UBC Theses and Dissertations

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UBC Theses and Dissertations

Synthetic studies of indole alkaloids McKague, Allan Bruce 1967

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S Y N T H E T I C S T U D I E S OF I N D O L E A L K A L O I D S by A L L A N BRUCE MCKAGUE B o S c e j McMaster U n i v e r s i t y , H a m i l t o n , Ontario^, 1962 A. T H E S I S S U B M I T T E D I N T H E R E Q U I R E M E N T S DOCTOR OF P A R T I A L F U L F I L M E N T OF FOR THE DEGREE OF P H I LOS OPHY i n the Department of C h e m i s t r y We accept t h i s t h e s i s as c o n f o r m i n g t o the 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 OF B R I T I S H COLUMBIA J a n u a r y s 1 9 6 ? In presenting t h i s t h e s i s i n p a r t i a l f u l f i l m e n t of the requirements f o r an advanced degree at the U n i v e r s i t y of B r i t i s h Columbia, I agree that che L i b r a r y shall, make i t f r e e l y a v a i l a b l e f o r reference and study. I f u r t h e r agree that permission f o r extensive copying of t h i s t h e s i s for* s c h o l a r l y purposes may be granted by the Head of my Department or by h i s representatives. I t i s understood that copying or p u b l i c a t i o n of t h i s t h e s i s f o r f i n a n c i a l gain s h a l l not be allowed without my w r i t t e n permission,, Department The U n i v e r s i t y of B r i t i s h Columbia Vancouver 8, Canada Date SP-e^r 22, I ^ i i • Abstract Two s y n t h e t i c approaches t o the Aspidosperma and Iboga c l a s s e s of I n d o l e a l k a l o i d s are described,, S e c t i o n A. d i s c u s s e s a p o s s i b l e s y n t h e t i c r o u t e t o the nine-membered r i n g a l k a l o i d quebrachamine (93a)° N i c o t i n i c a c i d (75) was reduced t o n i p e c o t i c a c i d h y d r o c h l o r i d e (76)9 which was e s t e r i f i e d t o y i e l d m e t h y l n i p e c o t a t e (77)= Attempted p r e p a r a t i o n of 3~carbomethoxy-3=°ethylpiperidine (67) by a l k y l a t i o n of (77) or o f i t s p -bromobenzamide d e r i v a t i v e (78) was unsuccessful„ The s u b s t i t u t e d p i p e r l d i n e (67) was then p r e p a r e d by another s y n t h e t i c sequence. A l k y l a t i o n s o f methyl c y a n o a c e t a t e l e d t o m e t h y l 3 ~ c h l o r o p r o p y l e t h y l c y a n o a c e t a t e (83)0 C a t a l y t i c r e d u c t i o n o f the l a t t e r n i t r i l e t o the c o r r e s p o n d i n g amine a l l o w e d c y c l i z a t i o n t o 3-carbomethoxy=3-ethylpiperidine (67)0 R e a c t i o n of 67 w i t h 2 - c a r b o e t h o x y - 3 - ( ^ - c h l o r o e t h y l ) - i n d o l e (66) p r o v i d e d 2~carboethoxy~3-(^-(3=carbomethoxy-3-ethyl-N-p i p e r i d y l ) - e t h y l ] - i n d o l e (68)„ Attempted a c y l o i n c o n d e n s a t i o n of the l a t t e r t o a nine-membered r i n g compound (69) was u n s u c c e s s f u l and l e d o n l y t o h y d r o l y s i s products„ S e c t i o n B d e s c r i b e s the f i r s t t o t a l s y n t h e s i s of the n i n e -membered r i n g compounds I4.00 and ljy3=> d i h y d r o c l e a v a m i n e (152) and (153)5 i s o m e r i c w i t h quebrachamine„ C o n v e r s i o n of 2 - e t h y l 1^3-propanediol (106) t o the monobenzyl e t h e r (107) f o l l o w e d t r e a t m e n t w i t h t h i o n y l c h l o r i d e p r o v i d e d 3 - b e n z y l o x y~ 2 - e t h y l -i i i p r o p y l c h l o r i d e (108)„ A l k y l a t i o n of malonlc e s t e r w i t h the l a t t e r a f f o r d e d d i e t h y l 3»benzyloxy - 2.-ethylpropylmalonate (109 )° A' second a l k y l a t i o n o f 109 w i t h e t h y l bromoacetate y i e l d e d d i e t h y l 2 ~ ( 2 ~ b e n z y l o x y m e t h y l b u t y l ) ~ 2 - c a r b o e t h o x y s u c c i n a t e (113 )° H y d r o l y s i s 9 d e c a r b o x y l a t i o n and r e - e s t e r i f i c a t i o n of t h i s t r i e s t e r p r o v i d e d the s u b s t i t u t e d s u c c i n i c e s t e r (71a) i n h i g h y i e l d o The s u c c i n i c es:ter (71a) was a l s o p r e p a r e d but i n low y i e l d by h y d r o l y s i s , d e c a r b o x y l a t i o n and r e ~ e s t e r i f i c a t i o n o f the m a l o n l c e s t e r (109) f o l l o w e d by a l k y l a t i o n w i t h e t h y l iodoacetate,, C o n d e n s a t i o n o f the s u c c i n i c e s t e r (71a) w i t h t r y p t a m i n e p r o v i d e d the s u c c i n i m i d e (130) w h i c h was reduced w i t h l i t h i u m aluminum h y d r i d e t o the t e r t i a r y amine (131) i n h i g h yield„ M e r c u r i c a c e t a t e o x i d a t i o n of the l a t t e r a f f o r d e d a m i x t u r e of I s o m e r i c c y c l i z e d compounds 9 one of which was the d e s i r e d b e n z y l e t h e r 72a „ C a t a l y t i c d e b e n z y l a t i o n y i e l d e d the c o r r e s p o n d i n g a m i n o a l c o h o l (llj-9) which was c o n v e r t e d t o the q u a t e r n a r y m e s y l a t e (73a) by t r e a t m e n t w i t h m e t h a n e s u l f o n y l chloride„ R e d u c t i v e c l e a v a g e of 73a w i t h sodium i n l i q u i d ammonia y i e l d e d [LOW and l\./3- d i h y d r o c l e a v a m i n e „ The s y n t h e s i s o f the i s o m e r i c d i h y d r o c l e a v a m i n e s couplet! w i t h o t h e r s y n t h e t i c work p r o v i d e s a g e n e r a l e n t r y i n t o the Aspidosperma and Iboga a l k a l o i d s , , i v Ta.ble o f Contents Page T. itl© Page O O O O C O O O O O O O O O O O O O O O O O O O O i Al'.t) S t l S c l C ' t o o o o o o o o o o o o o o o o o o o o o o o o o o t 5 i i T a b l e o f C o n t e n t s o o o o o o o o o o o o o o o o o o i v L i s t Of FX^UPeS o o o o o o o o o o o o o o o o o o o o V Acknowledgements O o o o o o o o 0 o o o 0 o 0 0 0 0 o v i i I n t r o d u c t i o n o 0 <> o 0 0 0 o o 0 0 o „ <> <> o o 0 0 0 o 0 o 1 DlSCUSSlOnooooooooooooooooooooooooo 21 S e C t i o n .Ai o o o o o o o o o o o o o o o o o o o o o 22 S e C t i O n Booooooooooooooooooooo 2 Exp e Is ime n t a JL O O O O O O O O O O O O O O O O O O O O O O O 9*7 B i b l i o g r a p h y o O o o o o 0 0 0 o o o 0 o o o o o 0 o o o o 13 k-V F i g u r e O O O O O O O O O O O O O O O O O O O O O O O O O O O O 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 Lj- o o o o o o o o o ^> o o 6. o a a o 8 0 9 10 o o o o o 11. 12 13 0 0 0 0 o o 0 0 0 0 0 0 0 0 0 0 0 0 0 ILL . 15 1 6 0 0 0 j O O O O O O O O O O O O O O O O O O O O O O O O O O O O 1 8 J - V - ' O O O O O O O O O O O O O O O O o o o o o o o o o o o o 1 Q - I - / O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O' 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O' O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O - O O O O O O O" o e o o O O ' 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 • 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O ' O O O O O O O O O O O O O O O O O O O O O O O O O O O O 20o 21 „ O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O ' Page 6 8 10 11 13 Ik 16 17 18 22 23 2LL 26 28 30 k3 LL6 k7 50 50 v i L i s t of F i g u r e s ( C o n t l d j F i g u r e Page 22 o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o 23 o o o o o o o o o o o o o o o o o o o o > o o o o o o o o o o ^ ? 6 ^ ^ I 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 o- 6 0 2 . ^ 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 60 2 6 0 0 0 0 * 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 60 2 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 63 CL 8 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 6 ^ 29 O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O " 6 6 3 ^ o o o o o o o o o o o o o o o o o o o o o o o o o o o o f t o 6 7 31 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 7"^-3 2 . 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 * Z 3 3 3 o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o 3 i L - | - o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o 3 3 * o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o ^ 8 3 ^ 6 o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o ' 7 9 3 ' 7 o o o o o o o o o o o o o o o o o o o o o o o o o o o o o > o » 8 2 ? 3 8 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 8 3 3 9 o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o 8 7 1-J- O o o o o o o o o o o o o o o o 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 8 8 jL|_ X o o o o o o o o o o o o o o o o o o o 0 0 0 0 0 0 0 0 0 0 t? 9 ^ v i i Acknowledgements I w i s h t o expr e s s my s i n c e r e thanks t o Dr. James P. Kutney f o r h i s c o n t i n u a l encouragement and h i s p r e v a i l i n g o p t i m i s m d u r i n g the c o u r s e of my r e s e a r c h , I am a l s o v e r y g r a t e f u l t o my w i f e f o r h e r c o n s t a n t a s s u r a n c e and f o r the p r e p a r a t i o n of t h i s m a n u s c r i p t . F i n a n c i a l a i d from the N a t i o n a l R e s e a r c h C o u n c i l of Canada i s g r e a t l y appreciated„ INTRODUCTION Nature has p r o v i d e d us w i t h a v a s t a r r a y of o r g a n i c compounds of v a r y i n g degrees of c o m p l e x i t y and i n t e r e s t „ A' l a r g e group of these compounds, known as a l k a l o i d s , have been of c o n s i d e r a b l e i n t e r e s t , even s i n c e b e f o r e the onset of s c i e n c e i n the modern sense of the word. A l k a l o i d s are n i t r o g e n o u s bases t h a t o c c u r i n p l a n t s , u s u a l l y l o c a l i z e d In the b a r k , r o o t s , seeds or l e a v e s . C e r t a i n a l k a l o i d s have l o n g been known to have c h a r a c t e r i s t i c and profound e f f e c t s on b i o l o g i c a l s ystems, and t h i s o b s e r v a t i o n u n d o u b t e d l y has p r o v i d e d the s t i m u l u s to t h e i r e x a m i n a t i o n i n ever i n c r e a s i n g d e t a i l . The i n d o l e a l k a l o i d s c o n s t i t u t e a l a r g e c l a s s of compounds r a n g i n g i n c o m p l e x i t y from s i m p l e d e r i v a t i v e s such as p s i l o c y b i n e ( 1 ) , the h a l l u c i n o g e n i c p r i n c i p l e of Mexican mushrooms, t o i n t r i c a t e r i n g systems such, as those found i n s t r y c h n i n e ( 2), the w e l l known p o i s o n . A p p r o x i m a t e l y s i x hundred i n d o l e a l k a l o i d s have been r e p o r t e d i s o l a t e d t o d a t e , and s t r u c t u r a l d e t e r m i n a t i o n s I! (2;) -2 c a r r i e d out on some t h r e e hundred of them „ C h a r a c t e r i z a t i o n of these compounds, as w i t h most newer n a t u r a l p r o d u c t s has been immensely a i d e d by modern s c i e n t i f i c i n s t r u m e n t a t i o n , , The use of such a n a l y t i c a l t o o l s as mass s p e c t r o m e t r y and n u c l e a r magnetic resonance s p e c t r o s c o p y has become s t a n d a r d p r a c t i c e as w i l l be i l l u s t r a t e d i n the d i s c u s s i o n s e c t i o n . The s t u d y o f the b i o s y n t h e s i s o f the i n d o l e a l k a l o i d s has r e c e n t l y become a f i e l d of i n t e n s i f i e d i n t e r e s t , , The e l u c i d a t i o n o f b i o c h e m i c a l pathways has been determined almost e x c l u s i v e l y by the use o f r a d i o a c t i v e l y l a b e l l e d p r e c u r s o r s and has l e d to r e m a r k a b l e progress„ The amino a c i d t r y p t o p h a n (3) has a s t r o n g s t r u c t u r a l s i m i l a r i t y t o the i n d o l e a l k a l o i d s , and has l o n g been f e l t t o be the p r e c u r s o r t o the i n d o l e p o r t i o n of the m o l e c u l e 0 R a d i o a c t i v e l y l a b e l l e d t r y p t o p h a n has now been shown by a v a r i e t y of workers t o be i n c o r p o r a t e d i n t o , s e r o t o n i n O4), p s i l o c y b i n e (1), gramine (5), a j m a l i n e ( 6 ) , s e r p e n t i n e (7) and r e s e r p i n e ^ (8),, as w e l l as v i n d o l i n e - ^ A ( 9 ) s i b o g a i n e ^ (10) s v i n d o l i n i n e (11) and c a t h a r a n t h i n e ^ (12 )„ I t i s f e l t t h a t t r y p t o p h a n i s d e c a r b o x y l a t e d t o t r y p t a m i n e w h i c h then undergoes c o n d e n s a t i o n r e a c t i o n s , I n c o n t r a s t t o the g e n e r a l agreement of d i f f e r e n t workers w i t h r e g a r d t o the " t r y p t o p h a n " p o r t i o n o f the i n d o l e a l k a l o i d s 9 the b i o g e n e t i c o r i g i n of the " n o n - t r y p t o p h a n " or C O ^ X Q u n i t ( t h i c k e n e d bonds In structures-.,below), has been' the s u b j e c t (14) of c o n s i d e r a b l e c o n t r o v e r s y . A number o f t h e o r i e s have been proposed f o r t h i s p o r t i o n of the alkaloids„ R e s u l t s w i t h i n the l a s t year or two, however, p r o v i d e v e r y s t r o n g e v i d e n c e f o r a monoterpene origin„ The monoterpene h y p o t h e s i s was o r i g i n a l l y 6 7 proposed by Thomas and Wenkert' at about the same time on the b a s i s of s t r u c t u r a l s i m i l a r i t i e s among many monoterpenes and the Cc^io p o r t i o n of the i n d o l e alkaloids„ M e v a l o n i c a c i d ( 1 6 ) , an i n t e r m e d i a t e i n terpene b i o s y n t h e s i s , has been shown t o be i n c o r p o r a t e d i n t o the Cc;_io p o r t i o n of v i n d o l i n e 8 ' 9 * 1 0 ( 9 ) , r e s e r p i n e 1 0 ( 8 ) , s e r p e n t i n e 8 * 1 2 ( 7 ) , 8 c a t h a r a n t h i n e ( 1 2 ) , 1 , 2 - d e h y d r o a s p i d o s p e r m i d i n e (111) and ft -i-i a j m a l i c i n e ' ( 1 3 ) ° G e r a n i o l ( 1 7 ) , i t s e l f a monoterpene 9 has been shown t o be a. p r e c u r s o r of a j m a l i c i n e , s e r p e n t i n e , TO 1 1 1 2 13 c a t h a r a n t h i n e and v i n d o l i n e ' 9 . More r e c e n t l y , B a t t e r s b y and co-workers 1^" have i n c o r p o r a t e d the monoterpene l o g a n i n 1 ^ (15>) i n t o the a l k a l o i d s a j m a l i c i n e , v i n d o l i n e and c a t h a r a n t h i n e . D e g r a d a t i o n o f the l a b e l l e d a l k a l o i d s has l e d t o the b i o g e n e t i c scheme shown i n F i g u r e 1„ S t r u c t u r e s 1 8 , 19 and 20 r e p r e s e n t the C]_Q u n i t s of the Corynanthe, Iboga and =5-F i g u r e 1 An a l t e r n a t e b i o g e n e t i c scheme f o r the d e r i v a t i o n of the n o n - t r y p t o p h a n p o r t i o n of the i n d o l e a l k a l o i d s was p r o -posed by Wenkert^ a t the same time as h i s monoterpene h y p o t h e s i s ( F i g u r e s 2$• Rearrangement o f pr e p h e n i c a c i d ( 2 1 ) , - a n i n t e r -mediate i n the b i o s y n t h e s i s of a r o m a t i c a c i d s , w i t h r e t e n t i o n of c o n f i g u r a t i o n of the m i g r a t i n g p y r u v a t e s i d e c h a i n , then h y d r a t i o n p r o v i d e s I n t e r m e d i a t e 22 whose s t r u c t u r e i s r e a d i l y d i s c e r n i b l e i n yohimbine (23)° C o n d e n s a t i o n of formaldehyde -6-F i g u r e 2.0 I n c o r p o r a t i o n of W e n k e r t 1 s SPF u n i t i n t o C o r y n a n t h e i n e and A j m a l i n e type A l k a l o i d s w i t h i n t e r m e d i a t e 22 f o l l o w e d by r i n g opening p o s s i b l y by a r e t r o - a l d o l mechanism l e a d s t o a " s e c o - p r e p h e n a t e - f o r m a l d e h y d e " (SPP) u n i t (2l|), a c r u c i a l i n t e r m e d i a t e w h i c h - c o u l d be i n c o r p o r a t e d not o n l y i n t o c o r y n a n t h e i n e (25) and a j m a l i c i n e (13) a l k a l o i d s but a l s o a j m a l i n e (6)' and s a r p a g i n e ( 2 6 ) . An i m p o r t a n t f e a t u r e of the p r e p h e n i c a c i d p r o p o s a l was t h a t i t accounted f o r the almost c o n s t a n t c o n f i g u r a t i o n observed at carbon-15 i n the i n d o l e a l k a l o i d s . Wenkert's SPF u n i t (2ii) c o n t a i n s the i d e n t i c a l carbon s k e l e t o n , w i t h the e x c e p t i o n o f one carbon atom, as t h a t proposed i n the monoterpene h y p o t h e s i s (18.), The subsequent c o n d e n s a t i o n s of the SPF u n i t proposed by Wenkert t h e r e f o r e c o u l d a p p l y t o t h i s monoterpene i n t e r m e d i a t e a t i t s a p p r o p r i a t e o x i d a t i o n l e v e l 0 Wenkert extended h i s p r o p o s a l t o i n c l u d e the Aspidosperma and Iboga groups of bases ( F i g u r e 3)» Condensation of the SPF u n i t w i t h t r y p t a m i n e was e n v i s a g e d as b e i n g f o l l o w e d by a r e t r o - M i c h a e l r e a c t i o n p r o v i d i n g the c l e a v a g e p r o d u c t 29° I f t h i s undergoes o r d i n a r y o x i d a t i o n - r e d u c t i o n changes, p i p e r i -d eines of v a r i o u s s t a t e s o f o x i d a t i o n are formed whose i n t r a -m o l e c u l a r M i c h a e l and Mannich r e a c t i o n s l e a d t o the Aspidosperma (30) a n d ^ I b o g a - l i k e (31) s k e l e t o n s r e s p e c t i v e l y . The bond making and bond b r e a k i n g p r o c e s s e s d e p i c t e d f o r the d e r i v a t i o n of the Aspidosperma and Iboga a l k a l o i d s are not u n l i k e those c u r r e n t l y proposed i n the monoterpene h y p o t h e s i s d e s c r i b e d e a r l i e r (18-^19 and 20). The use o f -8 F i g u r e 3« _ 9 -t r a n s a n n u l a r c y c l i z a t i o n a i n v o l v i n g i m i n i u m s a l t i n t e r m e d i a t e s i s p a r t i c u l a r l y i n t e r e s t i n g s i n c e Kutney and co-workers have demonstrated t h a t such r e a c t i o n s are c h e m i c a l l y f e a s i b l e and have l e d t o p a r t i a l s y n t h e s e s o f the Iboga and Aspidosperma-type s k e l e t o n s . (See F i g u r e s i i and 5°) D i h y d r o c l e a v a m i n e (32), a v a i l a b l e from the a l k a l o i d c a t h a r a n t h i n e 1 ^ (33), was c o n v e r t e d by m e r c u r i c a c e t a t e o x i d a t i o n v i a the i n t e r m e d i a t e i m i n i u m s a l t (3H-) s t o 1 Pi 7 - e t h y l - 5 ~ d e s e t h y l a s p i d o s p e r m i d i n e (35)» T h i s r e a c t i o n was then u t i l i z e d t o c o n v e r t the n a t u r a l l y o c c u r r i n g a l k a l o i d (-)-quebrachamine (36) t o the known a l k a l o i d ( + ) ~ a s p i d o s p e r m i d i n e 1 9 (37). A p p l i c a t i o n of the t r a n s a n n u l a r c y c l i z a t i o n t o carbomethoxydihydrocleavamine.' p r o v i d e d b o t h the Aspidosperma 20 and Iboga-type s k e l e t o n s . O x i d a t i o n of carbomethoxy-d i h y d r o c l e a v a m i n e (38) t o the i m i n i u m s a l t (39), f o l l o w e d by t r a n s a n n u l a r c y c l i z a t i o n p r o v i d e d p s e u d o - v i n c a d i f f o r m i n e (I4.O) -a v a r i a t i o n o f the Aspidosperma skeleton,. A l t e r n a t e l y , o x i d a t i o n i n the same r e a c t i o n m i x t u r e , t o the Iminium s a l t ( i l l ) f o l l o w e d by t r a n s a n n u l a r c y c l i z a t i o n p r o v i d e d the Iboga s k e l e t o n (IL2 ). I n the case of the i m i n i u m s a l t (1+1), the e t h y l group s t was e p i m e r i z e d v i a the enamine (I4.3) w i t h the r e s u l t t h a t the known Iboga a l k a l o i d c o r o n a r i d i n e and i t s epimer d i h y d r o c a t h a r a n t h i n e (ii2) were o b t a i n e d . 1 0 F i g u r e i t . T r a n s a n n u l a r C y c l i z a t i o n s P r o v i d i n g the Aspidosperma S k e l e t o n -11= F i g , 5 ° C o n v e r s i o n of Carbomethoxydihydrocleavamine i n t o the Aspidosperma and Iboga S k e l e t o n s 12-The t r a n s a n n u l a r c y c l i z a t i o n i s thus seen t o be a p o s s i b l e b i o s y n t h e t i c and a v e r s a t i l e s y n t h e t i c e n t r y i n t o the Aspidosperma and Iboga a l k a l o i d s . A s y n t h e s i s of the a p p r o p r i a t e nine-membered r i n g compounds l i k e quebrachamine, d i h y d r o c l e a v a m i n e , and carb o m e t h o x y d i h y d r o c l e a v a m i n e would e x p l o i t the v a l u e of the t r a n s a n n u l a r c y c l i z a t i o n t o the utmost and a f f o r d t o t a l s y n t h e s e s of l a r g e c l a s s e s of a l k a l o i d s . A- v a r i e t y of approaches t o the s y n t h e s i s of i n d o l e a l k a l o i d s has appeared In the literature„. However, those p e r t i n e n t t o the work h e r e i n , t h a t i s of the Aspidosperma and Iboga g r o u p s , are r e l a t i v e l y few, A. r e c e n t s y n t h e s i s of d e s e t h y l i b o g a m i n e v i a a f a i r l y s h o r t r o u t e was r e p o r t e d by H u f f m a n 2 1 and p r o v i d e s a u s e f u l model ( F i g u r e 6). E p o x i d a t i o n o f 3 - c y c l o h e x e n e - l - c a r b o x y l a t e (LLIJ.) w i t h m e t a c h l o r o p e r b e n z o i c a c i d t o a m i x t u r e of c i s and t r a n s e poxides s f o l l o w e d by r e a c t i o n w i t h t r y p t a m i n e gave a m i x t u r e o f amino a l c o h o l s , C y c l i z a t i o n of the amino a l c o h o l (ii6) from the t r a n s e p o x i d e , by h e a t i n g , p r o v i d e d the N - i n d o l y l -e t h y l i s o q u i n u c l i d o n e (li7)» C y c l i z a t i o n of the t o s y l a t e t o the i n d o l e r i n g gave d e s e t h y l i b o g a m i n e l a c t a m (LL8) w h i c h was reduced t o d e s e t h y l i b o g a m i n e (IL9 ) i n h i g h y i e l d , t! Op B u c h i e t a l were the f i r s t t o r e p o r t the t o t a l s y n t h e s i s o f an Iboga a l k a l o i d t o d a t e ^ » The r e a c t i o n sequence (aO The s y n t h e t i c work c o n t a i n e d i n t h i s t h e s i s l e a d i n g t o d i h y d r o c l e a v a m i n e and s u b s e q u e n t l y t o the Iboga a l k a l o i d s has now been p u b l i s h e d i n J o u r n a l o f the American Chemical S o c i e t y 88, 1+756 (1966). - 1 3 -i n v o l v e s the e l a b o r a t e c o n s t r u c t i o n of the i s o q u i n u c l i d i n e ( 5 0 ) v i a a c r u c i a l Hofmann rearrangement. Combination of 5 0 . w i t h ' / 3 - i n d o l y l a c e t y l c h l o r i d e gave the amide ( 5 1 ) w h i c h was c o n v e r t e d t h r o u g h the s e r i e s o f r e a c t i o n s d e p i c t e d i n F i g u r e ;7. t o ( i ) - i b o g a m i n e ( 5 2 ) and (-)-epiibogamine ( 5 3 ) • (1+9) H F i g u r e 6. (b) D i c y c l o h e x y l c a r b o d i i m i d e i n d i m e t h y l s u l f o x i d e -15-A n o t h e r r e c e n t i n v e s t i g a t i o n by Due and F e t i z o n ^ u s i n g an e n t i r e l y d i f f e r e n t approach l e d t o the s y n t h e s i s of an i b o g a i n e analogue ( 5 1 + ) and i s shown i n F i g u r e 8 . S t o r k 2 ^ r e p o r t e d the f i r s t s u c c e s s f u l t o t a l s y n t h e s i s o f d l - a s p i d o s p e r m i n e ( 5 7 ) and dl-quebrachamlne (36) as shown i n F i g u r e 9-« F i s c h e r i n d o l e c y c l i z a t i o n of the a p p r o p r i a t e l y p r e p a r e d phenylhydrazone (56) i s the key s t e p . More r e c e n t l y Ban ^ and co-workers r e p o r t e d a t o t a l s y n t h e s i s of a s p l d o s p e r m i n e a g a i n u s i n g the F i s c h e r i n d o l e c y c l i z a t i o n of i n t e r m e d i a t e 56 but P A of d i f f e r e n t stereochemistry„ Kuehne a l s o o b t a i n e d the i n t e r m e d i a t e 5 5 which would l e a d to aspldospermine and quebrachamine. A\n i n t e r e s t i n g r o u t e t o the Aspidosperma and H u n t e r i a 2 7 a l k a l o i d s has been r e p o r t e d by B a r t o n and Harley-Mason ' as i l l u s t r a t e d i n F i g u r e 10,. The f o r m a t i o n of ( X)-3 - m e t h y l a s p i d o -s p e r m i d i n e (60) from the i n t e r m e d i a t e ( 5 ^ ) i n v o l v e s a boron t r i f l u o r i d e induced r e a r r a n g e m e n t , w h i l e t r e a t m e n t of,58 w i t h osmium t e t r o x i d e and subsequent c l e a v a g e of the d i o l l e a d s t o (-)-eburnamine (61). As d i s c u s s e d e a r l i e r , the t r a n s a n n u l a r c y c l i z a t i o n o f a nine-membered r i n g i n t e r m e d i a t e p r o v i d e s a s y n t h e t i c r o u t e t o a l a r g e number o f a l k a l o i d s , Quebrachamine and d i h y d r o c l e a v a m i n e l e d t o the Aspidosperma s e r i e s w h i l e carbomethoxydibydro-cleavamine l e d t o the Iboga and V i n c a c l a s s e s * S i m i l a r l y carbomethoxyquebrachamine (62) .could be expected t o p r o v i d e -16-F i g u r e Q, -17-i) Pyrrol id in a. CH3-CH3CO=CHi 3) H a P , H O f l c C O O C W 3 I ,) Pyrrolidine. CH,0 O C \ 3) HO Ac, j-,aNoc 2) NHtf-OH (55) (57) ( R = OCHi) F i g u r e ,9.. T o t a l S y n t h e s i s of dl-A.spidospermine and d l -Quebrachamine - 1 8 -i) Pyrrol id in & CtfO COOCHs -19-v i n c a d i f f o r m i n e ( 6 3 ) a n a t u r a l l y o c c u r r i n g a l k a l o i d . A s y n t h e s i s of quebrachamine, d i h y d r o c l e a v a m i n e and t h e i r c o r r e s p o n d i n g carbomethoxy d e r i v a t i v e s t h e r e f o r e appeared d e s i r a b l e . F u r t h e r m o r e , s i n c e quebrachamine and d i h y d r o -cleavamine are e p i m e r i c , i t became of I n t e r e s t t o examine whether a s i m i l a r r o u t e t o these, compounds . themselves was a t t a i n a b l e , as such a r o u t e would c o n s t i t u t e a f a i r l y g e n e r a l s y n t h e s i s o f the a f o r e m e n t i o n e d a l k a l o i d s . I n a d d i t i o n t o the i n t r i n s i c v a l u e of the s y n t h e s i s o f d i h y d r o c l e a v a m i n e l i e s i t s c o n s i d e r a t i o n as a p o s s i b l e e v e n t u a l means of e n t r y t o d i m e r i c a l k a l o i d s , some of w h i c h are w e l l 2 9 known f o r t h e i r a n t i - l e u k e m i c p r o p e r t i e s . V i n b l a s t i n e and v i n c r i s t i n e ^ , o b t a i n e d from V i n c a r o s e a L i n n , have r e c e n t l y been shown by