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UBC Theses and Dissertations

Synthetic studies of indole alkaloids Abdurahman, Nizam 1967

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The U n i v e r s i t y of B r i t i s h Columbia .FACULTY OF GRADUATE STUDIES PROGRAMME OF THE FINAL ORAL EXAMINATION FOR THE DEGREE OF DOCTOR OF PHILOSOPHY of (NIZAM ABDURAHMAN A.R.C.S.T., University^ of Strathclyde, Glasgow, Scotland M.Sc, U n i v e r s i t y of B r i t i s h Columbia WEDNESDAY, SEPTEMBER 13, at 3:30 p.m. IN ROOM 225, CHEMISTRY BUILDING COMMITTEE IN CHARGE Chairman: B.N. Moyls E. Piers G.G.S. Dutton W. Cullen C.A. McDowell J. Schaeffer M. Smith External Examiner: W.A. Ayer Department of Chemistry U n i v e r s i t y of Alberta Edmonton, Alberta Research Supervisor: J.P. Kutney SYNTHETIC STUDIES OF INDOLE' ALKALOIDS . ABSTRACT Novel transannualr c y c l i s a t i o n reactions of nine-membered r i n g compounds l i k e quebrachamine, dihydrocleav-amine and carbomethoxydihydrocleavamine, previously described in this laboratory, provide an a t t r a c t i v e entry into the Aspidosperma, Vinca and Iboga a l k a l o i d s . In--this thesis two approaches to the synthesis of the nine-membered r i n g a l k a l o i d , quebrachamine, are described. The f i r s t section of this thesis discusses the synthesis of model compounds suitable for evaluating the acyloin condensation for the synthesis of t h i s a l k a l o i d . For this purpose, 3-carbomethoxypiperidine (98) was prepared by three d i f f e r e n t routes. In sequence (a), n i c o t i n i c acid (109) was methylated to give methyl nico-tinate (110) , which on c a t a l y t i c hydrogenation yielded (98). In sequence (b) , n i c o t i n i c a c i d was reduced i n the presence of d i l u t e aqueous ammonia and 5% rhodium on charcoal to provide nipecotic acid (111). E s t e r i f i -cation with diazomethane provided the desired p i p e r i d i n e (98). In sequence ( c ) , the desired material was prepared by an e s t e r i f i c a t i o n reaction of nipecotic acid hydro-chloride (111,a). The formation of the intermediate arylhydrazone (108,a) was accomplished v i a a Japp-KLingemann reaction from d i e t h y l #-chloropropylmalonate (108) and benzene-diazonium c h l o r i d e . The arylhdrazone (108,a) was then treated under the conditions of the Fischer indole synthesis to provide 2-carbo~ethoxy-3-(g-chloroethyl) -indole (97,a). T r a n s e s t e r i f i c a t i o n with methanol provided 2-carbomethoxy-3-(/3-chloroethyl)-indole (97,b). The pipe r i d i n e d e r i v a t i v e (98) was coupled with (97,a) and (97,b) to provide the coupling products (99,R=Et) and (99,R=Me). Attempted acylo i n condensations of these l a t t e r compounds to provide the nine-membered r i n g compound (100) are described. The second section of t h i s thesis describes a new t o t a l synthesis of (dl)-quebrachamine v i a a completely d i f f e r e n t sequence. Diethyl }f-benzyloxypropylethylmalo-nate (144) was preparedcby the condensation between - d i e t h y l ethylmalonate and l-chloro-3-benzyloxypropane (143.). A l k a l i n e hydrolysis of (144) -provided tf-benzyl-oxpropylethyl malonic acid (145), whichwas decarboxylated to give 2-( #-berizyloxypropyl)-butarioic acid (146). Ester i f i c a t i o n of (146) provided ethyl 2-(jf-benzyloxy-propyl)-butanoate (147), which by subsequent a l k y l a t i o n with triphenylmethyl sodium and e t h y l bromoacetate gave ethyls- (jj-benzyloxyprqpyl) - i - e t h y l s u c c i n a t e (148). Condensation of (148) with ttyptamine provided N- I3 L -(3-indolyl)-ethyl^)-c<.-(g-benzyloxypropyl) — e t h y l s u c -cinimide (123), which was reduced with l i t h i u m aluminum hydride to y i e l d N-CS-(3-indolyl)-ethyl_}-3-(tf-benzyloxy-propyl)-3-ethylpyrrolidine (124). i , Thy uncyclised benzyl ether.amine (124) was treated with an excess of mercuric, acetate to provide a crude product which was immediate_ly-reduced with sodium boro-hydride to give a mixture of the isomeric c y c l i c benzyl ether amines (125). C a t a l y t i c debenzylation provided three separable aminoalcohols (164) A, B and C. The r e l a t i v e l y abundant aminoalcohol B was converted to the quaternary ammonium s a l t (126) by treatment with methan-esulfonyl chloride in pyridine. Ring cleavage of (126) with sodium and l i q u i d ammonia yie l d e d (dl)-quebrachamine (1) . iPUBLICATIONS „ Abdurahman, D.A. A'pplegarth, G.G.S.-Dutton, D. McLardy, K.E. P i e r r e and B.I. Stephenson, Hemicelluloses of Four Coniferous Trees, Tappi, 47, 812 (1964) . P. Kutney, N. Abdurahman, P. LeQuesne, E. Piers and I. V l a t t a s , A New T o t a l Synthesis of (dl)-Quebracha-mine and (dl)-Aspidospermidine. A General Entry into the Aspidosperma A l k a l o i d s . J. Am. Chem. Soc. 88, 3656 (1966) GRADUATE STUDIES i e l d of Study: Chemistry Topics i n Organic Chemistry R. Bonnett R. Stewart J.P. Kutney Topics i n Physical Chemistry Topics i n Inorganic Chemistry Carbohydrate Chemistry Physical Organic Chemistry Recent Synthetic Methods i n Organic Chemistry Seminar i n Chemistry Organic Reaction Mechanism Heterocyclic Compounds A l k a l o i d Chemistry Isoprenoid Compounds Structure of Newer Natural Products .elated Studies: Organic Medicine Products J.A.R.' Coope R.F. Snider N. B a r t l e t t W.R. Cullen C. W i l l i s L.D. Hayward G.GiS. Dutton R. Stewart R.E. Pincock D.E. McGreer W. McRae J.P. Kutney R.E. Pincock F. McCapra J.P. Kutney T. Money T. Money T.H. Brown SYNTHETIC STUDIES OF INDOLE ALKALOIDS by NIZAM ABDURAHMAN A.R.C.S.T.. , U n i v e r s i t y of S t r a t h c l y d e , Glasgow, S c o t l a n d , 1958 M.Sc., U n i v e r s i t y of B r i t i s h Columbia, 1962 A THESIS SUBMITTED IN PARTIAL FULFILMENT OF THE REQUIREMENTS FOR THE DEGREE OF DOCTOR OF PHILOSOPHY 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 UNIVERSITY OF BRITISH COLUMBIA JUNE, 1967 In p r e s e n t i n g t h i s t h e s i s i n p a r t i a l f u l f i l m e n t o f t h e r e q u i r e m e n t s f o r an a d v a n c e d d e g r e e a t t h e U n i v e r s i t y o f B r i t i s h C o l u m b i a , I a g r e e t h a t t h e L i b r a r y s h a l l make i t f r e e l y a v a i l a b l e f o r r e f e r e n c e a nd S t u d y . I f u r t h e r a g r e e t h a t p e r m i s s i o n f o r e x t e n s i v e c o p y i n g o f t h i s t h e s i s f o r s c h o l a r l y p u r p o s e s may be g r a n t e d b y t h e Head o f my D e p a r t m e n t o r b y h.iJs r e p r e s e n t a t i v e s . I t i s u n d e r s t o o d t h a t c o p y i n g o r p u b l i c a t i o n o f t h i s t h e s i s f o r f i n a n c i a l g a i n s h a l l n o t be a l l o w e d w i t h o u t my w r i t t e n p e r m i s s i o n . D e p a r t m e n t The U n i v e r s i t y o f B r i t i s h C o l u m b i a V a n c o u v e r 8, C a n a d a ABSTRACT N o v e l t r a n s a n n u l a r c y c l i s a t i o n r e a c t i o n s of 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 arid c arbomethoxydihydrocleavamine, p r e v i o u s l y d e s c r i b e d i n t h i s l a b o r a t o r y , p r o v i d e an a t t r a c t i v e e n t r y i n t o the Aspidosperma, V i n c a and Iboga a l k a l o i d s . I n t h i s t h e s i s two approaches t o the s y n t h e s i s of the nine-membered r i n g a l k a l o i d , quebrachamine, are d e s c r i b e d . The f i r s t s e c t i o n of t h i s t h e s i s d i s c u s s e s the s y n t h e s i s of model compounds s u i t a b l e f o r e v a l u a t i n g the a c y l o i n c o n d e n s a t i o n f o r the s y n t h e s i s of t h i s a l k a l o i d . F o r t h i s purpose, 3 - c a r b o m e t h o x y p i p e r i d i n e (98) was prepared by t h r e e d i f f e r e n t r o u t e s . I n sequence (a)., n i c o t i n i c a c i d (109) was m e t h y l a t e d t o g i v e m e t h y l n i c o t i n a t e ( 1 1 0 ) , which on c a t a l y t i c h y d r o g e n a t i o n y i e l d e d ( 9 8 ) . I n sequence ( b ) , n i c o t i n i c a c i d was reduced i n the presence of d i l u t e aqueous ammonia and 5$ rhodium on c h a r c o a l t o p r o v i d e n i p e c o t i c a c i d ( i l l ) . B s t e r i f i c a t i o n w i t h diazomethane 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 ( 9 8 ) . I n sequence ( c ) , the d e s i r e d m a t e r i a l was p r e p a r e d by an e s t e r i f i c a t i o n r e a c t i o n of 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 ( i l l , a ) . The f o r m a t i o n of the i n t e r m e d i a t e a r y l h y d r a z o n e (108,a) was a c c o m p l i s h e d v i a a Japp-KiLngemann r e a c t i o n from d i e t h y l y - c h l o r o p r o p y l m a l o n a t e (108) and benzenediazonium c h l o r i d e . The arylhldrazone (108,a) was t h e n t r e a t e d under the c o n d i t i o n s - i i i -o f the F i s c h e r i n d o l e s y n t h e s i s t o p r o v i d e 2 - c a r b o e t h o x y - 3 -( p - c h l o r o e t h y l ) - i n d o l e ( 9 7 , a ) . T r a n s e s t e r i f i c a t i o n w i t h methanol p r o v i d e d 2 - c a r b o m e t h o x y - 3 - ( P - c h l o r o e t h y l ) - i n d o l e ( 9 7 , b ) . The p i p e r i d i n e d e r i v a t i v e (98) was cou p l e d w i t h ( 9 7 ,a) and (97,b) t o p r o v i d e the c o u p l i n g p r o d u c t s ( 9 9 , R=Et) and ( 9 9 , R=Me). Attempted a c y l o i n c o n d e n s a t i o n s of the s e l a t t e r compounds t o p r o v i d e the nine-membered r i n g compound (100) are d e s c r i b e d . The second s e c t i o n of t h i s t h e s i s d e s c r i b e s a new t o t a l s y n t h e s i s of (dl)-quebrachamine v i a a c o m p l e t e l y d i f f e r e n t sequence. D i e t h y l tf-benzyloxypropylethylmalonate (144) was prepared by the c o n d e n s a t i o n between d i e t h y l e t h y l m a l o n a t e and l - c h l o r o - 3 - b e n z y l o x y p r o p a n e ( 1 4 3 ) . A l k a l i n e h y d r o l y s i s of (144) p r o v i d e d ^ - b e n z y l o x y p r o p y l e t h y l m a l o n i c a c i d ( 1 4 5 ) , which was d e c a r b o x y l a t e d t o g i v e 2 - ( t f - b e n z y l o x y p r o p y l ) - b u t a n o i c a c i d ( 1 4 6 ) . E s t e r i f i c a t i o n of (146) p r o v i d e d e t h y l 2-( tf-benzyloxypropyl)-butanoate ( 1 4 7 ) , which by subsequent a l k y l a t i o n w i t h t r i p h e n y l m e t h y l sodium and e t h y l bromoacetate gave e t h y l < < - ( ^ - b e n z y l o x y p r o p y l ) -c ^ e t h y l s u c c i n a t e (148). C o n d e n s a t i o n of (148) w i t h t r y p t a m i n e p r o v i d e d N - Q P - ( 3 - i n d o l y l ) - e t h y l ) -al-( fl-benzyloxypropyl )-oC-e t h y l s u c c i n i m i d e ( 1 2 3 ) , which was reduced w i t h l i t h i u m aluminum h y d r i d e t o y i e l d N - [ £ - ( 3 - i n d o l y l ) - e t h y l ] - 3 - ( t f - b e n z y l o x y p r o p y l ) -3 - e t h y l p y r r o l i d i n e ( 1 2 4 ) . The u n c y c l i s e d b e n z y l e t h e r amine (124) was t r e a t e d w i t h an excess of m e r c u r i c a c e t a t e t o p r o v i d e a crude product which was i m m e d i a t e l y reduced w i t h sodium b o r o h y d r i d e t o g i v e a - i v -m i x t u r e of the i s o m e r i c c y c l i c b e n z y l e t h e r amines (125). C a t a l y t i c d e b e n z y l a t i o n p r o v i d e d t h r e e s e p a r a b l e a m i n o a l c o h o l s (164) A, B.and C. The r e l a t i v e l y abundant a m i n o a l c o h o l B was c o n v e r t e d t o the q u a t e r n a r y ammonium s a l t (126) by tr 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 c h l o r i d e i n p y r i d i n e . R i n g cleavage of (126) w i t h sodium and l i q u i d ammonia y i e l d e d (dl)-quebrachamine ( -V-TABLE OF CONTENTS Page TITLE PAGE i ABSTRACT i i TABLE OF CONTENTS v LIST OF FIGURES v i i ACKNOWLEDGEMENTS x . INTRODUCTION .1 ( i ) B i o g e n e s i s . 2 ( i i ) ; S y n t h e s i s of P o s s i b l e B i o g e n e t i c S i g n i f i c a n c e 18 ( i i i ) P r e v i o u s S y n t h e t i c Approaches 23 DISCUSSION 32 I . Scheme A 32 ( i ) S y n t h e s i s of the I n d o l e M o i e t y 35 ( i i ) S y n t h e s i s of the P i p e r i d i n e M o i e t y 39 ( i i i ) C o u p l i n g R e a c t i o n s 41 ( i v ) A c y l o i n C o n d e n s a t i o n , 46 I I . Scheme B 50 ( i ) S y n t h e s i s of the S u c c i n a t e D e r i v a t i v e 53 ( i i ) C o n d e n s a t i o n w i t h Tryptamine 56 ( i i i ) C y c l i s a t i o n 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 . 57 ( i v ) R e d u c t i o n of the Imide 60 (v) O x i d a t i v e C y c l i s a t i o n 65 Page ( v i ) D e b e n z y l a t i o n of the B e n z y l E t h e r w i t h Boron T r i b r o m i d e . .- 70 ( y i i ) Quaternary Ammonium S a l t F o r m a t i o n 70. ( v i i i ) R i n g Cleavage R e a c t i o n . . . . 71 ( i x ) D e b e n z y l a t i o n of the B e n z y l E t h e r Amines by C a t a l y t i c H y d r o g e n o l y s i s 71 EXPERIMENTAL 81 BIBLIOGRAPHY 115 - v i i -LIST OF FIGURES F i g u r e Page 1 4 2 4 3 6 4 , 8 5 •. 9 6 . . . . 10 7 12 8 . . . 12 9 13 10 16 11 17 12 , 19 13 21 14 22 15 22 16 . . 24 18... 27 1 9 . . . . 28 20 29 21 , 30 22 30 23 31 - v i i i -F i g u r e Page 24 33 25 . ... 33 26 34 27 35 28 36 29 38 30 40 31 • 43 32 44 33 45 34.. 49 35 49 36 51 37 52 38 53 39 57 40 59 41 . ... 61 42 62 44 66 45 69 46 72 F i g u r e Page 47 74 48 75 49 76 50 77 5 1 . . . . 