UBC Theses and Dissertations

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UBC Theses and Dissertations

A synthetic approach to the C/D ring system of steroids Pendleton, Nevil 1987

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A SYNTHETIC APPROACH TO THE C /D RING SYSTEM OF STEROIDS by N e v i l P e n d l e t o n B . S c , B r u n e i U n i v e r s i t y , L o n d o n , 1984 A THESIS SUBMITTED IN PARTIAL FULFILMENT OF THE REQUIREMENTS FOR THE DEGREE OF MASTER OF SCIENCE i n THE FACULTY OF GRADUATE STUDIES DEPARTMENT OF CHEMISTRY 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 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 S e p t e m b e r , 1987 c N e v i l P e n d l e t o n In presenting this thesis in partial fulfilment of the requirements for an advanced degree at the University of British Columbia, I agree that the Library shall make it freely available for reference and study. I further agree that permission for extensive copying of this thesis for scholarly purposes may be granted by the head of my department or by his or her representatives. It is understood that copying or publication of this thesis for financial gain shall not be allowed without my written permission. Department of ^HfcHt ST^Y The University of British Columbia 1956 Main Mall Vancouver, Canada V6T 1Y3 Date f f e QcJc, Hc??~ DE-6(3/81) ABSTRACT T h i s t h e s i s i s c o n c e r n e d w i t h an a p p r o a c h t o t h e s y n t h e s i s o f t he C/D r i n g s y s t e m and s i d e c h a i n o f s t e r o i d s w i t h 1 1 - o x y g e n f u n c t i o n a l i t y . ( + ) - 9 , 1 0 - D i b r o m o c a m p h o r (18) [ p r e p a r e d i n t h r e e s t e p s f r o m ( + ) - e n d o - 3 -bromocamphor ( 4 ) ] was c o n v e r t e d t o t h e d i e s t e r 144 i n s i x s t e p s . The d i e s t e r 144 underwen t a m o d i f i e d a c y l o i n r e a c t i o n t o p r o v i d e t h e s i l y l a t e d e n e d i o l a t e 154 . A n o v e l m e t h a n o l y s i s o f t h e a c y l o i n i n t e r m e d i a t e 154 gave a 1:1 m i x t u r e o f t h e i s o m e r i c t r i c y c l i c m e t h o x y -k e t o n e s 168 and 176 . O x i d a t i v e c l e a v a g e o f t h e s e m e t h o x y k e t o n e s 168 154 168 176 and 176 p r o v i d e d t h e i s o m e r i c a l d e h y d e s 178 and 180 w h i c h we re t h e n t r a n s f o r m e d i n t o t h e c o r r e s p o n d i n g i s o m e r i c e s t e r s 181 and 1 8 2 . T h i s r e p r e s e n t s a s y n t h e s i s o f t h e C /D r i n g s y s t e m o f s t e r o i d s w i t h i i 1 1 - o x y g e n f u n c t i o n a l i t y and e s t a b l i s h m e n t o f t h e c o r r e c t a b s o l u s t e r e o c h e m i s t r y a t C (13 ) and C ( 1 7 ) . 181 • • • 111 TABLE OF CONTENTS Page A b s t r a c t i i T a b l e o f C o n t e n t s i v L i s t o f F i g u r e s v L i s t o f A b b r e v i a t i o n s and Number i ng S y s t e m v i Acknow ledgemen ts v i i i 1. I n t r o d u c t i o n 1 1.1 The Use o f Camphor i n N a t u r a l P r o d u c t S y n t h e s i s 1 1.2 1 1 - O x y s t e r o i d s 10 1.3 A p p r o a c h e s t o t h e C/D R i n g S y s t e m o f S t e r o i d s w i t h F u n c t i o n a l i s e d S i d e C h a i n s 17 2 . D i s c u s s i o n 27 3 . E x p e r i m e n t a l 45 B i b l i o g r a p h y 65 A p p e n d i x 1 : 1 H 400 MHz NMR o f S e l e c t e d Compounds 69 A p p e n d i x 2 : S t e r e o v i e w and C r y s t a l D a t a o f T r i c y c l i c A l c o h o l 167 73 i v L I S T OF FIGURES F i g u r e T i t l e Page 1 *H 400 MHz NMR o f t h e E s t e r 181 41 2 *H 400 MHz NMR o f t h e E s t e r 182 42 v L I S T OF ABBREVIATIONS AND NUMBERING SYSTEM (a) L i s t o f A b b r e v i a t i o n s A c A c e t y l amu A t o m i c Mass U n i t ( s ) b r B r o a d ( i r ) Bu B u t y l DMAP 4 - D i m e t h y l a m i n o p y r i d i n e DMF N , N - D i m e t h y l f o r m a m i d e DMPU N , N - D i m e t h y l p r o p y l e n e u r e a DMSO D i m e t h y l s u l p h o x i d e E t E t h y l g l c G a s - l i q u i d C h r o m a t o g r a p h y h H o u r ( s ) 2 , 6 - H 2 , 6 - H y d r i d e S h i f t HMPA H e x a m e t h y l p h o s p h o r a m i d e i r I n f r a r e d Me M e t h y l 2 , 3 - M e 2 , 3 - M e t h y l S h i f t m/e Mass t o C h a r g e R a t i o m i n M i n u t e ( s ) mp M e l t i n g P o i n t Ms Me t h a n e s u l p h o n y l nmr N u c l e a r M a g n e t i c Re so n a nce P h P h e n y l v i TBDMS t e r t i a r y - B u t y l d i m e t h y l s i l y l THF T e t r a h y d r o f u r a n THP 2 - T e t r a h y d r o p y r a n y l t i c T h i n L a y e r Chromatog raphy TMS T r i m e t h y l s i l y l WM W a g n e r - M e e r v e i n S h i f t A b b r e v i a t i o n s f o r *H NMR D a t a d D o u b l e t dd D o u b l e t o f D o u b l e t s ddd D o u b l e t o f D o u b l e t s o f D o u b l e t s & Chemica l S h i f t i n ppm f rom the TMS S i g n a l J C o u p l i n g C o n s t a n t ( i n Hz) m M u l t i p l e t ppm P a r t s p e r M i l l i o n s S i n g l e t t T r i p l e t (b) Number i ng S y s t e m Camphor (1) and i t s d e r i v a t i v e s a r e numbered as shown b e l o w . The s t a n d a r d s t e r o i d n u m b e r i n g s y s t e m as shown i s u s e d t h r o u g h o u t t h i s t h e s i s . T h i s n u m b e r i n g s y s t e m i s a l s o u s e d when o n l y t h e C / D r i n g s u b - u n i t i s r e f e r r e d t o . v i i ACKNOWLEDGEMENT I w o u l d l i k e t o t h a n k D r . S t e v e R e t t i g who p e r f o r m e d the X - r a y c r y s t a l l o g r a p h i c a n a l y s i s and M r . B o r d a who c a r r i e d ou t t h e m i c r o a n a l y s e s . S p e c i a l t h a n k s go t o my t y p i s t w i f e Shamshad , who now knows t h e s t r u c t u r e o f ( + ) - 9 , 1 0 - d i b r o m o c a m p h o r ! F i n a l l y , I w o u l d l i k e t o t h a n k my r e s e a r c h s u p e r v i s o r , D r . Thomas Money , f o r a l l h i s s u p p o r t and g u i d a n c e . v i i i To Shamshad I x 1. INTRODUCTION 1.1 The Use o f Camphor i n N a t u r a l P r o d u c t S y n t h e s i s (+) -Camphor ( 1 ) , ( - ) - c a m p h o r and ( ± ) - c a m p h o r a l l o c c u r n a t u r a l l y . (+) -Camphor (1) c a n be i s o l a t e d f r o m t h e camphor l a u r e l whe reas ( - ) - c a m p h o r i s a c o n s t i t u e n t o f t h e o i l o f s a g e b r u s h . B o t h ( + ) - and ( - ) - f o rms o f camphor a r e c o m m e r c i a l l y a v a i l a b l e a l t h o u g h ( - ) - c a m p h o r c a n be more c h e a p l y p r e p a r e d i n t h e l a b o r a t o r y by o x i d a t i o n o f c o m m e r c i a l l y a v a i l a b l e ( - ) - b o r n e o l ( 2 ) . * Camphor i s a l s o p r e p a r e d i n d u s t r i a l l y f r o m a - p i n e n e (3) b u t t he p r o d u c t i s r a c e m i c . I 2 2 The a v a i l a b i l i t y o f camphor i n b o t h o p t i c a l l y p u r e e n a n t i o m e r i c f o r m s , t o g e t h e r w i t h i t s a b i l i t y t o be s e l e c t i v e l y f u n c t i o n a l i s e d a t C ( 3 ) , C ( 5 ) , C ( 6 ) , C ( 8 ) , C ( 9 ) and C (10 ) c a r b o n c e n t r e s , has r e s u l t e d i n i t s use as a v e r s a t i l e c h i r a l s t a r t i n g m a t e r i a l i n t h e e n a n t i o s p e c i f i c s y n t h e s i s o f n a t u r a l p r o d u c t s . I n a d d i t i o n , camphor d e r i v a t i v e s can u n d e r g o r i n g c l e a v a g e a t C ( l ) - C ( 2 ) , C ( 2 ) - C ( 3 ) and C ( l ) - C ( 7 ) . A r e v i e w o f t h e f u n c t i o n a l i s a t i o n o f camphor and i t s u s e i n n a t u r a l 2 p r o d u c t s y n t h e s i s h a s been p u b l i s h e d r e c e n t l y , and so o n l y a b r i e f o u t l i n e o f t h e i m p o r t a n t b r o m i n a t i o n and r i n g c l e a v a g e r e a c t i o n s i s p r o v i d e d b e l o w . 1 1 .1a C ( 3 ) and C ( 9 ) B r o m i n a t i o n Br Br Br J. 4 5 6 B r o m i n a t i o n o f camphor w i t h b r o m i n e i n a c e t i c a c i d t o y i e l d ( + ) - e n d o - 3 - b r o m o c a m p h o r (4) was c a r r i e d ou t by K i p p i n g and Pope i n 3 1 8 7 3 . F u r t h e r b r o m i n a t i o n c a n be c a r r i e d ou t by t r e a t m e n t o f ( • f ) - endo -3 -b romocamphor (4) w i t h b r o m i n e and c h l o r o s u l p h o n i c a c i d t o 4 5 6 p r o v i d e ( + ) - e n d o - 3 , 9 - d i b r o m o c a m p h o r ( 5 ) , ' ' and a s m a l l amount o f 7 8 7 ( + ) - e n d o - 3 , 9 , 9 - t r i b r o m o c a m p h o r ( 6 ) . * The mechan ism p o s t u l a t e d i n i t i a l l y i n v o l v e s Wagne r -Mee rwe in r e a r r a n g e m e n t o f ( 4 ) - e n d o - 3 - b r o m o -camphor (4_) (Scheme 1 ) . A N a m e t k i n s h i f t o f t h e e x o - m e t h y l g roup f o l l o w e d by Scheme 1 2 b r o m i n a t i o n p r o d u c e s i n t e r m e d i a t e 7_. A r e v e r s a l o f t h e r e a r r a n g e m e n t p r o c e s s e s (Pa thway A) p r o v i d e s ( + ) - e n d o - 3 , 9 - d i b r o m o c a m p h o r ( 5 ) . ( + ) - e n d o - 3 , 9 , 9 - T r i b r o m o c a m p h o r (6) i s p o s t u l a t e d t o be fo rmed by f u r t h e r b r o m i n a t i o n o f i n t e r m e d i a t e 7_ (Pathway B) b e f o r e r e v e r s a l o f t h e r e a r r a n g e m e n t p r o c e s s e s . 1 . l b 5 , 6 - D e h y d r o c a m p h o r D e r i v a t i v e s Br Br 4 9 12 I n 1 9 5 2 , N i s h i k a w a f o u n d t h a t t r e a t m e n t o f ( - f ) - e n d o - 3 , 9 -d ib romocamphor (5) i n c o l d f u m i n g s u l p h u r i c a c i d p r o d u c e d ( - ) - e n d o - 6 , 9 -d ib romocamphor (8) w i t h t h e o p p o s i t e c o n f i g u r a t i o n . L a t e r s t u d i e s ^ i n o u r l a b o r a t o r y have shown t h a t (+ ) - endo -3 -b romocampho r (4) c a n be s i m i l a r l y r e a r r a n g e d t o ( - ) - e n d o - 6-bromocamphor (9_) by t r e a t m e n t w i t h c h l o r o s u l p h o n i c a c i d a t 5 5 ° C . The p o s t u l a t e d mechan ism (Scheme 2) i n v o l v e s i n t e r c o n v e r s i o n o f t h e C ( 8 ) and C (10 ) m e t h y l g r o u p s and t h i s has been c o n f i r m e d by d e u t e r i u m l a b e l l i n g s t u d i e s . ^ I n t e r m e d i a t e 10 i s f o r m e d by W a g n e r - M e e r w e i n r e a r r a n g e m e n t f o l l o w e d by a N a m e t k i n 3 s h i f t o f t h e e x o - m e t h y l g r o u p . A s e c o n d Wagne r -Mee rwe in r e a r r a n g e m e n t f o l l o w e d by a 2 , 6 - h y d r i d e s h i f t and a f u r t h e r W a g n e r - M e e r w e i n r e a r r a n g e m e n t p r o v i d e s i n t e r m e d i a t e 11_ w h i c h r e v e r t s t o t h e camphor f r amework t o f o r m ( - ) - e n d o - 6 - b r o m o c a m p h o r ( 9 ) . 1 ( e x o ) Scheme 2 D e h y d r o h a l o g e n a t i o n o f ( - ) - e n d o - 6 - b r o m o c a m p h o r (9) p r o v i d e s 5 , 6 - d e h y d r o c a m p h o r ( 1 2 ) , p r e v i o u s l y s y n t h e s i s e d by m u l t i s t e p 12 13 p r o c e d u r e s . * S i m i l a r d e h y d r o h a l o g e n a t i o n o f ( - ) - e n d o - 6 , 9 -d ib romocamphor (8) p r o v i d e s 9 - b r o m o - 5 , 6 - d e h y d r o c a m p h o r ( 1 3 ) . 4 1 . 1 c C ( 8 ) - B r o m i n a t i o n Br Br 1 15 16 14 (+ ) -8 -Bromocamphor (14) c a n be c o n v e n i e n t l y p r e p a r e d f r o m camphor i n t h r e e s t e p s . ^ T r e a t m e n t o f camphor (1) w i t h b r o m i n e , a c e t i c a c i d and HBr gas [ w h i c h p r o v i d e s ( + ) - 3 , 3 - d i b r o m o c a m p h o r ( 1 5 ) ] f o l l o w e d by f u r t h e r b r o m i n a t i o n i n c h l o r o s u l p h o n i c a c i d g i v e s ( + ) - 3 , 3 , 8 - t r i b r o m o -camphor ( 1 6 ) . S e l e c t i v e d e b r o m i n a t i o n o f _16_ w i t h z i n c and a c e t i c a c i d p r o v i d e s (+ ) -8 -b romocamphor ( 1 4 ) . The C ( 8 ) - b r o m i n a t i o n p r o c e s s i s c o n s i d e r e d t o o c c u r by a mechan ism (Scheme 3) s i m i l a r t o t h a t i n v o l v e d 7 13 i n t h e C ( 9 ) - b r o m i n a t i o n o f (->-)-endo-3-bromocamphor ( 4 ) . ' 5 The c r u c i a l d i f f e r e n c e i s t h e p o s t u l a t e d o c c u r r e n c e o f 2 , 3 - e n d o - m e t h y l s h i f t s i n t h e C ( 8 ) - b r o m i n a t i o n r e a c t i o n as opposed t o t h e 2 , 3 - e x o - m e t h y l s h i f t s i n t he C ( 9 ) - b r o m i n a t i o n r e a c t i o n . A g a i n d e u t e r i u m l a b e l l i n g s t u d i e s ^ " * p r o v i d e s u p p o r t f o r t h i s m e c h a n i s m . 1 . I d 8 , 1 0 - and 9 , 1 0 - D i b r o m o c a m p h o r D e r i v a t i v e s Br I n an e x t e n s i o n o f t h e work c a r r i e d ou t by N i s h i k a w a and Eagiwara, i t was f o u n d t h a t p r o l o n g e d t r e a t m e n t o f ( + ) - e n d o - 3 , 9 - d i b r o m o c a m p h o r (5) w i t h b r o m i n e and c h l o r o s u l p h o n i c a c i d (5 d a y s ) gave p r e d o m i n a n t l y ( + ) - e n d o - 3 , 9 , 1 0 - t r i b r o m o c a m p h o r ( 1 7 ) A n a l o g o u s t r e a t m e n t o f (•f ) - e n d o - 3 , 8 - d i b r o m o c a m p h o r (19) [ p r e p a r e d by t r e a t m e n t o f ( + ) - 8 -bromocamphor (14) w i t h b r o m i n e ] gave ( + ) - e n d o - 3 , 8 , 1 0 - t r i b r o m o c a m p h o r ( 2 0 ) . S e l e c t i v e d e b r o m i n a t i o n o f 17_ and 20_ w i t h z i n c and a c e t i c a c i d p r o v i d e d ( + ) - 9 , 1 0 - d i b r o m o c a m p h o r (18) and ( + ) - 8 , 1 0 - d i b r o m o c a m p h o r (21) r e s p e c t i v e l y . 