X -ray a n a l y s i s ^ ! t o have the s t r u c t u r e s 6I4. and 6 5 r e s p e c t i v e l y . T h i s work c o n f i r m e d the p r e v i o u s s t r u c t u r a l assignment based on c h e m i c a l and s p e c t r o s c o p i c e v i d e n c e and most i m p o r t a n t l y p r o v i d e d the a b s o l u t e c o n f i g u r a -t i o n f o r t h i s m o l e c u l e . - 2 0 --21-DISCUSSION Two s y n t h e t i c r o u t e s were examined and i n v o l v e d e n t i r e l y d i f f e r e n t modes of g e n e r a t i o n of the a l l i m p o r t a n t n i n e -membered r i n g . F o r t h i s r e a s o n the d i s c u s s i o n has been d i v i d e d i n t o two s e c t i o n s , A and B, each d e a l i n g w i t h the a p p r o p r i a t e s y n t h e t i c approach. The i n i t i a l r o u t e which was b e i n g designed f o r the compound quebrachamine i s o u t l i n e d In F i g u r e 11 and u t i l i z e d the w e l l known a c y l o i n c o n d e n s a t i o n t o form the nine-membered r i n g . The a c y l o i n c o n d e n s a t i o n i s one of the few p r a c t i c a b l e methods a v a i l a b l e f o r g e n e r a t i n g medium s i z e r i n g s , where non-bonded i n t e r a c t i o n s become an Important c o n s i d e r a t i o n d u r i n g the r i n g c l o s u r e . T h i s method f a i l e d t o y i e l d the d e s i r e d compounds but i t i s a p p r o p r i a t e t o mention some of the c h e m i s t r y which was I n v o l v e d * The second r o u t e , a p p l i e d t o d i h y d r o c l e a v a m i n e and d e p i c t e d i n F i g u r e 12, c o n s i s t e d i n the g e n e r a t i o n o f the n i n e -membered r i n g by c l e a v a g e of a bond common to a f u s e d f i v e -and six-membered r i n g (73a )„ T h i s method was s u c c e s s f u l and r e s u l t e d i n the- f i r s t t o t a l s y n t h e s i s of d i h y d r o c l e a v a m i n e . A d d i t i o n a l work c a r r i e d out c o n c u r r e n t l y i n our l a b o r a t o r y by o t h e r workers and w h i c h i n v o l v e d the s u c c e s s f u l s y n t h e s i s of quebrachamine by the second r o u t e d e s c r i b e d , as w e l l as a s u c c e s s f u l c o n v e r s i o n of d i h y d r o c l e a v a m i n e i n t o carbomethoxy-d i h y d r o c l e a v a m i n e , w i l l be mentioned at the end of the d i s c u s s i o n . -22 S e c t i o n A The s y n t h e s i s of the d i e s t e r (68) d e s i r e d f o r a c y l o i n -c o n d e n s a t i o n was a c c o m p l i s h e d through the c o u p l i n g of 2 ~ c a r b o e t h o x y - 3 ( / 2 - c h l o r o e t h y l ) - i n d o l e (66) w i t h 3-carbomethoxy-3 - e t h y l p i p e r i d i n e (67)° The s y n t h e s i s of the s u b s t i t u t e d p i p e r i d i n e (67) i t s e l f i n v o l v e d two approaches. I n i t i a l l y i t was thought t h a t a s i m p l e carbon a l k y l a t i o n by s t a n d a r d p r o c edures of the e a s i l y o b t a i n a b l e 3-carbometh.oxy p i p e r i d i n e (77) (see F i g u r e 13) would be p o s s i b l e , a l k y l a t i o n o f 32 33 d l s u b s t i t u t e d a c e t i c e s t e r s b e i n g f a i r l y w e l l known 3 / \ 1-4 (66) c 1 / \ / N CU0OC (67) \ ^coo at (68.) F i g u r e 11 -23= (70) (71a) R = OEt (72a) R = H (71b) R = C O O C H 3 ( 7 2 b ) R = COOCH ( 7 3 a ) R = H f< ( 7 3 b ) R = C O O C H 3 (7l+a ) R = H (71+b) R = C O O C H 3 F i g u r e 12 N i c o t i n i c a c i d (75>) was reduced t o n i p e c o t i c a c i d h y d r o c h l o r i d e (76) by the r e p o r t e d method of p l a t i n u m oxide (Adams c a t a l y s t ) i n h y d r o c h l o r i c a c i The crude product a f t e r d r y i n g , e x h i b i t e d no a b s o r p t i o n i n the u l t r a v i o l e t r e g i o n and was t h e r e f o r e e s t e r i f i e d d i r e c t l y w i t h a b s o l u t e methanol and h y d r o c h l o r i c a c i d - ^ . The d e s i r e d m e t h y l n i p e c o t a t e - ^ (77) was thus prepared i n .35$ o v e r a l l y i e l d from n i c o t i n i c a c i d . ,coo H |4 a/pfOj (75) . C C O H V (76) C O C C H ? (77) EH coocl-ts Et- y ) o Br (67) (78) F i g u r e 13 The p i p e r i d i n e e s t e r (77) e x h i b i t e d a sharp t h r e e p r o t o n s i n g l e t i n the NMR spectrum at"/"" 6,30 due t o the methoxyl p r o t o n s . The s t r u c t u r a l assignment was a l s o s u p p o r t e d by the presence of a s t r o n g a b s o r p t i o n band i n the i n f r a r e d at 1725 cm~l due t o the e s t e r group and a broad a b s o r p t i o n a t 3250 cm" 1 (NH), E l e m e n t a l a n a l y s i s on the pa r e n t substance and on i t s c r y s t a l l i n e p-bromobenzamide d e r i v a t i v e (78) completed the c h a r a c t e r i z a t i o n of t h i s c ompound. I t was hoped t h a t t h i s e s t e r (77) c o u l d be a l k y l a t e d a t the -X-carbon w i t h o u t a l k y l a t i o n on n i t r o g e n by f i r s t i r r e v e r s i b l y g e n e r a t i n g the c a r b a n i o n w i t h sodium h y d r i d e , f o l l o w e d by the a d d i t i o n of e t h y l i o d i d e 0 A d d i t i o n of the -25-e s t e r t o sodium h y d r i d e i n t o l u e n e caused the e v o l u t i o n of gas and subsequent r e a c t i o n w i t h e t h y l i o d i d e was e v i d e n t by the f o r m a t i o n o f a p a l e y e l l o w precipitate„ P u r i f i c a t i o n o f the p r o d u c t by d i s t i l l a t i o n gave a c l e a r c o l o r l e s s o i l w h i c h , however, was i n d i c a t e d by i t s NMR spectrum t o be the N - e t h y l compound. The presence o f an e t h y l group was shown by the presence of a t h r e e p r o t o n t r i p l e t at; 7"8.'95 (-CHgCH-^) and a q u a r t e t at7'7°6 (-CH^CR^). The low c h e m i c a l s h i f t o f the methy l and methylene p r o t o n s s t r o n g l y suggested t h a t N - a l k y l a t i o n had o c c u r r e d and t h i s was s u b s e q u e n t l y v e r i f i e d when the d e s i r e d compound was prepared by ano t h e r r o u t e d e s c r i b e d l a t e r . S i n c e i t was f e l t t h a t the d e s i r e d e s t e r a n i o n had been formed s u c c e s s f u l l y w i t h , sodium h y d r i d e , p r e v e n t i o n of N - a l k y l a t i o n c o u l d be a c c o m p l i s h e d by c o n v e r s i o n of the b a s i c amine t o a n e u t r a l amide d e r i v a t i v e . Subsequent h y d r o l y s i s c o u l d t h e n l e a d t o the d e s i r e d p i p e r i d i n e (67) as shown i n F i g u r e II4.. The p-bromobenzamide d e r i v a t i v e (78) p r e p a r e d by s t a n d a r d t e c h n i q u e s ( p - b r o m o b e n z o y l c h l o r i d e In p y r i d i n e ) was a b e a u t i f u l l y c r y s t a l l i n e s o l i d . The i n f r a r e d spectrum of the l a t t e r showed the presence o f an e s t e r c a r b o n y l at 1730 cm"'-, an amide band a t 1630 c m - 1 and no a b s o r p t i o n i n the NH (3200 - 3500 cm'M region„ The NMR spectrum showed the methoxyl group as a sharp s i n g l e t at 7^ 6,3 and the a r o m a t i c _26-r e g i o n c o n t a i n e d a p a i r o f d o u b l e t s at7?'2.LL and 7^2</7-. as e x p e c t e d f o r two n o n - e q u i v a l e n t p a i r s o f protons,, 14 ,Cc?ocH_j fae.r,2.ayj c^h/on'cJe (77) (78) E M ,COOC.H-s J ^ Ef -|\r (67) H-F i g u r e I i i R e f l u x i n g a m i x t u r e o f t h e amide (78), s o d i u m h y d r i d e (10% e x c e s s ) and e t h y l i o d i d e (10% e x c e s s ) i n t o l u e n e c a u s e d th e s l o w e v o l u t i o n o f gas and the p r e c i p i t a t i o n o f a s o l i d 0 The r e a c t i o n p r o d u c t however was i n d i c a t e d - by t h i n l a y e r ' c h r o m a t o g r a p h y as b e i n g a m i x t u r e o f a t l e a s t f o u r compounds„ A l u m i n a c h r o m a t o g r a p h y i n i t i a l l y y i e l d e d a . w h i t e c r y s t a l l i n e compound i d e n t i f i e d as m e t h y l p-bromobenzoate ( 8 0 ) by c o m p a r i s o n w i t h an a u t h e n t i c sample (mixed m e l t i n g p o i n t -27-and s u p e r i m p o s a b l e i n f r a r e d s p e c t r a ) . T h i s compound was c o n s i s t e n t l y formed i n ILO t o 50$ y i e l d . C a r e f u l chromato-graphy a l s o e v e n t u a l l y l e d t o the s e p a r a t i o n of two o i l s and a more p o l a r amorphous s o l i d . The major o i l was o b v i o u s l y not the d e s i r e d compound (79) as i t e x h i b i t e d a b s o r p t i o n i n the o l e f i n i c r e g i o n o f the NMR spectrum. The minor o i l w h i c h w.;as d i f f i c u l t t o p u r i f y appeared t o have the g e n e r a l s p e c t r a l f e a t u r e s e x p ected f o r the d e s i r e d p r o d u c t , A l k y l a t i o n had o c c u r r e d as e v i d e n c e d by the presence o f a t h r e e p r o t o n t r i p l e t a t 7/9'.2 5 f o r the m e t h y l of an e t h y l group. Two d o u b l e t s i n t e g r a t i n g f o r f o u r p r o t o n s were p r e s e n t i n the a r o m a t i c r e g i o n at/2.lL and 7^ 2'. 7 and a methoxyl peak appeared at 1^6i3-although i t s i n t e g r a l was low. The c a r b o n y l r e g i o n o f the i n f r a r e d spectrum was almost i d e n t i c a l t o t h a t o f the s t a r t i n g amide (78) and e x h i b i t e d a b s o r p t i o n a t 1725 cm" 1 and 1630 cm" 1o T h i s compound was not c o m p l e t e l y c h a r a c t e r i z e d due t o s e p a r a t i o n d i f f i c u l t i e s and low y i e l d w h i c h a l s o made i t I m p r a c t i c a b l e as a s y n t h e t i c I n t e r m e d i a t e . The amorphous s o l i d w h i c h was o b t a i n e d / as"mentioned above 9 :again" showed • an" e t h y l g r o u p . ' l i k e l y p r e s e n t as a t r i p l e t , , appeared at 7^ 8.9 i n the NMR spectrum. A methoxyl f u n c t i o n was e v i d e n t as a s i n g l e t at 7^6.3 and two a r o m a t i c d o u b l e t s were a g a i n p r e s e n t . The I n t e g r a l i n the 6.5 t o 7^8.5 r e g i o n however i n d i c a t e d a number of p r o t o n s f a r i n excess of the d e s i r e d p r o d u c t . E s t e r and amide groups were i n d i c a t e d as b e i n g p r e s e n t by a b s o r p t i o n i n the i n f r a r e d a t 1725 cm~l and -28-I63O cm" 1. The p o l a r n a t u r e of t h i s m a t e r i a l suggested i t may-be a d i m e r i c or p o l y m e r i c substance and the f o r m a t i o n of methyl p-bromobenzoate i n the absence of any e x t e r n a l source of methoxide i n d i c a t e s t h a t i n t e r m o l e c u l a r c o n d e n s a t i o n s are not u n l i k e l y . The f o r m a t i o n o f methyl p-bromobenzoate can be r a t i o n a l i z e d by the type o f mechanism i n d i c a t e d i n F i g u r e 15. A l t e r n a t e l y the methoxide c o u l d a r i s e from d i r e c t n u c l e o p h i l i c d i s p l a c e m e n t by h y d r i d e ion„ 8 r F i g u r e 15 -29-Because o f the d i f f i c u l t i e s e ncountered i n the above r o u t e , the p r o d u c t s were not "examined f u r t h e r and ano t h e r method o f s y n t h e s i s o f the s u b s t i t u t e d p i p e r i d i n e (67) was examined. T h i s approach proved t o be s u c c e s s f u l and w i l l be d i s c u s s e d p r e s e n t l y , A p a r t i c u l a r l y c o n v e n i e n t s y n t h e s i s f rom c y a n o a c e t i c e s t e r i s shown i n F i g u r e 16 and had p r e v i o u s l y been r e p o r t e d f o r the p r e p a r a t i o n of 3-carboethoxy-3-phenylpiperidine^7(86), The p i p e r i d i n e r i n g i s g e n e r a t e d i n the f i n a l s t e p t h r o u g h r e d u c t i o n of a n i t r i l e group f o l l o w e d by c y c l i z a t i o n of the r e s u l t i n g c h l o r o a m i n e , A l k y l a t i o n of methy l c y a n o a c e t a t e (8l) w i t h e t h y l i o d i d e u s i n g sodium methoxide as b a s e ^ y i e l d e d a c l e a r c o l o r l e s s o i l upon d i s t i l l a t i o n . T h i s r e a c t i o n p r o d u c t was shown by gas chromatography t o be a. m i x t u r e of t h r e e components and NMR i n d i c a t e d the presence of two d i f f e r e n t t r i p l e t methyl resonances around 7<90 F r a c t i o n a l d i s t i l l a t i o n on a s p i n n i n g band column (25 t o 30 t h e o r e t i c a l p l a t e s ) f a i l e d t o s e p a r a t e the components w h i c h had a combined b o i l i n g range of f o u r degrees. S e p a r a t i o n of the major component wh i c h was e s t i m a t e d as 60% of the m i x t u r e was performed by gas chromatography on an A p i e z o n J column. T h i s was e a s i l y i d e n t i f i e d as the d e s i r e d a l k y l a t e d compound (82) by i t s NMR spectrum. T h i s spectrum showed a t h r e e p r o t o n t r i p l e t at7^8;9- (-CH2GH3) and a one p r o t o n t r i p l e t at?'6.5'5 f o r the hydrogen atom on the c a r b o n a t e ithe carbomethoxy - and. cyano groups. The methoxyl p r o t o n s appeared as a sharp t h r e e -30 p r o t o n s i n g l e t at?"6.25. The presence of these f u n c t i o n a l groups was a l s o s u p p o r t e d by n i t r i l e a b s o r p t i o n at 2230 cin"^ and e s t e r a b s o r p t i o n a t 171+0 cm~^ i n the i n f r a r e d spectrum. C0QCH1 COOCH*, CH 3 I : =»,. . —=* (81) cN (82) (83) Ha/pd 000c w 3 (814.) (4 (86) C O O C H j (67) 11 \ (85) F i g u r e 16 I t i s w e l l known t h a t d i a l k y l a t i o n of c y a n o a c e t i c e s t e r s i s an i n t e r f e r i n g s i d e r e a c t i o n and i s more s e r i o u s here than w i t h m a l o n i c e s t e r s 33. T h i s i s due t o the g r e a t e r a c i d i t y of c y a n o a c e t i c e s t e r s as compared to ma l o n i c e s t e r s , The s m a l l e s t component o f the m i x t u r e , a p p r o x i m a t e l y 10%, was s e p a r a t e d s i m i l a r l y and shown t o be u n r e a c t e d methyl c y a n o a c e t a t e ( i n f r a r e d spectrum and t h i n l a y e r chromatography) -31-The r e m a i n i n g component, r e p r e s e n t i n g about 30$ was a l s o s e p a r a t e d i n s m a l l q u a n t i t i e s and a g a i n shown t o have e s t e r and n i t r i l e a b s o r p t i o n i n the i n f r a r e d . T h i s compound was un d o u b t e d l y the d i a l k y l a t e d c y a n o a c e t i c e s t e r as the NMR spectrum of the i n i t i a l m i x t u r e had i n d i c a t e d two d i f f e r e n t . t r i p l e t m e t h y l groups , The presence o f a m i x t u r e i n s e p a r a b l e by d i s t i l l a t i o n a t t h i s p o i n t d i d not cause any p a r t i c u l a r d i f f i c u l t y i n the subsequent s t e p s i n c e m e t h y l e t h y l c y a n o a c e t a t e (82) was t o be a l k y l a t e d a g a i n w i t h bromochloropropane, The i n t r o d u c t i o n of t h i s l a r g e r group now a l l o w e d s e p a r a t i o n of the d e s i r e d d i a l k y l a t e d compound (83) by f r a c t i o n a l d i s t i l l a t i o n . The presence of methyl d i e t h y l c y a n o a c e t a t e d i d not i n t e r f e r e s i n c e i t c o u l d not be a l k y l a t e d a g a i n and had a s i g n i f i c a n t l y l o w e r b o i l i n g p o i n t than the d e s i r e d methyl 3 - c h l o r o p r o p y l e t h y l -c y a n o a c e t a t e (83), The presence o f u n r e a c t e d methyl cyano-a c e t a t e however c o u l d i n t e r f e r e i f m o n o a l k y l a t e d w i t h bromochloropropane s i n c e the r e s u l t i n g compound would d i f f e r f rom the d e s i r e d one m e r e l y by an e t h y l group, T h e r e f o r e , an excess of a l k y l h a l i d e was used a t t h i s p o i n t t o e f f e c t d i a l k y l a t i o n o f the meth y l c y a n o a c e t a t e s i n c e the r e s u l t i n g compound would c o n t a i n two l a r g e ' a l k y l groups and be c o n s i d e r a b l y h i g h e r b o i l i n g than the d e s i r e d compound. Indeed a l k y l a t i o n of the above m i x t u r e w i t h bromochloropropane37 u s i n g t h i s t e c h n i q u e l e d t o the p r e p a r a t i o n o f 83 i n 2>0% o v e r a l l y i e l d from m e t h y l c y a n o a c e t a t e . -32-The NMR s p e c t r u m of the c h l o r i d e c(8.3;)cwia<s i&3 ) '\'-e n good agreement w i t h the a s s i g n e d s t r u c t u r e . I t showed the presence of a m e t h o x y l group at-/<6.:2 (sharp t h r e e p r o t o n s i n g l e t ) and the m e t h y l p r o t o n s of the e t h y l group were r e v e a l e d as a t h r e e p r o t o n t r i p l e t c e n t r e d atY-8.95* A d i s t o r t e d two p r o t o n t r i p l e t appeared at 7^ 6.'.LL. due t o the ••• methylene a d j a c e n t t o the c h l o r i n e atom. The i n f r a r e d spectrum i n d i c a t e d an e s t e r c a r b o n y l a t 1735 cm" 1 and a n i t r i l e peak at 2220 cm" 1. Gas c h r o m a t o g r a p h i c e x a m i n a t i o n of t h i s m a t e r i a l (AYpiezon J column) i n d i c a t e d t h a t i t was v i r t u a l l y f r e e of c o n t a m i n a t i o n by o t h e r a l k y l a t i o n p r o d u c t s and an a n a l y t i c a l sample p r e p a r e d In t h i s manner gave a p o s i t i v e B e i l s t e i n h a l o g e n t e s t . R e d u c t i o n of the n i t r i l e (83) t o the amine w i t h a l a r g e excess o f p a l l a d i u m i n m e t h a n o l i c h y d r o c h l o r i c a c i d f o l l o w e d by treatment w i t h a l k a l i - ^ ? p r o v i d e d the d e s i r e d p i p e r i d i n e (67)° The r e d u c t i o n of the n i t r i l e d i d not go t o c o m p l e t i o n , u s u a l l y o n l y ILO t o $0% of the t h e o r e t i c a l amount of hydrogen b e i n g consumed. Recovery of the u n r e a c t e d n i t r i l e ( u s u a l l y 50 t o 60%) s e p a r a t e d from the amine was a c c o m p l i s h e d by p r e f e r e n t i a l e x t r a c t i o n . The i n i t i a l p r o d u ct of r e d u c t i o n was the s a l t (8I4.) which was made b a s i c and then a l l o w e d t o s t a n d f o r a p e r i o d o f a few days or warmed t o produce the c y c l i c amine (67) as i t s h y d r o c h l o r i d e s a l t . The l a t t e r then x^as c o n v e r t e d t o the f r e e base by a second t r e a t m e n t w i t h a l k a l i . -33-P u r i f i c a t i o n o f 3 - c a r b o m e t h o x y - 3 - e t h y l p i p e r i d i n e by vacuum d i s t i l l a t i o n was u s u a l l y accompanied by c o n s i d e r a b l e d e c o m p o s i t i o n so t h a t s m a l l q u a n t i t i e s n e c e s s a r y f o r s t r u c t u r a l and a n a l y t i c a l data were o b t a i n e d by gas chroma-tograp h y (Apiezon J column). The pure compound e x h i b i t e d a complex p a t t e r n i n the NMR spectrum, i m p o r t a n t f e a t u r e s b e i n g the presence of a sha r p t h r e e p r o t o n s i n g l e t at?r6.25 ( - C O O C H 3 ) and a t h r e e p r o t o n t r i p l e t c e n t e r e d at'/'-''9»2 (-C^CH^)0 The i n f r a r e d spectrum possessed a broad a b s o r p t i o n band a t 3250 cm" 1 (NH) and a sha r p peak a t 1725 cm" 1 (-COOCH^), A n a l y t i c a l and f u r t h e r s t r u c t u r a l e v idence f o r t h i s compound were p r o v i d e d from the 3,5-dihitrobenzamide d e r i -vative., (85)which was o b t a i n e d as a sharp m e l t i n g , e a s i l y c r y s t a l l i z e d p a l e y e l l o w compound whichpossessed c h a r a c t e r i s t i c s p e c t r a l f e a t u r e s . Two v e r y prominent bands a p p e a r e d ' i n . t h e c a r b o n y l r e g i o n of the i n f r a r e d spectrum due t o the methyl e s t e r (1725 cm - 1) and the amide (1630 cm - 1) grou p s . An ar o m a t i c peak was a l s o e a s i l y d i s c e r n i b l e at 3030 cm" 1. A th r e e p r o t o n t r i p l e t i n the NMR spectrum atT<9».2'5 p r o v i d e d e v i d e n c e f o r the presence of an e t h y l group and the methoxyl group appeared as a sha r p t h r e e p r o t o n s p i k e at 7^ 6.. 3° The ar o m a t i c r e g i o n of the NMR c o n s i s t e d of a one p r o t o n t r i p l e t a t ^0,9-and a two p r o t o n d o u b l e t a t T ^ l ' . i i . The low c h e m i c a l s h i f t of these a r o m a t i c p r o t o n s i s a t t r i b u t a b l e t o the presence of e l e c t r o n w i t h d r a w i n g s u b s t i t u e n t s on the r i n g , the l o w e r t r i p l e t b e i n g r e a d i l y a s s i g n e d t o the p r o t o n between the two n i t r o g r o u p s . The s p e c t r a l and a n a l y t i c a l data on t h i s d e r i v a t i v e as w e l l as the s p e c t r a l data on the p i p e r i d i n e I t s e l f s u f f i c e t o e s t a b l i s h the s t r u c t u r e of the compound„ The f i n a l s t e p i n the sequence t o p r o v i d e the i n t e r -mediate (68) f o r a c y l o i n c o n d e n s a t i o n proceeded w e l l . R e a c t i o n of the p i p e r i d i n e (67) w i t h 2 - c a r b o e t h o x y - 3 -( / 3 - c h l o r o e t h y l ) - i n d o l e ^ (66) i n a s e a l e d tube at 160~C p r o v i d e d the c o u p l i n g p r o d u c t (68). The l a t t e r was p u r i f i e d by column chromatography on alumina and was o b t a i n e d as a sha r p m e l t i n g c o l o r l e s s c r y s t a l l i n e s o l i d , / V C l • COOEt / \ V COOCH: (66) (67) (68) ,4 xCOoE"t-The i n f r a r e d s p e c t r u m o f the c o u p l i n g p r o d u c t (68) was —1 1 c h a r a c t e r i z e d by I n t e n s e bands a t 1730 cm" and 1675 cm due to the methyl and c o n j u g a t e d e t h y l e s t e r c a r b o n y l groups r e s p e c t i v e l y , A band at 3350 cm-"1- was a t t r i b u t a b l e t o the i n d o l e NH. The NMR spectrum a g a i n showed the presence of two d i f f e r e n t e s t e r g r o u p s , the methoxy group a p p e a r i n g as a t h r e e p r o t o n s i n g l e t at7"'6.35j, and the e t h y l group of the e t h y l e s t e r a p p e a r i n g as a t h r e e p r o t o n t r i p l e t a t 7^-8.6, ( - C 0 0 C H 2 C H 3 ) and a two p r o t o n q u a r t e t at 7^5.57 ( - C 0 0 C H ? CH3) -35-A second t h r e e p r o t o n t r i p l e t atf9.2 was r e a d i l y ' a s s i g n e d t o the methyl of the e t h y l group on the p i p e r i d i n e r i n g . The I n d o l e r i n g was shown by the a r o m a t i c a b s o r p t i o n w h i c h appeared i n the r e g i o n f 2 ."2-3iO i n the NMR spectrum and i t s t y p i c a l a b s o r p t i o n a t 228 and 297 m.u i n the u l t r a v i o l e t spectrum. F u r t h e r s t r u c t u r a l e v i d e n c e f o r compound 68 i n a d d i t i o n t o a n a l y t i c a l data was p r o v i d e d by e x a m i n a t i o n of i t s mass spectrum. The m o l e c u l a r i o n peak a t m/e 386 c o n f i r m e d the m o l e c u l a r f o r m u l a w h i l e an e x t r e m e l y i n t e n s e peak a t m/e I8J4. was dominant i n the spectrum. From the e x t e n s i v e data a v a i l a b l e on the f r a g m e n t a t i o n of i n d o l e a l k a l o i d s ^ , t h i s peak can be a t t r i b u t e d t o the fragment (87) a r i s i n g by s i m p l e c l e a v a g e of the bond f3 t o the p i p e r i d i n e n i t r o g e n . F r a g m e n t a t i o n of t h i s type was a l s o encountered i n o t h e r compounds prepar e d i n t h i s work t o be d i s c u s s e d l a t e r , , _ 3 6 -H a v i n g o b t a i n e d the c o u p l i n g product (68) i t now became p o s s i b l e t o s t u d y the a c y l o i n c o n d e n s a t i o n r e a c t i o n t o form the nine-membered r i n g . The a c y l o i n c o n d e n s a t i o n has been employed w i t h s p e c t a c u l a r s u c c e s s i n the s y n t h e s i s of medium s i z e d rIngs^'''- ,^" 2 ,^, Y i e l d s o b t a i n e d by o t h e r methods (e.g. Dieckmann, i n t e r m o l e c u l a r a l k y l a t i o n , e t c , ) are s a t i s f a c t o r y f o r f i v e , s i x and seven membered r i n g s , however, are poor f o r e i g h t t o f o u r t e e n membered r i n g s and r e a c h a minimum a t t e n , T h i s i s e x p l a i n e d by the f a c t t h a t non-bonded i n t e r a c t i o n s become i m p o r t a n t i n t h i s range and r e a c h a maximum i n the t e n -membered r i n g . R e p u l s i v e f o r c e s , t h e r e f o r e , h i n d e r the approach of the two ends of the molecule w h i c h i n i t s e l f i s l e s s l i k e l y as the c h a i n l e n g t h i n c r e a s e s , r e s u l t i n g i n a preponderance of p o l y m e r i z a t i o n over c y c l i z a t i o n . The y i e l d s o f c y c l i z a t i o n by the a c y l o i n method a l s o r e a c h a minimum at the ten-membered r i n g , but are s t i l l i n a r e s p e c t a b l e range ( u s u a l l y about 50$). The success of the a c y l o i n c o n d e n s a t i o n Is a r e s u l t of the r e a c t i o n o c c u r r i n g on the s u r f a c e of the sodium m e t a l . The e s t e r i s w e a k l y adsorbed on the s u r f a c e and s i n c e the sodium i s d i s p e r s e d as a f i n e sand, t h i s becomes i n e f f e c t , a r e a c t i o n at h i g h d i l u t i o n , r e d u c i n g i n t e r m o l e c u l a r i n t e r a c t i o n and p o l y m e r i z a t i o n . The method used f o r the a c y l o i n c o n d e n s a t i o n was t h a t d e s c r i b e d by L e o n a r d ^ - whereby a d i l u t e s o l u t i o n of the d i e s t e r was added to a v i g o r o u s l y s t i r r e d r e f l u x i n g s u s p e n s i o n of sodium i n t o l u e n e , I n i t i a l l y a r e l a t i v e l y low speed s t i r r e r 37-was used f o r the r e a c t i o n and the product was i n v e s t i g a t e d by t h i n l a y e r chromatography, Three compounds i n about e q u a l q u a n t i t i e s and w i t h R t v a l u e s s i m i l a r t o the s t a r t i n g m a t e r i a l c o u l d be seen on the c h r o m a t o p l a t e i n a d d i t i o n t o a v e r y p o l a r s u b s t a n c e . S e p a r a t i o n of the t h r e e s i m i l a r components was p o s s i b l e i n s m a l l q u a n t i