UBC Theses and Dissertations

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UBC Theses and Dissertations

Bicyclo(3.2.1)octan-8-ones Herbert, David John 1974

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B I C Y C L O [ 3 . 2 . 1 ] O C T A N - 8 - O N E S BY DAVID JOHN HERBERT B . S c , UNIVERSITY OF B R I T I S H COLUMBIA, 1 9 7 1 . A THESIS SUBMITTED IN PARTIAL FULFILLMENT OF THE REQUIREMENTS FOR THE DEGREE OF MASTER OF SCIENCE i n t h e Depar tmen t o f C h e m i s t r y We a c c e p t t h i s t h e s i s as c o n f o r m i n g t o t h e r e q u i r e d s t a n d a r d THE UNIVERSITY OF B R I T I S H May ,1974 COLUMBIA In p resent ing 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 of 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 t h a t the L i b r a r y s h a l l make i t f r e e l y a v a i l a b l e fo r reference and study. I f u r t h e r agree tha t permiss ion fo r e x t e n s i v e copying of t h i s t h e s i s fo r s c h o l a r l y purposes may be granted by the Head of my Department o r by h i s r e p r e s e n t a t i v e s . It i s understood that copying or p u b l i c a t i o n o f t h i s t h e s i s f o r f i n a n c i a l ga in s h a l l not be al lowed without my w r i t t e n p e r m i s s i o n . Department of QfeH IST^Y The U n i v e r s i t y of B r i t i s h Columbia Vancouver 8. Canada Date HM l°HH ABSTRACT The f i r s t p a r t o f t h i s t h e s i s i s concerned w i t h the development of a g e n e r a l s y n t h e t i c approach t o - t h e b i c y c l o ( 3 . 2 . 1 ) o c t a n e r i n g system. T h i s work r e s u l t e d i n t h e s u c c e s s f u l s y n t h e s i s o f 1 , 5 - d i m e t h y l b i c y c l o (3.2.1)octan-8-one(54) , 1 , 5 - d i m e t h y l b i c y c l o (3.2.1)oct-6-en-8-one(55) and 1 , 5 - d i m e t h y l - 6 - i s o p r o x y b i c y c l o (3.2.1)oct-6-en-8-one(56). A l k y l a t i o n of 2,6-dimethylcyclohexanone w i t h a l l y l bromide a f f o r d e d the o l e f i n i c ketones (78) and ( 7 9 ) . O z o n o l y s i s of the l a t t e r gave the keto aldehydes (80) and ( 8 1 ) , which underwent a f a c i l e i n t r a m o l e c u l a r a l d o l c ondensation t o a f f o r d a mixture of the b i c y c l i c a l c o h o l s (68) and ( 6 9 ) . The mesylates (94_) and (9_5_) were o b t a i n e d from the b i c y c l i c a l c o h o l s (68J and (69_) . The keto i o d i d e (70) , o b t a i n e d by t r e a t i n g a mixture of the mesylates (94) and (95) w i t h sodium i o d i d e i n r e f l u x i n g acetone, was dehydrohalogenated to a f f o r d the d e s i r e d b i c y c l i c ketone ( 5 5 ) . Hydrogenation of the l a t t e r over p a l l a d i u m a f f o r d e d the d e s i r e d b i c y c l i c ketone (_54) . Oxidation of a mixture of the keto alcohols (68) and (69) with C o l l i n ' s reagent afforded the diketone (71) which, under appropriate conditions, underwent O-alkylation to give the desired b i c y c l i c enol ether (56) . In the second part of t h i s t h e s i s , the stereo-chemistry of nu c l e o p h i l i c addition to the 8-keto group present in the b i c y c l i c ketones (54) , (55) and (56) was b r i e f l y investigated. The b i c y c l i c ketones (54), (55) and (56) were reduced with lithium aluminium hydride to aff o r d the b i c y c l i c alcohols (112), (113) and (114) . Hydrogenation of the alcohol (113) yielded the alcohol (112). Hydrolysis of the enol ether (114) gave the ketol (116) . Hydrogenolysis of the dithioketal(117) of the keto alcohol (116) with Raney-nickel afforded alcohol (112). Thus, the b i c y c l i c alcohols (112), (113) and (114) must have the same r e l a t i v e stereochemistry at C-8. The b i c y c l i c ketones (5_4_) , (5_5) and (5_6_) were also treated with one equivalent of methylithium under i d e n t i c a l conditions to form the corresponding t e r t i a r y alcohols (128), (129) and (130). These alcohols are also formed stereo-s e l e c t i v e l y and have the same r e l a t i v e stereochemistry as the corresponding secondary alcohols (112) , (113) and (114) . - i v -Resume o La premiere p a r t i e de c e t ouvrage d e c r i t une synthese g e n e r a l e des composes de type b i c y c l o ( 3 . 2 . 1 ) octane, e t p l u s specialement de l a d i m e t h y l - 1 , 5 - b i c y c l o (3 . 2 .1) octanone-8 (54_) , de l a dimethyl-1, 5 - b i c y c l o (3 . 2 .1) o c t -en-6-one-8 (5_5) e t de l a d i m e t h y l - 1 , 5 - i s o p r o p y l o x y - 6 - b i c y c l o (3.2.1)octen-6-one-8 (56). L ' a l k y l a t i o n de l a d i m e t h y l -2,6-cyclohexanone par l e bromure d ' a l l y l e a donne l e s cetones (7_8 & 79) . Par ozonolyse ces d e r n i e r e s p r o d u i s i r e n t l e s cetoaldehydes (80_ & 81) q u i , soumis aux c o n d i t i o n s d'une condensation i n t e r n e f u r e n t transformes en un melange des a l c o o l s b i c y c l i q u e s (68) e t (69). L'iodocetone (70), o obtenue en t r a i t a n t un melange des mesylates (94) e t (95) par 1'iodure de sodium dans 1 1 acetone b o u i l l a n t e , a ete e n s u i t e deshydrohalogenee pour donner l a cetone b i c y c l i q u e (55) . La cetone b i c y c l i q u e (5_4_) f u t obtenue par hydrogenation de l a cetone (5_5_) . L'oxydation du melange des c e t o a l c o o l s (68) e t (6_9) avec l e r e a c t i f de C o l l i n s p r o d u i s i t l a d i c e t o n e (71) - v -l a q u e l l e fournit 1'ether d'enol b i c y c l i q u e (5_6) par a l k y l a t i o n sur l'oxygene du c a r b o n y l e . La seconde p a r t i e de c e t t e these p r e s e n t e une breve d i s c u s s i o n de l a s t e r e o c h i m i e de 1 ' a d d i t i o n n u c l e o p h i l e sur l e r e s t e c a r b o n y l e des cetones b i c y c l i q u e s (54), (55) e t (56). Ces t r o i s cetones f u r e n t r e d u i t e s en a l c o o l s par 1 1 h y d r u r e de l i t h i u m e t d 1aluminium. L'hydrogenation de l ' a l c o o l (113) donne l ' a l c o o l (112). L ' h y d r o l y s e de 1'ether d'enol (56) s u i v i e de 1'hydrogenolyse du t h i o a c e t a l (117), obtenu a p a r t i r du c e t o a l c o o l (116), p r o d u i t l ' a l c o o l (112). C e c i demontre que l e s t r o i s a l c o o l s (112), (113) e t (114) ont l a meme s t e r e o c h i m i e r e l a t i v e en C-8. - v i -TABLE OF CONTENTS Page T I T L E PAGE . i ABSTRACT i i TABLE OF CONTENTS v i L I S T OF FIGURES v i i ACKNOWLEDGEMENTS v i i i PART I : SYNTHESIS OF THE DESIRED BICYCLO KETONES 1 INTRODUCTION PART I 2 1. P r e v i o u s s y n t h e t i c a p p r o a c h e s l e a d i n g t o t h e b i c y c l i c [ 3 . 2 . 1 ] r i n g s k e l e t o n 2 DISCUSSION PART I 10 1. G e n e r a l o u t l i n e o f t h e s y n t h e t i c a p p r o a c h used i n t h i s work 10 2 . S y n t h e s i s o f t h i s d e s i r e d b i c y c l o [ 3 . 2 . 1 ] o c t a n e s . 15 EXPERIMENTAL PART I 51 PART I I : INVESTIGATIONS INTO THE CHEMISTRY OF 8 KETO BICYCLO[3 .2 .1 ]OCTANONES 7 4 INTRODUCTION PART I I 75 DISCUSSION PART I I 80 EXPERIMENTAL PART I I 106 BIBLIOGRAPHY 116 - v i i -L I S T OF FIGURES F i g u r e Page 1 P.M.R. S p e c t r u m o f t h e D i k e t o n e (7_1) 18 2 P.M.R. S p e c t r u m o f t h e K e t o O l e f i n s (78) and (79_) 22 3 P.M.R. S p e c t r u m o f t h e K e t o l (60) 2.6 4 P.M.R. S p e c t r u m o f t h e K e t o l (6_9) . . 27 5 P.M.R. S p e c t r u m o f t h e D i o l (8_3) 31 6 P.M.R. S p e c t r u m o f t h e D i o l (8_4) 32 7 P.M.R. S p e c t r u m o f t h e D i o l (85_) 33 8 C o m p a r i s o n o f t h e P.M.R. S p e c t r a o f t h e D i o l s (83) & (8_4) 34 9 C o m p a r i s o n o f t h e P.M.R. S p e c t r a o f t h e D i o l s (83) & (85) 35 10 P.M.R. S p e c t r u m o f t h e K e t o O l e f i n (55) 43 11 P.M.R. S p e c t r u m o f t h e K e t o I o d i d e (7_0) 45 12 P.M.R. S p e c t r u m o f t h e B i c y c l i c K e t o n e (54) .... 48 13 P.M.R. S p e c t r u m o f t h e E n o l E t h e r (5_6_) 50 14 P.M.R. S p e c t r u m o f t h e B i c y c l i c A l c o h o l (112_) . . . 83 15 P.M.R. S p e c t r u m o f t h e B i c y c l i c A l c o h o l ( 1 1 3 ) . . . 84 16 P.M.R. S p e c t r a o f t h e B i c y c l i c A l c o h o l (113) c o n t a i n i n g v a r i o u s amounts o f E u ( f o d ) ^ 94 17 V a r i a t i o n i n t h e c h e m i c a l s h i f t f o r t h e d i f f e r e n t p r o t o n s o f t h e B i c y c l i c A l c o h o l (113) 95 18 P.M.R. S p e c t r u m o f t h e B i c y c l i c A l c o h o l ( 1 2 9 ) . . . 98 19 P.M.R. S p e c t r a o f t h e B i c y c l i c A l c o h o l (129) c o n t a i n i n g v a r i o u s amounts o f E u ( f o d ) ^ 100 20 V a r i a t i o n i n t h e c h e m i c a l s h i f t f o r t h e d i f f e r e n t p r o t o n s o f t h e B i c y c l i c A l c o h o l (1_2_9) 101 - v i i i -Acknowledgements I would l i k e to express my sincere thanks to Dr. E. Piers for his guidance and aid during the course of th i s work. I would also l i k e to thank the members of Dr. P i e r s ' research group and to my many friends f o r t h e i r moral support and techn i c a l a i d i n the preparation of t h i s t h e s i s . Special thanks to Miss L. Hon for her able typing of t h i s work. - 1 -Part I Synthesis Of The Desired Bicyclo[3.2.1]Octanones: 1,5-Dimethylbicyclo[3.2.1]octan-8-one; 1,5-Dimethyl-bicyclo[3.2.1]oct-6-en-8-one? And 1,5-Dimethyl-6-isopropoxybicyclo[3.2.1]oct~6-en-8-one 2 -PART I INTRODUCTION Since the following portion of t h i s thesis deals primarily with the synthesis of various substituted b i c y c l o (3.2.1)octanes, a b r i e f survey of some previous synthetic approaches to these types of compounds i s i n order. This survey i s by no means exhaustive and only touches on some of the material that has been published to date. The synthesis of substituted bicyclo(3.2.1)octanes has been achieved by a number of authors. Newman and Yu^ have reported an i n t e r n a l a l k y l a t i o n of the ketone (1) using lithium i n ether to synthesize the substituted bicyclo(3.2.1) octanes (2) and (3_) . The y i e l d of each compound was reported 1 2 - 3 -t o be i n t h e n e i g h b o u r h o o d o f 10%. The a c t i o n o f diazomethane on norcamphor (_4) and dehydronorcamphor (1), r e s u l t i n g i n t h e f o r m a t i o n o f t h e b i c y c l i c k e t o n e s (5), (6), (_3) and (9_) by r i n g e x p a n s i o n s , 2 has been r e p o r t e d by McKinney and P a t e l . 7 8 9 The y i e l d s o f t h e b i c y c l i c p r o d u c t s (5_) , ( 6 ) , (8_) and (9_) were dependent on t h e m o l a r amount o f d i a z o m e t h a n e u s e d ; t h e h i g h e s t y i e l d s r e p o r t e d were 3.9%, 26.5%, 5.1% and 42% r e s p e c t i v e l y . 3 Cope e t . a l . have r e p o r t e d t h e f o r m a t i o n o f e x o - b i c y c l o ( 3 . 2 . 1 ) o c t a n - 8 - o l (11) i n 16% y i e l d from t h e s o l v o l y s i s o f 4 - c y c l o a c e t e n - l - y l b r o s y ] a t e (10) w i t h t r i f l u o r o a c e t i c a c i d . 10 11 A c e t o l y s i s o f t h e b r o s y l a t e (_L2) was r e p o r t e d by 4 F e l k i n and L i o n t o g i v e a s e r i e s o f b i c y c l i c p r o d u c t s (1_3) , (14) , (1_5) , (1_6) , and (1_7) , w i t h (13_) b e i n g t h e m a j o r p r o d u c t ( 5 5 % ) . 12 13 1_4_ X = OAc 16 X 15 X = OH 17 X B i c y c l o ( 3 . 2 . 1 ) o c t a n - 2 - o n e and i t s c o r r e s p o n d i n g a l c o h o l s have been w i d e l y s t u d i e d by a number o f d i f f e r e n t 1,5,6,7,8 The most common method o f p r e p a r i n g t h e 5 a u t h o r s " b i c y c l i c k e t o n e (21) i s t h a t o f A l d e r and Windemuth -". The D i e l s - A l d e r p r o d u c t (1_8) o f c y c l o p e n t a d i e n e and a l l y la-mine was f i r s t h y d r o g e n a t e d o v e r p a l l a d i u m on C h a r c o a l and t h e n s u b j e c t e d t o d e a m i n a t i o n w i t h aqueous n i t r o u s a c i d t o f o r m , 19 A 20 A 6 H, B = OH OH, B == II 18 21 - 5 -i n low y i e l d , the b i c y c l i c a l c o h o l s (1_9) and (2_0) . A mixture of these a l c o h o l s was then o x i d i z e d to the d e s i r e d ketone (21). 9 L e B e l and Spurlock have r e p o r t e d the s y n t h e s i s of the b i c y c l o (3 . 2 .1) o c t - 2 - e n - 8 - o l s (25_) and (26). The s y n t h e s i s o f these a l c o h o l s was based on the N - p y r r o l i d y l ketone (22) o b t a i n e d by Stork and Landesman"*"^ from the condensation o f a c r o l e i n and N - l - p y r r o l i d y l - c y c l o p e n t e n e . Reduction of the N - p y r r o l i d y l ketone (22) w i t h l i t h i u m aluminium h y d r i d e a f f o r d e d the syn-amino a l c o h o l (23) . P y r o l y s i s o f the amine oxide (2_4) a f f o r d e d the e n d o - b i c y c l o (3.2.1)octan-3-ol (25) i n 18% y i e l d . 25 The exo a l c o h o l (2_6) was prepared, i n 84% y e i l d by e q u i l i -b r a t i o n o f the syn a l c o h o l (25) , i n a s e a l e d tube, u s i n g aluminium t - b u t o x i d e and f l u o r e n o n e . The pro d u c t mixture (20% 2_6 and 80% 25_) was separated by g.A.c. t e c h n i q u e s . 6 -25_ 25 26_ Recen t l y , H e s s ^ has r e p o r t e d a seven step s y n t h e s i s o f e n d o - b i c y c l o ( 3 . 2 . 1 ) o c t - 6 - e n - 8 - y l a c e t a t e ( 2 9 ) . The f i n a l step i n t h i s s y n t h e s i s i s the a c e t o l y s i s o f a mixture (80% endo and 20% exo) o f the t o x y l a t e s (21) and (28) to a f f o r d the a c e t a t e (29_) i n 71% y i e l d . 27,28. 29 The b i c y c l o ( 3 . 2 . 1 ) o c t a n e system i s i n c o r p o r a t e d i n t o many s t r u c t u r a l l y c o m p l i c a t e d n a t u r a l p r o d u c t s . Some of these substances have been t o t a l l y s y n t h e s i z e d and i t i s t h e r e f o r e p e r t i n e n t t o d i s c u s s b r i e f l y how t h i s b i c y c l i c system was prepared i n these syntheses. Again, no attempt has been made to be comprehensive and o n l y a few r e p r e s e n t a t i v e examples w i l l be g i v e n . 12 13 14 P i e r s e t . a l . ' ' have r e p o r t e d the t o t a l s y n t h e s i s o f a number of s e s q u i t e r p e n o i d s [ (-) -copacamphene (3_0), (-) -cyclocopacamphene (31), copaborneol (32) and ( - ) - y l a n g o - ( - ) -y l a n g o b o r n e o l (34), ( - ) - y l a n g o i s o b o r n e o l (35), camphor (3_3) , ( + )-s a t i v e n e (3_6) and ( + ) - c y c l o s a t i v e n e (3_7)] u s i n g the b i c y c l i c - 7 -diketones (38) and (39) as key i n t e r m e d i a t e s . The b i c y c l i c diketones (38) and (3_9) were formed i n 90% and 76% y i e l d r e s p e c t i v e l y by the i n t r a m o l e c u l a r C l a i s e n conden-s a t i o n of the keto e s t e r s (40) and (41) . These two r e a c t i o n s represent the only r e p o r t e d examples of the s y n t h e s i s of b i c y c l o ( 3 . 2 . 1 ) o c t a n e systems v i a i n t r a m o l e c u l a r C l a i s e n condensation. 41 39 - 8 -The b i c y c l i c ( 3 . 2.1) r i n g system i s a l s o i n c o r p o r a t e d i n the s t r u c t u r e o f many n a t u r a l l y o c c u r r i n g d i t e r p e n e s . B e l l , 15 I r e l a n d and Par t y k a have r e p o r t e d the s y n t h e s i s of (±)-kaurene (4_7) and (±)-astisirene (44) . The D r i n g o f these compounds was formed by means of an i n t e r n a l A l d o l condensa-t i o n . Thus, when the k e t a l s (4_2) and (4_5) were t r e a t e d w i t h h y d r o c h l o r i c a c i d they a f f o r d e d the k e t o l s (4_3) and (4_6) i n 95% y i e l d . These key i n t e r m e d i a t e s were transformed by a s e r i e s o f s t r a i g h t f o r w a r d r e a c t i o n s i n t o the d e s i r e d d i t e r p e n e s (44) and (47). In a s e r i e s o f communications d e a l i n g w i t h the s y n t h e s i s o f d i t e r p e n e s and d i t e r p e n e a l k a l o i d s , Masamune employed a t e t r a c y c l i c common i n t e r m e d i a t e , dl-16-keto-10-carboxy-17,20-bisnorkaurane (51). T h i s m a t e r i a l was - 9 -prepared from 6-benz y l o x y - l , 2 , 3 , 4 - t e t r a h y d r o n a p t h a l e n e - 2 -c a r b o x y l i c a c i d (48) by a l e n g t h y procedure. The most p e r t i n e n t s t e p i n the above t r a n s f o r m a t i o n s was the c y c l i -z a t i o n o f (4_9) i n t - b u t a n o l and potassium t - b u t o x i d e t o a f f o r d the t r i c y c l i c m a t e r i a l (50). 50 51 The b r i d g e d b i c y c l i c C/D r i n g s t r u c t u r e i s a l s o i n c o r p o r a t e d i n t o the s t r u c t u r e o f the t e t r a c y c l i c d i t e r p e n e p h y l l o c l a d e n e . 17 Turner e t . a l . have r e p o r t e d i n t h e i r paper d e a l i n g w i t h the t o t a l s y n t h e s i s o f p h y l l o c l a d e n e the f o r m a t i o n of t h i s b r i d g e d C/D r i n g by the p y r o l y s i s of the barium s a l t o f the d i a c i d (52) to a f f o r d the t e t r a c y c l i c ketone (5_3) i n 50% y i e l d . - 10 -PART I DISCUSSION 1. General o u t l i n e of the s y n t h e t i c approach used i n t h i s work The o b j e c t of the work pre s e n t e d i n t h i s p a r t of t h i s t h e s i s was the development o f a s y n t h e t i c r o u t e to the s u b s t i t u t e d b i c y c l o (3 . 