, and gave an u l t r a v i o l e t maximum at 232 mp and a strong carbonyl absorption at 6.11 p i n the i n f r a r e d spectrum. The n.m.r. spectrum (see f i g u r e 3 ) , which was s i m i l a r to that of i t s epimer 16, e x h i b i t e d a s i n g l e t at x 4.28, due to the o l e f i n i c proton, and three s i n g l e t s at x 8.62, 8.65 and 8.70 due to the three t e r t i a r y methyl groups. The s t r u c t u r a l assignment of the dienone 85_was based on the 0- 1 2 3 4 5 6 7 8 9 10x FIGURE 2: N.M.R. Spectrum of (±)-4-Demethylaristolone 16. - 40 -f o l l o w i n g s p e c t r a l data. The u l t r a v i o l e t spectrum of compound 85 e x h i b i t e d an intense maximum at 255 my, and i t s i n f r a r e d spte.ctrum: e x h i b i t e d a carbonyl ab s o r p t i o n at 5.98 y and a very strong double bond abso r p t i o n at 6.18 y. The n.m.r. spectrum of the cross-conjugated dienone 85_ e x h i b i t e d a broad s i n g l e t at x 4.13, due to the o l e f i n i c proton, two s i n g l e t s at x 7.68 and 8.06 due to the v i n y l methyls and a s i n g l e t at x 8.66 due to the t e r t i a r y methyl. I I I . The Stereochemistry of (±)-4-Demethylaristolone and (±)-5-epi-4-Demethylaristolone. Having c l e a r l y shown that the i n i t i a l l y proposed 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 a diazoketone of the type 74_ was a f e a s i b l e process, we wished to unequivocally determine the stereochemistry of the two c y c l i z a t i o n products, 1_6_ and 88_. In order to accomplish t h i s o b j e c t i v e , we planned t o convert the demethylaristolones i n t o r e l a t i v e l y simple decalone d e r i v a t i v e s which, h o p e f u l l y , could then be synthesized unambig-uously. I t had been w e l l documented that a,g-unsaturated ketones (47,48,49) undergo s t e r e o s e l e c t i v e lithium-ammonia r e d u c t i o n , y i e l d i n g the c o r r e s -ponding saturated ketones. Furthermore, i t had a l s o been shown (50) that c y c l o p r o p y l ketones i n which the three-membered r i n g i s i n conjugation with the carbonyl group a l s o undergo r e d u c t i o n w i t h l i t h i u m i n ammonia to a f f o r d saturated ketones i n which the c y c l o p r o p y l r i n g had been cleaved. Normally, the bond of the c y c l o p r o p y l r i n g which i s cleaved i s the one which overlaps the;best with the TT o r b i t a l . , of the carbonyl group. Therefore, i t appeared that the lithium-ammonia r e d u c t i o n would be an - 41 -appropriate r e a c t i o n f o r degrading the demethylaristolones to s u b s t i t u t e d decalones. Lithium-ammonia r e d u c t i o n (50) of (±)-4-demethylaristolone 1_6_ gave, i n q u a n t i t a t i v e y i e l d , (±)-9,10-dihydro-4-demethylaristolone 89. The f a c t that only the o l e f i n i c double bond had reduced and that the gem dim e t h y l c y c l o p r o p y l moiety had been r e t a i n e d was c l e a r l y shown by the s p e c t r a l data of the product 8SL The l a t t e r gave an u l t r a v i o l e t a b sorption maximum at 212.5 my [89 has a c a l c u l a t e d u l t r a v i o l e t absorp-t i o n maximum of 212 my, see r e f . (51)]. The n.m.r. spectrum o f the re d u c t i o n product 89_ showed three sharp s i n g l e t s (x 8.59, 8.87 and 8.97) due to the t e r t i a r y methyl groups, but gave no s i g n a l due to a v i n y l proton. When compound 89_was again subjected to r e d u c t i o n w i t h l i t h i u m i n ammonia, the c y c l o p r o p y l r i n g was opened as expected, to y i e l d the s u b s t i t u t e d decalone 90_ i n high y i e l d . The n.m.r. spectrum of 90_ e x h i b i t e d only one sharp s i n g l e t (x 8.89) f o r the t e r t i a r y methyl group and two doublets (x 9.08, J = 6.8 Hz, and x 9.17, J = 6.8 Hz) f o r the i s o p r o p y l methyl groups. Since the i s o p r o p y l group r o t a t e s i n a dissymmetric environment i t s two methyl groups are magn e t i c a l l y non-equivalent . An unambiguous synthesis of the decalone 90_ and subsequent c o r r e l a -t i o n w i t h the above r e d u c t i o n product would, of course, provide unequi-v o c a l proof f o r the stereochemistry of ( i ) - 4 - d e m e t h y l a r i s t o l o n e 16. A key intermediate i n the proposed synthesis was the known octalone 91_ (52), which could p o s s i b l y be elaborated to the d e s i r e d decalone 90_ by conjugate, 1,4-addition of an appropriate Grignard reagent to the - 42 -a,g-unsaturated ketone system. The synt h e s i s of the octalone 91_ was c a r r i e d out as f o l l o w s . According to the procedure of M a r s h a l l and Fanta (53), 2-methylcyclo-hexanone 75_ was condensed wit h methyl v i n y l ketone i n the presence of strong base to y i e l d the c i s - k e t o l 92. The l a t t e r was dehydrated to the octalone 9_3_ (53) with e t h a n o l i c potassium hydroxide. B i r c h r e d u c t i o n of compound 93^ i n the presence of ethanol (54) afforded a mixture of a l c o h o l s 94, which was o x i d i z e d with Jones reagent (55) to the known decalone 95 (52,54). Reaction of decalone 95_with bromine i n g l a c i a l a c e t i c a c i d (56) afforded the c r y s t a l l i n e bromoketone £6 (54) . The l a t t e r , when dehydrobrominated by treatment with a mixture of l i t h i u m bromide and l i t h i u m carbonate i n hot dimethylformamide (57) , afforded the de s i r e d octalone 91. H H - 43 -H H When octalone 91 was reacted with isopropenylmagnesium bromide i n the presence of cuprous c h l o r i d e i n te t r a h y d r o f u r a n (58,59), a mixture of products was obtained. Column chromatography of t h i s mixture gave, i n a d d i t i o n to a number of minor uncharacterized non-ketonic m a t e r i a l s (presumably r e s u l t i n g from 1,2-addition of the Grignard reagent to the carbonyl of 91, a 50% y i e l d of the conjugate a d d i t i o n product 97_. That the d e s i r e d 1,4-conjugate : a d d i t i o n had taken place was evident from the saturated ketone absorbance (5.88 y) and the t e r m i n a l o l e f i n absorbances (6.14, 11.25 y) i n the i n f r a r e d spectrum of compound 97_. The s t r u c t u r a l assignment of ketone 97_ was a l s o supported by i t s n.m.r. spectrum which e x h i b i t e d two m u l t i p l e t s (T 5.08, 5.45) due to the two o l e f i n i c protons, one m u l t i p l e t (x 8.23) due to the v i n y l methyl and one s i n g l e t (x 8.84) due to the t e r t i a r y methyl. I t i s noteworthy that the conjugate a d d i t i o n r e a c t i o n was completely s t e r e o s e l e c t i v e , s i n c e a c a r e f u l examination of the crude product o f the r e a c t i o n revealed that only one of the two p o s s i b l e epimeric 1,4-addition products was formed. Hydrogenation of the o l e f i n i c - 44 -ketone 97_ over Adam's c a t a l y s t produced the decalone 90, which was shown to be i d e n t i c a l (m.p., mixed m.p., i n f r a r e d ) w i t h the decalone 90_ obtained from the lithium-ammonia r e d u c t i o n of (t)-9,10-dihydro-4-demethylaristolone 89. The stereochemical outcome of the above conjugate a d d i t i o n r e a c t i o n r e q u i r e s comment. In t h i s connection, i t i s important to take note of the elegant work of M a r s h a l l and Andersen (60) who s t u d i e d the c u p r i c acetate c a t a l y z e d conjugate a d d i t i o n of v arious Grignard reagents to 1,l-dimethyl-trans-3-octal-2-one 98. B r i e f l y , these workers proposed that the conjugate i n t r o d u c t i o n of a Grignard reagent to octalones of the type 98^ (or 91) must, f o r s t e r e o e l e c t r o n i c reasons, take place v i a one (or both) of the two t r a n s i t i o n s t a t e s E_ and F_. In p a r t i c u l a r , they found t h a t , i n the absence of any large s t e r i c f a c t o r s , the c h a i r - l i k e t r a n s i t i o n s t a t e E_ was favored over the b o a t - l i k e t r a n s i t i o n s t a t e F_. Thus, the a d d i t i o n o f methylmagnesium i o d i d e to 98_ produced compound 99 as the major conjugate a d d i t i o n product, w i t h 100 being formed i n minor amounts. However, as the bulk of the Grignard reagent was incre a s e d , s t e r i c hindrance to a x i a l a ttack ( t r a n s i t i o n s t a t e E) a l s o increased and, w i t h phenylmagnesium bromide, the only product formed ( v i a t r a n s i t i o n s t a t e F) was 101. F i n a l l y , i n the case of i s o p r o p y l -magnesium bromide, s t e r i c hindrance to a x i a l approach was approximately balanced by the unfavorable nature of the b o a t - l i k e t r a n s i t i o n s t a t e F_, and the two products 102 and 103 were formed i n n e a r l y equal amounts. I f one now considers the conjugate a d d i t i o n of isopropenylmagnesium bromide to the octalone 91, i t i s immediately obvious that the important - 45 -100 R=CH3, R.j=H, R 2=CH 3 101 R=C.H , R=H, R =CH7 o b i 2. 5 103 R=(CH 3) 2CH, R =H, R2=CH f a c t o r i n t h i s case i s the presence of the angular methyl group. Molecular models show that i f s t e r e o e l e c t r o n i c c o n t r o l i s to be maintained i n the b o a t - l i k e t r a n s i t i o n s t a t e F_, then the incoming Grignard reagent must approach the molecule i n such a way that i t i s n e a r l y e c l i p s e d with the angular methyl group. The r e s u l t i n g s t e r i c and t o r s i o n a l s t r a i n (61,62) should o v e r r i d e the s t e r i c hindrance present i n t r a n s i t i o n s t a t e E_ and should ensure that the l a t t e r i s favored over t r a n s i t i o n s t a t e _F. Therefore, even though M a r s h a l l and Andersen (60) found that the conjugate a d d i t i o n of isopropylmagnesium bromide to octalone 98^ gave approximately equal amounts of the two epimers 102 and 103, we - 46 -f u l l y expected that the cuprous c h l o r i d e c a t a l y z e d 1,4-addition of isopropenylmagnesium bromide to octalone 91_ would be h i g h l y stereo-s e l e c t i v e and, furthermore, p r e d i c t e d that the product should possess the stereochemistry depicted i n 97. That the above p r e d i c t i o n regarding the stereochemistry of 97_ was c o r r e c t was shown unambiguously as f o l l o w s . K e t a l i z a t i o n of 9_7 with ethylene g l y c o l i n the presence o f a c a t a l y t i c amount of p_-t o l u e n e s u l f o n i c a c i d afforded the c r y s t a l l i n e k e t a l 104, m.p. 80-81°, i n 88% y i e l d . Compound 104 e x h i b i t e d absorbances i n i t s i n f r a r e d spectrum (6.15, 11.18 y) due t o t e r m i n a l o l e f i n i c double bond and i n i t s n.m.r. spectrum two m u l t i p l e t s (T 5.01, 5.20) due to the two o l e f i n i c protons, a m u l t i p l e t (x 6.10) due to the ethylene k e t a l protons, a m u l t i p l e t (x8.13) due to the v i n y l methyl, and a s i n g l e t (x 9.02) due to the t e r t i a r y methyl. Ozonolysis (63) of the o l e f i n i c k e t a l 104, fo l l o w e d by column chromatography of the crude product gave i n a d d i t i o n to the 4 diketone 105, the d e s i r e d keto k e t a l 106. The l a t t e r , upon r e a c t i o n wit h methylenetriphenylphosphorane i n dimethyl s u l f o x i d e (45) , gave a high y i e l d of the o l e f i n i c k e t a l 107. That the o l e f i n i c k e t a l 107 was epimeric with the o l e f i n i c k e t a l 104 was evident from the comparison of t h e i r melting p o i n t s and s p e c t r a l data. Compound 107 e x h i b i t e d m.p. 76-77° and an i n f r a r e d spectrum that was d i s t i n c t l y d i f f e r e n t from the i n f r a r e d spectrum of compound 104, p a r t i c u l a r l y i n the " f i n g e r -p r i n t " r e g i o n . The n.m.r. spectrum o f 107 e x h i b i t e d s i g n a l s s i m i l a r 4 I t should be noted that t h i s keto k e t a l was recovered unchanged a f t e r treatment w i t h base, thus i n d i c a t i n g that e p i m e r i z a t i o n had occurred e i t h e r during the ozo n o l y s i s and/or during the i s o l a t i o n and p u r i f i c a t i o n of the product. - 47 -to those present i n the n.m.r. spectrum of 104, yet at d i s t i n c t l y d i f f e r e n t chemical s h i f t s . Successive h y d r o l y s i s and hydrogenation of compound 107 produced the decalone 108 which again was d i f f e r e n t from the decalone 90_ obtained p r e v i o u s l y . 108 107 106 Obviously, the o v e r a l l e p i m e r i z a t i o n i n v o l v e d i n the conversion of 104 i n t o 107 r e q u i r e d that the isopropenyl group was a x i a l i n the s t a r t i n g m a t e r i a l 104, and e q u a t o r i a l i n the product 107. The e p i m e r i z a t i o n of the keto k e t a l 109 to the keto k e t a l 106 would be expected to be very f a c i l e , s ince t h i s would r e l i e v e the 1 , 3 - d i a x i a l i n t e r a c t i o n between the a c e t y l group and the a x i a l oxygen of the ethylene k e t a l i n compound 109. The above stereochemical p r e d i c t i o n regarding the conjugate a d d i t i o n of isopropenyl magnesium bromide to the a ,3-unsaturated ketone system of octalone 91_ was t h e r e f o r e c o r r e c t and the stereochemistry of the product 97_ was completely defined. - 48 -Th i s , i n t u r n , unambiguously e s t a b l i s h e d the stereochemistry of (±)-4-demethylaristolone 16. 109 106 The lithium-ammonia r e d u c t i o n of (±)-5-epi-4-demethylaristolone 88_ was a l s o c a r r i e d out. As i n the case of the epimeric (t)-4-demethyl-a r i s t o l o n e 16, r e d u c t i o n of 88_ was completely s t e r e o s e l e c t i v e and c l e a n l y produced, i n high y i e l d , only one dihydro d e r i v a t i v e 110. Lithium-ammonia r e d u c t i o n of the l a t t e r afforded the s u b s t i t u t e d decalone 111. Somewhat s u r p r i s i n g l y , t h i s decalone proved to be d i f f e r e n t from decalone 108, the s t r u c t u r e of which was unambigously defined. This observation could only lead to the i n t e r e s t i n g c o n c l u s i o n that the lithium-ammonia r e d u c t i o n of (I)-5-epi-4-demethylaristolone 88 had produced a dihydro d e r i v a t i v e with cis_-fused six-membered r i n g s . In cont r a s t to the normal stereochemical outcome of reductions of t h i s type (47,48,49) t h i s i s , to our knowledge, the f i r s t recorded example 1 (9) of a lithium-ammonia r e d u c t i o n of a s u b s t i t u t e d A *• J-octal-2-one which s t e r e o s e l e c t i v e l y gave the corresponding c i s - f u s e d decalone d e r i v a t i v e . - 49 -88 110 111 In order to attempt to r a t i o n a l i z e the stereochemical outcome o f the lithium-ammonia r e d u c t i o n of (±)-5-epi-4-demethylaristolone 88_ to i t s dihydro d e r i v a t i v e 110, i t would be i n s t r u c t i v e to examine the 1 9"' mechanisms proposed f o r the B i r c h r e d u c t i o n of A ' -octal-2-ones. Although the mechanism shown i n Chart 8 i s g e n e r a l l y accepted, there has been controversy regarding the geometry of the t r a n s i t i o n s t a t e (49). CHART 8: Mechanism of B i r c h Reduction of A ' -octal-2-ones. - 50 -I n i t i a l l y Stork and D a r l i n g (48) proposed that the geometry of the t r a n s i t i o n s t a t e would approach that of G_ or H, both of which have 9 t e t r a h e d r a l C carbon atoms. Other p o s s i b l e s t r u c t u r e s f o r the t r a n s i t i o n s t a t e were dismissed s i n c e they lacked the overlap of the carbanion with the i r - o r b i t a l s of the enolate-type system (stereo-e l e c t r o n i c c o n t r o l ) . Robinson however, argued that a t r a n s i t i o n s t a t e 9 i n which the C carbon atom i s t e t r a h e d r a l could not e x p l a i n the high 1 9 s t e r e o s e l e c t i v i t y of the B i r c h r e d u c t i o n of s u b s t i t u t e d A ' - o c t a l - 2 -ones (49). Instead he proposed that the t r a n s i t i o n s t a t e l i e s c l o s e r 9 i n geometry to the s t a r t i n g octalone which has a t r i g o n a l C' carbon atom. Robinson explained the high s t e r e o s e l e c t i v i t y of the reductions by c o n s i d e r i n g s u b t l e conformational changes i n the conversion of the r a d i c a l anion ( c f 11,2) i n t o the various p o s s i b l e t r a n s i t i o n s t a t e s . In the case of the B i r c h r e d u c t i o n of (±)-5-epi-4-demethylaristolone 88 i t was very d i f f i c u l t to p r e d i c t which of the p o s s i b l e t r a n s i t i o n s t a t e s c o n t a i n i n g a t r i g o n a l g-carbon atom would be favored, s i n c e the 1 9 st r u c t u r e s i n v o l v e d here were much more complex than the A ' - o c t a l - 2 -ones stud i e d by Robinson (49). However, i f one considers t r a n s i t i o n s t a t e s i n which the g-carbon approaches a t e t r a h e d r a l c o n f i g u r a t i o n then the r e s u l t s of the r e d u c 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 . Molecular models c l e a r l y show that p r o t o n a t i o n of the r a d i c a l anion .113 v i a a t r a n s i t i o n s t a t e approaching I_ (to e v e n t u a l l y a f f o r d a trans-fused decalone system) would i n v o l v e a severe non-bonded i n t e r a c t i o n between the angular methyl group and one of the c y c l o p r o p y l methyl groups. However, p r o t o n a t i o n v i a a t r a n s i t i o n s t a t e approaching JJ* (to a f f o r d ^ I t should be noted that s t e r e o e l e c t r o n i c c o n t r o l (48) could be maintained i n both I and J . - 51 -a cis-fused decalone system) could take place r e l a t i v e l y free of any serious non-bonded i n t e r a c t i o n s . Therefore, looking at the problem i n these terms, one can r e a d i l y p r e dict that J_ should be much preferred over I_, thus assuring the s t e r e o s e l e c t i v e formation of the observed product 110. ,NH. H' The work described i n t h i s part of the thesis c l e a r l y demonstrated that the synthesis of aristolone-type molecules v i a the i n i t i a l l y proposed intramolecular c y c l i z a t i o n of a s u i t a b l e diazoketone was f e a s i b l e . Therefore, it>appeared that a p p l i c a t i o n . o f t h i s general approach to the synthesis of aristolone i t s e l f would be f r u i t f u l , and, i n f a c t , t h i s was subsequently accomplished (16). F i n a l l y , the stereochemical proof of the model compound 16, as described i n t h i s part of the t h e s i s , l a i d the foundation for work concerned with a synthetic proof for the stereochemistry of a r i s t o l o n e (67). EXPERIMENTAL General M e l t i n g p o i n t s , which were determined on a Fisher-Johns m e l t i n g point!apparatus, and b o i l i n g p o i n t s are uncorrected. U l t r a v i o l e t s p e c t r a were 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 spectra were recorded on a Perkin-Elmer I n f r a c o r d model 137 spectro-photometer, while a l l comparison s p e c t r a were recorded on a P e r k i n -Elmer model 421 spectrophotometer. Nuclear magnetic resonance (n.m.r.) sp e c t r a were taken i n deuterochloroform s o l u t i o n on Varian A s s o c i a t e s spectrometers, model A-60, T-60 and/or model HA-100. S i g n a l p o s i t i o n s are given i n the T i e r s T s c a l e , with t e t r a m e t h y l s i l a n e as an i n t e r n a l 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. High r e s o l u t i o n mass spec t r a were recorded on an AEI, type MS9, mass spectrometer. G a s - l i q u i d chromatography ( g . l . c . ) was c a r r i e d out on an Aerograph Autoprep, model 700. The f o l l o w i n g columns (10 f t x 1/4 i n , unless otherwise stated) were employed, with the i n e r t , supporting m a t e r i a l being 60/80 mesh Chromosorb W i n each case: Column A, 20% FFAP; Column B, 15% QF-1; Column C, 20% Apiezon J ; Column D, 10% Apiezon J ; Column E (10 f t x 3/8 i n ) , 30% FFAP; ^ This general s e c t i o n i s a p p l i c a b l e to the experimental of both Part 1 and Part 2 of t h i s t h e s i s . - 53 -Column F (10 f t x 3/8 i n ) , 30% Carbowax 20 M; Column G (10 f t x 3/8 i n ) , 30% SE 30; Column H, 20% SE-30; Column I (10 f t x 3/8 i n ) , 30% Apiezon J . The s p e c i f i c column used, along with the columnxtemperature and c a r r i e r gas (helium) flow-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. 