t i e s . b y p r e p a r a t i v e t h i n l a y e r chromatography on a l u m i n a . One of these compounds was shown to be i d e n t i c a l t o the s t a r t i n g d i e s t e r (TLC and i n f r a r e d c o m p a r i s o n ) . The o t h e r two compounds e x h i b i t e d i n f r a r e d s p e c t r a which were r e m a r k a b l y s i m i l a r t o the s t a r t i n g compound and showed normal i n d o l e a b s o r p t i o n i n the u l t r a v i o l e t r e g i o n . The NMR spectrum of one of these i n d i c a t e d t h a t the e t h y l e s t e r o r i g i n a l l y a t t a c h e d t o the i n d o l e r i n g was absent but a new t h r e e proton' s i g n a l was p r e s e n t at 7^ 6.05 i n a d d i t i o n t o the methoxyl s p i k e a t ^6.35? observed i n the s t a r t i n g compound. The o t h e r a c y l o i n p r o d u c t , however, l a c k e d the methoxyl s i g n a l at-7^6.35-but now possessed a new t r i p l e t and q u a r t e t a t s l i g h t l y h i g h e r f i e l d than t h a t observed f o r the e t h y l e s t e r f u n c t i o n i n the s t a r t i n g d i e s t e r . I t t h e r e f o r e was apparent t h a t the s t a r t i n g u n s y m m e t r i c a l m e t h y l e t h y l e s t e r had s i m p l y undergone e s t e r exchange g i v i n g the d i m e t h y l and d i e t h y l e s t e r s r e s p e c t i v e l y . One of these compounds was l a t e r shown t o be i d e n t i c a l t o the a u t h e n t i c d i m e t h y l ester39 ( t h i n l a y e r c hromatography). The p o l a r m a t e r i a l was o n l y examined i n a p r e l i m i n a r y manner a t t h i s p o i n t as o n l y a s m a l l q u a n t i t y was. o b t a i n e d 0 - 3 8 -I t s i n f r a r e d spectrum i n d i c a t e d t h a t i t was a c a r b o n y l c o n t a i n i n g compound and the NMR spectrum i n d i c a t e d the presence of methyl and e t h y l e s t e r s i n the same r e g i o n as observed f o r the s t a r t i n g d i e s t e r . T h e i r i n t e g r a l s , however, were q u i t e low and a peak was p r e s e n t f o r a p p r o x i m a t e l y one p r o t o n a t 7"'=-l «7 • Subsequent a c y l o i n c o n d e n s a t i o n attempts u s i n g a h i g h speed s t i r r i n g a pparatus l e d t o the f o r m a t i o n of o n l y the p o l a r m a t e r i a l . The l a t t e r was o b t a i n e d i n pure form by. p r e p a r a t i v e t h i n l a y e r chromatography on s i l i c a g e l . T h i s p u r i f i e d m a t e r i a l c o n t a i n e d c a r b o n y l a b s o r p t i o n i n the i n f r a r e d r e g i o n } and a s l i g h t l y s h i f t e d I n d o l e a b s o r p t i o n was p r e s e n t i n the u l t r a v i o l e t r e g i o n , w i t h maxima now o c c u r r i n g a t 225 and 2:95 m/>, compared t o 227 and 298 mjut f o r the s t a r t i n g d i e s t e r . The NMR spectrum of t h i s p o l a r m a t e r i a l r e t a i n e d the same g e n e r a l f e a t u r e s as t h a t observed i n the crude m a t e r i a l mentioned above a l t h o u g h the e n t i r e spectrum was i l l - d e f i n e d . A. mass sp e c t r u m i n d i c a t e d t h i s was not the d e s i r e d a c y l o i n p r o d u c t as no s i g n i f i c a n t peaks were p r e s e n t f o r the p r e d i c t e d m o l e c u l a r i o n peak at m/e 312. A c y l o i n s may be o x i d i z e d t o <X-diketones by t r e a t m e n t w i t h chromium t r i o x i d e ^ . T h i s m a t e r i a l , however, c o u l d not be o x i d i z e d by t h i s method w i t h o u t d e s t r u c t i o n of the i n d o l e chromophoreo I t was r e a d i l y reduced by l i t h i u m aluminum h y d r i d e , so the crude a c y l o i n p r o d u c t c o n t a i n i n g no u n r e a c t e d d i e s t e r was t r e a t e d w i t h t h i s r e a g e n t . T h i s reduced m a t e r i a l - 3 9 was p u r i f i e d by p r e p a r a t i v e t h i n l a y e r chromatography on s i l i c a g e l and e x h i b i t e d no c a r b o n y l a b s o r p t i o n i n the i n f r a r e d r e g i o n . The NMR s p ectrum possessed two v e r y prominent s i n g l e t s a t ^ 5.? 35' and 7^  6... 5 , b o t h i n t e g r a t i n g f o r a p p r o x i m a t e l y two p r o t o n s . A. t h i r d broad s i n g l e t a t Y - k » ^ w a s s e n s i t i v e t o c o n c e n t r a t i o n s h i f t s and r e a d i l y exchanged w i t h d e u t e r i u m o x i d e . T h i s compound was t h e r e f o r e s t r o n g l y s u s p e c t e d t o be a d i o l and a c e t y l a t i o n w i t h a c e t i c a n h y d r i d e i n p y r i d i n e was c a r r i e d o u t . The NMR spectrum of the l a t t e r showed a down-f i e l d s h i f t o f r 0 . 5 7 and r 0 - . ' 5 0 r e s p e c t i v e l y f o r the two s i n g l e t s mentioned above and i n d i c a t e d t h a t the a l c o h o l i c f u n c t i o n s were p r i m a r y . The presence of a c e t a t e groups was a l s o i n d i c a t e d by two s h a r p s p i k e s a t y S . O i n the NMR s pectrum and c a r b o n y l a b s o r p t i o n at 1 7 2 5 cm" 1 i n the i n f r a r e d s pectrum. The d i a c e t a t e (88) p r e p a r e d from the a u t h e n t i c d i m e t h y l e s t e r by a s i m i l a r l i t h i u m aluminum h y d r i d e r e d u c t i o n and a c e t y l a t i o n was found t o be i d e n t i c a l t o the above d i a c e t a t e o b t a i n e d from the a c y l o i n c o n d e n s a t i o n s ( t h i n l a y e r chromatography on s i l i c a g e l , a l u m i n a , i n f r a r e d and mass s p e c t r o m e t r y ) . I t i s of i n t e r e s t t o p o i n t out t h a t the base peak i n the mass spectrum o c c u r r e d at m/e 198 and i s a t t r i b u t a b l e to the i o n (89) which a r i s e s by f r a g m e n t a t i o n of the type suggested e a r l i e r f o r compound ( 6 8 ) . The p o l a r n a t u r e o f the a c y l o i n c o n d e n s a t i o n p r o d u c t and i t s a b i l i t y t o be reduced t o an a l c o h o l w i t h l i t h i u m aluminum h y d r i d e i n d i c a t e d t h a t i t must have been an a c i d . T h i s was c o n f i r m e d as t r e a t m e n t of the a c y l o i n p r o d u c t w i t h diazomethane gave a m i x t u r e of two e s t e r s . One of these was I d e n t i c a l (by t h i n l a y e r chromatography) t o the d i e s t e r used f o r the a c y l o i n c o n d e n s a t i o n (68) w h i l e the o t h e r was i d e n t i c a l t o the a u t h e n t i c d i m e t h y l e s t e r . The p r o d u c t s a r i s i n g from the a c y l o i n c o n d e n s a t i o n r e a c t i o n m i x t u r e were t h e r e f o r e m e r e l y the two a c i d - e s t e r s (90) and ( 9 1 ) . ( 9 0 ) ( 9 1 ) T h i s e x p l a n a t i o n i s c o n s i s t e n t w i t h t h e o b s e r v e d r e a c t i o n s and s p e c t r a l d a t a and a l t h o u g h t h e d i a c i d o f compound 90 c o u l d a l s o g i v e t h e d i m e t h y l e s t e r on 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 i t w o u l d be s u r p r i s i n g i f i t s p o l a r i t y on t h i n l a y e r c h r o m a t o g r a p h y w o u l d be s u c h as t o make i t i n d i s t i n g u i s h -a b l e f r o m t h e e s t e r a c i d s . The l o w i n t e g r a l s o b s e r v e d f o r t h e e s t e r s i g n a l s i n t h e NMR s p e c t r u m o f t h e a c y l o i n p r o d u c t a r e a l s o e x p l i c a b l e i n t h e s e t e r m s . The p e a k a t y'-l.7 m e n t i o n e d e a r l i e r c o u l d be a t t r i b u t e d t o t h e c a r b o x y l p r o t o n . I n s p i t e o f g r e a t p r e c a u t i o n s w h i c h were t a k e n t o p r e v e n t s i m p l e h y d r o l y s i s o f t h e d i e s t e r s t o t h e m o n o - a c i d s 90 and 91, we were' n o t s u c c e s s f u l i n a c h i e v i n g t h e d e s i r e d c y c l i z a t i o n . U n f o r t u n a t e l y we were o n l y a b l e t o s t u d y t h e a c y l o i n r e a c t i o n w i t h m i l l i g r a m q u a n t i t i e s o f s t a r t i n g d i e s t e r and e v e n m i n u t e t r a c e s o f w a t e r ( u s u a l l y a b o u t 11+ mg, ) were s u f f i c i e n t t o c a u s e t h e above h y d r o l y s i s . R a t h e r t h a t s p e n d a good d e a l o f t i m e p r e p a r i n g l a r g e q u a n t i t i e s o f t h e d e s i r e d d i e s t e r we t u r n e d o u r a t t e n t i o n t o a c o m p l e t e l y d i f f e r e n t s e q u e n c e w h i c h was b e i n g i n v e s t i g a t e d c o n c u r r e n t l y i n o u r l a b o r a t o r y . I w o u l d now l i k e t o d i s c u s s t h i s w o r k w h i c h 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 d i h y d r o c l e a v a m i n e and c o n s t i t u t e s s e c t i o n B o f t h i s t h e s i s . -LL2-S e c t i o n B The key s t e p i n t h i s sequence centres on the r e d u c t i v e cleavage of a p a r t i c u l a r bond common to a f i v e and six-membered r i n g as shown below. I f t h i s cleavage i s performed on the intermediate 73a, the nine-membered r i n g compound, dihydro -cleavamine (7l+a) i s generated. S i m i l a r l y the intermediate 92a provides quebrachamine (93a)° The corresponding carbo-methoxy d e r i v a t i v e s (73b and 92b) would give r i s e to carbo-methoxydihydrocleavamine (7l+b) and carbomethoxyquebrachamine (v i n c a d i n e ) (93b) r e s p e c t i v e l y . (73a) R = R = H ,R = E t R = R = H , R = E t (92a) R = R " = H , R ' = Et ( 9 3 a ) R = R "= H , R = Et (73b) R = C O O C H _ , R'-= H , R " = Et' (7k*) R = C O O C H R ' = H,R"= Et (92b) R = C O O C H ^ R' = E t , R " = H (93b) R = C O O C H ^ , R ' = E t , R" = H The r e d u c t i v e c l e a v a g e of c a r b o n - n i t r o g e n bonds i n q u a t e r n a r y ammonium s a l t s i s a w e l l known r e a c t i o n and i s e s p e c i a l l y u s e f u l i n the a l k a l o i d f i e l d . A number of examples of i t s a p p l i c a t i o n t o a l k a l o i d s o f p a r t i c u l a r i n t e r e s t t o t h i s s t u d y have appeared r e c e n t l y i n the l i t e r a t u r e and deserve comment. The c l e a v a g e i s n o r m a l l y a c c o m p l i s h e d by the use o f sodium or l i t h i u m T n - l i q u i d ammonia. F o r example, the r e d u c t i o n o f the q u a t e r n a r y i o d i d e 9 1 + t o the r i n g opened compound (95) has been r e p o r t e d i n 89% y i e l d u s i n g s o d i u m i n l i q u i d a m m o n i a ^ . Ok) No. CHj (95) R e d u c t i o n o f the compound 96 by e i t h e r s o d i u m i n l i q u i d ammonia o r l i t h i u m a l u m i n u m h y d r i d e g i v e s a ten-membered r i n g c o m p o u n d ^ (97). T h i s r e a c t i o n and o t h e r s i m i l a r c l e a v a g e s r e p o r t e d by the same a u t h o r s ^ - 8 a r e shown i n F i g u r e 17. (96) tr i + C^ 3 6H Mcr/Nhj „ r — > !• (97) > F i g u r e 17 A. r i n g c l e a v a g e o f the q u a t e r n a r y s a l t 98 t o p r o v i d e , a ten-membered r i n g compound (99) has a l s o been s u c c e s s f u l l y c a r r i e d out i n o u r l a b o r a t o r y ^ 9 . (98) H (99) -kh-In a model s t u d y , d e s i g n e d f o r quebrachamine s y n t h e s i s , W'enkert, et a h ^ r e p o r t e d the c o n v e r s i o n of 100 t o 101 by means of l i t h i u m i n l i q u i d ammonia. I t can be s e e n , t h e r e f o r e , t h a t t h e r e was c o n s i d e r a b l e p r e c e d e n t f o r t h i s type of c l e a v a g e d e s i r e d i n the case of the q u a t e r n a r y s a l t s (73a and b) and (92a and b ) . A s t u d y of a s y n t h e t i c sequence l e a d i n g t o the compounds 73a and b and t h e i r p o s s i b l e c l e a v a g e t o the a p p r o p r i a t e nine-membered r i n g systems was t h e r e f o r e w a r r a n t e d . The work i n v o l v e d w i t h t h i s a s p e c t c o n s t i t u t e s the c e n t r a l p o r t i o n o f t h i s t h e s i s A p r o m i s i n g r o u t e t o the compounds 92a and b was c u r r e n t l y under s t u d y i n our l a b o r a t o r y and s i n c e these compounds are e p i m e r i c w i t h 73a and b, an analogous sequence u t i l i z i n g the a p p r o p r i a t e l y m o d i f i e d i n t e r m e d i a t e s was d e s i r a b l e . The under-l y i n g p r i n c i p l e i n v o l v e d here was t h a t the s y n t h e s i s of the i s o m e r i c e s t e r s ( 7 1 a , 102a) and (71b, 102b) f o l l o w e d by c o n d e n s a t i o n w i t h t r y p t a m i n e would h o p e f u l l y l e a d t o i n t e r -mediates w h i c h t h r o u g h a common s e r i e s of subsequent r e a c t i o n s would e v e n t u a l l y y i e l d d i h y d r o c l e a v a m i n e , quebrachamine and t h e i r c o r r e s p o n d i n g carbomethoxy d e r i v a t i v e s . -k5~ C=0 C O O E t / o c H ^ ( 7 1 a ) R = OEt (102a) R = OEt (71b) R = COOCH^ (102b) R = COOCH^ A'- s y n t h e s i s of the d i e s t e r s 102a and b had a l r e a d y been a c h i e v e d in> our l a b o r a t o r y ^ 1 by the scheme d e p i c t e d i n F i g u r e 18. An analogous s y n t h e s i s of the d i e s t e r 71a was now c o n s i d e r e d and t h i s sequence i s summarized i n F i g u r e 19° D i e t h y l e t h y l m a l o n a t e (105) was reduced t o 2 - e t h y l - l s 3 = p r o p a n e d i o l - ^ (106) i n 9 1 % y i e l d by means of l i t h i u m aluminum h y d r i d e i n t e t r a h y d r o f u r a n , The d i o l was c o n v e r t e d t o the monobenzyl e t h e r (107) by t r e a t m e n t w i t h sodium i n hot x y l e n e f o l l o w e d by r e a c t i o n w i t h b e n z y l c h l o r i d e ^ (77# y i e l d ) . The p r e f e r e n t i a l f o r m a t i o n of the monobenzyl e t h e r was ensured by u s i n g a 3sl molar r a t i o of the d i o l t o the sodium metal„ The r e s u l t i n g m i x t u r e of u n r e a c t e d d i o l and monobenzyl e t h e r was then s e p a r a t e d by f r a c t i o n a l d i s t i l l a t i o n . The i n f r a r e d s p e c t r u m of the d e s i r e d b e n z y l e t h e r possessed an a b s o r p t i o n band at 3300 cm."-1- (OH) and c h a r a c t e r i s t i c a r o m a t i c C-H out of p l a n e bending modes at 695 cm,"'1- and 71+0 cm.-l ( a l s o p r e s e n t i n a l l o t h e r b e n z y l e t h e r s r e p o r t e d s u b s e q u e n t l y ) . The NMR s p ectrum showed a f i v e p r o t o n s i n g l e t at Y2.7 f o r the a r o m a t i c p r o t o n s and a two p r o t o n s i n g l e t at7""5°5 f o r the b e n z y l methylene p r o t o n s . These two s i n g l e t s were a l s o v e r y c h a r a c t e r -i s t i c f o r a l l the subsequent compounds c o n t a i n i n g the b e n z y l -1+6-H 0 ( G H 2 ) 3 0 H Na COOEt ^CHpO(CH 2)3CH COOEt NaOEt E t l V COOEt 0CH2O(CH2) 3CCH 2CH3 COOEt (103) CH2CH3 ^CH 20(CH 2)3CHC00Et (101+) j^CNa Bf-CH 2C00Et V CH2CH3 j ^ G H ^ C H ^ C C O O E t CH 2C00Et 0CH 2C1 NaOEt C H 2 ( C 0 0 E t ) 2 KOH EtOH H2 S 0[+ 4 C°V. 0CH 2O(CH 2) 3OH S0C1-V J#CH 20(CH 2)3C1 COOH ^CH 20(CH 2)3CCH 2CH3 COOH -co 2 Y CH 2CH3 jZfeHgOfCH^CHCOOH ? H2 G H3 0CHPO(CH?),C"COOEt (102a) i 2 y 3 (102b) 0 CH 2CC00Et F i g u r e 18 COOEt CH'Et ! COOEt (105") s o c i o LiA'lH THP -9* CH-OH I 2 CHEt I CH 20H (106) CH 20CH 2J^ CI1JCOOEt ) 2 Mo o£j~ CHEt CH 2C1 (108) E t COOEt. j?iCH 20CH 2CHCH 2CCH 2C00Et COOEt (113) KOH H 2 0 E t COOH $CH 20CH 2CHCH 2CCH 2C00H COOH ( l i l t ) •CO. V CHoCOOH 0CH2OCH2CHCH2CHCOOH"' El ( 1 1 5 ) EtOH H2 S 01+ ^CH 20CH 2CHCH 2CHGOOEt V t CHoCOOEt (71a -.0 0 0CH2G1 N a CH 2OCH 2j2; CHEt CH 20H E t (107) COOEt 0CH 2OCH 2CHCH 2CH (109) . COOEt KOH H 20 w COOH jZfcH OCH„CHCH 5CH 2 2, 2 ( E t COOH (110 -CO. 0CH 2OCH 2CHCH 2CH 2COOH Et (111 ) V EtOH H 2S0^ 0CH 2OCH 2CHCH 2CH 2COOEt Et ' • (112) $CH 20CH 2CHCH 2CHC00Et Et CH 2CC00Et (71b) F i g u r e 19 -1+8-e t h e r m o i e t y . The C - m e t h y l g r o u p a p p e a r e d as a t h r e e p r o t o n t r i p l e t c e n t e r e d a t 7 ' 9 * l w h i l e a f o u r p r o t o n m u l t i p l e t c e n t e r e d a t 7'^  6 , i j . was a t t r i b u t e d t o t h e f o u r m e t h y l e n e p r o t o n s a d j a c e n t t o an o x y g e n atom, A t h r e e p r o t o n m u l t i p l e t i n t h e r e g i o n yQiO t o 8 , 9 c o u l d be a s s i g n e d t o t h e m e t h i n e and two m e t h y l e n e p r o t o n s a t t a c h e d d i r e c t l y t o a c a r b o n atom* The r e m a i n i n g s h a r p one p r o t o n s i n g l e t a t 7 ^ 7 . 2 was i d e n t i f i e d as t h e h y d r o x y l p r o t o n as i t c o m p l e t e l y d i s a p p e a r e d upon a d d i t i o n o f d e u t e r i u m o x i d e t o t h e s o l u t i o n and t h e spectrum, t a k e n a g a i n . I t was a d i s t i n c t i v e f e a t u r e o f t h e compounds e x a m i n e d i n t h i s s y n t h e t i c s e q u e n c e t h a t t h e y a l l p o s s e s s e d e x t r e m e l y i n f o r m a t i v e NMR s p e c t r a s o c o n s i d e r a b l e e m p h a s i s w i l l be p l a c e d on t h i s d a t a d u r i n g t h e d i s c u s s i o n . The e t h e r - a l c o h o l ( 1 0 7 ) was c o n v e r t e d t o t h e c h l o r i d e ( 1 0 8 ) i n 6 6 $ y i e l d by t r e a t m e n t w i t h t h i o n y l c h l o r i d e i n N s N - d i -m e t b y l a n i l i n e ^ . The r e s u l t i n g c h l o r i d e ( 1 0 8 ) showed no i n f r a r e d a b s o r p t i o n i n t h e h y d r o x y l r e g i o n b u t t h e a r o m a t i c p e a k s m e n t i o n e d above were p r e s e n t . The NMR s p e c t r u m l a c k e d t h e h y d r o x y l p r o t o n p e a k o b s e r v e d i n t h e s t a r t i n g e t h e r - a l c o h o l and t h e r e m a i n d e r o f t h e s p e c t r u m was c o n s i s t e n t w i t h t h e a s s i g n e d s t r u c t u r e ( 1 0 8 ) , The a r o m a t i c p r o t o n s a p p e a r e d a g a i n as a s h a r p f i v e p r o t o n s i n g l e t a t - / 2 , 7 and t h e b e n z y l m e t h y l e n e p r o t o n s as a s h a r p two p r o t o n s i n g l e t a t 7 ^ 5 ' , 5 , A f o u r p r o t o n m u l t i p l e t c e n t e r e d a t - ? Y 6 , l ) . 5 was a s s i g n e d t o t h e f o u r h y d r o g e n atoms a d j a c e n t t o t h e o x y g e n and c h l o r i n e atoms. The m e t h y l p r o t o n s o f t h e e t h y l g r o u p a p p e a r e d a s • a t h r e e p r o t o n t r i p l e t -1+9-c e n t e r e d a t T ^ . l , and t h e r e m a i n i n g t h r e e h y d r o g e n atoms (one m e t h i n e and two m e t h y l e n e ) a p p e a r e d as a m u l t i p l e t i n t h e r e g i o n ofV7.9 - 8,%, A l k y l a t i o n o f d i e t h y l m a l o n a t e w i t h t h e c h l o r i d e (108) u s i n g s o d i u m e t h o x i d e as b a s e - ^ p r o v i d e d d i e t h y l 3 ~ b e n z y l o x y -2 - e t h y l p r o p y l m a l o n a t e (109). The r e a c t i o n was s l u g g i s h and c o n s i s t e n t r e c o v e r i e s o f 50$ o f u n r e a c t e d h a l i d e were o b s e r v e d , T h i s was e a s i l y s e p a r a b l e f r o m t h e much h i g h e r b o i l i n g a l k y l a t e d m a l o n i c e s t e r (109) and a y i e l d o f 89$ was a t t a i n e d i n t h e r e a c t i o n . The i n f r a r e d s p e c t r u m o f t h e a l k y l a t i o n p r o d u c t showed s t r o n g c a r b o n y l a b s o r p t i o n a t 1735 cm," 1 due t o t h e e s t e r g r o u p s as w e l l as t h e two f a m i l i a r a r o m a t i c b a n d s , A g a i n t h e NMR s p e c t r u m ( F i g u r e 20) was i n v a l u a b l e i n e s t a b l i s h i n g t h e s t r u c t u r e o f t h i s compound. The b e n z y l e t h e r was a g a i n e v i d e n t by t h e p r e s e n c e o f a s h a r p f i v e p r o t o n s i n g l e t a t T'S,65 and a two p r o t o n s i n g l e t a t -r 5«5- A f o u r p r o t o n q u a r t e t c e n t e r e d a t 7 " 5*8 and a s i x - p r o t o n t r i p l e t ; , c e n t e r e d at7"8 08 were r e a d i l y a s s i g n e d t o t h e m e t h y l e n e and m e t h y l p r o t o n s o f t h e e t h y l e s t e r g r o u p s r e s p e c t i v e l y , A t h r e e p r o t o n m u l t i p l e t w h i c h a p p e a r e d a t 7"6.55 c o u l d be e a s i l y a n a l y z e d s i n c e t h e two p r o t o n s o f t h e m e t h y l e n e n e x t t o t h e o x y g e n o f t h e b e n z y l o x y g r o u p a b s o r b i n t h i s r e g i o n . The r e m a i n i n g p r o t o n r e s o n a t i n g a t t h i s f r e q u e n c y was e v i d e n t l y t h e one a t t a c h e d t o t h e c a r b o n a t om b e a r i n g t h e two c a r b o -e t h o x y g r o u p s . T h i s a s s i g n m e n t i s c o n f i r m e d by c o m p a r i s o n o f t h i s s p e c t r u m w i t h t h e NMR s p e c t r u m o f d i e t h y l e t h y l m a l o n a t e - 5 0 -E t COOEt jZfcH20CH2CHCH2CH COOEt J F i g u r e 20 Et j2fCH 20CH 2CHCH 2CH 2C00Et Hi M i 11; ~ t — 5" F i g u r e 2 1 where the analogous p r o t o n appears at - 7 * 6 . 8 0 A somewhat i s o l a t e d two p r o t o n m u l t i p l e t was apparent at7^8.05 and was a s s i g n e d t o the two prot o n s on the c a r b o n atom between the carbon atoms b e a r i n g the e t h y l group and the two carbomethoxy groups. T h i s assignment was made on the b a s i s of a NMR comparison w i t h the monoester (112) i n whi c h i t i s absent and the t r i e s t e r (113) t o be d i s c u s s e d l a t e r . F i n a l l y the methyl o f the e t h y l group appeared as a t h r e e p r o t o n t r i p l e t c e n t e r e d at-7"9.l5° I n i t i a l l y the r o u t e from t h i s m a l o n l c e s t e r t o the s u b s t i t u t e d s u c c i n i c e s t e r (71a) ( F i g u r e 19) was i n v e s t i g a t e d i n a manner analogous t o t h a t f o r the c o n v e r s i o n of the m a l o n l c e s t e r (103) t o the s u c c i n i c e s t e r (102a) shown i n F i g u r e 1 8 . I t was a l s o hoped t h a t t h i s sequence would p r o v i d e the - k e t o g l u t a r i c e s t e r (71b) ( F i g u r e 19) I s o m e r i c w i t h the o< - k e t o g l u t a r i c e s t e r (102b) ( F i g u r e 1 8 ) . Indeed the synthes-is o f the s u c c i n i c e s t e r (71a) by f i r s t c o n v e r t i n g i t t o the s u b s t i t u t e d e s t e r 112 and then a l k y l a t i n g w i t h e t h y l i o d o a c e t a t e was s u c c e s s f u l . However the a l t e r n a t e r o u t e v i a the t r i e s t e r (113) t o be d i s c u s s e d l a t e r was a n t i c i p a t e d t o proceed i n b e t t e r y i e l d and t h i s was s u b s e q u e n t l y v e r i f i e d . Thus, h y d r o l y s i s of the s u b s t i t u t e d m a l o n i c e s t e r (109) w i t h aqueous -potassium h y d r o x i d e - ^ , p r o v i d e d the c o r r e s p o n d i n g m a l o n l c a c i d (110) as a v i s c o u s o i l . T h i s compound c o u l d not be induced t o c r y s t a l l i z e but the s p e c t r a l data were i n a c c o r d w i t h the a s s i g n e d s t r u c t u r e . The NMR spectrum i n d i c a t e d 'the - 5 2 -absence of the e t h y l e s t e r p r o t o n s and a new a b s o r p t i o n peak appeared a t - 7 " 1 . 0 i n t e g r a t i n g f o r two t o t h r e e protons,, The c h e m i c a l s h i f t i s somewhat h i g h f o r the expected p o s i t i o n of the c a r b o x y l p r o t o n s ; ..however, the presence of v e r y broad a b s o r p t i o n i n the 3 5 0 0 t o 2 L L 0 0 cm." 1 r e g i o n of the i n f r a r e d s pectrum c o n f i r m e d the presence of c a r b o x y l i c a c i d f u n c t i o n s . Smooth d e c a r b o x y l a t i o n t o the monoacid ( 1 1 1 ) was_'ef fee t e d by h e a t i n g the v i s c o u s d i a c i d f o r f i v e hours at 1 2 0 ° C ^ 6 . The r e s u l t a n t v i s c o u s o i l was r e e s t e r i f l e d w i t h o u t p u r i f i c a t i o n by t r e a t m e n t w i t h e t h a n o l and s u l f u r i c a c i d t o p r o v i d e the s u b s t i t u t e d e s t e r 1 1 2 i n 7 5 % o v e r a l l y i e l d . T h i s monoester possessed c a r b o n y l a b s o r p t i o n at 1 7 3 0 cm." 1 i n the i n f r a r e d spectrum as w e l l as the two u s u a l a r o m a t i c bands. The NMR spectrum . ( F i g u r e 2 1 ) possessed a sharp f i v e p r o t o n s i n g l e t a t ' / 2 . 6 5 and a two p r o t o n s i n g l e t atY5°5 f ° r the b e n z y l e t h e r a r o m a t i c and methylene p r o t o n s r e s p e c t i v e l y . A two p r o t o n q u a r t e t c e n t e r e d a t j / 5 < > 8 5 a l o n g with, a t r i p l e t c e n t e r e d a t ? ^ 8 , 7 5 i n d i c a t e d the presence of one e t h y l e s t e r group. The methylene pro t o n s on the car b o n atom a d j a c e n t the b e n z y l ethe'r oxygen appeared as a broad two p r o t o n d o u b l e t a t ' T ' 6 . 6 and a two p r o t o n . m u l t i p l e t a t T : 7 . 6 5 / c o u l d be a t t r i b u t e d t o the methylene p r o t o n s on the carbon atom c*. t o the carbomethoxy group. The "malonic" 1 p r o t o n on the carbon atom between the two c a r b o e t h o x y groups observed i n the spectrum o f the m a l o n i c e s t e r ( 1 0 9 ) had d i s a p p e a r e d as had the two p r o t o n m u l t i p l e t a t - r * 8 . 0 5 a s s i g n e d e a r l i e r , , T h i s data i s c o n s i s t e n t w i t h the . . 