6 The mechan ism o f t h e b r o m i n a t i o n o f ( + ) - e n d o - 3 , 9 - d i b r o m o c a m p h o r (5) and o f ( + ) - e n d o - 3 , 8 - d i b r o m o c a m p h o r (19) h a s been p r o p o s e d t o i n v o l v e W a g n e r - M e e r w e i n r e a r r a n g e m e n t t o p r o v i d e t he camphene i n t e r m e d i a t e 22 (Scheme 4 ) . R e a c t i o n o f 22 w i t h b r o m i n e and s u b s e q u e n t r e a r r a n g e m e n t b a c k t o t h e camphor f ramework p r o v i d e s t h e t r i b r o m i n a t e d camphors 17_ and 2 0 . X = B r Y = H 20 22a Scheme 4 The d i b r o m o f e n c h o n e s 23 and 24_ (Scheme 5 ) a r e p r o d u c e d as b y - p r o d u c t s d u r i n g t he C ( 1 0 ) - b r o m i n a t i o n o f ( + ) - e n d o - 3 , 9 - d i b r o m o c a m p h o r (5) and 2 ( 4 ) - e n d o - 3 , 8 - d i b r o m o c a m p h o r ( 1 9 ) • The f o r m a t i o n o f t h e s e f e n c h o n e d e r i v a t i v e s i s p o s t u l a t e d t o o c c u r v i a a d o u b l e W a g n e r - M e e r w e i n 2 r e a r r a n g e m e n t as shown i n Scheme 5 . The s y n t h e t i c p o t e n t i a l o f ( + ) - 9 , 1 0 - d i b r o m o c a m p h o r (18) h a s been r e c e n t l y r e c o g n i s e d by t h e A l d r i c h C h e m i c a l Company f r o m whom i t i s now c o m m e r c i a l l y a v a i l a b l e . 7 Br Br Scheme 5 l . l e C l e a v a g e o f t h e Camphor C ( l ) - C ( 2 ) Bond C l e a v a g e o f t h e C ( l ) - C ( 2 ) bond i n camphor (1) and i n v a r i o u s camphor d e r i v a t i v e s r e s u l t s i n t h e f o r m a t i o n o f a f u n c t i o n a l i s e d 5-membered r i n g . Camphor (1) i t s e l f u n d e r g o e s c l e a v a g e upon 18 -22 p h o t o i r r a d i a t i o n t o g i v e t h e a l d e h y d e 2 5 . ( + ) - 9 , 1 0 - d i b r o m o c a m p h o r (18) c a n be c l e a v e d t o p r o v i d e t h e c y c l o p e n t a n o i d r i n g s y s t e m s 2_6, 27_ and 23 2 8 . 8 S t e v e n s and c o - w o r k e r s u t i l i s e d t h e C ( l ) - C ( 2 ) r i n g c l e a v a g e r e a c t i o n i n r o u t e s f r o m camphor (1) t o t h e C /D r i n g s y s t e m o f s t e r o i d s w i t h c o n t r o l o f s t e r e o c h e m i s t r y a t t h e C ( 1 3 ) , C (17 ) and C (20 ) c a r b o n c e n t r e s . (+ ) -9 -B romocamphor (29) was c o n v e r t e d t o ox ime e s t e r 30_ w h i c h underwen t r i n g c l e a v a g e o f t h e C ( l ) - C ( 2 ) bond t o g i v e c y a n o e s t e r 3 ^ w i t h t h e c o r r e c t a b s o l u t e s t e r e o c h e m i s t r y a t C (13 ) and C (17 ) (Scheme 6 ) . 33 32 Scheme 6 The c y a n o e s t e r (31) was t h e n c o n v e r t e d i n s e v e r a l s t e p s t o t h e s u l p h o n e i n t e r m e d i a t e 3_2_ w h i c h was c y c l i s e d t o p r o v i d e t h e h y d r i n d e n e d e r i v a t i v e 3 3 . The r e q u i r e d C ( 2 0 ) s t e r e o c h e m i s t r y was f o r m e d (Scheme 7) by s t e r e o s e l e c t i v e m e t h y l a t i o n o f (+ ) -9 -b romocamphor (29) t o g i v e 25 ( + ) - e n d o - 3 - m e t h y l - 9 - b r o m o c a m p h o r ( 3 4 ) . Subsequen t c o n v e r s i o n o f 34 t o t h e h y d r o x y - t o s y l a t e s 35a and 3 5 b , f o l l o w e d by o x i d a t i v e c l e a v a g e o f t h e C ( l ) - C ( 2 ) bond w i t h e e r i e ammonium n i t r a t e (CAN) r e s u l t e d i n f o r m a t i o n o f t h e k e y m o n o c y c l i c i n t e r m e d i a t e 3 6 . 9 I n c o r p o r a t i o n o f t he s t e r e o s e l e c t i v e m e t h y l a t i o n s t e p i n t h e f o r m e r Scheme 7 r o u t e (Scheme 6) w o u l d be e x p e c t e d t o p r o v i d e t h e s u l p h o n e d e r i v a t i v e 33 w i t h t he c o r r e c t a b s o l u t e s t e r e o c h e m i s t r y a t C ( 2 0 ) . 1.2 1 1 - O x y s t e r o i d s OH 39 One i m p o r t a n t g roup o f t h e 1 1 - o x y s t e r o i d s a r e t h e c o r t i c o s t e r o i d s w h i c h i n c l u d e c o r t i s o n e ( 3 7 ) , a l d o s t e r o n e ( 3 8 ) , and c o r t i c o s t e r o n e (39) 10 as r e p r e s e n t a t i v e e x a m p l e s . Common s t r u c t u r a l f e a t u r e s o f t h e s e compounds a r e t h e p r e s e n c e o f a h y d r o x y o r k e t o g roup a t C ( l l ) , a n enone f u n c t i o n a l i t y i n r i n g A and a -COCI^OH g roup a t C ( 1 7 ) . The c o r t i c o s t e r o i d s a r e among t h e most i m p o r t a n t r e g u l a t o r y h o r m o n e s , c o n t r o l l i n g w a t e r and m i n e r a l b a l a n c e , p r o t e i n and c a r b o h y d r a t e m e t a b o l i s m , i n f l a m m a t i o n o f t i s s u e s a s s o c i a t e d w i t h i n j u r i e s , a l l e r g i c 26 r e a c t i o n s and au to - immune p r o c e s s e s . A f t e r t h e i r t h e r a p e u t i c 27 i m p o r t a n c e v a s d i s c o v e r e d i n 1 9 4 9 , a c o n s i d e r a b l e e f f o r t was made t o 28 d e v e l o p s y n t h e t i c r o u t e s t o t h e s e compounds. One s y n t h e t i c d i f f i c u l t y was t h e i n t r o d u c t i o n o f a h y d r o x y l o r k e t o g roup a t C ( l l ) a l t h o u g h t h i s p r o b l e m was overcome by m i c r o b i o l o g i c a l o x i d a t i o n o f 29 d e s o x y p r e c u r s o r s , w h i c h e n a b l e d i n t r o d u c t i o n o f a h y d r o x y g roup a t C ( l l ) i n h i g h y i e l d . T h e r e a r e a l s o many 1 1 - o x y s t e r o i d s o t h e r t h a n t h o s e c l a s s i f i e d as c o r t i c o s t e r o i d s ; a d r e n o s t e r o n e (40) and 1 1 - k e t o p r o g e s t e r o n e (41) a r e two w e l l - k n o w n e x a m p l e s . R e c e n t l y t h e r e h a s been a r e s u r g e n c e o f ,0 40 41 i n t e r e s t i n t h e t o t a l s y n t h e s i s o f 1 1 - o x y s t e r o i d s . E f f o r t s have been f o c u s s e d on t h e f o r m a t i o n o f t h e 1 1 - o x y s t e r o i d s by an A + C / D — > ABCD a p p r o a c h , i n c o r p o r a t i n g a l d o l c o n d e n s a t i o n s , i n t r a m o l e c u l a r D i e l s - A l d e r r e a c t i o n s and t h e u s e o f o r g a n o s i l i c o n c h e m i s t r y . T h i s a p p r o a c h 28 c o n t r a s t s w i t h t h e e a r l y s y n t h e t i c a p p r o a c h e s t o 1 1 - o x y s t e r o i d s w h i c h 11 were b a s e d on t h e i n i t i a l c o n s t r u c t i o n of t he B / C r i n g s y s t e m . An o u t l i n e o f t h e r e c e n t a p p r o a c h e s t o t h e C/D r i n g s y s t e m o f 1 1 - o x y g e n a t e d s t e r o i d s i s p r o v i d e d b e l o w . 30 I n one a p p r o a c h (Scheme 8 ) , S t o r k and c o - w o r k e r s s y n t h e s i s e d r a c e m i c a d r e n o s t e r o n e (AO) f r o m e t h y l 2-iDethylacetoacetate. A l k y l a t i o n o f t h e d i a n i o n o f e t h y l 2 - m e t h y l a c e t o a c e t a t e w i t h a l l y l b r o m i d e f o l l o w e d by k e t a l i s a t i o n , o z o n o l y s i s and W i t t i g - H o r n e r a d d i t i o n o f 3 - m e t h o x y - 2 - ( o x o p r o p y l ) p h o s p h o n a t e gave t h e enone e s t e r 42_. The e s t e r g roup was t h e n c o n v e r t e d t o t h e c o r r e s p o n d i n g a l d e h y d e 43_. C y c l i s a t i o n w i t h z i r c o n i u m t e t r a - n - p r o p o x i d e f o rmed t h e D r i n g by an i n t r a m o l e c u l a r M i c h a e l a d d i t i o n . A l d o l c o n d e n s a t i o n gave t h e t r a n s - h y d r i n d e n o n e 44 ( 2 5 : 1 t r a n s : c i s r a t i o ) , w i t h 1 1 - o x y g e n f u n c t i o n a l i t y . C o n j u g a t e r~\ rt r~\ r~\ 0 0 0 o 0 0 0 Me 42 43 t 45 a d d i t i o n t o 2 - ( t r i m e t h y l s i l y l ) - l - p e n t e n - 3 - o n e f o l l o w e d by c y c l i s a t i o n and a c i d h y d r o l y s i s p r o v i d e d e n e d i o n e 4 5 . A l k y l a t i o n o f 45_ f r o m t h e c t - f a c e was a c c o m p l i s h e d by t r e a t m e n t o f t h e d i e n e d i o l a t e o f 45 w i t h 12 l - b r o m o - 3 - c h l o r o - 2 - b u t e n e . F i n a l l y , m i l d a c i d h y d r o l y s i s gave t h e a l k e n y l c h l o r i d e A6_ w h i c h was h y d r o l y s e d and t h e n c y c l i s e d t o p r o v i d e a d r e n o s t e r o n e ( A O ) . 31 I n a l a t e r i n v e s t i g a t i o n , S t o r k and c o - w o r k e r s d e v e l o p e d a s y n t h e t i c r o u t e t o 1 1 - k e t o p r o g e s t e r o n e ( A l ) (Scheme 9 ) . A n n u l a t i o n o f t h e p y r r o l i d i n e enamine o f c y c l o p e n t a n o n e (A7) w i t h t h e u n s a t u r a t e d k e t o e s t e r A8_ gave t h e b i c y c l i c k e t o e s t e r A9_. I n t r o d u c t i o n o f t h e C ( 1 7 ) s u b s t i t u e n t was a c h i e v e d by t r e a t i n g t h e d i e n o l a c e t a t e 50_ w i t h a c e t i c a n h y d r i d e and B F ^ e t h e r a t e t o g i v e e n o l a c e t a t e 5 1 . R e d u c t i o n o f t h e k e t o n e f o l l o w e d by c l e a v a g e o f t h e e n o l a c e t a t e gave enone 5 2 . A m e t h y l g roup was i n t r o d u c e d i n t o t h e 1 3 / S - p o s i t i o n by c o n j u g a t e a d d i t i o n o f a cyano g roup f o l l o w e d by s u c c e s s i v e r e d u c t i o n s t e p s . S u b s e q u e n t o x i d a t i o n o f t he c o r r e s p o n d i n g d i o x o l a n e gave t he p r o p i o n i c a c i d i n t e r m e d i a t e 5_3_ w h i c h was c o n v e r t e d v i a an i n t r a m o l e c u l a r D i e l s -A l d e r r e a c t i o n t o 1 1 - k e t o p r o g e s t e r o n e ( A l ) . A8 49 50 A l 53 Scheme 9 13 I n a r e c e n t i n v e s t i g a t i o n , S t o r k and c o - w o r k e r s d e v e l o p e d an e n a n t i o s e l e c t i v e r o u t e (Scheme 10) t o a d r e n o s t e r o n e ( 4 0 ) . Me 0,C^ ^ 5 1 55 R0,C Me02C I \ 0 0 R 0 2 c v £ > < MeO,C 54 57 CN P. 0 Me02C < ^ 60 C y c l o p e n t a n o n e a c e t i c e s t e r 54^ was u s e d as t h e s t a r t i n g m a t e r i a l and was p r e p a r e d i n t h e p r o p e r r e l a t i v e and a b s o l u t e s t e r e o c h e m i s t r y by t h e s t e r e o s e l e c t i v e i n t r a m o l e c u l a r M i c h a e l r e a c t i o n o f 5_5 u s i n g a c h i r a l e s t e r t o p r o d u c e t h e c o r r e c t c h i r a l i t y . P r o t e c t i o n o f t h e k e t o n e gave d i o x o l a n e 57_ w h i c h underwen t s t e r e o s e l e c t i v e a l k y l a t i o n w i t h a l l y l b r o m i d e t o g i v e 5 8 . The C r i n g was fo rmed by c o n v e r s i o n 14 t o t h e d i m e s y l a t e 59_ w h i c h was t h e n c y c l i s e d by r e a c t i o n w i t h m e t h y l c y a n o a c e t a t e t o g i v e c y a n o a c e t a t e 60_. D e c a r b o m e t h o x y l a t i o n o f 60_ f o l l o w e d by o x i d a t i o n o f t h e a n i o n o f t h e r e s u l t i n g n i t r i l e w i t h oxygen i n t r o d u c e d t h e C ( l l ) c a r b o n y l . H y d r o b o r a t i o n and PDC o x i d a t i o n t h e n p r o v i d e d t he t r a n s - h y d r i n d a n e d e r i v a t i v e 61^  w h i c h was c o n v e r t e d v i a an i n t r a m o l e c u l a r D i e l s - A l d e r r e a c t i o n t o a d r e n o s t e r o n e (40) ( c f . Scheme 9). I n t he a p p r o a c h (Scheme 11) t o 1 1 - o x y s t e r o i d s d e v e l o p e d by S n i d e r 33 and K i r k , c y c l i s a t i o n o f k e t o n e j62_ p r o v i d e d r a c e m i c h y d r i n d a n o n e 63. C o n v e r s i o n o f 63 t o enone 65, v i a t h e e p o x i d e 64, f o l l o w e d by c o n j u g a t e a d d i t i o n o f 3 - b u t e n y l m a g n e s i u m b r o m i d e p r o v i d e d t h e p e n t y n y l d e r i v a t i v e 66. I n t e r m e d i a t e 66 was o x i d i s e d t o t h e t r i o n e 67 and s u b s e q u e n t l y 67 68 Scheme 11 15 c y c l i s e d t o t he t r i c y c l i c e n e d i o n e 6 8 . The c o r r e s p o n d i n g e n e d i o n e 45 30 was u s e d by S t o r k and c o - w o r k e r s i n one o f t h e i r r o u t e s t o 1 1 - o x y s t e r o i d s as shown p r e v i o u s l y i n Scheme 8 . Denmark and Germanas u t i l i s e d a v i n y l s i l a n e a c y l a t i o n i n t h e s y n t h e s i s o f t h e t r a n s - h y d r i n d a n e d i o n e 72 (Scheme 1 2 ) . C o n j u g a t e 40 74 73 72 Scheme 12 a d d i t i o n o f 2 - t r i m e t h y l s i l y l v i n y l c u p r a t e t o 2 - m e t h y l c y c l o p e n t e n o n e f o l l o w e d by q u e n c h i n g o f t h e e n o l a t e w i t h t r i m e t h y l s i l y l c h l o r i d e gave t h e e n o l t r i m e t h y l s i l y l e t h e r 6 9 . The e t h e r 69_ was t h e n a l k y l 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 o p r o v i d e e s t e r 7 0 . C o n v e r s i o n o f 7_0_ t o a c i d c h l o r i d e 7_1 f o l l o w e d by an i n t r a m o l e c u l a r , L e w i s - a c i d c a t a l y s e d c y c l i s a t i o n gave t h e t r a n s - h y d r i n d a n e d i o n e 7 2 . I n t e r m e d i a t e 72 i s t h e n p o t e n t i a l l y c a p a b l e o f u n d e r g o i n g D i e l s - A l d e r r e a c t i o n w i t h a d i e n e s u c h as 7 3 . T h i s w o u l d p r o v i d e t h e D i e l s - A l d e r p r o d u c t 74_ w h i c h c o u l d be c o n v e r t e d t o 1 1 - k e t o s t e r o i d s s u c h as a d r e n o s t e r o n e 4 0 . 