6-Hydroxymethylene-2-methylcyclohexanone 7_6_ To an i c e - c o o l e d , s t i r r e d suspension of powdered sodium methoxide [prepared from 69.0 g (2.57 moles) of sodium metal and dry methanol under a dry atmosphere] i n 1.1 1 of dry benzene, kept under an atmosphere of dry n i t r o g e n , was added 169 g,i, (1.51 moles) of 2-methylcyclohexanone 75. 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 222 g (3.00 moles) of e t h y l formate was added. The mixture was warmed to room temperature and allowed to stand overnight. Water was added, the mixture was shaken u n t i l the p r e c i p i t a t e had d i s s o l v e d , and the la y e r s were separated. The organic l a y e r was ext r a c t e d with 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 with 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 x t r a c t s were washed with water and d r i e d over anhydrous sodium 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 192 g (91%) of the hydroxymethylene d e r i v a t i v e 7_6_ as a pale - y e l l o w o i l , b.p. 49-52° at 0.45 mm. L i t . b.p. 97-99° at 23 mm (39) and 87.5-92.5° at 14 mm (41). I n f r a r e d ( f i l m ) , 6 . 0 5 , 6.25 \i. - 54 -2-Methyl-6-n-butylthiomethylenecyclohexanone 77 A s o l u t i o n of the hydroxymethylene d e r i v a t i v e 76_ (191 g, 1.36 moles), n-butanethiol (136 g, 1.51 moles), and p_-toluenesulfonic a c i d (250 mg) i n 1 1 of dry benzene was r e f l u x e d i n a n i t r o g e n atmosphere under a Dean-Stark water separator f o r 6 h, at which time 24 ml (1.33 moles) 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 d r i e d over anhydrous sodium 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 289 g (86%) of the n-butylthiomethylene d e r i v a t i v e 77, b.p. 111-113° at 0.04 mm. L i t . b.p. 93-95° at 0.05 mm (39). I n f r a r e d ( f i l m ) , A 6.02, 6.50 y. r v J max 2-Methyl-2-methallyl-6-n-butylthiomethylenecyclohexanone 78^  To a s t i r r e d s o l u t i o n of potassium t-butoxide (140 g, 1.23 moles) i n 1200 ml of dry t_-butyl a l c o h o l was added 77 g (0.363 mole) of 2-methyl-6-n-butylthiomethylenecyclohexanone 77_ 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°. Freshly d i s t i l l e d m e t h a l l y l c h l o r i d e (174 g, 1.92 moles) was added and the r e a c t i o n mixture was r e f l u x e d under an atmosphere of dry n i t r o g e n f o r 2 h. A f t e r most of the solvent had been removed under reduced pressure, the residue was d i l u t e d with water and ex t r a c t e d thoroughly w i t h ether. The ether s o l u t i o n was washed with water and saturate d b r i n e , d r i e d over anhydrous sodium s u l f a t e , and concentrated. The r e s i d u a l o i l was d i s t i l l e d under reduced pressure to a f f o r d 78 g (70%) 20 of the a l k y l a t e d ketone 78_b.p. 101-103°.at 0.08 mm, n 1.4965. - 55 -U l t r a v i o l e t , X 280 mp (e = 12,100); i n f r a r e d ( f i l m ) , A 5.98, 6.31, nic ix nicix 10.92 y; n.m.r., x 2.40 ( t r i p l e t , IH, =CHSnBu), 5.20, 5.34 (two m u l t i p l e t s , 2H, =CH^), 8.89 ( s i n g l e t , 3H, t e r t i a r y methyl). Anal. Calcd. f o r C^H^OS: C, 72.12; H, 9.84; S, 12.03. Found: C, 72.07; H, 9.77; S, 11.94. 2-Methyl-2-methallylcyclohexanone 79_ A s t i r r e d s o l u t i o n of compound 78_ (65.8 g, 0.25 mole) i n 150 ml of 25% aqueous potassium hydroxide and 150 ml of ethylene g l y c o l was r e f l u x e d , under an atmosphere of n i t r o g e n , f o r 18 h. The r e a c t i o n mixture was steam d i s t i l l e d u n t i l the d i s t i l l a t e was c l e a r . The d i s t i l l a t e was saturated w i t h s a l t and the mixture was ex t r a c t e d w i t h three p o r t i o n s of ether. The combined e x t r a c t s were washed with saturated b r i n e , d r i e d over anhydrous sodium s u l f a t e , and concentrated. D i s t i l l a t i o n of the crude o i l gave 33.3 g (80%) of the d e s i r e d ketone 79, b.p. 54-58° at 0.6 mm, n^ 1.4772. I n f r a r e d ( f i l m ) , X 5.86, 6.10, — r ' D J max 11.16 y; n.m.r., x 5.18, 5.33 (two m u l t i p l e t s , 2H, =CH 2), 8.33 (broad s i n g l e t , 3H, v i n y l methyl), 8.92 ( s i n g l e t , 3H, t e r t i a r y methyl). Anal. Calcd. f o r C 1 1 H 1 o 0 : C, 79.47; H, 10.91. Found: C, 79.67; 11 I o H, 10.79. 2-Methyl-2-methylpropenylcyclohexanone 80 A s o l u t i o n of the ketone 79_ (36 g) and p_-toluenesulfonic a c i d (460 mg) i n 700 ml of dry benzene was r e f l u x e d under n i t r o g e n f o r 3 days. The s o l u t i o n was cooled, washed with saturated aqueous sodium bicarbonate - 56 -and wit h saturated b r i n e , d r i e d over anhydrous sodium s u l f a t e , and concentrated. D i s t i l l a t i o n of the crude product gave 27.7 g (77%) of a c l e a r o i l , b.p. 59-62° at 0.8 mm. G a s - l i q u i d chromatographic a n a l y s i s (column A, 170°, 75) 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 was a mixture, c o n s i s t i n g of approximately 80% of the d e s i r e d ketone 80, 17% s t a r t i n g m a t e r i a l 79_ and 3% of an u n i d e n t i f i e d compound. This mixture 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 through a spinning band column ( s t a i n l e s s s t e e l , 8 mm x 24 i n ) . The d i s t i l l a t i o n was c a r r i e d out at a pressure of 28 mm, and each f r a c t i o n was submitted to g a s - l i q u i d chromatographic a n a l y s i s (column A, 170°, 75). The i n i t i a l , small f r a c t i o n s (1 and 2), b.p. 105-112°, c o n s i s t e d mainly of the u n i d e n t i f i e d i m p u r i t y . F r a c t i o n s 3, 4 and 5 (15.1 g, b.p. 112-116°) contained the de s i r e d ketone 80, greater than 97% pure. F r a c t i o n 6 (3.3 g, b.p. 116-118°) contained approximately 80% of the d e s i r e d product 7_9 and 20% s t a r t i n g m a t e r i a l 7_9_. The s t i l l - p o t residue (6.4 g) c o n s i s t e d of a mixture of compounds 79_ (85%) and 80_ (15%) . An a n a l y t i c a l sample o f 2-methyl-2-methylpropenylcyclohexanone 80_ was c o l l e c t e d by p r e p a r a t i v e 20 g . l . c . (column A, 170°, 75) and e x h i b i t e d n^ 1.4767. I n f r a r e d ( f i l m ) , 5.88 y ; n.m.r., x 4.74 ( m u l t i p l e t , IH, v i n y l H), 8.31, 8.57 (doublets, 6H, v i n y l methyls, J = 1.5, 1.2 Hz, r e s p e c t i v e l y ) , 8.91 ( s i n g l e t , 3H, t e r t i a r y methyl). Anal. Calcd. f o r C „ H. o0: C, 79.47; H, 10.91. Found: C, 79.56; 11 l o H, 11.10. Reaction of Ketone 80 w i t h D i e t h y l Cyanomethylphosphonate A s t i r r e d suspension o f sodium hydride (10.9 g, 0.454 mole) i n dry - 57 -dimethyl s u l f o x i d e (220 ml) was slowly heated, under an atmosphere of 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 45 minutes). 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 d i e t h y l cyanomethylphosphonate (80.5 g, 0.455 mole) i n 150 ml of dimethyl s u l f o x i d e was added. A f t e r s t i r r i n g the r e a c t i o n mixture f o r 10 min, a s o l u t i o n of ketone 80_ (15.1 g, 0.091 mole) i n 40 ml of dimethyl s u l f o x i d e was added. The s o l u t i o n was heated at 100° overnight, cooled, d i l u t e d with water, and e x t r a c t e d three times with petroleum ether (b.p. 30-60°). The combined e x t r a c t s were washed three times with water and once with saturated b r i n e , d r i e d over anhydrous sodium s u l f a t e , and concentrated. D i s t i l l a t i o n of the crude product gave 16.3 g (95%) of a c l e a r o i l , b.p. 84-87° at 0.15 mm. A n a l y s i s by g . l . c . (column B, 200°, 100) showed that t h i s m a t e r i a l was a mixture, c o n t a i n i n g approximately 80% of the a,g-unsaturated n i t r i l e 81 and 20% of the 8,y-unsaturated n i t r i l e 82_. An a n a l y t i c a l sample of the major product was obtained by p r e p a r a t i v e g . l . c . (column B, 170°, 20 100) and e x h i b i t e d n,, 1.5069. U l t r a v i o l e t , A 219 my (e =10,900); 1 D max v i n f r a r e d ( f i l m ) , 4.55, 6.20 y; n.m.r. T 4.75 ( s i n g l e t , IH, =CHCN), 4.81 ( m u l t i p l e t , IH, v i n y l H), 8.28, 8.49 (doublets, 6H, v i n y l methyls, J = 1.4, 1.3 Hz, r e s p e c t i v e l y ) , 8.80 ( s i n g l e t , 3H, t e r t i a r y methyl). Mol. Wt. Calcd. f o r C 1 3H 1 QN: 189.152. Found (high r e s o l u t i o n mass spectrometry): 189.150. Although the minor isomer 81_ was not i s o l a t e d i n pure form, an HA-100 n.m.r. spectrum (sweepwidth 250 Hz ) of the mixture of 81_ and 82 c l e a r l y showed that the minor isomer was indeed the 8,y-unsaturated n i t r i l e 82. P e r t i n e n t n.m.r. s i g n a l s assigned to the l a t t e r compound - 58 -were: x4.10 ( m u l t i p l e t , y - o l e f i n i c p r o t o n ) , 8.32 ( s i n g l e t , presumably h a l f of a doublet due to a v i n y l methyl, w i t h the lower f i e l d h a l f of t h i s doublet being masked by a large s i g n a l centered at T 8.28), 8.39 (doublet, v i n y l methyl, J = 1.4 Hz), 8.86 ( s i n g l e t , t e r t i a r y methyl). The mixture a l s o gave s a t i s f a c t o r y a n a l y t i c a l data. Anal. Calcd. f o r C H^N: C, 82.48; H, 10.13. Found: C, 82.25; H, 10.35. Prep a r a t i o n of Car b o x y l i c Acid 83_ To a s o l u t i o n of potassium hydroxide (75 g) i n 390 ml of 95% ethanol was added 15.1 g (0.08 mole) of the mixture of n i t r i l e s 81_ and 82_. The s o l u t i o n was r e f l u x e d under an atmosphere of n i t r o g e n f o r 3 days. Most of the sol v e n t was removed under reduced pressure, and the res i d u e was d i l u t e d w i t h water. The mixture was washed with ether and then a c i d i f i e d with d i l u t e h y d r o c h l o r i c a c i d . The aqueous l a y e r was ext r a c t e d three times with ether. The combined e x t r a c t s were washed with water and saturated b r i n e , and then d r i e d over anhydrous sodium 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 gave 10.9 g (65%) of the 3,y-unsaturated c a r b o x y l i c a c i d 83, O f ) b.p. 118-122° at 0.05 mm, n^ u 1.5035. I n f r a r e d (CHC1,), X 2.9-4.1 r D ^ 3 ^ max (broad), 5.85 y; n.m.r., T 4.38 ( t r i p l e t , IH, y - v i n y l H), 4.95 ( m u l t i p l e t , IH, v i n y l H), 7.09 ( m u l t i p l e t , 2H, -CH^COOH), 8.36, 8.40 (doublets, 6H, v i n y l methyls, J = 1.5, 1.2 Hz, r e s p e c t i v e l y ) , 8.87 ( s i n g l e t , 3H, t e r t i a r y methyl). Anal. Calcd. f o r C, 7 H ^ 0 • C, 74.96; H, 9.68. Found: C, 74.80; 16 zo 2 H, 9.91. - 59 -Dienone 85, (-)-4-Demethylaristolone 16, and (+)-5-epi-4-Demethylaristolone 88 The 8,y-unsaturated c a r b o x y l i c a c i d 83_ (4.0 g, 20.6 mmoles) was d i s s o l v e d i n 0.1 N aqueous sodium hydroxide (22.6 mmoles), the water was removed under reduced pressure, and the residue was d r i e d i n a vacuum oven at 70°. To a s t i r r e d suspension of the r e s u l t i n g a c i d s a l t i n 80 ml of c o l d (0°), dry benzene was added 6 drops of p y r i d i n e , f o l l owed by 28 ml of o x a l y l c h l o r i d e . The s o l u t i o n was s t i r r e d at room temperature f o r 30 min, f i l t e r e d , and concentrated, under reduced pressure, at 40°. The crude a c i d c h l o r i d e 84 [ i n f r a r e d ( f i l m ) , A. r — L v • max 5.60 y; n.m.r. x 4.32 (broad m u l t i p l e t , IH, Y _ v i n y l p r o t o n ) , 4.93 ( m u l t i p l e t , IH, CH=CMe2), 6.54 ( m u l t i p l e t , 2H, a-protons), 8.31, 8.38 (doublets, 6H, v i n y l methyls, J = 1.3 Hz), 8.84 ( s i n g l e t , 3H, t e r t i a r y methyl)] thus obtained was immediately d i s s o l v e d i n 40 ml of dry ether and an excess of dry, a l c o h o l f r e e e t h e r e a l diazomethane was added. A f t e r 30 min the solvent was removed under reduced pressure, a f f o r d i n g the crude diazoketone 86. I n f r a r e d ( f i l m ) , X 4.80, 6.16 y: — v J max n.m.r., x 4.41 (broad m u l t i p l e t , IH, y - v i n y l p r o t o n ) , 4.72 ( s i n g l e t , IH, CHN 2), 4.90 ( m u l t i p l e t , IH, CH=CMe2), 7.07 ( m u l t i p l e t , 2H, a-protons), 8.33, 8.38 (doublets, 6H, v i n y l methyls, J = 1.3 Hz), 8.85 ( s i n g l e t , 3H, t e r t i a r y methyl). In a d d i t i o n to these s i g n a l s assigned to the 8,y-unsaturated diazoketone 86, the n.m.r. spectrum of the crude product a l s o e x h i b i t e d s i g n a l s f o r the dienone 85. The i n t e n s i t y of these s i g n a l s i n d i c a t e d t h a t compound 85_ was a s i g n i f i c a n t i m p u r i t y . The crude diazoketone was d i s s o l v e d i n 400 ml of cyclohexane and 8 g of anhydrous c u p r i c s u l f a t e was added. The r e s u l t i n g suspension was - 60 -s t i r r e d v i g o r o u s l y and r e f l u x e d under an atmosphere of n i t r o g e n f o r 2 h, at which time the i n f r a r e d absorption at 4.80 y had disappeared. The suspension was cooled, f i l t e r e d , washed with saturated aqueous sodium bicarbonate and w i t h saturated b r i n e , d r i e d over anhydrous sodium s u l f a t e , and concentrated. G a s - l i q u i d chromatographic a n a l y s i s (column C, 200°, 85) of the r e s u l t i n g crude product (3.77 g) showed that i t contained, i n a d d i t i o n to a number of minor components of short r e t e n t i o n time, three major components, 85, 16, and 88, i n a r a t i o of 2:2:1, r e s p e c t i v e l y . The crude product was r e f l u x e d f o r 10 min i n a mixture of ethanol (280 ml) and water (25 ml) c o n t a i n i n g 10 g of sodium hydroxide. The s o l u t i o n was concentrated under reduced pressure, the residue was d i l u t e d with water, and e x t r a c t e d thoroughly with ether. The ether s o l u t i o n was washed with water and saturated b r i n e , d r i e d over anhydrous sodium s u l f a t e and concentrated. A n a l y s i s of the crude product (2.32 g) by g . l . c . showed that a l l the minor components had been removed by t h i s treatment, l e a v i n g only a mixture of the three major components 85, 16, and &8_. A f t e r p a r t i a l s e paration of these compounds had been a f f e c t e d by column chromatography on Woelm n e u t r a l alumina, a c t i v i t y 1, an a n a l y t i c a l sample of each compound was obtained by p r e p a r a t i v e g . l . c . (column C, 200°, 85). 20 The cross-conjugated dienone 85, an o i l , e x h i b i t e d n^ 1.5408. U l t r a v i o l e t , A 255 my (e = 17,200); i n f r a r e d (CHC1J, A 5.98, IIlclX J IT13.X 6.18 y; n.m.r., T 4.13 (broad s i n g l e t , IH, v i n y l H, width at h a l f - h e i g h t = 2 Hz), 7.68, 8.06 ( s i n g l e t s , 6H, v i n y l methyls), 8.66 ( s i n g l e t , 3H, t e r t i a r y methyl). Anal. Calcd. f o r C1_H.lo0: C, 82.05; H, 9.54. Found: C, 81.94; l o l o H, 9.72. - 61 -This compound could a l s o be prepared by a l l o w i n g the a c i d c h l o r i d e 84 to stand at room temperature f o r 24 h, followed by d i s t i l l a t i o n , b.p. 75° (bath temperature) at 0.2 mm. This product was i d e n t i c a l w i t h 85_ described above. (±)-4-Demethylaristolone 16, an o i l , e x h i b i t e d the f o l l o w i n g s p e c t r a l p r o p e r t i e s . U l t r a v i o l e t , ^ m a x 235 my (e = 11,600); i n f r a r e d (CHC1 ), A 6.10 y; n.m.r., x 4.32 (broad s i n g l e t , IH, v i n y l H), 8.70, o msix 8.77, 8.83 ( s i n g l e t s , 9H, t e r t i a r y methyls). Mol. Wt. Calcd. f o r C^H^O: 204.151. Found (high r e s o l u t i o n mass spectrometry): 204.151. The c r y s t a l l i n e (!)-5-epi-4-demethylaristolone 88 was r e c r y s t a l l i z e d from petroleum ether (b.p. 60-80°) and e x h i b i t e d m.p. 86.5-87.5°. U l t r a v i o l e t , X 232 mP (e = 11,700); i n f r a r e d (CHC1,), x 6.11 P; U l c l X O U l c l X n.m.r., x 4.28 ( s i n g l e t , IH, v i n y l H), 8.62, 8.65, 8.70 ( s i n g l e t s , 9H, t e r t i a r y methyls). Mol. Wt. Calcd. f o r c 1 4 H 2 o 0 : 204.151. Found (high r e s o l u t i o n mass spectrometry): 204.150. Preparation of Ke t o l 92_ According to the method of M a r s h a l l and Fanta (53), 136.2 g (1.21 moles) of 2-methylcyclohexanone 75_ and 7.3 ml of a 3 M s o l u t i o n of sodium ethoxide i n ethanol were placed i n a flame d r i e d f l a s k equipped with a dropping funnel and a mechanical s t i r r e r . The r e a c t i o n v e s s e l and contents were cooled to -10° i n an ethanol-water (3:7 volume r a t i o ) dry i c e s l u s h bath. To the r e a c t i o n mixture was added 85.1 g (1.21 moles) of methyl v i n y l ketone over a 6 h p e r i o d , and the r e a c t i o n was - 62 -allowed to s t i r at -10° f o r an a d d i t i o n a l 6 h. The mixture was t r a n s -f e r r e d to a l a r g e separatory funnel c o n t a i n i n g saturated b r i n e and the r e s u l t i n g mixture was ext r a c t e d w i t h three p o r t i o n s of ether. The combined e x t r a c t s were washed with b r i n e and then d r i e d over anhydrous sodium s u l f a t e . A f t e r removal of the d r y i n g agent, the s o l u t i o n was concentrated to 1.7 1 and, while a d d i t i o n a l ether was removed on a steam bath, hexane was added to maintain the volume u n t i l c r y s t a l l i z a t i o n occurred. The cooled s o l u t i o n y i e l d e d 62.3 g (30%) of white c r y s t a l s . R e c r y s t a l l i z a t i o n from hexane:ether gave an a n a l y t i c a l sample of the keto 1 92., m.p. 121.5-122°. L i t . m.p. 120.8-121.4° (64). I n f r a r e d (KBr) , A 2.98, 5.85 y; n.m.r., x 8.87 ( s i n g l e t , 3H, t e r t i a r y methyl), 7.94 ( s i n g l e t , IH, hydroxyl proton by D2O exchange). Pre p a r a t i o n of Octalone 9_3_ A s o l u t i o n of k e t o l 92_ (61.2 g, 0.336 mole) and potassium hydroxide (86.5 g) i n 865 ml of 95% ethanol was rel u x e d under n i t r o g e n f o r 6.5 h. The s o l u t i o n was n e u t r a l i z e d with gaseous HC1 and concentrated under reduced pressure. The residue was d i l u t e d with saturated b r i n e and the r e s u l t i n g mixture was e x t r a c t e d thoroughly w i t h ether. The combined ether e x t r a c t s were washed with b r i n e , d r i e d over anhydrous sodium s u l f a t e and concentrated. The residue was d i s t i l l e d under reduced pressure to a f f o r d 38 g (62%) of the octalone £3, b.p. 73° at 0.4 mm. L i t . b.p. 70° at 0.3 mm and 82-83° at 0.7 mm (53). An a n a l y t i c a l sample, 2 0 c o l l e c t e d by g . l . c . (column H, 200°, 85), e x h i b i t e d n D 1.5249. L i t . n 2 5 1.5230 (53). U l t r a v i o l e t , A 239 my (e = 14,400); i n f r a r e d ( f i l m ) , - 63 -A 5.96, 6.17 p; n.m.r., x 4.29 ( s i n g l e t , IH, a - v i n y l p r o t o n ) , 8.74 ITlciX ( s i n g l e t , 3H, t e r t i a r y methyl). The 2,4-dinitrophenylhydrazone d e r i v a t i v e of the octalone £3 e x h i b i t e d m.p. 170.5°. L i t . m.p. 169° (65). Preparation of Decalone 95_ To one 1 of l i q u i d ammonia, which had been d i s t i l l e d from sodium metal, was added 46 g (2 moles) of sodium. A f t e r 15 min a s o l u t i o n of 54 g (0.33 mole) of octalone 93_ i n 50 ml of ether was added over a 5 min pe r i o d . The r e a c t i o n mixture was s t i r r e d f o r 1 h at -33° and then quenched by slow a d d i t i o n of 200 ml of absolute a l c o h o l . A f t e r the ammonia had evaporated, water was added to the r e s i d u e , and the mixture was thoroughly extracted w i t h ether. Removal of the solvent afforded a dark red o i l which slowly s o l i d i f i e d upon c o o l i n g . R e c r y s t a l l i z a t i o n from ethanol-water afforded 41.0 g (74%) of the a l c o h o l 94, m.p. 66-68°. L i t . m.p. 69-70° (66). To a s o l u t i o n of the a l c o h o l 94_ (41.0 g, 0.244 mole) i n 500 ml acetone at 0° was added a small excess of Jones reagent (55). A f t e r d e s t r o y i n g the excess o x i d i z i n g reagent with i s o p r o p y l a l c o h o l , the solvents were 