5 3 -c h e m i c a l s h i f t s one would expect on removal of one of the c a r b o e t h o x y groups. The u s u a l t h r e e p r o t o n t r i p l e t c e n t e r e d a t - y ^ ' l f o r the meth y l p r o t o n s of the e t h y l group was a l s o e v i d e n t on the spectrum, A l k y l a t i o n s of s u b s t i t u t e d a c e t i c e s t e r s u s i n g v e r y s t r o n g bases such a t r i p h e n y l m e t b y l sodium are f a i r l y w e l l known and were used s u c c e s s f u l l y , as mentioned b e f o r e , t o pre p a r e the s u b s t i t u t e d s u c c i n i c (102a) and < * - k e t o g l u t a r i c (102b) e s t e r s . The - k e t o g l u t a r i c e s t e r (71b) was of i n t e r e s t 0^ s i n c e Wenkert and c o - w o r k e r s ^ had condensed e t h y l c ^ - k e t o g l u t a r a t e (116) w i t h t r y p t a m i n e t o p r o v i d e the l a c t a m (117). The analogous r e a c t i o n on the s u b s t i t u t e d o < - k e t o g l u t a r a t e (71b) would have p o s s i b l y p r o v i d e d a v e r y c o n v e n i e n t r o u t e t o ' d i h y d r o c l e a v a m i n e , • y , K J > (116.) (117) ' The e n o l a t e of the monoester (112) was e a s i l y g e n e r a t e d w i t h t r i p h e n y l m e t h y l sodium i n e t h e r as e v i d e n c e d by the almost i n s t a n t a n e o u s d i s a p p e a r a n c e of the c h a r a c t e r i s t i c deep r e d c o l o r of the t r i p h e n y l m e t h y l a n i o n upon a d d i t i o n o f the e s t e r . When t h i s a d d i t i o n was i m m e d i a t e l y f o l l o w e d by the a d d i t i o n of e t h y l <X -bromopyruvate, p r e c i p i t a t i o n o f sodium bromide was v i r t u a l l y i n s t a n t a n e o u s . A n a l y s i s of the r e a c t i o n m i x t u r e , however, l e d o n l y t o an 80 - 85$ r e c o v e r y of u n r e a c t e d -5V monoester (112 ), and no bromopyruvate c o u l d be r e c o v e r e d . No d e s i r e d a l k y l a t i o n p r o d u c t c o u l d be i s o l a t e d and t h i n - l a y e r and gas chr o m a t o g r a p h i c e x a m i n a t i o n of the crude p r o d u c t i n d i c a t e d no s i g n i f i c a n t compounds o t h e r than s t a r t i n g m a t e r i a l and t r i p h e n y l m e t h a n e . When the s o l u t i o n o f the e s t e r 112 and t r i p h e n y l m e t h y l sodium were s t i r r e d f o r one hour b e f o r e the a d d i t i o n o f the bromopyruvate, a new compound was formed. T h i s m a t e r i a l was p u r i f i e d by column chromatography and proved t o be e x t r e m e l y h i g h b o i l i n g . • The NMR spectrum i n d i c a t e d t h i s was o b v i o u s l y not the d e s i r e d < x - k e t o g l u t a r i c e s t e r (71b) and appeared t o be most p r o b a b l y the s e l f c o n d e n s a t i o n p r o d u c t . T h i s would not be s u r p r i s i n g s i n c e s e l f - c o n d e n s a t i o n of s u b s t i t u t e d a c e t i c e s t e r s Is the w e l l known G l a i s e n e s t e r c o n d e n s a t i o n and t h i s i s known t o c o n s t i t u t e the most s e r i o u s s i d e r e a c t i o n i n the a l k y l a t i o n s of m o n o s u b s t i t u t e d a c e t i c e s t e r s ^ ' ^ . Attempted ^ 8 a l k y l a t i o n u s i n g the a n i o n o f d i m e t h y l s u l f o x i d e - ^ i n d i m e t h y l s u l f o x i d e was a l s o u n s u c c e s s f u l . When e t h y l i o d o a c e t a t e ^ 9 was added i m m e d i a t e l y t o the e n o l a t e o f the e s t e r 112, the r e a c t i o n was a g a i n v i r t u a l l y i n s t a n t a n e o u s and sodium i o d i d e p r e c i p i t a t e d . A n a l y s i s of the crude r e a c t i o n p r o d u c t under c o n d i t i o n s s i m i l a r t o t h a t f o r the p r o d u c t of the bromopyruvate r e a c t i o n ( t h i n - l a y e r and gas chromatography) c l e a r l y i n d i c a t e d the presence of a new minor compound but the major component was s t i l l the s t a r t i n g e s t e r . The new p r o d u c t was s e p a r a t e d and p u r i f i e d by column -55-chromatography on a l u m i n a , f o l l o w e d by d i s t i l l a t i o n t o p r o v i d e a low y i e l d of the s u c c i n i c e s t e r (71a). Gas chromatography on a 2 0 % S E 3 0 column- e f f e c t e d f u r t h e r p u r i f i c a t i o n of a s m a l l q u a n t i t y of t h i s m a t e r i a l f o r a n a l y t i c a l and s p e c t r a l d a t a . The d i e s t e r (71a) possessed an a b s o r p t i o n band i n the c a r b o n y l r e g i o n o f the i n f r a r e d spectrum at 1730 cm." 1 and the two f a m i l i a r a r o m a t i c bands, The NMR spectrum ( F i g u r e 2 2 ) was a g a i n v e r y i n f o r m a t i v e . The b e n z y l e t h e r was apparent from the f i v e p r o t o n s i n g l e t a t - r 2 . 7 and the two p r o t o n s i n g l e t atr^5»5» Two'almost superimposable q u a r t e t s appeared at r'5<.85 i n t e g r a t i n g f o r f o u r p r o t o n s and combined w i t h a t r i p l e t c e n t e r e d atY8.75 i n d i c a t e d the presence of two e t h y l e s t e r groups. The methylene pro t o n s on the carbon a d j a c e n t the oxygen of the b e n z y l o x y f u n c t i o n appear as a two p r o t o n m u l t i p l e t at -T6.6, and the t h r e e p r o t o n s on the carbon atoms to the two c a r b o e t h o x y groups appear i n the r e g i o n of 7*7 °0 t o 7 . 6 , A g a i n the methy l p r o t o n s of the e t h y l group appear as a t h r e e p r o t o n - t r i p l e t c e n t e r e d a t 7 ' 9 ° l . The u n s u c c e s s f u l attempt a t p r e p a r i n g the s u b s t i t u t e d c < - k e t o g I u t a r i c e s t e r (71b) and the low y i e l d of the s u c c i n i c e s t e r (71a) by t h i s a l k y l a t i o n t e c h n i q u e was p r o b a b l y due t o the f a c t t h a t the a n i o n of the monoester ( 1 1 2 ) was a c t i n g p r e f e r e n t i a l l y as a base, r a t h e r than a n u c l e o p h i l e . I f the a n i o n a b s t r a c t s a p r o t o n from t h e c < - c a r b o n of e t h y l bromopyruvate and e t h y l i o d o a c e t a t e i t would s i m p l y r e g e n e r a t e the ester".112-0 S i n c e the p r e p a r a t i o n o f the °<»ketoglutaric e s t e r - 5 6 E t jZfcH 20CH 2CHCH 2CHC00Et CH 2C00Et I 4-J l i - I -F i g u r e 22 Et COOEt 0CH2OCH2CHCH2CCH2COOEt COOEt 7 F i g u r e 23 -57-(71b) was not s u c c e s s f u l by the s i m p l e a l k y l a t i o n d i s c u s s e d , the p r e p a r a t i o n of the s u c c i n i c e s t e r (71a) was examined by the more d e s i r a b l e r o u t e u t i l i z i n g the t r i e s t e r 113. The a l k y l a t i o n o f the m a l o n i c e s t e r (109) w i t h e t h y l 60 bromoacetate u s i n g sodium e t h o x i d e as base p r o v i d e d a f a i r y i e l d of the t r i e s t e r (113) a l o n g w i t h a good r e c o v e r y o f s t a r t i n g m a t e r i a l . The use of sodium i n e t h e r ^ 1 i n p l a c e o f sodium e t h o x i d e } however, p r o v i d e d an improved y i e l d ( 6 0 % ) of the t r i e s t e r as w e l l as some r e c o v e r e d m a l o n i c e s t e r (30$). The t r i e s t e r was v e r y h i g h b o i l i n g (195 - 200°C at 0.25 mm.) and c o u l d be s e p a r a t e d f r o m the l o w e r b o i l i n g m a l o n i c e s t e r by f r a c t i o n a l d i s t i l l a t i o n . The c h a r a c t e r i s t i c f e a t u r e s i n the i n f r a r e d spectrum o f the e s t e r (113) were a g a i n the presence of e s t e r c a r b o n y l a b s o r p t i o n a t 1730 cm. - 1 and the two u s u a l a r o s i a t i c bands. The NMR spectrum ( F i g u r e 23) shows a number of i n t e r e s t i n g f e a t u r e s . The c h a r a c t e r i s t i c f i v e p r o t o n s i n g l e t aty-2.7 and a two p r o t o n s i n g l e t at7-"5»55 are the f a m i l i a r b e n z y l a r o m a t i c and methylene p r o t o n s r e s p e c t i v e l y . A s i x . p r o t o n m u l t i p l e t c e n t e r e d at-f-5„Q5 i s due t o the methylene p r o t o n s of the e t h y l e s t e r s and the two t r i p l e t s at7' /8,75 and 8.80 to the c o r r e s p o n d i n g methyl p r o t o n s . The c h e m i c a l s h i f t of the e s t e r protons of the m a l o n i c e s t e r would be expected to be s l i g h t l y d i f f e r e n t from, t h a t o f the newly i n t r o d u c e d e s t e r group because of the d i f f e r e n c e of an a d d i t i o n a l i n t e r v e n i n g carbon atom.- The methylene p r o t o n s on the carbon next t o the b e n z y l o x y group appear as a two - 5 8 -p r o t o n d o u b l e t a t " T < 6 o 7 and the a d d i t i o n a l peak observed i n the m a l o n i c e s t e r compound ( 1 0 9 ) (see F i g u r e 2 0 ) due t o the l o n e hydrogen atom on the carbon between the c a r b o e t h o x y groups has d i s a p p e a r e d . I n a d d i t i o n , the two p r o t o n m u l t i p l e t a t ' r / - 8 » 0 5 observed i n the spectrum of the m a l o n i c e s t e r . ( 1 0 9 ) has s h i f t e d s l i g h t l y down t o r ' ? , 9 - The c h e m i c a l s h i f t o c c u r r i n g upon the i n t r o d u c t i o n o f the a d d i t i o n a l e s t e r f u n c t i o n i s t h e r e f o r e c o n s i s t e n t w i t h the e a r l i e r assignment of t h i s m u l t i p l e t t o the two p r o t o n s on the carbon atom between those b e a r i n g the e t h y l and the two c a r b o e t h o x y groups. I t i s all so of i n t e r e s t t h a t t h i s m u l t i p l e t i s not p r e s e n t i n the NMR spectrum of the s u b s t i t u t e d s u c c i n i c e s t e r ( 7 1 a ) ( F i g u r e 2 2 ) . A new sharp two p r o t o n s i n g l e t w h i c h appeared a t f 6 . 9 5 w a s ^ u e t o the methylene protons on the carbon atom a d j a c e n t t o the newly i n t r o d u c e d c a r b o e t h o x y group. The methyl p r o t o n s of the e t h y l group a g a i n appeared as a t h r e e p r o t o n t r i p l e t a t - 7 ^ 9 . 1 5 . The t r i e s t e r ( 1 1 3 ) was h y d r o l y z e d w i t h p o t a s s i u m h y d r o x i d e - ^ to the c o r r e s p o n d i n g t r i a c i d ( l l l j . ) , o b t a i n e d as a n o n - c r y s t a l l i n e v i s c o u s o i l . NMR d a t a on the l a t t e r i n d i c a t e d complete removal of the e t h y l e s t e r groups and a t h r e e p r o t o n broad s i n g l e t appeared i n the ex p e c t e d r e g i o n ( 7 - 0 , / j , ) f o r the c a r b o x y l hydrogen atoms. D e c a r b o x y l a t i o n of the above t r i a c i d t o the s u c c i n i c a c i d d e r i v a t i v e ( 1 1 5 ) was e f f e c t e d by h e a t i n g the t r i a c i d a t 1 6 5 - 1 7 0 ° C f o r a p e r i o d of 3 - | h o u r s . The r e s u l t a n t brown v i s c o u s a c i d was e s t e r i f i e d by t r e a t m e n t w i t h e t h a n o l and -59-s u l f u r i c a c i d t o p r o v i d e the d e s i r e d s u c c i n i c e s t e r (71a) i n an o v e r a l l y i e l d of 78$ from the t r i e s t e r . The s u c c i n i c e s t e r p r e -pared i n " t h i s • manner was i d e n t i c a l by i n f r a r e d and NMR s p e c t r o -s c o p i c comparison as w e l l as by gas chromatography t o t h a t p r e -pared by the a l k y l a t i o n of the s u b s t i t u t e d e s t e r 112 w i t h e t h y l i o d o a c e t a t e ,; When the s u c c i n i c e s t e r f r o m e i t h e r of the d e s c r i b e d s y n t h e t i c r o u t e s was s u b j e c t e d t o c a r e f u l gas c h r o m a t o g r a p h i c a n a l y s i s an i n t e r e s t i n g phenomenon was o b s e r v e d . An a n a l y t i c a l l y pure sample appeared almost as one peak except f o r the presence of a s l i g h t s h o u l d e r when examined on a S E 3 0 (20%) column a t 260°C ( F i g u r e 2I4.) . T h i s s h o u l d e r became more pronounced a t 2[L5°C . E x a m i n a t i o n u s i n g a FFAP (20$) column showed the presence of two peaks at 2 6 5 ° c more e f f e c t i v e l y and t h i s was much more pronounced at 2l+5°C ( F i g u r e 25). C o l l e c t i o n and r e i n j e c t i o n of t h i s m a t e r i a l produced the same peak r a t i o s i n d i c a t i n g the compound was not b e i n g a l t e r e d by the gas ch r o m a t o g r a p h i c p r o c e d u r e . W h i l e t h i s m a t e r i a l s a t i s f i e d a l l the n e c e s s a r y c r i t e r i a t o s u p p o r t the s t r u c t u r e (71a) and appeared as one compound by t h i n - l a y e r chromatography, the presence of two d i a s t e r e o i s o m e r s was expected s i n c e the compound p o s s e s s e d two asymmetric c e n t r e s (see F i g u r e 2'6), S i n c e these as ynrmet>ric c e n t r e s would u l t i m a t e l y appear a t the two asymmetric c e n t r e s of d i h y d r o c l e a v a m i n e (7)4a, F i g , 2 6 i n d i c a t e d by the a s t e r i s k s ) , t h e i r d e m o n s t r a t i o n i n the s u c c i n i c e s t e r s s h o u l d be r e f l e c t e d by the s y n t h e s i s of the two known D < c i s o m e r i c d i h y d r o p l e a v a m i n e s (as w i l l be shown l a t e r ) . -60-SE 30 F i g u r e 21+ F F R P Figure. 2 5 E t 0CH2OCH2CHCH2CHC OOEt CR^COOEt (71a) (74a F i g u r e 2 6 -61-Because of the h i g h degree o f success i n the s y n t h e s i s o f the s u c c i n i c e s t e r (71a) v i a the t r i e s t e r ( 1 13 ) , a b r i e f attempt was made a t an analogous s y n t h e s i s of the aldehydo*-e s t e r (120) v i a a l k y l a t i o n of the ma l o n i c e s t e r (109) w i t h bromoacetaldehyde d i e t h y l a c e t a l ( 1 18 ) . The p r o d u c t (119) c o u l d p o s s i b l y then be d e c a r b o x y l a t e d and the aldehyde group regenerated„ E t COOEt OEt E t COOEt. +BrCH 2CH >^ j#CH 20CH 2CHCH 2CCH 2CH(0Et ) 2 jZfcHpOCHpCHCHpCH A OOEt (109) (118) OEt E t COOEt (119) — _^ jZ(CH 20CH 2CHCH 2CHC00Et CH 2CH0 (120) The c o n d e n s a t i o n of al d e h y d ' O ^ e s t e r s w i t h t r y p t a m i n e i s a w e l l known and v a l u a b l e s y n t h e t i c route„ I t s importance l i e s i n the f a c t t h a t the aldehyde group r e a c t s p r e f e r e n t i a l l y b e f o r e the e s t e r group w i t h the t r y p t a m i n e and can, t h e r e f o r e , be used t o d i r e c t the p o s i t i o n of the a l k y l s i d e c h a i n i n the r e s u l t a n t lactam., F o r example, the a l d e h y d o - e s t e r 121 condenses w i t h t r y p t a m i n e t o y i e l d the c y c l i z a t i o n p r o d u c t (122) w h i c h has been a s y n t h e t i c i n t e r m e d i a t e i n the s y n t h e s i s o f c e r t a i n H u n t e r i a and Aspidosperma a l k a l o i d r i n g systems 2'''. -62 (121 ) (122) S i m i l a r l y compound (123) has been condensed w i t h t r y p t a m i n e t o p r o v i d e the c y c l i z a t i o n product j(12LL)<, (70) CHpOC U n f o r t u n a t e l y bromoacetaldehyde d i e t h y l a c e t a l f a i l e d to r e a c t w i t h the m a l o n i c e s t e r (109) under the c o n d i t i o n s s u c c e s s f u l f o r the a l k y l a t i o n w i t h e t h y l bromoacetate„ T h i s a c e t a l i s a p p a r e n t l y r e l a t i v e l y i n e r t ^ ' ^ 5 ^ and t h i s made i t u n s u i t a b l e as an a l k y l a t i n g agent i n t h i s c a s e , We, t h e r e f o r e , proceeded t o the c o n d e n s a t i o n of the s u c c i n i c e s t e r (71a) w i t h t r y p t a m i n e as the analogous c o n d e n s a t i o n w i t h the i s o m e r i c e s t e r (102a) t o p r o v i d e the i m i d e (125) had r e c e n t l y been s u c c e s s f u l i n our l a b o r a t o r y ^ 1 , and i t s c y c l i z a t i o n t o the i n d o l e n u c l e u s was c u r r e n t l y b e i n g i n v e s ti-gated „ The r e s u l t s o f these p a r t i c u l a r c y c l i z a t i o n 66 s t u d i e s are shown i n F i g u r e 27» Thus the c o n d e n s a t i o n s of the s u c c i n i c e s t e r (71a) w i t h t r y p t a m i n e a t 190 - 200°C p r o v i d e d the d e s i r e d imide (130, -63-F i g u r e 27 -6k-F i g u r e 28) i n 77$ y i e l d . The crude imide was p u r i f i e d by column chromatography on al umina and remained as a l i g h t brown non-c r y s t a l l i n e gum. I t was p o s s i b l e , however, to d i s t i l l s m a l l q u a n t i t i e s of t h i s i m i d e f o r a n a l y t i c a l d a t a . The imide l e n t i t s e l f t o a s t r a i g h t f o r w a r d s t r u c t u r a l a n a l y s i s due t o the presence o f c e r t a i n v e r y c h a r a c t e r i s t i c s p e c t r o s c o p i c f e a t u r e s . The compound possessed a t y p i c a l i n d o l e a b s o r p t i o n i n the u l t r a v i o l e t r e g i o n (>ma.x 222, 27l|- ( s h ) , 283, 291 mu). In a d d i t i o n t o a b s o r p t i o n band a t 3320 c m - 1 (NH) i n the i n f r a r e d s p ectrum t h e r e appeared sharp bands at 1755 cm" 1 (medium i n t e n s i t y ) and 1685 cm" 1 ( s t r o n g ) , w h i c h are c h a r a c t e r -i s t i c of a five-membered r i n g imide^^. TheNMR spectrum ( F i g u r e 29) e x h i b i t e d a one p r o t o n s i n g l e t at-r ' 1 . 9 (NH) and a n i n e -p r o t o n m u l t i p l e t c e n t e r e d at?''2-. 7 due t o t h e a r o m a t i c p r o t o n s of the benzene r i n g s . The o< - p r o t o n on the h e t e r o c y c l i c r i n g of the m o i e t y appeared as a one p r o t o n d o u b l e t a t 7^3.0, The b e n z y l methylene p r o t o n s appeared as u s u a l as a two p r o t o n s i n g l e t a t y 5 • 5 5 • A two p r o t o n t r i p l e t a t 7 " 6 . 2 was a s s i g n e d t o the methylene p r o t o n s on the carbon atom a d j a c e n t the imide n i t r o g e n , and f o r m i n g p a r t of the e t h y l e n e b r i d g e t o the i n d o l e r i n g . The two pr o t o n s on the carbon atom a d j a c e n t t o the oxygen of the b e n z y l o x y group appeared as a m u l t i p l e t a t 7"6.65 and a t h r e e p r o t o n t r i p l e t appeared a t 7 " 9 o l 5 f o r the methyl protons of the e t h y l group* The mass spectrum of the s u c c i n i m i d e ( F i g u r e 3 0 ) p r o v i d e d f u r t h e r s t r u c t u r a l e v i d e n c e . The m o l e c u l a r i o n peak was -65 CO>£t cOpFt /OCH^ H (130) (71a) (131) MeOH 'IT ft (133) C H C r i j 8 H (13li-) E t I R = H 5 R" = CH 2CHCH 2OCH 20 and/or R = Hj R = CRgCHCRgOCHgjtf Et F i g u r e 2'8 H (135) (136) (137) - RELAT IVE -INTE NS ITY~-OJ O 418 - 6 8 -i n d l c a t e d as b e i n g the d e s i r e d v a l u e of 1+18 and the spectrum was dominated by peaks a t m/e 11+3, 130 and 91. The peaks a t m/e 11+3 and 130 are the c h a r a c t e r i s t i c i n d o l e f ragmen tsu-of the type (135) and ( 1 3 6 ^ r e s p e c t i v e l y commonly observed . 0 In many si m p l e i n d o l e a l k a l o i d s ^ - 0 . The peak a t m/e 91 i s undoubtedly due t o the c l e a v a g e of the b e n z y l group and subsequent p r o d u c t i o n of the t r o p y l i u m ion° (137). S t u d i e s i n our l a b o r a t o r y had by t h i s time e s t a b l i s h e d t h a t the i s o m e r i c imide (125) c o u l d be c y c l i z e d i n low y i e l d v i a B i s c h l e r - N a p i e r a l s k i r e a c t i o n ^ 9 but d u r i n g the course of t h i s r e a c t i o n the b e n z y l group was l o s t and the pr o d u c t i s o l a t e d was the e n o l l a c t a m (126). A l t h o u g h l o s s o f the b e n z y l e t h e r m o i e t y could be av o i d e d by c y c l i z a t i o n of the c h l o r i d e • (127 )j subsequent r e d u c t i o n of the l a c t a m (129) w i t h l i t h i u m aluminum h y d r i d e r e s u l t e d a l s o i n l o s s of the c h l o r i n e group. A l t h o u g h a l t e r n a t i v e s were p o s s i b l y a v a i l a b l e t o p r e c l u d e t h i s d i f f i c u l t y a n o t h e r approach t o the c y c l i z a t i o n of the five-membered r i n g t o the i n d o l e n u c l e u s was now thought 70 more advantageous. S t u d i e s by Wenkert and Wi c k b e r g ' had shown t h a t N - f / 3 - ( 3 - i n d o l y l ) - e t h y l ] ] - p i p e r i d i n e s c o u l d be c y c l i z e d onto the i n d o l e n u c l e u s by treatment w i t h m e r c u r i c a c e t a t e or o t h e r o x i d i z i n g a g e n t s . F o r example o x i d a t i o n of the amine (138) w i t h m e r c u r i c a c e t a t e p r o v i d e d a good y i e l d of the c y c l i z e d ' p r o d u c t (11+0). S i m i l a r o x i d a t i o n o f (139) l e d t o a m i x t u r e o f the i s o m e r i c p r o d u c t s (ll+la ,b) „ , - 6 9 -(li+O) R = R = H ( l l i l a ) R = H, R' = Et ( l l | l b ) R = E t , R = H The imide ( 1 3 0 ) was reduced w i t h l i t h i u m aluminum h y d r i d e i n t e t r a h y d r o f u r a n t o the t e r t i a r y amine ( 1 3 1 , see F i g u r e 28) i n 95$ y i e l d . The crude amine was p u r i f i e d by column chromatography on a l u m i n a and was o b t a i n e d as a l i g h t brown gum. S m a l l q u a n t i t i e s of t h i s compound, as w i t h the i m i d e , were r e a d i l y d i s t i l l a b l e under reduced p r e s s u r e and y i e l d e d a c l e a r c o l o r l e s s g l a s s . The i n f r a r e d s p ectrum of the amine e x h i b i t e d no a b s o r p t i o n i n the c a r b o n y l r e g i o n i n d i c a t i n g the imide f u n c t i o n had been removed and the u l t r a v i o l e t spectrum was t h a t of a normal i n d o l e . In a d d i t i o n t o the c h e m i c a l a n a l y s i s the -70-the m o l e c u l a r f o r m u l a was e s t a b l i s h e d by h i g h r e s o l u t i o n mass 71 s p e c t r o m e t r y as C26H3i|N2° (Found: 390. 267; C a l c . 390. 267) The mass spe c t r u m ( F i g u r e 31) was dominated by a v e r y i n t e n s e peak at m/e 260 w h i c h c o u l d be a t t r i b u t e d t o the s i m p l e f r a g m e n t a t i o n of the pa r e n t m o l e c u l e t o the i o n li+2. T h i s f r a g m e n t a t i o n mode i s analogous t o t h a t observed f o r the c o u p l i n g p r o d u c t (68) mentioned e a r l i e r . The presence of the b e n z y l e t h e r was a g a i n i n d i c a t e d , as i n the i m i d e , by a s t r o n g peak at m/e 91. lit-(11+2) I t now became i m p o r t a n t t o l o c a t e a c c u r a t e l y i n the NMR spectrum the c h e m i c a l s h i f t of the p r o t o n on the carb o n atom .c£ t o the n i t r o g e n o f the i n d o l e r i n g . I t s presence or absence i n the r e a c t i o n p r o d u c t s from the m e r c u r i c a c e t a t e o x i d a t i o n would be a measure of "the success of the c y c l i z a t i o n t o the amines (134, F i g u r e 2 8). F o r t u n a t e l y , t h i s p r o t o n i s u s u a l l y l o c a t e d at s l i g h t l y h i g h e r f i e l d than the o t h e r a r o m a t i c p r o t o n s of the i n d o l e r i n g , as shown by the a n a l y s i s o f s i m p l e i n d o l e s and tryptamines?2«73. These s t a d i e s have demonstrated t h a t t h i s p r o t o n u s u a l l y appears i n the range of7"'3.0 - 3-4 depending on c o n c e n t r a t i o n ^ and i s coupled t o the p r o t o n on • RELATIVE INTENSITY ---72-t h e i n d o l e n i t r o g e n a t o m. I n d e e d , e x a m i n a t i o n o f t h e NMR s p e c t r u m o f t h i s amine t a k e n a t 100 Mc/s ( F i g u r e 32) showed t h a t t h i s p r o t o n was l o c a t e d atr3»H as a d o u b l e t , A d d i t i o n o f d e u t e r i u m o x i d e c a u s e d t h i s d o u b l e t t o c o l l a p s e t o a s i n g l e t ( F i g u r e 32) d e m o n s t r a t i n g t h e c o u p l i n g m e n t i o n e d a b o v e . The r e m a i n d e r o f t h e a r o m a t i c p r o t o n s a p p e a r e d as a n i n e p r o t o n m u l t i p l e t c e n t e r e d a t 7^ 2.75 and t h e p r o t o n on t h e n i t r o g e n a t o m o f t h e i n d o l e n u c l e u s a p p e a r e d a t 7^ 1.55 as a b r o a d s i n g l e t . The b e n z y l m e t h y l e n e p r o t o n s a p p e a r e d as a two p r o t o n s i n g l e t a t 7^?. 55 and t h e m e t h y l e n e p r o t o n s on t h e c a r b o n atom a d j a c e n t t h e b e n z y l o x y f u n c t i o n a p p e a r e d as a two p r o t o n d o u b l e t a t 7^ 6,70, A t h r e e p r o t o n t r i p l e t at7"9»l5 was a g a i n due t o t h e m e t h y l p r o t o n s o f t h e e t h y l g r o u p . I t was now p o s s i b l e t o s t u d y t h e m e r c u r i c a c e t a t e o x i d a t i o n and c y c l i z a t i o n o f t h i s a m i n e . P r e l i m i n a r y i n v e s t i g a t i o n s i n d i c a t e d t h a t a c o n v e n i e n t method o f f o l l o w i n g t h e r e a c t i o n was t h r o u g h f u r t h e r o x i d a t i o n o f t h e a l r e a d y c y c l i z e d p r o d u c t (131+) t o t h e i m i n i u m s a l t 133 ( s e e F i g u r e 28). T h i s t y p e o f o x i d a t i o n , w h i c h was a l s o o b s e r v e d by W e n k e r t and W i c k b e r g ^ O i n t h e c a s e o f t h e compounds 138 and 139, p r o v i d e d a compound w i t h a c h a r a c t e r i s t i c c h r o m o p h o r e w h i c h a b s o r b e d a t 352 mu i n t h e u l t r a v i o l e t r e g i o n . T h i s o x i d a t i o n p r o d u c t was t h e n e a s i l y r e d u c e d w i t h s o d i u m b o r o h y d r i d e t o t h e d e s i r e d c y c l i z a t i o n p r o d u c t (131+). The a d d i t i o n o f d i l u t e s o d i u m h y d r o x i d e t o a s o l u t i o n o f t h e o x i d a t i o n p r o d u c t 133 c a u s e d a -73.