16 F u k u z a k i , Nakamura and Kuwa j ima s i m i l a r l y u s e d a v i n y l s i l a n e a c y l a t i o n i n a s y n t h e s i s o f t h e t r a n s - h y d r i n d a n e d i o n e 78 (Scheme 1 3 ) . The i n t e r m e d i a t e v i n y l s i l a n e 75 was p r e p a r e d f r o m 3 - m e t h y l - 2 - c y c l o h e x e n -1-one (76) i n s e v e r a l c o n v e n t i o n a l s t e p s . C y c l i s a t i o n o f 75_ p r o v i d e d 78 77 C/^O Scheme 13 — t h e c i s - e n o n e 77 w i t h 1 1 - o x y g e n f u n c t i o n a l i t y . The c o r r e s p o n d i n g t r a n s - e n o n e 78 was f o r m e d by i s o m e r i s a t i o n o f 77 w i t h _ p _ - t o l u e n e s u l p h o n i c a c i d . The t r a n s - s t e r e o c h e m i s t r y i s r e q u i r e d f o r s t e r e o s e l e c t i v e i n t r o d u c t i o n o f a s i d e c h a i n a t C ( 2 0 ) ( c f . Schemes 14 and 1 5 ) . 1.3 A p p r o a c h e s t o t he C/D R i n g Sys tem o f S t e r o i d s w i t h F u n c t i o n a l i s e d  S i d e C h a i n s R e p r e s e n t a t i v e e x a m p l e s o f s t e r o i d s p o s s e s s i n g f u n c t i o n a l i s e d s i d e c h a i n s i n c l u d e c h o l e s t e r o l ( 7 9 ) , c h o l e c a l c i f e r o l ( v i t a m i n D^) ( 8 0 ) , t h e p l a n t s t e r o i d s t i g m a s t e r o l (81) and t h e b i l e a c i d c h o l i c a c i d ( 8 2 ) • The b i o l o g i c a l a c t i v i t y o f s t e r o i d s w i t h f u n c t i o n a l i s e d s i d e c h a i n s h a s p romp ted c o n s i d e r a b l e r e s e a r c h i n t o t h e i r s y n t h e s i s . I n p a r t i c u l a r , 17 t h e r e h a s been i n t e r e s t i n v i t a m i n D. (80) and i t s m e t a b o l i t e s . These hormones r e g u l a t e c a l c i u m and p h o s p h a t e i o n c o n c e n t r a t i o n i n b l o o d p l a s m a . The m a j o r i t y o f r e c e n t i n v e s t i g a t i o n s i n t h i s a r e a have c o n c e n t r a t e d on t h e i n i t i a l c o n s t r u c t i o n o f t h e C/D r i n g s y s t e m . The s t r u c t u r a l s u b - u n i t s o f s y n t h e t i c i n t e r e s t c a n be r e p r e s e n t e d by t r a n s - h y d r i n d a n o n e d e r i v a t i v e s s u c h as 83 and 8 4 . S y n t h e t i c a p p r o a c h e s 0 83 84 18 t o t h e s e s t r u c t u r a l s u b - u n i t s o f s t e r o i d s r e q u i r e methods f o r c o n t r o l l i n g the s t e r e o c h e m i s t r y a t t h e C ( 1 3 ) , C ( 1 4 ) , C (17 ) and C (20 ) p o s i t i o n s . An o u t l i n e o f r e c e n t l y p u b l i s h e d a p p r o a c h e s i s p r o v i d e d b e l o w . 36 37 S e v e r a l r e s e a r c h g r o u p s , n o t a b l y t h o s e o f L y t h g o e , T r o s t and 38 J o h n s o n have u s e d t h e ' I n h o f f e n d i o l ' 8_5 a s a k e y i n t e r m e d i a t e i n t h e s y n t h e s i s o f s y s t e m s i n c o r p o r a t i n g a f u n c t i o n a l i s e d s i d e c h a i n . 36 J o h n s o n and c o - w o r k e r s s y n t h e s i s e d t he I n h o f f e n d i o l (85) (Scheme 14) i n 48% o v e r a l l y i e l d f r o m t h e b r o m i d e 8 6 . The k e y s t e p i n t h e s y n t h e s i s Scheme 14 was t h e L e w i s - a c i d c a t a l y s e d c y c l i s a t i o n o f t he a c e t a l 8_7 t o p r o v i d e t h e t r a n s - h y d r i n d a n e d e r i v a t i v e 88_ i n h i g h c h e m i c a l and o p t i c a l y i e l d . Remova l o f t h e c h i r a l a u x i l i a r y and a c e t y l a t i o n gave t h e b i c y c l i c a c e t a t e 89_ w h i c h unde rwen t h y d r o g e n a t i o n t o g i v e t h e c i s - o l e f i n 9 0 . The I n h o f f e n d i o l (85) was t h e n fo rmed f r o m 90_ u s i n g m e t h o d o l o g y d e v e l o p e d 39 by U s k o k o v i c and c o - w o r k e r s ( c f . Scheme 1 5 ) . 19 U s k o k o v i c and c o - w o r k e r s u s e d k e t o a c i d 91^ as a c h i r a l i n t e r m e d i a t e and t r a n s f o r m e d i t i n t o t h e b i c y c l i c k e t o n e 92 p r e v i o u s l y 41 r e p o r t e d by Windaus and Grundmann (Scheme 1 5 ) . S t e r e o s e l e c t i v e h y d r o g e n a t i o n o f k e t o a c i d 91 gave a t r a n s - h y d r i n d a n e d e r i v a t i v e w h i c h 92 96 95 Scheme 15 was c o n v e r t e d v i a t h e m e t h y l k e t o n e 9 3 , t o t h e c i s - o l e f i n 9 4 . The c r u c i a l r e a c t i o n t o i n t r o d u c e t h e c o r r e c t a b s o l u t e s t e r e o c h e m i s t r y a t C ( 2 0 ) was a c c o m p l i s h e d by an ene r e a c t i o n w i t h e t h y l p r o p i o l a t e t o g i v e d i e n e e s t e r 95_. S t e r e o s e l e c t i v e h y d r o g e n a t i o n o f 95_ e s t a b l i s h e d t he c o r r e c t a b s o l u t e s t e r e o c h e m i s t r y a t C (17 ) and s u b s e q u e n t r e d u c t i o n o f t he e s t e r g roup p r o v i d e d a l d e h y d e 96_. I n t e r m e d i a t e 96_ was c o n v e r t e d i n a s e r i e s o f c o n v e n t i o n a l s t e p s t o t h e Windaus and Grundmann k e t o n e 9 2 . C o u p l i n g o f k e t o n e 92_ w i t h an A r i n g component l e d t o t h e f i r s t t o t a l s y n t h e s i s o f ( + ) - l c t , 2 5 - d i h y d r o x y c h o l e c a l c i f e r o l ( 9 7 ) . U s k o k o v i c and 20 c o - w o r k e r s l a t e r d e v i s e d r o u t e s t o c a l c i t r i o l l a c t o n e (98) and l a , 2 5 ( S ) 2 6 - t r i h y d r o x y c h o l e c a l c i f e r o l (99) . A 3 44 W i l s o n and Haque u s e d an i n t r a m o l e c u l a r D i e l s - A l d e r r e a c t i o n c o n s t r u c t t he C/D r i n g s y s t e m o f s t e r o i d s (Scheme 1 6 ) . A l l y l i c -TMS HO 100 TMS 101 e - H 105a P-E 105b 104 103 Scheme 16 21 a l c o h o l 100 was c o n v e r t e d i n t o e s t e r 1 0 1 . H o m o - C l a i s e n r e a r r a n g e m e n t o f 101 p r o v i d e d a c i d 1 0 2 , w h i c h was c o n v e r t e d i n t h r e e s t e p s t o t h e a l d e h y d e 1 0 3 . R e a c t i o n o f 103 w i t h t h e d i a n i o n d e r i v e d f r o m l i t h i a t i o n o f 3 - v i n y l - 4 - p e n t e n - l - o l gave t e t r a e n e 1 0 4 . The i n t r a m o l e c u l a r D i e l s -A l d e r c y c l i s a t i o n o f 104 t h e n p r o v i d e d d i e n e s 105a and 105b ( 4 : 1 ) . 45 E x t e n s i o n o f t h i s work i n c l u d i n g a r e s o l u t i o n o f a l c o h o l 1 0 0 , e l a b o r a t i o n o f d i e n e 105a and s u b s e q u e n t c o u p l i n g t o an A r i n g component r e s u l t e d i n an a s y m m e t r i c s y n t h e s i s o f v i t a m i n D^ ( 8 0 ) . 46 T s u j i and c o - w o r k e r s s y n t h e s i s e d t h e h y d r i n d e n o n e 106 by a s y n t h e t i c r o u t e f r o m 108 w h i c h f e a t u r e d two C l a i s e n r e a r r a n g e m e n t s (Scheme 1 7 ) . The f i r s t C l a i s e n r e a r r a n g e m e n t o f t h e e t h e r f o r m e d by 106 107 110 Scheme 17 22 r e a c t i o n o f 108 w i t h t r i e t h y l o r t h o h e x e n a t e p r o v i d e d e s t e r 109 and e s t a b l i s h e d t h e c o r r e c t C ( 1 7 ) s t e r e o c h e m i s t r y . A s e r i e s o f s t e p s c o n v e r t e d 109 t o t h e v i n y l a l l y l e t h e r 1 1 0 , w h i c h underwen t a s e c o n d C l a i s e n r e a r r a n g e m e n t t o p r o v i d e a l d e h y d e 1 0 7 . O x i d a t i o n o f t h e t e r m i n a l d o u b l e bond o f 107 t o t h e m e t h y l k e t o n e , d e c a r b o n y l a t i o n o f t h e a l d e h y d e g roup and an a l d o l c o n d e n s a t i o n p r o v i d e d t h e h y d r i n d e n o n e 106 . 47 Desmae le and c o - w o r k e r s d e v i s e d a r o u t e t o t h e t r a n s - h y d r i n d a n e s u l p h o n e d e r i v a t i v e 111 (Scheme 1 8 ) . R e a c t i o n o f ynamine 112 w i t h 111 116 115 Scheme 18 2 - m e t h y l c y c l o p e n t e n o n e (113) gave t h e c y c l o b u t e n y l a m i n e (114) w h i c h was h y d r o l y s e d t o t h e s u b s t i t u t e d c y c l o p e n t a n o n e 1 1 5 . R e s o l u t i o n o f 115 f o l l o w e d by a s e r i e s o f c o n v e n t i o n a l s t e p s p r o v i d e d h y d r i n d e n o n e 116 . 23 S e v e r a l more s t e p s l e d t o t h e s u l p h o n e d e r i v a t i v e 111 u s i n g a p r o c e d u r e 48 d e v e l o p e d by L y t h g o e and Wa te rhouse i n t h e i r s y n t h e s i s o f l a - h y d r o x y p r e c a l c i f e r o l ( 1 1 7 ) . Z i e g l e r and M e n c e l u s e d an a n i o n i c o x y - C o p e r e a r r a n g e m e n t as t he k e y s t e p i n t h e s y n t h e s i s o f r a c e m i c t r a n s - h y d r i n d a n o n e 118 (Scheme 1 9 ) . 1 , 2 - A d d i t i o n o f d i t h i a n e 1 1 9 , d e r i v e d f r o m c r o t o n a l d e h y d e , 123 122 121 if 124 125 118 Scheme 19 24 t o 2 - m e t h y l c y c l o p e n t e n o n e (113) f o l l o w e d by an a n i o n i c o x y - C o p e r e a r r a n g e m e n t y i e l d e d e n o l a t e 1 2 0 . I n t e r m e d i a t e 120 was a l k y l a t e d ' i n s i t u ' w i t h a l l y l b r o m i d e t o g i v e k e t e n e d i t h i o a c e t a l 1 2 1 . T h i s e l e g a n t o n e - p o t p r o c e d u r e c o n t r o l l e d t h e s t e r e o c h e m i s t r y a t t h e C (17 ) and 0 ( 2 0 ) p o s i t i o n s . The k e t e n e d i t h i o a c e t a l 121 was c o n v e r t e d t o t h e m e t h y l e s t e r 1 2 2 . S e v e r a l c o n v e n t i o n a l r e a c t i o n s t h e n p r o v i d e d t h e k e t o a c i d 123 w i t h a s i x - c a r b o n s i d e c h a i n u n i t a t t a c h e d t o C ( 2 0 ) . The C r i n g was f o r m e d v i a e n o l l a c t o n e 124 t o p r o v i d e t h e h y d r i n d e n o n e 125 w h i c h was c o n v e r t e d by s t e r e o s e l e c t i v e r e d u c t i o n and e s t e r i f i c a t i o n to ' t h e t r a n s - h y d r i n d a n o n e 1 1 8 . F u k u m o t o , K a m e t a n i , and c o - w o r k e r s ' ^ d e v i s e d a r o u t e (Scheme 20) t o t h e t r a n s - h y d r i n d a n e s u l p h o n e d e r i v a t i v e 1 2 6 . The c h i r a l Scheme 20 25 h y d r i n d e n e d i o n e 127 was c o n v e r t e d i n s e v e r a l s t e p s t o t h e b i c y c l i c i n t e r m e d i a t e 1 2 8 . O z o n o l y s i s o f 128 f o l l o w e d by h y d r o l y s i s and a c e t a l i s a t i o n p r o v i d e d a c i d a c e t a l 1 2 9 . The c a r b o x y l i c a c i d g roup was c o n v e r t e d t o a m e t h y l g roup and a o n e - c a r b o n h o m o l o g a t i o n p r o v i d e d m o n o c y c l i c a l k e n e 1 3 0 . The C r i n g was t h e n c o n s t r u c t e d by i n t r a m o l e c u l a r a l k y l a t i o n o f t h e m e s y l a t e 131 t o g i v e t h e t r a n s - h y d r i n d a n e s u l p h o n e d e r i v a t i v e 1 2 6 . 26 2 . DISCUSSION The o b j e c t i v e o f t h i s i n v e s t i g a t i o n was t o d e v e l o p an e n a n t i o s p e c i f i c s y n t h e t i c r o u t e f r o m ( + ) - 9 , 1 0 - d i b r o m o c a m p h o r (18) t o t h e C/D r i n g s y s t e m and s i d e c h a i n o f s t e r o i d s c o n t a i n i n g 1 1 - o x y g e n f u n c t i o n a l i t y . The t a r g e t m o l e c u l e i s r e p r e s e n t e d by t he h y d r i n d e n o n e 132 w h i c h h a s t h e c o r r e c t a b s o l u t e s t e r e o c h e m i s t r y a t C ( 1 3 ) , C ( 1 7 ) and C ( 2 0 ) . The s y n t h e t i c s t r a t e g y (Scheme 21) i n v o l v e d t he c o n v e r s i o n o f ( + ) - 9 , 1 0 - d i b r o m o c a m p h o r (18) v i a t h e d i n i t r i l e 133 t o t h e c o r r e s p o n d i n g d i e s t e r 1 3 4 . A c y l o i n c y c l i s a t i o n o f t h i s d i e s t e r w o u l d t h e n y i e l d t h e 132 Scheme 21 27 t r i c y c l i c compound 135 w h i c h wou ld be e x p e c t e d t o unde rgo o x i d a t i v e c l e a v a g e t o p r o v i d e t he h y d r i n d e n e 136 . S t e r e o s e l e c t i v e a l k y l a t i o n o f t he c o r r e s p o n d i n g e s t e r 137 w o u l d p r o v i d e the t a r g e t m o l e c u l e 132 and w o u l d e n a b l e a v a r i e t y o f s i d e c h a i n s t o be i n t r o d u c e d a t C (20 ) w i t h t he d e s i r e d ' R ' - c o n f i g u r a t i o n . ( + ) - 9 , 1 0 - D i b r o m o c a m p h o r (18) was s y n t h e s i s e d f r om ( + ) - 3 - e n d o -bromocamphor (4) f o l l o w i n g p r e v i o u s l y d e v e l o p e d b r o m i n a t i o n p r o c e d u r e s . 