2 .1) octanones (5_4) , (55) and (56) . The p l a n n i n g of a s y n t h e t i c pathway can be d i v i d e d i n t o two main 54 55 56 a r e a s , the manner i n which the carbon s k e l e t o n i s assembled and the sequence i n which the s u b s t i t u e n t s or f u n c t i o n a l groups are i n t r o d u c e d . The c h o i c e o f an a p p r o p r i a t e s t a r t i n g m a t e r i a l must a l s o be c o n s i d e r e d d u r i n g the p l a n n i n g of any s y n t h e t i c pathway. However, the c h o i c e of the s t a r t i n g - 11 -m a t e r i a l i s most o f t e n the r e s u l t of a good s y n t h e t i c p l a n r a t h e r than the s t a r t o f one. The most l i k e l y approach to the s y n t h e s i s ( i n any a p p r e c i a b l e y i e l d ) o f the d e s i r e d b i c y c l i c carbon s k e l e t o n seemed t o be v i a the A l d o l o r C l a i s e n c ondensations o f an a p p r o p r i a t e i n t e r m e d i a t e . ALDOL CONDENSATION CLAISEN CONDENSATION Th i s method has the added advantage of p r o v i d i n g a handle on the two carbon b r i d g e of the b i c y c l i c r i n g system f o r the i n t r o d u c t i o n o f the d e s i r e d f u n c t i o n a l group (5_5_) or s u b s t i -t u e n t (56). The d e c i s i o n r e g a r d i n g the c h o i c e o f which type o f con d e n s a t i o n r e a c t i o n ( A l d o l o r C l a i s e n ) t h a t s h o u l d be used was com p l i c a t e d by the r e s u l t s o f s e v e r a l s t u d i e s p u b l i s h e d i n t he l i t e r a t u r e . The s u c c e s s f u l and h i g h y i e l d i n g C l a i s e n condensations done by P i e r s e t . a l . ' ' as w e l l as the 15 f r u i t f u l A l d o l condensations done by B e l l e t . a l . have a l r e a d y been d i s c u s s e d (see page 8 ) . The A l d o l condensation - 12 -o f (5_7) u n d e r a c i d i c c o n d i t i o n s was r e p o r t e d by M a r t i n e t . a l . t o a f f o r d an e p i m e r i c m i x t u r e o f t h e k e t o l s (58) and (59) a l o n g w i t h c o n s i d e r a b l e q u a n t i t y o f t h e c o r r e s p o n d i n g e t h e r s 57 5 £ ' 5 i 60,61 19 60 and (6_1) . C a l v i n e t . a l . , howeve r , i n t h e i r e l e g a n t pape r on t h e t o t a l s y n t h e s i s o f ( ± ) - t r i c h o d e r m i n r e p o r t e d t h e f a i l u r e o f t h e a l d e h y d e (6_2) t o unde rgo an i n t r a m o l e c u l a r a l d o l c o n d e n s a t i o n u n d e r a v a r i e t y o f e x p e r i m e n t a l c o n d i t i o n s . A s o l u t i o n t o t h e p r o b l e m was found by C a l v i n i n t h e work 18 20 done by M a r t i n e t . a l . ' on t h e r e d u c t i v e r e a r r a n g e m e n t o f 6 - e n o l - l a c t o n e s , s u c h as (6_3) , w i t h l i t h i u m t r i - t - b u t o x y -a l u m i n o h y d r i d e r e s u l t e d i n t h e f o r m a t i o n o f c y c l i c p r o d u c t s by i n t r a m o l e c u l a r a l d o l c o n d e n s a t i o n . C a r r u t h e r s and - 13 -21 Qureshi were a c t u a l l y a b l e t o i s o l a t e the aldehyde (65) d u r i n g a s i m i l a r r e d u c t i o n experiment u s i n g the S-enol-ether (64) and l i t h i u m t r i - t - b u t o x y a l u m i n o h y d r i d e . 64 65 66 ,67 In view of the s u c c e s s f u l r e s u l t s a c h i e v e d by P i e r s e t . a l . " * " ^ ' ^ ' ^ and the i n c o n s i s t e n c y o f the r e s u l t s 18 19 20 r e p o r t e d by ot h e r authors ' ' , w i t h r e s p e c t t o the i n t r a m o l e c u l a r A l d o l - t y p e c o n d e n s a t i o n , the C l a i s e n conden-s a t i o n r e a c t i o n was chosen over the a l t e r n a t i v e A l d o l method. However, as p o i n t e d out l a t e r , r e p e a t e d poor y i e l d s o f the d e s i r e d b i c y c l i c carbon s k e l e t o n prompted the i n v e s t i g a t i o n 18 20 of the p o s s i b l e s y n t h e t i c a p p l i c a t i o n of M a r t i n ' s ' r e d u c t i v e rearrangement scheme to t h i s work. When t h i s method a l s o proved to be o n l y p a r t i a l l y s u c c e s s f u l , the A l d o l c ondensation r e a c t i o n was i n v e s t i g a t e d and proved t o be more than adequate. The i n t r o d u c t i o n of the s u b s t i t u e n t s o r f u n c t i o n a l groups i n t o the b i c y c l i c system was ac h i e v e d i n a s t r a i g h t -forward manner. Since the A l d o l c ondensation products proved d i f f i c u l t to dehydrate even under a v a r i e t y of c o n d i t i o n s , - 14 -an a l t e r n a t i v e method was sought. The k e t o l s (68) and (69) were c o n v e r t e d ( v i a t h e i r m e s y l a t e s ) i n t o t h e k e t o i o d i d e (70) w h i c h r e a d i l y d e h y d r o h a l o g e n a t e d t o a f f o r d t h e d e s i r e d b i c y c l i c o l e f i n , (5J5) . C a t a l y t i c h y d r o g e n a t i o n o f t h i s m a t e r i a l a f f o r d e d t h e b i c y c l i c k e t o n e (5_4_) . A m i x t u r e o f k e t o l s (6_8) and (6_9) was r e a d i l y o x i d i z e d by C o l l i n s r e a g e n t t o a f f o r d t h e d i k e t o n e ( 1 1 ) . O - a l k y l a t i o n o f t h i s m a t e r i a l , under t h e a p p r o p r i a t e c o n d i t i o n s , a f f o r d e d t h e d e s i r e d b i c y c l i c k e t o n e (56 ) . - 15 -2. S y n t h e s i s o f the D e s i r e d B i c y c l o ( 3 . 2 . 1 ) o c t a n e s As mentioned e a r l i e r , i t was f e l t t h a t t h e d e s i r e d b i c y c l i c c a r b o n s k e l e t o n c o u l d be o b t a i n e d v i a C l a i s e n conden-s a t i o n o f an a p p r o p r i a t e i n t e r m e d i a t e , such as t h e k e t o e s t e r s (73) and (74_) . An e p i m e r i c m i x t u r e o f t h e s e compounds had been p r e v i o u s l y p r e p a r e d i n our l a b o r a t o r y ; however, t h e p r o c e d u r e used was r a t h e r l e n g t h y (see C h a r t I ) . T h e r e f o r e , t h e f i r s t o b j e c t i v e o f t h i s work was t h e i n v e s t i g a t i o n o f a more d i r e c t r o u t e t o t h e k e t o e s t e r s (7_3) and (7_4) and o f t h e i r subsequent c y c l i z a t i o n . The s y n t h e s i s o f t h e k e t o e s t e r s (73) and (74) was a c c o m p l i s h e d d i r e c t l y by a l k y l a t i o n o f t h e c o m m e r c i a l l y a v a i l a b l e 2 , 6 - d i m e t h y l c y c l o h e x a n o n e (7_2) . Thus, when t h e l i t h i u m e n o l a t e o f t h i s m a t e r i a l i n c o l d t e t r a h y d r o f u r a n was t r e a t e d w i t h m e t h y l b r o m o a c e t a t e , t h e r e was formed an e p i m e r i c m i x t u r e o f the k e t o e s t e r s (73_) and (74) i n 82% y i e l d . The p r o d u c t t h u s o b t a i n e d e x h i b i t e d s p e c t r o s c o p i c p r o p e r t i e s i d e n t i c a l w i t h t h o s e r e p o r t e d f o r t h e same m a t e r i a l o b t a i n e d v i a the p r o c e d u r e d e s c r i b e d i n C h a r t I . Mr. A. Mar, (B. Sc. T h e s i s , U n i v e r s i t y o f B r i t i s h C o l u m b i a , 1971) . 73,74 CHART I - 17 -OCH 72 74 Treatment of a mixture of the keto esters (73) and (74) with sodium b i s ( t r i m e t h y l s i l y l ) amide i n r e f l u x i n g 12 benzene , followed by quenching of the reaction mixture with a c e t i c acid, afforded a 41% y i e l d (based on unrecovered s t a r t i n g material) of the diketone 7JL. This material gave the following spectroscopic data. The in f r a r e d absorptions at 5.65 and 5.80 y are c h a r a c t e r i s t i c of the carbonyl 13 absorptions of t h i s type of b i c y c l i c dione . The p.m.r. spectrum of t h i s compound (see F i g . 1) exhibited three proton s i n g l e t s at x8.76 and x8.95 assigned to the bridgehead methyl groups and a pair of one proton doublets a x7.30 and T7.66 (Jjy_> = 19 Hz) which were at t r i b u t e d to the methylene protons adjacent to the carbonyl of the two carbon bridge. 0 = ^ 22'21 22 Repeated attempts using a variety of reaction conditions, to improve the y i e l d of t h i s reaction proved f r u i t l e s s . Therefore, i t was eventually decided to attempt an alternate synthetic approach, involving the preparation 18 2 0 and reduction ' of the enol lactone (IT) . It was hoped - 18 «-- 19 -t h a t t h i s w o u l d g i v e r i s e t o a m i x t u r e o f t h e k e t o l s (68) and (<59_) w h i c h c o u l d t h e n be o x i d i z e d t o t h e d i k e t o n e (71) . 6_8,6_9 71 H y d r o l y s i s o f t h e k e t o e s t e r s (73) and (74) i n r e f l u x i n g m e t h a n o l i c sod ium h y d r o x i d e a f f o r d e d a m i x t u r e o f t h e k e t o a c i d s (7_5) and (7_6) i n 80% y i e l d . The s p e c t r o -s c o p i c p r o p e r t i e s o f t h i s m a t e r i a l c o n f i r m e d t h a t h y d r o l y s i s had o c c u r r e d . T h i s i n t e r m e d i a t e , when t r e a t e d w i t h sod ium a c e t a t e i n r e f l u x i n g a c e t i c a n h y d r i d e , a f f o r d e d , i n 98% y i e l d , t h e e n o l l a c t o n e (11) . The p r o p o s e d s t r u c t u r e o f t h i s compound was s u p p o r t e d by i t s s p e c t r o s c o p i c p r o p e r t i e s . The two a b s o r p t i o n s i n t h e i n f r a r e d s p e c t r u m a t 5 .58 and 5 .82 y were a s s i g n e d t o t h e l a c t o n e c a r b o n y l and t o t h e o l e f i n i c d o u b l e b o n d , r e s p e c t i v e l y . The p . m . r . s p e c t r u m e x h i b i t s a t h r e e p r o t o n s i n g l e t a t x 8 . 9 5 a s s i g n e d t o t h e t e r t i a r y m e t h y l p r o t o n s , a t h r e e p r o t o n d o u b l e t a t x 8 . 5 0 ( J = 1 Hz) a s s i g n e d t o t h e v i n y l m e t h y l p r o t o n s , and a two p r o t o n s i n g l e t a t x 7 . 6 7 - 20 -w h i c h was a s s i g n e d t o the methylene p r o t o n s o f t h e l a c t o n e r i n g . R e d u c t i o n o f t h e e n o l l a c t o n e (77)using l i t h i u m t r i - t -b u t o x y a l u m i n o h y d r i d e i n d r y t e t r a h y d r o f u r a n a f f o r d e d a f t e r a c i d i c work-up, a m i x t u r e o f t h e k e t o l s (68) and (6_9) ( t h e s e k e t o l s a r e more f u l l y d e s c r i b e d on page 24) i n 54% y i e l d . I n o r d e r t o improve t h e y i e l d o f t h e r e a c t i o n , t h e use o f o t h e r r e d u c i n g a g e n t s , n o t a b l y d i i s o b u t y l a l u m i n i u m h y d r i d e , was i n v e s t i g a t e d . U n f o r t u n a t e l y , t h e s e f u r t h e r s t u d i e s f a i l e d t o i n c r e a s e t h e y i e l d o f t h e k e t o l s (68) and (69_) t o any e x t e n t . S i n c e t h e c o u r s e o f t h e s e r e d u c t i o n s has been 19 21 pr o p o s e d ' t o p r o c e e d v i a an i n t e r m e d i a t e a l d e h y d e (see page 12) w h i c h t h e n c y c l i z e s d u r i n g t h e a c i d i c work-up, a m i x t u r e o f t h e k e t o a l d e h y d e s (80) and (8JL) was p r e p a r e d v i a a d i f f e r e n t r o u t e and exposed t o c o n d i t i o n s s u i t a b l e t o e f f e c t t h e i r c y c l i z a t i o n (see C h a r t I I ) . Thus, when the l i t h i u m e n o l a t e o f 2 , 6 - d i m e t h y l -c y c l o h e x a n o n e i n t e t r a h y d r o f u r a n was t r e a t e d w i t h a l l y l b romide, t h e r e was formed i n 8 2% y i e l d an e p i m e r i c m i x t u r e o f t h e k e t o o l e f i n s (7_8) and (79_) . The i n f r a r e d s p ectrum o f th e m a t e r i a l e x h i b i t e d a b s o r p t i o n s a t 3.23, 5.86 and 6.10 u w h i c h were a s s i g n e d t o t h e s t r e t c h i n g v i b r a t i o n s o f an o l e f i n i c C-H bond, a six-membered c y c l i c k e t one and a mono-s u b s t i t u t e d o l e f i n i c d o u b l e bond r e s p e c t i v e l y . The p.m.r. spectrum o f t h i s m a t e r i a l ( F i g . 2) was i n t e r p r e t e d as - 21 -68,69 0 CHART II - 23 -follows. Of the various chair conformations of compounds (78) and (79) ((78) a, (78) b, (79)a, (79)b)), (78)b and (79)b were eliminated from consideration as unfavourable due to the 1,3 d i a x i a l i nteractions between the substituents on the quarter-nary carbon and the secondary methyl group. Thus, the p.m.r. spectrum (Fig. 2 ) of the mixture of' keto o l e f i n s (78) and (79) can be interpreted on the basis of (7_8)a and (79,) a being the most l i k e l y conformations present. a three proton doublet (J = 5-7 Hz) due to the equatorial secondary methyl groups present i n both (18)a and (79)a. Also, one would expect to observe two s i n g l e t s , one at about the chemical s h i f t as the secondary methyl group, due to the equatorial t e r t i a r y methyl group present i n (78) a and one at lower f i e l d , due to the t e r t i a r y methyl group present i n (79)a. The observed spectrum of the mixture of keto o l e f i n s (78) and (79) contains a three proton doublet at T h i s b e i n g t h e c a s e , o n e w o u l d e x p e c t t o o b s e r v e 78a 78b 79a 79b - 24 -T9.00 (J = 6 Hz) and s i n g l e t s at T8.84 and T8.97, together integrating for three protons. A mixture of the keto aldehydes (8_0) and (81) was prepared by ozonolysis of a mixture of the keto o l e f i n s (78) and {79). Thus, treatment of a solution of the keto o l e f i n s (78) and (7_9) i n methylene chloride at -78°C with ozone, afforded, af t e r work-up with zinc i n acetic acid, an epimeric mixture of the keto aldehydes (8_0) and (8_1) . A small amount of t h i s material was d i s t i l l e d and exhibited the appropriate spectroscopic properties. The i n f r a r e d spectrum exhibited strong saturated carbonyl absorbances at 5.82 and 5.85 y 9 and a week -C-H absorbance at 3.65 y. Proton magnetic resonance signals at xO.83, a one proton m u l t i p l e t , and at x7.57, a two proton doublet (J = 2 Hz), were i n agreement with the proposed structures f o r (80) and (81). The bulk of the unpurified material obtained from the ozonolysis of the keto o l e f i n s (78) and (7_9) was dissolved i n tetrahydrofuran and s t i r r e d with an equal volume of 1 N aqueous sodium hydroxide to affo r d , i n 7 0% y i e l d from the o l e f i n s (7_8) and (79_) , a mixture of the bicy-c l i c ketols (6_8) and (6_9) . An a n a l y t i c a l sample of each ketol was obtained by preparative g.l.c. The major ketol (69) exhibited i n f r a r e d absorptions at 2.85 and 5.75 y which were at t r i b u t e d to the hydroxyl and carbonyl f u n c t i o n a l i t i e s - 25 ~ respectively. The p.m.r. spectrum of t h i s material (Fig. 3) exhibited a one proton m u l t i p l e t at x6.00 assigned to the proton a to the hydroxyl group a one proton s i n g l e t at x7.48 assigned to the hydroxyl proton and two three proton s i n g l e t s at x9.02 and 9.03 which were assigned to the t e r t i a r y methyl protons. The minor ketol (6_8) exhibited i n f r a r e d absorptions at 2.86 and 5.77 y which were attr i b u t e d to the hydroxyl and carbonyl f u n c t i o n a l i t i e s present i n the molecules. The p.m.r. spectrum of t h i s ketol (Fig. 4) exhibited a one proton doublet of doublets at x5.90 (J = 3,8 Hz) assigned to the proton a to the hydroxyl group, a one proton m u l t i p l e t at T7.32 assigned to one of the methylene protons on the carbon adjacent to the hydroxyl bearing carbon, and two three proton singlets at x8.98 and x9.02 which were assigned to the t e r t i a r y methyl protons. The main approach used i n determining the stereo-chemistry of the ketols (6_8) and (6_9) was based upon the reaction sequence outlined i n Chart I I I . The general idea underlying t h i s series of reactions involved the projected reduction of the ketols (_58_) and (69_) to t h e i r corresponding d i o l s (,8_5) and (8_4), and comparing the d i o l s formed i n t h i s manner with the d i o l (8_3) formed by successive stereoselective reductions of the diketone (7_1) . It should be noted that t h i s proposal i s t o t a l l y co o *-> dl tt) O S 3 M 4J O <U A. CO 1 0) M 60 •H Figure 4 P.M.R. Spectrum of the Ketol (69). - 28 -dependent on knowing the stereochemical course of each of the reductions outlined on Chart I I I . In other words, one must assume that the reduction products (8_2) , (84_) and (8_5) a l l possess the same r e l a t i v e stereochemistry at C-8. This assumption was supported by r e s u l t s obtained i n a l a t e r part 3 21 of t h i s work and by several l i t e r a t u r e precedents ' . The reduction products (8_2) , (8_4) and (8_5) were assigned the endo hydroxy stereochemistry for the same reasons. The only reduction not covered by the above generalization i s the reduction of the C-6 ketone of compound ( 8 2 ) . However, since i t was f e l t that the reducing agent should approach t h i s carbonyl group from the less-hindered exo face of the b i c y c l i c system, i t too was predicted to give an alcohol of endo stereochemistry. Oxidation of a mixture of the b i c y c l i c ketols (68) and (69J using C o l l i n ' s reagent gave the b i c y c l i c diketone (7_1) . This material was i d e n t i c a l i n every respect to the b i c y c l i c diketone (11) prepared e a r l i e r (see page 17) . The diketone (7_1) was reduced with sodium boro-hydride i n ethanol to a f f o r d the ketol (8_2) , i n 85% y i e l d . The use of sodium borohydride was necessary to e f f e c t a r e g i o s e l e c t i v e as well as a stereoselective reduction of the diketone. Part of the p.m.r. spectrum of the ketol (82) namely a two proton p a i r of doublets at il.12 and x8.29 - 30 -( J = 19 Hz) c o n f i r m e d i t s s t r u c t u r e , s i n c e r e d u c t i o n o f t h e C-6 c a r b o n y l would have r e s u l t e d i n t h e l o s s o f t h e s e s i g n a l s . F u r t h e r r e d u c t i o n o f t h e k e t o l (8_2) w i t h l i t h i u m a l u m i n i u m h y d r i d e i n e t h e r a f f o r d e d t h e d i o l (8_3) . F i n a l l y , an a n a l y t i c a l sample o f each o f t h e k e t o l s (68_) and (6_9) was a l s o r e d u c e d w i t h l i t h i u m a l u m i n i u m h y d r i d e and gave t h e c o r r e s p o n d i n g d i o l s (83) and (8_4) , r e s p e c t i v e l y . Comparison of t h e p.m.r. s p e c