79 -X-ACKNOWLEDGEMENTS I w i s h t o ex p r e s s my s i n c e r e a p p r e c i a t i o n t o P r o f e s s o r J.P. Kutney f o r h i s e x c e l l e n t guidance and c o n s t a n t encouragement d u r i n g t he course of my r e s e a r c h . Thanks a r e a l s o due t o Dr. P. LeQuesne and Dr. E. P i e r s f o r t h e i r u s e f u l d i s c u s s i o n s . - F i n a n c i a l a i d from the U n i v e r s i t y of B r i t i s h Columbia and Ch e m c e l l (1963) L t d . i s v e r y g r a t e f u l l y acknowledged. INTRODUCTION At the dawn of e x p e r i m e n t a l o r g a n i c c h e m i s t r y j u s t over a c e n t u r y and a h a l f ago, S e r t u r n e r i s o l a t e d morphine from opium. A l t h o u g h he was not the f i r s t man t o i s o l a t e morphine, he d i d r e c o g n i s e i t t o have b a s i c p r o p e r t i e s , and r e f e r r e d t o i t as a " v e g e t a b l e a l k a l i " . M e i s n e r , i n 1818, proposed t h a t such " v e g e t a b l e a l k a l i s " s h o u l d be c a l l e d a l k a l o i d s . The noun became a c c e p t e d and today the word g e n e r a l l y denotes a b a s i c , p h y s i o l o g i c a l l y a c t i v e n i t r o g e n - c o n t a i n i n g n a t u r a l product,) Among the e a r l i e s t known a l k a l o i d s a r e the i n d o l e a l k a l o i d s , and some f i v e hundred of these bases have been o b t a i n e d from about t h r e e hundred p l a n t s , m o s t l y of the f a m i l y Apocynaceae. They a l s o occur t o a l e s s e r e x t e n t i n the A s c l e p i a d a c e a e , Loganiaceae and R u b i a c e a e f a m i l i e s . More t h a n t h r e e hundred s t r u c t u r e s have been e l u c i d a t e d and these are l i s t e d by Hesse i n a r e c e n t compilation"'". T h i s t h e s i s i s concerned w i t h the c h e m i s t r y of a. s e l e c t e d group of i n d o l e a l k a l o i d s , v i z . , the Aspidospermine group, and w i t h the b i o g e n e t i c c o n s i d e r a t i o n s a r i s i n g from t h e i r c h e m i s t r y . T h i s group of a l k a l o i d s , whose b a s i c carbon s k e l e t o n was not r e a d i l y accounted f o r i n e a r l i e r b i o s y n t h e t i c hypotheses, appears somewhat r e s t r i c t e d i n N a t u r e , o c c u r r i n g p r i n c i p a l l y i n the genera Aspidosperma, K o p s i a , P l e i o c a r p a and Stemmadenia. Q u e b r a c h a m i n e ( l ) , an a l k a l o i d of t h i s group, whose t o t a l s y n t h e s i s i s d e s c r i b e d i n t h i s t h e s i s , i s one of the most w i d e l y d i s t r i b u t e d . A l t h o u g h as an i n d o l e i t i s d i s t i n c t from the m a j o r i t y of the -2-members of t h i s group, which are d i h y d r o i n d o l e s , i t s obvious r e l a t i o n t o the o t h e r s j u s t i f i e s i t s i n c l u s i o n h e r e . E a r l i e r l i t e r a t u r e on quebrachamine ( l ) has been summarised . Most im p o r t a n t from a b i o g e n e t i c p o i n t of view i s the e x i s t e n c e i n n a t u r e of b o t h o p t i c a l enantiomelTs of quebrachamine ( l ) . ( i ) B i o g e n e s i s E v er s i n c e the s t r u c t u r e s of a l k a l o i d s were f i r s t e l u c i d a t e d , o r g a n i c c h e m i s t s have s p e c u l a t e d on t h e i r b i o s y n t h e s i s . S i n c e the a l k a l o i d s of the Yohimbine ( 2 ) , Aspidosperma ( 3 ) , Iboga (4) and Corynanthe (5) t y p e s c o n t a i n a common s t r u c t u r a l f e a t u r e , t h e 2 - a m i n o e t h y l ) - i n d o l e group, i t has been f e l t t h a t t r y p t o p h a n (6) or i t s d e c a r b o x y l a t i o n product t r y p t a m i n e (7) i s the p r e c u r s o r o f the a r o m a t i c p o r t i o n of t h e s e m o l e c u l e s . I n f a c t , l a b e l l i n g experiments have shown t h a t D L - t r y p t o p h a n -2-^C (8) i s i n c o r p o r a t e d by R a u w o l f i a s e r p e n t i n a i n t o a j m a l i n e ( 9 ) , s e r p e n t i n e (10) and r e s e r p i n e ( l l ) , and by V i n c a r o s e a i n t o v i n d o l i n e ( 1 2 ) 3 f i g u r e 1. DL-Tryptophan - 3 - C (13) 6 was a l s o i n c o r p o r a t e d by Tabernanthe i b o g a i n t o i b o g a i n e (14) , f i g u r e 2 . These experiments s t r o n g l y suggest t h a t a l l the i n d o l e and d i h y d r o i n d o l e a l k a l o i d s which c o n t a i n a £ - ( 2-amino-e t h y l ) - i n d o l e or B-(2-aminoethyl)-dihydroindole moiety are d e r i v e d i n p a r t from t r y p t o p h a n . R = a t - e t h y l , ( + ) isomer R = - e t h y l , (-) isomer (1) - 3 -The b i o g e n e s i s of t h e " n o n - t r y p t o p h a n " a l i p h a t i c Cg- or ^10~ P° r"ti° n o f the m o l e c u l e i s l e s s obvious t h a n t h a t o f the a r o m a t i c p o r t i o n . I n t o t a l , f o u r hypotheses have been advanced. 7 8 9 The f i r s t h y p o t h e s i s (Barger-Hahn ' ' ) suggested t h a t the s k e l e t o n of yohimbine (15) can be d e r i v e d from t r y p t a m i n e ( 7 ) , d i h y d r o x y p h e n y l a l a n i n e (16) and formaldehyde or i t s C-^-equivalent. T h i s p r o p o s a l was p a r t i c u l a r l y a t t r a c t i v e since., t r y p t a m i n e undergoes c o n d e n s a t i o n r e a c t i o n w i t h aldehydes under p h y s i o l o g i c a l c o n d i t i o n s t o y i e l d c a r b o l i n e d e r i v a t i v e s . F i g u r e 2 . I n c o r p o r a t i o n of DL-Tryptophan-3- 0 i n t o I b o g a i n e , -5-The i n t r o d u c t i o n of the carbomethoxy group was t h e n p o s t u l a t e d t o l e a d t o yohimbine ( 1 5 ) . Robinson suggested t h a t i t was p o s s i b l e t o account f o r the carbomethoxy group by e x p a n s i o n of the a r o m a t i c r i n g t o a t r o p o l o n e (17) which t h e n c o l l a p s e s t o a k e t o - a c i d or i t s e s t e r 1 ^ . The Barger-Hahn h y p o t h e s i s g a i n e d c o n s i d e r a b l e support as a consequence of the a t t r a c t i v e s u g g e s t i o n of Woodward 1 1, t h a t a r e l a t e d pathway i n v o l v i n g the f i s s i o n of the 3,4-dihydroxy-p h e n y l a l a n i n e - d e r i v e d r i n g E w i t h the i n c o r p o r a t i o n of a s i n g l e a c e t a t e u n i t , c o u l d s i m p l y account f o r the o r i g i n of s t r y c h n i n e ( 1 8 ) , f i g u r e 3. A v a l u a b l e consequence of t h i s p o s t u l a t e has been the s u c c e s s f u l b i o s y n t h e t i c a n t i c i p a t i o n of the s u b s e q u e n t l y determined s t r u c t u r e s of a number of o t h e r i n d o l e a l k a l o i d s , e.g. c o r y n a n t h i n e (19) and a j m a l i c i n e ( 2 0 ) , s a r p a g i n e (21) and a j m a l i n e (9) • The second h y p o t h e s i s was proposed by Wenkert and B r i n g i 1 ^ a f t e r they drew a t t e n t i o n t o the f o l l o w i n g l i m i t a t i o n s of the Barger-Hahn scheme: (a) i t does not r e a d i l y account f o r the p r e d o m i n a n t l y a l i p h a t i c c h a r a c t e r of the i n d o l e a l k a l o i d s c o n t a i n i n g a c a r b o c y c l i c r i n g E; (b) i t i s i n c o n s i s t e n t w i t h the o b s e r v a t i o n t h a t C-15 appears t o possess a unique a b s o l u t e c o n f i g u r a t i o n - the s i n g l e e x c e p t i o n b e i n g -akuammicine ( 2 2 ) ; (c) the p o s t u l a t e of the o r i g i n of the carbomethoxy group i n v o l v i n g a t r o p o l o n e i n t e r m e d i a t e i s c o n s i d e r e d t o be i n a d e q u a t e . 15 Wenkert t h e n suggested t h a t the n o n - t r y p t o p h a n p a r t i s d e r i v e d from c a r b o h y d r a t e s v i a a pathway i n v o l v i n g s h i k i m i c (23) and p r e p h e n i c a c i d s ( 2 4 ) . The key s t e p i n Wenkert's " P r e p h e n i c A c i d H y p o t h e s i s " ( f i g u r e 4) i s the rearrangement of p r e p h e n i c -6-F i g u r e 3- Barger-Hahn-Robinson-Woodward H y p o t h e s i s . -7-a c i d (24') by a 1 , 2 - s h i f t of the p y r u v y l s i d e c h a i n 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 , f o l l o w e d by h y d r a t i o n and c o n d e n s a t i o n w i t h a C - l e q u i v a l e n t which a f f o r d s u n i t ( 2 5 ) , r e a d i l y d i s c e r n i b l e i n yohimbine ( 1 5 ) . R e t r o - a l d o l i s a t i o n of the u n i t (25) y i e l d s the " seco-prephenate-formaldehyde" (SPP) u n i t (26) w hich on 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 y i e l d s the a l k a l o i d s c o r y n a n t h e i n e (19) and a j m a l i c i n e ( 2 0 ) , s a r p a g i n e (21) and a j m a l i n e ( 9 ) , as o u t l i n e d i n f i g u r e 5. One of the a t t r a c t i v e f e a t u r e s of t h i s scheme i s t h a t i t a c c ounts f o r the common s t e r e o c h e m i s t r y of the C-15 p o s i t i o n , where the hydrogen atom i s i n an o c - c o n f i g u r a t i o n . The b i o s y n t h e s i s of the S t r y c h n o s bases and the s t r u c t u a l l y more c o m p l i c a t e d Iboga and Aspidosperma a l k a l o i d s are encompassed i n t h i s scheme. C o n d e n s a t i o n of the f o r m y l a c e t a t e group of (27) -8-F i g u r e 4 . Wenkert's P r e p h e n i c A c i d H y p o t h e s i s . w i t h the._ o c - p o s i t i o n of the i n d o l e r i n g l e a d s t o the i n t e r m e d i a t e (28) which by a t r a n s a n n u l a r c y c l i s a t i o n t o the i m i n i u m i o n c o u l d account f o r the f o r m a t i o n of the s t r y c h n i n e s k e l e t o n . R e t r o - M i c h a e l c o n d e n s a t i o n of the t r y p t a m i n e - S P F complex (28) l e a d s t o (29) which can undergo c o n v e n t i o n a l o x i d a t i o n and r e d u c t i o n changes t o g i v e p i p e r i d e i n e s of v a r y i n g s t a t e s of o x i d a t i o n , e.g. (30) and ( 3 1 ) . M i c h a e l a d d i t i o n s of t h e s e compounds t o the - u n s a t u r a t e d a c i d system would a f f o r d the nine-membered r i n g compounds (32) and ( 3 3 ) , which c l o s e l y resemble the s k e l e t o n s of quebrachamine ( l ) and i t s s t r u c t u r a l isomer cleavamine (34) r e s p e c t i v e l y . T r a n s -a n n u l a r c y c l i s a t i o n s of (32) and (33) l e a d t o the Aspidosperma (35) and Iboga (36) s k e l e t a r e s p e c t i v e l y . The t h i r d p o s t u l a t e , the "Monoterpenoid H y p o t h e s i s " , was i n d e p e n d e n t l y proposed by Wenkert 1"* and Thomas 1^. These a u t h o r s -9-F i g u r e 5. I n c o r p o r a t i o n of the SPF U n i t i n t o C o r y n a n t h e i n e , Yohimbine, A j m a l i n e and S a r p a g i n e . -10-F i g u r e 6.. I n c o r p o r a t i o n of the SPF U n i t i n t o the Iboga and Aspidosperma A l k a l o i d s ' . -11-noted t h a t the n o n - a l k a l o i d a l g l y c o s i d e s , g e n t i o p i c r i n ( 3 7 ) , b a k a n k o s i n (38) and s w e r t i a m a r i n (39) had s t r u c t u r e s which c o u l d be based on the SPF u n i t . I t was a l s o noted t h a t c y c l o p e n t a n o i d monoterpenic g l u c o s i d e s , such as v e r b e n a l i n ( 4 0 ) , g e n i p i n (41) and a u c u b i n ( 4 2 ) , have the common carbon s k e l e t o n ( 4 3 ) . Cleavage of the c y c l o p e n t a n e r i n g as i n d i c a t e d ( f i g u r e 7) would g i v e r i s e t o the carbon s k e l e t o n of the SPF u n i t h a v i n g the r e q u i r e d s t e r e o c h e m i s t r y a t C-15 ( e q u i v a l e n t t o C-6 i n 43) i n the i n d o l e a l k a l o i d . The f o r m a t i o n of the more c o m p l i c a t e d Aspidosperma (3) and Iboga (4) s k e l e t a c o u l d t h e n f o l l o w the same course as suggested by the e a r l i e r p r e p h e n i c a c i d t h e o r y ( F i g u r e s 4, 5 and 6 ) . The f o u r t h h y p o t h e s i s t o account f o r the o r i g i n of the non-17 t r y p t a m i n e p o r t i o n was put f o r w a r d by S c h l i t t l e r and T a y l o r , f i g u r e 8. They suggested t h a t t h r e e m o l e c u l e s of acetyl-coenzyme A condense t o form a p o l y - / 3 - k e t o c h a i n (45) which by f u r t h e r -12-6 3 \ 44, b Aspidosperma S k e l e t o n F i g u r e 7. Wenkert-Thomas Monoterpene H y p o t h e s i s . F i g u r e 8 . S c h l i t t l e r - T a y l o r - L e e t e H y p o t h e s i s . c o n d e n s a t i o n w i t h formaldehyde a t C-20 and w i t h malonyl-coenzyme A at C-15 forms an i n t e r m e d i a t e (46) v e r y s i m i l a r t o Wenkert's SPF u n i t ( 2 6 ) . T h i s i n t e r m e d i a t e would t h e n condense w i t h t r y p t a m i n e t o g i v e the v a r i o u s i n d o l e a l k a l o i d s i n a manner s i m i l a r t o the l a t t e r p a r t of Wenkert's h y p o t h e s i s . -13-H O HO-CHxOH COOH NH 2 CH2 Cl-ICO^i-l CH, CH co3H 47 48 49 I n o r d e r t o d e c i d e between the s e hypotheses a g r e a t d e a l of 18 work has been c a r r i e d out u s i n g t r a c e r t e c h n i q u e s . L e e t e r e p o r t e d t h a t a j m a l i n e (9) i s o l a t e d from R a u w o l f i a s e r p e n t i n a p l a n t s which were f e d w i t h m e v a l o n i c - 2 - ^ C a c i d (47) or t y r o s i n e -(48) - whi c h i s a known p r e c u r s o r of 3 , 4 - d i h y d r o x y p h e n y l a l a n i n e (16) - was c o m p l e t e l y i n a c t i v e . These r e s u l t s r e n d e r e d u n l i k e l y the Woodward f i s s i o n h y p o t h e s i s and the monoterpene h y p o t h e s i s . A l a n i n e - 2 - ^ ^ C (49) was a l s o f e d t o t e s t Wenkert's p r e p h e n i c a c i d h y p o t h e s i s on the assumption t h a t p y r u v a t e formed by t r a n s a m i n a t i o n of a l a n i n e would be i n c o r p o r a t e d i n t o the s i d e c h a i n of pr e p h e n i c a c i d . However the a c t u a l p r e c u r s o r of the s i d e c h a i n of p r e p h e n i c a c i d i s phosphoenolpyruvate which i s not r e a d i l y formed from p y r u v i c a c i d i n v i v o . Thus no d e f i n i t e c o n c l u s i o n can be drawn from t h i s l a t t e r f i n d i n g , L e e t e " ^ ' a l s o f e d sodium a c e t a t e - l - ^ C t o R. s e r p e n t i n a and found t h a t h a l f the t o t a l a c t i v i t y of a j m a l i n e (9) was l o c a t e d a t C-3 and C-19 and e q u a l l y (8 46 F i g u r e 9* I n c o r p o r a t i o n of A c e t a t e i n t o A j m a l i n e . -14-d i s t r i b u t e d between these p o s i t i o n s , f i g u r e 9. I f i t i s assumed t h a t the r e m a i n i n g h a l f of the a c t i v i t y was shared between C-15 and C-17, t h e n t h i s would support the h y p o t h e s i s of T a y l o r . 20 However, B a t t e r s b y a l s o s t u d i e d the b i o s y n t h e s i s of a j m a l i n e (9) and o b t a i n e d r e s u l t s i n c o n t r a s t t o those of L e e t e . 