5 » l ? » 2 3 c f £ r g t g t e p £ n t h e s y n t h e t i c p l a n was t h e c o n v e r s i o n o f ( + ) - 9 , 1 0 - d i b r o m o c a m p h o r (18) t o t h e c o r r e s p o n d i n g d i n i t r i l e . P r e v i o u s a t t e m p t s i n o u r l a b o r a t o r y t o s y n t h e s i s e t h e d i n i t r i l e 139 by r e a c t i o n o f the e t h y l e n e k e t a l o f ( + ) - 9 , 1 0 - d i b r o m o c a m p h o r (138) w i t h s o d i u m c y a n i d e i n DMSO (o r DMF, HMPA, DMPU) were c o m p l i c a t e d by f r a g m e n t a t i o n o f t h e C ( l ) - C ( 2 ) b o n d . ^ c ' ^ T h i s f r a g m e n t a t i o n p r o v i d e d t h e m o n o c y c l i c compound 140 i n a d d i t i o n t o t h e d e s i r e d d i n i t r i l e 1 3 9 . To overcome t h i s f r a g m e n t a t i o n , i t was d e c i d e d t o r e d u c e ( + ) - 9 , 1 0 -139 H O ^ ^ o ^ X = B r o r CN 140 d ib romocamphor (18) and p r o t e c t t h e c o r r e s p o n d i n g a l c o h o l . R e d u c t i o n o f 18 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 p r o c e e d e d s m o o t h l y t o p r o v i d e 9 , 1 0 -d i b r o m o i s o b o r n e o l J_41 i n 92% y i e l d . C a p i l l a r y g l c ( O V - 1 0 1 , 190°C) and *H 400 MHz nmr showed t h e p r e s e n c e o f a s i n g l e e p i m e r . By a n a l o g y w i t h 28 52 t h e c o r r e s p o n d i n g r e d u c t i o n o f camphor (1) t h i s was assumed t o be t h e e x o - a l c o h o l 1 4 1 . Endo a t t a c k o f t h e h y d r i d e i o n i s f a v o u r e d o v e r exo a t t a c k , as t h e exo pa thway i s b l o c k e d by t h e C (7 ) m e t h y l g r o u p . N ^ B r HO, VS* H 141 The s e c o n d a r y a l c o h o l g roup was p r o t e c t e d as t he t e r t - b u t y l d i m e t h y l -s i l y l e t h e r . T r e a t m e n t o f 141 w i t h TBDMS t r i f l a t e and 2 , 6 - l u t i d e n e 53 i n d i c h l o r o m e t h a n e p r o v i d e d 9 , 1 0 - d i b r o m o i s o b o r n y l TBDMS e t h e r (142) i n h i g h y i e l d (90%) . The e t h e r 142 was t h e n r e a c t e d w i t h s o d i u m c y a n i d e i n DMF t o p r o v i d e 9 , 1 0 - d i c y a n o i s o b o r n y l TBDMS e t h e r (143) i n 96% y i e l d . The S^2 r e a c t i o n o f 142 was f a c i l i t a t e d by t he a d d i t i o n o f a c a t a l y t i c amount o f p o t a s s i u m i o d i d e . 141 142 143 144 The n e x t s t e p was t h e c o n v e r s i o n o f t h e d i n i t r i l e 143 t o t h e c o r r e s p o n d i n g d i e s t e r 144 . H o w e v e r , t he f i r s t a t t e m p t e d h y d r o l y s i s o f t h e n i t r i l e g r o u p s o f 143 w i t h 40% p o t a s s i u m h y d r o x i d e i n e t h y l e n e g l y c o l d i d n o t p r o v i d e t h e e x p e c t e d d i a c i d 1 4 5 . The i n f r a r e d s p e c t r u m o f t h e c r u d e p r o d u c t showed bands a t 3 6 0 0 - 2 4 5 0 cm * and 1710 cm * w h i c h 29 a r e t y p i c a l o f c a r b o x y l i c a c i d f u n c t i o n a l i t y . H o w e v e r , an a d d i t i o n a l c a r b o n y l s t r e t c h a t 1755 cm * was e v i d e n t . T r e a t m e n t o f t h e n i t r i l e h y d r o l y s i s p r o d u c t w i t h e t h e r e a l d i a z o m e t h a n e p r o v i d e d a w h i t e c r y s t a l l i n e s o l i d (55% y i e l d ) , w h i c h e x h i b i t e d a s h a r p m e l t i n g p o i n t ( 8 9 . 5 ° C ) . The i n f r a r e d s p e c t r u m showed two c a r b o n y l p e a k s ; one a t 1735 cm * c o r r e s p o n d i n g t o t h e e x p e c t e d m e t h y l e s t e r g roup and an a d d i t i o n a l peak a t 1775 cm \ w h i c h was c h a r a c t e r i s t i c o f a 5-membered l a c t o n e . I t was e v i d e n t t h a t a f t e r t h e s i l y l p r o t e c t i n g g roup h a d - J - S i O CN CN 0. >1 143 145 146 c l e a v e d (as e x p e c t e d i n s t r o n g b a s e ) , t h e h y d r o x y d i a c i d p r o d u c t 145 h a d c y c l i s e d t o p r o v i d e t h e a c i d l a c t o n e 146 i n t h e a c i d i c w o r k - u p c o n d i t i o n s . S u b s e q u e n t t r e a t m e n t o f 146 w i t h e t h e r e a l d i a z o m e t h a n e p r o v i d e d t he e s t e r l a c t o n e 1 4 7 . °nb —. ° C02Me 146 147 To p r e v e n t l a c t o n e f o r m a t i o n i t was d e c i d e d t o u s e an a l t e r n a t i v e p r o t e c t i n g g roup w h i c h w o u l d n o t c l e a v e u n d e r t h e n i t r i l e h y d r o l y s i s 30 c o n d i t i o n s . The m e t h o x y e t h o x y m e t h y l (MEM) g roup was c h o s e n due t o i t s s t a b i l i t y i n s t r o n g b a s e . I t w o u l d a l s o have t h e a d v a n t a g e o f p r o t e c t i n g t h e a l c o h o l g roup i n a s u b s e q u e n t a c y l o i n c o n d e n s a t i o n . 9 , 1 0 - D i b r o m o i s o b o r n y l MEM e t h e r (148) was p r e p a r e d (Scheme 22) i n 45% y i e l d u s i n g t h e p r o c e d u r e (MEM t r i e t h y l a m m o n i u m c h l o r i d e i n 54 a c e t o n i t r i l e ) r e p o r t e d b y C o r e y and c o - w o r k e r s . The l o w y i e l d f o r t h e p r o t e c t i o n s t e p was a t t r i b u t e d t o t h e u s e o f impure MEM r e a g e n t w h i c h was a y e l l o w o i l i n s t e a d o f a w h i t e c r y s t a l l i n e s o l i d . The MEM e t h e r 148 was c o n v e r t e d t o t h e d i n i t r i l e d e r i v a t i v e 9 , 1 0 - d i c y a n o -i s o b o r n y l MEM e t h e r (149) i n 61% y i e l d . Subsequen t n i t r i l e h y d r o l y s i s gave d i a c i d 150 w i t h e x p e c t e d r e t e n t i o n o f t h e MEM p r o t e c t i n g g r o u p . E s t e r i f i c a t i o n w i t h d i a z o m e t h a n e p r o v i d e d d i m e t h y l e s t e r 151 i n 54% y i e l d f r o m t h e d i n i t r i l e 1 4 9 . H o w e v e r , as h i g h e r y i e l d s were o b t a i n e d f r o m 9 , 1 0 - d i b r o m o i s o b o r n e o l 141 t o t h e c o r r e s p o n d i n g p r o t e c t e d d i n i t r i l e w i t h t he TBDMS g r o u p , i t was d e c i d e d t o r e v e r t t o t h e u s e o f t h i s p r o t e c t i n g g r o u p . I n t he p r o b l e m a t i c d i n i t r i l e h y d r o l y s i s ( 1 4 3 - 1 4 5 ) l a c t o n e f o r m a t i o n was e l i m i n a t e d by -Scheme 22 31 m o d i f y i n g t h e w o r k - u p p r o c e d u r e . The b a s i c r e a c t i o n m i x t u r e was c a r e f u l l y a c i d i f i e d w i t h 0 .1 N h y d r o c h l o r i c a c i d and i m m e d i a t e l y e x t r a c t e d w i t h e t h y l a c e t a t e t o p r e v e n t p r o l o n g e d e x p o s u r e o f t h e h y d r o x y d i a c i d 145 t o a c i d i c c o n d i t i o n s w h i c h f a v o u r l a c t o n e f o r m a t i o n . E s t e r i f i c a t i o n w i t h e t h e r e a l d i a z o m e t h a n e p r o v i d e d t he d i m e t h y l 143 145 152 e s t e r 152 i n 75% o v e r a l l y i e l d f r o m t h e d i n i t r i l e 1 4 3 . R e p r o t e c t i o n as t h e TBDMS e t h e r p r o v i d e d 144 i n 91% y i e l d . HO C 0 2 M e C0 2 Me -j-SiO • I C0 2 Me C0 2 Me 152 144 The a c y l o i n c o n d e n s a t i o n was emp loyed t o p r e p a r e t h e t r i c y c l i c s i l y l a t e d e n e d i o l a t e 154 f r o m d i e s t e r 144 . The f i r s t a t t e m p t e d C02Me C02Me -f-SiO 144 153 154 32 a c y l o i n c o n d e n s a t i o n was c a r r i e d ou t by r e f l u x i n g d i e s t e r 144 w i t h s o d i u m and t r i m e t h y l s i l y l c h l o r i d e (TMSC1) f o r 16 h i n d r y t o l u e n e . I n t h e s e m o d i f i e d a c y l o i n c o n d i t i o n s ( o f t e n r e f e r r e d t o as Ruh lmann c o n d i t i o n s ^ ) TMSC1 was added t o t r a p t h e i n t e r m e d i a t e e n e d i o l a t e 153 and i n h i b i t t h e o c c u r r e n c e o f a c o m p e t i n g D ieckmann c o n d e n s a t i o n . H o w e v e r , t h e o n l y c h a r a c t e r i s e d ' p r o d u c t ' r e c o v e r e d a f t e r w o r k - u p was u n r e a c t e d s t a r t i n g m a t e r i a l 144 . The r e a c t i o n was r e p e a t e d s e v e r a l t i m e s , t a k i n g e x t r a c a r e t o e x c l u d e a i r and m o i s t u r e b u t t h e r e was s t i l l no e v i d e n c e o f t h e s i l y l a t e d e n e d i o l a t e 154 . A l t h o u g h many s u c c e s s f u l a c y l o i n c y c l i s a t i o n s u s i n g t h e s e c o n d i t i o n s have been 56 r e p o r t e d , t h e o n l y r e a s o n a b l e y i e l d r e p o r t e d f o r 6-membered r i n g f o r m a t i o n i s t h e a c y l o i n c o n d e n s a t i o n o f d i m e t h y l a d i p a t e (154) w h i c h p r o v i d e s t h e s i l y l a t e d e n e d i o l a t e 1 5 6 . ^ 6 > 5 7 , 5 8 S i n c e t h e s e r e a c t i o n c o n d i t i o n s d i d n o t p r o v i d e t h e d e s i r e d p r o d u c t i t was d e c i d e d t o u s e a s o d i u m - p o t a s s i u m a l l o y i n a n h y d r o u s 59 e t h e r , i n s t e a d o f s o d i u m i n t o l u e n e . B l o o m f i e l d u s e d t h e s e c o n d i t i o n s t o f o r m the t r i c y c l i c 6-membered s i l y l a t e d e n e d i o l a t e s 158 and 160 i n o v e r 80% y i e l d f r o m t h e c o r r e s p o n d i n g d i e s t e r s 157 and 1 5 9 . A n a l o g o u s l y , i t was hoped t h a t t h e s i l y l a t e d e n e d i o l a t e 154 w o u l d f o r m 155 156 33 w i t h t h e u s e o f a more p o w e r f u l r e d u c i n g agen t and t h a t u s e o f e t h e r as a s o l v e n t w o u l d m i n i m i s e any s i d e - r e a c t i o n s . I n t h e i n i t i a l 159 160 e x p e r i m e n t w i t h s o d i u m - p o t a s s i u m a l l o y , t h e d e s i r e d s i l y l a t e d e n e d i o l a t e 154 was i n d e e d i s o l a t e d , a l t h o u g h some s t a r t i n g d i e s t e r 144 was a l s o e v i d e n t . The p r o b l e m o f u n r e a c t e d s t a r t i n g d i e s t e r 144 was overcome i n s u b s e q u e n t e x p e r i m e n t s by u s i n g a l a r g e r e x c e s s o f s o d i u m - p o t a s s i u m a l l o y and by i n c r e a s i n g t h e p o t a s s i u m : s o d i u m r a t i o . T h i s r e s u l t e d i n a n 86% y i e l d o f s i l y l a t e d e n e d i o l a t e 1 5 4 . The i n f r a r e d s p e c t r u m o f 154 showed a c h a r a c t e r i s t i c v i n y l e t h e r band a t 1690 cm t h e mass s p e c t r a showed t h e p a r e n t peak and an i n t e n s e f r agmen t a t m/e 73 [ l o s s o f ( C H 3 > 3 S i ] and t h e 1 H nmr ( C D C 1 3 > 270 MHz) s p e c t r u m showed the p r e s e n c e o f t h e t r i m e t h y l s i l y l o x y p r o t o n s . S i l y l a t e d e n e d i o l a t e s a r e s t a b l e u n d e r n o n - h y d r o l y t i c c o n d i t i o n s b u t a r e r e a d i l y c l e a v e d t o t he c o r r e s p o n d i n g a c y l o i n by a l c o h o l y s i s o r 34 a c i d - c a t a l y s e d h y d r o l y s i s . I t was d e c i d e d t o t r e a t 154 w i t h m e t h a n o l s i n c e a c i d i c c o n d i t i o n s w o u l d p r o b a b l y c l e a v e t h e TBDMS g roup and p r o v i d e a p r o d u c t w i t h two s e c o n d a r y a l c o h o l g r o u p s . The c r u d e s i l y l a t e d e n e d i o l a t e 154 was r e f l u x e d i n d r y m e t h a n o l and p r o v i d e d a 1:1 m i x t u r e o f t h e i s o m e r i c a c y l o i n s 161 and 162 i n 48% y i e l d f r o m t h e d i e s t e r 144 ( b a s e d on r e c o v e r e d 1 4 4 ) . The i s o m e r s were s e p a r a t e d by co lumn c h r o m a t o g r a p h y and a c y l o i n 161 was c o n v e r t e d t o t h e c o r r e s p o n d i n g k e t o a c e t a t e 163 i n 76% y i e l d . 