t r a ( F i g u r e s 5, 6, 7, 8, and 9) and i . r . s p e c t r a o f t h e d i o l s o b t a i n e d from t h e r e d u c t i o n o f (68) , (69_) and (8_2) c l e a r l y showed t h a t t h e d i o l o b t a i n e d by r e d u c t i o n o f t h e major k e t o l (69) was i d e n t i c a l w i t h t h e d i o l o b t a i n e d by s u c c e s s i v e r e g i o - and s t e r e o s e l e c t i v e r e d u c t i o n o f t h e d i k e t o n e ( 7 1 ) . F u r t h e r m o r e , the two d i o l s e x h i b i t e d i d e n t i c a l m e l t i n g p o i n t s , and t h e m e l t i n g p o i n t o f a m i x t u r e o f t h e two compounds was n o t d e p r e s s e d . On t h e o t h e r hand, the d i o l o b t a i n e d by r e d u c t i o n o f t h e m i n or k e t o l (6_8) was c l e a r l y d i f f e r e n t from t h e r e d u c t i o n p r o d u c t o f the d i k e t o n e (7_1) . T h e r e f o r e , i f t h e o r i g i n a l p r e d i c t i o n r e g a r d i n g r e d u c t i o n s t e r e o c h e m i s t r y was c o r r e c t , t h e s e r e s u l t s c l e a r l y e s t a b l i s h e d t h a t t h e major k e t o l p o s s e s s e d an endo h y d r o x y l group a t C-6, w h i l e t h e minor k e t o l had an exo h y d r o x y l group a t C-6. F u r t h e r s u p p o r t f o r the assignment o f t h e s t e r e o -c h e m i s t r y o f t h e k e t o l s (68) and (69) was t r e a t e d w i t h 3i, -CO 00 o •rl « 0) O 0 O u u o 0) Cu CO Pi P* LO 0) M 3 CO •H fe Figure 8 Comparision of the P.M.R. Spectra of the D i o l s (83). - 36 -p - t o l u e n e s u l f o n y l c h l o r i d e i n d r y p y r i d i n e , t h e minor (exo) k e t o l (6_8) r e a c t e d s m o o t h l y t o g i v e t h e exo t o s y l a t e (85) i n 70% y i e l d . The major (endo) k e t o l (69_) , on t h e o t h e r hand, was r e c o v e r e d (unchanged) from t h e r e a c t i o n m i x t u r e and no t r a c e o f any endo t o s y l a t e (8_6) was f o u n d . These r e s u l t s a r e c o n s i s t e n t w i t h a s s i g n e d s t e r e o c h e m i s t r y , 69 85 s i n c e one would e x p e c t t h e l e s s h i n d e r e d exo h y d r o x y l group t o e s t e r i f y more r a p i d l y t h a n t h e more h i n d e r e d endo a l c o h o l . The r e l a t i v e s t e r i c h i n d r a n c e o f t h e two h y d r o x y l groups was c l e a r l y shown by an i n s p e c t i o n o f m o l e c u l a r m o d e l s . A l a s t p i e c e o f e v i d e n c e i n s u p p o r t o f t h e p r o p o s e d a s s i g n m e n t o f t h e exo C-6 s t e r e o c h e m i s t r y f o r t h e two k e t o l s (_58_) and (6_9) came from an e x a m i n a t i o n o f t h e p.m.r. s p e c t r a o f t h e two c o r r e s p o n d i n g a c e t a t e s (87) and (88)/ r e s p e c t i v e l y . An e x a m i n a t i o n o f . t h e D r e i d i n g models o f t h e a c e t a t e s (87) and (8_8_) s u g g e s t e d t h a t t h e a c e t o x y m e t h y l p r o t o n s o f t h e exo a c e t a t e (8_7) would be s u b j e c t e d i n c e r t a i n c o n f o r m a t i o n s t o t h e s h i e l d i n g cone o f t h e C-8 c a r b o n y l group whereas t h o s e o f t h e endo a c e t a t e (88) would n o t . Thus, i t was p r e d i c t e d t h a t t h e a c e t o x y m e t h y l p r o t o n s o f t h e exo a c e t a t e (8_7) s h o u l d be s h i f t e d u p f i e l d from t h o s e o f the endo a c e t a t e ( 8 8 ) . Each o f t h e k e t o l s (68) and (6_9_) was c o n v e r t e d , w i t h o u t e p i m e r i z a t i o n a t C-6, i n t o t h e c o r r e s p o n d i n g a c e t a t e by t r e a t m e n t o f the former w i t h a c e t i c a n h y d r i d e i n p y r i d i n e . The p.m.r. s p e c t r a o f the two p r o d u c t s showed t h a t t h e s i g n a l due t o t h e a c e t o x y m e t h y l p r o t o n s o f t h e exo isomer (87) (x8.00) was i n d e e d a t h i g h e r f i e l d t h a n t h a t o f t h e endo isomer (8_8) ( x 7 . 9 0 ) , a l t h o u g h i t must be p o i n t e d o u t t h a t t h e c h e m i c a l s h i f t d i f f e r e n c e was not l a r g e . W i t h t h e s y n t h e s i s o f t h e b i c y c l i c c a r b o n s k e l e t o n a c h i e v e d , t h e second s y n t h e t i c o b j e c t i v e o f t h i s work was the f u r t h e r f u n c t i o n a l i z a t i o n . (or d e f u n c t i o n a l i z a t i o n ) o f t h e two c a r b o n b r i d g e t o g i v e t h e s u b s t i t u t e d b i c y c l i c k e t o n s ( 5 i ) , (55) and (56) . W i t h t h e p r e p a r a t i o n o f t h e k e t o l s (6_8) and (69) a l r e a d y a c h i e v e d , i t was f e l t t h a t d e h y d r a t i o n o f t h e k e t o l s (6_8) and (6_9) would r e a d i l y a f f o r d t h e o l e f i n i c k e t o ne (5_5) . C a t a l y t i c h y d r o g e n a t i o n o f t h e l a t t e r would be e x p e c t e d t o a f f o r d t h e d e s i r e d s a t u r a t e d k e t o n e ( 5 4 ) . F i n a l l y O - a l k y l a t i o n o f t h e d i k e t o n e (7__1) would be e x p e c t e d - 38 -to produce the t h i r d desired b i c y c l i c ketone (56). These reactions are outlined i n Chart IV. The attempted dehydration of a mixture of the ketols (6_8) and (6_9) using a number of d i f f e r e n t reagents under a va r i e t y of d i f f e r e n t reaction conditions, f a i l e d . Two well known procedures, employing as dehydrating agents p-toluenesulphonic acid i n benzene and th i o n y l chloride i n py r i d i n e gave no trace of an o l e f i n i c product. 22 Recently, Burgess et. a l . have reported the dehydration of secondary and t e r t i a r y alcohols v i a thermolytic decomposition of the s a l t s of the corresponding N-carbo-methoxysulfonate esters (91) . The l a t t e r was formed by the action of methyl (carbosulphamoyl) triethylammonium hydroxide inner s a l t (90) on the candidate alcohol (89). The inner I I - + -C-C-OH + CH 30 2CNS0 2N(CH 9CH 3) 3 89 90 >=< -C-C-0-S02NC02CH3 HN(CH 2CH 3) 3 + 91 + OS02NHC02CH3 HN(CH 2CH 3) 3 — s a l t (9_0) was prepared by reaction of chlorosulfonyl i s o -cyanate with triethylamine i n anhydrous methanol. Attempted dehydration of the ketols (6_8) and (6_9) v i a t h i s procedure - 40 -also f a i l e d to give any o l e f i n i c products, although i t was apparent that the corresponding esters of the inner s a l t (90) and the ketols (68) and (69) could be formed. dehydration of some secondary alcohols using triphenylphos-phite methiodide i n hexamethylphosphoramide. They observed, while t r y i n g to convert trans-4-tert-butylcyclohexanol into the corresponding c i s iodide by reaction of the former with 24 triphenylphosphite methiodide the formation of 4-t-butyl-cyclohexene i n excellent y i e l d . This observation prompted a successful study of t h i s reaction using a v a r i e t y of secondary 23 alcohols methiodide (9_2) was prepared following the procedure of 24 Landover and Rydon and was then allowed to react with a mixture of the ketols (68) and (69). Hutchins et. a l . 23 have reported the s e l e c t i v e In l i g h t of these f a c t s , triphenylphosphite (PhO) 3P + + CH^I * (PhO) 3PCH 3I 92 O H O 68,69 70 - 41 -The r e a c t i o n p r o d u c t however, p r o v e d t o be t h e k e t o i o d i d e (70) formed i n 52% y i e l d , r a t h e r t h a n t h e d e s i r e d o l e f i n . T h i s r e s u l t was not a l t o g e t h e r u n e x p e c t e d s i n c e t h e mechanism 7 f o r t h e r e a c t i o n was p r o p o s e d t o p r o c e e d v i a an i n t e r m e d i a t e i o d i d e w h i c h undergoes subsequent d e h y d r o h a l o g e n a t i o n i n d u c e d by t h e s o l v e n t . S i n c e t h e k e t o i o d i d e (7_0_) was now a v a i l a b l e , a s u i t a b l e means o f c a r r y i n g o u t i t s d e h y d r o h a l o g e n a t i o n was s o u ght. The use o f amine bases t o e f f e c t t h i s t y p e o f e l i -m i n a t i o n r e a c t i o n i s w e l l known. R e c e n t l y , t h e use o f 1 , 5 - d i a z o b i c y c l o (4.3.0)non-5-ene (93) t o e f f e c t t h e d e h y d r o -25 h a l o g e n a t i o n o f a v a r i e t y o f a l k y l h a l i d e s has been r e p o r t e d T h e r e f o r e t h i s p r o c e d u r e was a p p l i e d t o t h e k e t o i o d i d e (70) . Treatment o f t h e k e t o i o d i d e (70) i n r e f l u x i n g benzene w i t h 1,5-d i a z o b i c y c l o (4.3.0)non-ene a f f o r d e d t h e k e t o o l e f i n (55) i n 78% y i e l d . 70 9_2 55 The i n f r a r e d s p e c t r u m o f t h e l a t t e r e x h i b i t e d a b s o r p t i o n s a t 3.28 y ( o l e f i n i c C-H s t r e t c h i n g v i b r a t i o n ) and a t 5.70 and 5.73 y. The l a t t e r a b s o r p t i o n s were a t t r i b u t e d t o t h e c a r b o n y l group. I t s h o u l d be n o t e d t h a t c a r b o n y l - 42 -g roups i n b i c y c l i c sys t ems s u c h as (55) o f t e n g i v e r i s e t o 2 6 a d o u b l e a b s o r p t i o n s i g n a l . The p . m . r . s p e c t r u m o f t h e k e t o o l e f i n (55) ( F i g . 10) w h i c h was r e m a r k a b l y s i m p l e due t o t h e s y m m e t r i c a l n a t u r e o f t h i s compound, c o n s i s t e d o f t h r e e s h a r p s i n g l e t s a t x 4 . 0 5 , x 8 . 4 7 , and x 8 . 8 0 w h i c h i n t e g r a t e d f o r t w o , s i x , and s i x p r o t o n s r e s p e c t i v e l y . These r e s o n a n c e s c o u l d be r e a d i l y a s s i g n e d t o t h e o l e f i n i c p r o t o n s a t C-6 and C - 7 , t o t h e s i x p r o t o n s o f t h e t h r e e c a r b o n b r i d g e , and t o t h e s i x p r o t o n s o f t h e t e r t i a r y m e t h y l g r o u p s r e s p e c t i v e l y . I n v i e w o f t h e s u c c e s s o f t h e d e h y d r o h a l o g e n a t i o n p r o c e d u r e , a method t o t r a n s f o r m t h e k e t o l s (68) and (69) i n t o t h e k e t o i o d i d e (7_0) i n h i g h e r y i e l d was s o u g h t . The most s u c c e s s f u l p r o c e d u r e i n v o l v e d t h e f o r m a t i o n o f t h e m e s y l a t e s (94) and (95) w h i c h when t r e a t e d w i t h sod ium i o d i d e i n a c e t o n e gave t h e k e t o i o d i d e (7_0) i n an o v e r a l l y i e l d o f 6_8,69_ 9 4 , 9 5 70 78%. The m i x t u r e o f m e s y l a t e s (9_4) and (9_5) was n o t p u r i f i e d b u t was used d i r e c t l y i n t h e n e x t s t e p o f t h e s e q u e n c e . * i i : : : : - o - o - o - o - o -. I : .P : j : : : :-r.43..- | :. O O -CN r- . o o • ! o o W sT: O O -h - o - c -o _ o _ o "C3 : ; i : : I ..: t : : 1 ~.":X : • I : : 1 • ; I .: : t : . I I ' -o> O O 4-> 0) o n u o (1) c o 0) u 3 00 •H fe - 44 -However , t h e p . m . r . s p e c t r u m o f t h e c r u d e m i x t u r e o f mesy-l a t e s was a t t a i n e d and e x h i b i t e d s i n g l e t s a t x 6 . 9 2 and T 7 . 0 0 ( i n d i c a t i v e o f t h e CH^ p r o t o n s o f t h e m e s y l a t e g roup) i n a r a t i o o f a p p r o x i m a t e l y 3 t o 1. The k e t o i o d i d e (7_0) o b t a i n e d by r e a c t i o n o f t h e m i x t u r e o f m e s y l a t e s (9_4) and (95) w i t h sod ium i o d i d e i n a c e t o n e was i d e n t i c a l i n e v e r y r e s p e c t w i t h t h e k e t o i o d i d e o b t a i n e d p r e v i o u s l y (see page 40 ) . The a s s i g n m e n t o f t h e s t e r e o c h e m i s t r y a t t h e C-6 p o s i t i o n o f t h i s m a t e r i a l was ba sed on t h e f o l l o w i n g e v i d e n c e . The p . m . r . s p e c t r u m o f t h e k e t o i o d i d e (7_0) ( F i g . 11) was v e r y s i m i l a r t o t h a t o f t h e e x o - k e t o l (68) ( F i g . 3) i n d i c a t i n g t h a t t h e s e two compounds p o s s e s s e d t h e same r e l a t i v e s t e r e o c h e m i s t r y a t C - 6 . A l s o , t h e c h e m i c a l s h i f t o f t h e C-5 t e r t i a r y m e t h y l g r o u p , (T 8 . 9 7 ) as opposed t o t h e c h e m i c a l s h i f t o f t h e C - 1 t e r t i a r y m e t h y l g r o u p ( x 9 . 0 7 ) was i n agreement w i t h t h e g e n e r a l l y o b s e r v e d p a t t e r n f o r t h e s e compounds. T h u s , t h e p r e s e n c e o f an exo s u b s t i t u e n t (OH, OAc , I ) a t C-6 g e n e r a l l y r e s u l t e d i n a down f i e l d s h i f t o f t h e C-5 m e t h y l p r o t o n s r e l a t i v e t o t h e C - 1 m e t h y l p r o t o n s . F u r t h e r s u p p o r t f o r t h e exo s t e r e o c h e m i c a l a s s i g n m e n t can be i n f e r r e d f rom t h e o b s e r v e d f o r m a t i o n o f o n l y one i s o m e r o f t h e k e t o i o d i d e ( 7 0 ) . I f t h e r e a c t i o n can be assumed t o f o l l o w an SN2 mechanism f o r t h e d i s p l a c e m e n t o f t h e m e s y l a t e g roup by - 46 -i o d i d e , t h e n , s i n c e a m i x t u r e o f m e s y l a t e s (9_4) and (95) was use d , a m i x t u r e o f t h e i o d i d e s would be e x p e c t e d . That i s t o say, even though t h e major p r o d u c t e x p e c t e d would be the exo i s o m e r , (major m e s y l a t e i s o m e r i s endo) a s m a l l e r amount o f t h e endo i o d i d e s h o u l d a l s o be formed. The absence o f any endo i o d i d e ( s p e c t r a l data) can be e x p l a i n e d by a second SN2 d i s p l a c e m e n t i n v o l v i n g t h e i n i t i a l l y formed e n d o ^ i o d i d e , and i o d i d e i o n g i v i n g t h e t h e r m o d y n a m i c a l l y more s t a b l e exo i o d i d e . The exo i o d i d e (70) was pr o p o s e d t o be 94 70. 9_S 9 5 t h e more t h e r m o d y n a m i c a l l y s t a b l e p r o d u c t on t h e b a s i s o f m o l e c u l a r model p r e d i c t i o n s . T h i s p r o p o s a l was s u p p o r t e d i n p a r t by t h e 21 f i n d i n g s o f C a r r a t h u r s and Q u r e s h i . They have r e p o r t e d t h e r e l a t i v e l y smooth r e a c t i o n between p h o s p h o r y l c h l o r i d e and t h e endo k e t o l (97) t o form t h e c o r r e s p o n d i n g exo c h l o r i d e (98) . On t h e o t h e r hand t h e exo a l c o h o l (9_9) gave o n l y a poor y i e l d o f an impure p r o d u c t . 97 98 - 47 -15% of an impure pr o d u c t 99 S i n c e the f o r m a t i o n of the c h l o r i d e i n t h i s type r e a c t i o n i s g e n e r a l l y b e l i e v e d to take p l a c e by n u c l e o p h i l i c a t t a c k o f c h l o r i d e i o n on an i n i t i a l l y formed c h l o r o p h o s p h i t e , the above r e s u l t s can be e x p l a i n e d by p r o p o s i n g t h a t although the a t t a c k o f c h l o r i d e i o n from the l e s s h i n d e r e d exo face of the b i c y c l i c system (9_6_) i s f a c i l e , the a t t a c k o f c h l o r i d e from the more hi n d e r e d endo f a c e i s q u i t e s l u g g i s h . Trans-posing these r e s u l t s by analogy to the f o r m a t i o n o f the keto i o d i d e (7_0_) from the mixture o f mesylates (9_4) and (95) , one might p r e d i c t t h a t (70) would be the o n l y product even though the i s o m e r i c keto i o d i d e (96) might be formed i n i t i a l l y . That a t l e a s t some of the exo mesylate (95) was indeed converted i n t o the exo i o d i d e (70) (probably v i a the endo i o d i d e ) was c l e a r l y shown by the y i e l d of the f i n a l p r o d u c t . That i s , the o v e r a l l y i e l d of (70) (78% from the k e t o l s (68) and (6_9) ) i was g r e a t e r than the expected if> o n l y the endo mesylate were to r e a c t . C a t a l y t i c hydrogenation o f the keto o l e f i n (54) over p a l l a d i u m on c h a r c o a l a f f o r d e d , i n 88% y i e l d the b i c y c l i c ketone (5_5) . The p.m.r. spectrum o f t h i s m a t e r i a l ( F i g u r e 12) d i f f e r s i n some r e s p e c t s from the l i t e r a t u r e 27 v a l u e s r e p o r t e d by Krapcho and P e t e r s 1 . I - 49 -The f i n a l s e c t i o n of t h i s work concerned the s y n t h e s i s o f the t h i r d and f i n a l b i c y c l i c ketone (56) . The d i k e t o n e (7_1) , prepared by " C o l l i n ' s " o x i d a t i o n of a mixture of the k e t o l s (6_8_) and (6_9) (see page 28) or by the C l a i s e n condensation of the keto e s t e r s (73) and (74) (see page 17) was t r e a t e d w i t h sodium b i s ( t r i m e t h y l s i l y l ) a m i d e i n hexa-methyphosphoramide. A d d i t i o n o f i s o p r o p y l bromide to the r e s u l t i n g s o l u t i o n , f o l l o w e d by a p p r o p r i a t e work-up, a f f o r d e d a mixture of the s t a r t i n g m a t e r i a l (diketone (71)) and the d e s i r e d b i c y c l i c ketone (56). S e p a r a t i o n of t h i s mixture by column chromatography (150 g. of A c t i v i t y I I I alumina, continuous e l u t i o n w i t h a 1:1 mixture of (65-110) pet e t h e r and benzene) gave pure b i c y c l i c ketone (56) (65%, based on unrecovered s t a r t i n g m a t e r i a l ) . The i n f r a r e d spectrum of t h i s m a t e r i a l e x h i b i t e d a b s o r p t i o n s a t 3.23, 5.70, and 6.12 y which were a t t r i b u t e d to the o l e f i n i c C-H s t r e t c h i n g v i b r a t i o n , the c a r b o n y l f u n c t i o n a l i t y and the o l e f i n i c double bond o f the e n o l ether group r e s p e c t i v e l y . The p.m.r. spectrum of t h i s m a t e r i a l ( F i g . 