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 three times with ether. The combined e x t r a c t s were washed with water and saturated b r i n e , d r i e d over anhydrous magnesium s u l f a t e and concentrated. Vacuum d i s t i l l a t i n g of the residue afforded 33.0 g (83%) of the decalone 95, b.p. 80-82° at 0.8 mm. L i t . b.p. 69° at 0.1 mm (52). I n f r a r e d ( f i l m ) , A 5.85 vi; n.m.r., x 8.95 ( s i n g l e t , 3H, t e r t i a r y methyl). TQcLX - 64 -Bromination o f Decalone 95_ To a s o l u t i o n of 14.4 g (0.09 mole) of bromine i n 80 ml of g l a c i a l a c e t i c a c i d at 0°, was added, dropwise, a s o l u t i o n of decalone 95 (15.0 g, 0.09 mole) i n 100 ml g l a c i a l a c e t i c a c i d . A f t e r c o n t i n u i n g the r e a c t i o n f o r an a d d i t i o n a l 3 h at 0° the s o l u t i o n was poured i n t o 1 1 of crushed i c e and water. The mixture was ex t r a c t e d three times w i t h ether. The combined ether e x t r a c t s were washed t h r i c e with water, t h r i c e with saturated sodium bicarbonate, twice with water, and twice with saturated b r i n e . The ether s o l u t i o n was d r i e d over anhydrous magnesium s u l f a t e , and concentrated under reduced pressure. The residue was c r y s t a l l i z e d from ether to a f f o r d 14.0 g (61%) of the c r y s t a l l i n e bromoketone 96, m.p. 100-102°. L i t . m.p. 101-102° (66). I n f r a r e d (KBr), Vax ^'^^ U5 n.m.r., x 5.32 (X p o r t i o n of an ABX qu a r t e t , IH, COCHBr, J . v = 12 Hz, J _ v = 6 Hz), 8.86 ( s i n g l e t , 3H, t e r t i a r y methyl). A X DA P r e p a r a t i o n of Octalone 91_ A s t i r r e d suspension of l i t h i u m bromide (1.1 g) and l i t h i u m carbonate (1.6 g) i n 30 ml of dry dimethylformamide was heated, under an atmosphere o f n i t r o g e n , to 120°. A s o l u t i o n of the bromoketone 9_6 (1.5 g, 6.1 mmoles) i n 30 ml of dry dimethylformamide was added and the mixture was heated at 120° f o r 1.75 h. The r e a c t i o n mixture was cooled, f i l t e r e d , d i l u t e d with water, and ext r a c t e d three times with n-heptane. The combined e x t r a c t s were washed t h r i c e with water, d r i e d over anhydrous magnesium s u l f a t e and concentrated. D i s t i l l a t i o n of the crude product gave 0.91 g (90%) of octalone 91 as a c l e a r , c o l o r l e s s o i l , - 65 -b.p. 100° at 0.35 mm, n 2 0 1.5088. L i t . b.p. 69° at 0.1 mm, n 2 6 1.5006 (52). G a s - l i q u i d chromatographic a n a l y s i s (column D, 200°, 85) of t h i s m a t e r i a l showed that i t c o n s i s t e d of only one component. U l t r a -v i o l e t , A 229 my (e = 9,200); i n f r a r e d ( f i l m ) , A 5.95, 6.16 y; nicLx nicix n.m.r., x 3.33, 4.24 ( p a i r of doublets, 2H, (0=C)CH=CH and (0=C)CH=CH, r e s p e c t i v e l y , J = 9.8 Hz), 8.96 ( s i n g l e t , 3H, t e r t i a r y methyl). P r e p a r a t i o n of Decalone 97_ To a s t i r r e d , i c e - c o l d 1 M s o l u t i o n (120 ml) of isopropenylmagnesium bromide i n t e t r a h y d r o f u r a n was added 0.65 g of anhydrous cuprous c h l o r i d e . A s o l u t i o n of octalone 91_ (10.0 g, 0.061 mole) i n 40 ml of t e t r a h y d r o f u r a n was added dropwise, over a p e r i o d of 20 min. The r e a c t i o n mixture was s t i r r e d f o r 2 h at 0° and then poured i n t o 350 ml of aqueous ammonium chloride-ammonium hydroxide b u f f e r (pH = 8). The organic l a y e r was separated and the aqueous l a y e r was e x t r a c t e d three times w i t h ether. The combined organic s o l u t i o n was washed with d i l u t e ammonium hydroxide, water and 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 , f o l l o w e d by d i s t i l l a t i o n under reduced pressure, gave a product (10.7 g, b.p. 99-103° at 0.5 mm) which was shown by g a s - l i q u i d chromatographyic a n a l y s i s (column D, 180°, 80) to c o n t a i n , i n a d d i t i o n to a number of minor components, one major product (approximately 60% of the m i x t u r e ) . Chromatography of t h i s mixture on Woelm n e u t r a l alumina (300 g) a f f o r d e d , i n the f r a c t i o n s e l u t e d w i t h 4:1 benzene-ether, 5.2 g (50%) of decalone 97, as pale yellow c r y s t a l s . A c a r e f u l examination of the various - 66 -chromatography f r a c t i o n s showed that 97_ was the only carbonyl-contain-ing compound present i n the product. R e c r y s t a l l i z a t i o n of 97_ from hexane-ether afforded c l e a r , c o l o r l e s s p l a t e s , m.p. 83-84°. I n f r a r e d (KBr), X 5.88, 6.14, 11.25 y; n.m.r., x 5.08, 5.45 ( m u l t i p l e t s , 2H, UlclX =CH 2), 8.23 ( m u l t i p l e t , 3H, v i n y l methyl), 8.84 ( 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, 81.49; H, 10.75. Found: C, 81.33; H, 10.69. Lithium-ammonia Reduction of (±)-4-Demethylaristolone 1_6_ To 50 ml of l i q u i d ammonia, which had been d i s t i l l e d from sodium metal, was added 70 mg 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 15 min. A s o l u t i o n of (±)-4-demethylaristolone (16) (100 mg) i n 8 ml of anhydrous ether was added dropwise 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 1 h. A f t e r the r e a c t i o n had been quenched with ammonium c h l o r i d e , 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 with water. The aqueous l a y e r was saturated with s a l t and extracted three times w i t h ether. The combined e x t r a c t s were washed with saturated 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 y i e l d e d 90 mg (90%) of a c l e a r , c o l o 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 C, 200°, 85) showed that t h i s m a t e r i a l c o n s i s t e d of n e a r l y pure (±)-9,10-dihydro-4-demethylaristolone 89_, the only impurity being a small amount of s t a r t i n g m a t e r i a l 1_6_. An a n a l y t i c a l sample of compound 89, an o i l , was obtained by p r e p a r a t i v e g . l . c . (column C, 200°, 85). U l t r a v i o l e t , - 67 -A 212.5 my (e = 5,200); i n f r a r e d (CHC1 ), A 6.00 n.m.r., fficLX O IHcLX T 8.35, 8.94 ( p a i r of doublets, 2H, c y c l o p r o p y l protons, J = 8.0 Hz), 8.59, 8.87, 8.97 ( s i n g l e t s , 9H, t e r t i a r y methyls). Mol. Wt. Calcd. f o r C^H^O: 206.167. Found (high r e s o l u t i o n mass spectrometry): 206.166. Prep a r a t i o n of Decalone 90_ a) By Hydrogenation of Decalone 97 Hydrogenation (platinum oxide, ethanol) of compound 97 was c a r r i e d out at atmospheric pressure and room temperature. From 200 mg of 97, there was obtained, a f t e r f i l t r a t i o n of the hydrogenation mixture and concentration of the f i l t r a t e , 182 mg (91%) of the c r y s t a l l i n e decalone 90. R e c r y s t a l l i z a t i o n from n-hexane gave an a n a l y t i c a l sample, m.p. 49-50°. I n f r a r e d (CHC1J, A 5.85 y; n.m.r., x 8.89 ( s i n g l e t , 3H, O TIlclX t e r t i a r y methyl), 9.08, 9.17 (doublets, 6H, secondary methyls, J = 6.8 Hz) . Anal. Calcd. f o r C^H^O: C, 80.70; H, 11.61. Found: C, 80.95; H, 11.51. b) By Lithium-ammonia Reduction of (±)-9,10-Dihydro-4-demethyl-a r i s t o l o n e 89_ The lithium-ammonia r e d u c t i o n of compound 89_ was c a r r i e d out by a procedure i d e n t i c a l w i t h that used f o r the r e d u c t i o n of (i)-4-demethyl-a r i s t o l o n e 1_6_ (see above) . From 60 mg of 89_ there was obtained 58 mg of the crude c r y s t a l l i n e decalone 90_. R e c r y s t a l l i z a t i o n from n-hexane gave an a n a l y t i c a l sample, m.p. 49-50°. This m a t e r i a l was shown to be - 68 -i d e n t i c a l (m.p., mixed m.p., g . l . c . r e t e n t i o n time, i n f r a r e d spectrum) with compound 90_ obtained as described above. Prep a r a t i o n of K e t a l 104 A s o l u t i o n of the decalone 97_ (3.1 g, 15 mmoles), ethylene g l y c o l (3.72 g, 60 mmoles), and p_-toluenesulfonic a c i d (50 mg) i n 50 ml of dry benzene was r e f l u x e d under a Dean-Stark water separator f o r 20 h. The cooled s o l u t i o n was d i l u t e d w i t h 50 ml of ether and washed with 50 ml of aqueous sodium bicarbonate. The organic l a y e r was d r i e d and concentrated, a f f o r d i n g 3.93 g of c o l o r l e s s c r y s t a l s . R e c r y s t a l l i z a t i o n from n-hexane gave 3.31 g (88%) of the k e t a l 104 as c o l o r l e s s p l a t e s , m.p. 80-81°. I n f r a r e d (CHC1_), X 6.15, 9.07, 9.28, 11.18 y; n.m.r., o U l c l X T 5.01, 5.20 ( m u l t i p l e t s , 2H, =CH 2), 6.10 ( m u l t i p l e t , 4H, -OCh^Ch^O-), 8.13 ( m u l t i p l e t , 3H, v i n y l methyl), 9.02 ( s i n g l e t , 3H, t e r t i a r y methyl). Anal. Calcd. f o r C 1 £H 0 o: C, 76.75; H, 10.46. Found: C, 76.69; 16 26 I H, 10.39. Ozonolysis of K e t a l 104 A s o l u t i o n of 3.0 g (12 mmoles) of k e t a l 104 was d i s s o l v e d i n 150 ml of e t h y l acetate and the s o l u t i o n was cooled i n a dry ice-acetone bath. Ozone was bubbled through the s o l u t i o n u n t i l a blue c o l o r began to appear (approximately 15 min) and continued f o r a f u r t h e r 15 min. Platinum oxide (400 mg) was added and the r e a c t i o n mixture was subjected t o hydrogenation at room temperature and atmospheric pressure. A f t e r hydrogen uptake had ceased, the mixture was f i l t e r e d and the f i l t r a t e - 69 -was concentrated under reduced pressure. G a s - l i q u i d chromatographic a n a l y s i s (column B, 200°, 85) showed that the r e s i d u a l o i l (2.63 g) con s i s t e d of three components. This m a t e r i a l was subjected to column chromatography on Woelm n e u t r a l alumina (120 g ) . The f i r s t f r a c t i o n (500 mg) showed no carbonyl absorption i n i t s i n f r a r e d spectrum, and was not i n v e s t i g a t e d f u r t h e r . The f r a c t i o n s e l u t e d with 9:1 to 4:1 benzene-ether gave a t o t a l of 620 mg (21%) of the c r y s t a l l i n e keto k e t a l 106 which, upon r e c r y s t a l l i z a t i o n from n-hexane, e x h i b i t e d m.p. 74-74.5°. I n f r a r e d (CHC1,), A 5.88, 9.08, 9.28 y; n.m.r., x 6.06 ( s i n g l e t , 4H, O IT13.X -0CH 2CH 20-), 7.84 ( s i n g l e t , 3H, -COCH^), 9.09 ( s i n g l e t , 3H, t e r t i a r y methyl). A n a l . Calcd. f o r C ^ H ^ O ^ C, 71.38; H, 9.59. Found: C, 71.15; H, 9.47. The f r a c t i o n s from the above chromatography which were e l u t e d w i t h 4:1 to 7:3 benzene-ether aff o r d e d 1.0 g of o i l y c r y s t a l s which were r e c r y s t a l l i z e d from n-hexane to a f f o r d 840 mg (33%) of the diketone 105, m.p. 95-95.5°. I n f r a r e d (CHC1_), A 5.85 y;.n.m.r., x 7.80 ( s i n g l e t , *j IT13.X 3H, -C0CH 3), 8.83 ( 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, 74.95; H, 9.67. Found: C, 74.98; H, 9.89. Preparation of Ke t a l 107 A s t i r r e d suspension of sodium hydride (107 mg, 4.5 mmoles) i n 3 ml of dry dimethyl s u l f o x i d e was slow l y heated, under an atmosphere of n i t r o g e n , t o 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 45 min). The s o l u t i o n was cooled to room temperature - 70 -and a s o l u t i o n of methyltriphenylphosphonium bromide (1.9 g, 5.3 mmoles) i n 3 ml of dimethyl s u l f o x i d e was added. A f t e r s t i r r i n g the r e a c t i o n mixture f o r 10 min, a s o l u t i o n of keto k e t a l 106 (225 mg, 0.9 mmole) i n 10 ml dimethyl s u l f o x i d e was added. The r e a c t i o n was heated at 100° f o r 6 h, cooled, and poured i n t o 25 ml of c o l d water. The mixture was ex t r a c t e d thoroughly w i t h pentane. The combined e x t r a c t s were washed three times w i t h water and once with saturated b r i n e , and then d r i e d over anhydrous magnesium s u l f a t e . Upon removal of the solvent 203 mg (91%) of the c r y s t a l l i n e k e t a l 107 was obtained. An a n a l y t i c a l sample, r e c r y s t a l l i z e d from n-hexane, e x h i b i t e d m.p. 76-77°. I n f r a r e d (CHC1 ), X 6.14, 9.08, 9.28, 11.18 y ; n.m.r., x 5.05, o nicLx 5.34 ( m u l t i p l e t s , 2H, =CH 2), 6.04 ( s i n g l e t , 4H, -OCh^CH^O-), 8.26 ( m u l t i p l e t , 3H, v i n y l methyl), 9.17 ( 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, 76.75; H, 10.46.. Found: C, 77.00; H, 10.45. Pr e p a r a t i o n of Decalone 108 A s o l u t i o n of k e t a l 107 (186 mg, 0.75 mmole) i n a mixture of acetone (5 ml) and 10% h y d r o c h l o r i c a c i d (5 ml) was heated on a steam bath u n t i l most of the acetone had d i s t i l l e d . Water was added to the r e s i d u e , and the mixture was 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 washed with water and with saturated b r i n e , d r i e d over anhydrous magnesium s u l f a t e and concentrated. The crude product [156 mg; i n f r a r e d ( f i l m ) , X 5.85, 6.14, 11.20 y ] thus obtained was not max J p u r i f i e d f u r t h e r , but was subjected d i r e c t l y to hydrogenation (platinum - 71 -oxide, ethanol) at atmospheric pressure and room temperature. A f t e r hydrogen uptake had ceased, the mixture was f i l t e r e d and the f i l t r a t e concentrated under reduced pressure. D i s t i l l a t i o n of the crude hydro-genation product gave 110 mg of pure decalone 108 as a c l e a r , c o l o r l e s s 20 o i l , b.p. 95° (bath temperature) at 0.1 mm, n^ 1.4965. I n f r a r e d ( f i l m ) , X 5.85 y; n.m.r., x 9.01 ( s i n g l e t , 3H, t e r t i a r y methyl), 9.12, U l c l X 9.18 (doublets, 6H, secondary methyls, J = 6.5 Hz). Anal. Calcd. f o r C^H^O: C, 80.70; H, 11.61. Found: C, 80.63; H, 11.49. Lithium-ammonia Reduction of (i) - 5 - E p i - 4 - d e m e t h y l a r i s t o l o n e (88) The lithium-ammonia r e d u c t i o n of 88_ was c a r r i e d out i n a manner i d e n t i c a l w i t h that described p r e v i o u s l y f o r the r e d u c t i o n of (+)-4-demethylaristolone 1_6_ (see page 66 ) . From 100 mg of compound 88_ there was obtained 90 mg of crude product, c o n s i s t i n g n e a r l y e n t i r e l y of the dihydro. d e r i v a t i v e 109. An a n a l y t i c a l sample of the l a t t e r , an o i l , was obtained by pr e p a r a t i v e g . l . c . (column C, 200°, 85). U l t r a -v i o l e t , X 210 my (e = 4,800); i n f r a r e d (CHC1 ), X 5.99 y; n.m.r., U l c l X ' o IT13.X x 8.43, 9.04 ( p a i r of doublets, 2H, c y c l o p r o p y l protons, J = 8 Hz), 8.71, 8.74, 8.87 ( s i n g l e t s , 9H, t e r t i a r y methyls). Mol. Wt. Calcd. f o r C^H^O: 206.167. Found (high r e s o l u t i o n mass spectrometry): 206.167. - 72 -Lithium-ammonia Reductionvof Compound 109 Reduction of 60 mg of compound 109, v i a a procedure i d e n t i c a l w i t h that described p r e v i o u s l y f o r the r e d u c t i o n of 1_6_ (see page 6 6 ) , gave 55 mg of crude c r y s t a l l i n e m a t e r i a l . R e c r y s t a l l i z a t i o n from n-hexane afforded an a n a l y t i c a l sample of the decalone 111, m.p. 50.5-51°. I n f r a r e d (CHC1,), A 5.88 y; n.m.r., x 8.87 ( s i n g l e t , 3H, t e r t i a r y methyl), 9.08, 9.16 (doublets, 6H, secondary methyls, J = 6.5 Hz). Mol. Wt. Calcd. f o r C H 2 40: 208.183. Found (high r e s o l u t i o n mass spectrometry): 208.182. PART 2 Total Synthesis of (±)-Seychellene INTRODUCTION Str u c t u r e and Stereochemistry of (-)-Seychellene The sesquiterpene (-)-seychellene 13, a minor component of commercial p a t c h o u l i o i l , which i s derived from Pogostemon c a b l i n Benth. co-occurs w i t h p a t c h o u l i a l c o h o l 14_ (68) and s e v e r a l v o l a t i l e hydro-carbons (68) (e.g. a-bulnesene 114, a-guaiene 115, and g-patchoulene 116). The f i r s t i s o l a t i o n of (-)-seychellene was reported i n 1967 by Y. Hirose and co-workers (69), while 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 n a t u r a l product was reported by G. Ourisson and G. Wolff i n 1968 (12,13). The assignment of the s t r u c t u r e and absolute stereochemistry of t h i s hydrocarbon 1_3 was based upon spectroscopic evidence and upon a degradative sequence. 13 14 - 75 -114 115 116 The molecular formula f o r seychellene ( C ^ H ^ ) i n d i c a t e d 4 degrees of u n s a t u r a t i o n , one of which could be accounted f o r by a t e r m i n a l o l e f i n i c double bond ( i n f r a r e d , 6.10 and 11.36 ; n.m.r., x 5.02 and T 5.37, 2H). The carbon s k e l e t o n , t h e r e f o r e , must be t r i c y c l i c . The n.m.r. spectrum of seychellene 13_ a l s o i n d i c a t e d the presence of two t e r t i a r y methyl groups and one secondary methyl group. Oxidation o f the te r m i n a l double bond of seychellene was very d i f f i c u l t . Only a f t e r prolonged treatment with osmium t e t r o x i d e d i d hy d r o x y l a t i o n take p l a c e , y i e l d i n g a d i o l which, upon treatment with sodium p e r i o d a t e , afforded nor-seychellanone 117. This ketone, which e x h i b i t e d methyl s i g n a l s i n i t s n.m.r. spectrum s i m i l a r to those of seychellene 13, was als o very u n r e a c t i v e . When compound 117 was t r e a t e d with sodium methoxide i n MeOD, no deuterium exchange could be observed. This seemed to i n d i c a t e that the p o s i t i o n s a to the carbonyl were e i t h e r f u l l y s u b s t i t u t e d and/or were bridgehead p o s i t i o n s . Treatment of nor-seychellanone 117 with sodium amide i n benzene y i e l d e d the saturated b i c y c l i c amide 118, which, by n.m.r. evidence, was shown to possess a t e r t i a r y methyl group and two secondary methyl groups. This amide 118 was converted i n t o i t s corresponding c a r b o x y l i c a c i d 119 by treatment of the former with n i t r o u s oxide i n a c e t i c a c i d . - 76 -- 77 -Decarboxylation of the c a r b o x y l i c a c i d 119 with lead t e t r a a c e t a t e i n benzene y i e l d e d a mixture of o l e f i n s 120 and the a l c o h o l 121. Dehydrogenation of the o l e f i n s 120 over selenium gave 1,4-dimethyl-naphthalene 122. This experiment i n d i c a t e d that the t e r t i a r y methyl group i n compound 119 was i n a bridgehead p o s i t i o n and a l s o e s t a b l i s h e d the p o s i t i o n s of the secondary methyl groups. Therefore, only the p o s i t i o n of the c a r b o x y l i c a c i d f u n c t i o n a l i t y had to be determined i n order to e s t a b l i s h the gross s t r u c t u r e of 119. Oxi d a t i o n of a l c o h o l 121 with chromium t r i o x i d e i n a c e t i c a c i d gave ketone 123. Since, i n the l a t t e r compound, four protons could be exchanged with deuterium, using MeOD and sodium methoxide, the carbonyl groups t h e r e f o r e had to be located at e i t h e r carbon 7 or carbon 8. The ketone 123 was converted i n t o i t s corresponding ethylene k e t a l 124 and the mass spectrum of the l a t t e r compound e s t a b l i s h e d the p o s i t i o n of the carbonyl group. The presence of three of the major peaks i n t h i s spectrum was r a t i o n a l i z e d by Ourisson and co-workers as shown i n Chart 9. The. presence of a peak at m/e = 139 excluded p o s i t i o n 8 as the s i t e f o r the carbonyl group i n compound 125, sin c e compound 124a would have given r i s e to a peak at m/e = 153, r a t h e r than at m/e = 139, as was a c t u a l l y observed. Since the s t r u c t u r e of ketone 123 was thus e s t a b l i s h e d , the s t r u c t u r e of amide 118 could a l s o be assigned. Furthermore, s i n c e i n the tran s f o r m a t i o n of norseychellanone 117 i n t o t h i s amide 118, a t e r t i a r y methyl group became a secondary methyl group, s t r u c t u r e s A and - 78 -CHART 9: Mass S p e c t r a l Fragmentation of K e t a l 124 124a m/e 238 m/e 153 J3 represent the only two p o s s i b l e s t r u c t u r e s f o r nor-seychellanone 117. However, sin c e nor-seychellanone 117 e x h i b i t e d an i n f r a r e d absorption A B - 79 -at 5.85 p, the carbonyl group i n t h i s compound had to be i n a six-membered r i n g , thus excluding s t r u c t u r e B_. A l l t hat remained was to e s t a b l i s h the stereochemistry of the 4 methyl group at C . The c i r c u l a r dichroism