144 154 161 162 The s t r a t e g y was t h e n t o c l e a v e t h e TBDMS g roup t o g i v e d e p r o t e c t e d k e t o a c e t a t e 164 f o l l o w e d by CAN o x i d a t i v e c l e a v a g e o f 164 t o p r o v i d e t h e h y d r i n d e n o n e 1 6 5 . H o w e v e r , on r e p e a t i n g t h e m e t h a n o l y s i s s t e p , a g a i n w i t h c r u d e 154 no f r e e a c y l o i n s were i s o l a t e d . I n s t e a d , t he i s o m e r i c m e t h o x y k e t o n e s 166 and 167 ( 1 : 1 , 74% y i e l d ) were i s o l a t e d . The i n f r a r e d s p e c t r u m o f 166 and 167 showed no -OH s t r e t c h and t h e mass 35 154 166 167 s p e c t r a l d a t a showed a p a r e n t peak 14 amu h i g h e r t h a n t h e c o r r e s p o n d i n g a c y l o i n s 161 and 1 6 2 . P r o t o n nmr (CDC1 3» 400 MHz) c o n f i r m e d t h e p r e s e n c e o f t he m e t h y l e t h e r g r o u p . The m e t h o x y k e t o n e 166 was d e p r o t e c t e d w i t h f l u o r i d e i o n i n THF t o p r o v i d e t he a l c o h o l 1 6 8 . The s t r u c t u r e o f 168 was u n a m b i g u o u s l y c o n f i r m e d by X - r a y c r y s t a l l o g r a p h i c a n a l y s i s ( A p p e n d i x 2 ) . The m e t h y l e t h e r was shown t o o c c u p y t h e e q u a t o r i a l p r o s i t i o n i n t h e t r i c y c l i c s y s t e m . The i s o l a t i o n o f t h e m e t h o x y k e t o n e s 166 and 167 was an u n e x p e c t e d r e s u l t . No p r e c e d e n t f o r t h i s r e a c t i o n was f o u n d i n t h e l i t e r a t u r e , a l t h o u g h i t s h o u l d be n o t e d t h a t t h e s e a l c o h o l y s i s r e a c t i o n s were p e r f o r m e d on p u r i f i e d s i l y l a t e d e n e d i o l a t e s . I n o u r c a s e , t h e m e t h a n o l y s i s was p e r f o r m e d on t he c r u d e s i l y l a t e d e n e d i o l a t e . One h y p o t h e s i s i s t h a t some TMSC1 was s t i l l p r e s e n t w h i c h w o u l d r e a c t w i t h t h e m e t h a n o l t o p r o v i d e h y d r o c h l o r i c a c i d . A s o l u t i o n o f t he M e 3 S i C l + MeOH > M e 3 S i O C H 3 + H C l 36 c r u d e s i l y l a t e d e n e d i o l a t e 154 i n m e t h a n o l was s u b s e q u e n t l y f o u n d t o be a c i d i c t o l i t m u s . I n t he a c i d h y d r o l y s i s o f s i l y l a t e d e n e d i o l a t e s . T 169 H OH 170 M e 3 S i O S i M e 3 171 r e p r e s e n t e d by 1 6 9 , t h e p r o d u c t s a r e t h e a c y l o i n 170 and t h e d i s i l y l e t h e r 171 . ^ " * A mechan ism c o n s i s t e n t w i t h t h i s r e s u l t i s shown i n Scheme 23 37 Scheme 2 3 . P r o t c r a a t i o n o f t h e s i l y l a t e d e n e d i o l a t e 169 f o l l o w e d by n u c l e o p h i l i c a t t a c k o f w a t e r p r o v i d e s i n t e r m e d i a t e 172 . T h i s i n t e r m e d i a t e 172 c a n t h e n unde rgo d e s i l y l a t i o n t o p r o v i d e t h e d i s i l y l e t h e r 1 7 1 . L o s s o f a p r o t o n f r o m t h e oxon ium i o n i n t e r m e d i a t e 173 and s u b s e q u e n t t a u t o m e r i s a t i o n p r o v i d e s t h e a c y l o i n 1 7 0 . I n o u r c a s e , m e t h a n o l y s i s o f 154 i n a n h y d r o u s a c i d i c c o n d i t i o n s (Scheme 24) w i l l p r o v i d e t h e m e t h o x y k e t o n e s 166 and 1 6 7 . P r o t o n a t i o n o f t h e s i l y l a t e d e n e d i o l a t e 154 f o l l o w e d by n u c l e o p h i l i c a t t a c k o f m e t h a n o l w i l l p r o v i d e i n t e r m e d i a t e 174 . D e s i l y l a t i o n f o l l o w e d by l o s s o f a p r o t o n p r o v i d e s i n t e r m e d i a t e 1 7 5 , w h i c h t a u t o m e r i s e s t o t he m e t h o x y k e t o n e s 166 and 1 6 7 . 154 154a 154b -H 4 171 174a 174 175 166 Scheme 24 38 In subsequent methanolysis r e a c t i o n s of the s i l y l a t e d enediolate 154, a large excess of TMSC1 was added with the methanol. I t was hoped that t h i s would ensure methoxyketone formation and have the a d d i t i o n a l advantage of c l e a v i n g the TBDMS group under the a c i d i c c o n d i t i o n s . This e x p e c t a t i o n was r e a l i s e d and a c i d i c methanolysis of 154 provided a 1:1 mixture of the deprotected methoxyketones 168 and 176 i n 64% o v e r a l l y i e l d from the d i e s t e r 144. -T-SfO I OSiMej OSi'Mej 154 168 176 Oxidative cleavage of the C(l)- C ( 2 ) bond of the camphor skeleton (Scheme 25) was r e a d i l y accomplished with C A N ^ ' ^ f o l l o w i n g experimental procedure used by Stevens and co-workers ( c f . Scheme 7) on s i m i l a r borneol 2 A 62 and i s o b o r n e o l systems. ' This provided the isomeric aldehydes 178 and 180, and e s t a b l i s h e d the c o r r e c t absolute stereochemistry at C(13) and C(17). The r e a c t i o n of CAN with methoxyketones 168 and 176 • O M e MeO-T*-—L 0 H 168 177 178 39 r e s u l t e d i n t h e a p p e a r a n c e o f a deep r e d c o l o u r w h i c h was a t t r i b u t e d t o the f o r m a t i o n o f a 1:1 C A N : a l c o h o l c o m p l e x . The r e d c o l o u r f a d e d r a d i c a l i n t e r m e d i a t e s 177 and 1 7 9 . Due t o t h e u n s t a b l e n a t u r e o f t h e a l d e h y d e s 178 and 1 8 0 , o n l y p a r t i a l p u r i f i c a t i o n was a c h i e v e d by co lumn c h r o m a t o g r a p h y . H o w e v e r , t h e s p e c t r a l d a t a o f t he c r u d e k e t o a l d e h y d e s 178 and 180 was c o n s i s t e n t w i t h t h e p r o p o s e d s t r u c t u r e s i n w h i c h t he d o u b l e bond i s i n t he 6-membered r i n g i n 178 and i n t h e 5-membered r i n g i n 1 8 0 . A band a t 1675 cm * i n t he i n f r a r e d s p e c t r u m o f c r u d e 1 7 8 , a s s i g n e d t o t he c o n j u g a t e d k e t o n e g r o u p , i s c o n s i s t e n t w i t h the d o u b l e bond i n t he 6-membered r i n g . The *H nmr o f t h e c o r r e s p o n d i n g k e t o a l d e h y d e 180 showed a d o u b l e t o f d o u b l e t s ( J = 12 H z , 7 Hz) a t 6 3 . 8 3 w h i c h was a s s i g n e d t o t h e C (9 ) m e t h i n e p r o t o n and i s c o n s i s t e n t w i t h t h e d o u b l e bond i n t h e 5-membered r i n g . The a l d e h y d e s 178 and 180 were c o n v e r t e d by J o n e s o x i d a t i o n f o l l o w e d by e s t e r i f i c a t i o n ( d i a z o m e t h a n e ) t o t he c o r r e s p o n d i n g t o a p a l e y e l l o w as t h e o x i d a t i o n t o o k p l a c e . The o x i d a t i v e c l e a v a g e i s p r e s u m a b l y a o n e - e l e c t r o n p r o c e s s ^ and p r o c e e d s v i a t h e f r e e 178 181 0 180 182 40 e s t e r s 181 and 1 8 2 . The o v e r a l l y i e l d f r o m m e t h o x y k e t o n e s 168 and 176 t o 181 and 182 was 53%. The i s o m e r i c e s t e r s 181 and 1 8 2 , r e a d i l y s e p a r a t e d by co lumn c h r o m a t o g r a p h y , e x h i b i t e d s p e c t r a l d a t a c o n s i s t e n t w i t h t h e p r o p o s e d s t r u c t u r e s . I n t h e 400 MHz *H nmr s p e c t r u m o f 181 ( F i g u r e 1 ) , t h e m e t h i n e p r o t o n (H ) a p p e a r e d as a d o u b l e t o f d o u b l e t s ( J = 14 H z , 5 Hz) a t 6 3 . 9 5 due t o c o u p l i n g w i t h p r o t o n s H^ and H g , t h e l a r g e and s m a l l c o u p l i n g c o n s t a n t s c o n s i s t e n t w i t h i t s a x i a l p o s i t i o n . The v i n y l p r o t o n ( H ^ ) a p p e a r e d a s a t r i p l e t a t 6 5 . 7 8 ( J = 2 Hz ) due t o a l l y l i c c o u p l i n g w i t h p r o t o n s H^, and H^,. F u r t h e r c o n f i r m a t i o n o f t h e s t r u c t u r e was o b t a i n e d f r o m t h e i n f r a r e d ( i r ) s p e c t r u m , w h i c h showed a s t r o n g a b s o r p t i o n a t 1675 cm c h a r a c t e r i s t i c o f a c o n j u g a t e d k e t o n e . 5 4 t 2 1 PP° ° 400 MHz H nmr F i g u r e 1 41 I n t h e 400 MHz H n o r s p e c t r u m o f 182 ( F i g u r e 2 ) , t he m e t h i n e p r o t o n ( H „ ) a p p e a r e d a s a d o u b l e t o f d o u b l e t s ( J = 14 H z , 7 Hz) a t 6 3 . 0 2 due t o c o u p l i n g w i t h p r o t o n s H ^ and H ^ . The v i n y l p r o t o n ( H j ) a p p e a r e d as a m u l t i p l e t a t 6 5 . 5 2 . T h i s s i g n a l i s u p f i e l d o f t h e c o r r e s p o n d i n g v i n y l p r o t o n (H^) s i g n a l i n 1 8 1 , as i n t h i s i s o m e r t h e d o u b l e bond i s n o t c o n j u g a t e d t o the k e t o n e . C02Me 182 X _ r * L / I l . 4 3 2 1 PP t t c 400 MHz *H nmr F i g u r e 2 The f i n a l s t e p s i n the s y n t h e s i s a r e shown f o r e s t e r 181 i n Scheme 2 5 . P r o t e c t i o n o f t h e k e t o n e w o u l d p r o v i d e k e t a l e s t e r 1 8 3 . I n t r o d u c t i o n o f a s i d e c h a i n u n i t by a l k y l a t i o n o f t he e s t e r 183 a t C ( 2 0 ) i s e x p e c t e d t o g i v e t h e d e s i r e d * R f c o n f i g u r a t i o n a t ^C02Me 181 C02Me MeCK 183 Scheme 25 42 at C(20). The expectation of s t e r o e s e l e c t i v i t y i s based on the r e s u l t s of previous a l k y l a t i o n studies. 63 Wicha and Bal found that a l k y l a t i o n of the s t e r o i d a l systems 185 and 186 with various side chain units gave exclusive formation of the C(20) 'R' alkylated product (187-189). Partridge and co-workers 64 C0 2 Me 185 R= THP 166 R= H C 0 2 M e 20 ^ R 2 187 R *THP, R2= Me 188 Rj* H, R 2 = > C ^ ^ T ^ i i i Ra= H, R2= found that a l k y l a t i o n of the s t e r o i d a l systems 190 and 191 gave 192 and 193 ( l i t t l e or none of the corresponding 'S' alkylated product was ;o2Et X f T 1 I' THPO THPO' 190 X = H 191 X = OTHP 192 X = H 193 X • OTHP detected). In our laboratory, i t was found that a l k y l a t i o n of the c h i r a l ester 194 with various side chains proceeded with 95-100% s t e r e o s e l e c t i v i t y to provide 'R' alkylat e d products 195-198 i n 43 g r e a t e r t h a n 80% y i e l d . 65 The s t e r e o s e l e c t i v e a l k y l a t i o n was e x p l a i n e d by p o s t u l a t i n g e l e c t r o p h i l i c a t t a c k on t he l e s s - h i n d e r e d f a c e o f t h e p r e f e r r e d c o n f o r m a t i o n (199) o f t h e e n o l a t e o f 194 . S t o r k r e c e n t l y u s e d a s i m i l a r s t e r e o s e l e c t i v e a l k y l a t i o n i n t he s y n t h e s i s o f a d r e n o s t e r o n e (40) as shown p r e v i o u s l y i n Scheme 1 0 . T h u s , f r o m t h e above r e s u l t s , a s t e r e o s e l e c t i v e a l k y l a t i o n o f 183 f o l l o w e d by c o n v e r s i o n o f t h e e s t e r t o a m e t h y l g roup and d e k e t a l i s a t i o n i s e x p e c t e d t o p r o v i d e 1 8 4 . T h i s w o u l d c o m p l e t e t h e s y n t h e t i c p l a n as shown i n Scheme 2 1 , w i t h c o n t r o l o f t h e a b s o l u t e s t e r e o c h e m i s t r y a t C ( 1 3 ) , 194 195 R - CH 2 CH=CH 2 196 R = Me 197 R = CH 2 CMe»CH 2 198 R = ( C H 2 ) 3 C H M e 2 199 C(17 ) and C ( 2 0 ) . 44 3 . EXPERIMENTAL G e n e r a l M e l t i n g p o i n t s were d e t e r m i n e d on a K o f l e r m i c r o h e a t i n g s t a g e and a r e u n c o r r e c t e d . I n f r a r e d ( i r ) s p e c t r a were r e c o r d e d on a P e r k i n - E l m e r M o d e l 710B s p e c t r o p h o t o m e t e r and a r e c a l i b r a t e d w i t h t h e 1601 cm band o f p o l y s t y r e n e . A b s o r p t i o n p o s i t i o n s a r e g i v e n i n cm The p r o t o n n u c l e a r m a g n e t i c r e s o n a n c e s p e c t r a (*H nmr) were t a k e n i n d e u t e r o c h l o r o -f o r m and r e c o r d e d a t 270 MHz on a h o m e - b u i l t u n i t c o n s i s t i n g o f an O x f o r d I n s t r u m e n t 6 3 . 4 KG s u p e r c o n d u c t i n g magnet and a N i c o l e t 32 K compu te r and B r u k e r T T - 2 3 c o n s o l e . S p e c t r a a t 300 MHz were r e c o r d e d on a V a r i a n X L - 3 0 0 , and a t 400 MHz on a B r u k e r WH-400 i n s t r u m e n t . S i g n a l p o s i t i o n s a r e g i v e n i n p a r t s p e r m i l l i o n d o w n f i e l d f r o m t e t r a m e t h y l s i l a n e u s i n g t he 6 s c a l e . S i g n a l m u l t i p l i c i t y , c o u p l i n g c o n s t a n t s , and i n t e g r a t e d a r e a s a r e i n d i c a t e d i n p a r e n t h e s e s . Low r e s o l u t i o n mass s p e c t r a were d e t e r m i n e d on a V a r i a n MAT CH-4B mass s p e c t r o m e t e r . The m a j o r i o n f r a g m e n t a t i o n s a r e r e p o r t e d a s p e r c e n t a g e s o f t h e b a s e p e a k , and a r e q u o t e d as m/e_ v a l u e s . E x a c t mass measurements were d e t e r m i n e d by h i g h r e s o l u t i o n mass s p e c t r o s c o p y on a K r a t o s MS50 mass s p e c t r o m e t e r . G a s - l i q u i d c h r o m a t o g r a p h y was p e r f o r m e d on a H e w l e t t - P a c k a r d mode l 5830A gas c h r o m a t o g r a p h , c o n n e c t e d t o a 18835B c a p i l l a r y i n l e t s y s t e m and a 18850A t e r m i n a l . The co l umn ( 1 1 . 0 9 m x 0 . 2 2 mm) was p a c k e d w i t h OV-101 and h e l i u m was u s e d as t h e c a r r i e r g a s . X - r a y c r y s t a l l o g r a p h i c a n a l y s i s was c a r r i e d ou t by D r . S . R e t t i g . M i c r o a n a l y s e s were p e r f o r m e d by M r . P . B o r d a , M i c r o a n a l y t i c a l L a b o r a t o r y , 45 U n i v e r s i t y o f B r i t i s h C o l u m b i a , V a n c o u v e r . F l a s h co lumn c h r o m a t o g r a p h y was p e r f o r m e d u s i n g Merck s i l i c a g e l 6 0 , 2 3 0 - 4 0 0 mesh . T h i n l a y e r c h r o m a t o g r a p h y ( t i c ) was c a r r i e d ou t on Me rck s i l i c a g e l 60 F 2 ^ c o a t e c ^ p l a s t i c s h e e t s . V i s u a l i s a t i o n was e f f e c t e d w i t h a s p r a y o f ammonium m o l y b d a t e i n a 9 :1 e t h a n o l / s u l p h u r i c a c i d s o l u t i o n . A l l r e a c t i o n s i n v o l v i n g a i r o r m o i s t u r e s e n s i t i v e r e a g e n t s were p e r f o r m e d u n d e r an a t m o s p h e r e o f d r y a r g o n u s i n g e i t h e r oven o r f l a m e - d r i e d g l a s s w a r e . The p e t r o l e u m e t h e r was o f b o i l i n g r a n g e 35°C-60°C and was d i s t i l l e d p r i o r t o u s e . D r y s o l v e n t s were p r e p a r e d as f o l l o w s : a c e t o n i t r i l e and d i c h l o r o m e t h a n e by d i s t i l l a t i o n f r o m o c a l c i u m h y d r i d e ; d i m e t h y l f o r m a m i d e by d i s t i l l a t i o n f r o m 4A m o l e c u l a r s i e v e s ; d i e t h y l e t h e r and t e t r a h y d r o f u r a n by r e f l u x i n g o v e r 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 e d by d i s t i l l a t i o n ; t o l u e n e by d i s t i l l a t i o n f r o m c a l c i u m h y d r i d e f o l l o w e d by d i s t i l l a t i o n f r om sod ium and b e n z o p h e n o n e . (+ ) -3 -endo -B romocampho r (4) was o b t a i n e d f r om t h e A l d r i c h C h e m i c a l Company, I n c . ( + ) - 9 , 1 0 - D i b r o m o c a m p h o r (18) was p r e p a r e d f r o m ( + ) - 3 - e n d o - b r o m o -Br Br Br Br 4 5 11 18 i B r 2 / C 1 S 0 3 H / 1 h i i B r 2 / C l S 0 3 H / 5 d i i i B r 2 / H 0 A c / 0 ° C 46 camphor (4) i n 3 s t e p s as shown f o l l o w i n g t h e e x p e r i m e n t a l p r o c e d u r e u s e d by H u t c h i n s o n e t a l . T y p i c a l l y , 100 g -150 g o f ( + ) - e n d o -3-bromocamphor (A) p r o v i d e d 30 g -50 g o f ( + ) - 9 , 1 0 - d i b r o m o c a m p h o r (18) (25% o v e r a l l y i e l d ) . 