13) e x h i b i t e d a one p r o t o n s i n g l e t at x5.50 a s s i g n e d to the lone o l e f i n i c p r o t o n , a one proton heptet a t T5.65 a s s i g n e d to the methene prot o n of the i s o p r o p y l group and a p a i r of t h r e e proton d o u b l e t s a t T8.67 and T8.71 which were a t t r i b u t e d to the scondary methyls of the i s o p r o p y l group. Figure 13 P.M.R. Spectrum of the Enol Ether (56). - 51 -PART I EXPERIMENTAL B o i l i n g p o i n t s are u n c o r r e c t e d and r e f e r to the mean bath temperature d u r i n g a s h o r t path d i s t i l l a t i o n . M e l t i n g p o i n t s , which were determined on a K o f l e r b l o c k , are a l s o u n c o r r e c t e d . Routine i n f r a r e d s p e c t r a were r e c o r d e d on a Perkin-Elmer model 710 spectrophotomer. The p.m.r. s p e c t r a were reco r d e d on V a r i a n A s s o c i a t e s spectrometers, model T-60 or XL-100, u s i n g d e u t e r o c h l o r o f o r m as a s o l v e n t and 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 s tandard. S e l e c t e d s i g n a l p o s i t i o n s are g i v e n i n the T i e r s T s c a l e w i t h 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 p r o t o n assignments e n c l o s e d i n parentheses. U l t r a v i o l e t s p e c t r a were re c o r d e d i n methanol s o l u t i o n on a Unicam, model SP 800 s p e c t r o -photomer. G a s - l i q u i d chromatography (g.£.c.) was performed on an Aerograph u n i t , model 90-P u s i n g the f o l l o w i n g columns. - 52 -Column Description A 20% SE 30 on Chromosorb W (60/80 mesh), 10' x B 20% SE 30 on Chromosorb W (60/80 mesh), 5 1 x h II C 20% FFAP on Chromosorb W (60/80 mesh), 10' x h M D 10% Carbowax on Chromosorb W (60/80 mesh), 10' x h II A column temperature of 150°C and a gas flow (helium) of 100 ml/min were used as standard conditions for a l l the g.Jl.c. work. The s p e c i f i c column used i n each experiment i s indicated i n parentheses. Microanalyses were ably performed by Mr. P. Borda, Microanalytical Laboratory, University of B r i t i s h Columbia, Vancouver. Preparation of the Keto Esters (73) and (74) To a s t i r r e d solution of 1,1,1,3,3,3-hexamethyl-d i s i l a n e (64.6 g, 0.40 mole) and 300 ml of dry benzene under a nitrogen atmosphere was added 155 ml of n-butyllithium i n ether (0.39 mole). The r e s u l t i n g solution was refluxed for 2 h, a f t e r which the benzene was removed by d i s t i l l a t i o n at atmospheric pressure. To the remaining s o l i d was added 300 ml of dry THF and the r e s u l t i n g solution was cooled to 0°C. To t h i s solution was added 2,6-dimethylcyclohexanone (25.0 g, 0.20 mole). After a period of 0.5 h methyl bromo-acetate (9.10 g, 0.60 mole) was added over a span of a few minutes. The i c e bath was removed and the brownish-red - 53 -s o l u t i o n was s t i r r e d f o r 2 h. The THF was then removed under reduced p r e s s u r e and the crude product was e x t r a c t e d t h r i c e w i t h e t h e r . The e t h e r f r a c t i o n s were combined and s u c c e s -s i v e l y washed w i t h two p o r t i o n s of 3N aqueous h y d r o c h l o r i c a c i d , t h r e e p o r t i o n s o f a 10% aqueous sodium t h i o s u l p h a t e s o l u t i o n and f i n a l l y w i t h b r i n e , b e f o r e being d r i e d over anhydrous magnesium s u l p h a t e . The e t h e r was then removed under reduced p r e s s u r e to g i v e a l i g h t orange o i l . The o i l was d i s t i l l e d under reduced p r e s s u r e to a f f o r d 26.0 g (82% based on unrecovered s t a r t i n g m a t e r i a l ) of the keto (2) e s t e r s (73_) and (7_4) , a c l e a r l i q u i d , b.p. 80°C a t .15 mm; i . r . ( f i l m ) vm 3.46, 5.78, 5.88, 8.40 y; p.m.r. x6.35, 6.38 in. 9.x ( s i n g l e t s , 3H, methoxyl m e t h y l s ) , 8.73, 8.93 ( s i n g l e t s , 3H, t e r t i a r y m e t h y l s ) , 9.00 (doublet, 3H, secondary methyl, J = 6 Hz). A n a l . C a l c d . f o r c i _ L H 1 8 ° 3 : C ' 66.64; H, 9.15. Found: C, 66.84; H, 9.38. P r e p a r a t i o n of Sodium B i s ( t r i m e t h y l s i l y l ) a m i d e A s o l u t i o n of 100 g (0.62 mole) of 1,1,1,3,3,3-h e x a m e t h y l d i s i l a n e i n 200 ml of dry benzene was s l o w l y added (2) T h i s m a t e r i a l has p r e v i o u s l y been s y n t h e s i z e d i n our l a b o r a t o r i e s by Mr. A. Mar, (B. Sc. T h e s i s , U n i v e r s i t y of B r i t i s h Columbia, 1971). - 54 -to a s t i r r e d s l u r r y of sodium amide (20.0 g, 0.51 mole) i n 20 ml of dry benzene. The mixture was refluxed under a nitrogen atmosphere for 4 h. at which point the evolution of ammonia had ceased. The hot solution was f i l t e r e d through c e l i t e and the f i l t r a t e was evaporated to dryness under reduced pressure (vacuum pump) to aff o r d 70 g (75%) of the (3) desired sodium b i s ( t r i m e t h y l s i l y l ) a m i d e i n the form of a white c r y s t a l l i n e s o l i d . This material was not further p u r i f i e d , but was used d i r e c t l y . Preparation of 1,5-Dimethylbicyclo[3.2.1]octan-6,8-dione (71) In a t y p i c a l reaction, 10.0 g (59.2 mmole) of the keto esters (7_3) and (7_4) i n 400 ml of dry benzene was added over a period of 2 h to a re f l u x i n g s o l u t i o n of 45.0 g (0.23 mole) of sodium b i s ( t r i m e t h y l s i l y l ) a m i d e i n 100 ml of dry benzene, while the system was maintained under a nitrogen atmosphere. The r e s u l t i n g solution was refluxed f or 3 h, cooled to 0°C, and then poured into a ra p i d l y s t i r r i n g s olution of 100 ml of g l a c i a l a c e t i c a c i d i n 300 ml of i ce water. The en t i r e volume of l i q u i d was then place into a separatory funnel where the aqueous phase was removed and This material was previously synthesized by a number of students i n our laboratory using a s i m i l a r procedure. - 55 -subsequently e x t r a c t e d t h r i c e w i t h 100 ml p o r t i o n s of e t h e r . The combined o r g a n i c p o r t i o n s were washed w i t h s a t u r a t e d aqueous sodium b i c a r b o n a t e u n t i l n e u t r a l and then d r i e d over anhydrous magnesium s u l p h a t e . The o r g a n i c s o l v e n t was removed under reduced p r e s s u r e and the r e s u l t i n g o i l was d i s t i l l e d under reduced p r e s s u r e to a f f o r d 8 g of an o i l , (b.p. 65-80°C at .1 mm). T h i s o i l was s u b j e c t e d to column chromatography on s i l i c a g e l (320 g ) . Continuous e l u t i o n w i t h (65-110) p e t . ethe r a f f o r d e d 3 g (41%) of the b i c y c l i c d i k e t o n e (7_1) w h i l e e l u t i o n w i t h e t h e r a f f o r d e d 2 g of the s t a r t i n g m a t e r i a l , keto e s t e r s (73) and (74) . The d i k e t o n e (71) ^ was r e c r y s t a l l i z e d from hexanes and e x h i b i t e d , m.p. 56°C; i . r . ( f i l m ) v m a x 5.65, 5.80 y ; p.m.r. x7.30, 7.66 (A, B p a i r o f 9 d o u b l e t s , 2H, -CE2~C- J " A B = 19 Hz), 8.76 , 8.95 ( s i n g l e t s , 6H, t e r t i a r y m e t h y l s ) . A n a l . C a l c d . f o r C 1 0H 1 4C> 2: C, 72.26; H, 8.49. Found: C, 7 2.09; H, 8.29. P r e p a r a t i o n of the Keto A c i d s (7_5) and (76) A s o l u t i o n o f the keto e s t e r s (7_3_) and (7_4_) i n 170 ml o f 10% methanolic sodium hydroxide was heated under A p r e l i m i n a r y r e p o r t on t h i s compound has been made by Mr. A. Mar, (B. Sc. T h e s i s , U n i v e r s i t y of B r i t i s h Columbia). - 56 -r e f l u x f o r 2 h, c o o l e d , d i l u t e d w i t h s a t u r a t e d b r i n e and .e x t r a c t e d w i t h e t h e r (50 m l ) . The e t h e r e a l e x t r a c t was d i s c a r d e d . The a l k a l i n e aqueous l a y e r was a c i d i f i e d w i t h d i l u t e h y d r o c h l o r i c a c i d and the r e s u l t i n g mixture was e x t r a c t e d w i t h t h r e e 50 ml p o r t i o n s o f e t h e r . The combined eth e r e x t r a c t s were washed w i t h a s a t u r a t e d b r i n e s o l u t i o n and d r i e d over anhydrous magnesium s u l p h a t e . The s o l v e n t was removed under reduced p r e s s u r e to a f f o r d 8.8 g (80%) o f a c r y s t a l l i n e m a t e r i a l . A s m a l l sample o f t h i s m a t e r i a l was r e c r y s t a l l i z e d from e t h y l a c e t a t e - p e t e t h e r to g i v e an a n a l y t i c a l sample o f the keto a c i d (75) or (7_6) which e x h i b i t e d m.p. 109-110°C; i . r . (CHC1 3) v m a x 2.48, 5.87 y ; p.m.r. x8.97 (doublet, 3H, secondary methyl, J = 6.0 Hz), 8.84 ( s i n g l e t , 3H, t e r t i a r y m e t h y l ) , 2.47, 2.91 (A, B, ft q u a r t e t , 2H, -CH 2-C-0H, J " A B = 15 Hz), 1.24 (broad, IH, C0 2H) . A n a l . C a l c d . f o r c l 0 H 1 6 ° 3 : C ' 6 5 - 1 9 ? H> 8.75. Found: C, 65.23; H, 8.77. P r e p a r a t i o n o f the Enol Lactone (77) To a s t i r r e d s o l u t i o n o f the keto a c i d s (75) and (76) (7.58 g, 42.5 mmole) i n 170 ml of a c e t i c anhydride was added 2.18 g of anhydrous sodium a c e t a t e . The r e s u l t i n g s o l u t i o n was r e f l u x e d under a n i t r o g e n atmosphere f o r 2 h. The a c e t i c anhydride was removed under reduced p r e s s u r e and - 57 -the remaining material was thoroughly extracted with ether. The combined organic extracts were washed with water and dried over anhydrous magnesium sulphate. The solvent was removed under reduced pressure and the r e s u l t i n g o i l was d i s t i l l e d under reduced pressure to afford 7.08 g (98%) of the enol lactone (77) as a clear o i l , b.p. 42°C at .01 mm; i . r . (film) 5.55, 5.82, 8.08, 8.13 y ; p.m.r. T7.67 max (j) (singlet, 2H, -CH 2-C-), 8.50 (doublet, 3H, o l e f i n i c methyl, J = 1 Hz), 8.95 (singlet, 3H, t e r t i a r y methyl). Anal. Calcd. for C 1 Q H 1 4 0 2 : C, 72.26; H, 8.49. Found: C, 7 2.05; H, 8.56. Reduction of the Enol Lactone (77) (a) Lithium tri-t-butoxyaluminohydride To a s t i r r e d s olution of the enol lactone (77) (168 mg, 1 mmole) i n 5 ml of dry THF under a nitrogen atmosphere was added, over a period of .5 h, a solution of lithium tri-t-butoxyaluminohydride (500 mg, 2 mmole) i n 5 ml of dry THF. The reaction mixture was s t i r r e d at room temperature for 26 h, and then poured into d i l u t e aqueous hydrochloric acid. The r e s u l t i n g mixture was f i l t e r e d through c e l i t e and thoroughly extracted with ether. The organic extracts were combined and dried over anhydrous magnesium sulphate. The solvent was removed under reduced - 58 -p r e s s u r e and t h e r e s i d u a l m a t e r i a l was d i s t i l l e d unde r r e d u c e d p r e s s u r e t o a f f o r d 90 mg (54%) o f a c l e a r o i l , b . p . 8 0 ° a t 0 .2 mm. The i n f r a r e d and p . m . r . s p e c t r a o f t h i s m a t e r i a l were v e r y s i m i l a r t o t h o s e o b t a i n e d f rom a m i x t u r e o f t h e k e t o a l c o h o l s (6_8) and (6_9) , p r e p a r e d by a s u p e r i o r , a l t e r n a t i v e m e t h o d , as d e s c r i b e d l a t e r i n t h i s t h e s i s (see page 60 ) . (b) D i i s o b u t y l a l u m i n u m h y d r i d e To a s t i r r e d s o l u t i o n o f t h e e n o l l a c t o n e (77) (150 mg, 0 .90 mmole) i n 2 m l o f d r y benzene unde r a n i t r o g e n a t m o s p h e r e , was added o v e r a p e r i o d o f . 5 h , a s o l u t i o n o f d i i s o b u t y l a l u m i n u m h y d r i d e ( 2 . 2 mmole) i n benzene (2 m l ) . The r e a c t i o n m i x t u r e was s t i r r e d a t room t e m p e r a t u r e f o r 3 h b e f o r e b e i n g p o u r e d i n t o d i l u t e aqueous s u l p h u r i c a c i d . The o r g a n i c l a y e r was s e p a r a t e d , washed s u c c e s s i v e l y w i t h d i l u t e aqueous sod ium b i c a r b o n a t e and b r i n e , and t h e n d r i e d o v e r anhyd rous magnesium s u l p h a t e . The o r g a n i c s o l v e n t was removed u n d e r r e d u c e d p r e s s u r e and the r e s i d u a l m a t e r i a l was d i s t i l l e d under r e d u c e d p r e s s u r e t o a f f o r d 72 mg (50% y i e l d ) o f a c l e a r o i l , b . p . 46°C a t .01 mm. T h i s m a t e r i a l was shown by g.Z.c. (co lumn B ) , and by s p e c t r a l d a t a ( i n f r a r e d , p . m . r . ) t o c o n s i s t o f a m i x t u r e o f t h e k e t o a l c o h o l s (68) and (69) (see page 60) and t h e e n o l l a c t o n e (77) i n a r a t i o o f 1 8 : 8 2 . - 59 -P r e p a r a t i o n o f 2 - A l l y 1 - 2 , 6 - d i m e t h y l c y c l o h e x a n o n e (78) and (79) To a s t i r r e d s o l u t i o n o f 1 , 1 , 1 , 3 , 3 , 3 - h e x a m e t h y l -d i s i l a n e (64 .6 g , 0 .40 m o l e s ) i n 600 m l o f d r y benzene unde r a n i t r o g e n a tmosphere was added a s o l u t i o n o f 206 ml o f n - b u t y l l i t h i u m i n e t h e r (0 .39 m o l e s ) . 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 1 h and t h e n t h e b u l k o f t h e benzene was removed by d i s t i l l a t i o n . To t h e r e s i d u e was added 600 m l o f d r y THF and t h e r e s u l t i n g s o l u t i o n was c o o l e d t o 0 ° C . To t h i s s o l u t i o n was added 2 , 6 - d i m e t h y l c y c l o -hexanone (50 .4 g , 0 .40 mo les ) a n d , a f t e r 1 h , a l l y l b r o m i d e (145 g , 1.20 m o l e s ) . The i c e b a t h was removed and t h e y e l l o w s o l u t i o n was s t i r r e d a t room t e m p e r a t u r e f o r 2 h . Mos t o f t h e THF was t h e n removed under r e d u c e d p r e s s u r e and the r e s i d u a l m a t e r i a l was d i l u t e d w i t h w a t e r and t h e n t h o r o u g h l y e x t r a c t e d w i t h e t h e r . The combined o r g a n i c e x t r a c t s were s u c c e s s i v e l y washed w i t h two p o r t i o n s o f 3N aqueous h y d r o c h l o r i c a c i d , t h r e e p o r t i o n s o f a 10% aqueous sod ium t h i o s u l p h a t e s o l u t i o n and f i n a l l y w i t h b r i n e . The o r g a n i c s o l u t i o n was t h e n d r i e d o v e r anhyd rous magnesium s u l p h a t e . Removal o f t h e s o l v e n t unde r r e d u c e d p r e s s u r e a f f o r d e d 5 4 . 3 g (82%) o f 2 - a l l y l - 2 , 6 - d i m e t h y l c y c l o h e x a n o n e as a c l e a r o i l , b . p . 42°C a t .15 mm; i . r . ( f i l m ) v 3 . 2 3 , max 5 . 8 6 , 6 . 1 0 , 1 0 . 1 8 , 1 1 . 1 3 u ; p . m . r . x 4 . 0 4 - 4 . 4 2 , 4 . 9 2 , 5 .08 ( m u l t i p l e t s , 3H, o l e f i n i c p r o t o n s ) , 8 . 8 4 , 8 .97 ( s i n g l e t s , 3H, t e r t i a r y m e t h y l ) , 9 .00 ( d o u b l e t , 3H, s e c o n d a r y m e t h y l , J = 6 H z ) . - 60 -Anal. Calcd. for C^H^O: C, 79.46; H, 10.91. Found: C, 79.00; H, 10.70. Preparation of 6-endo (69) and 6-exo (68)-Hydroxy-l,5-dimethylbicyclo[3.2.1]octan-8-one. A s t i r r e d solution of 2-allyl-2,6-dimethylcyclo-hexanone (7_8) and (7_9) (65.0 g, .382 mole) i n 3 I of methylene chloride was cooled to -78°C i n a dry ice-acetone bath. A stream of ozone was introduced u n t i l the sol u t i o n had turned blue (2 h) and the reaction mixture was then flushed with oxygen u n t i l the blue colour had been discharged. The reaction mixture was allowed to warm to room temperature and was then added to 5 I of a 50% sol u t i o n of g l a c i a l a c e tic acid i n i c e water containing 200 g of massy zinc. The r e s u l t i n g mixture was s t i r r e d for 1 h. The en t i r e volume of l i q u i d was transferred to a separatory funnel and the organic layer was removed. The aqueous layer was extracted with three portions of methylene chloride. The combined organic phases were washed with water and with saturated aqueous sodium bicarbonate u n t i l neutral. The organic solution was dried over anhydrous magnesium sulphate and the solvent was removed under reduced pressure. A small amount of the r e s i d u a l crude material was d i s t i l l e d under reduced pressure to give an a n a l y t i c a l sample of a mixture of the - 61 -keto aldehydes (8_0) and. (8_1) which e x h i b i t e d , b.p. 73-75°C at .4 mm; i . r . ( f i l m ) v 3.65, 5.82, 5.85 y ; p.m.r. xO.83 n 3.x ( m u l t i p l e t , IH, aldehyde p r o t o n ) , 7.57 (doublet, 2H, 0 il -CH 3~C-H, J = 2 Hz), 8.35, 8.82 ( s i n g l e t s , 3H, t e r t i a r y m e t h y l ) , 9.07 (doublet, 3H, secondary methyl, J = 6 Hz). A n a l . C a l c d . f o r C 1 0H 1 8C> 2 : C, 71.39, H, 9.59. Found: C, 71.10; H, 9.78. The bulk of the mixture of keto aldehydes (8_0) and (81) was taken up i n 3 £ of THF and to t h i s s o l u t i o n was added 3 £ of IN sodium hydroxide. A f t e r t h i s s o l u t i o n had been s t i r r e d f o r 3 h i t was n e u t r a l i z e d by c a r e f u l a d d i t i o n of 6N h y d r o c h l o r i c a c i d . The bulk of the THF was removed under reduced p r e s s u r e and the remaining aqueous phase was thoroughly e x t r a c t e d w i t h e t h e r . The combined o r g a n i c l a y e r s were washed w i t h water and then d r i e d over anhydrous magnesium s u l p h a t e . The s o l v e n t was removed and the crude product was d i s t i l l e d under reduced p r e s s u r e to a f f o r d 44.7 g (70%) of a t r a n s p a r e n t o i l (b.p. 74-76°C a t 0.4 mm). The product was shown to be a mixture of the e p i m e r i c keto a l c o h o l s (6_9) and (68) i n a r a t i o of approximately 65-35 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 each epimer was o b t a i n e d by p r e p a r a t i v e g.