21 Leete was l a t e r unable t o reproduce h i s o r i g i n a l r e s u l t s , but r a t h e r o b t a i n e d r e s u l t s c o m p a t i b l e w i t h those of B a t t e r s b y . These r e s u l t s would a p p a r e n t l y e x c l u d e the " S c h l i t t e r - T a y l o r H y p o t h e s i s " . S i n c e s h i k i m i c a c i d i s the d i r e c t p r e c u r s o r of p r e p h e n i c 22 14 a c i d , Mothes f e d s h i k i m i c - U - "^C a c i d (23) t o C a t h a r a n t h u s roseu,s. and i s o l a t e d r a d i o a c t i v e v i n d o l i n e (12) and c a t h a r a n t h i n e ( 5 0 ) . Over 90$ of the t o t a l a c t i v i t y of v i n d o l i n e (12) was l o c a t e d i n the a r o m a t i c p a r t of the i n d o l e n u c l e u s . T h i s would te n d t o d i s p r o v e Wenkert's p o s t u l a t e t h a t s h i k i m i c a c i d i s the p r e c u r s o r of the non-aromatic p o r t i o n . I t i s w e l l r e c o g n i s e d t h a t due c a u t i o n must be e x e r c i s e d i n the i n t e r p r e t a t i o n of n e g a t i v e r e s u l t s i n i n c o r p o r a t i o n s t u d i e s . The s u c c e s s of f e e d i n g experiments depends on the c h o i c e of the p l a n t , the age of the p l a n t , the method of f e e d i n g and the a b i l i t y of the l a b e l l e d p r e c u r s o r t o be absorbed i n t o the p l a n t and t r a n s p o r t e d t o the s i t e of a c t i v e s y n t h e s i s . S i n c e none of t h e s e b i o g e n e t i c hypotheses has been u n e q u i v o c a l l y s u p p o r t e d by adequate f e e d i n g experiments r e i n v e s t i g a t i o n s of these t h e o r i e s has become n e c e s s a r y . 0 ^ 0 A "1/1 The i m p o r t a n t d i s c o v e r y by S c o t t ' , t h a t m e v a l o n i c - 2 - C a c i d l a c t o n e (51) i s i n c o r p o r a t e d i n t o the Aspidosperma-type -15-a l k a l o i d , v i n d o l i n e (12) by Catharanthus r o s e u s G. Don c o n c e n t r a t e d i n t e r e s t i n the Wenkert-Thomas t h e o r y . E s s e n t i a l l y i d e n t i c a l , 25 independent r e s u l t s have emerged from the work of A r i g o n i , who f e d sodium m e v a l o n a t e - 2 - ^ G (46) t o V i n c a r o s e a L i n n . D e g r a d a t i v e s t u d i e s showed t h a t one q u a r t e r of the t o t a l a c t i v i t y i n v i n d o l i n e (12) was l o c a t e d a t C-22. T h i s f i n d i n g i s i n agreement w i t h the mevalonoid n a t u r e of the non-tryptamine p o r t i o n . S c o t t , thus t e n t a t i v e l y proposed the t e r p e n o i d pathway shown i n f i g u r e .10, as a p o s s i b l e r o u t e t o the Yohimbine (2) Aspidosperma ( 3 ) and Iboga (4) t y p e s . B a t t e r s b y ^ a l s o showed t h a t m e v a l o n i c - 2 - ^ C a c i d (54) was i n c o r p o r a t e d by V i n c a r o s e a i n t o v i n d o l i n e (12) a j m a l i c i n e (20).. and s e r p e n t i n e (10) and t h a t the carbomethoxy groups (C-22) of a j m a l i c i n e (20) and c a t h a r a n t h i n e (50) had 24% and 23% of the t o t a l a c t i v i t y r e s p e c t i v e l y . Kuhn-Roth d e g r a d a t i o n of c a t h a r a n t h i n e e s t a b l i s h e d t h a t C - 6 , C-20 and C-21 were i n a c t i v e , w h i l e 3 - e t h y l p y r i d i n e o b t a i n e d by p a l l a d i u m d e h y d r o g e n a t i o n had 48% of the t o t a l a c t i v i t y . Thus a p a r t i a l assignment of r a d i o a c t i v i t y i n c a t h a r a n t h i n e (50) can be made: C-22, 23%; C-l+C-18 by d i f f e r e n c e 29%; and 48% l o c a t e d a t some p o i n t ( s ) i n C-2, C - 3 , C-5 and C-19, f i g u r e 11. A l l t h e s e r e s u l t s a re c o n s i s t e n t w i t h the' Wenkert-Thomas scheme and e l i m i n a t e s the a l t e r n a t e scheme by S c o t t , w h i c h r e q u i r e s t h a t 50% of the t o t a l a c t i v i t y be l o c a t e d a t C-22 i n the Iboga s k e l e t o n ( 5 0 ) . From th e s e r e p o r t s on the i n c o r p o r a t i o n of mevalonic a c i d i n t o a j m a l i c i n e ( 2 0 ) , s e r p e n t i n e ( 1 0 ) , c a t h a r a n t h i n e (50) and v i n d o l i n e (12) workers f e l t t h a t g e r a n i o l , which on c u r r e n t -16-12 SA F i g u r e 10. Mevalonate I n c o r p o r a t i o n Experiments by S c o t t and A r i g o n i . -17-S k e l e t a Aspidosperma S k e l e t o n F i g u r e 11. Mevalonate I n c o r p o r a t i o n E x p e r i m e n t s by B a t t e r s b y . knowledge of i s o p r e n o i d b i o s y n t h e s i s s h o u l d be a l o g i c a l p r e c u r s o r 2 7 2 8 29 30 f o r t h e s e a l k a l o i d s . I n f a c t B a t t e r s b y ' , A r i g o n i , S c o t t and t h e i r r e s e a r c h groups i n d e p e n d e n t l y d i s c o v e r e d t h a t g e r a n i o l (51) i s a p r e c u r s o r of the non-tryptamine p o r t i o n . The p a t t e r n of l a b e l l i n g found i n a j m a l i c i n e (20) c a t h a r a n t h i n e (50) and v i n d o l i n e (12) d e r i v e d from g e r a n i o l - 2 - 1 ^ C (51) was c o n s i s t e n t w i t h the f o r m a t i o n of the i n t e r m e d i a t e c y c l o p e n t a n o i d monoterpene ( 4 3 ) . Subsequent bond c l e a v a g e and rearrangements l e a d s t o the s t r u c t u r e s ( 4 4 ) , (55) and (56) which r e p r e s e n t the t h r e e a l k a l o i d a l f a m i l i e s -18-i n d i c a t e d , f i g u r e 11. F u r t h e r c o n f i r m a t i o n has r e c e n t l y been o f f e r e d by L e e t e ^ 1 who f e d g e r a n i o l - 3 - ^ C t o V i n c a r o s e a and i s o l a t e d c a t h a r a n t h i n e (50) and v i n d o l i n e (12) w i t h the l a b e l i n the expected p l a c e . The i n c o r p o r a t i o n of mevalonic a c i d and g e r a n i o l s t r o n g l y s u p p o r t s t h e s u g g e s t i o n t h a t the i n d o l e a l k a l o i d s are formed from a c y c l o p e n t a n o i d monoterpene. I n support of t h i s i d e a B a t t e r s b y has shown t h a t l o g a n i n ( 5 7 ) , a known c y c l o p e n t a n o i d monoterpenoid, i s i n c o r p o r a t e d i n t o the Iboga ( 4 ) , Aspidosperma (3) and Corynanthe (5) f a m i l i e s . ( i i ) Syntheses of P o s s i b l e B i o g e n e t i c S i g n i f i c a n c e A l t h o u g h the e a r l i e r s t a g e s of Wenkert's p r e p h e n i c a c i d scheme have been r e p l a c e d by the monoterpenoid h y p o t h e s i s , the l a t t e r s t a g e s of the p r e p h e n i c a c i d pathway remain an a t t r a c t i v e b a s i s f o r e x p e r i m e n t a l work. I n f a c t , c o n s i d e r a b l e support f o r the l a t t e r p a r t of t h i s p r o p o s a l can be found i n the r e a c t i o n s of c e r t a i n a l k a l o i d s . F o r i n s t a n c e , i n a c h e m i c a l c o r r e l a t i o n between c o n d y l o c a r p i n e (57) and akuammicine ( 5 8 ) , c a r r i e d out t o v e r i f y the a b s o l u t e c o n f i g u r a t i o n of the former (see f i g u r e 1 2 ) , the t r a n s f o r m a t i o n of c o n d y f o l i n e (59) t o t u b i f o l i n e (60) was p o s t u l a t e d t o occur t h r o u g h a r e v e r s i b l e r i n g opening t o the imini u m s a l t ( 6 1 ) . T h i s i n t e r m e d i a t e t h e n r e a r r a n g e s t o (62) and i s f o l l o w e d by a Me 57 -19-F i g u r e : i 2 . C o r r e l a t i o n between Condylocarpj.ne .arid Akuammicine.. t r a n s a n n u a l c y c l i s a t i o n s i m i l a r t o t h a t p o s t u l a t e d i n Wenkert's scheme, f i g u r e 6. A g r e a t d e a l of a t t e n t i o n has r e c e n t l y been f o c u s s e d on t r a n s a n n u l a r c y c l i s a t i o n p r o c e s s e s s i m i l a r t o those p o s t u l a t e d by Wenkert t o account f o r the b i o g e n e t i c f o r m a t i o n of the Aspidosperma (32 —> 35) and Iboga (33 —^36) s k e l e t a . The f i r s t -20-l a b o r a t o r y r e a l i z a t i o n of such a c y c l i s a t i o n t o p r o v i d e the 34 Aspidosperma s k e l e t o n was r e p o r t e d by Kutney . T h i s sequence ( f i g u r e 13) i n v o l v e s 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 of d i h y d r o c l e a v a m i n e (63) t o the i o n i c i n t e r m e d i a t e (64) which undergoes a t r a n s a n n u a l c y c l i s a t i o n r e a c t i o n t o g i v e the i n d o l e n i n e ( 6 5 ) . The f i n a l p roduct (66) was o b t a i n e d a f t e r h y d r i d e r e d u c t i o n of ( 6 5 ) . I t t h e n became apparent from the above r e s u l t s t h a t carbomethoxydihydrocleavamine (67) c o u l d undergo c y c l i s a t i o n s i n an a l t e r n a t i v e sense and l e a d t o Iboga- - and V i n c a — l i k e 35 36 systems. I n f a c t , Kutney ' was a b l e t o show t h a t 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 of carbomethoxydihydrocleavamine (67) l e a d s t o the iminium i n t e r m e d i a t e s (69) and (68) which v i a t r a n s a n n u l a r c y c l i s a t i o n r e a c t i o n s generate the Iboga (70) and (71) and V i n c a d i f f o r m i n e - t y p e (72) s k e l e t a r e s p e c t i v e l y . These r e s u l t s a re summarised i n f i g u r e 14. The i s o l a t i o n of b o t h c o r o n a r i d i n e (70) and d i h y d r o c a t h a r a n t h i n e (71) from the t r a n s a n n u l a r c y c l i s a t i o n of (69) i s not unexpected s i n c e t h i s iminium i n t e r m e d i a t e c o u l d i s o m e r i s e t o an enamine b e a r i n g a double bond between the C-4 and C-5 p o s i t i o n s . S e v e r a l i n t e r e s t i n g c o n c l u s i o n s may be drawn from a c o n s i d e r a t i o n of the s t e r e o c h e m i s t r y of these t r a n s a n n u l a r c y c l i s a t i o n s . I t was f e l t t h a t these r e a c t i o n s would proceed i n a c o m p l e t e l y s t e r e o s e l e c t i v e manner s i n c e the f o l d i n g of the nine-membered r i n g i n t e r m e d i a t e s would n e c e s s a r i l y p r o v i d e r i g i d c y c l i s a t i o n p r o d u c t s of unique s t e r e o c h e m i s t r y . I n f a c t , t h i s has been borne out i n the c y c l i s a t i o n s of (-)-quebrachamine ( l ) -21-63 66 \ ^ ^M' ^ 65 F i g u r e 1 3 . T r a n s a n n u l a r C y c l i s a t i o n of Dihydrocleavamine, t o o p t i c a l l y a c t i v e ( + ) - a s p i d o s p e r m i d i n e (72) ' ' , f i g u r e 15. S i n c e the a b s o l u t e c o n f i g u r a t i o n of the l o n e asymmetric 39 c e n t r e i n cleavamine had been determined by x- r a y a n a l y s i s , the a b s o l u t e c o n f i g u r a t i o n a t t h i s c e n t r e remains the same i n d i h y d r o c l e a v a m i n e ( 6 3 ) . I f , as i s t o be expected, the c o n f i g u r a t i o n of t h i s p o s i t i o n remains u n a l t e r e d i n the c y c l i s a t i o n p r o c e s s t o p r o v i d e the Iboga s k e l e t o n , the a b s o l u t e c o n f i g u r a t i o n of t h i s p o s i t i o n i n the Iboga a l k a l o i d s may be a s s i g n e d . W i t h t h i s e v i d e n c e t h e r e i s o n l y one c o n f o r m a t i o n w hich a l l o w s the C-18 and C-5 t o come i n t o r e a s o n a b l e p r o x i m i t y f o r bond f o r m a t i o n and i n t h i s c o n f o r m a t i o n the C-2-19-N-bridge i s <*-oriented. Thus the b r i d g e i n the r i g i d Iboga system w i l l have an ^ - o r i e n t a t i o n and not a 3 - o r i e n t a t i o n as suggested by p r e v i o u s w o r k e r s . The c o r r e c t a b s o l u t e c o n f i g u r a t i o n ' 40 -22-CoA*-7e 70 e t h y l group down 71 e t h y l group up Fi g u r e : 14. T r a n s a n n u l a r C y c l i s a t i o n of Carbomethoxy-d i h y d r o c l e a v a m i n e . F i g u r e 15. T r a n s a n n u l a r C y c l i s a t i o n of (-)-Quebrachamine. f o r the Iboga f a m i l y i s r e p r e s e n t e d by s t r u c t u r e s (70) and (7 1 ) . S i n c e a l l o f t h e s e t r a n s a n n u l a r c y c l i s a t i o n s made p o s s i b l e the i n t e r c o n v e r s i o n and i n t e r r e l a t i o n of the i m p o r t a n t and -23-w idespread groups of V i n c a , Aspidosperma and Iboga a l k a l o i d s , c o n s i d e r a b l e a t t e n t i o n was t h e n d i r e c t e d t o the s y n t h e s i s of compounds l i k e quebrachamine ( l ) , d i h y d r o c l e a v a m i n e (63) and carbomethoxydihydrocleavamine ( 6 7 ) . I t i s p a r t i c u l a r l y noteworthy i n t h i s c o n n e c t i o n t h a t the b r i d g e h e a d asymmetric c e n t r e i n quebrachamine ( l ) d i h y d r o c l e a v a m i n e (63) and carbomethoxydihydrocleavamine (67) d i r e c t s the s t e r i c course of the c y c l i s a t i o n p r o d u c t s . Hence a s y n t h e t i c scheme i n v o l v i n g the t r a n s a n n u l a r c y c l i s a t i o n as the p e n u l t i m a t e s t e p does not r e q u i r e s p e c i a l c o n s i d e r a t i o n o f the s t e r e o -c h e m i s t r y of the i n t e r m e d i a t e s i n the sequence. I n t h i s t h e s i s the t o t a l s y n t h e s i s of (dl)-quebrachamine ( l ) i s d e s c r i b e d by a s y n t h e t i c sequence which i s c o m p l e t e l y g e n e r a l . i n i t s a p p l i c a t i o n t o the p r e p a r a t i o n of nine-membered r i n g systems. I n f a c t ( d l ) - d i h y d r o c l e a v a m i n e (63) has a l s o been s y n t h e s i s e d by an analogous sequence^ 1' ( i i i ) P r e v i o u s S y n t h e t i c Approaches F i r s t of a l l i t i s a p p r o p r i a t e t o d e s c r i b e some r e c e n t work which p r e s e n t s s u c c e s s f u l s y n t h e s i s of some Aspidosperma and Iboga a l k a l o i d s . The f i r s t t o t a l s y n t h e s i s of d l - a s p i d o s p e r m i n e (73) and 42 ( dl)-quebrachamine ( l ) was a c h i e v e d by S t o r k , f i g u r e 16. I t i s i n t e r e s t i n g t o note t h a t the t r i c y c l i c amide (75) i n the F i s c h e r i n d o l e s y n t h e s i s w i t h o-methoxyphenylhydrazine gave o n l y i n d o l i c m a t e r i a l showing t h a t e n o l i s a t i o n , even under e q u i l i b r a t i n g c o n d i t i o n s , proceeds away from the r i n g j u n c t i o n . T h i s i s due t o the , f a c t : t h a t e n o l i s a t i o n i n the d e s i r e d -24-F i g u r e 16. S t o r k ' s S y n t h e s i s of (dl)-Quebrachamine and ( d l ) - A s p i d o s p e r m i n e . d i r e c t i o n would r e s u l t i n a s t r a i n e d five-membered r i n g c o n t a i n i n g t h r e e t r i g o n a l atoms. The product of r e d u c t i o n of t h i s k e t o amide (75) c o n t a i n s o n l y one t r i g o n a l atom, and the F i s c h e r s y n t h e s i s w i t h t h i s compound y i e l d e d an i n d o l e n i n e which was the d l - f o r m of 1 , 2 - d e h y d r o d e a c e t y l a s p i d o s p e r m i n e ( 7 7 ) . The f a c t t h a t t h i s p r o d uct had the c o r r e c t s t e r e o c h e m i s t r y d e r i v e s from the e q u i l i b r a t i o n of the asymmetric c e n t r e s a t C-12 and C-19 by the r e v e r s i b l e c o n v e r s i o n t o ( d l ) - 7 8 d u r i n g the F i s c h e r s y n t h e s i s , (77) b e i n g the most s t a b l e isomer. L i t h i u m aluminum h y d r i d e r e d u c t i o n o f (77) i n t r o d u c e s the hydrogen on the d e s i r e d s i d e of the.modecule. C y c l i s a t i o n of the phenylhydrazone of (76) l e a d s t o (79) which by r e d u c t i v e c l e a v a g e w i t h p o t a s s i u m b o r o h y d r i d e g i v e s (dl)-quebrachamine ( l ) . S e v e r a l p o s s i b l e r o u t e s toward the s y n t h e s i s of a s p i d o s p e r m i n e (73) have been i n v e s t i g a t e d by Ban . One of t h e s e ( f i g u r e , 17) reached the i n t e r m e d i a t e (80) which has the same p l a n a r s t r u c t u r e as the c o r r e s p o n d i n g i n t e r m e d i a t e (74) of S t o r k ' s sequence. A l t h o u g h these d i f f e r e d s t e r e o c h e m i c a l l y , Ban was a b l e t o prepare ( d l ) - a s p i d o s p e r m i n e (73) by s u b j e c t i n g (80) t o the same sequence of r e a c t i o n s as those c a r r i e d out i n S t o r k ' s s y n t h e s i s . T h i s f i n d i n g s u p p o r t s the e q u i l i b r a t i o n (77) ^ (78) suggested by S t o r k . I n a r e c e n t communication K u e h n e ^ d e s c r i b e s the s y n t h e s i s of the key t r i c y c l i c keto-amine (81 or 76) w i t h s t e r e o c h e m i s t r y (82a) and (82b) by a c o m p l e t e l y d i f f e r e n t r o u t e ( f i g u r e 18) from t h a t of S t o r k and Ban. The s t e r e o c h e m i s t r y of S t o r k ' s and Ban's keto-amines are shown by (76a) and ( 8 1 a ) . F i g u r e 17. Ban's S y n t h e s i s of ( d l ) - A s p i d o s p e r m i n e . A s u c c e s s f u l , s t e r e o c h e m i c a l ^ c o n t r o l l e d s y n t h e s i s of the t e t r a c y c l i c i n d o l e (83) by S a l l e y ^ suggested a f e a s i b l e pathway t o the s y n t h e s i s of the Iboga- s k e l e t o n . The c i s -and t r a n s - f u s e d C/D r i n g s of (83) were c o n s t r u c t e d from the c o r r e s p o n d i n g enedione (84) as o u t l i n e d i n f i g u r e 19. I t i s i n t e r e s t i n g t o note t h a t the c i s - k e t a l o x i m e (85) r e a r r a n g e s s p o n t a n e o u s l y t o the c i s - l a c t a m k e t a l (86) whereas the t r a n s -epimer r e a r r a n g e s more s l o w l y . T h i s i s b e l i e v e d t o be due t o the c o p l a n a r i t y of the p a r t i c i p a t i n g c e n t r e s . The f o r m a t i o n of the " i s o l a c t a m " (87) d u r i n g r i n g e x p a n s i o n has been e x c l u d e d . Because the Beckmann rearrangement proceeds w i t h a n t i - m i g r a t i o n ^ , the s t r u c t u r e of the two l a c t a m s (86) i n r e t r o s p e c t , v e r i f i e d the a n t i - s t e r e o c h e m i s t r y of b o t h oximes ( 8 5 ) . -27-O 82 82, a 82, b F i g u r e 18.. Kuehne' s S y n t h e s i s of the T r i c y c l i c Keto-Amine. The f i r s t t o t a l s y n t h e s i s of an Iboga a l k a l o i d ( d l ) - i b o g a m i n e 47 (88) and ( d l ) - e p i i b o g a m i n e (89) was a c c o m p l i s h e d by B u c h i . I n the above mentioned s y n t h e s i s the i n d o l e p o r t i o n i s f u s e d v i a a F i s c h e r i n d o l e s y n t h e s i s , onto a s u i t a b l e i n t e r m e d i a t e c o n t a i n i n g t h e r i n g s C, D and E, . f i g u r e 20. 48 C o n c u r r e n t l y w i t h B u c h i ' s s y n t h e s i s , Huffman r e p o r t e d the 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 ( 9 1 ) . I n a d d i t i o n t o p r o v i d i n g a new pathway t o the Iboga s k e l e t o n , t h i s s y n t h e s i s -28-F i g u r e 19. S a l l e y ' s Approach t o the S y n t h e s i s of the Iboga S k e l e t o n . c o n s t i t u t e s a new p r e p a r a t i o n of i s o q u i n u c l i d i n e s , f i g u r e 21. R e c e n t l y H a r l e y - M a s o n ^ s y n t h e s i s e d ( d l ) - e b u r n a m i n e (93) and ( d l ) - 3 - m e t h y l a s p i d o s p e r m i n e (94) from a common i n t e r m e d i a t e (95) w h i c h resembles the i n t e r m e d i a t e (44b) d e s c r i b e d i n the Wenkert-Thomas h y p o t h e s i s , f i g u r e 7. T h i s sequence i s summarised i n f i g u r e 22. 50 51 Very s h o r t l y a f t e r our work was p u b l i s h e d , Harley-Mason r e p o r t e d -the' t o t a l s y n t h e s i s of cK.- and £ - ( d l ) - d i h y d r o c l e a v a m i n e ' (63) by a sequence s i m i l a r t o o u r s . The f o r m a t i o n of the 52 |3 - c a r b o l i n e system was a c c o m p l i s h e d v i a a P i c t e t - S p e n g l e r c o n d e n s a t i o n of t r y p t a m i n e and the aldehyde t r i e s t e r ( 9 6 ) . H i s sequence i s summarised i n f i g u r e 23. -29-88, e t h y l group up 89, e t h y l group down F i g u r e 20. B u c h i 1 s S y n t h e s i s of ( d l ) — I b o g a m i n e and ( d l ) - E p i i b o g a m i n e . F i g u r e 22. Harley-Mason's S y n t h e s i s of (dl ) - E b u r n a m i n e and ( d l ) - 3 - M e t h y l a s p i d o s p e r m i n e . -31-96 « | Ma, Dihyd/rgcleavamine F i g u r e 23. Harley-Masons S y n t h e s i s of oL- and j i - ( d l ) -. d i h y d r o c l e a v a m i n e . DISCUSSION As a l r e a d y mentioned the t r a n s a n n u l a r c y c l i s a t i o n r e a c t i o n s of nine-membered r i n g compounds l i k e quebrachamine, d i h y d r o -cleavamine and t h e i r d e r i v a t i v e s p r o v i d e an a t t r a c t i v e s y n t h e t i c e n t r y i n t o the Aspidosperma, V i n c a and Iboga s e r i e s . I n t h i s t h e s i s are d e s c r i b e d two approaches t o the t o t a l s y n t h e s i s of the nine-membered r i n g a l k a l o i d , quebrachamine. I n the f i r s t approach, which w i l l be r e f e r r e d t o as scheme A, a s u i t a b l y s u b s t i t u t e d p i p e r i d i n e moiety i s f u s e d t o a /?>-ethylindole d e r i v a t i v e , and the f o r m a t i o n of the nine-membered r i n g i s en v i s a g e d as p r o c e e d i n g v i a an a c y l o i n c o n d e n s a t i o n , f i g u r e 24. I n ' t h e o t h e r approach, scheme B, the nine-membered r i n g and the p i p e r i d i n e r i n g are g e n e r a t e d s i m u l t a n e o u s l y by a r e d u c t i v e r i n g c l e a v a g e , f i g u r e 25. I . Scheme A The f i r s t s t e p of t h i s s y n t h e t i c . s e q u e n c e i n v o l v e s the p r e p a r a t i o n of the i n d o l e d e r i v a t i v e (97) and the p i p e r i d i n e d e r i v a t i v e (98) which are c o u p l e d t o g e t h e r t o g i v e the i n t e r m e d i a t e d i e s t e r ( 9 9 ) . Attempts t o c y c l i s e t h i s e s t e r 53 under a c y l o i n condensation-^ c o n d i t i o n s t o ge n e r a t e the n i n e -membered r i n g i n t e r m e d i a t e (100) a r e d e s c r i b e d . I t i s f i r s t a p p r o p r i a t e t o d i s c u s s some p r e l i m i n a r y 54 a i n v e s t i g a t i o n s ' i n t h i s l a b o r a t o r y which were d i r e c t e d toward the s y n t h e s i s of i n t e r m e d i a t e l i k e ( 9 9 ) , v i z . , (104) and (107). A R e i s s e r t s y n t h e s i s , f i g u r e 26, was used t o prepare 2-carbomethoxyindole ( l O l ) , w h i c h was heated w i t h - 3 3 -164 (dl)-Quebrachamine F i g u r e 25. G e n e r a l O u t l i n e of Scheme B. -34-104, X=H 2 F i g u r e 26.. 55 c h l o r o a c e t o n i t r i l e i n a Hoesch r e a c t i o n t o g i v e 2-carbomethoxy-3 - c h l o r o a c e t y l i n d o l e (102). A l k y l a t i o n of t h i s i n d o l e (102) w i t h the p i p e r i d i n e (98,a) gave the expected d i e s t e r ketone i n t e r m e d i a t e ( 1 0 3 ) . Attempts t o reduce t h i s k e t o n i c f u n c t i o n c a t a l y t i c a l l y or w i t h m e t a l h y d r i d e s t o g i v e the d i e s t e r (104) r e q u 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 were u n s u c c e s s f u l . A r e l a t e d i n t e r m e d i a t e (107) was sought as a • d e s i r a b l e model t o i n v e s t i g a t e the u t i l i t y of Dieckmann-type c y c l i s a t i o n i n t h i s s e r i e s . I t ' s s y n t h e s i s i s o u t l i n e d i n f i g u r e 27. 56 The i n d o l e - 2 - a c e t i c a c i d p r e p a r e d by the p u b l i s h e d procedure , was s u b j e c t e d t o a Hoesch r e a c t i o n w i t h c h l o r o a c e t o n i t r i l e t o g i v e 3 - c h l o r , o a c e t y l i n d o l e - 2 - a c e t i c a c i d m e t h y l e s t e r (105). -35-F i g u r e 27. A l k y l a t i o n of t h i s compound w i t h 3 - c a r b o m e t h o x y p i p e r j d i n e (98) y i e l d e d the expected i n t e r m e d i a t e (106). Attempts t o remove the k e t o n i c oxygen f u n c t i o n i n (106) by c o n v e n t i o n a l procedures were a l s o u n s u c c e s s f u l i n t h i s case. However, the d i e s t e r (107) was e v e n t u a l l y o b t a i n e d by the t r e a t m e n t of (106) w i t h d i b o r a n e i n d r y t e t r a h y d r o f u r a n a t 0°C. ( i ) S y n t h e s i s of the I n d o l e M o i e t y I n view of the d i f f i c u l t y e x p e r i e n c e d i n the removal of the oxygen f u n c t i o n i n the / 3 - e t h y l i n d o l e s i d e c h a i n of (103), -36-CO*, ft I 108 .) NaOFt 108, a SO, f /UL 97,a F i g u r e 28- S y n t h e s i s of the I n d o l e M o i e t y ( 9 7 , a ) . we t u r n e d our a t t e n t i o n t o the s y n t h e s i s of 2-carboethoxy-3-( j3 - c h l o r o e t h y l ) - i n d o l e ( 9 7 , a ) . A c o n v e n i e n t method f o r the p r e p a r a t i o n of e s t e r s of s u b s t i t u t e d i n d o l e - 2 - c a r b o x y l i c a c i d s 57 i s the F i s c h e r i n d o l e s y n t h e s i s , w h i c h i n v o l v e s the c y c l i s a t i o n o f an a r y l h y d r a z o n e of an ^(.-keto e s t e r w i t h a p r o t o n a c i d , or a Lewis a c i d as c a t a l y s t . The most c o n v e n i e n t method f o r . p r e p a r i n g a r y l h y d r a z o n e s of <*. - k e t o e s t e r s i s the Japp-58 Klingeman r e a c t i o n . T h i s p r o c e s s c o n s i s t s i n i t i a l l y of an e l e c t r o p h i l i c a t t a c k o f an a r y l d i a z o n i u m c a t i o n on the a n i o n i c carbon atom of an a c t i v e m e t h i n y l compound t o g i v e an azo-in t e r m e d i a t e . . The l a t t e r compound, under the c o n d i t i o n s of the c o u p l i n g r e a c t i o n o r d i n a r i l y undergo h y d r o l y s i s w i t h e x p u l s i o n of one of the o r i g i n a l carbon s u b s t i t u e n t s t o g i v e -37-an a r y l h y d r a z o n e . Our approach t o the p r e p a r a t i o n of (97,a) . i s o u t l i n e d i n f i g u r e 28. c q The d i e t h y l ^ - c h l o r o p r o p y l m a l o n a t e (108) was p r e p a r e d i n a.70$ y i e l d by t r e a t i n g the monosodium s a l t of d i e t h y l m a l o n a t e w i t h 1,3-chlorobromopropane. Attempted c o n d e n s a t i o n of the sodium s a l t of (108) w i t h benzene di a z o n i u m c h l o r i d e ^ - ^ l e d , t o the r e c o v e r y of the s t a r t i n g m a t e r i a l ( 1 0 8 ) . S i n c e the l a c k of r e a c t i o n may be due t o the r e g e n e r a t i o n of the s t a r t i n g m a t e r i a l i n aqueous media we d e c i d e d t o c a r r y out the Japp-Klingemann r e a c t i o n under anhydrous c o n d i t i o n s . For t h i s purpose anhydrous benzene d i a z o n i u m c h l o r i d e was r e a c t e d w i t h an a l c o h o l i c s o l u t i o n of the sodium s a l t of (108) a t 0°C. The r e a c t i o n m i x t u r e was a l l o w e d t o s t a n d o v e r n i g h t i n the r e f r i g e r a t o r and the crude r e a c t i o n p r o d u c t s u b j e c t e d t o a F i s c h e r i n d o l e s y n t h e s i s u s i n g s u l f u r i c a c i d as the c a t a l y s t . P u r i f i c a t i o n of the r e a c t i o n product by chromatography on.aluminum r e s u l t e d i n a 50$ r e c o v e r y of the s t a r t i n g m a t e r i a l (108) and a l s o a new c r y s t a l l i n e p r o d uct whose e l e m e n t a l a n a l y s i s suggested a f o r m u l a , C-^H^lTC^Cl. The u l t r a v i o l e t spectrum showed the t y p i c a l a b s o r p t i o n of an i n d o l e - 2 - c a r b o x y l i c e s t e r (/.max 296 mu) w h i l e the i n f r a r e d spectrum had sharp bands a t 3250 cm" 1 (-NH) and a t 1670 c m - 1 (-COOBt). The NMR spectrum ( f i g u r e 29) showed the normal m u l t i p l e t c e n t r e d a t T2.60 f o r the a r o m a t i c p r o t o n s on the i n d o l e n u c l e u s , a two-proton q u a r t e t a t T 5 . 