-= 74-d i s a p p e a r a n c e of the a b s o r p t i o n maximum at 352 mu and the appearance of two new maxima at 310 and 322 mu (see F i g u r e 33)• T h i s s p e c t r a l s h i f t i s i n d i c a t i v e of an imine-enamine s h i f t , as i n d i c a t e d i n F i g u r e 34 and observed i n s i m i l a r compounds^. I n i t i a l l y c o n s i d e r a b l e d i f f i c u l t i e s were encountered i n t h i s r e a c t i o n w i t h m e r c u r i c a c e t a t e . O x i d a t i o n , c y c l i z a t i o n and r e - o x i d a t i o n were i n d i c a t e d by the u l t r a v i o l e t s pectrum as b e i n g o n l y p a r t i a l . Y i e l d s were f a i r l y l o w (15 - 20$) and the complete s e p a r a t i o n of c y c l i z e d p r o d u c t s from u n c y c l i z e d s t a r t i n g m a t e r i a l was v i r t u a l l y i m p o s s i b l e on a p r a c t i c a l s c a l e . I n f a c t , i t was v e r y f o r t u n a t e t h a t among the m i x t u r e of c y c l i z e d p r o d u c t s one c o u l d always d i f f e r e n t i a t e the u n c y c l i z e d amine and the c y c l i z e d amines by t h i n - l a y e r chromatography. Antimony p e n t a c h l o r i d e i n carbon t e t r a -c h l o r i d e as a s p r a y r e a g e n t produced a c h a r a c t e r i s t i c green c o l o u r w i t h the c y c l i z e d compounds w h i l e the u n c y c l i z e d amine gave a l i g h t brown c o l o u r , A more c a r e f u l e x a m i n a t i o n of t h i s r e a c t i o n i n d i c a t e d t h a t the chromophoric system i n the r e a c t i o n m i x t u r e w h i c h had an a b s o r p t i o n maximum at 352 mu r a p i d l y degenerated d u r i n g the f i l t r a t i o n and o t h e r m a n i p u l a t i o n s r e q u i r e d d u r i n g the work-up. Exposure of a f a i r l y c o n c e n t r a t e d s o l u t i o n of the i m i n i u m s a l t (133) t o a i r d u r i n g the work-up l e d t o v i r t u a l l y no c y c l i z a t i o n p r o d u c t s and o n l y 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 . C o n s e q u e n t l y , the r e a c t i o n procedures were performed under an atmosphere of p u r i f i e d n i t r o g e n u s i n g d i l u t e s o l u t i o n s w i t h -75 F i g u r e 3k . -76-the r e s u l t t h a t an o v e r a l l 37% y i e l d of c y c l i z e d p r o d u c t s was o b t a i n e d . T h i n - l a y e r chromatography i n d i c a t e d t h a t a complex m i x t u r e of c y c l i z a t i o n p r o d u c t s was a t hand. C a r e f u l column chromatography on a lumina f a i l e d t o separate any s i g n i f i c a n t q u a n t i t i e s o f pure compounds, however, a c o m b i n a t i o n of column chromatography f o l l o w e d by p r e p a r a t i v e t h i n - l a y e r chromatography on alumina and/or s i l i c a g e l l e d t o the e v e n t u a l s e p a r a t i o n of s m a l l q u a n t i t i e s of f o u r compounds. These were d e s i g n a t e d A, B, C and c' on the b a s i s o f t h e i r Rf v a l u e s . A f i f t h v e r y minor c y c l i z e d amine D c o u l d not be s e p a r a t e d even by t h i s c o m b i n a t i o n of t e c h n i q u e s . The mass s p e c t r a of a l l f o u r compounds were examined and i n the case of the major p r o d u c t s (B and C) s u f f i c i e n t m a t e r i a l was o b t a i n e d pure t o a l l o w e x a m i n a t i o n of t h e i r NMR s p e c t r a (100 Mc/s). The mass- s p e c t r a of a l l these compounds (Figure- 350 were v e r y s i m i l a r and much d i f f e r e n t from t h a t observed f o r the u n c y c l i z e d amine (131). A- number of peaks p r e s e n t i n t h e i r f r a g m e n t a t i o n p a t t e r n s are p r e s e n t i n a l k a l o i d s of the t e t r a -h y d r o - y f i - c a r b o l i n e type^- 0, e.g. a j m a l i c i n e (13) and yohimbine (23.) »• A- s t r o n g m-l peak w h i c h appeared i n the s p e c t r a of a l l . f o u r compounds a l s o appears i n the a l k a l o i d s a j m a l i c i n e and yohimbine arid has been demonstrated as p a r t i a l l y a r i s i n g from the i o n ILLIL ( F i g u r e 36). A. s e r i e s of s i g n i f i c a n t peaks then appeared at m/e 156, 169, 170 and I8I4. which have been shown i n -the case of the a l k a l o i d s mentioned, t o a r i s e f r o m the i n d o l e -77-p o r t i o n of the m o l e c u l e . D e u t e r a t i o n s t u d i e s have e s t a b l i s h e d t h a t the l i k e l y fragments c o n t r i b u t i n g t o thes e peaks are those shown i n F i g u r e 36. The presence of the b e n z y l e t h e r m o i e t y was i n d i c a t e d by the presence of peaks at m/e 297 (m-91) and and m/e 91 ( t r o p y l i u m i o n ) . The i n d o l i c n a t u r e of a l l f o u r compounds was f u r t h e r shown by t h e i r t y p i c a l i n d o l e a b s o r p t i o n i n the u l t r a v i o l e t . . r e g i o n (Mnax 22$, 27k ( a h ) , 283, 291 mu) •. (13) CHpOO-OH H i g h r e s o l u t i o n mass s p e c t r o m e t r y e s t a b l i s h e d t h a t three' of these b e n z y l e t h e r s p o s s e s s e d the m o l e c u l a r f o r m u l a C26H32N2° ( F o u n d- R 9 388*251; B, 388*252; C, 388°252; C a l c : 388*251). The f o u r t h e t h e r (C«) I s o l a t e d was a l s o i n d i c a t e d by i t s mass s p e c t r u m as h a v i n g a m o l e c u l a r weight of 388. W h i l e these mass s p e c t r o m e t r i c r e s u l t s e s t a b l i s h e d t h a t the c y c l i z a t i o n had i n f a c t o c c u r r e d t o produce a m i x t u r e of I s o m e r i c ' p r o d u c t s , t h e r e remained the q u e s t i o n of the l o c a t i o n of the b e n z y l o x y p r o p y l s i d e c h a i n on the five-membered r i n g . As i n d i c a t e d by s t r u c t u r e 132 ( F i g u r e 28), t h e r e were two im i n i u m s a l t s w h i c h c o u l d be c o n s i d e r e d as p o s s i b l y c y c l i z i n g t o the i n d o l e n u c l e u s . A t h i r d i m i n i u m s a l t c o u l d a l s o be formed i n the r e a c t i o n m i x t u r e i n vh i c h the double bond was -79-F i g u r e 3'6 -80 e x o c y c l i c t o the five-membered r i n g . However, even i f the f o r m a t i o n of the l a t t e r was r e a l i z e d i t s c y c l i z a t i o n would l e a d t o a h i g h l y u n f a v o r a b l e four-membered r i n g . T h e r e f o r e , of the two p o s s i b l e c y c l i z a t i o n p r o d u c t s d e r i v a b l e from t h i s r e a c t i o n (72a and o n l y one (72a) would u l t i m a t e l y l e a d t o d i h y d r o c l e a v a m i n e . A l t h o u g h Wenkert and W i c k b e r g ^ had observed the f o r m a t i o n of b o t h - p o s s i b l e c y c l i z a t i o n p r o d u c t s l l L l a and b i n the c y c l i z a t i o n of A/-L/3 - O - i n d o l y l ) - e t h y l J -p i p e r i d i n e s (139), i t h a d been hoped t h a t the i n c r e a s e d s t e r i c e f f e c t s c r e a t e d -by the p r o x i m i t y of the s i d e c h a i n t o the i n d o l e p o r t i o n of the m o l e c u l e would m i n i m i z e or p r e c l u d e the f o r m a t i o n of isomer li|5« The two major c y c l i z e d b e n z y l e t h e r s (B and C) were examined by NMR s p e c t r o s c o p y (100 Mc/s:) and the s p e c t r a o b t a i n e d are shown i n F i g u r e 37 and 38 r e s p e c t i v e l y . R a d i c a l d i f f e r e n c e s were i m m e d i a t e l y apparent i n the s p e c t r a o f t h e s e two compounds, the most o u t s t a n d i n g of which was the aromatic r e g i o n . E t h e r C which was o b t a i n e d i n s l i g h t l y g r e a t e r amount than e t h e r B . i n t h i s r e a c t i o n , e x h i b i t e d a n i n e p r o t o n m u l t i p l e t i n the r e g i o n r2»5 t o 3«1 (see F i g u r e 38). The c h a r a c t e r i s t i c one p r o t o n - 8 1 -d o u b l e t at7^3»H i n the u n c y c l i z e d amine due t o the - p r o t o n on the i n d o l e n u c l e u s was now ab s e n t . By c o n t r a s t , some of the a r o m a t i c peaks i n the NMR spectrum of e t h e r B ( F i g u r e 37) were l o c a t e d at h i g h e r f i e l d , i n the r e g i o n 7^ 3.0 t o 3*5. A l t h o u g h the mass s p e c t r a l e v i d e n c e had a l r e a d y e s t a b l i s h e d t h a t e t h e r B was i n f a c t a c y c l i z e d compound, the absence of the <* - p r o t o n on the i n d o l e n u c l e u s was a l s o c o m p l e t e l y c o n f i r m e d by a d e u t e r a t i o n e x p e r i m e n t . Exchange of the p r o t o n on the i n d o l e n i t r o g e n atom w i t h d e u t e r i u m caused no change i n the a r o m a t i c r e g i o n o f the spectrum, The re a s o n f o r t h i s d r a m a t i c u p f i e l d s h i f t i n the a r o m a t i c r e g i o n of the NMR spectrum of e t h e r B became apparent upon e x a m i n a t i o n of o t h e r f e a t u r e s of the two s p e c t r a . The p r o t o n on the n i t r o g e n atom of the i n d o l e n u c l e u s was l o c a t e d a t yO.^O i n the spectrum of e t h e r B w h i l e i n e t h e r C i t appeared a t - r l . 8 0 . The methylene pro t o n s of the b e n z y l o x y group were l o c a t e d as two p r o t o n s i n g l e t s at7"5>«>30 and 5°60 In the s p e c t r a of e t h e r s B and C r e s p e c t i v e l y . The d o w n f i e l d s h i f t of the b e n z y l o x y methylene protons i n the spe c t r u m of e t h e r B r e l a t i v e t o e t h e r C r e v e a l e d the most i m p o r t a n t f e a t u r e of these s p e c t r a . A. d o u b l e t was p r e s e n t at-r5°60 i n the s p e c t r u m o f e t h e r B w h i c h i n t e g r a t e d f o r a p p r o x i m a t e l y one p r o t o n . The spectrum o f e t h e r C possessed a broad m u l t i p l e t i n t e g r a t i n g f o r a p p r o x i m a t e l y one p r o t o n In the r e g i o n 7^ 5*7. T h i s was p a r t i a l l y o b s c u r e d , however, by the methylene s i n g l e t of t he b e n z y l o x y group. NMR studies^°*^ of i n d o l e a l k a l o i d s of the t e t r a h y d r o - / ? - c a r b o l i n e type have shown t h a t the C-3 -82--81+-p r o t o n may be l o c a t e d as low as 7 ^ 5 « 5 depending on the conforma-t i o n of the m o l e c u l e o I n the case of the compound ll+6 t h i s p r o t o n appears as a m u l t i p l e t i n the r e g i o n T " ? * 8 t o 6.0^°„ if (11+6) W h i l e the d e s i r e d c y c l i z e d b e n z y l e t h e r C (72a) was expected t o e x h i b i t a one p r o t o n m u l t i p l e t f o r the p r o t o n a t C-3j, the u n d e s l r e d c y c l i z a t i o n p r o d u c t (II4.5) was expected t o show a d o u b l e t j one of the p r o t o n s at C-11+ now h a v i n g been r e p l a c e d by the b e n z y l o x y p r o p y l s i d e c h a i n . I t appeared, t h e r e f o r e , on the b a s i s of t h i s NMR s p e c t r a l d a t a , t h a t the u n d e s i r a b l e c y c l i z a t i o n p r o d u c t 11+5 was i n f a c t b e i n g o b t a i n e d , a l t h o u g h i n s l i g h t l y l o w e r y i e l d t h a n the d e s i r e d product 72a. The u p f i e l d s h i f t of the a r o m a t i c p r o t o n s of the i n d o l e n u c l e u s observed i n the spectrum of e t h e r B may be a t t r i b u t e d t o the p r o x i m i t y o f the b e n z y l o x y group. M o l e c u l a r models of the compound 11+5 show t h a t the benzene r i n g of the benzyloxy" group may be e a s i l y l o c a t e d d i r e c t l y beneath the i n d o l e n u c l e u s . Such an arrangement c o u l d cause a. s h i e l d i n g of the i n d o l e a r o m a t i c p r o t o n s and a l s o l e a d t o the d i f f e r e n c e s i n t h e c h e m i c a l s h i f t s of the i n d o l e (NH) and the b e n z y l o x y methylene p r o t o n s observed i n these two compounds. A s i m i l a r o r i e n t a t i o n - 8 5 -o f the b e n z y l o x y group w i t h r e s p e c t t o the i n d o l e nucleus i n the case of e t h e r C i s shown by m o l e c u l a r models t o be v e r y u n l i k e l y . I t now became e v i d e n t t h a t a s e p a r a t i o n o f the d e s i r e d c y c l i z a t i o n p r o d u c t s from the u n d e s i r e d compounds was r e q u i r e d as e p i m e r i c compounds w i t h the s t r u c t u r e U4.5 would not y i e l d dihydrocleavamine„ However, s e p a r a t i o n of compounds e p i m e r i c at C-3 and at the p o s i t i o n of the e t h y l group i n 72a would be u n n e c e s s a r y s i n c e the asymmetry a t C-3 i s l o s t d u r i n g the c l e a v a g e r e a c t i o n i n the f i n a l stages of the s y n t h e s i s w h i l e the s y n t h e s i s o f b o t h d i h y d r o c l e a v a m i n e s e p i m e r i c a t the p o s i t i o n of the e t h y l g r o u p , would be a d e s i r a b l e f e a t u r e . S i n c e s e p a r a t i o n o f the v a r i o u s b e n z y l e t h e r s was not f e a s i b l e on a s c a l e s u i t a b l e f o r c o n t i n u e d s y n t h e t i c work, the m i x t u r e of the c y c l i z e d and u n c y c l i z e d e t h e r s was c o n v e r t e d t o the c o r r e s p o n d i n g a l c o h o l s . Removal o f the b e n z y l e t h e r group i n a m i x t u r e o f the above compounds was a c c o m p l i s h e d i n 85$ y i e l d by c a t a l y t i c h y d r o g e n o l y s i s u s i n g p a l l a d i u m on c h a r c o a l i n g l a c i a l a c e t i c a c i d ? ? * ? 8 . T h i n - l a y e r chromatography o f the r e a c t i o n m i x t u r e i n d i c a t e d the presence o f f i v e c y c l i z e d compounds a g a i n by t h e i r c h a r a c t e r i s t i c c o l o r r e a c t i o n w i t h antimony p e n t a c h l o r i d e , as w e l l as the u n c y c l i z e d amino a l c o h o l . The a l c o h o l s had a g r e a t e r v a r i a t i o n i n Rf v a l u e s t h a n the c o r r e s p o n d i n g b e n z y l e t h e r s and the major a l c o h o l d e s i g n a t e d .G, was r e a d i l y s e p a r a t e d by column chromatography on a l u m i n a D - 8 6 -T h i s a l c o h o l was o b t a i n e d as an amorphous s o l i d and was i n d i c a t e d as b e i n g the d e s i r e d compound by i t s s p e c t r a l c h a r a c t e r i . s t i c s . H i g h r e s o l u t i o n mass s p e c t r o m e t r y e s t a b l i s h e d t h a t the m o l e c u l a r f o r m u l a was C 1 9 H 2 6 N 2 0 (Found? 2 9 8 ° 2 0 3 ; C a l c : 2 9 8 ° 2 0 5 ) » The mass spectrum (see F i g u r e 3 9 ) possessed s i g n i f i c a n t peaks at M-l ( 2 9 7 ) , m/e l 8 1 i s 1 7 0 , 1 6 9 and 1 5 6 , a l s o observed i n the mass s p e c t r a o f the b e n z y l e t h e r s . However, the s t r o n g peak at m/e 9 1 observed i n the s p e c t r a of the b e n z y l e t h e r s was l a c k i n g . The u l t r a v i o l e t a b s o r p t i o n was t h a t of a normal i n d o l e and the i n f r a r e d spectrum i n c h l o r o f o r m p o s s e s s e d a b s o r p t i o n i n the h y d r o x y l r e g i o n i - 1 ( 3 1 0 0 - 3 6 0 0 cm, ) i n a d d i t i o n t o the sharp s p i k e at 3 3 5 0 cm." (NH), The 1 0 0 Mc/s NMR spectrum ( F i g u r e 1 + 0 ) i n d i c a t e d t h a t the b e n z y l group had been removed as the a r o m a t i c r e g i o n now c o n s i s t e d of a f o u r p r o t o n m u l t i p l e t c e n t e r e d a t 7 ^ 2 , 8 5 and the two p r o t o n s i n g l e t of the b e n z y l o x y methylene group o r i g i n a l l y observed i n the r e g i o n T ' 5 ° 3 t o 5 » 7 had d i s a p p e a r e d . The removal of t h i s l a t t e r s i g n a l i n the NMR spectrum now c l e a r l y r e v e a l e d a broad one p r o t o n m u l t i p l e t atY^>„7o a s c r i b e d t o the C - 3 p r o t o n . That t h i s s i g n a l was not s i m p l y the h y d r o x y l i c p r o t o n was shown t h r o u g h d e u t e r i u m exchange, whi c h produced no e f f e c t on t h i s peak. The methylene p r o t o n s of the p r i m a r y a l c o h o l group were p r e s e n t as a broad s i n g l e t a t r 6 , 6 l and the m e t h y l p r o t o n s o f the e t h y l group appeared as a d i s t o r t e d t r i p l e t c e n t e r e d a t 7 ^ 9 o l 8 0 -88--89-The a l c o h o l C was e s t a b l i s h e d as b e i n g d e r i v e d from the e t h e r C i n a s e p a r a t e e x p e r i m e n t . A. s m a l l q u a n t i t y o f e t h e r C was p u r i f i e d by the chr o m a t o g r a p h i c procedures d e s c r i b e d e a r l i e r and h y d r o g e n o l y z e d under the i d e n t i c a l c o n d i t i o n s . The r e s u l t a n t a l c o h o l o b t a i n e d was shown by t h i n l a y e r chromatography t o be i d e n t i c a l t o a l c o h o l C o b t a i n e d from the h y d r o g e n o l y s i s of the e t h e r m i x t u r e , and d i f f e r e n t from a l l o t h e r I s o m e r i c a l c o h o l s o b t a i n e d . S m a l l q u a n t i t i e s o f t h r e e a d d i t i o n a l i s o m e r i c c y c l i z e d amino a l c o h o l s were o b t a i n e d by a c o m b i n a t i o n o f column- chromatography f o l l o w e d by p r e p a r a t i v e t h i n - l a y e r chromatography on s i l i c a g e l . The a l c o h o l d e s i g n a t e d B was formed i n s l i g h t l y l e s s q u a n t i t y than al c o h o l C and was su s p e c t e d as h a v i n g been d e r i v e d f r o m e t h e r B, H i g h r e s o l u t i o n mass s p e c t r o m e t r y p r o v i d e d the m o l e c u l a r f o r m u l a • C ^ O ^ A ^ O (Pound: 298*205; G a l e . 298°205)» The f r a g m e n t a t i o n p a t t e r n i n the mass spectrum (see F i g u r e 39) was s i m i l a r t o t h a t of a l c o h o l C and the u l t r a v i o l e t s p e c t r u m was a g a i n t h a t of a normal i n d o l e . The NMR s p e c t r u m ( F i g u r e c o n s i s t e d of a f o u r p r o t o n m u l t i p l e t i n the r e g i o n r2.5 t o 3.15 and no l o n g e r p o s s e s s e d the two p r o t o n s i n g l e t of the b e n z y l o x y methylene group at7'5°3» The removal o f the b e n z y l group was thus seen t o be accompanied by a d o w n f i e l d s h i f t o f the proto n s which were l o c a t e d a t 7^ 3.1'5'to 3.5 i n the b e n z y l e t h e r . T h i s s h i f t i s , t h e r e f o r e , i n a c c o r d w i t h the e a r l i e r s u g g e s t i o n t h a t the p r o t o n s of the i n d o l e n u c l e u s were s h i e l d e d t o some e x t e n t by the b e n z y l o x y F i g u r e i | l -91-group. An I s o l a t e d one p r o t o n d o u b l e t .was p r e s e n t at T'5.72 wh i c h was a s c r i b e d t o the C-3 p r o t o n o f the u n d e s i r e d c y c l i z e d amino a l c o h o l . A g a i n t h i s s i g n a l was not a f f e c t e d by exchange w i t h d e u t e r i u m o x i d e . The m e t h y l protons o f the e t h y l group as u s u a l appeared as a t h r e e p r o t o n t r i p l e t atT"9 . l 5 » The NMR spectrum of this.compound, t h e r e f o r e , s u p p o r t e d the e a r l i e r p r o p o s a l t h a t c y c l i z a t i o n was o c c u r r i n g d u r i n g the m e r c u r i c a c e t a t e r e a c t i o n t o p r o v i d e b o t h the d e s i r e d c y c l i z a t i o n p r o d u c t (72a;) and t h e u n d e s i r e d p r o d u c t (11+5)« The r e m a i n i n g two I s o m e r i c amino a l c o h o l s w h i c h were o b t a i n e d pure were a l s o i n d i c a t e d as p o s s e s s i n g the m o l e c u l a r f o r m u l a C 1 9 H 2 A n 2 ° b v t n e f o u n d v a l u e s 298°205 and 29&°20l+ ( C a l c . 298*205) . T h e i r mass s p e c t r a (see F i g u r e 39) were e s s e n t i a l l y the same as t h a t of the a l c o h o l s B and C and b o t h e x h i b i t e d normal i n d o l e u l t r a v i o l e t a b s o r p t i o n . I n s u f f i c i e n t q u a n t i t i e s o f t h e s e isomers were o b t a i n e d i n a pure s t a t e f o r NMR a n a l y s i s . The c o n v e r s i o n of the a l c o h o l II4.9 t o the q u a t e r n a r y s a l t (73a) d e s i r e d f o r r i n g c l e a v a g e was now examined. Spontaneous i n t r a m o l e c u l a r q u a t e r n i z a t i o n had been observed d u r i n g the e l u c i d a t i o n o f the s t r u c t u r e of r e s e r p i n e ? 9 and a s i m i l a r r e a c t i o n had been r e c e n t l y r e p o r t e d i n the l i t e r a t u r e . N. fin Yoneda and co-workers i n the s y n t h e s i s o f compounds c o n t a i n i n g the s a r p a g i n e r i n g s y s t e m (11+8) had a c h i e v e d the f i n a l r i n g f o r m a t i o n t h r o u g h t o s y l a t i o n of the a l c o h o l s 11+7 „ (147) (148) A\n analogous c o n v e r s i o n of the a l c o h o l 149 t o the q u a t e r n a r y s a l t was c a r r i e d out v i a the i n t e r m e d i a t e m e s y l a t e s . Treatment of compound 149 w i t h m e t h a n s u l f o n y l c h l o r i d e i n p y r i d i n e a t 0°C. p r o v i d e d an e t h e r I n s o l u b l e m a t e r i a l , p o s s i b l y the s a l t 15>0, which was t r e a t e d w i t h ammonia t o ensure the presence of the f r e e base ( l ^ l ) . T h i n - l a y e r c h r o m a t o g r a p h i c e x a m i n a t i o n of the r e a c t i o n p r o d u c t a t t h i s time i n d i c a t e d complete absence of the s t a r t i n g a l c o h o l and the presence o f two new green s p o t s , one at the base l i n e and one l e s s p o l a r than the s t a r t i n g a l c o h o l . T h i s p r o d u c t possessed an e s s e n t i a l l y normal i n d o l e a b s o r p t i o n i n the u l t r a v i o l e t r e g i o n . Upon s t a n d i n g f o r a p e r i o d of a few days the l e s s p o l a r spot g r a d u a l l y faded w i t h the appearance of a s t r o n g e r spot a t the base l i n e o f the t h i n - l a y e r c h r o m a t o g r a p h i c p l a t e . The q u a t e r n a r y s a l t . (73a). would be expected t o be a v e r y p o l a r compound so t h i s m a t e r i a l was s u b j e c t e d t o - r e d u c t i o n w i t h sodium i n l i q u i d ammonia^7 0 E x a m i n a t i o n of the crude p r o d u c t by t h i n - l a y e r chromatography i n d i c a t e d the presence of t h r e e compounds, two of w h i c h were i d e n t i c a l i n c o l o u r and Rf t o the a u t h e n t i c samples of the two i s o m e r i c d i h y d r o c l e a v a m i n e s . - 9 3 -(152:) (153) U n f o r t u n a t e l y the t h i r d component of t h e m i x t u r e had a' v e r y s i m i l a r Rf v a l u e to the two d i h y d r o c l e a v a m i n e s a l t h o u g h i t was r e a d i l y d i s t i n g u i s h a b l e by i t s c o l o u r . C a r e f u l a lumina chromatography of t h e t o t a l p r o d u c t p r o v i d e d a pure compound whi c h was i d e n t i c a l t o a u t h e n t i c [(.oodihydrocleavamine (153) by t h i n - l a y e r chromatography on both alumina and s i l i c a g e l w i t h r e s p e c t t o Rf and c o l o u r r e a c t i o n s o b t a i n e d w i t h a v a r i e t y of s p r a y r e a g e n t s . A mass sp e c t r u m of t h i s s y n t h e t i c compound was s u p e r i m p o s a b l e w i t h the mass spectrum o f an a u t h e n t i c sample o b t a i n e d from n a t u r a l s o u r c e s . -94-P r e p a r a t i v e t h i n - l a y e r chromatography of the r e m a i n i n g m i x t u r e of compounds a f f o r d e d a n other pure compound w h i c h was i d e n t i c a l t o an a u t h e n t i c sample of [(./^-dihydrocleavamine (152) by t h i n - l a y e r chromatography on alumina and s i l i c a g e l w i t h a v a r i e t y o f s p r a y r e a g e n t s , The mass spectrum of t h i s compound was i d e n t i c a l t o t h a t of a u t h e n t i c 4/3-dihydrocleavamine „ The s u c c e s s f u l r o u t e d e s c r i b e d here f o r the s y n t h e s i s o f the d i h y d r o c l e a v a m i n e s has a l s o been a p p l i e d t o quebrachamine (93a) by o t h e r workers i n our l a b o r a t o r y and has been 51 r e c e n t l y p u b l i s h e d , . „ The c o n d e n s a t i o n of the i s o m e r i c s u c c i n i c e s t e r d e r i v a t i v e (102a) w i t h t r y p t a m i n e and subsequent analogous c o n v e r s i o n s t o the q u a t e r n a r y m e s y l a t e (92a) f o l l o w e d by r e d u c t i o n t o quebrachamine has demonstrated t h a t t h i s i s i n f a c t a g e n e r a l r o u t e t o t h e quebrachamine and d i h y d r o c l e a v a m i n e s e r i e s . The s u c c e s s f u l c o n v e r s i o n of 4y8-dihydrocleavamine t o fti c a r b o m e t h o x y d i h y d r o c l e a v a m i n e has a l s o been a c c o m p l i s h e d i n our l a b o r a t o r y and w i l l now be mentioned b r i e f l y . O x i d a t i o n of [(./^-dihydrocleavamine (152) w i t h t - b u t y l h y p o c h l o r i t e 8 2 p r o v i d e d t h e c h l o r o i n d o l e n i n e (154) w h i c h was r e a c t e d w i t h p o t a s s i u m c y a n i d e 8 2 t o p r o v i d e a c y a n o d i h y d r o c l e a v a m i n e (155 )• The l a t t e r compound, on t r e a t m e n t w i t h m e t h a n o l i c h y d r o c h l o r i c a c i d p r o v i d e d c a r b o m e t h o x y ^ ^ - d i h y d r o c l e a v a m i n e (156) i d e n t i c a l i n a l l r e s p e c t s w i t h an a u t h e n t i c sample. An analogous c o n v e r s i o n of quebrachamine t o v i n c a d i n e i s c u r r e n t l y under studyo - 9 5 -I t can be s e e n , t h e r e f o r e , t h a t the s y n t h e t i c r o u t e d e s c r i b e d i n S.ection B i s not o n l y a g e n e r a l r o u t e t o d i h y d r o c l e a v a m i n e and quebrachamine but c o u p l e d w i t h the i n t r o d u c t i o n of a c a r b o -methoxy group as w e l l as the p r e v i o u s t r a n s a n n u l a r c y c l i z a t i o n s t u d i e s completes a g e n e r a l e n t r y i n t o the Iboga, Aspidosperma and V i n c a a l k a l o i d s . The use of v a r i o u s m e t h o x y l a t e d t r y p t a m i n e s i n t h i s s y n t h e t i c sequence would p r o v i d e a r o u t e t o a l k a l o i d s such as voa.cangin (157) and p y r i f o l i d i n (158) „ S h o r t l y a f t e r t h i s s y n t h e s i s of [jc(- and lL/3-dihyd-rocleava-mine and t h e c o r r e s p o n d i n g ij . y8~carbomethoxydihydrocleavam.ine had been p u b l i s h e d , a second s y n t h e s i s of the two i s o m e r i c d i h y d r o c l e a v a m i n e s appeared ~97~ E x p e r i m e n t a l ° F a r t A M e l t i n g p o i n t s were determined on a K o f l e r b l o c k and are u n c o r r e c t e d . The u l t r a v i o l e t (UV) s p e c t r a were r e c o r d e d In 95% e t h a n o l on a Cary 11 r e c o r d i n g s p e c t r o p h o t o m e t e r , and the i n f r a r e d ( I R ) s p e c t r a were ta k e n on P e r k i n - E l m e r Model 2 1 and Model 137 spectrometers= N u c l e a r magnetic resonance (NMR) s p e c t r a were r e c o r d e d i n d e u t e r i o c h l o r o f o r m a t 60 megacycles per second ( u n l e s s o t h e r w i s e i n d i c a t e d ) on a V a r l a n A60 instrument- and the c h e m i c a l s h i f t s are g i v e n i n the T i e r s T* s c a l e w i t h r e f e r e n c e t o t e t r a m e t h y l s i l a n e as the I n t e r n a l 'standard. Gas chromatography was performed on a W i l k i n s A e r o g r a p h A u t o p r e p , Model A-700. Mass s p e c t r a were r e c o r d e d on an A t l a s CH-Ij. mass s p e c t r o m e t e r and h i g h r e s o l u t i o n m o l e c u l a r w e i g ht d e t e r m i n a t i o n s were determined on an AEI MS'-9 mass spectrometer.. A n a l y s i s were c a r r i e d out by Dr. A1.. B e r n h a r d t , Mulheim ( R u h r ) , Germany, Miss C. J e n k i n s and Mr. P. Borda o f the rnicroa n a l y t i e a l l a b o r a t o r y , the U n i v e r s i t y o f B r i t i s h C o l umbia. S i l i c a G e l Gand Wbelm alumina c o n t a i n i n g e l e c t r o n i c phosphor were used f o r t h i n - l a y e r chromatography and Shawi n i g a n alumina d e a c t i v a t e d w i t h 3 ml. of 10% a c e t i c a c i d per 100 g. ( u n l e s s o t h e r w i s e i n d i c a t e d ) was used f o r column chromatography, N i p e c o t i c a c i d h y d r o c h l o r i d e (76) N i c o t i n i c a c i d (2.0.0 g., 0.163 mole) was d i s s o l v e d i n IN h y d r q c h l o r i c a c i d and hydrogenated i n the presence of p l a t i n u m o x i d e ( U 4 6 g.) at 1 .5 atmospheres p r e s s u r e u n t i l the uptake „ 9 8 -o f hydrogen had ceased ( a p p r o x i m a t e l y 3 h o u r s ) 0 The c a t a l y s t was removed by f i l t r a t i o n , b a r i u m h y d r o x i d e (73 g») was added, and any r e s u l t i n g p i p e r i d i n e was steam distilled„ The r e s i d u e of the steam d i s t i l l a t i o n was t r e a t e d w i t h an e x a c t amount o f s u l f u r i c a c i d t o n e u t r a l i z e the excess base and the r e s u l t a n t b a r i u m s u l f a t e removed by f i l t r a t i o n . E v a p o r a t i o n of the f i l t r a t e p r o v i d e d n i p e c o t i c a c i d h y d r o c h l o r i d e (23.1+ g . s 87$) mp. 2l+2-2l|l|.0 ( L i t o 3 ^ 239°) as a wh i t e s o l i d . T h i s crude a c i d p o s s e s s e d no u l t r a v i o l e t a b s o r p t i o n and was used d i r e c t l y f o r the p r e p a r a t i o n of methyl n i p e c o t a t e , , M e t h y l n i p e c o t a t e (77) Crude n i p e c o t i c a c i d h y d r o c h l o r i d e (20 g.) prepared by the r e d u c t i o n of n i c o t i n i c a c i d , was covered w i t h a %%> by weight s o l u t i o n o f hydrogen c h l o r i d e i n a b s o l u t e methanol (160 ml.) and the m i x t u r e r e f l u x e d f o r 10-12 h o u r s . The r e s u l t i n g s o l u t i o n was c o n c e n t r a t e d i n vacuo t o a p p r o x i m a t e l y 60 ml„, c o o l e d I n an i c e - b a t h and d i l u t e d w i t h e t h e r . T h i s c o o l e d s o l u t i o n was q u i c k l y t r a n s f e r r e d t o a s e p a r a t o r y f u n n e l and shaken w i t h a 30% sodium h y d r o x i d e s o l u t i o n . The- aqueous a l k a l i n e l a y e r was e x t r a c t e d w i t h two a d d i t i o n a l p o r t i o n s o f e t h e r , the e x t r a c t s b e i n g combined w i t h the o r i g i n a l e t h e r l a y e r and d r i e d over anhydrous sodium s u l f a t e . The e t h e r and most of the r e m a i n i n g a l c o h o l was ev a p o r a t e d and the r e s i d u a l y e l l o w o i l d i s t i l l e d under reduced p r e s s u r e t o p r o v i d e m e t h y l n i p e c o t a t e (6.7 g 0 , 3% y i e l d from n i c o t i n i c a c i d ) as a c l e a r c o l o r l e s s o i l , b.p. 53-54°/0«7 mm. ( L i t . . 