£. c. (column C ) . The major keto a l c o h o l (6_9) e x h i b i t e d , b.p. 100-102°C a t .25 mm; i . r . ( f i l m ) 2.85, 5.75, y; p.m.r. x6.00 ( p a i r of d o u b l e t s , IH, - 62 --CH-OH, J = 4 Hz, J = 9 Hz), 7.48 ( s i n g l e t , IH, h y d r o x y l p r o t o n ) , 9.02, 9.03 ( s i n g l e t s , 6H, t e r t i a r y m e t h y l s ) . A n a l . C a l c d . f o r C 1 Q H 1 6 0 : C, 71.39; H, 9.59. Found: C, 71.11; H, 9.71. The minor keto a l c o h o l (6_8_) was o b t a i n e d as a s o l i d and e x h i b i t e d , m.p. 82°C, i . r . (CHC1-.) v 2.75, 2.86, j in 3.x 5.77, y; p.m.r. x5.90 (doublet of d o u b l e t s , IH, -CHOH, J = 3 Hz, J = 8 Hz), 7.32 ( m u l t i p l e t , IH, un a s s i g n e d ) , 8.98, 9.02 ( s i n g l e t s , 6H, t e r t i a r y m e t h y l s ) . A n a l . C a l c d . f o r C l f J H 1 6 0 : C, 71.39; H, 7.59. Found: C, 71.30; H, 9.45. P r e p a r a t i o n o f the Diketone (77) To the s t i r r e d s o l u t i o n o f p y r i d i n e (1.90 g, 24.0 mmoles) i n 30 ml of methylene c h l o r i d e a t room tempera-t u r e was added chromium t r i o x i d e (1.20 g, 12.0 mmoles). The f l a s k was equipped w i t h a d r y i n g tube and the s o l u t i o n s t i r r e d f o r 0.5 h. Then 336 mg (2.00 mmoles) of a mixture of the k e t o l s (6_8_) and (69) i n a s m a l l amount of methylene c h l o r i d e was added 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. The s o l u t i o n was then decanted from the r e s i d u e which was washed wit h 15 ml of e t h e r . The combined o r g a n i c l a y e r s were washed w i t h t h r e e 20 ml p o r t i o n s o f 5% aqueous sodium hydroxide s o l u t i o n , 5% aqueous h y d r o c h l o r i c a c i d - 63 -s o l u t i o n and a s a t u r a t e d b r i n e s o l u t i o n . The o r g a n i c l a y e r was t h e n d r i e d o v e r anhydrous magnesium s u l p h a t e and concen-t r a t e d under r e d u c e d p r e s s u r e (35-38°C a t .1.5 mm) t o a f f o r d 286 mg (86%) o f t h e d i k e t o n e (7_7). T h i s m a t e r i a l was i d e n t i c a l i n e v e r y r e s p e c t t o t h e d i k e t o n e (11) o b t a i n e d p r e v i o u s l y (see page 54 ) . P r e p a r a t i o n o f 8 - e n d o - H y d r o x y - l , 5 - d i m e t h y l b i c y c l o [3.2.1]octane-6-one (82) A s t i r r e d s o l u t i o n o f t h e d i k e t o n e (11) (166 mg, 1 mmole) i n 3 ml o f d r y e t h a n o l was c o o l e d t o o°C by means o f an i c e b a t h b e f o r e 12 mg (0.30 mmole) o f sodium b o r o -h y d r i & e -,was added. The r e s u l t i n g s o l u t i o n was s t i r r e d a t 0°, under a n i t r o g e n atmosphere, f o r a p e r i o d o f 12 m i n u t e s . The o r g a n i c s o l v e n t was removed under r e d u c e d p r e s s u r e and th e r e s i d u e was t h o r o u g h l y e x t r a c t e d w i t h e t h e r . The combined o r g a n i c e x t r a c t s were d r i e d o v e r anhydrous magnesium s u l p h a t e . Removal o f t h e s o l v e n t and d i s t i l l a t i o n of t h e r e s i d u e under r e d u c e d p r e s s u r e a f f o r d 143 mg (85%) o f t h e k e t o l ( 8 2 ) , b.p. 79-81°C a t 0.1 mm; i . r . ( f i l m ) IUclX 2.86. 2.70 u; p.m.r. T6.50 ( s i n q l e t , I H, CH-OH, Wj , = 5 cps) , V -in 77.2, 8.29 ( p a i r o f d o u b l e t s , 2H, CH 2-C, J A B = 1 9 H z ) , 8.89. 9.02 ( s i n g l e t s , 6H, t e r t i a r y m e t h y l s ) . A n a l . C a l c d . f o r C 1 0 H 1 6 ° 2 : c ' 71.39; H, 9.59. Found: C, 71.32; H, 9.70. - 64 -R e d u c t i o n o f t h e K e t o l (82) To a s t i r r e d s o l u t i o n o f t h e k e t o l (8_2_) (100 mg, .59 mmoles) and 3 m l o f d r y e t h e r was added .8 ml o f a 1 m o l a r s o l u t i o n o f l i t h i u m a l u m i n i u m h y d r i d e and e t h e r . 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 3 h . and t h e n s o l i d sod ium s u l p h a t e d e c a h y d r a t e was a d d e d . The r e a c t i o n m i x t u r e was f i l t e r e d t h r o u g h c e l i t e and t h e r e s u l t i n g f i l t r a t e was c o n c e n t r a t e d unde r r e d u c e d p r e s s u r e . The r e s i d u a l m a t e r i a l was d i s t i l l e d unde r r e d u c e d p r e s s u r e t o a f f o r d 96 mg (96%) o f a g l a s s y d i o l ( 8 3 ) , b . p . 1 1 0 - 1 1 2 ° C a t . 03 mm;m.p . 5 9 - 6 0 ° C , i . r . ( C H C 1 3  v max 2 * 7 5 ' 2 ' 8 6 V> P - m . r . T 6 . 9 1 ( s i n g l e t , I H , CHOH a t C - 8 ) , 9 . 0 5 , 9 .0C ( s i n g l e t s , 6H, t e r t i a r y m e t h y l s ) -R e d u c t i o n o f t h e K e t o l (69) The k e t o l (69) was r e d u c e d w i t h l i t h i u m a l u m i n i u m h y d r i d e u s i n g a p r o c e d u r e i d e n t i c a l w i t h t h a t d e s c r i b e d i n t h e p r e v i o u s e x p e r i m e n t . T h u s , 42 mg ( 0 . 2 5 mmole) o f t h e k e t o l (69) a f f o r d e d 39 mg (90%) o f a g l a s s y d i o l (8_3) . T h i s m a t e r i a l was i d e n t i c a l i n e v e r y r e s p e c t w i t h t h e d i o l (83) o b t a i n e d i n t h e p r e v i o u s e x p e r i m e n t . R e d u c t i o n o f t h e K e t o l (68) The k e t o l (6_8) was r e d u c e d w i t h l i t h i u m a luminum h y d r i d e i n d r y e t h e r f o l l o w i n g the p r o c e d u r e o u t l i n e d i n - 65 -t h e two p r e c e d i n g e x p e r i m e n t s . T h u s , 3 0 mg (.178 mmole) o f t h e k e t o l (6_8) a f f o r d 30 mg (92%) o f a d i o l (84_) b.p. 105-110 a t .05 mm; i . r . (CHCl-,) v 2.74, 2.85 u ; p.m.r. x6.24 ( m u l t i p l e t , IH, CHOH a t C-6, J = 3 H z ) , J = 8 H z ) , x6.60 ( s i n g l e t , IH, CHOH a t C - 8 ) , 8.18 ( s i n g l e t , 2H, h y d r o x y l p r o t o n s ) , 9.03, 9.06 ( s i n g l e t s , 6H, t e r t i a r y m e t h y l s ) . P r e p a r a t i o n o f 6-exo- T o s y l o x y - 1 , 5 - d i m e t h y l b i c y c l o [ 3 . 2 . 1 ] octan-8-.one (85) To a s t i r r e d s o l u t i o n o f a m i x t u r e o f t h e k e t o l s (68) and (6_9) (500 mg, 2.9 mmoles i n a r a t i o o f 35:65, r e s p e c t i v e l y ) , i n 20 ml o f d r y p y r i d i n e a t 0°C was adde d 1.1 g o f f r e s h l y r e c r y s t a l l i z e d p - t o l u e n e s u l p h o n y l c h l o r i d e . The r e s u l t i n g m i x t u r e was m a i n t a i n e d a t 5°C f o r 24 h o u r s b e f o r e b e i n g p o u r e d i n t o a s l u r r y o f i c e and w a t e r . The c r y s t a l l i n e t o s y l a t e (86) was' removed by vacuum f i l t r a t i o n and r e c r y -s t a l l i z e d f r o m 30-60 p e t . e t h e r t o a f f o r d 227 mg (70% b a s e d on o n l y k e t o l (6_8) r e a c t i n g ) o f a w h i t e s o l i d , m.p. 1 4 7 - 1 4 8 ° C , i . r . ( C H C l o ) 5.75, 5.80, 6.04; p.m.r. x5.10 ( m u l t i p l e t , J ITlclX IH, CHOTs, J = 3 Hz, J = 8 H z ) , 7.53 ( s i n g l e t , 3H, m e t h y l o f t o l u e n e ) , 8.97, 9.06 ( s i n g l e t s , 6H, t e r t i a r y m e t h y l s ) . A n a l . C a l c d . f o r C 1 7 H 2 2 0 4 S : C, 63.33; H, 6.87; S, 9.94. Fou n d : C, 63.50; H, 6.84; S, 9.80. The f i l t r a t e f r o m t h e above f i l t r a t i o n v/as t h o r o u g h l y e x t r a c t e d - 66 -w i t h e t h e r and t h e combined o r g a n i c e x t r a c t s were washed w i t h d i l u t e aqueous h y d r o c h l o r i c a c i d b e f o r e b e i n g d r i e d o v e r anhydrous magnesium s u l p h a t e . The o r g a n i c s o l v e n t was removed and t h e r e s i d u e was d i s t i l l e d unde r r e d u c e d p r e s s u r e t o a f f o r d 220 mg o f t h e k e t o l (69_) ( i d e n t i f i e d by i t s p . m . r . s p e c t r u m ) . P r e p a r a t i o n o f 6 - e x o - A c e t o x y - l , 5 - d i m e t h y l b i c y c l o [ 3 . 2 . 1 ] o c t a n -8-one (87) To a s o l u t i o n o f t h e k e t o a l c o h o l (6_3_) (30 mg, 0 .18 mole) i n 1 m l o f d r y p y r i d i n e was added 0 .25 m l o f a c e t i c a n h y d r i d e and t h e r e s u l t i n g s o l u t i o n was a l l o w e d t o s t a n d a t room t e m p e r a t u r e f o r 80 h . A f t e r t h i s p e r i o d o f t i m e , 2 m l o f w a t e r was added and t h e r e s u l t i n g m i x t u r e was t h o r o u g h l y e x t r a c t e d c h l o r o f o r m . The combined o r g a n i c phases were washed w i t h t h r e e p o r t i o n s o f I N aqueous h y d r o -c h l o r i c a c i d and b r i n e b e f o r e b e i n g d r i e d o v e r anhyd rous magnesium s u l p h a t e . The o r g a n i c s o l v e n t was removed and the r e s i d u e was d i s t i l l e d unde r r e d u c e d p r e s s u r e t o a f f o r d 34 mg (100%) o f t h e k e t o a c e t a t e (8_7_) as a c l e a r o i l , b . p . 84°C a t .3 mm; i . r . ( f i l m ) v 5 . 7 4 , 5 . 7 6 , 8 .10 u ; p . m . r . max x 4 . 8 8 ( d o u b l e t o f d o u b l e t s , I H , - C H - 0 - C - C H 3 , J = 10 H z , J = 4 Hz) . , 7 .49 ( m u l t i p l e t , I H , u n a s s i g n e d , J = 14 H z , J = 8 H z ) , 8 .00 ( s i n g l e t , 3H, a c e t a t e m e t h y l ) , 8 . 9 6 , 9 .06 - 6 7 -( s i n g l e t s , 6H, t e r t i a r y m e t h y l s ) . A n a l . C a l c d . f o r c 1 2 H i 8 ° 3 : C ' 6 8 - 5 5 ' ' H ' 8.63. F o u n d : C, 68.53; H, 8.79. P r e p a r a t i o n o f 6 - e n d o - A c e t o x y - l , 5 - d i m e t h y l b i c y c l o [ 3 . 2 . 1 ] o c t a n -8-one (88) The k e t o a c e t a t e (8_8) was p r e p a r e d f o l l o w i n g t h e p r o c e d u r e d e s c r i b e d i n t h e p r e v i o u s e x p e r i m e n t . (see page 6 6 ) . The k e t o a l c o h o l (6_9) (30 mg, 0.18 mole) a f f o r d e d 34 mg (100%) o f t h e k e t o a c e t a t e (8_8) w h i c h e x h i b i t e d , b.p. 84°C a t .3 mm; i . r . ( f i l m ) v 5.70, 8.05 y; p.m.r. x5.11 max ( d o u b l e t o f d o u b l e t s , IH, -CH-OCCH 3, J = 10 Hz, J = 5 H z ) , 7.90 ( s i n g l e t , 3H, a c e t a t e m e t h y l ) , 9.05, 9.10 ( s i n g l e t s , 6H, t e r t i a r y m e t h y l s ) . A n a l . C a l c d . f o r c i 2 H l 8 ° 3 : C ' 6 8 - 5 5 ; H ' 8 - 6 3 -F o und: C, 68.81; H, 8.80. P r e p a r a t i o n o f T r i p h e n y l p h o s p h i t e M e t h i o d i d e A s t i r r e d s o l u t i o n o f t r i p h e n y l p h o s p h i t e (31.0 g, 0.10 mole) i n m e t h y l i o d i d e (21.0 g, 0.14 mole) u n d e r a n i t r o g e n a t m o s p h e r e was r e f l u x e d f o r 40 h . The r e a c t i o n m i x t u r e was t h e n c o o l e d t o room t e m p e r a t u r e and t h e e x c e s s m e t h y l i o d i d e and any o t h e r v o l a t i l e p r o d u c t s were removed u n d e r r e d u c e d p r e s s u r e . The b r o w n i s h s o l i d t h a t r e m a i n e d was - 68 -d i s s o l v e d i n a m i n i m a l amount o f d r y a c e t o n e (100 ml) and t h e n an e q u a l volume o f a n h y d r o u s e t h e r was add e d t o i n d u c e p r e c i p i t a t i o n . The o r g a n i c s o l v e n t was removed by d e c a n t a t i o n and t h e y e l l o w c r y s t a l s l e f t b e h i n d were r e c r y s t a l l i z e d i n t h e a b o v e manner t o y i e l d 24 g (54%) o f a w h i t e c r y s t a l l i n e s o l i d . T h i s m a t e r i a l decomposed upon s t a n d i n g and was k e p t u n d e r a n h y d r o u s e t h e r and t h e n r e c r y s t a l l i z e d f r o m a c e t o n e p r i o r t o u s e . P r e p a r a t i o n o f 6 - e x o - I o d o - l , 5 - d i m e t h y l b i c y c l o [ 3 . 2 . 1 ] o c t a n -8-one (70) (a) U s i n g T r i p h e n y l p h o s p h i t e M e t h i o d i d e To a s t i r r e d s o l u t i o n o f a m i x t u r e o f t h e k e t o a l c o h o l s (6_8) and (_59) (1.31 g, 7.80 mmole) i n 50 ml o f d r y HMPA u n d e r a n i t r o g e n a t m o s p h e r e was add e d 7.1 g (17.0 mmole) o f m e t h y l t r i p h e n o x y p h o s p h o n i u m i o d i d e and t h e r e s u l t i n g m i x t u r e was c o o l e d t o room t e m p e r a t u r e , p o u r e d i n t o i c e - c o l d IN a q u e o u s . s o d i u m h y d r o x i d e and t h e r e s u l t i n g m i x t u r e was t h o r o u g h l y e x t r a c t e d w i t h l i g r o i n . The c o m b i n e d o r g a n i c e x t r a c t s were washed w i t h w a t e r u n t i l n e u t r a l and d r i e d o v e r a n h y d r o u s magnesium s u l p h a t e . The o r g a n i c s o l v e n t and t h e r e s i d u a l m a t e r i a l was d i s t i l l e d u n d e r r e d u c e d p r e s s u r e t o a f f o r d 1.14 g (52%) o f t h e k e t o i o d i d e (7_0) a s a w h i t e c r y s t a l l i n e s o l i d , m.p. 7 5 ° - 7 7 ° C ; i . r . (CHCl^) v m = v 5.69, - 69 -5.72 y; p.m.r. x5.62 ( m u l t i p l e t , IH, -CH-I, J = 10 Hz, J = 7 H z ) , 8.91, 8.18 ( s i n g l e t s , 6H, t e r t i a r y m e t h y l ) . A n a l . C a l c d . f o r C,-H,_OI: C, 43.18; H, 5.44; I , 45.63. ± U I D F o u n d : C, 43.12; H, 5.40; I , 45.51. (b) V i a t h e , 6 - e x o (94) and 6-endo ( 9 5 ) - M e s y l o x y - 1 , 5 -d i m e t h y l b i c y c l o [ 3 . 2 . 1 ] o c t a n - 8 - o n e To a s t i r r e d s o l u t i o n o f a m i x t u r e o f t h e k e t o a l c o h o l s (6_8) and (6_9) (10.0 g, 59.6 mmole) i n 250 ml o f d r y p y r i d i n e was a d d e d 10.0 g (87 mmole) o f f r e s h l y d i s t i l l e d m e t h a n e s u l p h o n y l c h l o r i d e and t h e r e s u l t i n g m i x t u r e was m a i n t a i n e d a t 50°C f o r 24 h. The r e a c t i o n m i x t u r e was c o o l e d t o room t e m p e r a t u r e and p o u r e d i n t o 50 0 ml o f i c e - w a t e r . The aqueous p h a s e was t h o r o u g h l y e x t r a c t e d w i t h e t h e r and t h e c o m b i n e d o r g a n i c e x t r a c t s were washed w i t h d i l u t e a q ueous h y d r o c h l o r i c a c i d u n t i l t h e w a s h i n g s were a c i d i c . The e t h e r s o l u t i o n was t h e n d r i e d o v e r a n h y d r o u s magnesium s u l p h a t e . Removal o f t h e s o l v e n t u n d e r r e d u c e d p r e s s u r e a f f o r d e d a m i x t u r e o f t h e c r u d e . m e s y l a t e s (94) and (9_5) . The i n f r a r e d s p e c t r u m ( f i l m ) o f t h e l a t t e r showed no a b s o r p t i o n due t o OH and t h e p.m.r. s p e c t r u m showed two s i n g l e t s (due t o 0 S 0 2 C H 3 ) a t T6.92 and T 7 . 0 0 , i n a r a t i o o f a p p r o x i m a t e l y 3:1. The c r u d e m i x t u r e o f m e s y l a t e s (9_4) and (9_5) was d i s s o l v e d i n 250 ml o f d r y - 70 -a c e t o n e t o w h i c h 17.6 g o f s o d i u m i o d i d e was a d d e d . 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 60 h, c o o l e d t o room t e m p e r a t u r e and p o u r e d i n t o i c e - w a t e r . The aqueous p h a s e was t h o r o u g h l y e x t r a c t e d w i t h e t h e r and t h e c o m b i n e d o r g a n i c e x t r a c t s were washed w i t h w a t e r b e f o r e b e i n g d r i e d o v e r a n h y d r o u s magnesium s u l p h a t e . The o r g a n i c s o l v e n t was removed and t h e r e s i d u a l m a t e r i a l was d i s t i l l e d u n d e r r e d u c e d p r e s s u r e t o a f f o r d 13 g (78% f r o m t h e k e t o a l c o h o l s (6_8) and (69) o f a c r y s t a l l i n e m a t e r i a l , b.p. 8 0 - 9 0 ° C a t 1.4 mm. The p r o d u c t was r e c r y s t a l l i z e d f r o m e t h a n o l - p e t e t h e r (30-60) t o g i v e an a n a l y t i c a l sample w h i c h was shown t o be i d e n t i c a l w i t h t h e k e t o i o d i d e (70_) p r e p a r e d as d e s c r i b e d p r e v i o u s l y . P r e p a r a t i o n o f 1 , 5 - D i m e t h y l b i c y c l o [ 3 . 2 . 1 ] o c t - 6 - e n - 8 - o n e (55) To a s o l u t i o n o f t h e k e t o i o d i d e (7_0) (3.00 g, 10.8 mmole) i n 50 ml o f d r y b e n z e n e u n d e r a n i t r o g e n a t m o s p h e r e was added 1 , 5 - d i a z a b i c y c l o ( 4 . 3 . 1 ) n o n - 5 - e n e (3.00 g, 24 mmoles) and t h e 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 80 h. A t t h e end o f t h i s p e r i o d , t h e r e a c t i o n m i x t u r e was p o u r e d i n t o 50 ml o f IN aqueous s u l p h u r i c a c i d and t h e r e s u l t i n g m i x t u r e was e x t r a c t e d t h r i c e w i t h 50 ml p o r t i o n s o f e t h e r . The c o m b i n e d o r g a n i c e x t r a c t s were washed w i t h w a t e r u n t i l n e u t r a l and t h e n d r i e d o v e r a n h y d r o u s magnesium s u l p h a t e . - 71 -The o r g a n i c s o l v e n t was r e m o v e d a t a t m o s p h e r i c p r e s s u r e a n d t h e r e s u l t i n g c l e a r o i l was d i s t i l l e d u n d e r w a t e r a s p i r a t o r p r e s s u r e t o a f f o r d 1 g ( 7 8 % b a s e d o n u n r e c o v e r e d s t a r t i n g m a t e r i a l ) o f t h e k e t o o l e f i n (5_5) a n d 596 mg o f t h e s t a r t i n g m a t e r i a l ( 1 0 ) . The k e t o o l e f i n (5_5) e x h i b i t e d , b . p. 82°C a t 13 mm; u.v. A ^ v 278 my (e = 3 0 . 3 ) ; i . r . ( f i l m ) v „^ max max 3.28, 5.70, 5.73, 14.1 y; p.m.r. x4.05 ( s i n g l e t , 2H, CH=CH), 8.47 ( s i n g l e t , 6H, 3 c a r b o n b r i d g e p r o t o n s ) , 8.88 ( s i n g l e t , 6H, t e r t i a r y m e t h y l s ) . A n a l . C a l c d . f o r c 1 0 H 1 4 O : C ' 7 9 - 9 6 ; H ' 9 - 3 9 -F o u n d : C , 7 9 . 5 6 ; H , 9 . 3 1 . P r e p a r a t i o n o f 1 , 5 - D i m e t h y l b i c y c l o [ 3 . 2 . 1 ] o c t a n - 8 - o n e (54) A s o l u t i o n o f t h e k e t o o l e f i n (5_5) (3.90 g , 0.26 mmoles) i n 100 m l o f e t h a n o l was h y d r o g e n a t e d (room t e m p e r a -t u r e , a t m o s p h e r i c p r e s s u r e ) o v e r 4 00 mg o f 10% p a l l a d i u m o n c h a r c o a l f o r a p e r i o d o f 80 h. R e m o v a l o f t h e c a t a l y s t a n d s o l v e n t y i e l d e d 3.5 g (88%) o f t h e b i c y c l i c k e t o n e (5_4_) , a s a c o l o u r l e s s o i l , b.p. 84°C a t 13 mm; u . v . X 290 my ' • c max (e = 2 1 . 1 ) ; i . r . ( f i l m ) 5.74, 5.77 y; p.m.r. x8.99 UlclX ( s i n g l e t , 6H, t e r t i a r y m e t h y l s ) . A n a l . C a l c d . f o r C-^H.^0: C, 7 8 . 9 0 ; H, 1 0 . 5 9 . F o u n d : C, 78.94 ; H, 1 0 . 4 9 . - 72 -P r e p a r a t i o n o f 6 - 1 s o p r o p o x y - 1 , 5 - d i m e t h y l b i c y c l o [ 3 . 2 . 1 ] o c t - 6 - e n - 8 - o n e (56) To a s t i r r e d s o l u t i o n o f sod ium b i s ( t r i m e t h y l s i l y l ) amide (22 .0 g , 0 .12 mole) i n 300 m l o f HMPA under n i t r o g e n was added 1 0 . 