5 4 (-COOCI^CH^), a f o u r p r o t o n m u l t i p l e t a t 76.50 (-CH 2CH 2C1) and a t h r e e - p r o t o n t r i p l e t a t T8.60 (-COOCH^CH^). These s p e c t r a l d a t a were i n complete agreement w i t h the s t r u c t u r e ( 9 7 , a ) . -38--39-( i i ) S y n t h e s i s of the P i p e r i d i n e M o i e t y Next we t u r n e d our a t t e n t i o n t o the s y n t h e s i s of the p i p e r i d i n e d e r i v a t i v e r e q u i r e d f o r t h i s sequence. D i f f i c u l t i e s encountered by ot h e r i n v e s t i g a t o r s ^ ' ^ i n t h i s l a b o r a t o r y i n the p r e p a r a t i o n of 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 (98,a) l e d us t o c a r r y out model r e a c t i o n s w i t h a r e a d i l y a v a i l a b l e p i p e r i d i n e . As the model compound we s e l e c t e d 3-c.a.rbomethoxy-p i p e r i d i n e (98) which was s y n t h e s i s e d by t h r e e d i f f e r e n t r o u t e s , as shown i n f i g u r e 30. I n sequence ( a ) , n i c o t i n i c a c i d (109) was c o n v e r t e d t o i t s e s t e r by r e a c t i o n w i t h methanol and c o n c e n t r a t e d s u l f u r i c a c i d ^ . However, the r e d u c t i o n of me t h y l n i c o t i n a t e (110) 65 w i t h p l a t i n u m o x i d e i n g l a c i a l a c e t i c a c i d p r o v i d e 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 (98) i n a low y i e l d , and we t h e r e f o r e sought methods of p r e p a r i n g n i p e c o t i c a c i d ( i l l ) which on e s t e r i f i c a t i o n would y i e l d the d e s i r e d m a t e r i a l . A s t r a i g h t f o r w a r d c a t a l y t i c r e d u c t i o n (rhodium c a t a l y s t ) of n i c o t i n i c a c i d u n c o m p l i c a t e d by h y d r o g e n o l y t i c d e c a r b o x y l a t i o n has been r e c e n t l y r e p o r t e d by F r e i f e l d e r ^ . F o l l o w i n g h i s procedure we prepared (sequence, b) n i p e c o t i c a c i d ( i l l ) i n 80% y i e l d and the l a t t e r on e s t e r i f i c a t i o n w i t h diazomethane gave two compounds, which c o u l d not be s e p a r a t e d by chromatography or 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 spectrum of t h i s m i x t u r e showed a b s o r p t i o n bands a t 3230 cm 1 and 1710 cm 1 c o r r e s p o n d i n g t o the (-NH) and the (-COOMe) groups r e s p e c t i v e l y . The u l t r a v i o l e t spectrum had no a b s o r p t i o n above 230 mu, s u g g e s t i n g t h a t n e i g h t product arose from i n c o m p l e t e h y d r o g e n a t i o n . A p a r t from the sharp s i n g l e t a t fio.40 (-COOCH^) the NMR spectrum was complex. -40-109 HAS04 N' 98 110 109 109 4 ^ COOH C H a N A 98 H 111 Br 112 COOH tfz0H 98 111 .a F i g u r e 30. S y n t h e s i s of 3- C a r b o m e t h o x y p i p e r i d i n e . At t h i s time a crude sample of 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 ( i l l , a ) became a v a i l a b l e . , E s t e r i f i c a t i o n w i t h m e t h a n o l i c hydrogen c h l o r i d e (sequence, c) gave a pure sample of 3-carbomethoxy-p i p e r i d i n e ( 9 8 ) , whose NMR spectrum was v e r y s i m i l a r t o t h a t of the m i x t u r e o b t a i n e d above. The most o u t s t a n d i n g d i f f e r e n c e was the absence of the sharp s i n g l e t a t T7.75 i n the spectrum of the pure sample. T h i s s i g n a l c o u l d be a s s i g n e d t o the m e t h y l p r o t o n s of an N-methyl group. We thus f e l t . t h a t the o t h e r component of the m i x t u r e c o u l d be the N-methylated product (112), and b e i n g a t e r t i a r y amine i t s presence would not i n t e r f e r e w i t h the c o u p l i n g r e a c t i o n . I n f a c t , c o u p l i n g r e a c t i o n were c a r r i e d out u s i n g the pure and the impure samples and i n each case s i m i l a r r e l a t i v e r e s u l t s were o b t a i n e d . -41-( i i i ) Coupling: R e a c t i o n s Having completed the s y n t h e s i s of the d e s i r e d p i p e r i d i n e , we t u r n e d our a t t e n t i o n t o c o u p l i n g i t w i t h the i n d o l e m o i ety ( 9 7 , a ) . T h i s c o u l d be a c c o m p l i s h e d by h e a t i n g a s o l u t i o n of 2-carboethoxy-3 - ( f 2 - c h l o r o e t h y l ) - i n d o l e (97,a) and 3 - c a r b o m e t h o x y p i p e r i d i h e - ( 9 8 ) i n d r y dioxane i n a s e a l e d tube f o r 12 hours a t 160°C. Chromatography of the crude b a s i c product y i e l d e d a c r y s t a l l i n e compound whose e l e m e n t a l a n a l y s i s suggested a f o r m u l a ^20^26^2^4* The i n f r a r e d spectrum of t h i s s o l i d showed two c a r b o n y l a b s o r p t i o n bands a t 1710 c m - 1 and 1670 cm - 1. S i m i l a r bands appear i n the i n f r a r e d s p e c t r a of the s t a r t i n g m a t e r i a l s (97,a) and ( 9 8 ) . The u l t r a v i o l e t spectrum (Amax 228 and 296 mu) was i d e n t i c a l w i t h t h a t of the s t a r t i n g i n d o l e ( 9 7 , a ) . The NMR spectrum ( f i g u r e 31) showed a broad one-proton s i n g l e t a t TO.80 (-NH), the normal f o u r - p r o t o n m u l t i p l e t c e n t r e d a t T 2 . 6 0 f o r the a r o m a t i c p r o t o n s on the i n d o l e n u c l e u s , a two-proton q u a r t e t atT5«50 (-COOCH^CH^), a sharp t h r e e - p r o t o n s i n g l e t a t T6.03 (-COOCH^) and a t h r e e - p r o t o n t r i p l e t a t T 8 . 6 0 (-COOCHgCH^). These s p e c t r a l d a t a are i n complete a c c o r d w i t h the proposed s t r u c t u r e (99, R=Bt). D u r i n g the i n v e s t i g 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 i t s e l f , we found i t n e c e s s a r y t o prepare c o u p l i n g p r o d u c t s h a v i n g s i m i l a r e s t e r f u n c t i o n s a t t a c h e d t o the i n d o l e and. p i p e r i d i n e p o r t i o n s of the m o l e c u l e , eg. 99, R=Me. T h i s was done t o e l i m i n a t e d i f f i c u l t i e s due t o e s t e r exchange i n t h e . a c y l o i n c o n d e n s a t i o n (see l a t e r ) . F o r t h i s purpose we p r e p a r e d 2 - c a r b o m e t h o x y - 3 - 0 - c h l o r o e t h y l ) - i n d o l e by h e a t i n g (97,a) w i t h -42-a l a r g e excess of dry methanol i n the presence of c o n c e n t r a t e d s u l f u r i c a c i d . T h i s r e a c t i o n c o u l d be f o l l o w e d by o b s e r v i n g the d i s a p p e a r a n c e i n the NMR spectrum of the h i g h f i e l d t r i p l e t a t T8.60 due t o the me t h y l p r o t o n s of the e t h y l e s t e r . The met h y l p r o t o n s of the methy l e s t e r appeared as a sharp s i n g l e t at T6.06. The c o u p l i n g product (99, R=Me) was s y n t h e s i s e d by the procedure d e s c r i b e d f o r the p r e p a r a t i o n of (99> R=Et) .. A l t h o u g h the u l t r a v i o l e t and i n f r a r e d s p e c t r a of these p r o d c u t s were su p e r i m p o s a b l e , they were c l e a r l y d i s t i n g u i s h a b l e by t h e i r NMR s p e c t r a , f i g u r e s 31 and 32. The crude c o u p l i n g product c o u l d be s e p a r a t e d i n t o b a s i c and n o n - b a s i c f r a c t i o n s . The b a s i c f r a c t i o n c o n t a i n e d the c o u p l i n g product and the u n r e a c t e d p i p e r i d i n e . A p a r t from the u n r e a c t e d i n d o l e , d e r i v a t i v e , the no n - b a s i c f r a c t i o n , i n some i n s t a n c e s c o n t a i n e d a c r y s t a l l i n e b y - p r o d u c t . E l e m e n t a l a n a l y s i s suggested a f o r m u l a , C^-^HgNO^, wh i c h was c o n f i r m e d by a mass s p e c t r o m e t r i c m o l e c u l a r weight (m/e 187),. The u l t r a v i o l e t spectrum was i d e n t i c a l w i t h t h a t . o f the i n d o l e d e r i v a t i v e (97,b), w h i l e the i n f r a r e d spectrum c o n t a i n e d a c a r b o n y l a b s o r p t i o n a t 1690 cm 1 c h a r a c t e r i s t i c of an <*f?-unsaturated S - l a c t o n e , as w e l l as i n d o l e NH a b s o r p t i o n at 3250 cm - 1. The M R spectrum ( f i g u r e 33) had a broad one-proton a b s o r p t i o n a t TO.40 c h a r a c t e r i s t i c o f the i n d o l e NH, the normal f o u r - p r o t o n m u l t i p l e t c e n t r e d a t T2.60 f o r the a r o m a t i c p r o t o n s on the i n d o l e n u c l e u s , a two-proton t r i p l e t atT5.36 (-COOCIL^C^-) and a two-proton t r i p l e t atT6.90 (-C00CH„CH - ) . That these -43-Figure 32 7 8 - 4 6 -l a t t e r f o u r p r o t o n s are a t t a c h e d t o a d j a c e n t carbon atoms was e s t a b l i s h e d by d e c o u p l i n g e x p e r i m e n t s . T h i s evidence i s i n complete agreement w i t h the s t r u c t u r e ( 1 1 3 ) . ( i v ) A c y l o i n C o n d e n s a t i o n H a v i n g p r e p a r e d t h e n e c e s s a r y c o u p l i n g p r o d u c t s we next t u r n e d out a t t e n t i o n t o the a c y l o i n c o n d e n s a t i o n . U s i n g the i n t e r m e d i a t e (99» R=Et), the a c y l o i n c o n d e n s a t i o n was c a r r i e d out i n the presence of sodium and r e f l u x i n g t o l u e n e . The crude p r o d u c t , as shown by t h i n l a y e r chromatography, c o n t a i n e d t h r e e components h a v i n g R^ v a l u e s v e r y s i m i l a r t o t h a t of the s t a r t i n g m a t e r i a l . These t h r e e components were 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 , ;layer chromatography. A l t h o u g h t h e i r i n f r a r e d and u l t r a v i o l e t s p e c t r a were v e r y s i m i l a r t o t h a t of the s t a r t i n g m a t e r i a l , the NMR s p e c t r a suggested t h a t the major component was u n r e a c t e d s t a r t i n g m a t e r i a l and t h a t the.'other two components arose from e s t e r exchange. To a v o i d c o m p l i c a t i o n s r e s u l t i n g from e s t e r exchange we d e c i d e d t o study the a c y l o i n c o n d e n s a t i o n w i t h an i n t e r m e d i a t e h a v i n g s i m i l a r e s t e r groups, namely, (99, R=Me). P u r i f i c a t i o n of the crude a c y l o i n c o n d e n s a t i o n product y i e l d e d , i n a d d i t i o n t o 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 , a p o l a r f r a c t i o n which was m a i n l y one component. F u r t h e r c h a r a c t e r i s a t i o n of t h i s compound by s p e c t r o s c o p i c " . . . t e c h n i q u e s ' - u n s u c c e s s f u l . . '.. I n an attempt t o c h a r a c t e r i s e t h i s p o l a r m a t e r i a l we f e l t i t advantageous t o remove the c a r b o n y l f u n c t i o n w h i c h would be p r e s e n t i n the product of an a c y l o i n c o n d e n s a t i o n (see i n t e r m e d i a t e 100). R e d u c t i o n w i t h l i t h i u m aluminum - 4 7 -P o l a r M a t e r i a l from 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 114 115 I I dc a 0 N CH,Oflc CH,0<)c 99, R=Me 116 h y d r i d e i n t e t r a h y d r o f u r a n p r o v i d e d a product whose u l t r a v i o l e t spectrum (>jnax 224, 2 7 6 ( s h ) , 284, 292 mu) was c h a r a c t e r i s t i c of a t y p i c a l i n d o l e . The NMR spectrum c o n t a i n e d the normal m u l t i p l e t c e n t r e d a t T2.60 due t o 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 , a sharp two-proton s i n g l e t a t T 5 . 4 2 c h a r a c t e r i s t i c of the methylene p r o t o n s of a c a r b i n o l group a t t a c h e d t o an a r o m a t i c system ( c f . CgH^CH^OH a t 7^5.60) and a two p r o t o n d o u b l e t a t 7^6.65 (-CHCH^OH). A c e t y l a t i o n of t h i s compound w i t h a c e t i c a n h y d r i d e and p y r i d i n e y i e l d e d a d i a c e t a t e whose NMR spectrum c o n t a i n e d a two-proton s i n g l e t a t T4.80 and a two-proton d o u b l e t a t T6.05. T h i s d o w n f i e l d s h i f t of a p p r o x i m a t e l y 0.60 i n the resonance of the ©-methylene pr o t o n s -48-i s i n agreement w i t h the a c e t y l a t i o n s h i f t s observed f o r p r i m a r y a l c o h o l s . T h i s evidence s t r o n g l y s u g gests t h a t the compound a r i s i n g from the r e d u c t i o n w i t h l i t h i u m aluminum h y d r i d e i s the d i o l (114) which on a c e t y l a t i o n g i v e s the d i a c e t a t e ( 1 1 5 ) . A d d i t i o n a l e v i d e n c e s u p p o r t i n g t h i s assignment was o b t a i n e d by r e d u c i n g the c o u p l i n g product w i t h l i t h i u m aluminum h y d r i d e t o an a l c o h o l w h i c h was i d e n t i c a l w i t h ( 114). A c e t y l a t i o n of t h i s d i o l y i e l d e d the d i a c e t a t e ( 1 1 5 ) . These r e s u l t s show t h a t the crude a c y l o i n product i s a 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 i t s h y d r o l y s i s p r o d u c t ( s ) . One would expect t h i s t o be c o n f i r m e d by r e - e s t e r i f i c a t i o n of the crude r e a c t i o n w i t h diazomethane t o g i v e s t a r t i n g m a t e r i a l . B e f o r e p e r s u i n g t h i s thought, i t was n e c e s s a r y t o e s t a b l i s h t h a t no c o m p l i c a t e d s i d e r e a c t i o n s occured on r e - e s t e r i f i c a t i o n of the h y d r o l y s e d c o u p l i n g product w i t h diazomethane. F o r t h i s purpose we p r e p a r e d the d i a c i d (116) w h i c h was q u a n t i t a t i v e l y r e c o n v e r t e d t o the c o u p l i n g product (.99, R=Me) by t r e a t m e n t w i t h diazomethane, thus c o n f i r m i n g t h a t the o n l y r e a c t i o n o c c u r i n g was o - m e t h y l a t i o n . The crude a c y l o i n product on t r e a t m e n t w i t h diazomethane gave a m i x t u r e of compounds. One of these had the same v a l u e as t h a t of the c o u p l i n g product (99, R=Me). T h e r e f o r e we can conclude t h a t the crude a c y l o i n product i s a m i x t u r e of s t a r t i n g m a t e r i a l , components r e s u l t i n g from i t ' s h y d r o l y s i s and some o t h e r m a t e r i a l s , which have not y e t been f u l l y c h a r a c t e r i s e d . On account of the low y i e l d s and d i f f i c u l t i e s i n p u r i f y i n g the a c y l o i n c o n d e n s a t i o n product we proceeded - 4 9 -F i g u r e 3 4 . Yamada's C y c l i s a t i o n t o P r o v i d e the E i g h t -membered R i n g I n t e r m e d i a t e (118). F i g u r e 35. P o s s i b l e E x t e n s i o n t o Our Sequence A. i n v e s t i g a t e the second of the two major approaches, scheme B. I n the l i g h t of the p r e s e n t d i s c u s s i o n on the f o r m a t i o n of the nine-membered r i n g i t i s i n t e r e s t i n g t o mention the r e c e n t f i n d i n g s of Yamada^ who s y n t h e s i s e d the carbon s k e l e t o n of the 2 - a c y l i n d o l e a l k a l o i d s . The c r u c i a l s t e p i n t h i s s y n t h e s i s i s the i n t r a m o l e c u l a r c y c l i s a t i o n of (117) i n the presence of p o l y p h o s p h o r i c a c i d t o g i v e the eight-membered r i n g i n t e r m e d i a t e ( 1 1 8 ) , f i g u r e 3 4 . A v e r y a t t r a c t i v e e x t e n s i o n of our work would be t o prepare a s u i t a b l y s u b s t i t u t e d p i p e r i d i n e (120) wh i c h on c o u p l i n g w i t h an i n d o l e d e r i v a t i v e l i k e (119) would p r o v i d e the i n t e r m e d i a t e (121). C y c l i s a t i o n a c c o r d i n g t o Yamada's procedure s h o u l d g i v e the nine-membered r i n g i n t e r m e d i a t e ( 1 2 2 ) , f i g u r e 3 5 . - 5 0 -I I . Scheme B The c r u c i a l s t e p s of t h i s approach are o u t l i n e d i n f i g u r e 2 5 . B e f o r e d i s c u s s i n g our e x p e r i m e n t a l , r e s u l t s i n d e t a i l i t i s a p p r o p r i a t e t o r e v i e w b r i e f l y the e x p e r i m e n t a l r e s u l t s of o t h e r workers s i n c e t h e s e p r o v i d e d some encouragement f o r the p o s s i b l e success of an a t t r a c t i v e and g e n e r a l approach t o the s y n t h e s i s of nine-membered r i n g s . The f i r s t c r u c i a l s t e p i s the f o r m a t i o n of the i n d o l o p y r r o c o l i n e d e r i v a t i v e ( 1 2 5 ) . A l t h o u g h t h e r e are no examples of the f o r m a t i o n of t h i s system by the c y c l o d e h y d r a t i o n of an N - [ 3 - ( 3 - i n d o l y l ) -e t h y l ] - s u c c i n i m i d e ( 1 2 7 ) , c y c l o d e h y d r a t i o n s of amides, as i n the B i s c h l e r - N a p i e r a l s k i s y n t h e s i s , i s w e l l k nown^. W e n k e r t ^ was unable t o c y c l i s e the imide (127) t o the i n d o l o p y r r o c o l i n e system (128) w i t h phosphorus o x y c h l o r i d e , which as been g e n e r a l l y 71 the reagent of c h o i c e . M o r r i s o n a l s o found t h a t the c y c l i s a t i o n of N - f / 3 - ( 3 - i n d o l y l ) e t h y l ) - g l u t a r i m i d e (129) under s i m i l a r c o n d i t i o n s was u n s u c c e s s f u l . However when phosphorus p e n t o x i d e was used M o r r i s o n was a b l e t o i s o l a t e the d e s i r e d ene-lactam (130) i n a 31% y i e l d . - 5 1 -F i g u r e 36. Wenkert's S y n t h e s i s of O c t a h y d r o f l a v o p e r e i r i n e . An a l t e r n a t e approach t o the s y n t h e s i s of the i n d o l o p y r r o c o l i n e d e r i v a t i v e (125) i s based on the o x i d a t i v e c y c l i s a t i o n of the i n t e r m e d i a t e amine ('124). which i s r e a d i l y prepared by 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 i n t e r m e d i a t e • ( 1 2 3 ) . 