3 6 82.-81+°/6 mm.). - 9 9 -I n f r a r e d ( f i l m ) : 1 7 2 5 (-COOCH^), 3 2 5 0 (-NH) cm,' 1. NMR s i g n a l s : 6 . 3 ( s i n g l e t , 3H S - O C H 3 ) . Pound: C, 5 8 . 6 1 ; H, 9 c 2 5 ; N, 9,9$. G a l e , f o r CyH^OgNr C 5 5 8 . 7 2 ; H, 9 . 1 5 ; N, 9 . 7 8 » M e t h y l n i p e c o t a t e p-bromobenzamide ( 7 8 ) A m i x t u r e of methyl n i p e c o t a t e ( 1 . 0 go, 7 ° 0 1 . m o l s ) , p-bromobenzoyl c h l o r i d e ( 2 . 2 g», 0 . 0 1 0 mols )'•' and p y r i d i n e ( 1 5 ml „ ) brought i n t o s o l u t i o n by s l i g h t warming and a l l o w e d t o s tand a t room temperature f o r 21) . h o u r s . The s o l u t i o n was then c o n c e n t r a t e d I n vacuo t o a p p r o x i m a t e l y 5 m l . , then poured i n t o i c e - c o l d d i l u t e ammonium h y d r o x i d e ( 3 0 ml.) w i t h r a p i d s t i r r i n g . The r e s u l t a n t w h i t e p r e c i p i t a t e was removed by f i l t r a t i o n , washed w i t h water and a i r d r i e d , R e c r y s t a l l i -z a t i o n of t h i s m a t e r i a l from methanol-water p r o v i d e d the pure amide as c o l o r l e s s p l a t e l e t s , mp. 1 0 9 . 5 - 1 1 0 „ 0 ° C „ Pi I n f r a r e d ( K B r ) : 1 7 3 0 (-COOCH^), 1 6 3 0 (-CN-Jem."1. U l t r a v i o l e t , >max„ (loge ) t 2 2 8 (IL .11) iru*. NMR s i g n a l s : 2 » 1 + ( d o u b l e t , 2H, a r o m a t i c ) , 2 . 7 ( d o u b l e t , 2H, a r o m a t i c ) , 6 . 3 ( s i n g l e t , 3H, - O C H 3 K Pounds C, 5 1 . 7 0 ; - H, 5 ° 1 0 ; N, 1 + . 2 3 ; 0, 11+,66; B r , 2 1 L . 7 0 . C a l c . f o r C 1 j ^ H l 6 0 3 N B r : - C, 5 1 . 5 5 ; H, 1 + . 9 5 ; N, 1 + . 3 0 ; 0 , l i j . . 7 1 ; B r , 2 1 + . 8 0 . M e t h y l e t h y l e y a n o a c e t a t e ( 8 2 ) To a s o l u t i o n o f sodium ( 7 « 1 go, 0 . 3 0 8 mols) i n a b s o l u t e methanol ( 1 2 5 ml.)"was added a s o l u t i o n of methyl c y a n o a c e t a t e ( 3 0 g., 0.301+ mols) i n a b s o l u t e methanol ( 1 2 5 m l . ) . The r e a c t i o n m i x t u r e was c o o l e d w i t h s t i r r i n g i n an i c e - b a t h -100-d u r i n g the a d d i t i o n , , The r e s u l t a n t s o l u t i o n was a l l o w e d t o warm t o room t e m p e r a t u r e , s t i r r e d f o r 10 m i n u t e s , then e t h y l i o d i d e (5l„0 g „, 0,327 mols ) added d r o p w i s e . The r e a c t i o n . f l a s k was c o o l e d i n t e r m i t t e n t l y d u r i n g t h i s a d d i t i o n , as c o n s i d e r a b l e h e a t was e v o l v e d . The m i x t u r e was then s t i r r e d a t room temperature f o r a f u r t h e r !•§- h o u r s , a f t e r w h i c h time i t was n e a r l y n e u t r a l t o litmus». Most of the methanol was removed by d i s t i l l a t i o n and the r e s i d u a l dark r e d m i x t u r e of l i q u i d and sodium i o d i d e t r a n s f e r r e d t o a s e p a r a t o r y funnel,, Ice w a t e r , c o n t a i n i n g a few m l . of c o n c e n t r a t e d h y d r o c h l o r i c a c i d was added, and the m i x t u r e e x t r a c t e d t h r e e times w i t h e t h e r . The e t h e r e x t r a c t s were combined, washed w i t h c o l d w a ter t o n e u t r a l i t y and d r i e d over anhydrous sodium s u l f a t e . E v a p o r a t i o n o f the e t h e r p r o v i d e d an orange o i l w h i c h was d i s t i l l e d under reduced p r e s s u r e t o g i v e a c l e a r c o l o r l e s s o i l (31 go) bp, 110-ll8°/ 38 mm. NMR s i g n a l s : 8„9 and 9*0 (two t r i p l e t s , -CH2CH3), T h i s p r o d u c t was shown by gas chromatography ( d e t a i l e d c o n d i t i o n s below) as b e i n g a m i x t u r e of t h r e e components, the major (60$) b e i n g the d e s i r e d m e t h y l e t h y l c y a n o a c e t a t e . S m a l l q u a n t i t i e s o f the m e t h y l e t h y l c y a n o a c e t a t e were s e p a r a t e d by gas chromatography on an a n a l y t i c a l 20$ A p i e z o n J column (I4.5/6O Chrom W9 5' x -^ "!, column temperature 110°C h e l i u m f l o w r a t e 90 m l / m i n 0 ) o I n f r a r e d ( f i l m ) : 17I4.O (-COOCH3), 2230 (-C=N) cmo" 1, NMR s i g n a l s r 6„25 ( s i n g l e t , 3H, -OCH3), 8„9 ( t r i p l e t , 3 H , .-CH2CH3), 6.55 ( t r i p l e t , I H , NC-CHCOOCH3). -101-Pound: C, 56.22:; H, 6.93, N, 11.55- C a l c . f o r C 6 H 9 N 0 2 r C, 56.68° H, 7.13; N, 11.02. S i m i l a r i s o l a t i o n of the s m a l l e s t component of the m i x t u r e (10$) a l l o w e d i t s i d e n t i f i c a t i o n as u n r e a c t e d m e t h y l c y a n o a c e t a t e ( s u p e r i m p o s a b l e i n f r a r e d s p e c t r a and t h i n - l a y e r c h r o m a t o g r a p h i c p r o p e r t i e s - s i l i c a g e l , benzene). The t h i r d component of the m i x t u r e (30$) was a l s o i s o l a t e d i n s m a l l q u a n t i t y . I n f r a r e d ( f i l m ) : 1740 (-COOCH3), 2230 (-car) cm." 1. M e t h y l 3 - c h l o r o p r o p y l e t h y I c y a n o a c e t a t e (83) To a s o l u t i o n o f sodium (l5«6 g. s 0.680 moles) i n a b s o l u t e methanol (350 ml.) was added a m i x t u r e of m e t h y l e t h y l c y a n o -a c e t a t e , m e t h y l c y a n o a c e t a t e and methyl d i e t h y l c y a n o a c e t a t e as o b t a i n e d i n the above experiment (101 g„, c o n t a i n i n g a p p r o x i m a t e l y 0.58 moles of m a t e r i a l which can be a l k y l a t e d ) w i t h s t i r r i n g . A f t e r a p p r o x i m a t e l y 15 m i n u t e s , l-bromo-3-c h l o r o p r o p a n e (186 g„, 1.18 moles) was added d r o p w i s e . The r e s u l t a n t m i x t u r e was warmed o n l y s l i g h t l y u n t i l the i n i t i a l h e at o f r e a c t i o n had subsided', then r e f l u x e d f o r 2 hours a f t e r w h i c h time the s o l u t i o n was n e u t r a l t o l i t m u s . The methanol was l a r g e l y removed In vacuo and the r e s i d u a l m i x t u r e of s o l i d and orange o i l t r a n s f e r r e d t o a s e p a r a t o r y f u n n e l . C o l d w a t e r c o n t a i n i n g a. few m l . of c o n c e n t r a t e d h y d r o c h l o r i c a c i d was added and the o i l w h i c h s e p a r a t e d taken up i n e t h e r . The aqueous l a y e r was e x t r a c t e d t w i c e more w i t h e t h e r , the e x t r a c t s combined, washed w i t h w a t e r t o n e u t r a l i t y and d r i e d over 102 anhydrous sodium s u l f a t e . C o n c e n t r a t i o n of the e t h e r s o l u t i o n gave an orange o i l w h i c h was d i s t i l l e d at 5 mm. p r e s s u r e t h r o u g h a 15 cm. V i g r e u x column. The f i r s t f r a c t i o n , b.p. 35=1+0°C was r e c o v e r e d bromochloropropane f o l l o w e d by a m i x t u r e of m e t h y l d i e t h y l c y a n o a c e t a t e ( I d e n t i c a l by gas chromatography t o t h a t o b t a i n e d by a l k y l a t i o n o f m e t h y l cyano-a c e t a t e w i t h e t h y l i o d i d e above) and methyl 3 - c h l o r o p r o p y l -e t h y l c y a n o a c e t a t e (50 g.) b o i l i n g i n the range 82-11+0° (m o s t l y 82-95°)' Pure m e t h y l 3 - c h l o r o p r o p y l e t h y l c y a n o a c e t a t e then was o b t a i n e d (60 g„, 30$ o v e r a l l y i e l d f r om m e t h y l c y a n o a c e t a t e ) as a c l e a r c o l o r l e s s o i l bp 11+0-11;8° ( m o s t l y • II4.I4.—II4.70)» -An a n a l y t i c a l sample was o b t a i n e d by gas chromatography on an A p i e z o n J column (1+5/60 Chrom. W, 5' x \"\ column temperature 210°, h e l i u m p r e s s u r e 50] p s i . ) I n f r a r e d ( f i l m ) ? 1735 (-COOCH3), 2220 (-G=N) cm." 1. NMR s i g n a l s : 6.2 ( s i n g l e t , 3H, - O G H 3 ) , 8.95 ( t r i p l e t , 3H, -CH 2CH 3), '6.1+ ( d i s t o r t e d , t r i p l e t , 2H, -CH 2C1) . Pound: C, 52.61+j H, 7.10; N, 6.56. C a l c . f o r C 9 H i ^ N 0 2 C i : C, 53-13; H, 6.93; N, 6.88. 3-Carbomethoxy°3°ethylpiperidine (67) M e t h y l 3 - c h l o r o p r o p y l e t h y l c y a n o a c e t a t e (8.0 g., 0.0393 moles) was added over 1 h o u r . t o a s t i r r e d s u s p e n s i o n of Pd (8.0 g o , 10$ on c h a r c o a l ) i n a b s o l u t e me t h a i o l (100 ml.) t o w h i c h SN h y d r o c h l o r i c a c i d i n a b s o l u t e methanol (20 ml.) had been added. S t i r r i n g at room temperature was c o n t i n u e d f o r 21; hours at w h i c h time a p p r o x i m a t e l y 1100 m l , o f hydrogen -103-(55-60% of the t h e o r e t i c a l amount) had been consumed and up-take had e s s e n t i a l l y c e a s e d. The c a t a l y s t was removed by f i l t r a t i o n and the f i l t r a t e e v a p o r a t e d t o a s m a l l volume. E t h e r and water were added, the m i x t u r e t r a n s f e r r e d t o a s e p a r a t o r y f u n n e l and the l a y e r s s e p a r a t e d . The aqueous a c i d i c l a y e r was e x t r a c t e d once more w i t h e t h e r , the e t h e r e x t r a c t s combined and washed once w i t h w a t e r , the water wash b e i n g added t o the o r i g i n a l aqueous l a y e r . The e t h e r l a y e r was d r i e d over anhydrous sodium s u l f a t e and l a t e r combined w i t h t h a t o b t a i n e d from the r e d u c t i o n of another 8 g-„ (83)0 These were eva p o r a t e d t o g i v e e s s e n t i a l l y pure r e c o v e r e d n i t r i l e (9.0 g., 56% r e c o v e r y ) . The aqueous a c i d i c l a y e r was then made s t r o n g l y b a s i c by the a d d i t i o n of i c e - c o l d 30% sodium h y d r o x i d e s o l u t i o n and e x t r a c t e d t h r e e times w i t h e t h e r . The b a s i c e t h e r e x t r a c t s were combined, d r i e d r a p i d l y over anhydrous sodium s u l f a t e and e v a p o r a t e d t o y i e l d a p a l e y e l l o w o i l ( a p p r o x i m a t e l y 3 g«) w h i c h was a l l o w e d t o stand f o r 2 days. T h i s o i l upon s t a n d i n g became i n c r e a s i n g l y v i s c o u s and a f t e r 2 days was e t h e r i n s o l u b l e . T h i s c o n v e r s i o n c o u l d a l s o be a c c o m p l i s h e d by h e a t i n g the o i l b r i e f l y on a steam b a t h . E t h e r and a s m a l l amount of water was added t o the m a t e r i a l s o b t a i n e d i n t h i s manner from two r e d u c t i o n s (8.0 g, of n i t r i l e h a v i n g been used i n each experiment) f o l l o w e d by c o l d 30% sodium h y d r o x i d e . The r e s u l t a n t m i x t u r e s were,combined i n a s e p a r a t o r y f u n n e l and t h e l a y e r s s e p a r a t e d . The aqueous l a y e r was then e x t r a c t e d w i t h two a d d i t i o n a l p o r t i o n s of ether and the combined e x t r a c t s were d r i e d over anhydrous sodium s u l f a t e . E v a p o r a t i o n of the s o l v e n t gave the d e s i r e d p i p e r i d i n e (Ji.8 g., 8 2 % crude y i e l d ) as a pale yellow o i l p o s s e s s i n g a c h a r a c t e r i s t i c p i p e r i d i n e odour. This m a t e r i a l was used without f u r t h e r p u r i f i c a t i o n f o r the r e a c t i o n with 2-carboethoxy-3-(/?-cbloro-e t h y l ) - l n d o l e (66). Vaccuum d i s t i l l a t i o n of a small amount ( 2 0 0 mg.) of t h i s compound at 1.50° (bath temperature) at 0 , 1 mm. provided a sample f o r the p r e p a r a t i o n of the 3 , 5 -dinitrobenzamide d e r i v a t i v e ( 8 5 ) . F u r t h e r p u r i f i c a t i o n of the d i s t i l l e d m a t e r i a l was e f f e c t e d by gas chromatography on an Apiezon J column (I4.5/6O Chrom W. 5' x ij:"', column temperature 1 5 0 ° , h e l ium flow r a t e 9 0 ml/min.). I n f r a r e d ( f i l m ) r 1 7 2 5 (-COOCH3), 325'0 (NH) cm." 1. NMR s i g n a l s : 6.25 ( s i n g l e t , 3'H, -OCH3), 9 . 2 ( t r i p l e t , 3H,-CH 20H3). Repeated elemental a n a l y s i s ( f i v e d e t e rminations) gave u n s a t i s f a c t o r y r e s u l t s f o r carbon and hydrogen. 3 - C a r b o m e t h o x y - 3 - e t h y l p l p e r i d l n e - 3 . 5-dTnltrobenzamide ( 8 5 ) The reagent 3 , 5 - d i n i t r o b e n z o y l c h l o r i d e was f r e s h l y prepared a s f o l l o w s : 3 , 5 - d i n i t r o b e n z o i c a c i d (l)j.O mg ., 0.66 m. mols) and phosphorus p e n t a c h l o r i d e (llj.5 mg., 0 . 7 0 m. moles) were warmed g e n t l y on a flame In a small t e s t -tube u n t i l the r e a c t i o n was I n i t i a t e d . A f t e r the r e a c t i o n was complete and the r e s u l t a n t l i q u i d c o o l e d , a f e w ml. of petroleum ether (30-60°) was added i n order to p r e c i p i t a t e 3 , 5 - d i n i t r o b e n z o y l c h l o r i d e . The petroleum ether w a s removed - 1 0 5 -w i t h a p i p e t and the 3 9 5 - d i n i t r o b e n z o y l c h l o r i d e washed twiice more w i t h p e t r o l e u m e t h e r t o remove t r a c e s of phosphorus o x y c h l o r i d e 0 3 ™ C a r b o m e t h o x y - 3 - e t h y l p i p e r i d i n e ( 9 0 mg., 0 . 5 3 m. mols) was added, and a f t e r the i n i t i a l r e a c t i o n had s u b s i d e d the m i x t u r e was warmed g e n t l y i n the steam b a t h f o r 5 m i n u t e s . The p r o d u c t was d i s s o l v e d i n e t h e r . a n d washed s u c c e s s i v e l y w i t h 5 $ h y d r o c h l o r i c a c i d , w a t e r , 5 $ sodium h y d r o x i d e , and f i n a l l y w a t e r . S i n c e the p r o d u c t tended t o c r y s t a l l i z e f r o m e t h e r , the s o l v e n t was e v a p o r a t e d d i r e c t l y to y i e l d a c r y s t a l l i n e r e s i d u e which was r e c r y s t a l l i z e d once from, methanol t o p r o v i d e the pure amide as p a l e y e l l o w n e e d l e s , mp. 1 2 2 . 0 - 1 2 2 . 5 ° ° I n f r a r e d ( K B r ) : 1 7 2 5 (-COOCH^), 1 6 3 0 (-CN-), 3 0 3 0 ( a r o m a t i c ) cm." 1. U l t r a v i o l e t , > max ( l o g e ) : 2 3 0 ( l + o 3 0 ) m/4, NMR s i g n a l s : 6 . 3 ( s i n g l e t , 3 H , -0CH_ 3), 9 . 2 5 ( t r i p l e t , 3 H , -CH 2CH 3), 0 . 9 ( t r i p l e t , I H , a r o m a t i c ) , 1 . 1 ) . ( d o u b l e t , 2H, a r o m a t i c ) . Found: G, 5 2 . 6 5 ? H, 5 . 1 * 4 ; N, l l . l j . 8 y 0 , 3 0 . 7 4 ° C a l c . f o r C^H-^OyN^ C, 5 2 . 6 0 ; H, 5 o 2 l + ; N, 1 1 . 5 0 ; 0, 3 0 . 6 6 . 2-Carboe'"thoxy - 3-r^ - ( 3 - c a r b o m e t h o x y - 3 - e t h y l - N - p i p e r i d y l ) -e t h y l j - i n d o l e ( 6 8 ) " ~ ~ ~ 2 - C a r b o e t h o x y - 3 - ( / S - c h l o r o e t h y l ) - i n d o l e ( 6 6 ) ( 2 o 0 g . , 8 . 0 m mols) and 3 - c a r b o m e t h o x y - 3 ' = e t h y l p i p e r i d ine ( 2 . 8 g., 16 . 1 + m mols) i n dioxane ( 2 5 ml.) were heated i n a t h i c k - w a l l e d s e a l e d tube i n a p r e s s u r e bomb f o r 2 0 hours at 1 6 0 ° , the tube h a v i n g been s a t u r a t e d w i t h d r y n i t r o g e n b e f o r e s e a l i n g . A f t e r c o o l i n g t o room temperature the tube was opened, the dioxane s o l u t i o n decanted from the gummy, i n s o l u b l e m a t e r i a l and e v a p o r a t e d . The gummy r e s i d u e r e m a i n i n g i n the tube was conblned w i t h t h i s -106-r e a c t i o n p r o d u c t by t h o r o u g h l y washing the tube w i t h e t h e r and w a t e r . The r e s u l t a n t m i x t u r e was a c i d i f i e d by the a d d i t i o n of c o n c e n t r a t e d h y d r o c h l o r i c a c i d and shaken i n a s e p a r a t o r y f u n n e l . The l a y e r s were s e p a r a t e d and the e t h e r l a y e r was d r i e d over anhydrous magnesium s u l f a t e and c o n c e n t r a t e d t o g i v e e s s e n t i a l l y pure u n r e a c t e d s t a r t i n g i n d o l i c e s t e r (1.2 g., 60% r e c o v e r y ) . The above aqueous l a y e r was washed w i t h a s m a l l amount of e t h e r , ( d i s c a r d e d ) , then made b a s i c by the c a r e f u l a d d i t i o n of s o l i d p o t a s s i u m c a r b o n a t e , s a t u r a t e d w i t h sodium c h l o r i d e , and e x t r a c t e d t h r e e times w i t h e t h e r . The e t h e r e x t r a c t s were combined, washed w i t h a s m a l l amount of w a t e r and d r i e d over anhydrous magnesium s u l f a t e . E v a p o r a t i o n of t h e e t h e r gave a b a s i c f r a c t i o n (1„6 g . ) which by t h i n - l a y e r chromatography ( a l u m i n a , c h l o r o f o r m , p o t a s s i u m permanganate s p r a y ) showed m a i n l y one s p o t . T h i s m a t e r i a l was chromatographed on alumina (120 g.) and e l u t i o n w i t h benzene-ether (3*1) y i e l d e d the d e s i r e d compound (1.0 g . ) . The l a t e r f r a c t i o n s o f t h i s chromatography c o n t a i n e d a s l i g h t l y more p o l a r compound w h i c h c o u l d be removed by r echromatography. C r y s t a l l i z a t i o n of the pure p r o d u c t from p e t , e t h e r (60-80°) gave v e r y p a l e orange c r y s t a l s , mp. 10IL-106°, r e c r y s t a l l i z a t i o n of w h i c h p r o v i d e d an a n a l y t i c a l sample as c o l o r l e s s prisms mp. 105".5-106.5°« I n f r a r e d ( K B r ) : 1730 ( - C O O C H 3 ) , 1675 (-COOEt), 3350 (NH) cm.""1. U l t r a v i o l e t ; ^max ( l o g e)r 229 ( i i . 3 5 ) , 298 (1+. 2ii ) wyx. NMR s i g n a l s : 0,92 (broad s i n g l e t , 1H, NH), 2 .2-3.0 ( m u l t i p l e t s , -107-l\E9 a r o m a t i c ) , 5.57 ( q u a r t e t , 2H, -OCH 2CH 3), 6.35 ( s i n g l e t , 3 H ) , T 0 C H 3 ) , 8.6 ( t r i p l e t , - O C H 2 C H 3 ) , 9 . 2 ( t r i p l e t , 3H, -CH 2CH_ 3). Mass spectrum M.W!. 386, base peak m/e I8I4.0 Found: C, 6 8 . 3 8 ; H, 7.77; N, 7.i | 0 ; 0 , 1 6 . 6 3 . C a l c . f o r C 2 2H 3 0N 2 0 ^ : ' C, 6 8 . 3 7 ; H, 7 . 8 2 ; N, 7.25? 0, 16 . 5 6 . Attempted A c y l o i n C o n d e n s a t i o n o f the D i e s t e r (68) Toluene w h i c h had been f r e s h l y d i s t i l l e d f r o m sodium was a g a i n d i s t i l l e d from sodium under d r y n i t r o g e n i n t o a t h r e e - n e c k e d r e a c t i o n v e s s e l equipped w i t h a h i g h speed s t i r r e r and a d i l u t i o n chamber a t t a c h e d t o a condenser. The t o l u e n e c o l l e c t e d i n the r e a c t i o n f l a s k was then c o n t i n u o u s l y d i s t i l l e d t h r o u g h the d i l u -t i o n chamber t o remove waiter from the apparatus ( c o n t i n u e d f o r § h o u r ) . F r e s h l y c u t sodium (90 mg.) was added t o the r e a c t i o n f l a s k c o n t a i n i n g t h e r e f l u x i n g t o l u e n e (30-I|.0 ml.) and the d i e s t e r 68 (300 mg., O.78 m mols) added t h r o u g h the d i l u t i o n chamber c o n t a i n i n g t o l u e n e ( a p p r o x i m a t e l y 50 ml.) over a p e r i o d of I4. hours w h i l e the sodium s u s p e n s i o n was b e i n g s t i r r e d a t lj.000-5000 rpm„ A f t e r t h e a d d i t i o n o f the d i e s t e r was complete the m i x t u r e was r e f l u x e d w i t h s t i r r i n g f o r an a d d i t i o n a l 2% h o u r s . The r e a c t i o n m i x t u r e was c o o l e d i n an i c e - b a t h and g l a c i a l a c e t i c a c i d added u n t i l the m i x t u r e was n e u t r a l t o l i t m u s . , The p r e c i p i t a t e d m a t e r i a l was removed by f i l t r a t i o n , washed w i t h e t h e r and the combined f i l t r a t e and washings then d r i e d over anhydrous sodium s u l f a t e . The r e s i d u e was then washed w e l l w i t h c h l o r o f o r m and the c h l o r o f o r m s o l u t i o n was d r i e d over anhydrous sodium s u l f a t e . E v a p o r a t i o n o f the t o l u e n e - e t h e r and c h l o r o f o r m f r a c t i o n s p r o -v i d e d brown gums (85 mg. and 205 mg. r e s p e c t i v e l y ) which were -108-i n d l c a t e d by t h i n - l a y e r chromatography ( a l u m i n a , benzene e t h y l a c e t a t e ( 5 : 1 ) , and s i l i c a g e l , methanol) as c o n t a i n i n g e s s e n t i a -l l y the same m a t e r i a l and no s t a r t i n g d i e s t e r . P r e p a r a t i v e t h i n - l a y e r chromatography on s i l i c a g e l (0 ,5 mm., methanol) on a p o r t i o n of the combined p r o d u c t s a f f o r d e d a p o l a r p r o d u c t (60$ r e c o v e r y ) as an amorphous s o l i d , one spot by t h i n - l a y e r chromatography. I n f r a r e d ( C H C I 3 ) : 1720 cm. - 1 ( c a r b o n y l ) . U l t r a v i o l e t , 7-max 2 225, 295 m//. NMR s i g n a l s : 6 . 0 (broad m u l t i p l e t , 1-1.5H) s 6.1+0 (broad s i n g l e t , 1.5H)„-L i t h i u m Aluminum H y d r i d e R e d u c t i o n of the A c y l o i n P r o d u c t The crude a c y l o i n p r o d uct (175 mg.) was d i s s o l v e d i n dry t e t r a h y d r o f u r a n (10 ml.) and added t o a s u s p e n s i o n o f l i t h i u m aluminum h y d r i d e (175 mg.) i n dry t e t r a h y d r o f u r a n (18 m l . ) . The r e s u l t i n g m i x t u r e was r e f l u x e d f o r 2,-g- h o u r s , then c o o l e d i n an i c e - s a l t b a t h and the excess l i t h i u m aluminum h y d r i d e d e s t r o y e d by the c a r e f u l a d d i t i o n of i c e - w a t e r . C h l o r o f o r m was added and the m i x t u r e f i l t e r e d t h r o u g h C e l i t e w hich i n t u r n was washed w e l l w i t h c h l o r o f o r m . The combined f i l t r a t e and washings were d r i e d over anhydrous p o t a s s i u m c a r b o n a t e , then e v a p o r a t e d t o y i e l d a brown o i l (155 mg.). A p o r t i o n o f t h i s m a t e r i a l (108 mg.) was p u r i f i e d by p r e p a r a t i v e t h i n l a y e r chromatography on s i l i c a g e l p l a t e s (20 x 20 cm., 0„5 mm,,, e t h y l a c e t a t e - m e t h a n o l , 2:1) t o p r o v i d e a p u r i f i e d p r o d u c t (50 mg.). T h i s was a g a i n p u r i f i e d by the same p r o c e s s t o y i e l d a pure p r o d u c t (1+0 mg.). I n f r a r e d (CHCI3): no c a r b o n y l . U l t r a v i o l e t ; max: 225, 272. ( s h ) , 281+., 2.92 m/*, NMR s i g n a l s : 0 . 