curves of nor-seychellanone 117 and of decalone 125 were i n accord with t h e i r assigned s t r u c t u r e s . Furthermore, these c i r c u l a r dichroism measurements a l s o showed that the absolute c o n f i g u r a t i o n of (-)-seychellene 13 was the same as that of p a t c h o u l i a l c o h o l 14. DISCUSSION I. General Approach When one attempts to devise a sequence f o r the synthesis of a complex n a t u r a l product such as a p o l y c y c l i c sesquiterpene, one should f i r s t c a r e f u l l y study a molecular model of the compound. Often, 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 sesquiterpene w i l l y i e l d an intermediate that 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 . With appropriate f u n c t i o n a l i z a t i o n of t h i s intermediate i n a way which would a l l o w c y c l i z a t i o n back to 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 , the major problem i n the planning of the s y n t h e t i c sequence may be solved. Thus, i n planning a p o s s i b l e s y n t h e s i s of (+)-seychellene 15, t h i s general approach was employed. In order to f a c i l i t a t e the i n t r o d u c t i o n of the t e r m i n a l o l e f i n i c double bond, only bonds i n c l o s e p r o x i m i t y to t h i s f u n c t i o n a l i t y could be reasonably considered f o r cleavage (see Chart 10). Of the s i x p o s s i b l e proposed intermediates f o r c y c l i z a t i o n shown i n Chart 10, the ones with obvious s t r u c t u r a l complexity were not considered. Hence, f o r example, the 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 compounds of the type depicted i n 125 or 126 would i t s e l f be q u i t e d i f f i c u l t , and the p o s s i b l e use of these intermediates i n the s y n t h e s i s of ( i ) - s e y c h e l l e n e 15 was not i n v e s t i g a t e d . - 81 -CHART 10: Planning the Synthesis of (+)-Seychellene 13 The c y c l i z a t i o n o f a compound o f t h e t y p e d e p i c t e d i n 127 seemed q u i t e a t t r a c t i v e , and i n d e e d , a s i m i l a r i n t e r m e d i a t e 128 has v e r y r e c e n t l y been p r e p a r e d f o r t h e s y n t h e s i s o f p a t c h o u l i a l c o h o l 14_ ( 7 0 ) . However, a s y n t h e t i c sequence t o (±)-seychellene T3_ e m p l o y i n g compound 127 was r e j e c t e d s i n c e t h i s i n t e r m e d i a t e r e q u i r e d t h e c o n s t r u c t i o n o f a t h r e e - c a r b o n s i d e c h a i n c o n t a i n i n g a c e n t e r o f asymmetry. The - 83 -s t e r e o s e l e c t i v e synthesis of a c y c l i c systems possessing c h i r a l centers i s g e n e r a l l y more d i f f i c u l t than the s t e r e o s e l e c t i v e synthesis of those systems i n which the asymmetry i s a s s o c i a t e d with a r i n g . For example, i n the p r e v i o u s l y mentioned synt h e s i s of p a t c h o u l i a l c o h o l L4 4 a mixture of compound 128 and i t s C epimer was prepared and employed as a s y n t h e t i c intermediate. Although, i n order to prepare a s e y c h e l l e n e - l i k e carbon s k e l e t o n the p o s s i b i l i t y of c a r r y i n g out an i n t e r n a l a l d o l condensation o f compounds 129, 130 or 131 might at f i r s t s i g h t seem a t t r a c t i v e , i t s u f f e r s from two p o s s i b l e problems. F i r s t of a l l , s i n c e a l d o l conden-sa t i o n s are r e v e r s i b l e unless dehydration of the r e s u l t i n g k e t o l takes place (71), the e q u i l i b r i u m between the s t a r t i n g keto aldehyde (129, 130 or 131) and the corresponding k e t o l might l i e on the si d e of the s t a r t i n g m a t e r i a l . Secondly, i f the k e t o l d i d form, the r e a c t i o n might p o s s i b l y reverse when one attempts to remove the carbonyl. An intermediate of the type depicted i n 132 seemed to be the best choice f o r the c r u c i a l c y c l i z a t i o n . F i r s t of a l l , i t i s a r e l a t i v e l y - 84 -simple decalone system ( i g n o r i n g s t e r e o c h e m i s t r y ) . Secondly, an enolate 7 anion could be generated s p e c i f i c a l l y at the C p o s i t i o n . T h i r d l y , the l e a v i n g group i s on a primary carbon atom and hence should be r e l a t i v e l y e a s i l y d i s p l a c e d by an i n t e r n a l n u c l e o p h i l e ( i . e . the enolate anion). F o u r t h l y , molecular models of 132 c l e a r l y i n d i c a t e d t h a t , i n an 6 7 appropriate conformation of t h i s molecule, C and C are i n very c l o s e p r o x i m i t y . F i n a l l y , the synthesis of ( i ) - s a t i v e n e 133 performed by J.E. McMurry i n 1968 (84), from the keto t o s y l a t e 134 v i a the ketone 135, provided a d d i t i o n a l support f o r the proposed c y c l i z a t i o n of compound 132. 134 135 133 I I . S t e r e o s e l e c t i v e T o t a l Synthesis of (±)-Seychellene Having considered s e v e r a l b i c y c l i c systems which, upon appropriate c y c l i z a t i o n , would y i e l d the t r i c y c l i c s k e l e t o n of seyche l l e n e , we set out to synthesize the c r u c i a l , chosen int e r m e d i a t e , keto t o s y l a t e 136. This c r u c i a l intermediate, upon treatment with an appropriate base, would be expected to undergo c y c l i z a t i o n to y i e l d nor-seychellanone 117 This ketone 117 would subsequently be converted i n t o (+)-seychellene 13 by standard procedures. - 85 -The synth e s i s of the keto t o s y l a t e 136 would r e q u i r e unambiguous i n t r o d u c t i o n o f fo u r asymmetric centers. 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 s y n t h e s i s was the Wieland-Miescher ketone 137 (72) . This compound possessed the necessary f u n c t i o n a l i t y i n the A r i n g ( i . e . the a ,3-unsaturated ketone system) f o r the i n t r o d u c t i o n o f the methyl groups and the t o s y l a t e f u n c t i o n a l i t y . In a d d i t i o n , compound 137 already contained the d e s i r e d ketone f u n c t i o n a l i t y i n the B r i n g . The Wieland-Miescher ketone 137 was prepared from 1,3-cyclohexane-dione 138 employing l i t e r a t u r e procedures. According to the procedure of M.S. Newman et_.al_. (73) , methylation of 1,3-cyclohexanedione 138 was achieved wit h methyl i o d i d e i n the presence of aqueous sodium hydroxide to a f f o r d a 37% y i e l d of c r y s t a l l i n e 2-methyl-l,3-cyclohexanedione 139. - 86 -Robinson a n n e l a t i o n of the methylated dione 139 with l-diethylamino-3-butanone i n a r e f l u x i n g benzene-pyridine s o l u t i o n a f f o r d e d , a f t e r d i s t i l l a t i o n and c r y s t a l l i z a t i o n , the Wieland-Miescher ketone 137 i n 70% y i e l d (74). Before commencing the e l a b o r a t i o n of r i n g A, i t was necessary to p r o t e c t the saturat e d carbonyl group i n r i n g B. Although the s e l e c t i v e conversion of the saturated carbonyl group of the Wieland-Miescher ketone 137 i n t o the corresponding ethylene k e t a l 140 had been achieved by Corey et- a L (75), i t was f e l t t h a t t h i s p r o t e c t i n g group would make the stereochemical assignment of a l a t e r (proposed) key s y n t h e t i c intermediate very d i f f i c u l t (see page 91 ). Therefore, according to the procedure of Boyce and Whitehurst (76) the saturat e d carbonyl group of 137 was reduced s e l e c t i v e l y with sodium borohydride, l e a v i n g the a,3-unsaturated carbonyl group i n t a c t . The product, obtained i n 89% y i e l d , was the keto a l c o h o l 141. Moreoever, t h i s r e d u c t i o n was h i g h l y s t e r e o s e l e c t i v e s i n c e only one epimer, having the hydroxyl group c i s to the angular methyl group, was produced. This stereochemical f e a t u r e was very important f o r the stereochemical assignment of the same key intermediate mentioned above (see page 90 ). The r e a c t i o n o f keto a l c o h o l 141 with dihydropyran i n the presence of anhydrous hydrogen 138 139 137 Continued - 87 -141 142 140 c h l o r i d e afforded the known tetrahydropyranyl ether d e r i v a t i v e 142 (77) i n 94% y i e l d . The tetrahydropyranyl (THP) p r o t e c t i n g group was chosen s i n c e i t i s s t a b l e to b a s i c c o n d i t i o n s , and i n e r t to a wide range I t should be noted t h a t the tetrahydropyranyl (THP) p r o t e c t i n g group possesses a center of asymmetry, and s i n c e i t cannot be introduced s t e r e o s e l e c t i v e l y , compound 142 e x i s t s as a mixture of two epimers (142a and 142b). This probably accounts f o r the large m.p. range of compound 142 and f o r the large m.p. ranges of subsequent c r y s t a l l i n e s y n t h e t i c intermediates c o n t a i n i n g the THP f u n c t i o n a l i t y . Since the isomer r a t i o may vary, depending upon c r y s t a l l i z a t i o n , the me l t i n g ' p o i n t s are not always r e p r o d u c i b l e . Moreover, complex n.m.r. spectra may r e s u l t when the s i g n a l s f o r the one isomer do not c o i n c i d e w i t h those of the other. Mixtures of isomers which r e s u l t from the asymmetry of the THP group w i l l be r e f e r r e d to as one compound. - 88 -of r e a c t i o n c o n d i t i o n s . Moreoever, the p r o t e c t i n g group can be r e a d i l y removed under m i l d a c i d c o n d i t i o n s (77). At t h i s p o i n t i t would be advantageous to d i g r e s s and to examine the key intermediate which was mentioned i n the preceding paragraph. In the proposed t o t a l synthesis of (±)-seychellene, pr e p a r a t i o n of ketone 143 was f e l t to be e s s e n t i a l f o r the 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 the c r u c i a l keto t o s y l a t e 136. Assuming th a t the stereochemistry of the t e r t i a r y methyl groups and of the OTHP group were c o r r e c t l y assigned as shown i n s t r u c t u r e 143, the stereochemistry of the secondary methyl group could be assigned on a t h e o r e t i c a l b a s i s . Upon examination of the non-bonded i n t e r a c t i o n s present i n the two c h a i r - c h a i r conformers, 143a and 143b (see Chart 11), of the 3-methyl epimer 143, i t i s evident that conformer 143a i s the more s t a b l e . The severe 1 , 3 - d i a x i a l i n t e r -a c t i o n s present i n conformation 143b, but absent i n conformation 143a are mainly r e s p o n s i b l e f o r t h i s r e l a t i v e s t a b i l i t y . S i m i l a r l y , upon examination of conformers 144a and 144b i t i s evident that the l a t t e r conformer i s the more s t a b l e . This r e l a t i v e s t a b i l i t y i s mainly due to the presence of a 1 , 3 - d i a x i a l methyl-methyl i n t e r a c t i o n i n 144a, as compared with a 1 , 3 - d i a x i a l methyl-OTHP i n t e r a c t i o n i n 144b. Therefore, 143 144 89 OR CHART 11: s 143a 4-syn-axial CH^-H 1-skew CH 3-CH 3 1-syn-axial XH 2-H 1-skew CH3-OR 1- skew :CH2OR 2- 3-methyl ketone _r R=OTHP f / 3-syn-axial CH3~H 1-skew CH 3-CH 3 | 2-syn-axial 'CH.?-H 1-1 , 3 - d i a x i a l ;CH 2~CH 3 1 - 1 , 3 - d i a x i a l CH3-OR 1-skew CH3-OR 1-syn a x i a l OR-H 1-3-methyl ketone '/" OR 144a 144b 4-syn-axial CH3~H 1-skew CH 3-CH 3 1 - 1 , 3 - d i a x i a l CH 3-CH 3 1-syn-axial ;CH2~H 1-skew CH3-OR 1- skew CH2-OR 2- 3-methyl ketone 2- s y n - a x i a l CH3~H 1-skew CH -C« 3 3- s y n - a x i a l "CH2~H 1-1,3- d i a x i a l CRj-OR 1-skew CH -OR 1-syn a x i a l OR-H 1-3-methyl ketone E-,,- = ( 1 - 1 , 3 - d i a x i a l CTL-OR) - (1-3-methyl ketone) 144b-143a ^ 3 = 2.2 k c a l - 0.35 k c a l =1.85 k c a l The magnitude of t h i s i n t e r a c t i o n was assigned the same average value as that f o r the 1 , 3 - d i a x i a l CH3-OH i n t e r a c t i o n . The assumption that these two i n t e r a c t i o n s were approximately equal i n magnitude was based on the f a c t that the s y n - a x i a l OH-H, OCH3-H, OAc-H, and OTos-H i n t e r a c t i o n s are a l l approximately equal i n value (78). 90 -when the e q u i l i b r i u m between epimer 143 and 144 i s examined only the more s t a b l e conformer of each compound need be considered ( i . e . 143a and 144b) (see Chart 11). An estimate of the energy d i f f e r e n c e between these two conformers i n d i c a t e s that epimer 143 would be present, i n an e q u i l i b r i u m mixture of epimers 143 and 144, to the extent of at l e a s t 95%. Therefore, treatment of compound 143 and/or 144 under e p i m e r i z i n g c o n d i t i o n s would e s t a b l i s h the stereochemistry o f the secondary methyl group of the product, s i n c e t h i s product should be compound 143 with the secondary methyl group i n a g - o r i e n t a t i o n . I f the r e d u c t i o n of the Wieland-Miescher ketone 137 had given the keto a l c o h o l 145, with the hydroxyl group trans to the angular methyl group, one would have to examine the e q u i l i b r i u m between epimers 146 and 147, i n s t e a d of that between 143 and 144. In an a n a l y s i s s i m i l a r to that employed f o r compounds 143 and 144, i t can be shown that the non-bonded i n t e r a c t i o n s i n v o l v e d i n the more s t a b l e c h a i r - c h a i r conforma-t i o n of 147 are le s s severe than the non-bonded i n t e r a c t i o n s i n the more s t a b l e c h a i r - c h a i r conformation of compound 146. Therefore, the more s t a b l e epimer i n t h i s case would be compound 147. I t i s obvious t h a t , i n s o f a r as the t o t a l s ynthesis of ( i ) - s e y c h e l l e n e L3 i s concerned, 147 possesses the wrong c o n f i g u r a t i o n f o r the secondary methyl group. The above two analyses c l e a r l y showed the importance of the ste r e o -chemical outcome of the borohydride r e d u c t i o n o f the Wieland-Miescher ketone 137. OTHP OTHP 145 - 91 -I f , i n order to p r o t e c t the saturated carbonyl group, the Wieland-Miescher ketone 137 had been converted to the mono-ethylene k e t a l 140, a s i m i l a r problem to that mentioned above would have been encountered. Once again, the e q u i l i b r i u m between keto k e t a l s 148 and 149 would l i e on the s i d e of the undesired epimer 149. 0 0 140 148 149 Having thus set the i n i t i a l goal of s y n t h e s i z i n g the ketone 143, two routes were considered i n order to achieve t h i s g o a l . The f i r s t route to be described, although the longer of the two, proved to be a very e f f i c i e n t sequence f o r the s y n t h e s i s of ketone 143. The second route at one stage produced an expected isomeric mixture which presented a serious s eparation problem. Although the synthesis of ketone 143 was not achieved using the second route, t h i s sequence was c a r r i e d through p a r t way, i n order to supply some stereochemical i n f o r m a t i o n . The synthesis of ketone 143 v i a the f i r s t route was accomplished as f o l l o w s (see Chart 12). The i n t r o d u c t i o n of the second angular methyl group was accomplished by the conjugate a d d i t i o n of l i t h i u m dimethylcuprate to the a,3-unsaturated ketone system of compound 142 (79,80) . This reagent was chosen f o r the conjugate a d d i t i o n s i n c e i t - 92 -had been shown to be of greater general u t i l i t y than the copper-c a t a l y z e d methylmagnesium h a l i d e reagents (59) . Moreover, the l i t h i u m dimethylcuprate reagent gives v i r t u a l l y no 1,2-addition product (79) and a f f o r d s higher y i e l d s of d e s i r e d product (81) than the Grignard reagents. I t should a l s o be noted that these organo-copper reagents A 1 9 add very s t e r e o s e l e c t i v e l y to A ' -octal-2-ones, of which ketone 142 i s an example, to give as the s o l e conjugate a d d i t i o n product, the corresponding decalones possessing a c i s r i n g j u n c t i o n (59,81,82). A l l of these observations made the l i t h i u m dimethylcuprate reagent very a t t r a c -t i v e f o r the proposed s y n t h e s i s . Since the conjugate a d d i t i o n to an a,3-unsaturated ketone system such as 142 generates 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 t r a p the enolate anion 150 w i t h a c e t y l c h l o r i d e (83) . I t was expected that the r e s u l t i n g enol acetate 151 would be of greater s y n t h e t i c u t i l i t y than ketone 152, which would be obtained by quenching the enolate anion 150 with a proton source. A f t e r performing the l i t h i u m dimethylcuprate a d d i t i o n under a wide v a r i e t y o f c o n d i t i o n s , i t was found that low concentrations of the organo-copper reagent and low r e a c t i o n temperatures, followed by r a p i d quenching of the r e a c t i o n mixture w i t h excess a c e t y l c h l o r i d e gave the best r e s u l t s . In order t o 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 ice-ammonium hydroxide mixture. A f t e r i s o l a t i o n and p u r i f i c a t i o n , the enol acetate 151 was obtained i n 88% y i e l d . The i n f r a r e d absorptions at 5.72 and 5.93 p c l e a r l y showed the presence of the enol acetate carbonyl group and the double bond, 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 c place was a l s o evident from the n.m.r. spectrum of the product, which - 93 -showed, i n a d d i t i o n to the a c e t y l methyl group (x 7.93), two t e r t i a r y methyl groups (x 9.05 and x 9.09). Epoxidation of the enol acetate double bond was accomplished w i t h m-chloroperbenzoic a c i d to a f f o r d the epoxy acetate 153 (82). The p e r a c i d was expected t o attack the double bond of the enol acetate 151 from the l e s s hindered s i d e of the molecule to give the a-epoxide. This assumption was based on l i t e r a t u r e precedent, which has e s t a b l i s h e d that a double bond found i n t h i s p o s i t i o n i n a c i s - f u s e d d e c a l i n system i s l e s s s t e r i c a l l y hindered to approaching reagents from the convex s i d e of the molecule [ f o r examples see r e f . (84) and (85)]. A c a r e f u l examination of molecular models shows t h i s i s q u i t e reasonable. The i n f r a r e d spectrum of the crude product obtained from the epoxidation no longer showed a double bond absorption, but d i d e x h i b i t a strong carbonyl absorption at 5.74 y. Since the epoxy acetate 153 was unstable to column chromatography and to the f a i r l y high temperatures necessary f o r d i s t i l l a t i o n , the crude product was thermally rearranged (86) to the corresponding keto acetate 154. The mechanism of the thermal rearrangement of epoxy acetates has been shown by Williamson and co-workers (86) to i n v o l v e acetate m i g r a t i o n w i t h i n v e r s i o n of c o n f i g -u r a t i o n (see 153-«»-154, Chart 12). Therefore, on the b a s i s of t h i s mechanism the stereochemistry of the acetate was assigned as shown i n 154. The s p e c t r o s c o p i c p r o p e r t i e s of t h i s c r y s t a l l i n e compound substant-i a t e d the assigned s t r u c t u r e 154. The i n f r a r e d spectrum e x h i b i t e d a strong carbonyl absorption at 5.80 y. The n.m.r. spectrum showed a one-proton, s i n g l e t (x 4.77) f o r the proton adjacent to the acetate .group, a three-proton s i n g l e t (x 7.84) f o r the acetate methyl, and two three-proton s i n g l e t s - 94 -CHART 12: OTHP AcO 151 .OTHP OTHP OTHP 150 OTHP 154 R=THP 155 R=H 142 OTHP 152 OR 157 R=THP 158 R=H OTHP OR 143 160 R=THP 161 R=H - 95 -(T 8.53 and x 8.73) f o r the t e r t i a r y methyl groups. In order to e s t a b l i s h that the keto acetate 154 was an isomeric mixture only with respect to i t s THP group (see footnote 7, page 87 ), a small sample was subjected to a c i d h y d r o l y s i s (77). The r e s u l t i n g a l c o h o l 155, obtained i n high y i e l d , e x h i b i t e d a sharp m e l t i n g p o i n t (m.p. 195.0-195.5°). The n.m.r. spectrum e x h i b i t e d a one-proton s i n g l e t (T 4.80) f o r the proton adjacent to the acetate group, a one-proton m u l t i p l e t (T 6.44) f o r the proton