9 , 1 0 - D i b r o m o i s o b o r n e o l 1A1 To a c o l d (0 C) s o l u t i o n o f ( + ) - 9 , 1 0 - d i b r o m o c a m p h o r (18) i n THF (25 m L ) , was added l i t h i u m a l u m i n i u m h y d r i d e ( 0 . 1 2 g , 3 . 2 0 m m o l ) . A f t e r 3 h 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 o n t o an i c e / 1 N h y d r o c h l o r i c a c i d m i x t u r e and e x t r a c t e d 3 t i m e s w i t h e t h e r . The comb ined e t h e r e a l l a y e r s were washed w i t h w a t e r , d r i e d (MgSO^,) and c o n c e n t r a t e d . P u r i f i c a t i o n by f l a s h c h r o m a t o g r a p h y ( s i l i c a g e l ; p e t r o l e u m e t h e r / e t h e r 5 : 1 ) p r o v i d e d 9 , 1 0 - d i b r o m o i s o b o r n e o l (1A1) as a c o l o u r l e s s o i l ( 1 . 8 5 g , 92%) ; i r ( f i l m ) : 3A00 ( b r ) , 12A0 , 1 0 7 5 , 10A0 c m ' 1 ; « ( C D C 1 3 , A00 M H z ) : 1 .20 ( I H , m ) , 1 .29 ( 3 H , s; CH_ 3 ) , 1 .A6 ( I H , m ) , 1 . 6 3 - 1 . 8 8 ( A H , m ) , 2 . 2 1 ( 2 H , m, 1 p r o t o n e x c h a n g e a b l e w i t h D^), 3 .2A ( I H , d , J - 10 H z ) , 3 . A 7 ( I H , d , J = 10 H z ) , 3 . 5 1 ( I H , d , J - 10 H z ) , * T h i s i s a m o d i f i c a t i o n o f t h e p r o c e d u r e u s e d by Dadson e t a l ^ . A7 3 . 7 7 ( I H , d , J <= 10 H z ) , 4 . 0 1 ( I H , m, c o l l a p s e s t o dd i n D 2 0 , J « 7 H z , 4 H z ; CHOH); m/e ( r e l a t i v e i n t e n s i t y ) : 2 3 3 / 2 3 1 ( M + - B r , 3 / 6 ) , 215 ( 1 4 ) , 213 ( 1 6 ) , 188 ( 7 1 ) , 186 ( 7 3 ) , 151 ( 4 1 ) , 109 ( 5 5 ) , 107 ( 1 0 0 ) ; E x a c t mass c a l c d . f o r C 1 ( ) H 1 6 0 B r 2 - B r : 2 3 3 . 0 3 6 4 / 2 3 1 . 0 3 8 4 ; f o u n d : 2 3 3 . 0 3 6 3 / 2 3 1 . 0 3 9 7 ; A n a l , c a l c d . f o r C 1 ( ) H 1 6 O B r 2 : C 3 8 . 4 9 , H 5 . 1 7 , B r 5 1 . 2 1 ; f o u n d : C 3 8 . 4 4 , H 5 . 2 0 , B r 5 1 . 0 5 . 9 , 1 0 - D i b r o m o i s o b o r n y l TBDMS E t h e r (142) 1*1 142 To a c o l d (0°C) s o l u t i o n o f 9 , 1 0 - d i b r o m o i s o b o r n e o l (141) ( 1 . 3 0 g , 4 . 1 7 mmol) i n d i c h l o r o m e t h a n e (20 mL) was added 2 , 6 - l u t i d e n e ( 0 . 9 mL, 10 mmol) and TBDMS t r i f l a t e ( 1 . 2 mL, 5 . 2 m m o l ) . A f t e r 2 . 5 h o f s t i r r i n g a t 0°C t h e s o l u t i o n was p o u r e d o n t o w a t e r and washed s u c c e s s i v e l y w i t h 0 . 1 N h y d r o c h l o r i c a c i d , w a t e r , s a t u r a t e d ammonium c h l o r i d e s o l u t i o n and w a t e r . The o r g a n i c l a y e r was t h e n d r i e d (MgSO^) and c o n c e n t r a t e d . P u r i f i c a t i o n by f l a s h c h r o m a t o g r a p h y ( s i l i c a g e l ; p e t r o l e u m e t h e r / e t h e r 5 : 1 ) p r o v i d e d 9 , 1 0 - d i b r o m o i s o b o r n y l TBDMS e t h e r (142) as a c o l o u r l e s s o i l ( 1 . 6 0 g , 90%) ; i r ( f i l m ) : 2 9 6 5 , 2 9 0 0 , 2 8 6 0 , 1 2 5 5 , 1 1 2 5 , 1085 c m " 1 ; 6 ( C D C 1 3 , 400 M H z ) : 0 , 0 7 ( 3 H , s ) , 0 . 1 1 ( 3 H , 0 . 8 8 [ 9 H , s ; S i C ( C H _ 3 ) 3 ] , 1 .16 ( I H , m ) , 1 .27 ( 3 H , s ; C H 3 ) , 1.39 ( I H , m ) , 1 .75 ( 4 H , m ) , 2 . 2 2 ( I H , m ) , 3 . 2 5 ( I H , d , J = 10 H z ) , 3 . 3 7 ( I H , d , J = 10 H z ) , 3 . 5 4 ( I H , d d , J = 10 H z , 1 H z ) , 3 . 7 0 ( I H , d , J = 10 H z ) , 48 3 . 9 1 ( I H , d d , J = 7 H z , 4 H z ; C H O S i ) ; m/e ( r e l a t i v e i n t e n s i t y ) : 3 7 1 / 3 6 9 / 3 6 7 tf-Cfa, 5 / 9 / 4 ) , 347 ( 2 8 ) , 345 ( 2 9 ) , 215 ( 4 7 ) , 213 ( 4 9 ) , 133 ( 8 2 ) , 107 ( 9 0 ) , 105 ( 5 2 ) , 93 ( 4 7 ) , 91 ( 5 9 ) , 79 ( 6 2 ) , 75 ( 9 9 ) , 81 73 ( 1 0 0 ) ; E x a c t mass c a l c d . f o r C ^ H ^ O B r ^ i - C ^ : 3 7 0 . 9 6 8 8 ; f o u n d : 3 7 0 . 9 6 7 5 ; A n a l , c a l c d . f o r C 1 6 H 3 Q O B r 2 S i : C 4 5 . 0 8 , H 7 . 0 9 , B r 3 7 . 4 9 ; f o u n d : C 4 5 . 3 6 , H 7 . 2 0 , B r 3 7 . 2 0 . 9 , 1 0 - D i c y a n o i s o b o r n y l TBDMS E t h e r (143) 142 143 To a so l u t i o n o f 9 , 1 0 - d i b r o m o i s o b o r n y l TBDMS e t h e r (143) ( 1 . 0 0 g , 2 . 3 4 mmol) i n DMF (50 m L ) , v a s added sod ium c y a n i d e ( 0 . 4 7 g , 9 . 6 0 mmol) and a c a t a l y t i c amount o f p o t a s s i u m i o d i d e (10 mg, 0 . 0 6 m m o l ) . The r e a c t i o n m i x t u r e was h e a t e d a t 110°C f o r 48 h , c o o l e d , p o u r e d o n t o b r i n e , e x t r a c t e d t h r e e t i m e s w i t h e t h e r , d r i e d (MgSO^) and c o n c e n t r a t e d . P u r i f i c a t i o n by co lumn c h r o m a t o g r a p h y ( s i l i c a g e l ; p e t r o l e u m e t h e r / e t h e r 1 :1) p r o v i d e d 9 , 1 0 - d i c y a n o i s o b o r n y l TBDMS e t h e r (143) as a w h i t e c r y s t a l l i n e s o l i d ( 0 . 7 2 g , 96%), mp 7 1 - 7 3 ° C ; i r ( C H C 1 3 ) : 2 9 6 0 , 2 9 0 0 , 2 8 6 0 , 2 2 5 0 , 1 2 5 5 , 1 1 1 0 , 1080 c m " 1 ; & ( C D C 1 3 , 400 M H z ) : 0 . 0 7 ( 3 H , s ) , 0 . 1 1 ( 3 H , s ) , 0 . 8 9 [ 9 H , s ; S i C ( C H _ 3 ) 3 ] , 1 .28 ( I H , m ) , 1 .32 ( 3 H , a; C H 3 ) , 1.44 ( I H , m ) , 1.73 ( 2 H , m ) , 1.82 ( 2 H , m ) , 2 . 1 3 ( I H , m ) , 2 . 2 6 ( I H , d , J = 17 H z ) , 2 . 3 1 ( I H , d , J = 17 H z ) , 2 . 3 8 ( I H , d d , J = 17 H z , 1 H z ) , 49 2 . 5 7 ( I H , d , J - 17 H z ) , 3 . 8 2 ( I H , t , J - 5 . 5 H z ; C H O S i ) ; m/e ( r e l a t i v e i n t e n s i t y ) : 261 ( M + - C 4 H g , 1 0 0 ) , 120 ( 1 4 ) , 75 ( 8 1 ) : E x a c t mass c a l c d . f o r C 1 8 H 3 0 O N 2 S i " C 4 H 9 : 2 6 1 . 1 4 2 3 ; f o u n d : 2 6 1 . 1 4 2 6 ; A n a l , c a l c d . f o r C 1 8 H 3 0 O N 2 S i : C 6 7 , 8 7 » H 9 * 4 9 > N 8 ' 7 9 » f o u n d : c 6 7 . 9 1 , H 9 . 4 3 , N 8 . 7 8 . H y d r o l y s i s o f 9 , 1 0 - D i c y a n o i s o b o r n y l TBDMS E t h e r (143) 143 146 147 To a s o l u t i o n o f 9 , 1 0 - d i c y a n o i s o b o r n y l TBDMS e t h e r (143) (180 mg, 0 . 5 6 6 mmol) i n e t h y l e n e g l y c o l (10 mL) was added 40% p o t a s s i u m h y d r o x i d e s o l u t i o n (10 m L ) . The s o l u t i o n was r e f l u x e d f o r 1 6 . 5 h , c o o l e d , a c i d i f i e d w i t h 1 N h y d r o c h l o r i c a c i d and e x t r a c t e d t h r e e t i m e s w i t h e t h e r . The comb ined e t h e r e a l l a y e r s were washed w i t h w a t e r and d r i e d (MgSO^) . Remova l o f t h e s o l v e n t gave c r u d e 146 as a y e l l o w o i l (275 m g ) ; i r ( C H C 1 3 ) : 3 6 0 0 - 2 4 5 0 , 1 7 5 5 , 1710 c m " 1 . The c r u d e a c i d - l a c t o n e 146 was d i s s o l v e d i n e t h e r (5 mL) t r e a t e d w i t h a n e x c e s s o f e t h e r e a l d i a z o m e t h a n e and a l l o w e d t o s t a n d o v e r n i g h t . C o n c e n t r a t i o n and t h e n p u r i f i c a t i o n by co l umn c h r o m a t o g r a p h y ( s i l i c a g e l ; p e t r o l e u m e t h e r / e t h e r 3 : 1 ) p r o v i d e d t h e l a c t o n e - e s t e r 147 as a w h i t e c r y s t a l l i n e s o l i d (130 mg, 76%), mp 8 9 . 5 ° C ; i r ( C H C l 3 ) : 1 7 7 5 , 1 7 3 5 , 1070 c m " 1 ; 6 ( C D C 1 3 > 400 K H z ) : 1 .08 ( 3 H , s ; CH_ 3 ) , 1 .32 ( 2 H , m ) , 1.86 ( I H , m ) , 1 .95 ( 2 H , m ) , 2 . 24 ( 3 H , m ) , 2 . 3 7 ( I H , d , J = 14 H z ) , 2 . 4 9 ( 2 H , d , J = 1 .5 H z ) , 3 . 6 9 ( 3 H , s ; C 0 2 C H _ 3 ) , 4 . 2 7 ( I H , d d , J = 8 H z , 4 H z ; CHOCO); 50 m/e ( r e l a t i v e i n t e n s i t y ) : 238 ( M + , 8 ) , 220 ( 2 9 ) , 207 ( 2 9 ) , 102 ( 1 0 0 ) ; E x a c t mass c a l c d . f o r C ^ H ^ O ^ : 2 3 8 . 1 2 0 5 ; f o u n d : 2 3 8 . 1 2 0 8 . A n a l , c a l c d . f o r C 1 3 H l g 0 4 : C 6 5 . 5 3 , H 7 . 6 1 ; f o u n d : C 6 5 . 4 4 , H 7 . 5 8 . 9 , 1 0 - D i b r o m o i s o b o r n y l MEM E t h e r (148) 141 148 To a s o l u t i o n o f 9 , 1 0 - d i b r o m o i s o b o r n e o l (141) ( 2 . 0 0 g , 6 .41 mmol) i n d r y a c e t o n i t r i l e (25 mL) was added MEM t r i e t h y l a m m o n i u m c h l o r i d e ( 4 . 5 g , 2 0 . 0 mmol) f r e s h l y p r e p a r e d f r o m MEM c h l o r i d e and t r i e t h y l a m i n e . 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 22 h , c o o l e d , p o u r e d o n t o w a t e r , and e x t r a c t e d t h r e e t i m e s w i t h e t h e r . The comb ined e t h e r e a l l a y e r s were washed w i t h w a t e r , d r i e d (MgSO^) and c o n c e n t r a t e d . P u r i f i c a t i o n by f l a s h c h r o m a t o g r a p h y ( s i l i c a g e l ; p e t r o l e u m e t h e r / e t h e r 5 : 1 ) y i e l d e d t h e MEM e t h e r 148 as a c o l o u r l e s s o i l ( 1 . 1 4 g , 45%) ; i r ( f i l m ) : 2 9 5 0 , 2 8 8 0 , 1035 c m " 1 ; 6 ( C D C 1 3 , 400 M H z ) : 1 .22 ( I H , m ) , 1.24 ( 3 H , s ; CH_ 3 ) , 1 .46 ( I H , m ) , 1 . 7 0 - 1 . 9 0 ( 4 H , m ) , 2 . 2 0 ( I H , m ) , 3 . 2 5 ( I H , m ) , 3 . 3 8 ( I H , m ) , 3 . 3 9 ( 3 H , s ; 0CH_ 3 ) , 3 . 5 5 ( 3 H , m ) , 3 . 74 ( 3 H , m ) , 3 . 8 5 ( I R , m; CHOMEM), 4 . 7 5 ( 2 H , m; - O C f l ^ - ) ; m/e ( r e l a t i v e i n t e n s i t y ) : 3 2 1 / 3 1 9 ( M + - B r , 0 . 4 / 0 . 4 ) , 2 9 7 / 2 9 5 / 2 9 3 ( M + - 0 M E M , 2 / 4 / 2 ) , 89 ( 1 0 0 ) , 59 ( 6 5 ) ; E x a c t mass c a l c d . f o r C ^ H ^ O ^ r ^ - B r : 3 2 1 . 0 8 8 8 / 3 1 9 . 0 9 0 8 ; f o u n d : 3 2 1 . 0 9 0 1 / 3 1 9 . 0 9 2 7 . 51 9 , 1 0 - D i c y a n o i s o b o r n y l MEM E t h e r (149) MEMO Br >Br MEMO CN 148 149 To a s o l u t i o n o f 9 , 1 0 - d i b r o m o i s o b o r n y l MEM e t h e r (148) ( 1 . 5 2 g , 3 . 8 1 mmol) i n DMF (50 mL) was added s o d i u m c y a n i d e ( 0 . 7 2 g , 1 4 . 6 mmol) and t h e r e a c t i o n m i x t u r e h e a t e d a t 90°C f o r 48 h . The s o l u t i o n was c o o l e d , p o u r e d o n t o b r i n e , e x t r a c t e d t h r e e t i m e s w i t h e t h e r , d r i e d (MgSO^) and c o n c e n t r a t e d . P u r i f i c a t i o n by f l a s h c h r o m a t o g r a p h y ( s i l i c a g e l ; p e t r o l e u m e t h e r / e t h e r 1:1) p r o v i d e d 9 , 1 0 - d i c y a n o i s o b o r n y l MEM e t h e r (149) a s a c o l o u r l e s s o i l ( 0 . 6 8 g , 61%); i r ( f i l m ) : 2 9 6 0 , 2 9 0 0 , 2 2 5 0 , 1040 c m " " 1 ; <$ ( C D C 1 3 , 400 M H z ) : 1 .30 ( 3 H , s ; CH_ 3 ) , 1.31 ( I H , m ) , 1.51 ( I H , m ) , 1 .75 ( 2 H , m ) , 1 .88 ( 2 H , m ) , 2 . 1 5 ( I H , m ) , 2 . 2 7 ( I H , d , J = 17 H z ) , 2 . 3 5 ( I H , d , J = 17 H z ) , 2 . 3 9 ( I H , d , J = 17 H z ) , 2 . 6 6 ( I H , d , J = 17 H z ) , 3 . 3 5 ( 3 H , s ; 0CH_ 3 ) , 3 . 5 7 ( 2 H , m ) , 3 . 7 2 ( 2 H , m ) , 3 . 9 1 ( I H , d d , J = 7 H z , 4 H z ; CHOMEM), 4 . 7 0 (d) and 4 . 7 7 (d) ( 2 H , AB q u a r t e t , J = 7 H z ; - 0 C H _ 2 0 - ) ; m/e ( r e l a t i v e i n t e n s i t y ) : 187 ( M + - 0 M E M , 2 1 ) , 89 ( 1 0 0 ) , 59 ( 8 1 ) ; E x a c t mass c a l c d . f o r C 1 6 H 2 4 0 3 N 2 ~ C 4 H 9 ° 3 : 1 8 7 . 1 2 3 5 ; f o u n d : 1 8 7 . 1 2 3 7 . A n a l , c a l c d . f o r C 1 , H o / 0 , N o : C 6 5 . 7 3 , 16 24 3 2 H 8 . 2 7 , N 9 . 5 8 ; f o u n d C 6 5 . 4 5 , H 8 . 3 0 , N 9 . 7 0 . 52 To a s o l u t i o n o f 9 , 1 0 - d i c y a n o i s o b o r n y l MEM e t h e r (149) ( 0 . 5 3 g , 182 mmol) i n e t h y l e n e g l y c o l (20 mL) was added 40% p o t a s s i u m h y d r o x i d e (20 m L ) . The s o l u t i o n was r e f l u x e d f o r 18 h , c o o l e d , washed w i t h e t h e r , c a r e f u l l y a c i d i f i e d t o pH 3 and e x t r a c t e d t h r e e t i m e s w i t h e t h e r . The comb ined e t h e r e a l l a y e r s were washed w i t h w a t e r , d r i e d (MgSO^) and c o n c e n t r a t e d t o p r o v i d e c r u d e d i a c i d 150 as a p a l e y e l l o w s o l i d ( 0 . 4 1 g ) ; i r ( C H C l - j ) : 3 6 0 0 - 2 5 0 0 , 2 9 6 0 , 2 9 0 0 , 1710 ( b r ) , 1040 c m " 1 ; a ( C D C 1 3 , 400 M H z ) : 1.17 ( 3 H , s ; CH_ 3 ) , 1.19 ( I H , m ) , 1 .59 ( 2 H , m ) , 1 .80 ( 3 H , m ) , 2 . 0 9 (d) and 2 . 3 5 (d) ( 2 H , AB q u a r t e t , J = 14 H z ; C H 2 C 0 2 H ) , 2 . 