0 g (0 .06 mole) o f t h e b i c y c l i c d i k e t o n e (71) and t h e 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 a t room t e m p e r a t u r e f o r 15 m i n . The r e a c t i o n m i x t u r e was c o o l e d t o 0°C and 37 g (0 .30 mole) o f i s o p r o p y l b r o m i d e was added i n a c o n t i n u o u s s t r e a m . The i c e b a t h was removed and t h e r e a c t i o n m i x t u r e was s t i r r e d a t room t e m p e r a t u r e f o r 45 m i n . The r e a c t i o n m i x t u r e was added t o 500 m l o f i c e - b r i n e and t h e r e s u l t i n g m i x t u r e was e x t r a c t e d t h o r o u g h l y w i t h e t h e r . The combined e t h e r e x t r a c t s were washed w i t h w a t e r and d r i e d o v e r anhydrous magnesium s u l p h a t e . The o r g a n i c s o l v e n t was removed under r e d u c e d p r e s s u r e t o a f f o r d 8 .00 g o f a c l e a r o i l . G . £ . c . a n a l y s i s (column A) o f t h i s o i l i n d i c a t e d t h a t i t c o n s i s t e d o f a m i x t u r e o f t h e b i c y c l i c e n o l e t h e r (56) and t h e s t a r t i n g m a t e r i a l , t h e b i c y c l i c d i k e t o n e ( 7 1 ) . P u r i f i c a t i o n o f t h i s m a t e r i a l was e f f e c t e d by co lumn c h r o m a t o g r a p h y on A c t i v i t y I I I a l u m i n a (150 g ) . C o n t i n u o u s e l u t i o n w i t h ( 6 5 - 1 1 0 ° ) p e t . e t h e r a f f o r d e d 7 . 1 g (65% based on u n r e c o v e r e d s t a r t i n g m a t e r i a l ) o f t h e b i c y c l i c e n o l e t h e r (56) e x h i b i t e d , b . p . 5 5 - 5 6 ° C a t 0 .3 mm, u . v . X 238 my — max (e = 6 6 0 ) ; i . r . ( f i l m ) v 3 . 2 3 , 5 . 7 0 , 6 .12 y ; p . m . r . x 5 . 5 0 - 73 -( s i n g l e t , IH, CH = C-OR), 5.65 (heptet, IH, (CH 3) 2CH-0, J = 6 Hz), 8.67, 8.71 ( p a i r of d o u b l e t s , 6H, OCH-(CH 3) 2 J = 6 Hz), 8.92, 8.98 ( s i n g l e t s , 6H, t e r t i a r y m e t h y l s ) . A n a l . C a l c d . f o r c 1 3 H 2 o 0 2 : C ' 7 4 - 9 6 ; H ' 9 - 6 8 -Found: C, 74.99; H, 9.86. P a r t I I I n v e s t i g a t i o n s i n t o the Chemistry Bicyclo[3.2.1]Octan-8-ones - 75 -P a r t I I INTRODUCTION S i n c e t h e f o l l o w i n g p o r t i o n o f t h i s work d e a l s b r i e f l y w i t h one a s p e c t o f t h e c h e m i s t r y o f t h r e e s u b -s t i t u t e d b i c y c l o [3.2.1]octan-8-ones a s h o r t r e v i e w o f t h e known c h e m i s t r y o f t h e b i c y c l o ( 3 . 2 .1) o c t a n e r i n g system . i s i n o r d e r . T h i s r e v i e w i s by no means meant t o c o v e r a l l o f t h e m a t e r i a l a v a i l a b l e b u t r a t h e r t o g i v e one a g e n e r a l p i c t u r e o f p a s t r e s e a r c h i n t h i s a r e a . The c h e m i s t r y o f t h e b i c y c l o ( 3 . 2 . 1 ) o c t a n e r i n g s y s t e m t h a t has been r e p o r t e d t o d a t e u s u a l l y c o n c e r n s C-8 s u b s t i t u t e d d e r i v a t i v e s . The most commonly used s u b s t i t u e n t was t h e c a r b o n y l group. However, a number o f s t u d i e s have d e a l t w i t h t h e e p i m e r i c C-8 a l c o h o l s o r some o f t h e i r c o r r e -s p o n d i n g d e r i v a t i v e s . 3 Cope e t . a l . have r e p o r t e d t h e r e d u c t i o n o f t h e u n s u b s t i t u t e d b i c y c l o ( 3 .2.1)octan-8-one (100) . They found t h a t t h e ketone (100) when t r e a t e d under a v a r i e t y o f r e d u c t i v e c o n d i t i o n s gave p r e d o m i n a n t l y t h e endo a l c o h o l (101) . - 76 -1) P t 0 2 , H 2 , H ; e n d o , >99% 2) N a , wet e t h e r ; endo , 87% 3) NaBH_j, p y r i d i n e ; endo , 64% 4) N a , i s o p r o p a n o l ; e n d o , 95% 100 101 T h i s phenomenon o f a p p a r e n t h i g h s t e r e o s e l e c t i v i t y i n t h e r e d u c t i o n o f b i c y c l o (3. 2 . 1 ) o c t a n - 8 - o n e s has a l s o 9 been o b s e r v e d by L e b e l and S p u r l o c k . They found t h a t t h e r e d u c t i o n o f t h e o l e f i n i c k e t o n e (102) a l s o p r o c e d e d i n a manner w h i c h a f f o r d e d m a i n l y t h e endo p r o d u c t . The h i g h e r e x o / e n d o p r o d u c t r a t i o s o b t a i n e d f rom t h e r e d u c t i o n o f t h e 1) N a B H 4 , m e t h a n o l ; e n d o , 91% 2) N a B H 4 , p y r i d i n e ; e n d o , 75% ^ ^ \ ^ 3) N a , wet e t h e r ; endo , 70% 102 102a 4) N a , i s o p r o p a n o l ; endo , 70' k e t o n e (102) compared t o t h o s e o b t a i n e d f rom t h e r e d u c t i o n o f (100) were a t t r i b u t e d t o t h e absence i n t h e fo rmer c a s e o f any 1,3 d i a x i a l i n t e r a c t i o n s be tween t h e i n c o m i n g r e a g e n t and t h e h y d r o g e n atoms a t C-2 and C - 4 . T h i s w o u l d p r o v i d e f o r a r e l a t i v e l y l e s s h i n d e r e d a p p r o a c h f o r a r e d u c i n g r e a g e n t a c r o s s t h e s i x membered r i n g i n k e t o n e (102) . - 77 -The s o l v o l y s i s o f s u b s t i t u t e d and u n s u b s t i t u t e d b i c y c l o [ 3 . 2 . 1 ] o c t a n - 8 - y l t o s y l a t e s has o c c u p i e d t h e a t t e n t i o n 9 11 2 8 o f s e v e r a l r e s e a r c h g r o u p s ' ' 9 L e b e l and S p u r l o c k h a v e r e p o r t e d a l a r g e d i f f e r e n c e i n s o l v o l y t i c r e a c t i v i t y b e t w e e n t h e s y n and a n t i p - t o l u e n e -s u l p h o n a t e s (103) and ( 1 0 4 ) , r e s p e c t i v e l y . 103 104 105 They c o n c l u d e d t h a t t h e r a t e a c c e l e r a t i o n e x h i b i t e d by t h e a n t i i s o m e r (104) i s due t o n e i g h b o u r i n g g r o u p p a r t i c i p a t i o n by t h e o l e f i n i c d o u b l e b o n d . The s t r u c t u r e a n d s t e r e o -c h e m i s t r y o f e a c h o f t h e p r o d u c t s i s o l a t e d f r o m t h e s o l v o l y s i s o f (104) c o u l d be c o n v e n i e n t l y accommodated by p o s t u l a t i n g t h a t i o n i z a t i o n o f (104) d e r i v e d s u b s t a n t i a l a n c h i m e r i c a s s i s t a n c e by f o r m a t i o n o f t h e n o n c l a s s i c a l i o n ( 1 0 5 ) . S i m i l a r l y , Hess"''"'" has p r o p o s e d t h a t t h e r e s u l t s o f p r o d u c t s t u d i e s and t h e i n t e r p r e t a t i o n o f t h e r a t e d a t a - 78 -f o r the s o l v o l y s i s of endo-bicyclo (3.2.1)oct-6-en-8-yl t o s y l a t e (106) support a s i g n i f i c a n t amount of anchimeric assistance by the carbon-carbon double bond. 5 106 The s o l v o l y t i c studies on the b i c y c l o (3.2.1) octane r i n g system have not been s o l e l y confined to C-8 substituted tosylates. The s o l v o l y t i c behaviour of exo-and-endo-bicyclo (3.2.1)octane-6-tosylates has also been studied . The s o l v o l y t i c studies performed on the exo isomer (107) suggested the formation of the n o n - c l a s s i c a l ion (109) by i o n i z a t i o n of (107) with p a r t i c i p a t i o n of the 4,5 sigma bond. The b i c y c l o (3.2.1 )oct-2-en-3-ols (110) and (111) 7 29 have been reported by Goering et. a l . ' . Once again the corresponding tosylates of these alcohols were prepared i n order to study the carbonium ion ( s o l v o l y t i c reactions) i n (3.2.1) b i c y c l i c systems. 110 79 -111 - 80 -PART I I DISCUSSION I t s h o u l d be e v i d e n t f r o m t h e p r e c e d i n g i n t r o -d u c t i o n t h a t t h e b i c y c l o (3 . 2 . 1 ) o c t a n e s y s t e m s h ave r e c e i v e d a r e a s o n a b l e amount o f a t t e n t i o n i n t h e c h e m i c a l l i t e r a t u r e . The b u l k o f t h e work t h a t has b e e n r e p o r t e d t o d a t e h a s d e a l t w i t h t h e n a t u r e o f t h e c a r b o n i u m i o n s f o r m e d f r o m t h e s e s y s t e m s and w i t h t h e s t e r e o c h e m i c a l c o u r s e o f t h e r e d u c t i o n ( u s i n g m a i n l y m e t a l h y d r i d e s ) o f c a r b o n y l f u n c t i o n a l i t i e s p r e s e n t i n t h e s e s y s t e m s . I n o r d e r t o add t o t h e known c h e m i s t r y o f t h e b i c y c l o ( 3 . 2 . 1 ) o c t a n e s y s t e m , an i n v e s t i g a t i o n o f t h e s t e r e o -c h e m i c a l c o u r s e o f n u c l e o p h i l i c a d d i t i o n t o t h e c a r b o n y l o f t h e b i c y c l o (3 . 2 .1) o c t a n e - 8 - o n e s (5_4_) , (5_5) and (5_6) was u n d e r t a k e n . The b i c y c l i c k e t o n e (5_4) , when t r e a t e d w i t h l i t h i u m a l u m i n i u m h y d r i d e i n r e f l u x i n g e t h e r , a f f o r d e d t h e b i c y c l i c a l c o h o l ( 1 1 2 ) , i n 81% y i e l d (see C h a r t V ) . - 82 -This material exhibited absorptions at 2.74 y and 2.85 y i n the inf r a r e d which are c h a r a c t e r i s t i c of non-bonded and hydrogen bonded hydroxyl stretching v i b r a t i o n s . The absence of any absorptions i n the carbonyl region confirmed that complete reduction has occurred. The product was shown by g.fc.c. (colums A, C, and D) to consist of one and only one isomer. This conclusion was supported by the sharp melting point (48°-49°C) of the product. The p.m.r. spectrum of t h i s material (Fig. 14) also provided strong evidence that only one stereoisomer was present since only one resonance (T6.84, singlet) was recorded for a proton a to the hydroxyl group. Obviously i f both stereoisomers were present one would expect two d i f f e r e n t signals i n th i s region a r i s i n g from the difference i n the chemical s h i f t of a C-8 exo or endo proton. The assignment of the C-8 stereochemistry of t h i s alcohol (112) w i l l be dealt with l a t e r (see page 85). The o l e f i n i c ketone (55) was treated with l i t h i u m aluminium hydride using the same conditions that were used for the b i c y c l i c ketone (5_4) . This resulted i n the formation of the b i c y c l i c alcohol (113) i n 90% y i e l d . This material exhibited the expected spectroscopic properties. The i n f r a -red spectrum exhibited absorptions at 2.73 y and 2.83 y which are c h a r a c t e r i s t i c of an O-H and a =C-H stretching v i b r a t i o n . The p.m.r. spectra of t h i s alcohol (Fig. 15) exhibited a two proton s i n g l e t at T4.46 attributed to the ro O Xi o o o •H u >. •H M 0) U I u u o p. to Pi 3d fe m <u M 00 •rt fe - 85 -o l e f i n i c p r o t o n s , a one p r o t o n s i n g l e t a t x6.76 a t t r i b u t e d t o t h e p r o t o n a t o t h e h y d r o x y l g r o u p , and a s i x p r o t o n s i n g l e t a t x9.00 w h i c h was a t t r i b u t e d t o t h e two b r i d g e h e a d m e t h y l g r o u p s . The a s s i g n m e n t o f t h e C-8 s t e r e o c h e m i s t r y o f t h i s a l c o h o l (113) i s d i s c u s s e d b e l o w . F i n a l l y , the k e t o n e (56) was r e d u c e d u n d e r c o n d i -t i o n s i d e n t i c a l w i t h t h o s e u s e d f o r t h e two p r e v i o u s r e d u c t i o n s . Thus, t h e k e t o n e (56_) a f f o r d e d t h e a l c o h o l (114) i n 85% y i e l d . T h i s m a t e r i a l e x h i b i t e d s p e c t r o s c o p i c d a t a i n a c c o r d a n c e w i t h i t s a s s i g n e d s t r u c t u r e . I n f r a r e d a b s o r p t i o n s a t 2.74 y, 2.85 y, and 6.20 y a t t e s t e d t o t h e p r e s e n c e o f an O-H g r o u p , o f a =C-H m o i e t y and o f an e n o l e t h e r (C=C-0-) l i n k a g e . The p.m.r. s p e c t r a o f t h i s m a t e r i a l was a l s o i n a c c o r d w i t h i t s a s s i g n e d s t r u c t u r e . The a s s i g n m e n t o f t h e C-8 s t e r e o c h e m i s t r y o f t h i s a l c o h o l i s d i s c u s s e d i n t h e f o l l o w i n g p a g e s . The f i r s t s t e p i n a s s i g n i n g t h e s t e r e o c h e m i s t r y o f t h e C-8 s u b s t i t u e n t o f t h e a l c o h o l s ( 1 1 2 ) , ( 1 1 3 ) , and (114) i n v o l v e d t h e c o n v e r s i o n o f t h e a l c o h o l s (113) and (114) i n t o t h e a l c o h o l ( 1 1 2 ) . Once t h i s c o r r e l a t i o n had b e e n made, i t w o u l d be n e c e s s a r y t o show u n a m b i g u o u s l y t h e s t e r e o c h e m i s t r y o f o n l y one o f t h e t h r e e a l c o h o l s . The s y n t h e t i c scheme e m p l o y e d f o r t h e c o n v e r s i o n o f t h e a l c o h o l s (113) and (114) i n t o t h e a l c o h o l (112) c a n be f o u n d i n C h a r t V I . - 87 -H y d r o g e n a t i o n o f t h e o l e f i n i c a l c o h o l (113 ), o v e r p a l l a d i u m on c h a r c o a l (room t e m p e r a t u r e , a t m o s p h e r i c p r e s s u r e ) a f f o r d e d an a l c o h o l i c p r o d u c t i n 91% y i e l d . T h i s m a t e r i a l e x h i b i t e d s p e c t r o s c o p i c d a t a i d e n t i c a l w i t h t h o s e o b t a i n e d f r o m t h e b i c y c l i c a l c o h o l (112) (see e x p e r i m e n t a l s e c t i o n , pp. 106 and 111). The a l c o h o l (114), i n e t h e r , was t r e a t e d w i t h 70% aqueous p e r c h l o r i c a c i d and a f f o r d e d a f t e r s u i t a b l e work-up, a k e t o l i n 81% y i e l d . T h i s m a t e r i a l e x h i b i t e d s p e c t r o s c o p i c and p h y s i c a l p r o p e r t i e s i d e n t i c a l w i t h t h o s e r e c o r d e d f o r t h e k e t o l (8_2) ( s e e page 28 ) . T r e a t m e n t o f t h i s k e t o l i n a c e t i c a c i d w i t h 1 , 2 - e t h a n e d i t h i o l and b o r o n t r i f l u o r i d e e t h e r a t e gave a m i x t u r e o f t h e k e t o l (82) and i t s c o r r e s p o n d i n g t h i o k e t a l d e r i v a t i v e (115). T h i s m i x t u r e was c h r o m a t o g r a p h e d on 35 g o f s i l i c a g e l . E l u t i o n w i t h l i g r o i n a f f o r d e d t h e d i -t h i o k e t a l (115) i n 85% y i e l d ( b a s e d on u n r e c o v e r e d k e t o l (8_2_) ) . The i n f r a r e d s p e c t r u m o f t h i s m a t e r i a l showed no a b s o r p t i o n s i n c a r b o n y l r e g i o n . The p.m.r. s p e c t r a o f t h e d i t h i o k e t a l e x h i b i t e d a p a i r o f d o u b l e t s a t x7.46 and T7.75 ( J , n = 15 Hz) w h i c h were a s s i g n e d t o t h e m e t h y l e n e p r o t o n s o f C-6. H y d r o g e n a l y s i s o f t h e t h i o k e t a l (115) w i t h R a n e y - n i c k e l i n r e f l u x i n g e t h a n o l a f f o r d e d t h e b i c y c l i c a l c o h o l (112) i n 75% y i e l d . T h i s a l c o h o l was a l s o shown by i t s s p e c t r o s c o p i c and p h y s i c a l p r o p e r t i e s t o be i d e n t i c a l w i t h t h e a l c o h o l (112). - 88 -The above c o r r e l a t i o n s show t h a t t h e a l c o h o l s ( 1 1 2 ) , ( 1 1 3 ) , and (114) a l l have t h e same s t e r e o c h e m i s t r y a t C-8. T h e r e f o r e , d e t e r m i n a t i o n o f t h e s t e r e o c h e m i s t r y o f any one o f t h e t h r e e a l c o h o l s w o u l d a u t o m a t i c a l l y a l l o w f o r t h e a s s i g n m e n t o f t h e s t e r e o c h e m i s t r y o f t h e o t h e r two components as w e l l . I n l i g h t o f r e p o r t s a l r e a d y i n t h e l i t e r a t u r e , t h e a l c o h o l s ( 1 1 2 ) , ( 1 1 3 ) , and (114) were t e n t a t i v e l y a s s i g n e d t h e endo s t e r e o c h e m i s t r y . I n o r d e r t o s u p p o r t t h e a s s i g n m e n t , an a t t e m p t was made t o o b t a i n t h e e p i m e r i c exo a l c o h o l f r o m t h e k e t o o l e f i n . The k e t o o l e f i n (5_4) was c h o s e n s i n c e t h e s i m p l i c i t y o f t h e p.m.r. s p e c t r a o f i t s a l c o h o l s w o u l d a i d i n t h e a s s i g n m e n t o f t h e h y d r o x y l g r o u p c o n f i g u r a t i o n s . R e d u c t i o n o f t h e k e t o o l e f i n (5_4) u n d e r a v a r i e t y o f r e a c t i o n c o n d i t i o n s , c a l c i u m i n ammonia , s o d i u m b o r o -9 h y d r i d e i n p y r i d i n e and a l u m i n i u m i s o p r o p o x i d e i n i s o -propanol''"''" a f f o r d e d o n l y t h e endo a l c o h o l ( 1 1 3 ) . T h u s , e a c h o f t h e s e r e d u c t i o n s was c o m p l e t e l y s t e r e o s e l e c t i v e i n t h e same s e n s e as t h e l i t h i u m a l u m i n i u m h y d r i d e r e d u c t i o n . The endo m e s y l a t e (116) was p r e p a r e d f r o m t h e endo a l c o h o l (113) u s i n g m e s i t y l c h l o r i d e and p y r i d i n e . A t t e m p t e d d i s p l a c e m e n t o f t h e m e s i t y l g r o u p o f t h i s m a t e r i a l by s e v e r a l o x y g e n n u c l e o p h i l e s s u c h a s a c e t a t e and b e n z o a t e i n o r d e r t o i n v e r t t h e s t e r e o c h e m i s t r y o f t h e C-8 p o s i t i o n p r o v e d u n s u c c e s s f u l . - 89 -S i n c e t h e exo a l c o h o l (117.) was u n a v a i l a b l e f o r c o m p a r a t i v e s t u d i e s , t h e endo s t e r e o c h e m i s t r y was a s s i g n e d t o t h e a l c o h o l (113) f o r t h e f o l l o w i n g r e a s o n s . i c a l s h i f t s o f t h e o l e f i n i c p r o t o n s o f t h e a n t i a n d s y n n o r b o r n e n o l s (118) and (119) a r e T4.03 and T3.82, r e s p e c t i v e l y . When t h e a c e t a t e s (120) and (121) o f t h e c o r r e s p o n d i n g n o r b o r n e n o l s (118) and (119) r e s p e c t i v e l y were e x a m i n e d , t h e a u t h o r s o b s e r v e d t h a t t h e c h e m i c a l s h i f t o f t h e o l e f i n i c p r o t o n s o f t h e a n t i a c e t a t e (120) (T4.05) was r e l a t i v e l y u n c h a n g e d f r o m t h o s e o f t h e a n t i a l c o h o l ( 1 1 8 ) . However, i n t h e c a s e o f t h e s y n a c e t a t e ( 1 2 1 ) , t h e c h e m i c a l s h i f t o f t h e o l e f i n i c p r o t o n s (x4.00) was s i g n i f i c a n t l y d i f f e r e n t f r o m t h o s e o f t h e s y n a l c o h o l (119) ( T 3 . 