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 of the t e t r a h y d r o c a r b o l i n e type by o x i d a t i v e or r e d u c t i v e c y c l i s a t i o n s from 2,3-seco p r e c u r s o r s 72 73 has been r e c e n t l y reported,, ' . Of p a r t i c u l a r i n t e r e s t t o 73 our sequence i s Wenkert's , s y n t h e s i s of o c t a h y d r o f l a v o -p e r e i n e s ( l 3 l ) by 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 o f N - ( J 3 - ( 3 - i n d o l y l ) - e t h y l ) - 3 - e t h y l p i p e r i d i n e (132), see f i g u r e 36. The f o r m a t i o n of q u a t e r n a r y ammonium s a l t s of the type (126) i n the i n d o l e a l k a l o i d s e r i e s i s well-known. F o r i n s t a n c e , i n an attempted p r e p a r a t i o n of the o - t o s y l a t e of i b o x y g a i n e ( 1 3 3 ) , the t o s y l a t e r e a d i l y underwent an i n t e r n a l c y c l i s a t i o n and on l y the i o n i c t o s y l a t e of the q u a t e r n a r y compound (134) 74 c o u l d be i s o l a t e d . An example which bears a c l o s e r e l a t i o n s h i p - 5 2 -F i g u r e 37.. t o our i n t e r m e d i a t e i s the q u a t e r n a r y s a l t (115) prepar e d by D o l b y 7 5 . R e d u c t i v e c l e a v a g e of a C-N bond i n a q u a t e r n a r y ammonium s a l t , w h i c h i s p r o b a b l y the most i m p o r t a n t r e a c t i o n i n our sequence has a l s o been used i n the a l k a l o i d f i e l d . Examples c l o s e l y r e l a t e d t o our sequence can be found i n the f o r m a t i o n of a nine-membered system (137) by means of a lithium-ammonia" -r e d u c t i o n of the i n t e r m e d i a t e ( 1 3 6 ) , and the 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 q u a t e r n a r y ammonium s a l t ( 1 3 5 ) . A d d i t i o n a l e vidence t o support the g e n e r a l i t y of t h i s r e a c t i o n -53-H0CH 2CH 2CH 20H Na (141) !6H5C L 2 « ~ " 2 V " 2 V " 2 ; q 6 H 5 C H 2 c i -COOEt C rH,_CH„0C!HoCHnCH C - Et -COOEt (144) NaOH COOH C.H CCH OCH CH CH 0C-Et 6 5 2 2 2 2 6 o Q H (145) gooEt H-C-Et COOEt A -CO, CH 2COOEt (c H ) c Na C.H CH OCH CH CH C-COOEt < 6 5 ' 3  b ^  d Z d dM BrCH 2C00Et (148) C cH cCH o0CH oCH oCH o0H b o 2 2 2 d (142) I S0C1, C cH cCH o0CE_CH oCH oCl 6 5 2 2 2 2 (143) H C^CH^OCH^CH^CH^CCOOH (146) E t EtOH^ H 2 S ° 4 C^-HCH0CH oCHCH_C-COOEt 6 5 2 2 2 2£ t (147) F i g u r e 38. S y n t h e s i s of the S u c c i n a t e D e r i v a t i v e ( 1 4 8 ) . comes from r e c e n t i n v e s t i g a t i o n s i n our l a b o r a t o r y , i n which the m e t h i o d i d e of d i h y d r o c o r y n a n t h e a l e t h l e n e a c e t a l , ( l 3 9 ) i s reduced i n the presence of sodium and l i q u i d ammonia, t o g i v e the compound ( 1 4 0 ) , see f i g u r e 37. ( i ) S y n t h e s i s of the S u c c i n a t e D e r i v a t i v e We w i l l now t u r n our d i s c u s s i o n t o the s y n t h e s i s of the d i e t h y l s u c c i n a t e d e r i v a t i v e r e q u i r e d f o r the 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 . The s u c c e s s f u l sequence l e a d i n g t o t h i s compound i s o u t l i n e d i n f i g u r e 38. S i n c e t h i s work has a l r e a d y 54 a been p r e s e n t e d i n a p r e v i o u s t h e s i s ' i t ' w i l l not be n e c e s s a r y t o d i s c u s s i t i n g r e a t d e t a i l . 77 tf-Benzyloxypropanol (142) was prepare d i n 65$ y i e l d by condensing the monosodium s a l t of p r o p a n e - 1 , 3 - d i o l (141) w i t h - 5 4 -b e n z y l c h l o r i d e . The tr e a t m e n t of (142) w i t h t h i o n y l c h l o r i d e 7ft gave l - c h l o r o - 3 - b e n z y l o x y p r o p a n e (143) i n 80$ y i e l d , and t h i s compound on a l k y l a t i o n w i t h d i e t h y l e t h y l m a l o n a t e y i e l d e d d i e t h y l tf-benzyloxypropylethylmalonate (144) i n 47$ y i e l d . The most c h a r a c t e r i s t i c f e a t u r e s of the NMR spectrum of (144) a r e , a f i v e - p r o t o n s i n g l e t a t T2.75 due t o the a r o m a t i c p r o t o n s , a two-proton s i n g l e t a t T5.56 due t o the b e n z y l methylene, a two-proton t r i p l e t a t 76 .5 .8 a r i s i n g from the p r o p y l methylene a d j a c e n t t o . t h e e t h e r oxygen, a f o u r - p r o t o n q u a r t e t a t 7 5 . 8 6 and a s i x - p r o t o n t r i p l e t a t 78.82 due t o the two e t h y l e s t e r groups, and f i n a l l y a t h r e e - p r o t o n t r i p l e t a t 79.20 due t o the m e t h y l p r o t o n s of the e t h y l s u b s t i t u e n t . The resonances at 2.75, 5 .56 and 7 6 . 5 8 i n t h i s compound due t o the b e n z y l o x y p r o p y l group, are a t s i m i l a r p o s i t i o n s i n subsequent compounds c o n t a i n i n g t h i s group, a n d ' w i l l hot be s p e c i f i c a l l y mentioned i n each case. H y d r o l y s i s of (144) w i t h po t a s s i u m h y d r o x i d e gave the c r y s t a l l i n e } f - b e n z y l o x y p r o p y l e t h y l m a l o n i c a c i d ( 1 4 5 ) . The NMR spectrum no l o n g e r c o n t a i n e d the q u a r t e t at T 5 . 8 6 and the t r i p l e t a t 78.82 due t o the e t h y l e s t e r groups, but c o n t a i n e d a new sharp s i n g l e t a t 7 - 1 . 5 0 a s s i g n a b l e t o the two c a r b o x y l i c a c i d p r o t o n s . The mother l i q u o r s from the c r y s t a l l i s a t i o n of (145) c o n t a i n e d two p o l a r compounds, as shown by t h i n l a y e r chromatography. One of these had an R^ v a l u e i d e n t i c a l t o t h a t of the d i a c i d ( 1 4 5 ) . The NMR spectrum of t h i s m i x t u r e ( q u a r t e t a t 7 5.82 and. a t r i p l e t a t T 8.80) suggested t h a t the o t h e r component was the monoester d e r i v a t i v e ( 1 4 9 ) . T h i s s u g g e s t i o n was co n f i r m e d when (149) was d e c a r b o x y l a t e d t o g i v e e t h y l 2 - ( t f - b e n z y l o x y p r o p y l ) - b u t a n o a t e ( 1 4 7 ) , i d e n t i c a l w i t h the m a t e r i a l p r e p a r e d i n a subsequent r e a c t i o n . COOEt A COOEt C cH_CH o0CH oCH oCH o6Bt > C.H cCH o0CH oCH oCH oCEt 6 5 2 2 2 2 C 0 0 H _ C Q a 6 5 2 2 2 2£ 149 147 fl'-Benzyloxypropylethyl m a l o n i c a c i d (145) was smoothly d e c a r b o x y l a t e d a t 160°C t o p r o v i d e the 2 - ( < f - b e n z y l o x y l p r o p y l ) -b u t a n o i c a c i d ( 1 4 6 ) , w h i c h was used f o r subsequent r e a c t i o n w i t h o u t f u r t h e r p u r i f i c a t i o n . The crude a c i d (146) was e s t e r i f i e d 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 e t h y l 2-(i3f-benzyloxypropyl)-butanoate (147). I n a d d i t i o n t o the a b s o r p t i o n s a r i s i n g from the presence of the b e n z y l o x y p r o p y l group, the M R spectrum showed the presence of a one-proton m u l t i p l e t a t?" 7.80 due t o the t e r t i a r y p r o t o n ( - 6 H C 0 0 E t ) , a two-proton q u a r t e t a t T5.95 and a t h r e e - p r o t o n t r i p l e t a t T8.85 due t o the e t h y l e s t e r f u n c t i o n . The monoester (147) was a l k y l a t e d w i t h «^-bromoe t h y 1 a c e t a t e i n the presence of t r i p h e n y l m e t h y l sodium t o g i v e the d e s i r e d s u c c i n a t e d e r i v a t i v e (148) i n 40% y i e l d . The p u r i t y of (148) was most c o n v e n i e n t l y a s s e s s e d by vapor phase chromatography; the s u c c i n a t e (148) h a v i n g a l o n g e r r e t e n t i o n time (3x t h a t of the monoester, 147). The NMR spectrum showed a new sharp two-proton s i n g l e t a t T7.40 due t o the methylene -56-p r o t o n s (-icH^COOEt). The two e s t e r groups were not m a g n e t i c a l l y e q u i v a l e n t g i v i n g r i s e t o two q u a r t e t s and two t r i p l e t s a t T5.92 and T8.82 r e s p e c t i v e l y . 81 Attempts t o prepare (148) u s i n g m e t h y l s u l f i n y l • c a r b a n i o n as the base r e s u l t e d i n the t o t a l r e c o v e r y of the s t a r t i n g m a t e r i a l (147) ( i i ) C o n d e n s a t i o n w i t h Tryptamine Having the r e q u i r e d s u c c i n a t e d e r i v a t i v e a t hand we next c o n s i d e r e d the 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 . Indeed we were a b l e t o o b t a i n the imide (123) by r e f i u x i n g a m i x t u r e of t r y p t a m i n e and the s u c c i n a t e e s t e r (148) f o r 48 h*". i n . d i e t h y l e n e g l y c o l monoethyl e t h e r . The crude imid e (123) was p u r i f i e d by chromatography on a l u m i n a and i n s p i t e of numerous attempts i t r e s i s t e d c r y s t a l l i s a t i o n from a v a r i e t y of s o l v e n t s . E l e m e n t a l a n a l y s i s suggested a f o r m u l a , ^26^30^2^3' w k ^ c k w a s s u p p o r t e d by the m o l e c u l a r ion; peak(m/e 418), f i g u r e 4 0 , i n the mass spectrum. The u l t r a v i o l e t spectrum showed the t y p i c a l a b s o r p t i o n of an i n d o l e (^max 224, 2 7 5 ( s h ) , 282, 290 mu), and the i n f r a r e d spectrum showed two c a r b o n y l a b s o r p t i o n bands a t 1760 cm-"'" (weak) and 1690 c m - 1 ( s t r o n g ) which 79 are: c h a r a c t e r i s t i c of the s u c c i n i m i d e system . I n a d d i t i o n t o the b e n z y l o x y p r o p y l group the NMR spectrum showed a one-p r o t o n d o u b l e t a t T3.60 due t o the o(.-proton on the i n d o l e 80 n u c l e u s , two t r i p l e t s a t ?6.18 and T?.00 a r i s i n g from the e t h y l e n e b r i d g e , a two-proton s i n g l e t a t 71.6.0 due t o the methylene of the s u c c i n i m i d e moiety and f i n a l l y a t h r e e -p r o t o n t r i p l e t a t T9.26 due t o the m e t h y l p r o t o n s of the e t h y l s u b s t i t u e n t . -57-P i g u r e 39. ( i i i ) ^ C y c l i s a t i o n 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 The next s t e p i n the sequence i n v o l v e d the c y c l i s a t i o n of the s u c c i n i m i d e r i n g onto the d l - p o s i t i o n of the i n d o l e n u c l e u s . F o r t h i s purpose the 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 was f i r s t c o n s i d e r e d . F o l l o w i n g the e x p e r i m e n t a l c o n d i t i o n s d e s c r i b e d 71 by M o r r i s o n , the c y c l i s a t i o n of the imide (123) t o p r o v i d e the d e s i r e d ene-lactam (150) was accompanied by the l o s s of the b e n z y l o x y group t o g i v e a t e r m i n a l double bond. T h i s p r o d u c t , w h i c h was o b t a i n e d i n poor y i e l d (5%) would r e q u i r e subsequent h y d r a t i o n of the t e r m i n a l o l e f i n i c double bond t o enable the q u a t e r n a r y ammonium s a l t t o be f i n a l l y formed. -58-I n a c o n c u r r e n t i n v e s t i g a t i o n ( f i g u r e 39) the y - c h l o r o - p r o p y l analogue of the imide ( 1 5 1 ) , which would not be expected t o undergo e l i m i n a t i o n under B i s c h l e r - N a p i e r a l s k i c o n d i t i o n s was employed. The c h l o r o compound was c y c l i s e d under the same c o n d i t i o n s t o p r o v i d e the d e s i r e d i n t e r m e d i a t e (152) i n 18% y i e l d . T h i s was smoothly reduced w i t h p l a t i n u m o x i d e i n a c e t i c a c i d t o the c h l o r o l a c t a m (153). However, r e d u c t i o n of t h i s l a c t a m w i t h l i t h i u m aluminum h y d r i d e was accompanied by the h y d r o g e n o l y s i s of the c h l o r i n e group. S i n c e t h i s r e a c t i o n product (154) no l o n g e r possessed any f u n c t i o n a l i t y i n the p r o p y l s i d e c h a i n , i t too was i m p r a c t i c a l f o r our s y n t h e s i s . W i t h these e x p e r i m e n t a l f a c t s i n hand we c o n s i d e r e d the c y c l i s a t i o n of the imide (123) u s i n g m i l d e r c o n d i t i o n s . F o r t h i s purpose we reduced the r e a c t i o n time and changed the s o l v e n t from x y l e n e t o t o l u e n e . Treatment of the imide (123) under th e s e c o n d i t i o n s p r o v i d e d an amorphous y e l l o w s o l i d (10%) HC1 whose u l t r a v i o l e t spectrum Qmax 224, 313, 326 mu; Amax 395 mu) 71 was i n p e r f e c t agreement w i t h t h a t r e p o r t e d f o r compound (1 3 0 ) . The mass spectrum ( f i g u r e 40) had a m o l e c u l a r i o n peak (m/e 310) w h i c h cor r e s p o n d s t o the m o l e c u l a r f o r m u l a , £^^22^2^2' a n c ^ a s t r o n g peak at (M-18) c o r r e s p o n d i n g t o the l o s s of water. These s p e c t r a l p r o p e r t i e s a r e i n agreement w i t h the s t r u c t u r e (155) w h i c h now p o s s e s s e s the s u i t a b l y f u n c t i o n a l i s e d p r o p y l s i d e c h a i n . Due t o i t s s u s c e p t i b i l i t y t o a i r o x i d a t i o n , the crude c y c l i s a t i o n product was hydrogenated u s i n g p l a t i n u m oxide i n a c e t i c a c i d . The i n d o l i c u l t r a v i o l e t , spectrum of t h i s crude h y d r o g e n a t i o n product i n d i c a t e d t h a t the double bond of the -60-l a c t a m r i n g had been s a t u r a t e d . A complete s e p a r a t i o n of the p r o d u c t s of h y d r o g e n a t i o n was u n s u c c e s s f u l and the low y i e l d s of t h e s e r e a c t i o n s caused us t o c o n s i d e r the a l t e r n a t e r o u t e t o the f o r m a t i o n of the i n d o l o p y r r o c o l i n e system. 