9 0 ( s i n g l e t , I H , -NH), 2.1+-3.1 ( m u l t i -p l e t , 1+H, a r o m a t i c ) , 1+.1+0 (broad s i n g l e t s u b j e c t t o c o n c e n t r a t i o n -109-s h i f t s and exchanged by d e u t e r i u m o x i d e , -OH), 5*35 ( s i n g l e t , 2H) 9 6.1+5 (broad s i n g l e t , 2H), 9 = 25 ( t r i p l e t , 3H, - C H 2 C H 3 ) . A c e t y l a t i o n of the A l c o h o l Obtained from R e d u c t i o n o f the  A c y l o i n P r o d u c t The a l c o h o l o b t a i n e d as d e s c r i b e d above (13 mg.) was t r e a t e d w i t h anhydrous p y r i d i n e (0.5 ml.) and a c e t i c a n h y d r i d e (0.05 ml.) and the m i x t u r e warmed t o near r e f l u x f o r 1 h o u r . The p y r i d i n e was ev a p o r a t e d under a st r e a m of n i t r o g e n , the r e s i d u e d i s s o l v e d i n c h l o r o f o r m and d r i e d over anhydrous p o t a s s i u m c a r b o n a t e . E v a p o r a t i o n of the s o l v e n t p r o v i d e d a dark brown gum. NMR s i g n a l s : 2.1L-3°0 ( a r o m a t i c ) , li .78 ( s i n g l e t ) , 5*95 ( s i n g l e t ) , 8„0 (two s i n g l e t s , - O O C H 3 ) , 9.2:0 ( t r i p l e t , 3H, - C H 2 C H 3 ) . T h i s m a t e r i a l was p u r i f i e d by p r e p a r a t i v e t h i n - l a y e r chromatography on s i l i c a g e l (20 x 20 cm., 0.5 mm., benzene rethy1 a c e t a t e , 1:1) t o p r o v i d e a l i g h t brown gum (9 mg.). I n f r a r e d ( f i l m ) r 3300 (-NH), 1725 ( - O C O C H 3 ) cm." 1. U l t r a v i o l e t , >max: 221;, 273 281+, 292.5 m//. Mass spectrumr base peak m/e 198. 2 - H y d r O x y m e t h y i - 3 C ^ - ( 3 - e t h y l - 3 - h y d r o x y m e t h y l - N - p l p e r i d y l ) - e t h y l j - i n d o l e d i a c e t a t e (boJ Thi s compound was prepare d from a u t h e n t i c 2-carbomethoxy-3 ~ [ ^ ~ ( 3 - c a r b o m e t h o x y - 3 ~ e t h y l - N - p i p e r i d y l ) - e t h y l ] - i n d o l e by r e d u c t i o n and a c e t y l a t i o n In the i d e n t i c a l manner t o t h a t d e s c r i b e d above f o r the a c y l o i n c o n d e n s a t i o n p r o d u c t . The d i a c e t a t e o b t a i n e d was i d e n t i c a l to t h a t d e s c r i b e d above ( i n f r a r e d , mass s p e c t r a , t h i n - l a y e r chromatography - s i l i c a g e l , benzene - e t h y l a c e t a t e , 1:1, a l u m i n a , benzene - e t h y l - 1 1 0 -a c e t a t e , 5 * 1 ) . E a t e r i f l c a t i o n of the A c y l o i n C o n d e n s a t i o n P r o d u c t Ihe crude a c y l o i n c o n d e n s a t i o n product (20 mg.) was d i s s o l v e d i n c h l o r o f o r m (0 . 5 ml.) and diazomethane i n e t h e r (2 m l . , a p p r o x i m a t e l y 0.1+ M) was added ( e f f e r v e s c e n c e ) . A f t e r s t a n d i n g f o r one hour w i t h o c c a s s i o n a l s h a k i n g the s o l v e n t was e v a p o r a t e d under a s t r e a m of n i t r o g e n and a f u r t h e r s o l u t i o n o f diazomethane i n e t h e r (2 ml.) was added, d i r e c t l y t o the o i l y r e s i d u e . A f t e r one hour the p r o d u c t was i n v e s t i g a t e d by t h i n - l a y e r chromatography (aluminum, benzene - e t h y l a c e t a t e , 5:1) and shown t o c o n t a i n b o t h 2 -carboethoxy-3 - r / 3 - ( 3 - c a r b o m e t h o x y - 3 - e t h y l - N - p i p e r i d y l )- ethyl// - i n d o l e and the c o r r e s p o n d i n g d i m e t h y l e s t e r by comparison w i t h a u t h e n t i c samples. - I l l -E x p e r i m e n t a l - F a r t B  2 : - E t h y l - l 0 3 - p r o p a n e d i o l (106)-To a s t i r r e d s u s p e n s i o n of l i t h i u m aluminum h y d r i d e (30 g , , 0 ,79 moles) i n d r y t e t r a h y d r o f u r a n (750 ml) under dry n i t r o g e n , was added over a p e r i o d of 1+5 minutes a s o l u t i o n of d i e t h y l e t h y l m a l o n a t e (91+ g » , 0.50 moles) i n dry t e t r a h y d r o f uran (250 m l ) . The r e s u l t i n g mixture, was r e f l u x e d w i t h s t i r r i n g under dry n i t r o g e n f o r 6 h o u r s . The r e a c t i o n m i x t u r e was then c o o l e d t o 0-5° i n an i c e - s a l t b a t h and c o l d w a t e r added c a r e -f u l l y t o d e s t r o y e x c e s s l i t h i u m aluminum h y d r i d e . A f t e r h a v i n g been a l l o w e d t o come t o room temperature and t o sta n d f o r 10-15 minutes the m i x t u r e was f i l t e r e d t h r o u g h C e l i t e t o remove i n o r g a n i c m a t e r i a l . The p r e c i p i t a t e was washed w e l l w i t h hot t e t r a h y d r o f u r a n and the combined f i l t r a t e and washings were c o n c e n t r a t e d by vacuum d i s t i l l a t i o n . The r e s u l t a n t v i s c o u s o i l was t a k e n up i n f r e s h t e t r a h y d r o f u r a n and d r i e d over anhydrous magnesium s u l f a t e . The o i l o b t a i n e d by ev a p o r a -t i o n of t h e t e t r a h y d r o f u r a n was d i s t i l l e d under reduced p r e s s u r e to p r o v i d e 2 - e t h y l - l ,3-propanediol (1+7.5 g o , 91$ y i e l d ) as a c l e a r c o l o r l e s s o i l , bp, 92-9l+°/0.7 mm. ( L i t , ^ 3 87°/0.5 mm,). I n f r a r e d ( f i l m ) : '3300 cm, - 1 (-0H), no c a r b o n y l a b s o r p t i o n , 3-Benzyloxy-2-ethylpropanol (107) F r e s h l y c u t sodium (1,06 g., 0,01+6 moles) was added i n s m a l l p i e c e s t o a hot (115-120°) s t i r r e d s o l u t i o n of 2-ethyl-1,3-propanediol (11+.1+ g,, 0,138 moles) i n dry x y l e n e (6 m l ) , the temperature b e i n g m a i n t a i n e d by removing or a p p l y i n g the -112-heat source as r e q u i r e d . When a l l t h e sodium, had r e a c t e d (ii5 min.) b e n z y l c h l o r i d e (6.5 g . , 0.051 moles) was added drop-w i s e , the temperature a g a i n m a i n t a i n e d as above. The r e s u l t i n g m i x t u r e was s t i r r e d a t 120° f o r 1 ho u r , then a l l o w e d to c o o l t o room temperature and f i l t e r e d t o remove the sodium c h l o r i d e (2.69 g » ) o The f i l t r a t e was c o n c e n t r a t e d i n vacuo and the r e s u l t a n t v i s c o u s y e l l o w o i l d i s t i l l e d under n i t r o g e n and a t reduced p r e s s u r e t h r o u g h a s p i r a l t a n t a l u m d i s t i l l a t i o n column (5 mm. x 33 cm.), equipped w i t h h e a t i n g j a c k e t . A f t e r removal of t h e x y l e n e , u n r e a c t e d 2 - e t h y l - 1 , 3 - p r o p a n e d i o l (9.1 g . ) , bp. 102-108°/2 mm. was f i r s t o b t a i n e d , f o l l o w e d by 3<=-benzyloxy-2-ethylpropanol (6.88 g., 77% y i e l d ) , as a c l e a r c o l o r l e s s o i l , bp. 130-133° / 2 mm. I n f r a r e d ( f i l m ) : 3300 (OH),. 7I1O, 695 ( a r o m a t i c ) cm." 1. NMR s i g n a l s : 2.70 ( s i n g l e t , 5H, a r o m a t i c ) , 5.50 ( s i n g l e t , 2 H , C ^ C H g O - ) , 6J4 ( m u l t i p l e t , ILH, C 6 H 5 C H 2 O C H 2 - , and H O C H 2 -), 7.2 ( s i n g l e t , 1 H , -OH), 8.0-8.9 ( m u l t i p l e t s , 3H, - C H C H 2 C H 3), 9.1 ( t r i p l e t , 3H, -CH2CH3). Pound: C, 7I+.01; H, 9.58; 0, 16.60. C a l c . f o r C 1 7 H l 8 0 2 : G, 71+.19, H, 9.3l+s 0, I6.IJ.7 3 - B e n z y l o x y - 2 - e t h y l p r o p y l c h l o r i d e (108) T h i o n y l c h l o r i d e (18.5 g«. 0.155 moles) was added d r o p -wise t o a s t i r r e d m i x t u r e of 3 - b e n z y l o x y - 2 - e t h y l p r o p a n o l (107) ( 2 9 . 0 g o , 0.150 moles) and N , N - d i m e t h y l a n i l l n e (20.0 g„, 0.165 m o l e s ) , the temperature b e i n g m a i n t a i n e d below IL5° by c o o l i n g i n an i c e - b a t h . The r e s u l t a n t m i x t u r e was s t i r r e d f o r |- hour a t LL5° t h e n poured i n t o d i l u t e h y d r o c h l o r i c a c i d -113-c o n t a i n e d i n a s e p a r a t o r y f u n n e l . The heavy o i l which s e p a r a t e d was removed w i t h c h l o r o f o r m , washed once w i t h d i l u t e h y d r o -c h l o r i c a c i d t o remove any N , N - d i m e t h y l a n i l i n e , then washed w i t h s e v e r a l p o r t i o n s of water u n t i l n e u t r a l t o l i t m u s paper. The c h l o r o f o r m s o l u t i o n was d r i e d over anhydrous sodium s u l f a t e and the p a l e y e l l o w o i l r e s u l t i n g on e v a p o r a t i o n of t h e c h l o r o -form was d i s t i l l e d under reduced p r e s s u r e t o y i e l d 3 - b e n z y l o x y -2 - e t h y l p r o p y l c h l o r i d e (21.0 g., 6 6 $ y i e l d ) as a c l e a r c o l o r -l e s s o i l , bp. 8 8 - 9 0 o / 0 o 3 m m . I n f r a r e d ( f i l m ) : 7 3 5 , 6 9 5 ( a r o m a t i c ) cm." 1. NMR s i g n a l s : 2.70 ( s i n g l e t , 5H, a r o m a t i c ) , 5 . 5 0 ( s i n g l e t , 2H, C^H^CH^O-), 6.1+5 ( m u l t i p l e t , 1+H, CAH5CH2OCH2- and C1CH 2-), 7 . 9 - 8 . 8 ( m u l t i p l e t , 3 H , -CHCH2CH3), 9.10 ( t r i p l e t , 3 H , -CH2CH.3). Found: C, 6 7 . 3 9 ? H, 8.10. C a l c . f o r C i 2 H i 7 0 C l : C , 6 7 . 7 5 ; H, 8 . 0 6 . D i e t h y l 3 - b e n z y l o x y - 2 - e t h y l p r o p y l m a l o n a t e ( 1 0 9 ) F r e s h l y c u t sodium ( 3 . 6 8 g., 0.16 moles) was added i n s m a l l p i e c e s t o a b s o l u t e e t h a n o l ( 7 5 ml) w i t h s t i r r i n g . The s o l u t i o n o f sodium e t h o x i d e was a l l o w e d t o c o o l t o about 5 0 ° t h e n d i e t h y l malonate ( 3 7 g., 0.23 moles) was added over a 10 minute p e r i o d . The r e s u l t i n g s o l u t i o n was heated t o r e f l u x and 3 - h e n z y l o x y - 2 - e t h y l p r o p y l c h l o r i d e ( 3 2 . 5 g«, 0 . 1 5 3 moles) added dropwise over a 3 hour p e r i o d , a f t e r w hich time the m i x t u r e was r e f l u x e d f o r a f u r t h e r 20 h o u r s . Most of the e t h a n o l was removed by d i s t i l l a t i o n , then the c o o l e d m i x t u r e of sodium c h l o r i d e and o i l poured i n t o c o l d water c o n t a i n i n g a c e t i c a c i d (10 m l ) . The l a y e r s were s e p a r a t e d and the - l l l i -aqueous l a y e r e x t r a c t e d t h r e e times w i t h e t h e r . The s e p a r a t e d o i l and e t h e r e x t r a c t s were combined and washed once w i t h w a t e r , t w i c e with, a 10% sodium b i c a r b o n a t e s o l u t i o n and f i n a l l y once w i t h a s a t u r a t e d sodium c h l o r i d e s o l u t i o n . A f t e r d r y i n g over anhydrous sodium s u l f a t e and e v a p o r a t i o n o f the s o l v e n t , a v i s c o u s y e l l o w o i l was o b t a i n e d . T h i s p r o d u c t was d i s t i l l e d a t reduced p r e s s u r e t o y i e l d , i n the i n i t i a l f r a c t i o n s , u n r e a c t e d d i e t h y l m a l o n a t e , t h e n 3-b e n z y l o x y - 2 - e t h y l p r o p y l c h l o r i d e (16.8 g., 52% r e c o v e r y ) and f i n a l l y d i e t h y l 3-t>enzyloxy-2=ethylpropyl malonate (22 g», 89% y i e l d . 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 ) as a p a l e y e l l o w o i l bp. l55-l60 oA>.3 mm. I n f r a r e d ( f i l m ) : 1735 (-COOEt), 690, 735 ( a r o m a t i c ) cm." 1. NMR s i g n a l s : 2.65 ( s i n g l e t , 5 H , a r o m a t i c ) , 5»50 ( s i n g l e t , 2H, C 6H^CH 20-), 5.8O ( q u a r t e t , i i H , -OCH2CH3), 6.55 ( m u l t i p l e t , 3H, C^CH^OCH^- and -CH(C00ET)2), 8.05 ( m u l t i p l e t , 2H, -CI^CH(COOEt) 2), 8.8 ( t r i p l e t , -OCH2CH3), 9.15 ( t r i p l e t , 3H, -CHCH2CH3). Found: C, 68.17y"H, 8.5. C a l c . f o r C 1 9H2805; C, 67.83? H, 8.39. 3°Benzyloxy-2-ethylpropylmalonic a c i d (110) To a c o l d s t i r r e d s o l u t i o n of p o t a s s i u m h y d r o x i d e (5.9 g.) In w a t e r (9 ml) and e t h a n o l (1 ml) was added d i e t h y l 3-b e n z y l o x y - 2 - e t h y l p r o p y l m a l o n a t e (109) (9.0 g., 0.02.68 moles) over 1^ h o u r s . The m i x t u r e was the n s t i r r e d w i t h c o o l i n g i n an i c e b a t h , f o r f o u r h o u r s , then a l l o w e d t o st a n d at room tempera-t u r e o v e r n i g h t . The r e s u l t a n t y e l l o w s o l u t i o n was e x t r a c t e d t w i c e w i t h e t h e r , then c o o l e d i n an i c e - b a t h , d i l u t e d w i t h w a t e r -115-(10 ml) and e t h e r ( 2 0 ml) and made s t r o n g l y a c i d i c ( t o Congo red paper) by the c a r e f u l a d d i t i o n of c o n c e n t r a t e d h y d r o -c h l o r i c a c i d . The l a y e r s were s e p a r a t e d and the aqueous a c i d i c l a y e r e x t r a c t e d t w i c e w i t h e t h e r . The combined e t h e r e x t r a c t s were washed t w i c e w i t h w a t e r , once w i t h s a t u r a t e d sodium c h l o r i d e s o l u t i o n and d r i e d over anhydrous sodium s u l f a t e . E v a p o r a t i o n of the s o l v e n t p r o v i d e d an e x t r e m e l y v i s c o u s o i l which d i d not c r y s t a l l i z e upon s t a n d i n g or upon t r i t u r a t i o n w i t h v a r i o u s s o l v e n t s . I n f r a r e d ( f i l m ) : 3500-2 1 + 0 0 , 1710 (-C00H) cm.- 1. NMR s i g n a l s : 1 .0 (broad s i n g l e t , 2H, -C00H), 2.61 ( s i n g l e t , 5H, a r o m a t i c ) , 5.J4.9 ( s i n g l e t , 2H, C 6 H 5 C H 2 O - ) , 9.11 ( t r i p l e t , 3H, -CH2CH3). 1 +-Benzyloxymethylhexanolc a c i d (111) The crude m a l o n i c a c i d (110) ( a p p r o x i m a t e l y 7-5 g•) was heated i n an o i l b a t h a t 120° f o r 5 hours and the r e s u l t i n g . l i g h t brown v i s c o u s o i l which c o u l d not be induced t o c r y s t a l l i z e was not p u r i f i e d f u r t h e r . I n f r a r e d ( f i l m ) : 1710 ( - C 0 0 H ) cm." 1. NMR s i g n a l s : -0.6 (broad s i n g l e t , I H , - C 0 0 H ) , 2.65 ( s i n g l e t , 5H, a r o m a t i c ) , 5.50 ( s i n g l e t , 2H, C^H^CH^O-), 6.60 ( d o u b l e t , 2H, C A H 5 C H 2 O C H 2 - ) , 7.6 ( m u l t i p l e t , 2H, - C H 2 C 0 0 H ) , 9.11 ( t r i p l e t , 3H, - C H 2 C H 3 ) . E t h y l l+-benzyloxymethylhexanoate (112) The crude a c i d (111) ( a p p r o x i m a t e l y 5 S«) was d i s s o l v e d i n anhydrous e t h a n o l ( 2 0 ml) c o n t a i n i n g c o n c e n t r a t e d s u l f u r i c a c i d (1 ml) and the s o l u t i o n r e f l u x e d f o r 1-| h o u r s . The r e s u l t i n g s o l u t i o n was a l l o w e d t o c o o l then poured i n t o c o l d -116-w ater and e x t r a c t e d t w i c e w i t h e t h e r . The combined e x t r a c t s were washed s u c c e s s i v e l y w i t h w a t e r , 5% sodium b i c a r b o n a t e and s a t u r a t e d sodium c h l o r i d e s o l u t i o n s , then d r i e d over anhydrous sodium s u l f a t e . The e t h e r was ev a p o r a t e d and the r e s i d u a l yellow, o i l d i s t i l l e d under reduced p r e s s u r e t o p r o v i d e e t h y l i i =benzyloxymethylhexanoate ( 5 °3 g., 75% y i e l d from the m a l o n i c e s t e r 109) as a c l e a r c o l o r l e s s o i l , bp. 122-128° /b.6 mm. I n f r a r e d ( f i l m ) : . 1730 (-COOEt), 735 s 695 ( a r o m a t i c ) cm." 1. NMR s i g n a l s : 2 .65 ( s i n g l e t , 5H, a r o m a t i c ) , 5 °50 ( s i n g l e t , 2H, CfcH^CH^O-), 5*85 ( q u a r t e t , 2H, - O C H 2 C H 3 ) , 6.60 (broad d o u b l e t , 2H, G^H^C^OCH^-), 7.65 ( m u l t i p l e t , 2H, -CH 2C00Et) p. 8.75 ( t r i p l e t , - O C H 2 C H 3 ) , 9.10 ( t r i p l e t , 3H, -CHCH2CH3). Found: C, 7 2 . 3 ^ ; H, 9 .27 ; 0, l 8 . 5 1 i . C a l c . f o r c 1 6 h 2 ! L ° 3 s C» 7 2 o 6 9 5 h> 9 .15 , 0, 18 .16 . P r e p a r a t i o n o f T r i p h e n y l m e t h y l sodium Sodium (3 g») i n dry x y l e n e (10 ml) was warmed c a r e f u l l y w i t h a flame u n t i l i t m e l t e d . The f l a s k was f l u s h e d w i t h d r y n i t r o g e n and mercury (200 g„) added v e r y c a u t i o u s l y t o the melted sodium. The r e s u l t a n t m i x t u r e was al l o w e d t o c o o l t o room temperature under n i t r o g e n and the s u p e r n a t a n t x y l e n e d e c a n t e d . A\nhydrous e t h e r (50 ml) and t r i p h e n y l m e t h y l c h l o r i d e (11 g.) was added, the f l a s k w e l l s t o p p e r e d , t h e n shaken f o r 6 h o u r s . The r e s u l t a n t dark r e d s o l u t i o n of t r i p h e n y l m e t h y l sodium was then d i l u t e d w i t h anhydrous e t h e r (80 ml) and m a i n t a i n e d w e l l s e a l e d . The s o l u t i o n was t r a n s f e r r e d under d r y n i t r o g e n t o a b u r e t f o r a measured a d d i t i o n t o the r e a c t i o n -117-f l a s k and f o r s t a n d a r d i z a t i o n by t i t r a t i o n w i t h ac i d 8 1 + . The c o n c e n t r a t i o n as determined by t h i s method on v a r i o u s o c c a s i o n s was 0.18-0.22 No D i e t h y l 2 - ( 2 - b e n z y l o x y m e t h y l b u t y l ) - s u c c i n a t e (71a) A\n e t h e r s o l u t i o n o f 0„22 !N t r i p h e n y l m e t h y l sodium (86.5 m l 9 0 o019 moles) was q u i c k l y run i n t o a round bottomed f l a s k t h a t had been f l u s h e d w i t h d r y n i t r o g e n . The e s t e r (112) (5»0 g ° 9 0.019 moles) was Immediately added and the s o l u t i o n s t i r r e d f o r 2 m i n u t e s . E t h y l i o d o a c e t a t e (l|.»05 g., 0.019 moles) was th e n added dropwise and the r e s u l t a n t m i x t u r e s t i r r e d f o r j% hour a t room t e m p e r a t u r e . G l a c i a l a c e t i c a c i d (2.5 ml) was added to remove any excess b a s e s , the m i x t u r e f i l t e r e d t o remove sodium i o d i d e and the f i l t r a t e d r i e d over anhydrous sodium s u l f a t e . The e t h e r was e v a p o r a t e d and the r e s i d u a l l i g h t brown o i l chromatographed on al u m i n a 750 go)° T r i p h e n y l m e t h a n e was I n i t i a l l y e l u t e d w i t h p e t r o l e u m ether=benzene ( I p l ) . The u n r e a c t e d s t a r t i n g e s t e r (2.5 g. ) was removed w i t h p e t r o l e u m ether-benzene (2:1) and (1:1) but was contam i n a t e d w i t h s m a l l amounts of t r i p h e r i y l c a r b i n o l . Ad-m i x t u r e of 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 and p r o d u c t (1.6 g„) was the n e l u t e d w i t h benzene, again c o n t a m i n a t e d w i t h a s m a l l amount o f t r i p h e n y l c a r b i n o l w h i c h c r y s t a l l i z e d f r om the m i x t u r e 0 T h i s e s t e r m i x t u r e was s e p a r a t e d from the t r i p h e n y l c a r b i n o l by means o f a p i p e t and rechroraatographed on alumina (96 g . ) . C a r e f u l e l u t i o n w i t h p e t r o l e u m ether-benzene (3:1) p r o v i d e d s t a r t i n g m a t e r i a l i n the i n i t i a l f r a c t i o n s , f o l l o w e d by the d e s i r e d p r o d u c t . F u r t h e r p u r i f i c a t i o n by vacuum - 1 1 8 -d l a t i l l a t i o n ( 1 3 0 - 1 8 0 ° , b a t h t e m p e r a t u r e / 0 . 1 mm) y i e l d e d the d e s i r e d s u c c i n i c e s t e r ( 3 8 . 0 mg») as a c l e a r c o l o r l e s s o i l . Gas chromatography on a 2 0 % SE 3 0 a n a l y t i c a l column ( 6 0 / 8 0 Chrom W., 10' x f " column temp. 2 3 0 ° , h e l i u m f l o w r a t e 9 0 ml/rain.) p r o v i d e d an a n a l y t i c a l sample. I n f r a r e d ( f i l m ) : . 1 7 3 0 (-COOEt), 7 3 5 , 6 9 0 ( a r o m a t i c ) cm." 1. NMR s i g n a l s : 2 . 7 0 ( s i n g l e t , 5H, a r o m a t i c ) , 5 » 5 0 ( s i n g l e t , 2H, C ^ C I ^ O - ) 5 « 8 5 (two q u a r t e t s , liH, - O C H 2 C H 3 ) , 6 . 6 0 ( m u l t i p l e t , 2H, C 6H^CH 20CH 2-), 7 . 0 5 ( m u l t i p l e t , 1H, -CHCOOEt), 7ok ( m u l t i p l e t , 2H, -CH 2C00Et), 8 . 7 5 ( t r i p l e t , - O C H 2 C H 3 ) , 9 . 1 ( t r i p l e t , 3H, -CHCH2CH3). Found: C, 6 8 „ I L 2 ° H, 8 . 7 9 c C a l c . f o r C 2 0 H 3 0 O 5 : C, 6 8 . 5 1 ; ; H, 8 . 6 3 o D e t a i l e d gas c h r o m a t o g r a p h i c e x a m i n a t i o n was performed on an a n a l y t i c a l 2 0 % SE 3 0 column ( 6 0 / 8 0 Chrom W.) , 1 0 * x J ' " , h e l i u m f l o w r a t e 1 0 0 ml/min„, column temperature 2 l i 5 ° and 260°C., a l s o c on 2 0 % FFAP ( 6 0 / 8 0 Chrom W.), 10' x i m , h e l i u m f l o w r a t e TOO ml/min., column t e m p e r a t u r e 21L5° and 2 6 5 ° ° D i e t h y l 2 ° ( 2 - b e n z y l o x y m e t h y l b u t y l ) - 2 - c a r b o e t h o x y s u c c i n a t e ( 1 1 3 ) F r e s h l y c u t sodium ( 1 . 7 1 g», 0 . 0 7 5 moles) was added t o d r y x y l e n e i n a round bottomed 3 - n e c k e d f l a s k equipped w i t h an e x t e r n a l s t i r r i n g motor. The x y l e n e was heated u n t i l the sodium melted and the s t i r r e r t u r n e d on and o f f a few times t o d i s p e r s e the sodium as a f i n e sand. The x y l e n e was a l l o w e d t o c o o l t o room temperature and a l a r g e p o r t i o n was de c a n t e d . Anhydrous e t h e r was added and decanted from the sodium a few times t o remove the r e m a i n i n g x y l e n e . The sodium sand was f i n a l l y c o v e r e d w i t h anhydrous e t h e r ( 1 0 0 m l ) . The m a l o n i c -119-e s t e r ( 1 0 9 ) ( 2 5 g o , 0 . 0 7 5 moles) was added and the m i x t u r e r e f l u x e d f o r 3 hours a t whi c h time e v o l u t i o n of hydrogen had ceased and a l l the sodium had d i s a p p e a r e d . E t h y l bromoacetate ( 1 2 , 7 g . s 0 „ 0 7 6 moles) was c a r e f u l l y added dropwise t o the p a l e green s o l u t i o n of the malonate s a l t and the r e s u l t i n g s o l u t i o n s t i r r e d a t room temperature f o r •§ h o u r , then r e f l u x e d f o r 1 h o u r . The r e a c t i o n m i x t u r e was poured i n t o c o l d water c o n t a i n i n g a s m a l l amount o f a c e t i c a c i d , and the l a y e r s s e p a r a t e d . The aqueous l a y e r was e x t r a c t e d t w i c e f u r t h e r w i t h e t h e r p the combined e x t r a c t s washed once w i t h w a t e r , t h e n d r i e d over anhydrous sodium s u l f a t e . The e t h e r was evaporated and the r e m a i n i n g y e l l o w v i s c o u s o i l d i s t i l l e d under reduced p r e s s u r e u s i n g a C l a i s e n head w e l l wrapped w i t h g l a s s w o o l . I n i t i a l l y a m i x t u r e o f u n r e a c t e d s t a r t i n g m a l o n i c e s t e r and the t r i e s t e r ( l I | . o 5 g°) d i s t i l l i n g i n the range l 4 0 ° - 1 9 0 ° / 0 . 2 mm. was o b t a i n e d . An e s t i m a t e by NMR s p e c t r o s c o p y r e v e a l e d the t r i e s t e r and m a l o n i c e s t e r were i n a r a t i o of 2 : 1 . The subsequent f r a c t i o n o f the d i s t i l l a t i o n c o n t a i n e d pure d e s i r e d t r i e s t e r ( 1 0 . 9 g o ) b p . 1 9 0 - 2 0 0 ° / 0 . 2 mm. R e d i s t i l l a t i o n of the l o w e r b o i l i n g f r a c t i o n when combined w i t h o t h e r r e a c t i o n p r o d u c t s p r o v i d e d a d d i t i o n a l t r i e s t e r . The o v e r a l l y i e l d was 7 8 $ based 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 n f r a r e d ( f i l m ) : 1 7 3 0 (-COOEt), 6 9 5 , . 7 3 0 ( a r o m a t i c ) cm." 1. NMR s i g n a l s : 2 . 7 0 ( s i n g l e t , 5H, a r o m a t i c ) , 5 . 5 5 ( s i n g l e t , 2H, CAH^CR^O-), 5 . 8 5 ( m u l t i p l e t , 6H, - O C H 2 C H 3 ) , 6 . 7 ( d o u b l e t , 2H, C 6 H 5 C H 2 O C H 2 - ) 6 . 9 5 ( s i n g l e t , -120-2H, - C H 2 C 00Et), 7.9 ( m u l t i p l e t , 2H -CHCH 2C(COOEt) 2), 8.75* 8.80 (two t r i p l e t s , -0CH2CH_3), 9.15 ( t r i p l e t , 3H, CH2CH_3). Pound:: C, 65.06; H, 7.95. C a l c . f o r C ^ R ^ O y : C, 65.38., H, 8.11. 2— ( 2 - B e n z y l o x y m e t h y l b u t y l ) - 2 - c a r b o x y s u c . c i n i e a c i d (III)-) A\ m i x t u r e of the t r i e s t e r .(113) (11.5 g., 0.0273 moles) and a 25$ s o l u t i o n o f p o t a s s i u m h y d r o x i d e (0.0905 moles) i n 95$ e t h a n o l was r e f l u x e d f o r 5 h o u r s . The a l c o h o l was d i s t i l l e d and the r e s i d u e t a k e n up i n water and e x t r a c t e d t w i c e w i t h e t h e r . The aqueous a l k a l i n e s o l u t i o n was. c o o l e d i n an i c e -b a t h and made s t r o n g l y a c i d i c ( t o Congo r e d paper) by the c a r e f u l a d d i t i o n o f c o n c e n t r a t e d h y d r o c h l o r i c a c i d . The . r e s u l t a n t m i x t u r e was e x t r a c t e d t w i c e w i t h e t h e r , the e x t r a c t s combined and washed t w i c e w i t h water, then d r i e d over anhydrous sodium s u l f a t e . E v a p o r a t i o n o f the e t h e r gave a v e r y v i s c o u s l i g h t brown o i l w h i c h d i d not c r y s t a l l i z e upon s t a n d i n g or upon t r i t u r a t i o n w i t h v a r i o u s s o l v e n t s . I n f r a r e d ( f i l m ) : 1715 (-C00H) cm." 1. NMR s i g n a l s : -0.1). (broad s i n g l e t , 3H, -C00H), 2.69 ( s i n g l e t , 5H, a r o m a t i c ) , 5.55 ( s i n g l e t , 2H,- CAH5CH 20-), 6.7 (broad d o u b l e t , 2H, C AH ^ C H ^ O C H ^ - ) , 6.85 (broad s i n g l e t , 2H, -CH2C00H), 8.0 ( m u l t i p l e t , 2H, - C H C H 2 C ( C 0 0 H ) 2 ) j , 9.2 ( t r i p l e t , 3H, -CH 2CH_3). 2-(2-Benzyloxymethylbutyl)°succlnic a c i d (115) The crude t r l a c i d (111).) o b t a i n e d above ( a p p r o x i m a t e l y 9 g#,'). was heated a t 165-170° f o r a p e r i o d o f 3 h o u r s . The crude p r o d u c t was r e f l u x e d i n a 20$ aqueous s o l u t i o n of p o t a s s i u m -121-h y d r o x i d e (2.5 m o l e s ) , t o remove any a n h y d r i d e , (2 -3 hours or u n t i l a c l e a r s o l u t i o n was obtained)„ The aqueous s o l u t i o n was then c o o l e d i n an i c e b a t h , made s t r o n g l y a c i d i c ( t o Congo r e d paper) by the c a r e f u l a d d i t i o n of c o n c e n t r a t e d 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 times w i t h e t h e r . The combined e x t r a c t s were washed t w i c e w i t h w a t e r , d r i e d over anhydrous sodium s u l f a t e , and ev a p o r a t e d t o p r o v i d e the crude s u c c i n i c a c i d as a m i x t u r e of c r y s t a l s and v i s c o u s o i l . I n f r a r e d ( f i l m ) : 1700 (-C00H), 71L0, 695 ( a r o m a t i c ) cm." 1. NMR s i g n a l s : 1.0£ {.broad s i n g l e t , -COOH), 2.70 ( s i n g l e t , 5H, a r o m a t i c ) , 5»50 ( s i n g l e t , 2H, C ^ C H ^ O - ) , 6 o60 ( m u l t i p l e t , 2H, C6H5CH2OCH2-) p 7.3' ( v e r y broad m u l t i p l e t , 3H, -CH 2C00H, -CHC00H) P 9.15 ( t r i p l e t , 3H, -CH^H^). D i e t h y l 2 - ( 2 - b e n z y l o x y m e t h y l b u t y l ) - s u c c i n a t e (71a) The crude s u c c i n i c a c i d (115) ( a p p r o x i m a t e l y 7 g») was d i s s o l v e d i n a b s o l u t e e t h a n o l (20 ml) c o n t a i n i n g c o n c e n t r a t e d s u l f u r i c a c i d (1 ml) and r e f l u x e d f o r 1-|- h o u r s . The r e s u l t a n t s o l u t i o n was c o o l e d and poured i n t o c o l d water and e x t r a c t e d t w i c e w i t h e t h e r . The combined e x t r a c t s were washed -twice w i t h w a t e r , once w i t h 5% sodium b i c a r b o n a t e s o l u t i o n , and once w i t h w a t e r , then d r i e d over anhydrous sodium s u l f a t e . E v a p o r a -t i o n of the e t h e r p r o v i d e d a l i g h t y e l l o w o i l w h i c h was d i s t i l l e d under reduced p r e s s u r e (bath temp. 135- l65°/0°5 mm) t o p r o v i d e the pure s u c c i n i c e s t e r (7.1il| g., 78% y i e l d from the t r i e s t e r 113) as a c l e a r c o l o r l e s s o i l . S p e c t r a l and gas c h r o m a t o g r a p h i c p r o p e r t i e s of t h i s s u c c i n i c e s t e r 122-d e r i v a t l v e were i d e n t i c a l t o those f o r the compound o b t a i n e d by the a l t e r n a t e r o u t e as d e s c r i b e d e a r l i e r , N-Q?