8 2 ) . T h u s , C l a r k a n d W a r k e n t i n were a b l e t o d i f f e r e n t i a t e b e t w e e n t h e s y n and a n t i a l c o h o l s (119) and (118) by u t i l i z i n g t h e c h e m i c a l s h i f t s o f t h e o l e f i n i c p r o t o n s o f t h e n o r b o r n e n e s ( 1 1 8 ) , ( 1 1 9 ) , ( 1 2 0 ) , and ( 1 2 1 ) . C l a r k and W a r k e n t i n 30 have r e p o r t e d t h a t t h e chem-118 119 120 121 - 90 -T h i s t y p e o f phenomena has a l s o been o b s e r v e d i n the bicyclo(3.2.1) oct-6-enes. Hess"1""1" has o b s e r v e d t h a t t h e r e i s a l m o s t no d i f f e r e n c e between the c h e m i c a l s h i f t o f t h e o l e f i n i c p r o t o n s o f e n d o - b i c y c l o ( 3 . 2 . 1 ) o c t - 6 - e n - 8 - o l (122) ( x 4 . l l ) and t h o s e o f e n d o - 8 - a c e t o x y - b i c y c l o (3.2.1)oct-6-ene (123) (T4.13). 125 126 I f t h e proposed s t e r e o c h e m i s t r y o f t h e endo o l e f i n i c a l c o h o l (113) i s c o r r e c t , t h e n t h e r e s h o u l d be v e r y l i t t l e d i f f e r e n c e i n t h e c h e m i c a l s h i f t s o f the o l e f i n i c p r o t o n s o f the endo o l e f i n i c a l c o h o l (113) and i t s c o r r e s -p onding a c e t a t e (124) o r m e s y l a t e (116). The a c e t a t e and m e s y l a t e o f t h e endo o l e f i n i c a l c o h o l (113) were p r e p a r e d i n t h e u s u a l manner ( a c e t i c a n h y d r i d e i n p y r i d i n e and m e s i t y l c h l o r i d e i n p y r i d i n e , r e s p e c t i v e l y ) . 113 124 116 - 91 -The c h e m i c a l s h i f t s f o r t h e o l e f i n i c p r o t o n o f t h e t h r e e compounds ( 1 1 3 ) , (124) , and (116) a r e x 4 . 4 6 , 4 . 5 0 and 4 . 4 3 , r e s p e c t i v e l y . O b v i o u s l y , t h e r e i s l i t t l e change i n t h e s e c h e m i c a l s h i f t s . T h i s i s i n a c c o r d w i t h t h e r e s u l t s o b t a i n e d by C l a r k and W a r k e n t i n f o r t h e a n t i (endo)-norbornenes ( 1 1 8 ) and (1_2_0) . The most c o n v i n c i n g p i e c e o f e v i d e n c e f o r t h e p r o p o s e d endo s t e r e o c h e m i s t r y f o r t h e b i c y c l i c a l c o h o l s ( 1 1 2 ) , ( 1 1 3 ) , and ( 1 1 4 ) comes from t h e v a r i a t i o n i n t h e c h e m i c a l s h i f t o f t h e d i f f e r e n t p r o t o n s o f t h e b i c y c l i c a l c o h o l ( 1 1 3 ) (5) w i t h i n c r e a s i n g amounts o f E u ( f o d ) 3 , a l a n t h a n i d e s h i f t r e a g e n t . L a n t h a n i d e s h i f t r e a g e n t s , n o t a b l y E u ( f o d ) 3 , have been used t o d e t e r m i n e m o l e c u l a r c o n f i g u r a t i o n s f o r a number o f compounds. A q u a n t i t a t i v e e x p l a n a t i o n o f t h i s phenomenon as w e l l as s e v e r a l examples o f t h e a ssignment o f m o l e c u l a r geometry u s i n g l a n t h a n i d e s h i f t r e a g e n t s can be found i n an e x c e l l e n t r e v i e w t e x t o f s h i f t r e a g e n t s and t h e i r a p p l i c a t i o n 3 1 t o p.m.r. s p e c t r o s c o p y The magnitude o f t h e o b s e r v e d s h i f t o f a p a r t i c u l a r p r o t o n can be e x p l a i n e d , f o r our p u r p o s e s , as p r i m a r i l y dependent on t h e d i s t a n c e t h e p r o t o n i s from t h e s i t e o f the E u ( f o d ) 3 f o r t r i s ( 6 , 6 , 7 , 7 , 8 , 8 , 8 - h e p t a f l u o r o - 2 , 2 - d i m e t h y l -3 , 5 - o c t a m e d i o n a t o ) e u r o p i u m ( I I ) . - 92 -c omplex f o r m e d between t h e s h i f t r e a g e n t and t h e s u b s t r a t e ( 1 1 3 ) . S i n c e t h e c o r r e c t i n t e r p r e t a t i o n o f o b s e r v e d c h e m i c a l s h i f t s i n l a n t h a n i d e s h i f t e x p e r i m e n t s i s hampered by s o l v e n t e f f e c t s , t e m p e r a t u r e e f f e c t s , and a number o f e x p e r i m e n t a l d i f f i c u l t i e s , t h e r e s u l t s p r e s e n t e d h e r e a r e o n l y o f a q u a l i t a t i v e n a t u r e . b i c y c l i c a l c o h o l s (113) and (117) i t seemed e v i d e n t t h a t i n t h e c a s e o f t h e endo a l c o h o l (113) t h e d i s t a n c e b e t w e e n t h e l a n t h a n i d e atom ( c o m p l e x e d w i t h t h e h y d r o x y l g r o u p ) and t h e 3 o r i e n t e d m e t h y l e n e p r o t o n s ( a t C-2 andC-4) o f t h e t h r e e c a r b o n b r i d g e w o u l d be l e s s t h a n t h e d i s t a n c e between t h e l a n t h a n i d e atom and t h e o l e f i n i c p r o t o n s . On t h e o t h e r hand, i n t h e c a s e o f t h e exo a l c o h o l ( 1 1 7 ) , t h e o p p o s i t e w o u l d be t r u e . T h e r e f o r e , i f t h e b i c y c l i c a l c o h o l (113) had t h e p r o p o s e d endo s t e r e o c h e m i s t r y , t h e n a d d i t i o n o f an i n c r e a s i n g amount o f E u ( f o d ) 3 t o a s o l u t i o n o f t h e b i c y c l i c a l c o h o l (113) w o u l d be e x p e c t e d t o r e s u l t i n a g r e a t e r c hange i n t h e c h e m i c a l s h i f t o f t h e 3 o r i e n t e d m e t h y l e n e p r o t o n s ( a t C-2 and C-4) o f t h e t h r e e c a r b o n b r i d g e t h a n i n t h e c h e m i c a l s h i f t o f t h e o l e f i n i c p r o t o n s ( a t C-6 a n d C - 7 ) . From an e x a m i n a t i o n o f m o l e c u l a r m o d e l s o f t h e 113 HO 117 - 93 -The p.m.r. s p e c t r a o b t a i n e d a f t e r a d d i n g an i n c r e a s i n g amount o f E u ( f o d ) 3 t o a s o l u t i o n o f t h e endo b i c y c l i c a l c o h o l ( 1 1 3) a r e r e p r o d u c e d i n F i g u r e 1 6 . F i g u r e 1 7 , a p l o t o f t h e c h e m i c a l s h i f t s o f v a r i o u s p r o t o n s w i t h i n c r e a s i n g amount o f E u ( f o d ) 3 , c l e a r l y d e m o n s t r a t e s t h a t t h e c h e m i c a l s h i f t s c h ange i n a l i n e a r f a s h i o n w i t h t h e i n c r e a s e i n c o n c e n t r a t i o n o f t h e s h i f t r e a g e n t . T h i s i s i n 32 a c c o r d w i t h o t h e r f i n d i n g s . I t i s a l s o e v i d e n t f r o m t h e above p l o t t h a t t h e m a g n i t u d e o f t h e c h a n g e o f c h e m i c a l s h i f t s f o r v a r i o u s p r o t o n s was q u i t e d i f f e r e n t . T h u s , t h e s h i f t o f t h e o l e f i n i c p r o t o n s was q u i t e s m a l l , t h e s h i f t o f t h e b r i d g e h e a d t e r t i a r y m e t h y l g r o u p s was i n t e r m e d i a t e , and t h e s h i f t o f two o f t h e p r o t o n s on t h e m e t h y l e n e g r o u p s o f t h e t h r e e c a r b o n b r i d g e was r e l a t i v e l y l a r g e . P r e s u m a b l y t h e two p r o t o n s i n q u e s t i o n were t h e a x i a l o r i e n t e d p r o t o n s a t C -2 and C - 4 . T h u s , one may c o n c l u d e t h a t t h e d i s t a n c e b etween t h e o l e f i n i c p r o t o n s and t h e l a n t h a n i d e atom i s g r e a t e r t h a n b e t w e e n t h e l a n t h a n i d e atom and t h e m e t h y l e n e b r i d g e p r o t o n s i n q u e s t i o n . T h i s c o n c l u s i o n c o n f i r m s t h e p r o p o s e d endo s t e r e o c h e m i s t r y f o r t h e b i c y c l i c a l c o h o l ( 1 1 3 ) , and, i n t u r n , a l s o e s t a b l i s h e s t h e s t e r e o c h e m i s t r y o f t h e b i c y c l i c a l c o h o l s ( 1 1 2) and ( 1 1 4 ) . I n o r d e r t o more f u l l y document t h e h i g h s t e r e o -s e l e c t i v i t y shown by t h e r e a c t i o n o f n u c l e o p h i l e s w i t h ' 1 ^^^^^^^^ vVv/v J l . L! E 1 I c J I. Jl VO 16 P.M.R. Spectra of the B i c y c l i c A l c o h o l ( 113 ) containing various amounts of Eu( fod) 3 : A, 0.0 mg; B , 5.0 mg; C, 15 mg; D, 25 mg; E, 35 mg. 5 io 15 xy jo 35 Figure 17 V a r i a t i o n i n the chemical s h i f t for the d i f fe ren t protons H , H , and H of a b c 'the B i c y c l i c Alcohol ( 113 ) wi th increasing amount of Eu(fod).j. S t ra ight l i n e s shown are leas t squares der ived. - 96 -b i c y c l o ( 3 . 2 . 1 ) o c t a n - 8 - o n e s t h e r e a c t i o n b etween m e t h y l l i t h i u m and t h e t h r e e b i c y c l i c k e t o n e s ( 5 4 ) , ( 5 5 ) , and (56) was i n v e s t i g a t e d ( C h a r t V I I ) . The b i c y c l i c k e t o n e (5_4) when t r e a t e d w i t h m e t h y l -l i t h i u m a f f o r d e d a f t e r a c i d i c work-up, t h e a l c o h o l (125) , i n 85% y i e l d . T h i s m a t e r i a l e x h i b i t e d h y d r o x y l a b s o r p t i o n s a t 2.75 y and 2.85 y and no c a r b o n y l a b s o r p t i o n s i n i t s i n f r a r e d s p e c t r u m . . The p.m.r. s p e c t r u m o f t h i s a l c o h o l e x h i b i t e d a t h r e e p r o t o n s i n g l e t a t x8.94 a t t r i b u t e d t o t h e m e t h y l g r o u p a t o t h e h y d r o x y l g r o u p and a s i x p r o t o n s i n g l e t a t x9.14 w h i c h was a t t r i b u t e d t o t h e b r i d g e h e a d t e r t i a r y m e t h y l s . When t h e o l e f i n i c a l c o h o l (5_5_) was s u b j e c t e d t o t h e same r e a c t i o n c o n d i t i o n s as a b o v e , i t a f f o r d e d t h e o l e f i n i c a l c o h o l (126) i n 89% y i e l d . The s p e c t r o s c o p i c p r o p e r t i e s o f t h i s a l c o h o l were s i m i l a r t o t h o s e r e c o r d e d f r o t h e o l e f i n i c a l c o h o l ( 1 1 3 ) . The p.m.r. s p e c t r u m o f t h e o l e f i n i c a l c o h o l (126) ( F i g . 18) m i r r o r s t h a t o f t h e o l e f i n i c a l c o h o l (113) (see page 82 ) e x c e p t f o r t h e t h r e e p r o t o n s i n g l e t a t x8.96 w h i c h i s due t o t h e C-8 m e t h y l g r o u p p r e s e n t i n ( 1 2 6 ) . The a l c o h o l (127) was o b t a i n e d , a s e x p e c t e d by t r e a t m e n t o f t h e k e t o n e (5_6) w i t h m e t h y l l i t h i u m . The p.m.r. s p e c t r u m o f t h i s m a t e r i a l a l t h o u g h more c o m p l i c a t e d t h a n t h a t o f t h e a l c o h o l ( 1 1 4 ) , was i n a c c o r d w i t h i t s p r o p o s e d s t r u c t u r e . - 97 CHoLi CH 0LI CHoLi CHART VII - 99 -T h u s , as m i g h t h ave been e x p e c t e d f r o m t h e e a r l i e r r e s u l t s r e p o r t e d i n t h i s s e c t i o n o f t h e t h e s i s t h e f o r m a t i o n o f t h e a l c o h o l s ( 1 2 5 ) , ( 1 2 6 ) , and (127) was a l s o s t e r e o -s e l e c t i v e . No t r a c e , i n e i t h e r t h e g . I . c . t r a c e s (columns A, C, a n d D) o r i n t h e p.m.r. s p e c t r a o f t h e s e a l c o h o l s , o f any o t h e r i s o m e r was f o u n d . The s t e r e o c h e m i s t r y o f t h e b i c y c l i c a l c o h o l s (125) , (126) , and (127) was a l s o a s s i g n e d as b e i n g endo. The r e a s o n s f o r t h i s endo a s s i g n m e n t a r e s i m i l a r t o t h o s e p r o p o s e d f o r t h e b i c y c l i c a l c o h o l s ( 1 1 2 ) , ( 1 1 3 ) , and ( 1 1 4 ) . S i n c e t h e b i c y c l i c a l c o h o l s (125) , (126) and (127) were f o r m e d c o m p l e t e l y s t e r e o s e l e c t i v e l y and i n l i g h t o f t h e r e s u l t s o b t a i n e d i n a n e a r l i e r p a r t o f t h i s work (se e page 87) i t was f e l t t h a t t h e s e a l c o h o l s w o u l d a l l h a v e t h e same r e l a t i v e s t e r e o c h e m i s t r y . T h u s , i t w o u l d o n l y be n e c e s s a r y t o show u n a m b i g u o u s l y t h e s t e r e o c h e m i s t r y o f one o f t h e t h r e e a l c o h o l s (125) , (126) , and (127) . Once a g a i n , a l a n t h a n i d e s h i f t r e a g e n t e x p e r i m e n t seemed t o o f f e r t h e b e s t c h a n c e o f d e t e r m i n i n g t h e s t e r e o -c h e m i s t r y o f t h e o l e f i n i c a l c o h o l (126) . As b e f o r e , an i n c r e a s i n g amount o f E u ( f o d ) 3 was a d d e d t o a s o l u t i o n o f t h e a l c o h o l and t h e p.m.r. s p e c t r u m o f t h e r e s u l t i n g s o l u t i o n was o b t a i n e d . F i g u r e 19 c l e a r l y d e m o n s t r a t e s t h e n a t u r e o f t h e v a r i o u s s h i f t s o b t a i n e d , w h i l e F i g u r e 20 d e m o n s t r a t e s t h e l i n e a r i t y o f t h e r e l a t i o n s h i p b e t w e e n t h e c h e m i c a l s h i f t Figure 19 P.M.R. Spectra of the B i c y c l i c A l cohol ( 12 6) containing various amounts of E u ( f o d ) 3 : A, 0.0 mg; B, 15 mg; C, 25 mg; D, 40 mg. - 102 -and t h e c o n c e n t r a t i o n o f s h i f t r e a g e n t . The m a g n i t u d e o f t he change o f c h e m i c a l s h i f t s f o r v a r i o u s p r o t o n s o f t he o l e f i n i c a l c o h o l (126) was q u i t e d i f f e r e n t . However , as was t h e c a s e w i t h t h e o l e f i n i c a l c o h o l (113) , t h e s h i f t o f t h e o l e f i n i c p r o t o n s was q u i t e s m a l l compared t o t h e s h i f t o f t h e a x i a l l y o r i e n t e d m e t h y l e n e p r o t o n s a t C-2 and C-4 o f t he t h r e e c a r b o n b r i d g e . T h u s , one may c o n c l u d e , i n a f a s h i o n s i m i l a r t o t h a t a r g u e d f o r t he o l e f i n i c a l c o h o l ( 1 1 3 ) , t h a t t h e l a n t h a n i d e atom i s c l o s e r t o t h e m e t h y l e n e p r o t o n s o f t h e t h r e e c a r b o n b r i d g e t h a n i t i s t o t h e o l e f i n i c p r o t o n s . I f t h i s i s t h e c a s e , t h e n t h e o l e f i n i c a l c o h o l (126) , a n d , i n t u r n , t h e a l c o h o l s (125) and (127) must a l l have an endo o r i e n t e d h y d r o x y l g r o u p . R e d u c t i o n o f t h e k e t o n e s (5_4) , (55) and (5_6_) w i t h l i t h i u m a l u m i n i u m h y d r i d e and t h e a d d i t i o n o f m e t h y l l i t h i u m a c r o s s t h e c a r b o n y l o f t h e above compounds has been shown t o p r o d u c e o n l y one o f two p o s s i b l e d i a s t e r e o m e t r i c a l c o h o l s n a m e l y , t h e endo i s o m e r . These r e s u l t s m e r i t a few f u r t h e r r e m a r k s . P o s s i b l e e x p l a n a t i o n s f o r t h e s t e r e o c h e m i c a l r e s u l t s o f t h e r e d u c t i o n o f k e t o n e s by m e t a l h y d r i d e s have 33 . . been p r o p o s e d by numerous i n v e s t i g a t o r s . R e c e n t m v e s t i -34 35 36 37 g a t i o n s ' ' ' have s u p p o r t e d t h e v i e w t h a t a l l m e t a l h y d r i d e - k e t o n e r e d u c t i o n s , w h e t h e r the k e t o n e i n q u e s t i o n i s h i n d e r e d o r n o t , have t r a n s i t i o n s t a t e s t h a t r e s e m b l e t h e - 103 -r e a c t a n t s i n geometry, and t h e r e d u c t i o n s t e r e o c h e m i s t r y i s d e t e r m i n e d by a c o m b i n a t i o n o f s t e r i c i n t e r f e r e n c e s , t o r s i o n a l s t r a i n and e l e c t r o s t a t i c e f f e c t s i n t h e t r a n s i t i o n s t a t e . As p r e v i o u s l y m e n t i o n e d , t h e r e d u c t i o n o f t h e b i c y c l i c k e t o n e (100) w i t h sodium b o r o h y d r i d e i n p y r i d i n e gave b o t h p o s s i b l e i s o m e r s , i n a r a t i o o f 64:36 (endo:exo). S i n c e r e d u c t i o n s w i t h t h i s r e a g e n t a r e g e n e r a l l y known t o 3 8 g i v e t h e p r o d u c t o f " s t e r i c a p p r o a c h c o n t r o l " one may c o n c l u d e t h a t t h e l e s s h i n d e r e d s i d e o f t h e c a r b o n y l group l i e s towards t h e two c a r b o n b r i d g e i n b i c y c l o ( 3 . 2 . 1 ) o c t a n -8-one syste m s . T h i s c o n c l u s i o n i s borne o u t by m o l e c u l a r models o f t h e b i c y c l o ( 3 . 2 . 