123 I n o r d e r t o study the a l t e r n a t e approach i t was f i r s t n e c e s s a r y t o i n v e s t i g a t e methods of r e d u c i n g the imide (123) t o the b e n z y l e t h e r amine (124). ( i v ) R e d u c t i o n of the Imide (123) The im i d e (123) was reduced w i t h l i t h i u m aluminum h y d r i d e under m i l d c o n d i t i o n s t o p r o v i d e the d e s i r e d b e n z y l e t h e r amine (124) as a c l e a r o i l which r e s i s t e d c r y s t a l l i s a t i o n . . 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 , w h i l e the i n f r a r e d spectrum l a c k e d the c h a r a c t e r i s t i c imide a b s o r p t i o n . The NMR spectrum ( f i g u r e 41) showed the presence of the b e n z y l o x y p r o p y l group, a one-proton d o u b l e t a t T3.22 due t o thec<-hydrogen on the i n d o l e n u c l e u s and a two-proton s i n g l e t a t T 7 . 5 9 ("N'-CH -C^-). The m o l e c u l a r f o r m u l a , C*2gH.^N2'0, 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 s p e c t r o m e t r y , which p r o v i d e d the v a l u e 390.269 ( c a l c u l a t e d v a l u e 390.267). The mass spectrum ( f i g u r e 43) a l s o r e v e a l e d the expected f r a g m e n t a t i o n t o p r o v i d e the base peak -61--63--64-157 m/e = 144 158 m/e = :143 160 m/e = 91 156. m/e = 260 a t m/e 260 due t o the s t a b l e i o n (156). The peaks a t m/e 144, 143 and 130,. a s s i g n e d t o the fragments (157,. 158 and 159, op r e s p e c t i v e l y ) are due t o the i n d o l e nucleus.. . The peak at m/e 91 i s due t o the t r o p y l i u m i o n (160) which o r i g i n a t e s from the b e n z y l group. D u r i n g the i n v e s t i g a t i o n s of the r e d u c t i o n of the i m i d e , i t was noted t h a t t r e a t m e n t w i t h l i t h i u m aluminum h y d r i d e under v i g o r o u s c o n d i t i o n s l e d t o h y d r o g e n o l y s i s of the b e n z y l -65-group. The u l t r a v i o l e t spectrum of t h i s a m i n o a l c o h o l ( l 6 l ) had a t y p i c a l i n d o l e a b s o r p t i o n p a t t e r n , w h i l e the NMR spectrum ( f i g u r e 42) l a c k e d the a b s o r p t i o n s due t o the b e n z y l group. The new two-proton t r i p l e t a t T6.40 i s due t o the methylene p r o t o n s of the pr i m a r y a l c o h o l and the broad one-proton s i n g l e t a t T6.80 was- a s s i g n e d t o the h y d r o x y l p r o t o n on the b a s i s of i t s d i s a p p e a r a n c e on a d d i t i o n of D 20. Deuterium exchange a l s o caused the d o u b l e t a t T 3 . 0 5 due t o t h e ^ - p r o t o n on the i n d o l e n u c l e u s c o l l a p s e s t o a s i n g l e t . I t i s noteworthy t h a t i n . c o n t r a s t t o the NMR spectrum ( f i g u r e 41) of the u n c y c l i s e d b e n z y l e t h e r , the amine (161) shows no n - e q u i v a l e n c e f o r the methylene p r o t o n s ( - N - C H 2 - C £ o . The mass spectrum ( f i g u r e 43) showed a m o l e c u l a r i o n peak (m/e 300) i n agreement w i t h the e m p i r i c a l f o r m u l a , C ^ B ^ g ^ O , and the expected f r a g m e n t a t i o n t o a base peak a t m/e 170 due t o the s t a b l e fragment ( 1 6 2 ) . The presence of peaks a t m/e 144, 143 and 130 due t o the i n d o l e n u c l e u s were a l s o n o t e d . (v) O x i d a t i v e C y c l i s a t i o n H a ving p r e p a r e d the b e n z y l e t h e r amine (124) we now t u r n e d t o the p r e p a r a t i o n of the i n t e r m e d i a t e ( 1 2 5 ) . I n view of the r e c e n t a p p l i c a t i o n s of m e r c u r i c a c e t a t e i n the o x i d a t i v e 34-37 t r a n s a n n u l a r c y c l i s a t i o n s i n t h i s l a b o r a t o r y and by 73 Wenkert i t was c o n s i d e r e d an a p p r o p r i a t e reagent f o r our purpose. I t was f o r t u n a t e t h a t the m e r c u r i c a c e t a t e - i n d u c e d c o n v e r s i o n of (124) t o (125) l e d f u r t h e r t o the o v e r o x i d i s e d p r o d u c t ( 1 6 3 ) . The f o r m a t i o n of t h i s l a t t e r substance made i t p o s s i b l e t o f o l l o w the p r o g r e s s of the r e a c t i o n by o b s e r v i n g -66-(dl)-Quebrachamine 166 F i g u r e 44 ^ -67-the appearance of a new a b s o r p t i o n (Amax 353 mu) i n the u l t r a v i o l e t spectrum. Optimum y i e l d s of the c y c l i s e d m a t e r i a l s were o b t a i n e d when (a)_, the o x i d a t i o n was a l l o w e d t o proceed a t room temperature f o r 12 hours b e f o r e r e f l u x i n g and (b)^ the crude p r o d u c t s of the o x i d a t i o n were im m e d i a t e l y reduced w i t h sodium b o r o h y d r i d e . M o l e c u l a r models suggest t h a t t h i s l a t t e r r e d u c t i o n would p r o b a b l y proceed i n a n o n - s t e r e o s p e c i f i c manner s i n c e t h e r e was no apparent p r e f e r e n c e f o r e i t h e r dLor ft approach of the r e d u c i n g agent. A l t h o u g h t h e r e are t h r e e d i r e c t i o n s i n which the o x i d a t i o n can o c c u r , o n l y the two e n d o c y c l i c iminium i o n s would l e a d t o c y c l i s e d p r o d u c t s . One would expect the c y c l i s a t i o n of the iminium s a l t (165) t o occur t o a l e s s e r e x t e n t s i n c e i t would g i v e r i s e t o the s t e r i c a l l y l e s s f a v o r e d s t r u c t u r e (166), f i g u r e 44. A g r e a t d e a l of d i f f i c u l t y was encountered i n the attempted s e p a r a t i o n of the crude m i x t u r e of s t e r e o i s o m e r i c components r e s u l t i n g from the c y c l i s a t i o n r e a c t i o n . I n f a c t , we were not s u c c e s s f u l i n a c h i e v i n g complete r e s o l u t i o n of t h i s m i x t u r e and the s p e c t r a l d a t a quoted were o b t a i n e d on a m i x t u r e of. components. The major f r a c t i o n s c o n t a i n e d t h r e e components whose R^ v a l u e s , by t h i n l a y e r chromatography, were v e r y s i m i l a r t o each o t h e r and t o t h a t of the s t a r t i n g m a t e r i a l (124). A p a r t i a l s e p a r a t i o n of the l e a s t p o l a r component from the other two was accompanied by l a r g e l o s s e s of m a t e r i a l . Even i n t h i s i n s t a n c e i t was s t i l l impure and c o m p l e t e l y d e f i n i t i v e s p e c t r a l -68-d a t a c o u l d not be o b t a i n e d . However, s p e c t r a l d a t a on the r e m a i n i n g m i x t u r e c o n t a i n i n g the two more p o l a r components gave v a l u a b l e i n f o r m a t i o n and i t i s t h e r e f o r e p r e s e n t e d i n d e t a i l . The u l t r a v i o l e t spectrum e x h i b i t e d a normal i n d o l e a b s o r p t i o n w h i l e the NMR spectrum showed t h a t the b e n z y l o x y group was s t i l l p r e s e n t and t h a t the d o u b l e t a t T 3 . 2 0 due t o the <<-proton on the i n d o l e r i n g was absent. T h i s i n d i c a t e s t h a t t h e m i x t u r e d i d not c o n t a i n any u n c y c l i s e d m a t e r i a l . F u r thermore, the appearance of a sharp s i n g l e t a t T8.04 (•N-CH_2~c£) i n d i c a t e d t h a t a t l e a s t one of the components i n t h i s m i x t u r e must r e p r e s e n t the d e s i r e d c y c l i c s t r u c t u r e (125). The a l t e r n a t e c y c l i s a t i o n p r o d uct (166) would e x h i b i t a m u l t i p l e t f o r the methylene p r o t o n s a t t a c h e d t o the b a s i c n i t r o g e n . The mass spectrum suggested a m o l e c u l a r i o n a t m/e 388 whose a c c u r a t e mass' i n the h i g h - r e s o l u t i o n mass spectrum was 388.251 ( c a l c u l a t e d f o r C 2 6 H 3 2 N 2 0 , 588.251). T h i s l a t t e r r e s u l t s u p p o r t e d the above NMR d a t a and suggested t h a t these i n s e p a r a b l e components were i s o m e r i c c y c l i c p r o d u c t s . The most d i a g n o s t i c peaks i n the mass spectrum were found a t m/e 184, 170, 169, and 156. These f o u r peaks, a t t r i b u t a b l e t o fragments (167-171, f i g u r e 45) have been shown t o be op a s s o c i a t e d w i t h a s u b s t i t u t e d t e t r a h y d r o - p - c a r b o l i n e system^ and c o u l d t h u s o n l y a r i s e from compounds h a v i n g a c y c l i c s t r u c t u r e . A l t h o u g h the above e x p e r i m e n t a l problem was not c o m p l e t e l y overcome, we f e l t t h a t i t would not be n e c e s s a r y t o s e p a r a t e the expected c y c l i c p r o d u c t s s i n c e ( a ) , the asymmetric c e n t r e a t C-3 (see 125) would be d e s t r o y e d i n the f i n a l r i n g opening - 6 9 -170 m/e = 169 171 m/e = 156 F i g u r e 45. Fragments 1 a r i s i n g from a S u b s t i t u t e d T e t r a h y d r o -p - c a r b o l i n e System. -70-r e a c t i o n t o g i v e quebrachamine and ( b ) , the asymmetric centice a t C-5 merely determines which o p t i c a l isomer of quebrachamine i s formed, as quebrachamine poss e s s e s o n l y one asymmetric c e n t r e . A l t h o u g h the above s p e c t r a l d a t a p r o v i d e s no more th a n s t r o n g s u g g e s t i v e evidence f o r the presence of t h r e e c y c l i c p r o d u c t s , c o n c l u s i v e r e s u l t s come f o r t h from our subsequent d e b e n z y l a t i o n experiments where we were a b l e t o i s o l a t e t h r e e i s o m e r i c a l c o h o l s . ( v i ) D e b e n z y l a t i o n of the B e n z y l E t h e r Amines (125) w i t h BBr^ I n our i n i t i a l i n v e s t i g a t i o n s the b e n z y l group was removed by b r i e f t r e atment w i t h boron t r i b r o m i d e t o p r o v i d e a s o l i d amorphous m i x t u r e of c y c l i s e d a m i n o a l c o h o l s . The u l t r a v i o l e t spectrum of the l a t t e r showed a t y p i c a l i n d o l e a b s o r p t i o n , w h i l e the NMR spectrum i n d i c a t e d a complete absence o f b e n z y l e t h e r p r o t o n s i g n a l s . The mass spectrum showed a m o l e c u l a r i o n a t m/e 298, and the u s u a l peaks a s s o c i a t e d w i t h a s u b s t i t u t e d t e t r a h y d r o - / 8 - c a r b o l i n e d e r i v a t i v e ( v i d e s u p r a ) . I t was on t h i s m i x t u r e of c y c l i c a m i n o a l c o h o l s t h a t we i n i t i a l l y i n v e s t i g a t e d the l a t t e r s t e p s of the sequence as i n d i c a t e d below. ( v i i ) Q uaternary Ammonium S a l t F o r m a t i o n P r e c e d e n t f o r the f o r m a t i o n of q u a t e r n a r y s a l t s by i n t r a m o l e c u l a r n u c l e o p h i l i c d i s p l a c e m e n t of a t o s y l o x y group 7 A 87 e x i s t s i n the l i t e r a t u r e ' . Repeated attempts t o prepare the t o s y l a t e e s t e r of the m i x t u r e of a m i n o a l c o h o l s was u n s u c c e s s f u l . However, on treatment w i t h m e t h a n e 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, the i n i t i a l l y formed m e s y l a t e -71-e s t e r proceeded t o q u a t e r n i s e s p o n t a n e o u s l y t o p r o v i d e a water s o l u b l e s a l t . The water s o l u t i o n was c o n c e n t r a t e d t o dryness t o g i v e the s a l t as an amorphous powder. The u l t r a v i o l e t spectrum of t h i s m a t e r i a l possessed e s s e n t i a l l y a normal i n d o l e a b s o r p t i o n . ( v i i i ) R i n g Cleavage R e a c t i o n The u l t i m a t e s t e p of the s y n t h e s i s i s a r i n g c l e a v a g e of the above mentioned q u a t e r n a r y s a l t . R e d u c t i o n w i t h sodium and l i q u i d ammonia p r o v i d e d the d e s i r e d (dl)-quebrachamine ( l ) , w hich was 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 the n a t u r a l m a t e r i a l ( t h i n l a y e r chromatography, superimposable i n f r a r e d s p e c t r a , mass s p e c t r a , , see f i g u r e 46 ), The f o r m a t i o n of quebrachamine v e r i f i e s , i n r e t r o s p e c t , t h a t a t l e a s t one of the i s o m e r i c b e n z y l e t h e r amines has the d e s i r e d s t r u c t u r e (125), and a l s o t h a t the a m i n o a l c o h o l and the q u a t e r n a r y s a l t a r i s i n g from (125) must possess the s t r u c t u r e s ( l 6 k ) and (126) r e s p e c t i v e l y . A l t h o u g h the s y n t h e s i s of (dl)-quebrachamine was f o r m a l l y completed, i t was c l e a r l y d e s i r a b l e t o o b t a i n some f u r t h e r i n f o r m a t i o n on the l a t e r s t e p s of the sequence. For t h i s purpose, we r e i n v e s t i g a t e d the d e b e n z y l a t i o n experiments i n the hope t h a t a s e p a r a t i o n of the c y c l i s e d components c o u l d be a c h i e v e d a t the a l c o h o l s t a g e . ( i x ) , D e b e n z y l a t i o n of the B e n z y l E t h e r Amines (125) by C a t a l y t i c H y d r o g e n o l y s i s Another d e b e n z y l a t i o n t e c h n i q u e was c o n s i d e r e d s i n c e i t might Figure 46 p o s s i b l y 'Mead t o a l e s s , c o m p l e x ' m i x t u r e of p r o d u c t s . 