adjacent to the hydroxyl group, as w e l l as three sharp three-proton s i n g l e t s at T 7.85, x 8.59 andx8.70 f o r the acetate methyl group and the two t e r t i a r y methyl groups, r e s p e c t i v e l y . - The r e a c t i o n of the keto acetate 154 with three equivalents of methyltriphenylphosphorane i n dimethyl s u l f o x i d e at 50° f o r 2.5 hours r e s u l t e d i n s e l e c t i v e r e a c t i o n w i t h the ketone carbonyl. When more vigorous r e a c t i o n c o n d i t i o n s were employed ( i . e . higher temperatures and/ or increased concentrations of y l i d e ) p a r t i a l or complete removal of the a c e t y l group, presumably by the attack of the y l i d e on the acetate carbonyl, a l s o took p l a c e . However, under these c o n d i t i o n s the y i e l d o f r e a c t i o n product was s i g n i f i c a n t l y decreased. Using the m i l d e r , s e l e c t i v e c o n d i t i o n s , o l e f i n 156 was obtained, a f t e r p u r i f i c a t i o n of the crude product, i n 73% y i e l d . That only r e a c t i o n w i t h the ketone carbonyl had taken place was evident from the t e r m i n a l o l e f i n i c double bond absorptions at 3.30, 6.08 and 11.22 y, and from the strong acetate carbonyl absorption at 5.78 y i n the i n f r a r e d spectrum of product 156. In the n.m.r. spectrum the proton adjacent to the acetate group appeared at x 4.63 and had thus s h i f t e d downfield somewhat from i t s p o s i t i o n i n the keto acetate 154. The s i g n a l s due to the o l e f i n i c protons were - 96 -p a r t i a l l y masked by the s i g n a l s due to the protons a s s o c i a t e d w i t h the OTHP group. However, a three-proton s i n g l e t (x 7.81) f o r the acetate methyl group was c l e a r l y v i s i b l e , and two three-proton s i n g l e t s (x 8.73 and x 8.85) f o r the t e r t i a r y methyl groups were al s o present. Since attempted hydrogenation of o l e f i n 156,. employing conventional c a t a l y s t s , would probably have r e s u l t e d i n at l e a s t p a r t i a l hydrogenolysis of the a l l y l i c acetate (87), the c a t a l y s t t r i s ( t r i p h e n y l p h o s p h i n e ) c h l o r o -rhodium (88) was chosen f o r the hydrogenation (89). In a d d i t i o n to a l l e v i a t i n g the problem of hydrogenolysis, the complex rhodium c a t a l y s t , because of i t s l a r g e s t e r i c b u l k , has the added advantage of normally reducing o l e f i n i c double bonds very s t e r e o s e l e c t i v e l y (90). The acetate 157, obtained i n high y i e l d from t h i s hydrogenation, e x h i b i t e d a strong carbonyl absorption at 5.77 y and no o l e f i n i c absorptions i n the i n f r a r e d spectrum. Since the n.m.r. spectrum of 157 showed two d i s t i n c t s i n g l e t s at x 7.89 and x 7.91, together i n t e g r a t i n g f o r three protons and a t t r i b u t a b l e to the acetate methyl group (see footnote 7, page 87 ), a small amount of t h i s m a t e r i a l was subjected to a c i d h y d r o l y s i s i n order to remove the THP p r o t e c t i n g group. The r e s u l t i n g product 158,. as shown by i t s sharp m e l t i n g p o i n t (m.p. 94.5-95.0°) and by i t s s p e c t r a l p r o p e r t i e s , was c l e a r l y homogeneous, and thus supported the f a c t that hydrogenation of 156 was completely s t e r e o s e l e c t i v e . That the stereochemistry o f the secondary methyl group was 3 as shown i n s t r u c t u r e s 157 and 158 was subsequently e s t a b l i s h e d unambiguously (see page 100). The i n f r a r e d spectrum of a l c o h o l 158, taken i n chloroform s o l u t i o n , e x h i b i t e d absorptions at 2.80 and at 2.95 y due to the presence of f r e e and hydrogen bonded hydroxyl - 97 -groups, r e s p e c t i v e l y , and a carbonyl absorption at 5.81 p . Of p a r t i c u l a r importance i n the n.m.r. spectrum was the one-proton doublet (T 5.08, J = 2 Hz) a t t r i b u t e d to the proton adjacent to the acetate group and the one-proton m u l t i p l e t (T 5.70, peak width at h a l f height -20 Hz) a t t r i b u t e d to the proton adjacent to the hydroxyl group. The OH 158a 158b 159b - 98--observed coupling o f these two s i g n a l s not only supported the proposal regarding stereochemistry of the acetate group, but a l s o i n d i c a t e d the d i r e c t i o n of the conformational e q u i l i b r i u m (assuming that the st e r e o -chemistry of the secondary methyl group was 8 ). Examination of the c h a i r - c h a i r conformational r e p r e s e n t a t i o n s of compound 158 and of i t s epimeric acetate 159 i n d i c a t e d that the preceding n.m.r. s i g n a l s could be expected only i f the compound i n question had s t r u c t u r e 158, with conformer 158a predominating. In conformer 158a the proton adjacent to the acetate group i s e q u a t o r i a l and i s coupled w i t h a v i c i n a l a x i a l proton and hence, a small coupling constant would be expected. A l s o , i n t h i s conformer the proton adjacent to the hydroxyl group i s a x i a l and i s coupled with both an a x i a l and an e q u a t o r i a l proton. The large coupling constant which would be expected from the a x i a l - a x i a l coupling would, t h e r e f o r e , e x p l a i n the large width of the s i g n a l due to the proton adjacent to the hydroxyl group. The st e r e o -chemical assignment of the acetate group on the ba s i s o f the n.m.r. spectrum of 158 i s t h e r e f o r e , i n agreement with the assignment made on the b a s i s of the mechanism f o r the thermal rearrangement of epoxy acetates (see page 93 ). That the conformational e q u i l i b r i u m f o r compound 158 l i e s towards conformer 158a can be r e a d i l y r a t i o n a l i z e d on the b a s i s of the non-bonded i n t e r a c t i o n s present i n conformers 158a and 158b. This r e l a t i v e s t a b i l i t y i s mainly due to the presence of a 1 , 3 - d i a x i a l methyl-hydroxyl i n t e r a c t i o n and a 1 , 3 - d i a x i a l methyl-ring methylene i n t e r a c t i o n present i n 158b, as compared with two 1 , 3 - d i a x i a l a c e t a t e - r i n g methylene i n t e r -a c t i o n s present i n 158a. When co n s i d e r i n g compound 159, i t i s obvious - 99 -that the three severe 1 , 3 - d i a x i a l i n t e r a c t i o n s present i n conformer 159b but absent i n conformer 159a would r e s u l t i n a conformational e q u i l i b r i u m which would g r e a t l y favour the l a t t e r conformer. However, f o r conformer 159a a large coupling constant f o r the proton adjacent to the acetate would be expected, i n s t e a d of the observed small coupling constant, s i n c e both t h i s proton, as w e l l as the proton to which i t i s coupled, are a x i a l . The remainder of the n.m.r. spectrum f o r compound 158 e x h i b i t e d a three-proton s i n g l e t at T 7.91 a t t r i b u t e d to the acetate methyl group, and two three-proton s i n g l e t s at x 9.03 and x 9.14, which were a t t r i b u t e d to the t e r t i a r y methyl groups. The secondary methyl groups d i s p l a y e d a doublet at x 9.23 (J = 6 Hz). Base h y d r o l y s i s of acetate 157 affo r d e d the c r y s t a l l i n e a l c o h o l 160 (m.p. 115-117°) i n 84% y i e l d . A small sample of compound 160 was converted to the corresponding d i o l 161, which was subsequently employed to e s t a b l i s h the stereochemical outcome of the preceding hydrogenation (156 •> 157). The d i o l 161 e x h i b i t e d a sharp m e l t i n g p o i n t (m.p. 139.0-139.5°) and e x h i b i t e d the expected hydroxyl absorbances i n the i n f r a r e d spectrum. The protons adjacent to the hydroxyl groups were r e a d i l y d i s t i n g u i s h a b l e i n the n.m.r. spectrum. The proton e x h i b i t e d a p a i r of doublets at x 5.63, due to the X pa r t of an ABX system, w i t h = 11 Hz and J ^ ^ = 5 Hz, while the proton e x h i b i t e d a doublet at x 6.68 with J = 3 Hz. As i n the case of compound 158, the n.m.r. s i g n a l f o r the proton c l e a r l y e s t a b l i s h e d the d i r e c t i o n of the conformational e q u i l i b r i u m . The large AX coupling i n d i c a t e s that the proton must be a x i a l . This i s i n agreement w i t h the expected \ - 100 -conformational e q u i l i b r i u m shown below. Conformer 161a, with the a x i a l 161a 161b C proton, should be p r e f e r r e d over conformer 161b si n c e the former lack s the severe 1 , 3 - d i a x i a l methyl-ring methylene i n t e r a c t i o n present i n the l a t t e r . Other p e r t i n e n t n.m.r. s i g n a l s f o r compound 161 appeared at T 9.10 (doublet, secondary methyl group) and at x 9.17 ( s i n g l e t , two overlapping t e r t i a r y methyl groups). In order to preserve the THP p r o t e c t i n g group, o x i d a t i o n of a l c o h o l 160 was a f f e c t e d w i t h the chromium t r i o x i d e - p y r i d i n e complex (Cr0 3-2C 5H 5N) (91), and afforded a 77% y i e l d of ketone 143. As discussed p r e v i o u s l y (see page 8 8 ) , the stereochemistry of the secondary methyl group i n t h i s compound could be p r e d i c t e d on a t h e o r e t i c a l b a s i s . Since the ketone recovered a f t e r s u b j e c t i n g a small sample of compound 143 to epi m e r i z i n g c o n d i t i o n s (NaOMe i n r e f l u x i n g methanol) was i d e n t i c a l w i t h the s t a r t i n g m a t e r i a l (m.p., mixed m.p., and n.m.r. spectrum), the secondary methyl group must have the 8 c o n f i g u r a t i o n as shown i n s t r u c t u r e 143. The assigned s t r u c t u r e was a l s o supported by s p e c t r a l data. A strong carbonyl absorption at 5.91 y was present i n the i n f r a r e d spectrum. The n.m.r. spectrum (see f i g u r e 4) showed two three-proton s i n g l e t s (x 8.92 and x 9.01) a t t r i b u t e d to the t e r t i a r y FIGURE 4. N.M.R. Spectrum of Ketone 143. - 102 -methyl groups and a three-proton doublet (x 9.03, J = 6.5 Hz) a t t r i b u t e d to the secondary methyl group. Thus, the s t r u c t u r e of ketone 143 seemed to i n d i c a t e that hydro-genation of the o l e f i n i c acetate 156 had occurred by attack of the hydrogenating complex from the convex s i d e ( i . e . the a side) of the molecule. However, i n order to e s t a b l i s h that e p i m e r i z a t i o n had not taken place during the o x i d a t i o n of 160 w i t h chromium t r i o x i d e - p y r i d i n e , a small sample of compound 143 was reduced with l i t h i u m aluminum hydride. Examination of molecular models of ketone 143 c l e a r l y i n d i c a t e d t h a t the l e s s hindered s i d e of the carbonyl was the convex (a) s i d e , thus assuring that the l i t h i u m aluminum hydride r e d u c t i o n product should be compound 160. Indeed, the a l c o h o l obtained from t h i s r e d u c t i o n e x h i b i t e d s p e c t r a l data ( i n f r a r e d and n.m.r.) i d e n t i c a l w i t h that of a l c o h o l 160 prepared from the acetate 158 as p r e v i o u s l y described (see page 99 ). However, the a l c o h o l from t h i s r e d u c t i o n e x h i b i t e d a m e l t i n g p o i n t (m.p. 124-127°) which was d i f f e r e n t from the melting p o i n t (m.p. 115-117°) of the a l c o h o l prepared from acetate 158 (see footnote 7, page 87 ). Removal of the THP p r o t e c t i n g groups from the l i t h i u m aluminum hydride r e d u c t i o n product y i e l d e d d i o l 161, which was i d e n t i c a l (m.p., mixed m.p., and i n f r a r e d spectrum) with the d i o l prepared from acetate 158 v i a compound 160 (see page 99 ). In a d d i t i o n to e s t a b l i s h i n g the stereochemical outcome of the hydrogenation (156 -> 157), t h i s c o r r e l a t i o n a l s o provided e x c e l l e n t a d d i t i o n a l evidence f o r the stereochemistry at the acetoxy-bearing carbon i n compounds 154 to 158, i n c l u s i v e . The second proposed route f o r the synthesis of ketone 143 employed - 103 -the decalone d e r i v a t i v e 152, obtained by conjugate a d d i t i o n of l i t h i u m dimethylcuprate to the a,B-unsaturated ketone system o f compound 142, fol l o w e d by quenching of the r e a c t i o n mixture with h y d r o c h l o r i c a c i d . In c o n t r a s t to the good y i e l d (88%) of d e s i r e d product obtained from the p r e v i o u s l y described quenching procedure using a c e t y l c h l o r i d e , the y i e l d of the d e s i r e d compound 152 was, i n t h i s case, c o n s i d e r a b l y lower ('v 50%) . A n a l y s i s of the product seemed to i n d i c a t e that during the a c i d quenching some 1,2-addition to the saturated carbonyl group of 152 had taken p l a c e . Furthermore, p a r t i a l removal of the THP p r o t e c t i n g group had al s o occurred. A l t e r n a t i v e l y , when the enol acetate 151 was t r e a t e d w i t h potassium carbonate i n methanol-water, the d e s i r e d ketone 152 was obtained i n 80% y i e l d , and the conversion of 142 i n t o 152 v i a the enol acetate 151 was thus much more convenient and e f f i c i e n t than the more d i r e c t conversion employing a c i d quenching. The i n f r a r e d spectrum of compound 152 e x h i b i t e d a strong saturated carbonyl at 5.88p . In the n.m.r. spectrum the t e r t i a r y methyl groups appeared as three-proton s i n g l e t s at x 9.04 and x 9.08. Removal of the THP p r o t e c t i n g group from ketone 152 with o x a l i c a c i d i n methanol afforded the c r y s t a l l i n e keto a l c o h o l 162, which a f t e r r e c r y s t a l l i z a t i o n s t i l l e x h i b i t e d a r a t h e r broad mel t i n g p o i n t 9 range (m.p. 179-182). The i n f r a r e d spectrum of t h i s compound e x h i b i t e d the expected saturated carbonyl absorption at 5.89 y and hydroxyl absorptions at 5.80 and 5.95 y. The n.m.r. spectrum e x h i b i t e d , i n a d d i t i o n to a " t r i p l e t " (x 5.85) f o r the proton adjacent to the hydroxyl 9 A s i m i l a r phenomenon has been observed by M a r s h a l l et a l (82) - 105 -group and a s i n g l e t (x 9.04) f o r the methyl group, a doublet (x 9.08, J = 0.8 Hz) f o r the angular methyl g r o u p . ^ In order to demonstrate that t h i s s i g n a l was indeed a doublet and not two s i g n a l s from d i f f e r e n t isomeric compounds, the protons adjacent to the carbonyl were exchanged with deuterium, using sodium methoxide i n deuterium oxide- dioxane. That a l l four protons a to the carbonyl had exchanged, to give compound 165, was evident from the mass spectrum of t h i s compound, which e x h i b i t e d a molecular i o n peak at m/e 200. The n.m.r. spectrum o f t h i s compound now e x h i b i t e d two sharp s i n g l e t s at x 9.05 and x 9.09 f o r the angular methyl groups, as w e l l as a " t r i p l e t " at x 5.88 f o r the proton adjacent to the hydroxyl group. Thus t h i s experiment c o n c l u s i v e l y e s t a b l i s h e d that the C"^  methyl group was coupled with a proton (pres-umably the a proton) adjacent to the carbonyl. The ketone 152 was converted, by successive treatments with m e t h y l l i t h i u m i n ether, i n t o the c r y s t a l l i n e t e r t i a r y a l c o h o l 164• The l a t t e r , obtained i n 74% y i e l d , 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 . Dehydration of t h i s a l c o h o l 164 with t h i o n y l c h l o r i d e i n benzene-pyridine at 0° y i e l d e d a product whose n.m.r. spectrum i n d i c a t e d i t to be a mixture of o l e f i n i c compounds, with the THP p r o t e c t i n g group i n t a c t . When t h i s mixture was subjected to g a s - l i q u i d chromatographic a n a l y s i s (200°) the presence o f three compounds, 165, 166 and 167, i n a r a t i o of 48:39:13 r e s p e c t i v e l y , was i n d i c a t e d . The s p e c t r a l data of these compounds i n d i c a t e d that during the s u b j e c t i o n to g a s - l i q u i d chromatographic c o n d i t i o n s , the THP ^ For a p o s s i b l e explanation of t h i s phenomenon see reference 92. - 106 -p r o t e c t i n g group had, i n each case, been l o s t . The two major components were i s o l a t e d by p r e p a r a t i v e g . l . c . and were completely c h a r a c t e r i z e d . The i n f r a r e d s p e c t r a of compounds 165 and 166 were s i m i l a r and e x h i b i t e d the expected hydroxyl absorptions. The s t r u c t u r a l assignments of the two major components were made on the b a s i s of t h e i r r e s p e c t i v e o l e f i n i c s i g n a l s i n the n.m.r. sp e c t r a . . The o l e f i n i c proton of the f i r s t and major component 165 appeared as a quartet (T 5.06) w i t h a small coupling constant of 0.7 Hz. The appearance of the quartet can be r a t i o n a l i z e d on the b a s i s of a l l y l i c c oupling between the v i n y l proton and the adjacent v i n y l methyl group. The o l e f i n i c proton f o r the second com-ponent 166, on the other hand, e x h i b i t e d a more complex m u l t i p l e t (T 4.76) w i t h a peak width at h a l f height equal to 9 Hz. The increased complexity of t h i s s i g n a l , as w e l l as increased peak width, can be a t t r i b u t e d to a d d i t i o n a l c oupling of the o l e f i n i c proton with the adjacent r i n g protons. Other p e r t i n e n t s i g n a l s f o r compound 165 were at T 6.07 ( m u l t i p l e t , proton adjacent to the hydroxyl group), T 8.38 (broad s i n g l e t , v i n y l methyl group), and x 9.13 and x 9.15 (two s i n g l e t s , t e r t i a r y methyl groups). For compound 166 s i m i l a r n.m.r. s i g n a l s were found at x 6.37 ( m u l t i p l e t , proton adjacent to the hydroxyl group) x 8.34 (broad s i n g l e t , v i n y l methyl group), and x 9.13 ( s i n g l e t , two overlapping t e r t i a r y methyl groups). Compound 167 was not f u l l y c h a r a c t e r i z e d and the s t r u c t u r a l assignment was based only upon the i n f r a r e d spectrum, which showed absorptions at 3.00 y f o r the hydroxyl group, and at 6.10 and 11.37 y f o r the t e r m i n a l o l e f i n i c double bond. G a s - l i q u i d chromatographic separation of the mixture of o l e f i n s - 107 -obtained by dehydration of 164 proved to be u n s a t i s f a c t o r y on the b a s i s of the poor t o t a l recovery. Moreover, i t a l s o caused the u n d e s i r a b l e l o s s of the THP p r o t e c t i n g group, which could not be r e i n t r o d u c e d ( i n t o compound 165, f o r example) without i s o m e r i z a t i o n of the o l e f i n i c double bond. Since no e f f i c i e n t method f o r the separation of the o l e f i n s was found, t h i s route f o r the synthesis of ketone 145 was abandoned. Although our goal of the synthesis of the s u b s t i t u t e d decalone 145 was not r e a l i z e d by t h i s r o u t e , the o l e f i n i c a l c o h o l 165 was used to provide a d d i t i o n a l support f o r the stereochemical assignment of d i o l 161 (see page 99 ). Hydroboration of compound 165 by attack of borane from the l e s s hindered side of the o l e f i n i c double bond, followed by treatment of the intermediate alkylborane with a l k a l i n e hydrogen peroxide was expected to give d i o l 168. That the d i o l obtained from the hydroboration was d i f f e r e n t from d i o l 151 was evident from t h e i r r e s p e c t i v e m e l t i n g p o i n t s , and from appropriate spectroscopic data. The i n f r a r e d spectrum of d i o l 168 c l e a r l y d i f f e r e d from that of d i o l 151, p a r t i c u l a r l y i n the " f i n g e r p r i n t " r e g i o n . Furthermore, the n.m.r. spectrum of 168 was s i g n i f i c a n t l y d i f f e r e n t from the n.m.r. spectrum of 151 (see page 99). The s i g n a l s f o r the protons adjacent to the hydroxyl groups were of p a r t i c u l a r i n t e r e s t . In compound 168, the broad m u l t i p l e t (x 5.96, peak width at h a l f height = 20 Hz) f o r the proton i n d i c a t e d that t h i s proton must be a x i a l , and the doublet (x 