- (3-IndoIyl ) - e t h y l l - 3 - ( 2 - b e n z y l o x y m e t h y l b u t y l )- s u c c i n i m i d e (130) Tryptamine h y d r o c h l o r i d e (5" g . ) was suspended i n 5"% sodium h y d r o x i d e s o l u t i o n i n a s e p a r a t o r y f u n n e l and shaken t h r e e times w i t h e t h e r t o e x t r a c t the f r e e base. The combined e x t r a c t s were washed t h r e e times w i t h w a t e r and d r i e d over anhydrous magnesium s u l f a t e . E v a p o r a t i o n of the s o l v e n t p r o v i d e d the c r y s t a l l i n e t r y p t a m i n e mp. 116-117° ( L i t . 116°). A\ m i x t u r e o f t r y p t a m i n e (3»1 g». 0.0191). m o l e s ) , t r y p t a m i n e h y d r o c h l o r i d e (lf>0 mg. ) and the s u c c i n i c e s t e r (71a) (2.2 g., 0.0063 moles ) was r e f l u x e d i n f r e s h l y d i s t i l l e d 2;-(2-EthoxyethoxyJ - e t h a n o l (30 m l , bp. 190-200°C) f o r 50 hours under dry•nitrogen„ The r e s u l t a n t m i x t u r e was then a l l o w e d t o c o o l t o room t e m p e r a t u r e , t a k e n up i n e t h e r and washed t h r e e times w i t h w a t e r , f i v e times w i t h 10% a c e t i c a c i d t o remove t r y p t a m i n e and t h r e e times w i t h w a t e r . The green e t h e r e a l s o l u t i o n was d r i e d over anhydrous sodium s u l f a t e and e v a p o r a t e d t o g i v e a dark brown gum ( a p p r o x i m a t e l y 3«1 g . ) . T h i s m a t e r i a l was chrbmatographed on alumina (175" g») and the d e s i r e d Imide e l u t e d w i t h benzene and benzene-ether ( l i : l ) as a l i g h t brown gum (2.02. g. - d r i e d t o c o n s t a n t w e i g h t , 77% y i e l d ) . A. s m a l l q u a n t i t y of t h i s m a t e r i a l was d i s t i l l e d under • vacuum t o p r o v i d e an a n a l y t i c a l sample as an almost c o l o r l e s s l i g h t brown g l a s s bp. 260-270°/0.005 mm (-bath temp,). -123 I n f r a r e d ( N u j o l ) : 3320 (NH), 1755 (medium), 1685 ( s t r o n g ) ( i m i d e ) 71+0 and 695 ( a r o m a t i c ) cm." 1. U l t r a v i o l e t , >- max (log & ): 222. (1+.57), 283 (3.79) ryu. NMR s i g n a l s : 1.9 (broad s i n g l e t , I H , N H ) , 2.7 ( m u l t i p l e t , 9H, a r o m a t i c ) , 3.00 ( d o u b l e t ^ l H , c < - p r o t o n o f i n d o l e ) , 5.55 ( s i n g l e t , 2H, C A H £ C H 20-), 6.20 ( t r i p l e t , 2H, -CH 2N) S 6.65 ( m u l t i p l e t , 2H, C A H 5 C H 2 0 C H 2 - ) , 9.15 ( t r i p l e t , 3H, - C H 2 C H 3 ) . Mass spectrum: M.W. 1+18; main peaks?, m/e 11+1+, 11+3, 130,91. Found: C, 71+.81; Hp 7..1+0; N, 6.52. " C a l c . f o r C ^ H ^ N ^ : Cg 71+.61; H, 7.23; N s 6.69. N-f_ / 8-(3-Indolyl)-ethyl J-3-(2-benzyloxymethylbutyl )-p y r r o l i d i n e (13U The imide (130) (925 mg., 2.21 m moles) in dry tetrahydro-furan (25 ml) was added to a s t i r r e d suspension of l i t h i u m aluminum hydride (250 mg., 6.60 m moles) In dry tetrahydrofuran (25 ml), and the r e s u l t i n g mixture refluxed with s t i r r i n g under dry nitrogen f o r 8-§- hours. The reduction product was then cooled in cold water and the excess lithium aluminum hydride destroyed by the careful addition of cold wet t e t r a -hydrof uran. The mixture was allowed to warm to room temperature and after allowing to stand for a few minutes i t was f i l t e r e d through Gelite to remove InoEganic s a l t s . The Gellte was then washed well with hot tetrahydrofuran and the combined f i l t r a t e and washings were dried over anhydrous sodium s u l f a t e . Evapora-tion of the solvent yielded the crude amine (925 mg) as a pale yellow o i l . Chromatography of this material on alumina -124-( 5 0 g o ) and e l u t i o n w i t h benzene and benzene-ether (I4. t X ) p r o v i d e d the pure amine ( 8 l 5 mg. - d r i e d t o c o n s t a n t w e i g h t , 9 5 $ y i e l d ) as a v e r y p a l e y e l l o w gum which g r a d u a l l y darkened upon s t a n d i n g . ".Vacuum d i s t i l l a t i o n o f a s m a l l q u a n t i t y p r o v i d e d an a n a l y t i c a l sample bp. 2 1 + 0 - 2 5 0 ° , ( b a t h temp.)/ 0 o 0 0 5 mm. as a c l e a r c o l o r l e s s g l a s s . I n f r a r e d ( n e a t ) : 3 3 5 0 (NH), 7 3 5 and 6 9 5 ( a r o m a t i c K'cm."1. U l t r a v i o l e t a >max ( l o g e ) : 2 2 2 ( 4 . 5 6 ) , 2 8 3 ( 3 » 8 0 ) mMo NMR s i g n a l s ( 1 0 0 Mc/s): 1 . 5 5 (broad s i n g l e t , I H , NH), 2 . 7 5 ( m u l t i p l e t , 9H, a r o m a t i c ) , 3 . 1 1 ( d o u b l e t , I H , c* - p r o t o n of i n d o l e = c o l l a p s e s t o s i n g l e t upon a d d i t i o n o f D 2 0 ) , 5 - 5 5 ( s i n g l e t , 2H, C^CH^O-•) 9 6 . 7 0 (doublet^, 2H, C A H 5 C H 2 0 C H 2 - ) 9 9 . 1 5 ( t r i p l e t , 3H, -CHgCH-j) „ Mass spectrum: base peak m/e 2 6 0 , s t r o n g m/e 9 1 . Found: C , 8 0 . 0 2 ; H, 8 . 8 2 ? N, 7 . 3 5 . G a l e , f o r C 2 6 H 3 4 N 2 O : C, 7 9 . 9 5 ; H, 8 . 7 8 ; N, 7 ° 1 7 . M o l e c u l a r wt. 3 9 0 . 2 6 7 ( C a l c . 3 9 0 . 2 6 7 ) . M e r c u r i c A c e t a t e O x i d a t i o n o f the Amine ( 1 3 1 ) M e r c u r i c a c e t a t e ( 3 . 4 0 g . , 0 . 0 1 0 7 moles) and the amine 1 3 1 ( 5 0 0 mg., 1 " 0 2 8 m moles) were r e f l u x e d i n anhydrous methanol ( 2 6 0 ml) c o n t a i n i n g g l a c i a l a c e t i c a c i d ( 7 . 5 ml) f o r 4i- hours under h i g h l y p u r i f i e d n i t r o g e n ("L" g r a d e , Canadian L i q u i d A i r L t d . ) The r e a c t i o n was f o l l o w e d by p e r i o d i c a l l y t r e a t i n g an a l i q u o t o f the m i x t u r e w i t h hydrogen s u l f i d e gas and o b s e r v i n g the development o f the a b s o r p t i o n peak o f the s u p e r n a t a n t , a t 3 5 3 m/*. The r e s u l t a n t g r e e n i s h - y e l l o w m i x t u r e was a l l o w e d t o c o o l and 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 1 d i s c (medium p o r o s i t y ) , i n t o a 3-necked round bottomed -125-f l a s k , to remove the mercurous a c e t a t e ( l e l 8 g», 1.8 m o l e s ) . The f i l t r a t e was warmed t o a p p r o x i m a t e l y 50°, a f l o w of p u r i f i e d n i t r o g e n b e i n g c o n t i n u o u s l y passed t h r o u g h one neck of the f l a s k p then hydrogen s u l f i d e gas bubbled i n t o the s o l u t i o n f o r 15 minutes t o d e s t r o y mercury complexes. The r e s u l t a n t p r e c i p i t a t e of mercury s u l f i d e s was removed by f i l t r a t i o n , under a n i t r o g e n atmosphere t h r o u g h a n o t h e r s i n t e r e d g]a ss d i s c '-as d e s c r i b e d above except t h a t C e l i t e was used as a f i l t e r a i d and a h i g h vacuum ( o i l pump) w;as employed t o a i d f i l t r a t i o n . I t Is i m p o r t a n t t o emphasize t h a t optimum y i e l d s In t h i s r e a c t i o n are o b t a i n e d o n l y i f the e n t i r e o p e r a t i o n d e s c r i b e d above i s conducted under an i n e r t atmosphere. F o r t h i s purpose^ an ap p a r a t u s c o n s i s t i n g of a s e r i e s of t h r e e - n e c k e d f l a s k s i n t e r c o n n e c t e d by bent a d a p t e r s , which a l r e a d y c o n t a i n e d the s i n t e r e d g l a s s d i s c s , was used. In t h i s manner, a d d i t i o n o f r e a g e n t s , f i l t r a t i o n , e t c . , c o u l d be c o n v e n i e n t l y c a r r i e d out under an atmosphere of dry n i t r o g e n . Sodium b o r o h y d r i d e (2.2 g.) was i m m e d i a t e l y added t o the f i l t r a t e and the s o l u t i o n s t i r r e d under n i t r o g e n f o r [|. hours a f t e r w h i c h time the a b s o r p t i o n peak at 353 m/zhad c o m p l e t e l y d i s a p p e a r e d . The s o l u t i o n was then c o n c e n t r a t e d t o a p p r o x i m a t e l y 20 ml and p a r t i t i o n e d between c h l o r o f o r m and w a t e r . The aqueous l a y e r was e x t r a c t e d t w i c e more w i t h c h l o r o -form, the e x t r a c t s combined and washed t w i c e w i t h w a t e r , t w i c e w i t h 5$ sodium h y d r o x i d e s o l u t i o n and t w i c e more w i t h -126-w a t e r . A f t e r d r y i n g over anhydrous sodium s u l f a t e , the c h l o r o f o r m was e v a p o r a t e d t o y i e l d a brown gum (J+30 mg) whic h was chromatographed on alumina (20 g o ) . E l u t l o n w i t h benzene:ether ( l i : l and 1:1) removed a m i x t u r e o f the c y c l i z e d b e n z y l e t h e r s o f i n c r e a s i n g p o l a r i t y and these were d e s i g n a t e d A, B, C, c' (C and C* were i n d i s t i n g u i s h a b l e by t h i n l a y e r chromatography•on a l u m i n a ) and D as w e l l as u n c y c l i z e d s t a r t i n g m a t e r i a l ( t o t a l 175 mg). I n i t i a l l y a m i x t u r e of isomers A and B w;as o b t a i n e d , f o l l o w e d by m i x t u r e s of isomers B, C, C~ and a s m a l l amount of u n c y c l i z e d m a t e r i a l , E l u t l o n w i t h methanol y i e l d e d an a d d i t i o n a l m i x t u r e of isomers C, C' and D a l o n g w i t h some p o l a r m a t e r i a l , ( t o t a l 160 mg) whi c h was r e -chromatographed t o g i v e a d d i t i o n a l isomers C, c' and D (35 mg„)o The t o t a l weight o f the c y c l i z e d p r o d u c t was 210 mg ( y i e l d 37% based on an e s t i m a t e by t h i n - l a y e r chromatography of 20% u n c y c l i z e d m a t e r i a l b e i n g p r e s e n t ) . T h i s t o t a l m i x t u r e was used f o r the p r e p a r a t i o n of the c o r r e s p o n d i n g a l c o h o l s . S m a l l q u a n t i t i e s of pure b e n z y l e t h e r s were o b t a i n e d by p r e p a r a t i v e t h i n - l a y e r chromatography (as d e s c r i b e d below) of t h e p a r t i a l l y s e p a r a t e d m i x t u r e s o b t a i n e d above by column chromatography. A m i x t u r e o f one o f the minor isomers A and one of the major isomers B (16 mg) were s p o t t e d on a t h i n - l a y e r c h r o m a t o p l a t e ( a l u m i n a , 20 x 20 cm.,. 0„3 mm t h i c k n e s s ) and developed i n b e n z e n e : e t h y l a c e t a t e (2.5:1). The developed p l a t e was examined under u l t r a v i o l e t l i g h t w h i l e s t i l l w e t s -127-and the bainds c o r r e s p o n d i n g t o isomers A" and B s c r a p e d o f f and e x t r a c t e d s e p a r a t e l y w i t h methanol. The e x t r a c t s were 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 d i s c , washing w e l l w i t h methanol and the f i l t r a t e s e v a p o r a t e d t o d r y n e s s 0 The r e s u l t a n t r e s i d u e s were taken up i n anhydrous e t h e r and removed from any alumina by means of a p i p e t . E v a p o r a t i o n o f the e t h e r s o l u t i o n s p r o v i d e d pure isomer A (3 mg) as a m i x t u r e of c r y s t a l s and gum, U l t r a v i o l e t , . > max: 226, 274 ( s h ) , 283, 291 m,Uo M o l e c u l a r weight 388,251° C a l c . f o r G 2 6 H32 N2°-388,251 and pure isomer B (9 mg), as a p a l e green g l a s s . I n f r a r e d ( f i l m ) : 32I4.O (-NH), 740 and 695 ( a r o m a t i c ) cm," 1. U l t r a v i o l e t , > maxt 226, 275 ( s h ) , 283, 291 HVM, NMR s i g n a l s (100 Mc/s):: 0.50 ( s i n g l e t , I H , -NH), 2,5-3°5 ( m u l t i p l e t , a r o m a t i c ) , 5°30 ( s i n g l e t , 2H, C^H^CHgO-), 5„60' (broad d o u b l e t a p p r o x i m a t e l y I H , CC-3H), 6,32 ( q u a r t e t , C A H 5 C H 2 O C H 2 - ) , 9,10 ( t r i p l e t , - C H 2 C H 3 ) , M o l e c u l a r w e i g h t : 388,252. The f r a c t i o n s as o b t a i n e d In the above column chromato-graphy and w h i c h appeared I n i t i a l l y t o be a pure e t h e r C were found by t h i n l a y e r chromatography on . s i l i c a g e l (methanol) t o c o n t a i n another minor isomer now d e s i g n a t e d (1 . A m i x t u r e of these two isomers (30 mg) was s e p a r a t e d by p r e p a r a t i v e t h i n - l a y e r chromatography on s i l i c a g e l (20 x 20 cm,, 0,3 mm, m e t h a n o l ) . The bands were s e p a r a t e d as d e s c r i b e d above t o p r o v i d e the pure major isomer C (13 mg) as a c l e a r p a l e green g l a s s . I n f r a r e d ( f i l m ) : 3300 (-NH), 740 and 695 ( a r o m a t i c ) cm," 1. U l t r a v i o l e t , > max: 225, 273 ( s h ) , 282, 290 m/x. - 1 2 8 NMR s i g n a l s ( 1 0 0 Mc/s): l o 8 0 ( s i n g l e t , I H, -NH), 2 , 5 ~ 3 ° 1 ( m u l t i p l e t , 9 H , a r o m a t i c ) , no d o u b l e t at 3 ° 1 1 , 5 ° 6 0 ( s i n g l e t , 2H, C A H 5 G H 2 O - ) , 5 ° 7 5 (broad m u l t i p l e t , I H , C - 3 H ) , 6 , 8 ( d o u b l e t , C6H5-GH2OCH2-),.. 9.25 ( t r i p l e t , 3H , - C H 2 C H 3 ). M o l e c u l a r w e i g h t r 3 8 8 o . 2 ' 5 2 and pure isomer C ( 3 mg) as a c l e a r p a l e green g l a s s . U l t r a v i o l e t , Mnax 22.5,. 2 ? 5 ( s h ) , 2 8 2 , 5 , 290.5 m/*:. M o l e c u l a r w e i g h t 3 8 8 . H y d r o g e n o l y s l s o f the M i x t u r e o f C y c l i z e d B e n z y l E t h e r s A m i x t u r e o f the b e n z y l e t h e r s o b t a i n e d as d e s c r i b e d above ( 2 3 5 mg) and p a l l a d i u m ( 2 3 5 mg, 1 0 $ on c h a r c o a l ) i n g l a c i a l a c e t i c a c i d ( 2 5 ml) was s t i r r e d under an atmosphere o f hydrogen f o r 3 i f hours a f t e r w h i c h time the uptake had e s s e n t i a l l y ceased ( a p p r o x i m a t e l y 8 0 $ of the t h e o r e t i c a l amount consumed). The c a t a l y s t was removed by f i l t r a t i o n and the a c e t i c a c i d e v a p o r a t e d i n vacuo. The r e s i d u a l gum was taken up i n c h l o r o -form, the l a t t e r washed w i t h 5 $ sodium h y d r o x i d e s o l u t i o n , then t w i c e w i t h water and f i n a l l y d r i e d over anhydrous sodium s u l f a t e . E v a p o r a t i o n of the c h l o r o f o r m y i e l d e d a p a l e orange gum ( 1 6 5 mg,) which by t h i n - l a y e r chromatography ( a l u m i n a , e t h y l a c e t a t e , antimony p e n t a c h l o r i d e i n carb o n t e t r a c h l o r i d e , 1 : 1 as s p r a y r e a g e n t ) showed the presence of u n r e a c t e d b e n z y l e t h e r s as w e l l as a m i x t u r e of more p o l a r green s p o t s and one p o l a r brown s p o t . The crude p r o d u c t was chromat'ographed on alu m i n a ( 1 0 g,, d e a c t i v a t e d w i t h 0 , 5 ml, 1 0 $ a c e t i c a c i d ) , E l u t l o n w i t h benzene: e t h y l e t h e r ( 1 : 1 ) removed the u n r e a c t e d b e n z y l e t h e r s ( 6 5 mg,. 2 8 $ r e c o v e r y ) . E t h e r : methanol (99?1) removed a m i x t u r e of t h e - 1 2 9 -a l c o h o l s d e s i g n a t e d A. and B (21 mg) and e t h e r : methanol ( 9 8 „ 2 ) removed a m i x t u r e of a l c o h o l s B and B (5 mg). C o n t i n u e d e l u t l o n w i t h e t h e r : m e t h a n o l ( 9 8 , 2 and 9 5 ° 5 ) removed a f u r t h e r m i x t u r e of a l c o h o l s B, B and the u n c y c l i z e d amino a l c o h o l ( l i 9 mg). The u n c y c l i z e d amino a l c o h o l was i d e n t i c a l , by t h i n - l a y e r chromatography t o t h a t p r e p a r e d by h y d r o g e n o l y s i s of a s m a l l amount of u n c y c l i z e d b e n z y l e t h e r . E l u t i o n w i t h e t h e r rme than o l ( 9 5 " : 5" t o 9 : 1 ) then removed the major pure c y c l i z e d a l c o h o l C ( 2 6 mg) as an amorphous w h i t e s o l i d w h i l e e l u t l o n w i t h e t h e r ; m e t h a n o l ( l i : l ) removed r e s i d u a l a l c o h o l C ( 6 mg). A l t h o u g h a v e r y minor a l c o h o l d e s i g n a t e d D was observed i n t h i n - l a y e r chromatography of the crude p r o d u c t as b e i n g more p o l a r than C 5 t h i s m a t e r i a l was not r e c o v e r e d from the column. The t o t a l w eight of the amino a l c o h o l s (10? mg) r e p r e s e n t e d an 8 3 % y i e l d . Rechromatography of the m i x t u r e of c y c l i z e d a l c o h o l s B, B and the u n c y c l i z e d amino a l c o h o l a l l o w e d complete s e p a r a t i o n o f these c y c l i z e d a l c o h o l s from the u n c y c l i z e d a l c o h o l s . • A l c o h o l C. I n f r a r e d (CHCT^): 3 5 0 0 , 3 3 5 0 , 3 1 5 0 (-NH and ~0H) cm.' 1. U l t r a v i o l e t , > max: 2 2 5 , 2 7 3 ( s h ) , 2 8 2 , 2 9 0 rajj. NMR s i g n a l s ( 1 0 0 Mc/s ) r Oj+O (-NH), 2 . 5 - 3 . 0 ( m u l t i p l e t , LLH, a r o m a t i c ) , 5 * 7 8 ( m u l t i p l e t , 1H, G-3H), 6 . 6 1 (broad s i n g l e t , -CH 20H), 9 o l 8 ( d i s t o r t e d t r i p l e t , 3H,- -CHjCH^) „ M o l e c u l a r w e i g h t : 2 9 8 . 2 0 3 . C a l c . f o r C 1 9 H 2 6 N 2 0 ? 2 9 8 . 2 0 5 . P r e p a r a t i v e t h i n - l a y e r chromatography of a m i x t u r e of a l c o h o l s A and B ( 3 0 mg) on s i l i c a g e l ( 2 0 x 2 0 cm., 0 . 3 mm, - 1 3 0 -methanol) was performed. The bands removed from the p l a t e were e x t r a c t e d w i t h methanol and f i l t e r e d . E v a p o r a t i o n of the f i l t r a t e p r o v i d e d r e s i d u e s which were ta k e n up i n c h l o r o f o r m to remove any s i l i c a g e l and the s o l v e n t evaporated a g a i n t o y i e l d pure a l c o h o l A (9 mg) and pure a l c o h o l B (16 mg) b o t h as wh i t e amorphous s o l i d s . P r e p a r a t i v e t h i n - l a y e r chromatography on a m i x t u r e of a l c o h o l s B and B (11 mg) u s i n g the same c o n d i -t i o n s p r o v i d e d an a d d i t i o n a l q u a n t i t y of pure a l c o h o l B (5 mg) and pure a l c o h o l B (2 mg) as amorphous s o l i d s . A l c o h o l A.- U l t r a v i o l e t , ^ max: 226, 273 ( s h ) , 282,5, 290.5.m/(, M o l e c u l a r w e i g h t ? 298.205. A l c o h o l B. ' I n f r a r e d (CHC1 3): 3^4-00, 3330, 3200 (-NH and -OH) cm," 1. U l t r a v i o l e t , > max: 22:6, 274 ( s h ) , 283, 291 m/A NMR s i g n a l s (100 M c / s ) : 2„50-3»l5 ( m u l t i p l e t , a p p r o x i m a t e l y I+H, a r o m a t i c ) , 5.72 ( d o u b l e t , 0.7H, C-3H), 9.15 ( t r i p l e t , . -CH 2CH 3)„ M o l e c u l a r weight:. 298.205. A l c o h o l fi'. U l t r a v i o l e t , > max: 226, 27k ( s h ) , 282.5, 290.5 m/^ o M o l e c u l a r w e i g h t : 298„20ILC  H y d r o g e n o l y s l s o f C y c l i z e d B e n z y l E t h e r C The e t h e r C (8 mg) o b t a i n e d pure by p r e p a r a t i v e t h i n - l a y e r chromatography as d e s c r i b e d e a r l i e r was t r e a t e d w i t h p a l l a d i u m c a t a l y s t a c c o r d i n g t o the procedure used above f o r the i s o m e r i c m i x t u r e . The pro d u c t o b t a i n e d (5 mg) was i d e n t i c a l by t h i n -l a y e r chromatography ( a l u m i n a , e t h y l a c e t a t e , s i l i c a g e l , methanol) t o a l c o h o l C i s o l a t e d from the h y d r o g e n o l y s l s o f the m i x t u r e o f e t h e r s and d i f f e r e n t from the i s o m e r i c a l c o h o l s A, - 1 3 1 -B and B»„ M e s y l a t i o n o f A l c o h o l G A. s o l u t i o n of the a l c o h o l C (1+3 mg) i n d r y p y r i d i n e ( 0 . 3 m l 9 d i s t i l l e d from p o t a s s i u m h y d r o x i d e ) was c o o l e d i n an i c e bath and added t o i c e - c o l d me t h a n e s u l f o n y l c h l o r i d e (120 mg) i n a s m a l l t e s t - t u b e . The r e s u l t a n t l i g h t orange s o l u t i o n was a l l o w e d t o stand i n a r e f r i g e r a t o r f o r 16 hours a f t e r w h i c h time the s o l u t i o n was dark r e d . The m a j o r i t y o f the p y r i d i n e was e v a p o r a t e d under a s t r e a m of n i t r o g e n w i t h the a i d of s l i g h t warming, and the l a s t t r a c e s f i n a l l y removed on an o i l pump. The gummy red r e s i d u e was washed t w i c e w i t h anhydrous e t h e r , t r e a t e d w i t h w a t e r (0.5 ml) which appeared t o p a r t i a l l y d i s s o l v e the p r o d u c t , and washed t w i c e f u r t h e r w i t h benzene. Ammonium h y d r o x i d e (1 m l , 6N) was added and t h e aqueous m i x t u r e e x t r a c t e d t h o r o u g h l y w i t h c h l o r o f o r m ( u n t i l the c o l o r o f the e x t r a c t was o n l y p a l e y e l l o w ) . The r e s u l t a n t d a r k r e d c h l o r o -form was d r i e d q u i c k l y over anhydrous sodium s u l f a t e and evap o r a t e d t o p r o v i d e a dark r e d gum (60 mg). T h i n - l a y e r chromatography ( a l u m i n a , e t h y l a c e t a t e , antimony p e n t a c h l o r i d e s p r a y ) showed the complete absence of the s t a r t i n g a l c o h o l (Rj. 0.25-0.30) and the presence of a l e s s p o l a r green s p o t (Rj:0„70) as w e l l as a green s p o t on the base l i n e . U l t r a v i o l e t , >maxr 226, 282, 289 ( s h o u l d e r at 273 d i s t o r t e d , p r o b a b l y due t o presence of p y r i d i n e ) . T h i s p r o d u c t was a l l o w e d t o stand i n a vacuum d e s s i c a t o r f o r \\ days a f t e r w h i c h time I t was v e r y h y g r o s c o p i c and t h i n - l a y e r chromatography i n d i c a t e d a c o n s i d e r a b l e I n c r e a s e i n . i n t e n s i t y of the base l i n e spot r e l a t i v e - 1 3 2 -t o the spot which was l e s s p o l a r t h a n the s t a r t i n g a l c o h o l , R e f l u x i n g the m a t e r i a l i n ch l o r o f o r m , f o r a few minutes d i d not n o t i c e a b l y a l t e r the r e l a t i v e q u a n t i t i e s of t h e s e two s p o t s so t h i s m a t e r i a l was used f o r the f o l l o w i n g r e d u c t i o n . R e d u c t i o n o f the Q u a t e r n a r y M e s y l a t e (73s 1) The m e s y l a t e o b t a i n e d as d e s c r i b e d above (30 mg) was p l a c e d i n a round bottom t h r e e - n e c k e d f l a s k equipped w i t h a dry i c e t r a p and an ammonia i n l e t , ( T h i s o p e r a t i o n was c a r r i e d out as r a p i d l y as p o s s i b l e but the amorphous mesylate t u r n e d gummy v e r y q u i c k l y ) , A'mmonia (5 ml) was run i n t o the f l a s k and sodium (50 mg) added t o t h e s u s p e n s i o n . The r e s u l t i n g b l u e s o l u t i o n was s t i r r e d f o r 20 minutes t h e n quenched w i t h ammonium c h l o r i d e . The ammonia was a l l o w e d t o e v a p o r a t e and the r e s i d u e p a r t i t i o n e d between c h l o r o f o r m and w a t e r . The l a y e r s were s e p a r a t e d and the c h l o r o f o r m l a y e r washed t h r e e times w i t h w a t e r and d r i e d over anhydrous sodium s u l f a t e . E v a p o r a t i o n of t h e c h l o r o f o r m p r o v i d e d a brown r e s i d u e (20 mg) , Chromatography of t h i s m a t e r i a l on a l u m i n a (1.0 g) and e l u t i o n w i t h benzene removed the major pr o d u c t (8 mg) w h i c h by t h i n - l a y e r chromatography on s i l i c a g e l ( c h l o r o f o r m ? e t h y l a c e t a t e , 1:1, antimony p e n t a c h l ' o r i d e ) c o n t a i n e d b o t h !|<x - and 1+/3 - d i h y d r o c l e a v a m i n e as w e l l as a t h i r d component which had an Rj: v a l u e i n t e r m e d i a t e between the two cleavamine d e r i v a t i v e s . •The above proc e d u r e was r e p e a t e d on the r e m a i n i n g mesylate (28 mg) t o y i e l d an a d d i t i o n a l i d e n t i c a l m i x t u r e (7 mg). The combined p r o d u c t s (15 mg) were chromatographed on 133 alumina (10 g„, Wbelm), E l u t l o n w i t h e t h e r y i e l d e d pure [LD(-d i h y d r o c l e a v a m i n e (1 mg) which was i d e n t i c a l t o an a u t h e n t i c sample (mass s p e c t r o m e t r y , t h i n - l a y e r chromatography on s e v e r a l systems - s i l i c a g e l , c h l o r o f o r m : e t h y l a c e t a t e 1:1, antimony p e n t a c h l o r i d e and 1% e e r i e ammonium s u l f a t e i n Q$%> p h o s p h o r i c a c i d as s p r a y r e a g e n t s ; a l u m i n a , p e t r o l e u m e t h e r :benzene 1L:1, same s p r a y reagents). C o n t i n u e d e l u t l o n w i t h e t h e r removed a m i x t u r e o f the t h r e e compounds (8 mg) w h i c h was then f u r t h e r purified„ P r e p a r a t i v e t h i n - l a y e r chromatography on s i l i c a g e l (20 x 20 cm, 9 0„3 mm, c h l o r o f o r m : e t h y l a c e t a t e 1:1) was performed on t h i s m i x t u r e . As the bands c o r r e s p o n d i n g t o Ily^-dihydrocleavamine and the unknown compound o c c u r r i n g between the two d i h y d r o c l e a v a m i n e s o v e r l a p p e d e x t e n s i v e l y , o n l y the v e r y top p o r t i o n of the d e s i r e d band was removed and e x t r a c t e d w i t h methanol. E x t r a c t i o n o f the r e s i d u e uponremoval of the methanol, w i t h c h l o r o f o r m and e v a p o r a t i o n of the s o l v e n t p r o v i d e d pure iiyg-dihydrocleavamine (1 mg) w h i c h was i d e n t i c a l t o an a u t h e n t i c sample (mass s p e c t r o m e t r y , t h i n - l a y e r chromatography In s e v e r a l systems - s i l i c a g e l , c h l o r o f o r m : e t h y l a c e t a t e . 1:1, and a l u m i n a , p e t r o l e u m ether:benzene IL:1, u s i n g s p r a y s mentioned above). 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