1 )octan-8-one system (128) w h i c h s u g g e s t e d l e s s s t e r i c i n t e r a c t i o n between th e C-6 and C-7 methylene p r o t o n s and an a p p r o a c h i n g n u c l e o p h i l e t h a n between t h e C-2 and C-4 m e t h y l e n e p r o t o n s and t h e a p p r o a c h i n g n u c l e o p h i l e . (more hindered}- ( l e s s h i n d e r e d ) 128 By a n a l o g y , r e d u c t i o n o f any o f t h e b i c y c l i c k e t o n e s (54_) , (5_5) and (56) would be e x p e c t e d t o l e a d t o t h e p r e f e r e n t i a l f o r m a t i o n o f t h e c o r r e s p o n d i n g endo a l c o h o l s ( 1 12), (113) and (114_)... However, i n t h e l a t t e r - 104 -r e d u c t i o n s , t h e i s o m e r r a t i o (>99:1, endo:exo) was q u i t e u n e x p e c t e d . A p o s s i b l e e x p l a n a t i o n f o r t h e f o r m a t i o n o f o n l y t h e endo i s o m e r i n t h e s e r e d u c t i o n s may a r i s e from an i n t e r a c t i o n i n the t r a n s i t i o n s t a t e s o f t h e s e r e d u c t i o n s between t h e b r i d g e h e a d m e t h y l groups ( p r e s e n t i n (54_) , (55) and (5_6) b u t n o t i n (100) ) and t h e oxygen o f t h e c a r b o n y l group. Scheme I I Schemes I and I I show t h e f o r m a t i o n o f t h e exo and endo i s o m e r s r e s p e c t i v e l y . I n o r d e r t o form t h e exo i s o m e r (Scheme I) one must overcome t h e t o r s i o n a l s t r a i n imposed on t h e system by t h e passage o f t h e oxygen atom by t h e two b r i d g e h e a d m e t h y l g r o u p s . / These ( p o t e n t i a l ) i n t e r -a c t i o n s a r e however a b s e n t i n t h e f o r m a t i o n o f t h e endo a l c o h o l (Scheme T I ) . Thus, the t r a n s i t i o n s t a t e l e a d i n g t o Scheme I - 105 -t h e exo a l c o h o l w o u l d be e x p e c t e d t o be h i g h e r i n e n e r g y t h a n t h e t r a n s i t i o n s t a t e l e a d i n g t o t h e endo a l c o h o l . T h e r e f o r e , one w o u l d e x p e c t a h i g h e r p r o p o r t i o n o f t h e endo a l c o h o l t o be f o r m e d . S i n c e i n t h e a b s e n c e o f t h e m e t h y l g r o u p s ( r e d u c t i o n o f (100)) t h e i s o m e r r a t i o a l r e a d y f a v o u r s t h e endo p r o d u c t , t h e s e a d d i t i o n a l t o r s i o n a l e f f e c t s m i g h t be r e s p o n s i b l e f o r t h e h i g h e r ( 99:1) s t e r e o s e l e c t i v i t y i n t h e r e d u c t i o n o f t h e b i c y c l i c k e t o n e s (5_4_) , (5_5) and ( 5 6 ) . I t s h o u l d be n o t e d t h a t s i n c e N c a n be any n u c l e o p h i l e , t h e a b o v e r e a s o n i n g c a n be a p p l i e d t o t h e f o r m a t i o n o f o n l y t h e endo a l c o h o l s (125) , (12_6) and (127) when t h e b i c y c l i c k e t o n e s ( 5 4 ) , (55) and (56) were t r e a t e d w i t h m e t h y l l i t h i u m . - 106 -PART I I EXPERIMENTAL F o r g e n e r a l e x p e r i m e n t a l i n f o r m a t i o n s e e p. 51. R e d u c t i o n o f t h e B i c y c l i c K e t o n e (54) To a s t i r r e d s o l u t i o n o f l i t h i u m a l u m i n i u m h y d r i d e (30.0 mg, 0.80 mmole) i n 0.8 m l o f a n h y d r o u s e t h e r u n d e r a n i t r o g e n a t m o s p h e r e was add e d 100 mg (0.64 mmole) o f t h e b i c y -c l i c k e t o n e (54_) i n 8 m l o f e t h e r . The r e a c t i o n m i x t u r e was r e f l u x e d f o r 3 h and t h e n s o l i d s o d i u m s u l p h a t e d e c a h y d r a t e was added. The r e a c t i o n m i x t u r e was f i l t e r e d t h r o u g h c e l i t e and t h e r e s u l t i n g f i l t r a t e was c o n c e n t r a t e d u n d e r r e d u c e d p r e s s u r e . The r e s i d u a l m a t e r i a l was d i s t i l l e d u n d e r r e d u c e d p r e s s u r e t o a f f o r d 83 mg (81%) o f t h e b i c y c l i c a l c o h o l ( 1 1 2 ) , b.p. 1 2 0 ° C a t 15 mm; m.p. 4 8 - 4 9 ° C ; i . r . . ( C H C l , ) v _ 2.74, 2.85 y; p.m.r. T6.84 ( s i n g l e t , IH, -CH-OH), 9.04 ( s i n g l e t , 6H, t e r t i a r y m e t h y l s ) . A n a l . C a l c d . f o r C ^ H ^ O : C, 77.87; H, 11.76. Found: C, 77.72; H, 11.67. R e d u c t i o n o f t h e B i c y c l i c E n o l E t h e r (56) The b i c y c l i c e n o l e t h e r (56) was r e d u c e d w i t h l i t h i u m a l u m i n i u m h y d r i d e f o l l o w i n g t h e p r o c e d u r e d e s c r i b e d i n t h e p r e v i o u s e x p e r i m e n t . The b i c y c l i c e n o l e t h e r (5_6) (102 mg, 0.49 mmole) was r e d u c e d w i t h 49 mg (1.39 mmole) o f l i t h i u m a l u m i n i u m h y d r i d e t o a f f o r d 86 mg (85%) o f t h e b i c y c l i c a l c o h o l (114) - 107 -m.p. 51 - 5 2 ° C ; i . r . (CHCl,,) v 2.74, 2.85, 6.20 y; p.m.r. x5.78 ( s i n g l e t , H, CH=C), 5.80 ( h e p t e t , IH, ( C H 3 ) 2 C - H , J = 6 H z ) , 8.57, 8.60 ( p a i r o f d o u b l e t s , 6H, C - ( C H 3 ) 2 , J = 6 Hz) 9.81, 9.94 ( s i n g l e t s , 6H, t e r t i a r y m e t h y l s ) . A n a l . C a l c d . f o r C 1 3 H 2 2 ° 2 : C ' 7 4 - 2 4 ; H ' i O . 5 4 . Found: C, 74.29, H, 10.74. R e d u c t i o n o f t h e B i c y c l i c O l e f i n i c K e t o n e (55) (a) W i t h L i t h i u m A l u m i n i u m H y d r i d e The b i c y c l i c o l e f i n i c k e t o n e (55) was r e d u c e d w i t h l i t h i u m a l u m i n i u m h y d r i d e f o l l o w i n g t h e p r o c e d u r e d e s c r i b e d i n t h e two p r e v i o u s e x p e r i m e n t s (see p a g e s 106 and 107). The b i c y c l i c o l e f i n i c k e t o n e (55) (100 m g , 0 . 6 6 mmole) was r e d u c e d w i t h l i t h i u m a l u m i n i u m h y d r i d e (30.0 mg, 0.80 mmole) t o a f f o r d 92 mg (90%) o f t h e b i c y c l i c a l c o h o l (1131 m.p. 6 1 - 6 2 ° C ; i . r . (CHCl,) v m a 2.73, 2.83 y; p.m.r. T4.46 ( s i n g l e t , 2H, CH=CH), 6.76 ( s i n g l e t , IH, -CH-OH), 8.44 ( s i n g l e t , IH, h y d r o x y l p r o t o n ) , 9.00 ( s i n g l e t , 6H, t e r t i a r y m e t h y l s ) . A n a l . C a l c d . f o r C, nH, rO: C, 78.90; H, 10.59. 1 U l b Found: C, 78.90; H, 10.56. (b) By means o f t h e M e e r v e i n - P o n d o f f - V e r l e y R e d u c t i o n To a s o l u t i o n o f t h e b i c y c l i c o l e f i n i c k e t o n e (55) (75.0 mg, 0.50 mmole) i n 1 ml o f d r y i s o p r o p y l a l c o h o l was - 108 -adde d 0.1 ml o f a s t o c k s o l u t i o n o f a l u m i n i u m i s o p r o p o x i d e ( p r e p a r e d f r o m 2.70 g (0.10 mole) o f a l u m i n i u m and 50 ml o f i s o p r o p y l a l c o h o l ) . The r e a c t i o n m i x t u r e was s e a l e d i n a t u b e and m a i n t a i n e d a t 50°C f o r 4 d a y s . The r e a c t i o n m i x t u r e was c o n c e n t r a t e d u n d e r r e d u c e d p r e s s u r e and t h e r e s i d u a l m a t e r i a l was d i l u t e d w i t h 10 ml o f a 5% aqueous s o d i u m h y d r o x i d e . The a l k a l i n e s o l u t i o n was t h o r o u g h l y e x t r a c t e d w i t h e t h e r and t h e c o m b i n e d e t h e r e x t r a c t s were d r i e d o v e r a n h y d r o u s magnesium s u l p h a t e . The o r g a n i c s o l v e n t was removed and t h e r e s i d u e d i s t i l l e d u n d e r r e d u c e d p r e s s u r e t o a f f o r d 65 mg (86%) o f t h e b i c y c l i c o l e f i n i c a l c o h o l (113) , b.p. 1 1 0 - 1 1 2 ° C a t 15 mm. (c) W i t h Sodium B o r o h y d r i d e i n P y r i d i n e To a s t i r r e d s o l u t i o n o f s o d i u m b o r o h y d r i d e (20.0 mg, 0.53 mmole) i n 1 ml o f p y r i d i n e was add e d 50 mg (0.33 mmole) o f t h e k e t o o l e f i n (55) i n 2 ml o f p y r i d i n e . The r e a c t i o n m i x t u r e was s t i r r e d a t 1 0 0 ° C f o r 16 h, c o o l e d t o room t e m p e r a t u r e and t h e n 2 ml o f a 5% aqueous s o d i u m h y d r o x i d e s o l u t i o n was a d d e d . The r e a c t i o n m i x t u r e was s t i r r e d f o r 2 h a t room t e m p e r a t u r e and t h e n t h o r o u g h l y e x t r a c t e d w i t h e t h e r . The comb i n e d e t h e r e x t r a c t s were s u c c e s s i v e l y washed w i t h two p o r t i o n s o f 6N aqueous h y d r o -c h l o r i c a c i d , two p o r t i o n s o f a s a t u r a t e d aqueous s o d i u m - 109 -b i c a r b o n a t e s o l u t i o n , and f i n a l l y w i t h b r i n e . The o r g a n i c s o l v e n t was d r i e d o v e r a n h y d r o u s magnesium s u l p h a t e and removed u n d e r r e d u c e d p r e s s u r e . The r e s i d u a l m a t e r i a l was d i s t i l l e d u n d e r r e d u c e d p r e s s u r e t o a f f o r d 42 mg (83%) o f t h e b i c y c l i c o l e f i n i c a l c o h o l (113) b.p. 1 2 0 ° C a t 15 mm. (d) W i t h C a l c i u m i n Ammonia To a r e f l u x i n g s o l u t i o n o f 60 mg (1.80 mmoles) o f c a l c i u m m e t a l i n 15 ml o f a n h y d r o u s ammonia was a d d e d 50 mg (0.33 mmoles) o f t h e b i c y c l i c o l e f i n i c k e t o n e (55) i n 3 ml o f a n h y d r o u s e t h e r . The r e a c t i o n m i x t u r e was r e f l u x e d f o r 30 m i n . and t h e n 0.2 m l o f a b s o l u t e e t h a n o l was added t o d e s t r o y t h e e x c e s s l i t h i u m . The r e a c t i o n m i x t u r e was p o u r e d i n t o w a t e r and t h o r o u g h l y e x t r a c t e d w i t h e t h e r . The c o m b i n e d e t h e r e x t r a c t s were d r i e d o v e r a n h y d r o u s magnesium s u l p h a t e . The o r g a n i c s o l v e n t was removed and t h e r e s i d u e was d i s t i l l e d u n d e r r e d u c e d p r e s s u r e t o a f f o r d 30 mg (60%) o f t h e b i c y c l i c a l c o h o l (113) b.p. 1 2 0 ° C a t 15 mm. P r e p a r a t i o n o f 8 - e n d o - A c e t o x y - l , 5 , d i m e t h y l b i c y c l o [ 3 . 2 . 1 ]  o c t a n - 6 - e n e (124) The a c e t a t e (124) was p r e p a r e d f o l l o w i n g t h e p r o c e d u r e d e s c r i b e d i n an e a r l i e r e x p e r i m e n t (see page 66 ) . The b i c y c l i c o l e f i n i c a l c o h o l (113) (85.0 mg. 0.56 mmole) - 110 -a f f o r d e d 96 mg (84% b a s e d on u n r e c o v e r e d s t a r t i n g m a t e r i a l ) o f a m i x t u r e o f t h e a c e t a t e (124) and t h e o l e f i n i c a l c o h o l (113) ( i n a r a t i o o f 9 2 : 8 ) . An a n a l y t i c a l sample o f t h e a c e t a t e (124) e x h i b i t e d , b.p. 84°C a t 16 mm; i . r . ( f i l m ) v 3.27, 3.76, 8.07 y ; p.m.r. x4.50 ( s i n g l e t , 2H, CH=CH), max Q 5.40 ( s i n g l e t , IH, -CH-OAc), 7.94 ( s i n g l e t , 3H, 0 - C - C H 3 ) , 9.08 ( s i n g l e t , 6H, t e r t i a r y m e t h y l s ) . A n a l . C a l c d . f o r C 1 2 H l g 0 2 : C, 74.19; H, 9.34. F o u n d : C, 74.86; H, 9.65. P r e p a r a t i o n o f 8-endo_-Mesytoxy-l, 5 - d i m e t h y l b i c y c l o [3 . 2 .1]  o c t a n - 6 - e n e (116) To a s o l u t i o n o f t h e b i c y c l i c o l e f i n i c a l c o h o l (113) (152 mg, 1 mmole) i n 15 ml o f d r y p y r i d i n e was added 170 mg (1.5 mmoles) o f f r e s h l y d i s t i l l e d m e t h a n e s u l p h o n y l c h l o r i d e . The r e a c t i o n m i x t u r e was m a i n t a i n e d a t 50°C f o r 24 h, c o o l e d t o room t e m p e r a t u r e , and t h e n 3 0 ml o f i c e - w a t e r was a d d e d . The r e a c t i o n m i x t u r e was t h o r o u g h l y e x t r a c t e d w i t h e t h e r and t h e c o m b i n e d e t h e r e x t r a c t s were s u c c e s s i v e l y washed w i t h t h r e e p o r t i o n s o f 10% aqueous s o d i u m b i s u l p h a t e , t h r e e p o r t i o n s o f 10% aqueous h y d r o c h l o r i c a c i d , and f i n a l l y w i t h b r i n e . The o r g a n i c s o l v e n t was d r i e d o v e r a n h y d r o u s magnesium s u l p h a t e . The s o l v e n t was removed u n d e r r e d u c e d p r e s s u r e and t h e r e s i d u e was r e c r y s t a l l i z e d f r o m h e x a n e s t o - I l l -a f f o r d 180 mg (73%) o f t h e c r y s t a l l i n e m e s y l a t e (116) , m.p. 50 - 5 1 ° C ; i . r . (CHC1,) v 3.26, 8.55 \i; p.m.r. T4.43 -J ITlclX ( s i n g l e t , 2H, CH=CH), 5.70 ( s i n g l e t , IK, -CH-OMs), 6.95 ( s i n g l e t , 3H, S 0 3 C H 3 ) , 8.93 ( s i n g l e t , 6H, t e r t i a r y m e t h y l s ) . A n a l . C a l c d . f o r C 1 1 H 1 8 ° 3 S : C ' 5 7 , 3 8 ; H ' 7 - 8 8 ' ' s> 13.89. F o u n d : C, 57.30; H, 8.00, S, 13.67. H y d r o g e n a t i o n o f t h e O l e f i n i c A l c o h o l (113) A s o l u t i o n o f t h e o l e f i n i c a l c o h o l (113) (40.0 mg, 0.26 mmole) i n 3 ml o f e t h a n o l was h y d r o g e n a t e d (room t e m p e r a t u r e , a t m o s p h e r i c p r e s s u r e ) o v e r 10 mg o f 10% p a l l a d i u m on c h a r c o a l f o r a p e r i o d o f 2 4 h . Removal o f t h e c a t a l y s t and s o l v e n t y i e l d e d 37 mg (91%) o f t h e b i c y c l i c a l c o h o l (112) , m.p. 4 8 - 4 9 ° C . T h i s m a t e r i a l e x h i b i t e d s p e c t r o s c o p i c d a t a i d e n t i c a l w i t h t h o s e r e c o r d e d f o r t h e b i c y c l i c a l c o h o l (112) (see page 106) . H y d r o l y s i s o f t h e E n o l E t h e r (114) A s o l u t i o n o f t h e e n o l e t h e r (114) (82 mg, 0.39 mmole) i n 2 ml o f e t h e r was added t o 1.5 ml o f 70% aqueous p e r c h l o r i c a c i d . The r e a c t i o n m i x t u r e was s t i r r e d a t room t e m p e r a t u r e f o r 1.5 h. The o r g a n i c s o l v e n t was removed and s u c c e s s i v e l y washed w i t h two p o r t i o n s o f i c e - w a t e r , two p o r t i o n s o f d i l u t e aqueous s o d i u m b i c a r b o n a t e , and f i n a l l y - 112 -w i t h b r i n e . The o r g a n i c s o l v e n t was d r i e d o v e r a n h y d r o u s magnesium s u l p h a t e a n d r e m o v e d u n d e r r e d u c e d p r e s s u r e . . The r e s i d u a l m a t e r i a l was d i s t i l l e d u n d e r r e d u c e d p r e s s u r e t o a f f o r d 53 mg (81%) o f t h e k e t o l (8_2) (b.p. 7 9 - 8 1 ° C a t 0.1 mm). T h i s m a t e r i a l e x h i b i t e d s p e c t r o s c o p i c d a t a i d e n t i c a l w i t h t h o s e r e c o r d e d f o r t h e k e t o l (82) p r e p a r e d i n a n e a r l i e r e x p e r i m e n t ( s e e page 63) . P r e p a r a t i o n o f t h e D i t h i o k e t a l (115) To a s o l u t i o n o f t h e k e t o l (8_2) (339 mg, 2.00 mmole) i n 15 m l o f a c e t i c a c i d was a d d e d 1.5 m l o f 1,2-e t h a n e d i t h i o l a n d 0.7 ml o f b o r o n t r i f l u o r i d e e t h e r a t e . The m i x t u r e was s t i r r e d u n d e r n i t r o g e n f o r 24 h a n d t h e n d i l u t e d w i t h e t h e r . E x c e s s s o l i d s o d i u m b i c a r b o n a t e was a d d e d a n d t h e r e s u l t i n g m i x t u r e was c a r e f u l l y d i l u t e d w i t h c o l d w a t e r . The o r g a n i c l a y e r was s e p a r a t e d , washed s u c c e s s i v e l y w i t h a q u e o u s s o d i u m b i c a r b o n a t e , w a t e r , and b r i n e a n d t h e n d r i e d o v e r a n h y d r o u s magnesium s u l p h a t e . Removal o f t h e s o l v e n t a f f o r d e d 4 93 mg o f a m i x t u r e o f t h e d i t h i o k e t a l (115) and t h e k e t o a l c o h o l (8_2) . The r e a c t i o n p r o d u c t was c h r o m a t o g r a p h e d on 35 g o f s i l i c a g e l . E l u t i o n w i t h l i g - r o i n a f f o r d e d 376 mg (85% b a s e d on u n r e c o v e r e d s t a r t i n g m a t e r i a l ) o f t h e d i t h i o -k e t o l (115) and 60 mg o f t h e s t a r t i n g m a t e r i a l , t h e k e t o l (115) o b t a i n e d by r e c r y s t a l l i z a t i o n o f t h i s m a t e r i a l f r o m - 113 -l i g r o i n , e x h i b i t e d , m.p. 6 8 - 6 9 ° C ; i . r . (CHCl,) v 2.75, = ' i t - 3 / m a x 2.85 y; p.m.r. x6.49 ( s i n g l e t , IH, -CH-OH), 7.46, 7.75 (A,B q u a r t e t , 2H, - C H 2 - C S 2 C 2 H 4 , J = 15 H z ) , 8.95, 9.02 ( s i n g l e t s , 6H, t e r t i a r y m e t h y l s ) . A n a l . C a l c d . f o r C^Yi^OS^ C, 59.00; H, 8.25; S, 26.20. F o u n d : C, 58.92; H, 8.29; S, 26.00. H y d r o g e n o l y s i s o f t h e D i t h i o k e t a l (115) To a s o l u t i o n o f t h e d i t h i o k e t a l (115) (50.0 mg, 0.20 mmole) i n 10 ml o f e t h a n o l was add e d a b o u t 2 g o f W-2 Raney n i c k e l and t h e r e s u l t i n g m i x t u r e was r e f l u x e d u n d e r n i t r o g e n f o r 15 m i n . The r e a c t i o n m i x t u r e was f i l t e r e d a nd t h e f i l t r a t e was e v a p o r a t e d u n d e r r e d u c e d p r e s s u r e . D i s t i l l a t i o n o f t h e r e s i d u a l m a t e r i a l u n d e r r e d u c e d p r e s s u r e g ave 24 mg (75%) o f t h e b i c y c l i c a l c o h o l (112) . T h i s m a t e r i a l was i d e n t i c a l i n e v e r y r e s p e c t w i t h t h e b i c y c l i c a l c o h o l ( 1 1 2 ) . P r e p a r a t i o n o f 8 - e n d o - H y d r o x y - l , 5 , 8 - t r i m e t h y l b i c y c l o [ 3 . 2 . 1 ] o c t a n e (125) To a s t i r r e d s o l u t i o n o f t h e b i c y c l i c k e t o n e (54) (50.0 mg, 0.33 mmole) i n 3 ml o f d r y e t h e r u n d e r a n i t r o g e n a t m o s p h e r e and c o o l e d by an i c e - b a t h was added 0.3 ml o f a 2 M s o l u t i o n o f m e t h y l l i t h i u m (0.60 mmole). The r e a c t i o n m i x t u r e was s t i r r e d a t room t e m p e r a t u r e f o r 1 h and t h e n 2 - 114 -ml o f i c e - w a t e r a d d e d . The r e a c t i o n m i x t u r e was a c i d i f i e d and t h e o r g a n i c p h a s e was removed. The aqueous p h a s e was e x t r a c t e d w i t h e t h e r and t h e co m b i n e d e t h e r e x t r a c t s were washed w i t h b r i n e and d r i e d o v e r a n h y d r o u s magnesium s u l -p h a t e . The o r g a n i c s o l v e n t was removed and t h e r e s i d u e was d i s t i l l e d u n d e r r e d u c e d p r e s s u r e t o a f f o r d 47 mg (85%) o f t h e b i c y c l i c a l c o h o l ( 1 2 5 ) , b .p. 1 0 5 - 1 1 0 ° C a t 15 mm; m.p. 39 - 4 0 ° C ; i . r . (CHCl,) v m 2.75, 2.85 y; p.m.r. x8.94 ( s i n g l e t , 3H, CH 3~C-OH), 9.14 ( s i n g l e t , 6H, t e r t i a r y m e t h y l s ) . A n a l . C a l c d . f o r c 1 1 H 2 o 0 : C ' 7 8 - 5 1 ' " H ' H - 9 8 . Fo u n d : C, 78.80; H, 12.20. P r e p a r a t i o n o f 8 - e n d o - H y d r o x y - l , 5 - 8 - t r i m e t h y l b i c y c l o [ 3 . 2 . 1 ]  o c t a n - 6 - e n e (126) The o l e f i n i c a l c o h o l (126) was p r e p a r e d f o l l o w i n g t h e p r o c e d u r e d e s c r i b e d i n t h e p r e v i o u s e x p e r i m e n t ( s e e page 113). The o l e f i n i c k e t o n e (5_5) (50 mg, 0.33 mmole) a f f o r d e d 50 mg (89%) o f t h e o l e f i n i c a l c o h o l (126) , m.p. 5 1 - 5 2 ° C ; i . r . (CHC1 3) v m a x 2.75, 2.85 y; p.m.r. x4.56 ( s i n g l e t , 2H, CH=CH) , 8.96 ( s i n g l e t , 3H, CH-jC-OH) , 8.15 ( s i n g l e t , 6H, t e r t i a r y m e t h y l s ) . A n a l . C a l c d . f o r c 1 1 H i g O : C, 79.46; H, 10.91. F o u n d : C, 79.38; H, 10.94. - 115 -P r e p a r a t i o n of the 8-endo-Hydroxy-l,5,8-trimethyl-6-isopropoxy-b i c y c l o [ 3 . 2 . 1 ] o c t a n - 6 - e n e (127) The b i c y c l i c a l c o h o l (127) was prepared f o l l o w i n g the procedure d e s c r i b e d i n an e a r l i e r experiment (see page 113). The r e a c t i o n mixture however was not s u b j e c t e d t o a c i d i c c o n d i t i o n s i n o r d e r to prevent the p o s s i b l e h y d r o l y s i s of the e n o l e t h e r f u n c t i o n a l i t y . The b i c y c l i c ketone (56) (208 mg, 1.00 mmole) a f f o r d e d 200 mg (90%) of the b i c y c l i c a l c o h o l (127), b.p. 93-95°C a t 15 mm; i . r . (CHC1-) v 2.88, j) iricix 3.28, 6.24 y; p.m.r. T5.82 (heptet, IH, H C ( C H 3 ) 2 , J = 6 Hz), 5.95 ( s i n g l e t , IH, CH=CDR), 8.73 (doublet, 6H, i s o p r o p y l methyls, J = 6 Hz), 8.05, 9.09, 9.19 ( s i n g l e t s , 9H, C-1, C-5, C-8 t e r t i a r y m e t h y l s ) . A n a l . 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