6.43, J = 9.8 Hz) f o r the C*' proton i n d i c a t e d that t h i s proton must als o be a x i a l . These s i g n a l s , t h e r e f o r e , i n d i c a t e d that compound 168 must e x i s t predominantly i n conformation 168a as would be expected when one considers the numerous severe 1 , 3 - d i a x i a l i n t e r a c t i o n s present i n conformer 168b. The other p e r t i n e n t n.m.r. s i g n a l s f o r compound 168 - 108 -OH 168a 168b were at x 8.99 (doublet, secondary methyl group) and at x 9.13 ( s i n g l e t , two overlapping t e r t i a r y methyl groups). Since both d i o l 151 and i t s C 5 epimer, d i o l 168, had been prepared, and sin c e t h e i r n.m.r. sp e c t r a were i n f u l l accord w i t h the assigned s t r u c t u r e s and with the p e r t i n e n t p r e d i c t e d conformational e q u i l i b r i a , there can be l i t t l e doubt about t h e i r stereochemistry. Having s u c c e s s f u l l y synthesized the key ketone 145 and having e s t a b l i s h e d i t s stereochemistry, the e l a b o r a t i o n of t h i s compound to the keto t o s y l a t e 136 was c a r r i e d out. Conversion of the ketone 145 to o l e f i n 169 was f i r s t attempted us i n g methyltriphenylphosphorane i n dimethyl s u l f o x i d e (45). Presumably because the ketone carbonyl i s i n a s t e r i c a l l y crowded environment, the W i t t i g r e a c t i o n was very slow. Moreover, the poor y i e l d of d e s i r e d o l e f i n , and the d i f f i c u l t y encountered with the sep a r a t i o n of the o l e f i n from triphenylphosphine oxide made t h i s r e a c t i o n u n s u i t a b l e . Therefore ketone 143, upon successive treatments w i t h m e t h y l l i t h i u m , was converted i n t o the c r y s t a l l i n e t e r t i a r y a l c o h o l 170 i n 70% y i e l d . The i n f r a r e d spectrum d i s p l a y e d the usual hydroxyl absorptions. The n.m.r. spectrum e x h i b i t e d a s i n g l e t (x 8.23) a t t r i b u t e d to the t e r t i a r y methyl group adjacent to the - 109 -hydroxyl group and a doublet (x 8.80) a t t r i b u t e d to the secondary methyl group. However, f o r each t e r t i a r y , angular methyl groups there were two s i g n a l s (x 8.65, x 8.67, x 8.90 and x 8.92) d i s p l a y e d i n the n.m.r. spectrum. This could be explained once again on the b a s i s of an isomeric mixture due to the asymmetric center i n the THP group (see footnote 7, page 87). Dehydration of the t e r t i a r y a l c o h o l with t h i o n y l c h l o r i d e i n benzene-pyridine afforded a q u a n t i t a t i v e y i e l d of the crude o l e f i n 169. The amount of d e s i r e d o l e f i n 169 i n t h i s crude product was greater than 73%, s i n c e conversion of the crude o l e f i n 169 i n t o the t o s y l a t e 174 (vide i n f r a ) was c a r r i e d out i n 73% o v e r a l l yield.'''''" The presence of the t e r m i n a l o l e f i n i c double bond was c l e a r l y evident from the strong absorptions at 6.15 and 11.13 y i n the i n f r a r e d spectrum. The n.m.r. spectrum, however, was too complex f o r c l e a r a n a l y s i s , presumably because o l e f i n 159 was an epimeric mixture due to the asymmetric center i n the THP group (see footnote 7, page 87) and because the crude product could a l s o be contaminated with a small amount of the isomeric o l e f i n possessing the e n d o c y c l i c double bond.^"*" In order to c h a r a c t e r i z e the product more f u l l y , removal of the THP p r o t e c t i n g group was attempted. However, t h i s could not be achieved without causing the p a r t i a l i s o m e r i z a t i o n of the t e r m i n a l o l e f i n i c double bond i n t o the more s u b s t i t u t e d p o s i t i o n . G a s - l i q u i d chromatographic ^ I t should be noted that the crude product may w e l l c o n t a i n some of the isomeric o l e f i n which possess the en d o c y c l i c double bond. However, the n.m.r. spectrum of the crude product showed no sub-s t a n t i a l s i g n a l s i n the v i n y l methyl r e g i o n , and the amount of the isomeric o l e f i n was, t h e r e f o r e , q u i t e s m a l l . - 110 -a n a l y s i s of the crude dehydration product on two d i f f e r e n t columns a l s o caused i s o m e r i z a t i o n of the double bond, with each column g i v i n g a d i f f e r e n t isomer r a t i o . Moreover, s u b j e c t i o n o f the crude product to g a s - l i q u i d chromatographic c o n d i t i o n s a l s o caused removal of the THP p r o t e c t i n g group. However, i n order to demonstrate that during the dehydration of 170 no s k e l e t a l rearrangement had taken p l a c e , a n a l y t i c a l samples o f o l e f i n s 171 and 172 were c o l l e c t e d by p r e p a r a t i v e g . l . c . The i n f r a r e d and n.m.r. sp e c t r a of these two compounds were i n complete accord with t h e i r assigned s t r u c t u r e s . The i n f r a r e d spectrum o f 171 e x h i b i t e d absorptions at 2.77 and/2.90 y due to the hydroxyl group, and absorptions at 6.13 and 11.10 y due t o the terminal o l e f i n i c double bond. The two-proton m u l t i p l e t i n the n.m.r. spectrum at x 5.14 als o c l e a r l y demonstrated the presence of a terminal o l e f i n i c double bond. The one-proton broad m u l t i p l e t at x 6.20 was a t t r i b u t e d to the proton adjacent to the hydroxyl group, the three-proton doublet at x 8.90 was a t t r i b u t e d to the secondary methyl group, and the two three-proton s i n g l e t s at x 8.91 and x 9.05 were a t t r i b u t e d to the t e r t i a r y methyl groups. The i n f r a r e d spectrum of 172 e x h i b i t e d , i n a d d i t i o n to the expected hydroxyl absorptions, a weak absorption at 6.12 y due to the t e t r a - s u b s t i t u t e d double bond. The n.m.r. spectrum e x h i b i t e d no o l e f i n i c protons, but i n s t e a d showed a broad s i n g l e t at x 8.28 which was a t t r i b u t e d to the two overlapping v i n y l methyl groups. In a d d i t i o n , the n.m.r. spectrum d i s p l a y e d a broad, one-proton m u l t i p l e t at x 6.20 due to the proton adjacent to the hydroxyl groups and two three-proton s i n g l e t s at x 9.00 and x 9.03 due to the t e r t i a r y methyl groups. - I l l -In order to construct the necessary l e a v i n g group present i n the keto t o s y l a t e 136 the crude o l e f i n 169 was subjected to hydroboration i n t e t r a h y d r o f u r a n , followed by decomposition of the intermediate alkylborane by treatment of the l a t t e r w i t h a l k a l i n e hydrogen peroxide. The r e s u l t i n g crude a l c o h o l 173, upon r e a c t i o n w i t h p_-toluenesulfonyl c h l o r i d e i n p y r i d i n e , was converted i n t o the c r y s t a l l i n e t o s y l a t e 174, i n an o v e r a l l y i e l d of 73% from the alkene 169. As the previous r e d u c t i o n of ketone 143 had shown (see page 102 ), the a t t a c k of borane on the double bond of 169 was expected to take place from the l e s s hindered convex s i d e ( i . e . the a side) of the molecule to y i e l d the d e s i r e d stereo-chemistry at C^. The absorptions at 6.28, 7.42, 8.54, and 10.54 p i n the i n f r a r e d spectrum of compound 174 supported the presence of a t o s y l a t e - 112 -group. The n.m.r. spectrum, which was p a r t i c u l a r l y i n s t r u c t i v e , e x h i b i t e d two doublets (x 2.15 and x 2.63) due to the aromatic protons, a s i n g l e t (x 7.53) due to the aromatic methyl group, two s i n g l e t s (x 8.90 and x 8.94) a t t r i b u t e d to the t e r t i a r y methyl groups, and a doublet (x 9.12) a t t r i b u t e d to the secondary methyl group. OTHP OTHP OTHP 136 175 Removal of the THP p r o t e c t i n g group from 174 by treatment of the l a t t e r w i t h a c a t a l y t i c amount of p_-toluenesulfonic a c i d i n r e f l u x i n g methanol (77) affor d e d the c r y s t a l l i n e a l c o h o l 175 i n 77% y i e l d . The sharp mel t i n g p o i n t and s p e c t r a l data i n d i c a t e d that the product was homogeneous. The n.m.r. spectrum showed, i n a d d i t i o n to a " t r i p l e t " (x 5.84) a t t r i b u t e d to the protons adjacent to the t o s y l a t e group and a m u l t i p l e t (x 6.60) a t t r i b u t e d to the proton adjacent to the hydroxyl - 113 -group, s i g n a l s very s i m i l a r to those o f compound 174. Ox i d a t i o n o f the a l c o h o l 175 under the m i l d c o n d i t i o n s of the Sar e t t o x i d a t i o n (chromium t r i o x i d e - p y r i d i n e ) (91) a f f e c t e d the conversion of a l c o h o l 175 i n t o the ketone 136 without d e s t r u c t i o n or l o s s of the t o s y l a t e l e a v i n g group. The c r u c i a l keto t o s y l a t e 136 was obtained i n 94% y i e l d and e x h i b i t e d s p e c t r a l data i n complete accord with the assigned s t r u c t u r e . The i n f r a r e d spectrum e x h i b i t e d a saturated carbonyl absorption at 5.91 y and absorptions at 6.28 and 8.53 y f o r the t o s y l a t e group. The n.m.r. spectrum (see f i g u r e 5) d i s p l a y e d two doublets (x 2.14 and x 2.60) a t t r i b u t e d t o the aromatic protons, and a s i n g l e t (x 7.53) a t t r i b u t e d to the aromatic methyl group. The two protons adjacent to the t o s y l a t e group appeared as a complex m u l t i p l e t centered at x 5.84. The two t e r t i a r y methyl groups appeared at x 8.97 and x 9.20, while the doublet due to the secondary methyl group appeared at x 9.04. Having thus obtained the keto t o s y l a t e 136, with the re q u i r e d stereochemistry at a l l four asymmetric c e n t e r s , the c r u c i a l (proposed) 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 136 to (i)-nor-seychellanone 117 could now be t e s t e d , and was, i n f a c t , found to be extremely f a c i l e . Thus, treatment of the keto t o s y l a t e 136 with d i m e t h y l s u l f i n y l carbanion i n dimethyl s u l f o x i d e at 75° f o r two hours gave, i n 90% y i e l d , ( i ) - n o r -seychellanone 117. G a s - l i q u i d chromatographic a n a l y s i s showed that the product c o n s i s t e d of only one component. The i n f r a r e d spectrum e x h i b i t e d a s a t u r a t e d carbonyl absorption at 5.84 y, and showed no absorptions due to a t o s y l a t e group. The n.m.r. spectrum (see f i g u r e 6) d i s p l a y e d none of the low f i e l d s i g n a l s which were present i n the n.m.r. spectrum of the keto t o s y l a t e 136. The n.m.r. spectrum of ketone 117 e x h i b i t e d FIGURE-5. N.M.R. Spectrum of Keto Tosylate 136. x - 115 -only high f i e l d s i g n a l s o f which two three-proton s i n g l e t s (x 9.03 and 9.06) were a t t r i b u t e d to the t e r t i a r y methyl groups, and a three-proton doublet (x 9.20) was a t t r i b u t e d to the secondary methyl group. Since Ourisson and Wolff (12,13) had observed that the carbonyl group of nor-seychellanone 117, prepared from (-)-seychellene L3, was very u n r e a c t i v e , the conversion of t h i s compound to seychellene using the W i t t i g reagent, methyltriphenylphosphorane, was not attempted. Instead t h i s ketone 117 was t r e a t e d with excess m e t h y l l i t h i u m and was thus converted i n t o the t e r t i a r y a l c o h o l 176 i n a q u a n t i t a t i v e y i e l d . Dehydration of t h i s compound could only occur i n an e x o c y c l i c manner, si n c e both r i n g p o s i t i o n s adjacent to the a l c o h o l f u n c t i o n are bridgehead 13 176 - 118 -p o s i t i o n s . Thus, dehydration of the t e r t i a r y a l c o h o l 176 with t h i o n y l c h l o r i d e i n benzene-pyridine afforded a q u a n t i t a t i v e y i e l d of (±)-seychellene 1_3. 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 e x h i b i t e d s p e c t r a l data ( i n f r a r e d , n.m.r., mass spectrum) and g . l . c . 12 r e t e n t i o n time i d e n t i c a l with those of authentic (-)-seychellene 13. The i n f r a r e d spectrum of ( i ) - s e y c h e l l e n e 13_ e x h i b i t e d absorptions at 3.26, 6.11, and 11.42 y c l e a r l y a t t r i b u t a b l e to an e x o c y c l i c o l e f i n i c double bond. In the n.m.r. spectrum the o l e f i n i c protons appeared as two doublets (J = 1.5 Hz) at x 5.23 and x 5.41. A one-proton m u l t i p l e t 7 at x 7.78 was a t t r i b u t e d t o the a l l y l i c proton at C . The t e r t i a r y methyl groups appeared as sharp three-proton s i n g l e t s at x 9.06 and x 9.19, while vthe secondary methyl group appeared as a doublet (J = 6.5 Hz) at x 9.27. Thus, i n c o n c l u s i o n , the s t r u c t u r e L3_ proposed f o r seychellene by Ourisson and Wolff (12,13) has been f u l l y corroborated by the preced-ing s t e r e o s e l e c t i v e synthesis of t h i s compound. This c o n s t i t u t e s the f i r s t t o t a l s y n t h e s i s of (1)-seychellene. We are g r a t e f u l to Professor G. Ourisson f o r a sample of authentic (-)-seychellene. EXPERIMENTAL Preparation of 2-Methyl-l,3-cyclohexanedione 139 To a s o l u t i o n of 88 g (2.2 moles) of sodium hydroxide and 250 g (2.23 moles) of 1,3-cyclohexanedione 158 i n 535 ml of water and 160 ml of dioxane was added 406 g (2.88 moles) of methyl i o d i d e . The r e a c t i o n mixture was s t i r r e d and r e f l u x e d under a n i t r o g e n atmosphere f o r approximately 10 h, then cooled and l e f t overnight at room temperature. The mixture was cooled to -10° and the c r y s t a l l i n e m a t e r i a l c o l l e c t e d by f i l t r a t i o n o f the mixture through a coarse c i n t e r e d g l ass f u n n e l . The. c r y s t a l l i n e m a t e r i a l was washed with two p o r t i o n s of i c e - c o l d water. R e c r y s t a l l i z a t i o n of the crude product from 95% ethanol afforded 93 g (37%) of 2-methyl-l,3-cyclohexanedione 139, m.p. 205-207°. L i t . m.p. 208-210° (73). Preparation of Wieland.-Miescher Ketone 137 A mixture of 238 g (1.89 moles) of 2-methyl-l,3-cyclohexanedione 139, 170 ml of dry p y r i d i n e , 2.5 1 of dry benzene and 322 g (2.25 moles of f r e s h l y d i s t i l l e d l-diethylamino-3-butanone was r e f l u x e d f o r 18 h. 13 For general i n f o r m a t i o n see page 52. - 120 -A f t e r c o o l i n g , the s o l u t i o n was s u c c e s s i v e l y washed with 2 1 of 7.5% h y d r o c h l o r i c a c i d , two 2 1 p o r t i o n s - o f water and with saturated b r i n e . The organic s o l u t i o n was d r i e d over anhydrous magnesium s u l f a t e and then concentrated. D i s t i l l a t i o n of the residue under reduced pressure af f o r d e d 257 g (77%) of the dione 157, b.p. 132-134° at 0.15 mm. L i t . b.p. 109-115° at 0.05 mm (74). This m a t e r i a l c r y s t a l l i z e d on standing. R e c r y s t a l l i z a t i o n of the d i s t i l l e d product from ether gave 235 g (70%) of the Wieland-Miescher ketone 128, m.p. 48-49°. L i t . m.p. 47-48° (74). U l t r a v i o l e t , A 244 my (e = 11,900); i n f r a r e d (CHC1„), A 5.85, TH3-X o nicix 6.02, 6.18 y; n.m.r., T 4.14 (broad s i n g l e t , IH, o l e f i n i c p r o t o n ) , 8.50 ( s i n g l e t , 3H, t e r t i a r y methyl). P r e p a r a t i o n of Keto A l c o h o l 141 A s o l u t i o n of 3.24 g (0.0858 mole) of sodium borohydride i n 375 ml of 100% ethanol was added over one hour to a s t i r r e d s o l u t i o n of 51.8 g (0.290 mole) o f dione 128 i n 750 ml of 100% ethanol at 0°. A f t e r the r e a c t i o n had been allowed to continue f o r an a d d i t i o n a l 15 min, 20 ml of g l a c i a l a c e t i c a c i d was added. The solvent was removed under reduced pressure and the r e s i d u e a l m a t e r i a l was d i l u t e d with chloroform. The organic s o l u t i o n was washed twice w i t h water, d r i e d over anydrous magnesium s u l f a t e and concentrated. Vacuum 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 a f f o r d e d 46.5 g (89%) of keto a l c o h o l 131, b.p. 150-153° at 0.1 mm. L i t . b.p. 140° at 0.25 mm (76). U l t r a v i o l e t , A 240 my (e = r ^ J '• max ^ 13,500); i n f r a r e d ( f i l m ) , A ,3.00, 6.05, 6.21 y; n.m.r., x 4.12 IH3.X (broad s i n g l e t , IH, o l e f i n i c p r o t o n ) , 6.45 ( m u l t i p l e t , IH, -CHOH), 8.63 ( s i n g l e t , 3H, t e r t i a r y methyl). Preparation of Tetrahydropyranyl Ether 142 Anhydrous hydrogen c h l o r i d e was bubbled i n t o a s o l u t i o n of keto a l c o h o l '141 (174 g, 0.66 mole) and of dihydropyran (123 g, 1.47 moles) i n methylene c h l o r i d e (560 ml) u n t i l the mixture grew warm. A f t e r the r e s u l t i n g s o l u t i o n had been allowed to stand f o r 3 h at room temperature i t was d i l u t e d w i t h 400 ml of methylene c h l o r i d e and then washed w i t h saturated sodium bicarbonate s o l u t i o n and with saturated b r i n e . The s o l u t i o n was d r i e d over anhydrous magnesium s u l f a t e and concentrated. C r y s t a l l i z a t i o n of the residue from hexane-ether afforded 240 g (94%) of the tetrahydropyranyl ether 152, m.p. 40-45°. L i t . m.p. 55-60° (77) ( f o r an explanation of t h i s discrepancy see footnote 7, page 87). U l t r a v i o l e t , X 239 my (e = 13,900); i n f r a r e d (CHC1,), UlclX «J X 6.02, 6.20 y; n.m.r., x 4.24 (broad s i n g l e t , IH, o l e f i n i c p r o t o n ) , i 5.36 ( m u l t i p l e t , IH, -0CH0-), 8.80 ( s i n g l e t , 3H, t e r t i a r y methyl). Preparation of Enol Acetate 151 To a s t i r r e d suspension of cuprous i o d i d e (68.7 g, 0.36 mole) i n dry ether (1250 ml) under a n i t r o g e n atmosphere and at -25° (dry i c e -carbon t e t r a c h l o r i d e s l u s h bath) was added 305 ml of 2.35 M m e t h y l l i t h i u m i n ether. A small amount of cuprous i o d i d e was added u n t i l a small amount of yellow 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 dimethyl-cuprate s o l u t i o n was added a s o l u t i o n o f the a,3-unsaturated ketone 142 (35 g, 0.132 mole) i n dry ether (1250 ml) over a 20 min p e r i o d . 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 70 min. The - 122 -c o o l i n g bath was removed and a s o l u t i o n of a c e t y l c h l o r i d e (187 g, 1.65 moles): i n dry ether (1250 ml) was added over a 5 min p e r i o d . 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 o f approximately 1:2. The yellow residue which remained i n the r e a c t i o n v e s s e l was destroyed with an a d d i t i o n a l amount of the ammonium hydroxide-ice mixture, and the r e s u l t i n g s o l u t i o n was added to the preceding mixture. The ether l a y e r was separated and the aqueous s o l u t i o n was e x t r a c t e d once with ether. The combined ether s o l u t i o n was washed with d i l u t e ammonium hydroxide, water and saturated b r i n e , d r i e d over anhydrous magnesium s u l f a t e and concentrated. The r e s i d u a l m a t e r i a l was subjected to column chromatography on 60-100 mesh f l o r i s i l . The f r a c t i o n s e l u t e d w i t h 1:1 ether-benzene contained 30.6 g (79%) of the enol acetate 142• The l a t t e r f r a c t i o n s were subjected once again to column chromatography and an a d d i t i o n a l 2.9 g (9%) of compound 142 was obtained. A l l traces of solvent were removed from the above m a t e r i a l under reduced pressure (vacuum pump 0.1 mm, 50°) to a f f o r d an a n a l y t i c a l 20 sample, n^ 1.4987. I n f r a r e d ( f i l m ) , X 5.72, 5.93 u; n.m.r., x 5.04 r ' D <..»