1 6 (d) and 2 . 7 3 (d) ( 2 H , AB q u a r t e t , J = 16 H z ; C H 2 C 0 2 H ) , 2 . 2 6 ( I H , m ) , 3 . 4 0 ( 3 H , s ; 0CH_ 3 ) , 3 . 5 6 ( 2 H , m ) , 3 . 6 8 ( 2 H , m ) , 3 . 7 5 ( 2 H , s ; 2 x C 0 2 H ) , 3 . 9 2 ( I H , d d , J = 7 H z , 4 H z ; CHOMEM), 4 . 6 5 (d) and 4 . 7 1 (d) ( 2 H , AB q u a r t e t , J = 7 H z ; - 0 C H _ 2 0 - ) ; m/e ( r e l a t i v e i n t e n s i t y ) : 330 ( M + , 0 . 2 ) , 315 ( M + - C H 3 , 1 ) , 59 ( 1 0 0 ) ; E x a c t mass c a l c d . f o r C^n^O^: 3 3 0 . 1 6 7 8 ; f o u n d 3 3 0 . 1 6 8 5 . The c r u d e d i a c i d 150 was d i s s o l v e d i n e t h e r (5 mL ) , t r e a t e d w i t h an e x c e s s o f e t h e r e a l d i a z o m e t h a n e and a l l o w e d t o s t a n d o v e r n i g h t . Remova l o f t he s o l v e n t p r o v i d e d an o i l w h i c h was p u r i f i e d by co lumn c h r o m a t o g r a p h y ( s i l i c a g e l ; e t h e r ) t o p r o v i d e d i e s t e r 151 as a c o l o u r l e s s o i l 53 (354 mg, 54%) ; i r ( f i l m ) : 2 9 5 0 , 1 7 3 5 , 1 2 0 0 , 1040 c m " 1 ; 6 ( C D C 1 3 , 400 M H z ) : 1 .10 ( 3 H , s ; CH_ 3 ) , 1 .15 ( I H , m ) , 1 .52 ( 2 H , m ) , 1.79 ( 3 H , m ) , 2 . 0 6 (d) and 2 . 2 9 (d) ( 2 H , AB q u a r t e t , J = 14 H z ; CH_ 2 C0 2 Me) , 2 . 1 0 (d) and 2 . 6 8 (d) ( 2 H , AB q u a r t e t , J = 16 H z ; C H 2 C 0 2 M e ) , 2 . 1 9 ( I H , m ) , 3 . 3 8 ( 3 H , s ; CH_ 3 ) , 3 . 5 2 ( 2 H , m ) , 3 . 6 3 ( 3 H , s ; C 0 2 C H _ 3 ) , 3 . 6 5 ( 2 H , m ) , 3 . 6 6 ( 3 H , s ; C 0 2 C H _ 3 ) , 3 . 8 4 ( I H , d d , J = 7 H z , 4 . 5 H z ; CHOMEM), 4 . 6 4 (d) and 4 . 7 0 (d) ( 2 H , AB q u a r t e t , J = 7 H z ; - O C H _ 2 0 - ) ; m/e ( r e l a t i v e i n t e n s i t y ) : 327 ( M + - O C H 3 , 0 . 1 ) , 253 (M + -OMEM, 6 ) , 89 ( 1 0 0 ) , 59 ( 9 5 ) ; E x a c t mass c a l c d . f o r C l g H 3 0 O 7 - O C H 3 : 3 2 7 . 1 8 0 7 ; f o u n d 3 2 7 . 1 8 1 0 . A n a l , c a l c d . f o r C l g H 3 C ) 0 7 : C 6 0 . 3 2 , H 8 . 4 4 ; f o u n d : C 6 0 . 5 0 , H 8 . 6 0 . D i a c i d 145 and D i e s t e r 152 143 145 152 To a s o l u t i o n o f d i n i t r i l e 143 (180 mg, 0 . 5 6 6 mmol) i n e t h y l e n e g l y c o l (15 mL) was added p o t a s s i u m h y d r o x i d e s o l u t i o n ( 3 . 0 g i n 3 . 0 mL w a t e r ) . The s o l u t i o n was r e f l u x e d (130°C) f o r 48 h , c o o l e d , washed w i t h e t h e r , c a r e f u l l y a c i d i f i e d w i t h 0 . 1 N h y d r o c h l o r i c a c i d and e x t r a c t e d t h r e e t i m e s w i t h e t h y l a c e t a t e . The comb ined o r g a n i c l a y e r s were washed w i t h b r i n e and d r i e d ( M g S O ^ ) . Remova l o f s o l v e n t p r o v i d e d t h e c r u d e d i a c i d 145_ a s a y e l l o w o i l (220 m g ) ; i r ( f i l m ) : 3 7 0 0 - 2 4 0 0 , 2 9 7 0 , 2 8 9 0 , 1710 ( b r ) , 1 0 8 0 , 1040 c m " 1 . The c r u d e d i a c i d 145 was d i s s o l v e d i n e t h e r (5 m L ) , t r e a t e d w i t h a n e x c e s s o f e t h e r e a l 54 d i a z o m e t h a n e and a l l o w e d t o s t a n d o v e r n i g h t . C o n c e n t r a t i o n and p u r i f i c a t i o n by co lumn c h r o m a t o g r a p h y ( s i l i c a g e l ; p e t r o l e u m e t h e r / e t h e r 1 :1) p r o v i d e d t h e d i e s t e r 152 as a c o l o u r l e s s o i l (115 mg, 75%); i r ( f i l m ) : 3 7 0 0 - 3 2 5 0 , 1735 c m " 1 ( b r ) ; 4 ( C D C 1 3 , 400 M H z ) : 1 .10 ( I H , m ) , 1 .16 ( 3 H , s; C H 3 ) , 1.51 ( I H , m ) , 1 . 6 1 - 1 . 8 5 ( 4 H , m ) , 2 . 0 4 (d) and 2 . 2 7 (d 2 . 2 7 (d) ( 2 H , AB q u a r t e t , J = 13 H z ; C H 2 C 0 2 M e ) , 2 . 1 3 (d) and 2 . 6 6 (d) ( 2 H , AB q u a r t e t , J - 13 H z ; C H 2 C 0 2 M e ) , 2 . 2 1 ( I H , m ) , 3 . 0 8 ( I H , d , J - 3 H z , e x c h a n g e a b l e w i t h D 2 0 ; O H ) , 3 . 6 6 ( 3 H , s ; C 0 2 C H _ 3 ) , 3 . 6 9 ( 3 H , s ; C 0 2 C H _ 3 ) , 3 . 8 4 ( I H , m; CHOH). D e c o u p l i n g t he p r o t o n a t 6 3 . 0 8 c a u s e s t he s i g n a l a t 6 3 . 8 4 t o s i m p l i f y t o a d o u b l e t o f d o u b l e t s ( J = 7 . 5 H z , 4 . 5 H z ) . D e c o u p l i n g a t 6 2 . 1 3 c a u s e s t h e d o u b l e t a t 6 2 . 6 6 t o c o l l a p s e t o a s i n g l e t ; m/e ( r e l a t i v e i n t e n s i t y ) : 239 (M + -OCH 3 » 1 ) , 238 ( 1 ) , 197 ( 3 9 ) , 153 ( 1 0 0 ) ; E x a c t mass c a l c d . f o r C 1 4 H 2 2 0 5 " C H 3 0 : 2 3 9 . 1 2 8 3 ; f o u n d : 2 3 9 . 1 2 6 6 . A n a l , c a l c d . f o r C 1 A H 9 9 0 , . : C 6 2 . 2 0 , H 8 . 2 0 ; f o u n d : C 6 2 . 4 2 , H 8 . 2 5 . D i e s t e r 144 C 0 2 M e 152 To a c o l d (0°C) s o l u t i o n o f t h e h y d r o x y d i e s t e r 152 ( 0 . 5 8 8 g , 2 . 1 8 mmol) i n d i c h l o r o m e t h a n e (20 mL) was added 2 , 6 - l u t i d e n e ( 1 . 0 m l , 1 1 . 2 mmol) and TBDMS t r i f l a t e ( 1 . 3 mL, 5 . 6 6 mmo l ) . A f t e r . I \ ^ C 0 2 M e + f ^ C 0 2 M e 144 55 2 . 5 h o f s t i r r i n g a t 0 C , t h e s o l u t i o n wa6 p o u r e d o n t o w a t e r and washed s u c c e s s i v e l y w i t h 0 . 1 N h y d r o c h l o r i c a c i d , w a t e r , s a t u r a t e d ammonium c h l o r i d e s o l u t i o n and w a t e r . The o r g a n i c l a y e r was t h e n d r i e d (MgSO^) and c o n c e n t r a t e d . P u r i f i c a t i o n by f l a s h c h r o m a t o g r a p h y ( s i l i c a g e l ; p e t r o l e u m e t h e r / e t h e r 5 : 1 ) p r o v i d e d d i e s t e r 144 as a c o l o u r l e s s o i l ( 0 . 7 6 g , 91%) ; i r ( f i l m ) : 2 9 6 5 , 2 9 0 0 , 2 8 6 0 , 1735 ( b r ) c m " 1 ; a ( C D C 1 3 , 400 M H z ) : 0 . 0 7 ( 3 H , s) , 0 . 1 1 ( 3 H , s), 0 . 8 8 [ 9 H , s; S i C ( C H _ 3 ) 3 ] , 1 .15 ( I H , m ) , 1 .18 ( 3 H , s; C H ^ ) , 1.56 ( 2 H , t , J « 7 . 5 H z ) , 1 .77 ( 3 H , m ) , 2 . 0 9 (d) and 2 . 3 1 (d) ( 2 H , AB q u a r t e t , J = 14 H z ; CH_ 2 C0 2 Me) , 2 . 2 0 ( I H , m ) , 3 . 6 6 ( 3 H , s ; C 0 2 C H _ 3 ) , 3 . 6 9 ( 3 H , s ; C 0 2 C H _ 3 ) , 4 . 0 0 ( I H , t , J = 5 . 5 H z ; C H O S i ) ; m/e ( r e l a t i v e i n t e n s i t y ) : 369 ( M + - C H 3 , 1 ) , 353 ( M + - 0 C H 3 , 1 ) , 327 ( 1 0 0 ) ; E x a c t mass c a l c d . f o r C 2 0 H 3 6 ° 5 S i " C 4 H 9 : 3 2 7 ' 1 6 2 8 ; f o u n d : 3 2 7 . 1 6 2 9 . A n a l , c a l c d . f o r C 2 0 H 3 6 ° 5 S i : C 6 2 - A 6 » H 9 * A 3 5 f o u n d : c 6 2 . 5 8 , H 9 . 5 5 . A c y l o i n R e a c t i o n o f D i e s t e r 144 : I s o l a t i o n o f A c y l o i n s 161 and 162 144 154 161 162 To a s t i r r e d d i s p e r s i o n o f s o d i u m - p o t a s s i u m a l l o y [ f o r m e d u n d e r an a r g o n a t m o s p h e r e b y m e l t i n g s o d i u m ( 0 . 2 0 g , 8 . 6 mmol) and p o t a s s i u m ( 0 . 2 5 g , 6 . 4 mmol) w i t h a h e a t - g u n ] i n a n h y d r o u s e t h e r (25 mL) was added a m i x t u r e o f d i e s t e r 144 ( 1 . 0 2 g , 2 . 6 6 mmol) and f r e s h l y d i s t i l l e d TMSC1 ( 2 . 0 mL, 16 mmol) i n a n h y d r o u s e t h e r (200 m L ) . The r e a c t i o n 56 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 20 h , vacuum f i l t e r e d t h r o u g h a s i n t e r e d g l a s s f u n n e l and the s o l v e n t removed t o y i e l d t h e c r u d e s i l y l a t e d e n e d i o l a t e 154 as a p a l e y e l l o w o i l ( 1 . 3 g ) . The c r u d e 154 was d i s s o l v e d i n d r y m e t h a n o l (200 mL) and r e f l u x e d f o r 16 h . Remova l o f t h e s o l v e n t p r o v i d e d an o i l w h i c h showed t h r e e m a j o r compounds by t i c . P u r i f i c a t i o n by co lumn c h r o m a t o g r a p h y ( s i l i c a g e l ; p e t r o l e u m e t h e r / e t h e r 3 : 1 ) gave s t a r t i n g m a t e r i a l 144 ( 0 . 3 7 g , 36%). F u r t h e r e l u t i o n p r o v i d e d t h e a c y l o i n 161 as a c o l o u r l e s s o i l (150 mg, 23% b a s e d on 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 ) ; i r ( f i l m ) : 3500 ( b r ) , 2 9 6 0 , 2 9 0 0 , 2 8 6 0 , 1 7 1 5 , 1080 c m " 1 ; 0 ( C D C 1 3 , 400 K H z ) : 0 . 0 0 ( 3 H , s ) , 0 . 0 2 ( 3 H , s ) , 0 . 8 8 [ 9 H , s ; S i C ( C H _ 3 ) 3 ] , 1 .00 ( I H , m) , 1 .10 ( I H , m ) , 1 .37 ( I H , m ) , 1.40 ( 3 H , s ; C H 3 ) , 1 . 6 0 - 1 . 7 3 ( 2 H , m ) , 1 .80 ( I H , d d , J = 12 H z , 7 . 5 H z ) , 2 . 04 ( I H , d d , J = 12 H z , 7 . 5 H z ) , 1.91 ( I H , m) , 1.99 ( I H , m) , 2 . 2 8 (d) and 2 . 8 0 (d) ( 2 H , AB q u a r t e t , J = 14 H z ; CH_ 2C=0), 3 . 5 6 ( 2 H , m, 1 p r o t o n e x c h a n g e a b l e w i t h D 2 0 ; CHOSi and O H ) , 4 . 3 1 ( I H , d d , J =12 H z , 7 . 5 H z ; CHOH); m/e ( r e l a t i v e i n t e n s i t y ) : 309 ( M + - C H 3 , 1 ) , 267 ( M ^ C ^ , 9 1 ) , 129 ( 8 4 ) , 75 ( 1 0 0 ) ; E x a c t mass c a l c d . f o r C l g H 3 2 0 3 S i - C A K 9 : 2 6 7 . 1 4 1 6 ; f o u n d : 2 6 7 . 1 4 1 5 . A n a l , c a l c d . f o r C . - H - . O - S i : C 6 6 . 6 2 , — — — ID J/ j H 9 . 9 4 ; f o u n d : C 6 6 . 4 8 , H 9 . 9 0 . F u r t h e r e l u t i o n p r o v i d e d t h e i s o m e r i c a c y l o i n 162 a s a c o l o u r l e s s o i l (160 mg, 25% b a s e d on 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 ) ; i r ( f i l m ) : 3500 ( b r ) , 2 9 6 0 , 2 9 0 0 , 2 8 6 0 , 1 7 1 5 , 1080 c m " 1 ; m/e ( r e l a t i v e i n t e n s i t y ) : 309 ( M + - C H 3 , 1 ) , 267 ( M + - C A H g , 7 2 ) , 75 ( 1 0 0 ) ; E x a c t mass c a l c d . f o r C 1 8 H 3 2 ° 3 S i ~ C 4 E 9 : 2 6 7 , 1 A 1 6 i f o u n d : 2 6 7 . 1 4 1 4 . 57 K e t o a c e t a t e 163 — —• —-161 163 The a c y l o i n 161 (75 mg, 0 . 2 3 mmol) was d i s s o l v e d i n d r y p y r i d i n e (10 mL) and t r e a t e d w i t h a c e t i c a n h y d r i d e ( 0 . 1 mL, 1.1 mmol) and DMAP (50 mg, 0 . 4 1 mmol) a t room t e m p e r a t u r e f o r 16 h . Wate r (10 mL) was a d d e d , and t h e n t h e r e a c t i o n m i x t u r e was e x t r a c t e d t h r e e t i m e s w i t h e t h e r , washed w i t h s a t u r a t e d s o d i u m b i c a r b o n a t e s o l u t i o n , d r i e d (MgSO^) and c o n c e n t r a t e d . P u r i f i c a t i o n by co l umn c h r o m a t o g r a p h y ( s i l i c a g e l ; p e t r o l e u m e t h e r / e t h e r 3 : 1 ) p r o v i d e d t h e k e t o a c e t a t e 163 as a c o l o u r l e s s o i l (64 mg, 76%); i r ( f i l m ) : 1 7 5 0 , 1 7 2 5 , 1 2 3 5 , 1080 c m " 1 ; & ( C D C 1 3 , 400 M H z ) , 0 . 0 0 ( 3 H , s ) , 0 . 0 2 ( 3 H , s ) , 0 . 8 8 [ 9 H , s ; S i C ( C H _ 3 ) 3 ] , 1 .03 ( I H , m ) , 1 .13 ( I H , m ) , 1.44 ( 3 H , s ; C H 3 ) , 1 .46 ( I H , m ) , 1.72 ( I H , m ) , 1 .82 ( 2 H , m ) , 1 .93 ( 2 H , m ) , 2 . 0 0 ( I H , m ) , 2 . 1 5 ( 3 H , s ; C H 3 0 C 0 ) , 2 . 2 3 (d) and 2 . 8 1 (d) ( 2 H , AB q u a r t e t , J - 14 H z ; CH_ 2C=0), 3 . 5 6 ( I H , d d , J = 7 . 5 H z , 3 H z ; C H O S i ) , 5 . 4 2 ( I H , d d , J = 1 2 . 5 H z , 7 H z ; C H O A c ) ; m/e ( r e l a t i v e i n t e n s i t y ) : 351 ( M + - C H 3 , 1 ) , 309 ( M + - C 4 H 9 , 7 0 ) , 249 ( 3 4 ) , 117 ( 5 7 ) , 75 ( 1 0 0 ) ; E x a c t mass c a l c d . f o r C ^ H ^ O ^ i : 3 0 9 . 1 5 2 2 ; f o u n d : 3 0 9 . 1 5 2 5 . A n a l , c a l c d . f o r C ^ H ^ O ^ S i : C 6 5 . 5 3 , H 9 . 3 5 ; f o u n d : C 6 5 . 8 0 , H 9 . 4 1 . 58 A c y l o i n R e a c t i o n o f D i e s t e r 144 : I s o l a t i o n o f S i l y l a t e d E n e d i o l a t e 154 and M e t h o x y k e t o n e s 166 and 167 144 154 166 167 To a s t i r r e d d i s p e r s i o n o f s o d i u m - p o t a s s i u m a l l o y [ f o rmed u n d e r an a r g o n a t m o s p h e r e b y m e l t i n g sod ium ( 0 . 6 g , 26 mmol) and p o t a s s i u m ( 1 . 0 g , 26 mmol) w i t h a h e a t gun] i n anhyd rous e t h e r (25 ml ) was added a m i x t u r e o f d i e s t e r 144 ( 2 . 8 g , 7 .29 mmol) and f r e s h l y d i s t i l l e d TMSC1 ( 1 0 . 0 mL, 7 9 . 0 mmol) i n a n h y d r o u s e t h e r (175 m L ) . The r e a c t i o n m i x t u r e , w h i c h d e v e l o p e d a p u r p l e c o l o u r , was s t i r r e d f o r 40 h a t room t e m p e r a t u r e and m o n i t o r e d by c a p i l l a r y g l c ( O V - 1 0 1 , 2 2 5 ° C ) . The m i x t u r e was t h e n vacuum f i l t e r e d t h r o u g h a s i n t e r e d g l a s s f u n n e l and t h e r e a c t i o n f l a s k and f i l t e r f u n n e l washed w i t h a n h y d r o u s e t h e r . Remova l o f t h e s o l v e n t p r o v i d e d a p a l e y e l l o w o i l ( 3 . 6 8 g ) , a s m a l l p o r t i o n o f w h i c h ( 0 . 1 2 6 g) was p u r i f i e d by co l umn c h r o m a t o g r a p h y ( s i l i c a g e l ; p e t r o l e u m e t h e r / e t h e r 3 : 1 ) t o p r o v i d e t h e s i l y l a t e d e n e d i o l a t e 154 a s a c o l o u r l e s s o i l ( 0 . 1 0 g , 86%) ; i r ( f i l m ) : 2 9 6 0 , 2 9 0 0 , 2 8 6 0 , 1690 c m " 1 ; 6 ( C D C 1 3 , 270 M H z ) : 0 . 0 1 [ 6 H , s ; O S i ( C H _ 3 ) 2 ] , 0 . 1 6 [ 9 H , s ; S i ( C H 3 ) 3 ] , 0 . 1 8 [ 9 H , s ; S i ( C H 3 ) 3 ] , 0 . 8 8 [ 9 H , s ; S i C ( C H _ 3 ) 3 ] , 1 .00 ( I H , m ) , 1 .10 ( 3 H , s ; CH_ 3 ) , 1 . 5 0 - 1 . 8 0 ( 8 H , m ) , 2 . 2 9 ( I H , m ) , 2 . 4 9 ( I H , m ) , 3 . 