>. m a x ' I ( m u l t i p l e t , IH, v i n y l p r o t o n ) , 5.37 ( m u l t i p l e t , IH, -0CH0-), 7.93 ( s i n g l e t , 3H, acetate methyl), 9.05, 9.09 ( s i n g l e t s , 6H, t e r t i a r y methyls). Anal. Calcd. f o r C i gH Q 0 : C, 70.77; H, 9.38. Found: C, 70.66; H, 9.45. Epoxidation of Enol Acetate 151 A s o l u t i o n of the enol acetate 151 (30.7 g, 0.095 mole) and 68 g (0.356 mole) of 85% m-chloroperbenzoic a c i d i n 1500 ml of dry benzene - 123 -was s t i r r e d i n the dark f o r 48 h. The p r e c i p i t a t e was removed by f i l t r a t i o n and washed with benzene. The combined f i l t r a t e and washings were washed with three p o r t i o n s of 10% aqueous sodium hydroxide. The combined aqueous washings were ex t r a c t e d w i t h ether. The combined benzene s o l u t i o n and ether e x t r a c t s were washed with water and saturat e d b r i n e , then d r i e d over anhydrous magnesium s u l f a t e and concentrated under reduced pressure, y i e l d i n g 30.6 g (95%) of the epoxy acetate 153. This m a t e r i a l could not be p u r i f i e d f u r t h e r since i t was heat l a b i l e , and unstable t o column chromatography. The crude product e x h i b i t e d the f o l l o w i n g s p e c t r a l data: i n f r a r e d ( f i l m ) , X 5.74 y; i n.m.r. T 5.31 ( m u l t i p l e t , IH, -0CH0-), 7.05 ( s i n g l e t , IH, epoxy p r o t o n ) , 7.95 ( s i n g l e t , 3H, acetate methyl), 9.10, 9.18 ( s i n g l e t s , 6H, t e r t i a r y methyls). P r e p a r a t i o n of Keto Acetate 154 The epoxy acetate 153 (30.6 g) was heated at 160° f o r 30 min under a n i t r o g e n atmosphere. The r e s u l t i n g m a t e r i a l was c r y s t a l l i z e d from hexane-ether to a f f o r d 22.6 g (73%) of the keto acetate 154, m.p. 120-123°. I n f r a r e d (CHC1-), X 5.80 y; n.m.r., x 4.77 ( s i n g l e t , IH, «j nicix i -CHOAc), 5.34 ( m u l t i p l e t , IH, -0CH0-), 7.84 ( s i n g l e t , 3H, acetate methyl), 8.53, 8.73 ( s i n g l e t s , 6H, t e r t i a r y methyls). Anal. Calcd. f o r C 1 9H 3 ( )0 5: C, 67.43; H, 8.93. Found: C, 67.27; H, 8.89. Removal of the THP P r o t e c t i n g Group from 154 A s o l u t i o n of 400 mg (1.18 mmoles) of the keto acetate 154 and a - 124 -c a t a l y t i c amount of p_-toluenesulfonic a c i d i n 25 ml methanol was heated on a steam bath f o r approximately 30 min u n t i l 10 ml of solvent remained. The remaining solvent was removed under reduced pressure and the residue was d i l u t e d w i t h ether. The s o l u t i o n was washed with saturated sodium bicarbonate s o l u t i o n , water and saturated b r i n e , then d r i e d over anhydrous magnesium s u l f a t e and concentrated. C r y s t a l l i z a t i o n of the residue from ether a f f o r d e d 240 mg (80%) of the a l c o h o l 155 m.p. 195.0-195.5°. I n f r a r e d (CHC1_), A 2.78, 2.88, 5.80 u; n.m.r., x 4.80 o IT13-X ( s i n g l e t , IH, -CHOAc), 6.44 ( m u l t i p l e t , IH, -CHOH), 7.85 ( s i n g l e t , 3H, acetate methyl), 8.59, 8.70 ( s i n g l e t s , 6H, t e r t i a r y methyls). Anal. Calcd. f o r c14tt22°4: C' 6 6 A 2 > H> 8 - 7 2 - Found: C, 66.26; H, 8.80. Preparation of O l e f i n 156 A s t i r r e d suspension of sodium hydride (3.1 g, 0.129 mole) i n dry d i m e t h y l s u l f o x i d e (260 ml) was slowly heated, under an atmosphere of 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 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 (53.5 g, 0.15 mole) i n dry dimethyl s u l f o x i d e (220 ml) was added. A f t e r s t i r r i n g the r e a c t i o n mixture f o r 10 min, a s o l u t i o n of keto acetate 154 (14.5 g, 0.043 mole) i n dry dimethyl s u l f o x i d e (340 ml) was added. The r e a c t i o n mixture was heated at 50° f o r 2.5 h, cooled and d i l u t e d w i t h 500 ml of water. The r e s u l t i n g mixture was e x t r a c t e d three times with pentane. The combined e x t r a c t s were washed twice w i t h water, d r i e d over anhydrous magnesium s u l f a t e and concentrated. The crude o i l - 125 -was subjected t o column chromatography on 60-100 mesh f l o r i s i l . The f r a c t i o n e l u t e d w i t h 3:1 benzene-ether contained 10.6 g (73%) of the d e s i r e d o l e f i n 156, n^° 1.4971. I n f r a r e d ( f i l m ) , A 3.30, 5.78, 6.08, ' D J max ' 11.22 y; n.m.r., x 4.63 ( m u l t i p l e t , IH, -CHOAc), 5.16, 5.37 ( m u l t i p l e t s , i 3H, =CH2 and -OCHO-overlapping), 7.81 ( s i n g l e t , 3H, acetate methyl), 8.73, 8.85 ( s i n g l e t s , 6H, t e r t i a r y methyls). Anal. Calcd. f o r c 2 o H 3 2 ° 4 : C j 7 1- 5 9> n> 9-59. Found: C, 71.51; H, 9.69. Hydrogenation of O l e f i n 156 A s o l u t i o n of o l e f i n 156 (6.3 g, 18.8 mmoles) and t r i s ( t r i p h e n y l -phosphine)chlororhodium (1.2 g) i n benzene (250 ml) was subjected to hydro-genation at room temperature and atmospheric pressure. Hydrogen uptake ceased a f t e r approximately 18 h. The solvent was removed under reduced pressure and 1:1 hexane-ether was added. The p r e c i p i t a t e that formed was removed by f i l t r a t i o n and the f i l t r a t e chromatographed on a short column of a c t i v i t y I I Shawinigan alumina. The d e s i r e d acetate was e l u t e d with 1:1 hexane-ether. A f t e r removal of the solvent under reduced pressure a c l e a r c o l o u r l e s s o i l remained, which c r y s t a l l i z e d on standing. R e c r y s t a l l i z a t i o n from hexane gave 5.7 g (90%) of the d e s i r e d m a t e r i a l 157, m.p. 83-86°. I n f r a r e d (CHC1„), A 5.77 y; o max i n.m.r. x 5.10 ( m u l t i p l e t , IH, -CHOAc), 5.30 ( m u l t i p l e t , IH, -0CH0-), 7.89, 7.91 ( s i n g l e t s , 3H, acetate methyls from the two d i f f e r e n t isomers) (see footnote 7 page 87 ), 9.03, 9.08 ( s i n g l e t s , 6H, t e r t i a r y methyls), 9.22 (doublet^ 3H, secondary methyl, J = 6 Hz). - 126 -Anal. Calcd. f o r C H^O : C, 70.97; H, 10.12. Found: C, 70.68; H, 9.97. Removal of the THP P r o t e c t i n g Group from 157 The procedure employed f o r the removal of the THP p r o t e c t i n g group was i d e n t i c a l with that used f o r the p r e p a r a t i o n of compound 154 (see page 123)• From 388 mg of compound 157 there was obtained, a f t e r c r y s t a l l i z a t i o n from e t h y l acetate, 180 mg (70%) of the a l c o h o l 158 , m.p. 94.5-95.0°. I n f r a r e d ( C H C I J , X 2.80, 2.95, 5.81 y; n.m.r. o nicix T 5.08 (doublet, IH, -CHOAc, J = 2 Hz), 5.70 (broad m u l t i p l e t , IH, -CHOH), 7.91 ( s i n g l e t , 3H, acetate methyl), 9.03, 9.14 ( s i n g l e t s , 6H, t e r t i a r y methyls), 9.23 (doublet, 3H, secondary methyl, J = 6 Hz). Anal. Calcd. f o r C l rH„,0 T: C, 70.83; H, 10.30. Found: C, 70.55; l b ZD o H, 10.27. H y d r o l y s i s of the Acetate 157 A s o l u t i o n of the acetate 157 (6.0 g) and potassium hydroxide (24 g) i n ethanol (210 ml) and water (24 ml) was r e f l u x e d f o r 4.5 h. The solvent was removed under reduced pressure and the re s i d u e d i l u t e d w i t h water. The r e s u l t i n g mixture was thoroughly e x t r a c t e d with ether. The combined e x t r a c t s were washed with water and saturated b r i n e , and then d r i e d over anhydrous magnesium s u l f a t e and concentrated. R e c r y s t a l l i z a t i o n of the residue from hexane y i e l d e d 4.42 g (84%) of the a l c o h o l 160, m.p. 115-117°. I n f r a r e d (CHC1 ) , X 2.80, 2.95 y; ~~ o nicix t n.m.r., x 5.30 ( m u l t i p l e t , IH, -0CH0-), 9.11 (doublet, 3H, secondary - 127 -methyl, J = 7 Hz, the u p f i e l d h a l f of the doublet was masked by the t e r t i a r y methyl s i g n a l s ) , 9.13, 9.17 ( s i n g l e t s , 6H, t e r t i a r y methyls). Anal. Calcd. f o r C l oH__0,: C, 72.93; H, 10.88. Found: C, 72.78; l o oZ J H, 10.77. Removal of the THP P r o t e c t i n g Group from 160 The procedure employed f o r the removal of the THP p r o t e c t i n g group was i d e n t i c a l w i t h that used f o r the p r e p a r a t i o n of compound 154 (see page 123 ). From 337 mg of a l c o h o l 160 there was obtained, a f t e r c r y s t a l l i z a t i o n from e t h y l a c e t a t e , 217 mg (90%) of the d i o l 161, m.p. 139.0-139.5°. I n f r a r e d (CHC1,), A 2.80, 2.95 p ; n.m.r., T 5.63 o nicix (X p o r t i o n of an ABX q u a r t e t , IH, C 1 : LH0H, J = 11 Hz, J B X = 5 Hz) , 6.68 (doublet, IH, C5H0H, J = 3 Hz), 9.10 (doublet, 3H, secondary methyl, J = 7 Hz), 9.17 ( s i n g l e t , 6H, two overlapping t e r t i a r y methyl s i g n a l s ) . Anal. Calcd. f o r C-^H^O^ C, 73.54; H, 11.39. Found: C, 73.66; H, 11.38. Prep a r a t i o n o f Ketone 143 To 100 ml of dry p y r i d i n e s t i r r e d at 0° was added 4.0 g (40 mmoles) of chromium t r i o x i d e . To the r e s u l t i n g s o l u t i o n was added 2.96 g (10 mmoles) of the c r y s t a l l i n e a l c o h o l 160 d i s s o l v e d i n 50 ml of dry p y r i d i n e . A f t e r the r e a c t i o n mixture had been allowed to s t i r at room temperature f o r 18 h, water was added and the mixture e x t r a c t e d three times wit h ether. The ether s o l u t i o n was concentrated and the residue was d i l u t e d with benzene. The benzene s o l u t i o n was washed three times w i t h water, once with sa t u r a t e d b r i n e , and was then d r i e d over anhydrous - 128 -magnesium s u l f a t e and concentrated. There was obtained a q u a n t i t a t i v e y i e l d of crude product, which upon c r y s t a l l i z a t i o n from hexane afforded 1.39 g (47%) of ketone 143, m.p. 96-98°. I n f r a r e d (CHC1„), A 5.91 y; o max i n.m.r., T 5.40 ( m u l t i p l e t , IH, -0CH0-), 8.92, 9.01 ( s i n g l e t s , 6H, t e r t i a r y m ethyls), 9.03 (doublet, 3H, secondary methyl, J = 6.5 Hz). Anal. Calcd. f o r C l o H T n 0 7 : C, 73.43; H, 10.27. Found: C, 73.55; l o J U O H, 10.47. The m a t e r i a l obtained from the mother l i q u o r s of the above c r y s t a l l i z a t i o n was subjected to column chromatography on 60-100 mesh f l o r i s i l . The f r a c t i o n s e l u t e d with benzene contained an a d d i t i o n a l 0.89 g (30%) of ketone 143<. Although the i n f r a r e d spectrum of t h i s m a t e r i a l was v i r t u a l l y i d e n t i c a l w i t h the spectrum of c r y s t a l l i n e ketone, the o i l could not be c r y s t a l l i z e d . A mixture of the c r y s t a l l i n e m a t e r i a l and the o i l was used f o r subsequent r e a c t i o n s i n v o l v i n g ketone 143. Lithium Aluminum Hydride Reduction of Ketone 143 To a s t i r r e d s o l u t i o n of 76 mg (2.06 mmoles) of l i t h i u m aluminum hydride i n 10 ml of dry ether was added a s o l u t i o n of 400 mg (1.36 mmoles) of ketone 143 i n 10 ml dry ether. 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 excess l i t h i u m aluminum hydride was destroyed by c a r e f u l a d d i t i o n of water, and the r e s u l t i n g mixture was f i l t e r e d through a s i n t e r e d glass f u n n e l . The f i l t r a t e was washed with water and s a 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. The crude residue was c r y s t a l l i z e d - 129 -from hexane to a f f o r d 377 mg (94%) of a l c o h o l 160, m.p. 124-127°. Although the m.p. of t h i s m a t e r i a l was somewhat d i f f e r e n t from t h a t of the a l c o h o l prepared by h y d r o l y s i s of the acetate (see page 126 ) ( f o r an e x p l a n a t i o n of the m.p. discrepancy see footnote 7, page 8 7 ) , the i n f r a r e d and n.m.r. spec t r a were i d e n t i c a l . Removal of the tetrahydropyranyl ether p r o t e c t i n g group (procedure as on p. 123) a f f o r d e d , i n 92% y i e l d the d i o l 161, which was i d e n t i c a l (m.p., mixed m.p., i n f r a r e d spectrum) with the p r e v i o u s l y prepared d i o l (see page 127 ). Preparation of.Ketone 152 A s o l u t i o n Of 7.46 g (23.2 mmoles) of enol acetate 151 and 2.8 g (20.2 mmoles) of potassium carbonate i n 120 ml methanol and 20 ml water was s t i r r e d at room temperature f o r 1 h. A f t e r the solvent had been removed under reduced pressure the remaining residue was d i l u t e d with water. The r e s u l t i n g mixture was 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 washed with water and saturated b r i n e , d r i e d over anhydrous magnesium s u l f a t e and concentrated. R e c i y s t a l l i z a t i o n of the residue from hexane a f f o r d e d 5.1 g (80%) of the ketone 152, m.p. 84-86°. I n f r a r e d (CHC1„), X 5.88 y; n.m.r., x 5.31 ( m u l t i p l e t , o nicix i IH, -0CH0-), 9.02, 9.10 ( s i n g l e t s , 6H, t e r t i a r y methyls). Anal. Calcd. f o r C.-H.-O,: C, 72.82; H, 10.06. Found: C, 73.00; 1 / 2o 6 H, 10.02. - 130 -Removal of THP P r o t e c t i n g Group from 152 A s o l u t i o n of 400 mg (1.44 mmoles) of compound 152 and 100 mg (1.12 mmoles) of o x a l i c a c i d i n 20 ml methanol was r e f l u x e d f o r 6 h. 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 e x t r a c t e d three times w i t h ether. The combined e x t r a c t s were washed with 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. C r y s t a l l i z a t i o n of the residue from hexane-ether a f f o r d e d 210 mg (75%) of the keto a l c o h o l 162, m.p. 179-182°. I n f r a r e d (CHC1J, X 1 o in 3. x 2.80, 2.95, 5.89 p ; n.m.r., x 5.85 ( " t r i p l e t " , IH, -CHOH), 9.04 ( s i n g l e t , 3H, C 1 t e r t i a r y methyl), 9.08 (doublet, 3H, C 1 0 t e r t i a r y methyl, J = 0.8 Hz). Anal. Calcd. f o r C 1 2 H 2 Q 0 2 : C, 73.43; H, 10.27. Found: C, 73.59; = H, 10.41. Deuteration of Keto A l c o h o l 162 A s o l u t i o n of 150 mg (0.77 mmole) of keto a l c o h o l 162 and 12 mg of anhydrous potassium carbonate i n 3 ml of deuterium oxide and'3 ml of dioxane was r e f l u x e d f o r 17 h. The s o l u t i o n was cooled and d i l u t e d w i t h water. The mixture was e x t r a c t e d w i t h two p o r t i o n s of ether. The combined e x t r a c t s were washed with saturated b r i n e , d r i e d over anhydrous magnesium s u l f a t e and concentrated. C r y s t a l l i z a t i o n of the residue from hexane-ethyl acetate afforded 105 mg (69%) of the deuterated ketone 163, which e x h i b i t e d a molecular i o n peak at e/m 200 (low r e s o l u t i o n mass spectrometry) corresponding to the i n t r o d u c t i o n of 4 - 131 -deuteriums. I n f r a r e d (CHC1 ) , A . >. 2.80, 2.95, 4.55, 5.91 y; n.m.r. o UlclX x 5.88 ( " t r i p l e t " , IH, -CHOH), 9.05, 9.09 ( s i n g l e t s , 6H, t e r t i a r y methyls). P r e p a r a t i o n of T e r t i a r y A l c o h o l 164 To a s o l u t i o n o f 6.94 g (24.8 mmoles) of ketone 152 was added 40 ml of 2.35 M m e t h y l l i t h i u m i n ether. 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 f o r 24 h. The excess m e t h y l l i t h i u m was destroyed by c a r e f u l a d d i t i o n of water. The aqueous l a y e r was separated and ex t r a c t e d once w i t h ether. The combined ether s o l u t i o n was washed with water and with saturated b r i n e , d r i e d over anhydrous magnesium s u l f a t e and concentrated. C r y s t a l l i z a t i o n o f the residue from hexane afforded 5.4 gm (74%) of the t e r t i a r y a l c o h o l 164. The m a t e r i a l obtained from the mother l i q u o r s o f c r y s t a l l i z a t i o n showed some carbonyl absorption i n i t s i n f r a r e d spectrum and was t h e r e f o r e again subjected to r e a c t i o n w i t h m e t h y l l i t h i u m as described above. A f t e r work-up and c r y s t a l l i z a t i o n there was obtained an a d d i t i o n a l 0.33 g (4%) of the d e s i r e d a l c o h o l 164. An a n a l y t i c a l sample, c r y s t a l l i z e d from hexane, e x h i b i t e d m.p. 134-136°. In f r a r e d (CHC1-), A 2.82, 2.98 y; n.m.r., T 5.23 ( m u l t i p l e t , IH, «j UlclX i -0CH0-), 8.76,. 8.87, 9.07 ( s i n g l e t s , 9H, t e r t i a r y methyls). Anal. Calcd. f o r C 1 0H_J) • C, 72.93; H, 10.88. Found: C, 72.99; H, 10.81. Dehydration of T e r t i a r y A l c o h o l 164 To a s t i r r e d s o l u t i o n of 5.4 g (16.4 mmoles) of t e r t i a r y a l c o h o l - 132 -164 i n 130 ml of dry benzene and 92 ml of dry p y r i d i n e at 0° was added, over a 5 min p e r i o d , a s o l u t i o n of 1.6 ml (19.2 mmoles) of t h i o n y l c h l o r i d e i n 85 ml of dry benzene. The r e a c t i o n mixture was s t i r r e d at 0° f o r an a d d i t i o n a l 15 min and then poured i n t o r a p i d l y s t i r r e d i c e water. The organic l a y e r was separated and the aqueous l a y e r was ext r a c t e d with benzene. The combined organic e x t r a c t s were washed with two po r t i o n s o f water and one p o r t i o n of saturated b r i n e , d r i e d over anhydrous magnesium s u l f a t e , and concentrated. A n a l y s i s of the crude r e a c t i o n mixture by g . l . c . (column D, 200°, 100) revealed the presence of three o l e f i n s , 165, 166 and 167, i n a r a t i o of 48:39:13, r e s p e c t i v e l y . The s p e c t r a l data of these compounds i n d i c a t e d the l o s s of the THP p r o t e c t i n g group. A sample of each compound was obtained by p r e p a r a t i v e g . l . c . (column I , 240°, 200). O l e f i n 165, c r y s t a l l i z e d from hexane, e x h i b i t e d m.p. 88-89°. I n f r a r e d (CHC1,), X 2.80, 2.95 y; n.m.r., x 5.06 (quartet, IH, o nicix o l e f i n i c proton, J = 0.7 Hz), 6.70 (broad m u l t i p l e t , IH, -CHOH), 8.38 (broad s i n g l e t , 3H, v i n y l methyl), 9.13, 9.15 ( s i n g l e t s , 6H, t e r t i a r y methyls) . Anal. Calcd. f o r C^H^O: C, 80.35; H, 11.41. Found: C, 80.10; H, 11.35. O l e f i n 166, c r y s t a l l i z e d from hexane, e x h i b i t e d m.p. 80-81°. I n f r a r e d (CHC1 ), X 2.80, 2.95 y; n.m.r., x 4.76 ( m u l t i p l e t , IH, o nicix o l e f i n i c proton, peak width at h a l f height 9 Hz), 6.37 (broad m u l t i p l e t , IH, -CHOH), 8.34 (broad s i n g l e t , 3H, v i n y l methyl), 9.13 ( s i n g l e t , 6H, overlapping t e r t i a r y methyls). Anal. Calcd. f o r C^H^O: C, 80.35; H, 11.41. Found: C, 80.38; H, 11.36. - 133 -O l e f i n 167 e x h i b i t e d i n f r a r e d ( f i l m ) , X 3.00, 6.10, 11.37 y. Hydroboration of O l e f i n 165 To a s o l u t i o n of 174 mg (1.0 mmole) of alkene 165 i n 7 ml of dry t e t r a h y d r o f u r a n , under a n i t r o g e n atmosphere, was added 1.5 ml of 1 M borane i n t e t r a h y d r o f u r a n . A f t e r the r e a c t i o n was allowed to proceed f o r 2 h at room temperature the excess borane was destroyed by c a r e f u l a d d i t i o n of water. To the r e s u l t i n g s o l u t i o n 2 ml of 10% sodium hydroxide s o l u t i o n and 2 ml of 30% hydrogen peroxide was added. A f t e r the r e a c t i o n was allowed to proceed at room temperature f o r 2 h water was added and the mixture was e x t r a c t e d w i t h three p o r t i o n s of methylene c h l o r i d e . 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 and concentrated. C r y s t a l l i z a t i o n of the r e s i d u e from e t h y l acetate afforded 105 mg (55%) of d i o l 168, m.p. 153-154°. In f r a r e d (CHC1 ), X 2.82, 2.95 y; n.m.r., x 5.96 (broad m u l t i p l e t , o nicix IH, C n H 0 H ) , 6.43 (doublet, IH, C5H0H, J = 9.8 Hz), 8.99 (doublet, 3H, secondary methyl, J = 5.8 Hz), 9.13 ( s i n g l e t , 6H, overlapping t e r t i a r y methyls). This d i o l was t h e r e f o r e c l e a r l y d i f f e r e n t from d i o l 161 prepared p r e v i o u s l y (see page 127 ). Anal. Calcd. f o r C H 2 40 : C, 73.54; H, 11.39. Found: C, 73.42; H, 11.51. Preparation of T e r t i a r y A l c o h o l 170 To a s o l u t i o n of 3.5 g (13 mmoles) of ketone 143 i n 25 ml dry ether was added 11.1 ml of 2.35 M m e t h y l l i t h i u m . The r e a c t i o n mixture was s t i r r e d at room temperature overnight. A f t e r c a r e f u l quenching of the - 134 -r e a c t i o n mixture w i t h water, the mixture was 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 washed with 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. Since the i n f r a r e d spectrum of the crude product s t i l l showed a weak carbonyl absorption the crude product was once again subjected to r e a c t i o n w i t h m e t h y l l i t h i u m as described above, f o l l o w e d by the same work-up procedure. The r e s u l t i n g crude product was subjected to column chromato-graphy on 60-100 mesh f l o r i s i l . The f r a c t i o n s e l u t e d w i t h 1:1 benzene-ether y i e l d e d an o i l from which was obtained by c r y s t a l l i z a t i o n from hexane, 2.4 g (65%) of the t e r t i a r y a l c o h o l 170, m.p. 93-95°. The l a t t e r f r a c t i o n s from the chromatography s t i l l contained some of the s t a r t i n g ketone 143. This m a t e r i a l was t h e r e f o r e again subjected t o the o r i g i n a l r e a c t i o n c o n d i t i o n s , work-up and p u r i f i c a t i o n to a f f o r d an a d d i t i o n a l 200 mg (5%) of a l c o h o l 170. I n f r a r e d (CHC1,), X 2.80, — Q H 3 max 2.95 y; n.m.r., x 8.23 ( s i n g l e t , 3H, C ), 8.65, 8.67 ( s i n g l e t s , 3H, ' XCH 3 t e r t i a r y methyls of the two isomers) (see footnote 7, page 87 ), 8.80 (doublet, 3H, secondary, methyl, J = 6Hz), 8.-90, 8.92 ( s i n g l e t s , 3H, t e r t i a r y methyls of the two isomers) (see footnote 7, page 87). Anal. Calcd. f o r C i g H 3 4 0 3 : C, 73.50; H, 11.04. Found: C, 73.30; H, 10.88. Prep a r a t i o n of O l e f i n 169 To a s t i r r e d s o l u t i o n of a l c o h o l 170 (1.0 g, 3.33 mmoles) i n dry benzene (15 ml) and dry p y r i d i n e (10 ml) at 0° was added, dropwise, a s o l u t i o n of t h i o n y l c h l o r i d e (322 y l , 4.04 mmoles) i n benzene (10 ml). - 135 -The r e a c t i o n was allowed to proceesd f o r 35 min at 0°. The r e a c t i o n mixture was poured i n t o r a p i d l y s t i r r e d i c e water, and e x t r a c t e d three times with benzene. The organic s o l u t i o n was washed with water and saturated b r i n e , d r i e d over anhydrous magnesium s u l f a t e and concentrated to a f f o r d a q u a n t i t a t i v e y i e l d of the o l e f i n 169. An a n a l y t i c a l sample was obtained from column chromatography of the crude product on 60-100 20 mesh f l o r i s i l ( e l u t a n t 4:1 benzene-ether) and e x h i b i t e d n^ 1.5118. I n f r a r e d ( f i l m ) , A. m a x 6.15, 11.13 y. The n.m.r. spectrum was too complex f o r a n a l y s i s , probably because of the isomeric mixture (see footnote 7, page 87 and footnote 11, page 109). Anal. Calcd. f o r C i nH_.0„: C, 78.03; H, 11.03. Found: C, 78.10 H, 11.03. Removal of THP P r o t e c t i n g Group from 169 Removal of the tetrahydropyranyl p r o t e c t i n g group from compound 169 under the c o n d i t i o n s employed p r e v i o u s l y (see page 123 ) r e s u l t e d i n the i s o m e r i z a t i o n o f the double bond. I t was found that the p r o t e c t i n g group could be removed by g . l . c ; however, t h i s a l s o r e s u l t e d i n i s o m e r i z a t i o n o f the double bond. G a s - l i q u i d chromatographic a n a l y s i s of compound 169 employing column D (210°, 100) y i e l d e d o l e f i n s 172 and 171 i n a-ratio of approximately 2:3, and when column C (230°, 100) was employed the r a t i o was reversed to 3:2. An a n a l y t i c a l sample of o l e f i n 171, c o l l e c t e d by g . l . c . (column D, 210°, 100) and c r y s t a l l i z e d from hexane, e x h i b i t e d m.p. 69-70°. I n f r a r e d (CHC1„), X 2.77, 2.90, 6.13, 11.10 y; n.m.r., x 5.14 O ITlclX ( m u l t i p l e t , 2H, =CH ), 6.20 (broad m u l t i p l e t , IH, -CHOH), 8.90 (doublet, - 136 -3H, secondary methyl, J = 6 Hz), 8.91, 9.05 ( s i n g l e t s , 6H, t e r t i a r y methyls). Anal. Calcd. f o r C^H^O: C, 80.71; H, 11.61. Found: C, 80.61; H, 11.70. An a n a l y t i c a l sample of o l e f i n 172, c o l l e c t e d by g . l . c . (column D, 210°, 100) and c r y s t a l l i z e d from hexane, e x h i b i t e d m.p. 104-105°. In f r a r e d (CHC1J, A 2.76, 2.90, 6.12 y; n.m.r., T 6.20 (broad O IT13.X m u l t i p l e t , IH, -CHOH), 8.28 (broad s i n g l e t , 6H, v i n y l methyls), 9.00, 9.03 ( s i n g l e t s , 6H, t e r t i a r y methyls). Anal. Calcd. f o r C^H^O: C, 80.71; H, 11.61. Found: C, 80.91; H, 11.57. Prep a r a t i o n of Tosylate 174 To a s o l u t i o n of the crude alkene 169 (1.06 g, 3.66 mmoles) i n 25 ml of dry te t r a h y d r o f u r a n under a n i t r o g e n atmosphere was added 7.32 ml o f 1 M borane i n te t r a h y d r o f u r a n . A f t e r the r e a c t i o n had been allowed to proceed f o r 2 h, water was added c a r e f u l l y to destroy the excess borane. To t h i s mixture was added 6 ml of 10% sodium hydroxide s o l u t i o n and 6 ml of 30% hydrogen peroxide s o l u t i o n . The r e s u l t i n g mixture was s t i r r e d f o r 1 h, d i l u t e d with water and extr a c t e d with three p o r t i o n s of methylene c h l o r i d e . 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 and concentrated under reduced pressure. The crude product from the preceding hydroboration was d i s s o l v e d i n 8 ml of dry p y r i d i n e and 880 mg (4.63 mmoles) of p_-toluenesulfonyl c h l o r i d e added. The r e a c t i o n mixture was s t i r r e d at room temperature - 137 -f o r 1.5 h, c o l d water was added and the r e s u l t i n g mixture was thoroughly e x t r a c t e d with ether. The combined organic l a y e r was washed with sa t u r a t e d sodium bicarbonate, water, and saturated b r i n e , d r i e d over anhydrous magnesium s u l f a t e and concentrated. C r y s t a l l i z a t i o n of the crude product from hexane afforded 704 mg of the t o s y l a t e 174. The m a t e r i a l obtained from the mother l i q u o r s of t h i s c r y s t a l l i z a t i o n showed an absorption due to the hydroxyl group i n the i n f r a r e d spectrum, and was t h e r e f o r e again subjected to r e a c t i o n with p_-toluene-s u l f o n y l c h l o r i d e as described above. A f t e r work-up and c r y s t a l l i z a t i o n an a d d i t i o n a l 523 mg of compound 174 was obtained. The o v e r a l l y i e l d of t o s y l a t e 174 from the alkene 169 was 73%. An a n a l y t i c a l sample, r e c r y s t a l l i z e d from ether, e x h i b i t e d m.p. 117-117.5°. I n f r a r e d (CHCl^), A 6.28, 7.42, 8.54, 10.54 p ; n.m.r., T 2.15, 2.63 (doublets, 4H, max i aromatic protons, J = 8 Hz), 5.37 ( m u l t i p l e t , IH, -0CH0-), 7.53 ( s i n g l e t , 3H, aromatic methyl), 8.90, 8.94 ( s i n g l e t s , 6H, t e r t i a r y methyls), 12 9.12 (doublet, 3H, secondary methyl, J = 6.5 Hz). Anal. Calcd. f o r C_.H.nOrS: C, 67.21; H, 8.68; S, 6.91. Found: z6 4u 5 C, 67.12; H, 8.55; S, 7.01. Removal of the THP P r o t e c t i n g Group from 174 The procedure employed f o r the removal of the tetrahydropyranyl p r o t e c t i n g group was i d e n t i c a l with t h a t used f o r the p r e p a r a t i o n of 12 I t should be noted that the HA-100 n.m.r. spectrum i n the u p f i e l d r e g i o n d i s p l a y e d peaks f o r both isomers (see footnote 7, page 8 7 ) . - 1 3 8 -compound 154 (see page 123) . From 704 mg of c r y s t a l l i n e t o s y l a t e 174 there was obtained, a f t e r c r y s t a l l i z a t i o n from hexane-ether, 310 mg (77%) of the a l c o h o l 175, m.p. 117-118°. I n f r a r e d (CHC1„), A 3.17, 6.25, 8.51 y; n.m.r., x 2.15, 2.62 (doublets, 4H, aromatic protons, J = 8 Hz), 5.84 ( " t r i p l e t " , 2H, -CH^Tos), 6.60 ( " t r i p l e t " , IH, -CHOH), 7.53 ( s i n g l e t , 3H, aromatic methyl), 8.87, 9.00 ( s i n g l e t s , 6H, t e r t i a r y methyls), 9.12 (doublet, 3H, secondary methyl, J =6.5 Hz). Anal . Calcd. f o r C n H 3 2 0 4 S : C, 66.28; H, 8.48; S, 8.4.1, Found: C, 66.11; H, 8.38; S, 8.65. Prep a r a t i o n of Keto Tosyl a t e 136 To a s o l u t i o n of 400 mg (4.0 mmoles) of chromium t r i o x i d e i n dry p y r i d i n e was added a s o l u t i o n of 400 mg (1.1 mmoles) of the c r y s t a l l i n e a l c o h o l 175 i n 2 ml of dry p y r i d i n e . A f t e r being s t i r r e d overnight at room temperature, the r e a c t i o n mixture was d i l u t e d w i t h water and thoroughly extracted w i t h ether. The ether s o l u t i o n was concentrated under reduced pressure and the residue d i l u t e d w i t h benzene. The benzene s o l u t i o n was washed with three p o r t i o n s o f water and with one p o r t i o n of saturat e d b r i n e , d r i e d over anhydrous magnesium s u l f a t e and concentrated. C r y s t a l l i z a t i o n of the r e s i d u a l m a t e r i a l from 100% ethanol afforded 375 mg (94%) of the keto t o s y l a t e 136, m.p. 108.0-108.5°. I n f r a r e d (CHC1„), A 5.91, 6.28, 8.53 y; n.m.r., x 2.14, j fflcLX 2.60 (doublets, 4H, aromatic protons, J = 8 Hz), 5.84 ( m u l t i p l e t , 2H, -CH^OTos), 7.53 ( s i n g l e t , 3H, aromatic methyl), 8.97 ( s i n g l e t , 3H, t e r t i a r y methyl), 9.03 (doublet, 3H, secondary methyl, J - 7 Hz, down-f i e l d h a l f of doublet was masked by a t e r t i a r y methyl s i g n a l ) , 9.20 - 139 -( s i n g l e t , 3H, t e r t i a r y methyl). Anal. Calcd. f o r C 2 1H 0 S: C, 66.64; H, 7.99; S, 8.45. Found: C, 66.66; H, 7.92; S, 8.65. Prepa r a t i o n of (±)-nor-Seychellanone •117 A suspension of sodium hydride (33.6 mg, 1.4 mmoles) i n 1 ml of dry dimethyl s u l f o x i d e was heated to 75° under a n i t r o g e n atmosphere, and kept at that temperature u n t i l f r o t h i n g had ceased (approximately 45 min). To the r e s u l t a n t s o l u t i o n of d i m e t h y l s u l f i n y l carbanion was added 267 mg (0.70 mmole) of the keto t o s y l a t e 136 i n 2 ml of dry dimethyl s u l f o x i d e . The r e a c t i o n mixture was s t i r r e d at 75° f o r 2 h, cooled and d i l u t e d with water. The mixture was thoroughly e x t r a c t e d w i t h hexane. The combined ex t r a c t s were washed twice w i t h water, d r i e d over anhydrous magnesium s u l f a t e and concentrated. 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 at reduced pressure gave 131 mg (90%) of ( i ) - n o r -seychellanone 117, b.p. 120° (bath temperature) at 0.2 mm. This m a t e r i a l was shown to be one component by g . l . c . (column I , 180°, 100 and column D, 200°, 100). I n f r a r e d ( f i l m ) , A 5.85 p; n.m.r., x 9.03, nicix 9.06 ( s i n g l e t s , 6H, t e r t i a r y methyls), 9.20 (doublet, 3H, secondary methyl, J = 6.5 Hz). Anal. Calcd. f o r C^H^O: C, 81.50; H, 10.75. Found: C, 81.39; H, 10.55. Preparation of ( i ) - S e y c h e l l e n e 13 To a s o l u t i o n of 110 mg (0.50 mmole) of (±)-nor-seychellanoneJTl7 • - 140 -i n 3 ml of dry ether was added 2.1 ml of 2.35 M m e t h y l l i t h i u m . 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 f o r 2 days. The excess m e t h y l l i t h i u m was destroyed by c a r e f u l a d d i t i o n of water, and the aqueous l a y e r was thoroughly e x t 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 saturated b r i n e , d r i e d over anhydrous magnesium s u l f a t e and concentrated. The t e r t i a r y a l c o h o l 176 thus obtained was dehydrated without f u r t h e r p u r i f i c a t i o n . To a s t i r r e d s o l u t i o n of t h i s crude t e r t i a r y a l c o h o l 176 i n 2.5 ml dry benzene and 1.6 ml dry p y r i d i n e at 0° was added 52 y l (0.55 mmole) of t h i o n y l c h l o r i d e i n 1.5 ml of dry benzene. 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 35 min at 0°. The r e a c t i o n mixture was poured i n t o r a p i d l y s t i r r e d i c e water and the aqueous l a y e r thoroughly e x t r a c t e d w i t h benzene. The combined e x t r a c t s were washed twice with water and once with saturated 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 afforded a q u a n t i t a t i v e y i e l d of (+)-seychellene L3. An a n a l y t i c a l sample was prepared by pr e p a r a t i v e g . l . c . (column G, 225°, 200), and e x h i b i t e d s p e c t r a l data ( i n f r a r e d , n.m.r., mass spectrum) and g . l . c . r e t e n t i o n time (column H, 180°, 90) i d e n t i c a l with those of authentic (-)-seychellene 13. I n f r a r e d ( f i l m ) , A 3.26, 6.11, 11.42y ; n.m.r., T 5.23, 5.41 (doublets, nicix 2H, =CH2, J = 1.5 Hz), 7.78 ( m u l t i p l e t , IH, ^ CH-C=CH2), 9.06, 9.19 ( s i n g l e t s , 6H, t e r t i a r y methyls), 9.27 (doublet, 3H, secondary methyl, J = 6.5 Hz). Mole. Wt. Calcd. f o r C^H^O: 204.188. Found (high r e s o l u t i o n mass spectrometry): 204.188. - 141 -BIBLIOGRAPHY 1. G. Weissman i n Comparative Phytochemistry. Ed., T. Swain. Academic Press, Inc., New York. 1966. p. 97. 2. J.H. Richards and J.B. Hendrickson. The Biosynthesis of S t e r o i d s , Terpenes and Acetogenins. W.A. Benjamin, Inc., New York. 1964. 3. W. Parker, J.S. Roberts, and R. Ramage. Quart. Rev. 21_, 331 (1967). 4. G. Ourisson, S. M u n a r a l l i , and C. Ehret. I n t e r n a t i o n a l Tables of Selected Constants, V o l . 15, Data R e l a t i v e to Sesquiterpenoids. Pergamon Press, New York, 1966. 5. U.R. Nayak and S. Dev. Tetrahedron L e t t e r s 243 (1963). 6. K. Nakanishi, M. Ohashi, M. Tada, and Y. Yamada. Tetrahedron 21_, 1231 (1965). 7. K. Ohkuma, F.T. A d d i c o t t , O.E. Smith, and W.E. Thiessen. Tetrahedron L e t t e r s 2529 (1965). 8. L.H. Zalkow, A.M. Shaligram, and Shih-En Hu. Tetrahedron 2_2, 337 (1966). 9. G.D. J o s h i , S.K. Paknkar, S.N. K u l k a r n i , and S.C. Bhattacharyya. Tetrahedron 2_2, 1651 (1966) . 10. G. Buchi, F. Greuter, and T. Tokoroyama. Tetrahedron L e t t e r s 827 (1962). 11. G. Buchi, M. Schach, 0. Wittenau, and D.M. White. J . Am. Chem. Soc. 81, 1968 (1959). 12. G. Wolff and G. Ourisson. Tetrahedron L e t t e r s 3849 (1968). 13. G. Wolff and G. Ourisson. Tetrahedron 25_, 4903 (1969). 14. G. Buchi, W.D. MacLeod, J r . , and J . P a d i l l a 0. J . Am. Chem. Soc. 86, 4438 (1964). 15. E. P i e r s , W. de Waal, and R.W. B r i t t o n . Chem. Comm. 188 (1968); E. P i e r s , W. de Waal, and R.W. B r i t t o n . Can. J . Chem. 47_, 4299 (1969). 16. E. P i e r s , R.W. B r i t t o n , and W. de Waal. Can. J . Chem. 47_, 831 (1969). 17. E. P i e r s , R.W. B r i t t o n , and W... de Waal. Chem. Comm. 1069 (1969). 18. J.B. Hendrickson. Tetrahedron 7, 82 (1959). - 142 -19. G. Popjak. Tetrahedron L e t t e r s 19 (1959). 20. S. Shaykin, J . Law, A.H. P h i l l i p s , T.T. Tchen, and K. Block. Proc. Nat. Acad. S c i . (Wash.) 44, 998 (1958). 21. F. Lynen^ H. Eggerer, U. Henning, and I. Kes s e l . Angew. Chem. 7£, 738 (1960). 22. F. Lynen. Chem. Weekbl. 43_, 581 (1960). 23. J . S t r e i t h , P. P e s n e l l e , and G. Ourisson. B u l l . Soc. Chim. France 518 (1963). 24. J . Vrkoc, J . Krepinsky, V. Herout, and F. Sorm. C o l l . Czech. Chem. Comm. 29, 795 (1964). 25. T. Kariyone and S. Na i t o . J . Pharm. Soc. Japan 75, 1511 (1955). 26. L. Bauer, C L . B e l l , J.E. Gearieu, and H. Takeda. J . Pharm. S c i . 56, 336 (1967). 27. S. Furukawa and N. Soma. J . Pharm. Soc. Japan 81_, 559 (1961); S. Furukawa, K. Oyamada, and N. Soma. J . Pharm. Soc. Japan 81, 565 (1961); S. Furukawa. J . Pharm. Soc. Japan 81_, 570 (1961). 28. R.B. Bates, G. Buchi, T. Matsuura, and R.R. Sh a f f e r . J . Am. Chem. Soc. 82_, 2327 (1960) . 29. F. Sorm, M. Holub, V. Sykora, J . M l e z i v a , M. S t r e i b l , J . P l i v a , B. Schneider, and V. Herout. C o l l . Czech. Chem. Comm. 18, 512 (1953). 30. C. Berger, M. Franck-Newmann, and G. Ourisson. Tetrahedron L e t t e r s 3451 (1968). 31. R.M. Coates and J.E. Shaw. Chem. Comm. 515 (1968). 32. R.M. Coates and J.E. Shaw. Chem. Comm. 47 (1968). 33. G. Stork and J . F i c i n i . J . Am. Chem. Soc. 83_, 4678 (1961). 34. (a) W. von E. Doering, E.T. F o s s e l , and R.L. Kaye. Tetrahedron 21, 25 (1965); (b) H.O. House, S. G. Boots, and V.K. Jones. J . Org. Chem. 3£, 2519 (1965), and references t h e r e i n . 35. M.M. Fawzi and CD. Gutsche. J . Org. Chem. 31_, 1390 (1966). 36. F. Medina and A. Manjarrez. Tetrahedron 20_, 1807 (1964). 37. H.O. House and 0. Kramar. J . Org. Chem. 28, 3362 (1963). - 143 -38. H.O. House and B.M. Tr o s t . J . Org. Chem. 30, 2502 (1965). 39. R.E. I r e l a n d and J.A. M a r s h a l l . J . Org. Chem. 21_, 1615 (1962). 40. J.F.W. McOmie i n Advances i n Organic Chemistry: Methods and Res u l t s . V o l . 3_. Ed. R.A. Raphael, E.C. T a y l o r , and H. Wynberg. W i l e y - I n t e r s c i e n c e , New York, 1963. p. 191. 41. W.S. Johnson and H. Posvic. J . Am. Chem. Soc. 69_, 1361 (1947). 42. W.S. Wadsworth and W.D. Emmons. J . Am. Chem. Soc. 83, 1733 (1961). 43. S. T r i p p e t t . Quart. Rev. 17_, 407 (1963). 44. A.K. Base and R.T. D a h i l l , J r . J . Org. Chem. 30_, 505 (1965). 45. E.J. Corey and M. Chaykovsky. J . Am. Chem. Soc. 87, 1345 (1965), and references t h e r e i n . 46. R.R. Rando and W. von E. Doering. J . Org. Chem. 33_, 1671 (1968). 47. F. Johnson. Chem. Rev. 68, 375 (1968). 48. G. Stork and S.D. D a r l i n g . J . Am. Chem. Soc. 86_, 1761 (1964). 49. M.J.T. Robinson. Tetrahedron 21, 2475 (1965). 50. W.G. Dauben and E.J. Deviny. J . Org. Chem. 31_, 3794 (1966). 51. W.F. Dauben and G.H. Berezin. J . Am. Chem. Soc. 89_, 3449 (1967). 52. R.B. Woodward, F. Sondheimer, 0. Taub, K. Heusler, and W.M. McLamore. J . Am. Chem. Soc. 7_4, 4223 (1952). 53. J.A. M a r s h a l l and W.J.Fanta. J . Org. Chem. 29, 2501 (1964). 54. J.A. M a r s h a l l , N. Cohen, and K.R. Arenson. J . Org. Chem. 30, 762 (1965). 55. K. Bowden, I. M. H e i l b r o n , E.R.H. Jones, and B.C.L. Weedon. J . Chem. Soc. 39 (1946). 56. A. Butenandt and A. Wolff. Chem. Ber. 68_, 2091 (1946). 57. E.J. Corey and A.G. Hartmann. J . Am. Chem. Soc. 87_, 5736 (1956). 58. H.O. House, R.A. Latham, and CD. S l a t e r . J . Org. Chem. 31_, 2667 (1966). 59. E. P i e r s and R.J. Keziere. Can. J . Chem. 47, 137 (1969). - 144 -60. J.A.Marshall and N.H. Andersen. J . Org. Chem. 31_, 667 (1966). 61. M. Cherest, H. F e l k i n , and N. Prudent. Tetrahedron L e t t e r s 2199 (1968) . 62. M. Cherest and H. F e l k i n . Tetrahedron L e t t e r s , 2205 (1968). 63. P.S. B a i l e y . Chem. Rev. 5_8, 925 (1958). 64. N.C. Ross and R. Levine. J . Org. Chem. 29, 2341 (1964). 65. E.C. Du Fue, F.J. M c Q u i l l i n , and R. Robinson. J . Chem. Soc. 53 (1937). 66. M. Yanagita and A. Tahara. J . Org. Chem. 18_, 792 (1953). 67. E. P i e r s , R.W. B r i t t o n and W. de Waal. Can. J . Chem. 47, 4307 (1969) . 68. R.B. Bates and R.C. S l a v e l . Chem. § Ind. 1715 (1962). 69. N. Tsubaki, K. Nishimura, and Y. Hirose. B u l l . Chem. Soc. Japan 40, 597 (1967). 70. S. Danishefsky and D. Dumas. Chem. Comm. 1287 (1968). 71. H.O. House. Modern Sy n t h e t i c Reactions. W.A. Benjamin, Inc. N.Y. 1965. 72. P. Wieland and H. Miescher. Helv. Chim. Acta 33_, 2215 (1950). 73. A.B. Mekler, S. Ramachandran, S. Swaminathan, and M.S. Newman. Organic Synthesis. 41_, 56 (1961). 74. S. Swaminathan and M.S. Newman. Tetrahedron 2_, 88 (1958). 75. E.J. Corey, M. Ohno, R.B. M i t r a , and P.A. Vatakencherry. J . Am. Chem. Soc. 86, 478 (1964). 76. C.B.C. Boyce and J.S. Whitehurst. J . Chem. Soc. 2680 (1960). 77. T.A. Spencer, T.D. Weaver, R.M. V i l l a r i c a , F.J. F r i a r y , J . P o s l e r , and M.A. Schwartz. J . Org. Chem. 33_, 712 (1968). 78. E.L. E l i e l , N.L. A l l i n g e r , S.J. Angyal, and G.A. Morrison. Conformational A n a l y s i s . I n t e r s c i e n c e P u b l i s h e r s . 1966. 79. H.O. House, W.L. Respess, and G.M. Whitesides. J . Org. Chem. 31_, 3128 (1966). 80. H.O. House and W.F. F i s h e r s , J r . J . Org. Chem. 33_, 949 (1968). - 145 -81. J.A.Marshall and H. Roebke. J . Org. Chem. 33_, 840 (1968). 82. J.A. M a r s h a l l , W.I. Fanta, and H. Roebke. J . Org. Chem. 31_, 1016 (1966). 83. J.A. M a r s h a l l and A.R. H o c h s t e t l e r . J . Am. Chem. Soc. 91_, 648 (1969). 84. J.E. McMurry. J . Am. Chem. Soc. 90, 6821 (1968). 85. C.H. Heathcock, R.A. Badger, and J.W. Pa t t e r s o n , J r . J . Am. Chem. Soc. 89, 4133 (1967). 86. W.L. Williamson, J . I . Coburn, and M.F. Herr. J . Org. Chem. 32_, 3934 (1967). 87. M.C. Dart and H.B. Henbest. J . Chem. Soc. 3563 (1960). 88. J.A. Osborn, F.J. J a r d i n e , J.F. Young, and G. Wilkinson. J . Chem. Soc. (A), 1711 (1966) . 89. A.J. B i r c h and K.A.M. Walker. J.'chem. Soc. (C) , 1894 (1966). 90. C. D j e r a s s i and J . G u t z w i l l e r . J . Am. Chem. Soc. 88_, 4537 (1966); A.J. B i r c h and K.A.M. Walker. Tetrahedron L e t t e r s 4939 (1966). 91. G.I. Poos, G.E. A r t h , R.E. Beyler, and L.H. S a r e t t . J . Am. Chem. Soc. 75, 422 (1953) . 92. K.L. Williamson, T. Howell, and T.A. Spencer. J . Am. Chem. Soc. 88, 325 (1966) . 

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