5 7 ( I H , m; C H O S i ) ; m/e ( r e l a t i v e i n t e n s i t y ) : 468 ( M + , 2 5 ) , 321 ( 6 5 ) , 75 ( 6 6 ) , 73 ( 1 0 0 ) ; E x a c t mass c a l c d . f o r C 2 Z ( H 4 8 0 3 S i 3 : 4 6 8 . 2 9 1 1 ; f o u n d : 4 6 8 . 2 9 1 2 . 59 The r e m a i n i n g c r u d e s i l y l a t e d e n e d i o l a t e 154 ( 3 . 5 5 g) was d i s s o l v e d i n d r y m e t h a n o l (200 mL) and r e f l u x e d f o r 16 h . Remova l o f t h e s o l v e n t p r o v i d e d an o i l w h i c h i n d i c a t e d one compound by c a p i l l a r y g l c ( O V - 1 0 1 , 190°C) b u t showed two s p o t s on t i c . Column c h r o m a t o g r a p h y ( s i l i c a g e l ; p e t r o l e u m e t h e r / e t h e r 3 : 1 ) p r o v i d e d t h e m e t h o x y k e t o n e 166 as a c o l o u r l e s s o i l (890 mg, 44%) ; ro/e ( r e l a t i v e i n t e n s i t y ) : 338 ( M + , 1 ) , 323 ( M + - C H 3 , 2 ) , 281 ( 1 0 0 ) . F u r t h e r e l u t i o n p r o v i d e d t he i s o m e r i c m e t h o x y k e t o n e 167 as a w h i t e c r y s t a l l i n e s o l i d ( 610 mg, 30%) , mp 5 8 - 5 9 ° C ; i r ( C H C 1 3 ) : 2 9 6 0 , 2 8 7 5 , 2 8 6 0 , 1 7 2 0 , 1 1 1 5 , 1075 c m " 1 ; 6 ( C D C L j , 400 M H z ) : - 0 . 0 4 ( 3 H , s ) , - 0 . 0 3 ( 3 H , s ) , 0 . 8 0 [ 9 H , s ; S i C ( C H _ 3 ) 3 ] , 1 .02 ( 3 H , s ; C H 3 ) , 1 .20 ( 2 H , m) , 1 . 6 8 - 1 . 9 1 ( 4 H , m ) , 2 . 0 5 ( 4 H , m ) , 2 . 5 0 ( I H , d , J = 13 H z ) , 3 . 4 4 ( 3 H , s ; 0CH_ 3 ) , 3 . 6 1 ( I H , d d , J • 7 H z ; 2 H z ; C H O S i ) , 3 . 9 6 ( I H , d d , J = 11 H z , 9 H z ; CHOMe); m/e ( r e l a t i v e i n t e n s i t y ) : 338 ( M + , 1 ) , 323 ( M + - C H 3 , 1 ) , 281 ( 1 0 0 ) ; E x a c t mass c a l c d . f o r C ^ H ^ O g S i : 3 3 8 . 2 2 7 7 ; f o u n d : 3 3 8 . 2 2 8 3 . A n a l , c a l c d . f o r C i g H 3 A 0 3 S i : C 6 7 . 4 1 , H 1 0 . 1 2 ; f o u n d : C 6 7 . 4 0 , H 1 0 . 0 0 . T r i c y c l i c A l c o h o l 168 166 168 To m e t h o x y k e t o n e 166 (880 mg, 2 . 6 mmol) was added t e t r a b u t y l a m m o n i u m f l u o r i d e (20 mL, 20 mmol : 1 M s o l u t i o n i n THF) and t h e s o l u t i o n s t i r r e d f o r 1 h a t room t e m p e r a t u r e . The r e a c t i o n m i x t u r e was e x t r a c t e d t h r e e 60 t i m e s w i t h e t h y l a c e t a t e and t h e comb ined o r g a n i c l a y e r s washed w i t h w a t e r , d r i e d (MgSO^) and c o n c e n t r a t e d . P u r i f i c a t i o n by co lumn c h r o m a t o g r a p h y ( s i l i c a g e l ; e t h e r ) p r o v i d e d t h e t r i c y c l i c a l c o h o l 168 as a w h i t e c r y s t a l l i n e s o l i d (330 mg, 57%). R e c r y s t a l l i s a t i o n f r o m e t h e r / p e n t a n e p r o v i d e d c o l o u r l e s s n e e d l e s mp 130-131 C ; i r ( C H C 1 3 ) : 3 6 2 0 , 3475 ( b r ) , 1720 , 1120 c m " 1 ; 6 ( C D C 1 3 > 400 M H z ) : 1.01 ( I H , m ) , 1.11 ( I H , m ) , 1 .43 ( 3 H , s ; CH_ 3 ) , 1 .48 ( I H , m ) , 1 . 6 5 - 1 . 9 9 ( 6 H , m, one p r o t o n e x c h a n g e a b l e w i t h D j O ) , 2 . 0 3 ( I H , m ) , 2 . 2 8 (d) and 2 . 8 7 (d) ( 2 H , AB q u a r t e t , J = 1 3 . 5 H z ; CH_ 2 C0), 3 . 4 8 ( 3 H , s ; OCE^), 3 . 6 8 ( I H , d d , J = 7 . 5 H z , 3 H z ; CH0H) , 3 .94 ( I H , d d , J = 12 H z , 7 H z ; CHOMe); m/e ( r e l a t i v e i n t e n s i t y ) : 224 ( M + , 3 0 ) , 206 ( 1 1 ) , 79 ( 1 0 0 ) ; E x a c t mass c a l c d . f o r C 1 3 H 2 0 ° 3 : 2 2 * ' 1 4 1 2 ' f o u n d 2 2 4 . 1 4 0 6 . A n a l , c a l c d . f o r C 1 3 H 2 0 ° 3 : C 6 9 , 6 1 > H 8 ' 9 9 5 f o u n d C 6 9 . 5 0 , H 9 . 0 0 . The s t r u c t u r e was c o n f i r m e d by X - r a y c r y s t a l l o g r a p h i c a n a l y s i s . A c y l o i n R e a c t i o n o f D i e s t e r 144 : I s o l a t i o n o f T r i c y c l i c A l c o h o l s 168 and 176 144 154 168 176 To s o d i u m - p o t a s s i u m a l l o y ( 0 . 4 g , 17 mmol s o d i u m ; 1.2 g , 31 mmol p o t a s s i u m ) d i s p e r s e d i n a n h y d r o u s e t h e r (25 mL) was added a m i x t u r e o f d i e s t e r 144 ( 2 . 4 2 g , 6 . 3 mmol) and f r e s h l y d i s t i l l e d TMSC1 (10 mL, 7 9 . 0 mmol) i n a n h y d r o u s e t h e r (175 m L ) . The r e a c t i o n m i x t u r e 61 was s t i r r e d f o r 40 h a t room t e m p e r a t u r e and worked up as b e f o r e t o p r o v i d e t h e c r u d e s i l y l a t e d e n e d i o l a t e 154 . The c r u d e 154 was d i s s o l v e d i n d r y m e t h a n o l (200 mL) and a f u r t h e r q u a n t i t y o f t r i m e t h y l s i l y l c h l o r i d e (5 mL, 40 mmol) was a d d e d . 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 16 h , c o o l e d and t h e m e t h a n o l removed i n v a c u o . The r e s i d u e was d i s s o l v e d i n e t h y l a c e t a t e (100 m L ) , washed w i t h b r i n e u n t i l n e u t r a l t o l i t m u s , d r i e d (MgSO^) and c o n c e n t r a t e d . P u r i f i c a t i o n by f l a s h c h r o m a t o g r a p h y ( s i l i c a g e l ; e t h e r ) p r o v i d e d a 1:1 m i x t u r e o f i s o m e r i c t r i c y c l i c a l c o h o l s 168 and 176 a s a p a l e y e l l o w o i l ( 0 . 9 0 g , 64%); 6 ( C D C 1 3 > 300 M H z ) : 1 6 8 : 1 .43 ( 3 H , s ; CH_ 3 ) , 2 . 2 8 (d) and 2 . 8 7 (d) ( 2 H , AB q u a r t e t , J = 1 3 . 5 H z ; C H 2 C = 0 ) , 3 . 4 8 ( 3 H , s ; 0CH_ 3 ) , 3 . 6 8 ( I H , m; CEOH) , 3 . 9 4 ( I H , d d , J = 12 H z , 7 H z ; CHOMe); 1 7 6 : 1.06 ( 3 H , s ; CH_ 3 ) , 2 . 5 7 ( I H , d , J = 1 3 . 5 H z ) , 3 . 4 9 ( 3 H , s ; OCELj) , 3 . 6 8 ( I H , t , J • 5 H z ; CHOMe), 4 . 0 5 ( I H , d d , J = 11 H z , 7 H z ; CHOMe). I s o m e r i c E s t e r s 181 and 182 176 180 182 62 To a c o l d (0 C) s o l u t i o n o f i s o m e r i c t r i c y c l i c a l c o h o l s 168 and 176 ( 0 . 9 g , 4 . 0 mmol) i n a c e t o n i t r i l e (5 mL) and w a t e r (3 mL) was added a c o l d (0°C) s o l u t i o n o f e e r i e ammonium n i t r a t e ( 5 . 7 g , 1 0 . 4 mmol) i n w a t e r (5 m L ) . The r e a c t i o n m i x t u r e , w h i c h i m m e d i a t e l y d e v e l o p e d a deep r e d c o l o u r , was s t i r r e d a t 0°C f o r 15 m i n . and t h e n warmed t o room t e m p e r a t u r e and s t i r r e d f o r a f u r t h e r 20 m i n . D u r i n g t h i s t i m e t h e r e a c t i o n m i x t u r e f a d e d t o a p a l e y e l l o w . The s o l u t i o n was e x t r a c t e d t h r e e t i m e s w i t h e t h y l a c e t a t e , washed w i t h b r i n e and d r i e d (MgSO^) . Remova l o f t h e s o l v e n t p r o v i d e d t he c r u d e a l d e h y d e s 178 and 180 as a p a l e y e l l o w o i l ( 0 . 8 6 g ) . P u r i f i c a t i o n o f t h e a l d e h y d e s was d i f f i c u l t due t o t h e i r i n s t a b i l i t y . H o w e v e r , p a r t i a l p u r i f i c a t i o n was a c h i e v e d by co lumn c h r o m a t o g r a p h y ( s i l i c a g e l ; p e t r o l e u m e t h e r / e t h e r 1 :1) t o p r o v i d e c r u d e k e t o a l d e h y d e 180 as a p a l e y e l l o w o i l ; f i ( C D C l 3 , 270 M H z ) : 0 . 8 5 ( 3 H , s; CH_ 3 ) ; 3 . 0 1 [ I H , d d , J = 14 H z , 7 H z ; one C (8 ) p r o t o n ] , 3 . 4 5 ( 3 H , s ; OCE^), 3 . 8 3 ( I H , d d , J = 12 H z , 7 H z ; CHOMe), 5 . 4 9 ( I H , m; v i n y l p r o t o n ) , 9 . 7 9 ( I H , t , J = 2 H z ; CHO) . F u r t h e r e l u t i o n p r o v i d e d c r u d e k e t o a l d e h y d e 178 as a p a l e y e l l o w o i l ; i r ( f i l m ) : 1730 , 1675 c m " 1 ; <j ( C D C 1 3 > 400 M H z ) ; 1.12 ( 3 H , s ; CH_ 3 ) , 3 . 5 8 ( 3 H , s ; 0CH_ 3 ) , 3 . 9 5 ( I H , d d , J - 13 H z , 5 H z ; CHOMe), 5 . 8 0 [ I H , t , J = 2 H z ; C ( E ) v i n y l p r o t o n ] , 9 . 8 2 ( I H , t , J = 2 H z ; CHO) . To a s o l u t i o n , o f t h e c r u d e a l d e h y d e s 178 and 180 i n a c e t o n e (10 mL) was added a s o l u t i o n o f c h r o m i c a c i d , p r e p a r e d by d i s s o l v i n g chromium t r i o x i d e ( 1 . 2 g , 12 mmol) i n w a t e r (20 mL) and c o n c e n t r a t e d s u l p h u r i c a c i d ( 1 . 0 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 f o r 2 h a t room 63 t e m p e r a t u r e . The a c e t o n e was t h e n removed i n v a c u o and t he r e s i d u e e x t r a c t e d t h r e e t i m e s w i t h e t h y l a c e t a t e . The comb ined o r g a n i c l a y e r s were washed w i t h b r i n e and d r i e d ( M g S 0 A ) . Remova l o f t h e s o l v e n t p r o v i d e d a p a l e y e l l o w o i l ( 0 . 9 g) w h i c h was d i s s o l v e d i n e t h e r (20 m L ) , t r e a t e d w i t h an e x c e s s o f d i a z o m e t h a n e , and a l l o w e d t o s t a n d o v e r n i g h t . Remova l o f t h e e t h e r p r o v i d e d an o i l w h i c h showed two m a j o r components by g l c ( O V - 1 0 1 , 1 9 0 ° C ) . F l a s h c h r o m a t o g r a p h y ( s i l i c a g e l ; p e t r o l e u m e t h e r / e t h e r 2 : 1 ) gave t he e s t e r 182 as a c o l o u r l e s s o i l (300 mg, 30%) ; i r ( f i l m ) : 3 0 5 0 , 1725 ( b r ) c m " 1 ; 6 ( C D C 1 3 , 400 M H z ) : 0 . 8 5 ( 3 H , s ; CH_ 3 ) , 2 . 0 7 ( I H , m ) , 2 . 2 5 - 2 . 6 2 ( 7 H , m ) , 3 . 0 2 ( I H , d d , J = 14 H z , 7 H z ) , 3 . 4 5 ( 3 H , s ; 0CH_ 3 ) , 3 . 6 8 ( 3 H , s ; C 0 2 C H _ 3 ) , 3 . 84 ( I H , d d , J = 12 E z , 7 H z ; CHOMe), 5 . 5 2 ( I H , m, CH=) ; m/e ( r e l a t i v e i n t e n s i t y ) : 252 ( M + , 5 8 ) , 220 ( 5 9 ) , 208 ( 5 8 ) , 149 ( 6 5 ) , 119 ( 7 3 ) , 105 ( 7 9 ) , 91 ( 1 0 0 ) ; E x a c t  mass c a l c d . f o r C 1 A H 2 Q 0 A : 2 5 2 . 1 3 6 1 ; f o u n d : 2 5 2 . 1 3 5 5 . A n a l , c a l c d . f o r C 1 A H 2 0 0 A : C 6 6 . 6 5 , H 7 . 9 9 ; f o u n d C 6 6 . 5 2 , B 8 . 0 0 . F u r t h e r e l u t i o n p r o v i d e d t he i s o m e r i c e s t e r 181 as a c o l o u r l e s s o i l (230 mg, 23%) ; i r ( f i l m ) : 1 7 3 5 , 1675 c m " 1 ; 6 ( C D C 1 3 > 400 M H z ) : 1 .12 ( 3 E , s ; C E 3 ) , 1 .62 ( I H , m ) , 1.76 ( I H , t , J = 13 H z ) , 2 . 1 0 ( 2 H , m ) , 2 . 2 8 ( 2 H , m ) , 2 . 4 7 ( 2 H , m ) , 2 . 6 2 ( I H , m ) , 3 . 5 7 ( 3 H , s ; 0 C E _ 3 ) , 3 . 6 9 ( 3 E , s ; C 0 2 C H 3 ) , 3 . 9 5 ( I H , d d , J = 14 H z , 5 H z ; CHOMe), 5 . 7 8 ( I H , t , J - 2 H z ; CE= ) ; m/e ( r e l a t i v e i n t e n s i t y ) : 252 ( M + , 0 . 4 ) , 222 ( 2 2 ) , 194 ( 2 1 ) , 121 ( 1 0 0 ) ; E x a c t mass c a l c d . f o r C 1 8 H 2 0 ° 4 : 2 5 2 . 1 3 6 1 ; f o u n d : 2 5 2 . 1 3 6 6 . A n a l , c a l c d . f o r C^B^O^: C 6 6 . 6 5 , E 7 . 9 9 ; f o u n d : C 6 6 . 6 3 , E 7 . 9 8 . 64 BIBLIOGRAPHY 1. R . V . S t e v e n s , K . T . Chapman and H . N . W e l l e r , J . O r g . C h e m . , 1 9 8 0 , 4 5 , 2 0 3 0 . 2 . T . 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Commun., 1 9 8 6 , 288. 68 APPENDIX 1 S 4 3 2 i ppo 0 400 MHz XH nmr 69 70 71 72 APPENDIX 2 Bono l e n g t h s (A) w i t h e s t i m a t e d s t a n d a r d d e v i a t i o n s i n p a r e n t h e s e s Bond L e n g t h ( A ) Bond L e n g t h ( A ) 0 ( 1 ) - C ( 3 ) 1 . 2 1 2 ( 2 ) C ( 3 ) - C U ) 1 . 5 2 2 ( 3 ) 0 ( 2 ) - C U ) 1 . 4 1 6 ( 2 ) C ( 4 ) - C ( 5 ) 1 . 5 4 5 ( 3 ) 0 ( 2 ) - C ( 1 3 ) 1 . 4 0 8 ( 3 ) C ( 5 ) - C ( 6 ) 1 . 5 2 8 ( 3 ) 0 ( 3 ) - C ( 9 ) 1 . 4 2 1 ( 3 ) C ( 6 ) - C ( 7 ) 1 . 5 5 0 ( 2 ) C ( 1 ) - C ( 2 ) 1 . 5 1 9 ( 3 ) C ( 6 ) - C ( 1 2 ) 1 . 5 3 4 ( 3 ) C < 1 ) - C ( 6 ) 1 . 5 5 5 ( 2 ) C ( 7 ) - C ( B ) 1 . 5 4 3 ( 3 ) C ( 1 ) - C ( 9 ) 1 . 5 3 6 ( 3 ) C ( 7 ) - C ( 1 1 ) 1 . 5 3 4 ( 3 ) C ( l ) - C O O ) 1 . 5 4 1 ( 3 ) C ( B ) - C ( 9 ) 1 . 5 4 7 ( 3 ) C ( 2 ) - C < 3 ) 1 . 5 1 1 ( 3 ) C ( 1 0 ) - C ( 1 1 ) 1 . 5 4 3 ( 3 ) Bond a n g l e s (deg) w i t h e s t i m a t e d s t a n d a r d d e v i a t i o n s i n p a r e n t h e s e s Bonds A n g l e ( d e g ) Bonds A n g l e ( d e g ) C ( 4 ) - 0 ( 2 ) - C ( 1 3 ) 113, . B ( 2 ) C O ) - C ( 6 ) - C ( 5 ) 1 0 9 . 61 ( 1 4 ) C ( 2 ) - C ( l ) - C ( 6 ) 1 1 3 . . B 8 ( 1 5 ) C O ) - C ( 6 ) - C ( 7 ) 9 2 . 6 2 (13) C ( 2 > - C O ) - C ( 9 ) 116 . . 9 ( 2 ) C O ) - C I 6 I - C I 1 2 ) 116 . , 3 ( 2 ) C ( 2 ) - C ( 1 ) - C O O ) U 3 . B ( 2 > C ( 5 ) - C ( 6 ) - C ( 7 ) 116. . 8 ( 2 ) C ( 6 ) - C O ) - C ( 9 ) 103 . 8 9 ( 1 5 ) C ( 5 ) - C I 6 I - C I I 2 ) i o e . . 4 ( 2 ) C ( 6 ) - C O ) - C O O ) 101, .81 ( 1 5 ) C ( 7 ) - C ( 6 ) - C ( 1 2 ) 112 . . 7 ( 2 ) C ( 9 ) - C O ) - C O O ) 104 . 9 ( 2 ) C ( 6 ) - C ( 7 ) - C ( 6 ) 101 . , 9 6 ( 1 5 ) C ( 1 ) - C ( 2 ) - C ( 3 ) 108 . . 6 ( 2 ) C ( 6 ) - C ( 7 ) - C ( 1 1 ) 103 . . 4 ( 2 ) 0(1 ) - C ( 3 ) - C ( 2 ) 122. . 3 ( 2 ) C ( 8 ) - C ( 7 ) - C ( 1 1 ) 106 . , 9 ( 2 ) 0( 1 ) - C ( 3 ) -0 ( 4 ) 122 , . 3 ( 2 ) C ( 7 ) - C ( 6 ) - C ( 9 ) 1 04 . , 0 ( 2 ) C ( 2 ) - C ( 3 ) - C ( 4 ) 115 , . 4 ( 2 ) 0 ( 3 ) - C ( 9 ) - C O ) 1 15. , 0 ( 2 ) 0 ( 2 ) - C ( 4 ) - C ( 3 ) 111, . 4 ( 2 ) 0 ( 3 ) - C ( 9 ) - C ( 8 ) 109 . . 5 ( 2 ) 0 ( 2 ) - C ( 4 ) - C ( 5 ) 108 . 8 ( 2 ) C O ) - C ( 9 ) - C ( 8 ) 102, . 2 ( 2 ) C ( 3 ) - C ( 4 ) - C ( 5 > 111 . 8 1 ( 1 5 ) C O ) - C O 0 ) - C ( 1 1 ) 1 04 , . 6 ( 2 ) C ( 4 ) - C ( 5 ) - C ( 6 ) 111. . 2 ( 2 ) C ( 7 ) - C O D - C O O ) 101 . . 8 ( 2 ) 73 

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