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 ' was attempted, and indeed gave p u r e r p r o d u c t s . Removal of the b e n z y l group was a g a i n e v i d e n t from the s p e c t r a l d a t a and chromatographic c h a r a c t e r i s t i c s of the r e a c t i o n p r o d u c t s . By c a r e f u l column chromatography we were a b l e to, s e p a r a t e t h r e e a l c o h o l s , r e f e r r e d t o as A, B, and C i n o r d e r of i n c r e a s i n g p o l a r i t y . W h i l s t a l c o h o l C was o b t a i n e d as a g r e e n i s h gum, a l c o h o l s A and B were c r y s t a l l i n e . These t h r e e compounds showed i d e n t i c a l 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 s p e c t r a , w h i l e the mass s p e c t r a (see f i g u r e 47) a l l c o n t a i n e d a m o l e c u l a r i o n peak at m/e 298, and peaks a t 297, 184, 170, 169 and 156. These l a t t e r f o u r fragments have been observed i n the mass spectrum of the b e n z y l either amines and t h e i r s i g n i f i c a n c e has a l r e a d y been d i s c u s s e d . H i g h r e s o l u t i o n mass sp 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 these t h r e e a m i n o a l c o h o l s each possessed "the m o l e c u l a r f o r m u l a C^E^^^Q (Pound: A, 298.204; B, 298.205 ; C, 298.206 ; C a l c . 298.205). The NMR s p e c t r a ( f i g u r e s 48-50) i n d i c a t e d t h a t the b e n z y l group had been removed, and a l s o t h a t t h e s e compounds a l l l a c k e d the a b s o r p t i o n due t o t h e ^ - p r o t o n on the i n d o l e n u c l e u s ( c f . NMR spectrum of u n c y c l i s e d a m i n o a l c o h o l , f i g u r e 4 2 ) . A m i n o a l c o h o l B, which appeared t o be the major component, showed a two-proton s i n g l e t a t T8.00 which we b e l i e v e , as a l r e a d y mentioned p r e v i o u s l y , c o u l d o n l y a r i s e from a compound h a v i n g c y c l i s e d i n the d e s i r e d sense. S i n c e we have a l r e a d y shown t h a t these l a t t e r substances must be c y c l i c p r o d u c t s t h i s r e s u l t Figure 47 -76--77-T O oo u l - J O O < o •H 4. "* 4 m -78-suggests t h a t e i t h e r A or C have t h i s s i g n a l s h i f t e d u p f i e l d or e l s e t h a t they possess an u n d e s i r a b l e c y c l i c system. Another i n t e r e s t i n g d i f f e r e n c e which i s n o t e d i n the NMR s p e c t r a i s the presence of a one-proton m u l t i p l e t a t low f i e l d i n a A (7*5.90) and C (T5.80) but the absence of t h i s s i g n a l i n B. T h i s s i g n a l may be a s s i g n e d t o the C^-Hproton and i t s c h e m i c a l s h i f t may be dependent on the s t e r e o c h e m i s t r y and t h e r e b y the c o n f o r m a t i o n of the a m i n o a l c o h o l i n q u e s t i o n . 73 Wenkert has suggested t h a t the broad one-proton m u l t i p l e t a t 7*5.80-6-.00 i n the NMR spectrum of compound (128) i s c h a r a c t e r i s t i c of C^-H i n a c i s - p y r r o c o l i n e c o n f i g u r a t i o n . He a l s o p o i n t s out t h a t i n compound (131) the C^-H resonance can v a r y f r o m T 6 . 8 0 ( a x i a l ) t o 7*5• 54 ( e q u a t o r i a l ) . The above d a t a was c l e a r l y c o n s i s t e n t w i t h c y c l i c s t r u c t u r e s f o r a l c o h o l s A, B and C and i t was now n e c e s s a r y t o t r y and a s s i g n d e f i n i t i v e s t r u c t u r e s f o r these compounds. I t i s noted t h a t s t r u c t u r e ( 1 6 4 ) , w h i c h l e a d s t o quebrachamine, c o n t a i n s two asymmetric c e n t e r s and t h e o r e t i c a l l y f o u r s t e r e o i s o m e r s (2 d l p a i r s ) are p o s s i b l e . One might t h e r e f o r e expect t h a t two of the above a l c o h o l s (each b e i n g a d l p a i r ) may possess the g r o s s s t r u c t u r e ( 1 6 4 ) . I n f a c t , we were a b l e t o c o n v e r t the r e l a t i v e l y abundant a l c o h o l B t o (dl)-quebrachamine by the m e s y l a t i o n - r e d u c t i o n sequence, thus i n d i c a t i n g t h a t a t l e a s t t h i s a l c o h o l has the d e s i r e d s t r u c t u r e . Due t o i n s u f f i c i e n t q u a n t i t i e s of the a l c o h o l s A and C we were unable t o persue f u r t h e r c h e m i c a l i n v e s t i g a t i o n s on these isomers a t t h i s time.' We hope t h a t t h i s l a t t e r q u e s t i o n w i l l be c l a r i f i e d i n subsequent i n v e s t i g a t i o n s i n our l a b o r a t o r y . -79-I n a c o n c u r r e n t i n v e s t i g a t i o n i n our l a b o r a t o r y , ( d l ) -86 d i h y d r o c l e a v a m i n e (63) was s y n t h e s i z e d by the sequence o u t l i n e d i n f i g u r e 51. I t i s t o be noted t h a t t h i s pathway p a r a l l e l s the s y n t h e t i c scheme o u t l i n e d f o r quebrachamine and e s t a b l i s h e s the g e n e r a l i t y of t h i s a p p r o a c h . f o r the s y n t h e s i s of nine-membered r i n g i n t e r m e d i a t e s . F i g u r e 51. Synthesis: of D i h y d r o c l e a v a m i n e and Carbomethoxy-d i h y d r o c l e a v a m i n e . -80-An i m p o r t a n t e x t e n s i o n of the cleavamine sequence i n v o l v e d the i n t r o d u c t i o n of the e s t e r group at t o complete the t o t a l s y n t h e s i s of carbomethoxy d i h y d r o c l e a v a m i n e ( 6 7 ) . I n v i e w of p r e v i o u s work t h i s e x t e n s i o n a l s o completes the t o t a l s y n t h e s i s 'of ( d l ) - c o r o n a r i d i n e (70) and ( d l ) - d i h y d r o c a t h a r a n t h i n e ( 7 1 ) . I t i s now of g r e a t i n t e r e s t t o i n v e s t i g a t e the s i m i l a r i n t r o d u c t i o n of a carbomethoxy group at of. the quebrachamine m o l e c u l e . This.work would complete the t o t a l s y n t h e s i s of a known Y i n c a a l k a l o i d , v i n c a d i n e (172) and s i n c e the l a t t e r 35 36 w ould o b v i o u s l y undergo 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 another a l k a l o i d , v i n c a d i f f o r m i n e ( 1 7 5 ) , i t s p o t e n t i a l i n the t o t a l s y n t h e s i s of a whole s e r i e s of V i n c a a l k a l o i d s i s now apparent. Some of these i n v e s t i g a t i o n s are now underway i n our l a b o r a t o r y . (172) (173) -81-EXPERIMENTAL 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 i n methanol 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 (IR) s p e c t r a were t a k e n on a P e r k i n Elmer I n f r a c o r d . 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/sec. ( u n l e s s o t h e r w i s e s t a t e d ) on a V a r i a n A60 i n s t r u m e n t ; the l i n e p o s i t i o n s or c e n t r e s of m u l t i p l e 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 i n t e r n a l standard;; the m u l t i p l i c i t y , and i n t e g r a t e d a r e a and type of p r o t o n s are i n d i c a t e d i n p a r e n t h e s e s . S i l i c a G e l G and Woelm alumina were used f o r t h i n l a y e r chromatography; the type of absorbent and the s o l v e n t system used f o r development are g i v e n i n p a r e n t h e s e s . The al u m i n a used f o r column chromatography was Shawinigan reagent grade d e a c t i v a t e d w i t h 3% of 10% aqueous a c e t i c a c i d ( u n l e s s o t h e r w i s e s t a t e d ) . A n a l y s e s were performed by Dr. A. B e r n h a r d t and a s s o c i a t e s , Mulheim ( R u h r ) , Germany and by Mr. !P. Borda, the M i c r o a n a l y t i c a l L a b o r a t o r y , U n i v e r s i t y of B r i t i s h Columbia. Mass s p e c t r a were determined u s i n g an A t l a s CH-4 mass s p e c t r o m e t e r , w h i l e h i g h r e s o l u t i o n m o l e c u l a r weight d e t e r m i n a t i o n s were c a r r i e d out on AEI MS-9 i n s t r u m e n t . Scheme A E x p e r i m e n t a l S e c t i o n  M e t h y l n i c o t i n a t e (110) To a s o l u t i o n of n i c o t i n i c a c i d (109) (123 g, 1 mole) i n -82-dry methanol (310 ffil), was added c o n c e n t r a t e d s u l f u r i c a c i d (155 m l ) , and the m i x t u r e r e f l u x e d f o r 3 h r . P a r t of the methanol was d i s t i l l e d (200 ml) and the r e s t of the r e a c t i o n m i x t u r e poured i n t o i c e - w a t e r . The m i x t u r e was e x t r a c t e d 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 e x t r a c t washed w i t h water, 5$ sodium b i c a r b o n a t e s o l u t i o n , and water a g a i n , and th e n d r i e d over anhydrous magnesium s u l f a t e . The c h l o r o f o r m was removed under reduced p r e s s u r e and the r e s u l t i n g crude o i l (130 g) d i s t i l l e d t o g i v e the d e s i r e d m a t e r i a l (115 g, 84$), bp 65°/l mm, ( l i t 6 4 , 118.5725 mm). N i p e c o t i c a c i d (111) A s u s p e n s i o n of 24.6 g (0.2 mole) of n i c o t i n i c a c i d (109) i n w a ter (200 ml) was t r e a t e d w i t h 15N ammonia (40 ml) and hydrogenated i n the presence of 9.0 g of 5$ rhodium on carbon at room temperature and 2 atmospheres p r e s s u r e . H y d r o g e n a t i o n was c o n t i n u e d u n t i l the UV" spectrum showed no a b s o r p t i o n above 240 mu. The r e a c t i o n m i x t u r e was f i l t e r e d t h r o u g h C e l i t e and the f i l t r a t e was concentrated, t o dryn e s s under reduced p r e s s u r e . To ensure complete removal of water the r e s i d u e was t r e a t e d w i t h anhydrous benzene and r e c o n c e n t r a t e d . The y i e l d of the crude product (20 g, 80$), mp 254-260° ( l i t 6 6 , mp 260-61°). 5- C a r b o m e t h o x y p i p e r i d i n e (98) (a) A s o l u t i o n of m e t h y l n i c o t i n a t e (110) (23.5 g, 0.17 mole) i n dry methanol (80 ml) and g l a c i a l a c e t i c a c i d (20 ml) was hydrogenated i n the presence of p l a t i n u m oxide (0.39 g) and -83-under 1.3-3 atmospheres p r e s s u r e . A f t e r the uptake of hydrogen had ceased the c a t a l y s t was removed by f i l t r a t i o n t h r o u g h C e l i t e , and the f i l t r a t e was c o n c e n t r a t e d under reduced p r e s s u r e below 50°. The r e s u l t i n g m i x t u r e was c o o l e d i n i c e and c o n c e n t r a t e d p o t a s s i u m h y d r o x i d e (40%) added s l o w l y , u n t i l the m i x t u r e was j u s t a l k a l i n e . D u r i n g t h i s a d d i t i o n , care was t a k e n t o keep the temperature of the m i x t u r e below 5°. The f r e e base was e x t r a c t e d w i t h e t h e r and the e t h e r e x t r a c t washed w i t h water, d r i e d over anhydrous sodium s u l f a t e and c o n c e n t r a t e d under reduced p r e s s u r e . The crude o i l (18 g) was d i s t i l l e d t o g i v e the d e s i r e d m a t e r i a l (5 g, 2 0 % ) , bp 70-75°/l mm, ( l i t 6 5 , 102-107°/5 mm). I n f r a r e d ( f i l m ) : 3230 (-NH), 1710 (-COOCH^) cm" 1. NMR s i g n a l s : 6.40 ( s i n g l e t , 3H, -COOCH^), 8.26 ( s i n g l e t , 1H, -NH). (b) t h e crude n i p e c o t i c a c i d ( i l l ) (20 g) o b t a i n e d as d e s c r i b e d above was suspended i n dry methanol (10 ml) and the r e s u l t a n t m i x t u r e was c o o l e d i n an i c e b a t h . E t h e r e a l diazomethane was added s l o w l y u n t i l a y e l l o w c o l o r p e r s i s t e d . The r e a c t i o n f l a s h was then removed from the i c e b a t h and h e l d at room temperature f o r 6 h r . Removal of the s o l v e n t under reduced p r e s s u r e p r o v i d e d a p a l e y e l l o w syrup w h i c h was p u r i f i e d by d i s t i l l a t i o n (15 g, bp 65-7°/2 mm). 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 ) i n d i c a t e d two major components. • P u r i f i c a t i o n by chromatography on Woelm alumina a c t i v i t y I was u n s u c c e s s f u l . F r a c t i o n a l . d i s t i l l a t i o n - u s i n g a N e s t e r - F a u s t 450x6 mm s p i n n i n g band column gave a f o r e r u n (8.8 g, bp 45°/0'l mm) -84-w h i c h on e x a m i n a t i o n 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 ) was e n r i c h e d i n the u n d e s i r e d m a t e r i a l ( 1 1 3 ) . The l a t e r f r a c t i o n s (combined w e i g h t , 3-0 g, bp 37°/k'/.mm) was shown 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 ) t o c o n t a i n m a i n l y the d e s i r e d m a t e r i a l ( 9 8 ) . I n f r a r e d ( f i l m ) : 3230 (-NH), 1710 (-COOCH^) cm - 1. U l t r a v i o l e t spectrum: no a b s o r p t i o n above 230 mu. NMR s i g n a l s : 6.40 ( s i n g l e t , -COOCH^)-, 7.80 ( s i n g l e t , .^NCH^), 8.26 ( s i n g l e t , -NH). (c ) 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 ( i l l , a ) (8 g, 0.05 mole) was mixed w i t h 80 ml o f 5$ m e t h a n o l i c hydrogen c h l o r i d e and the r e s u l t i n g s o l u t i o n was r e f l u x e d f o r 12 h r . The s o l v e n t was removed under reduced p r e s s u r e and the r e s u l t i n g s o l i d t r e a t e d w i t h i c e c o l d c o n c e n t r a t e d sodium h y d r o x i d e (30$). The f r e e base was e x t r a c t e d w i t h e t h e r and the e t h e r e x t r a c t washed w i t h s a t u r a t e d sodium c h l o r i d e s o l u t i o n , d r i e d over magnesium s u l f a t e and t h e n c o n c e n t r a t e d under reduced p r e s s u r e . The r e s u l t i n g g r e en l i q u i d was d i s t i l l e d t o g i v e the d e s i r e d m a t e r i a l (98) as a c l e a r l i q u i d (3.6 g, 52$, bp 50°/l mm). I n f r a r e d ( f i l m ) : 3230 (-NH) and 1710 (-COOCH^) cm - 1. NMR s i g n a l s : 6.40 ( s i n g l e t , 3H, -COOCH^), 8.26 ( s i n g l e t , 1H, -NH). D i e t h y l y - c h l o r o p r o p y l m a l o n a t e (108) • A s o l u t i o n of. d i e t h y l malonate (130 g, 0.81 mole) and 1,3-chlorobromopropane (130 g, 0.82 mole) i n anhydrous e t h e r (200 ml) was added i n one p o r t i o n t o a s o l u t i o n of sodium e t h o x i d e (52.5 g, 0.75 mole) i n dry e t h a n o l (250 m l ) . The r e a c t i o n m i x t u r e was m a i n t a i n e d a t 35° f o r 4 h r and th e n -85-a l l o w e d t o s t a n d a t room temperature f o r 24 n r . The r e a c t i o n m i x t u r e was poured i n t o water (600 ml) and e x t r a c t e d w i t h e t h e r . The either e x t r a c t was washed w i t h water and s a t u r a t e d aqueous sodium c h l o r i d e , 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 under reduced p r e s s u r e . The r e s u l t i n g o i l was d i s t i l l e d t o g i v e the d e s i r e d m a t e r i a l (118 g, 7 0 % ) , bp 80°/0.2 mm, ( l i t 5 9 , bp 142/v10 mm). I n f r a r e d ( f i l m ) : 1730 (-C00CH 2CH 5) cm" 1. NMR s i g n a l s : 5.75 ( q u a r t e t , 4H, 2x-C00CH 2CH 5), 6.56 ( t r i p l e t > 2H, -CH^CHpCl), 6.75 [ t r i p l e t * 1H, -CH 2CH(C00CH 2CH 5) 2"] , 8.10 ( m u l t i p l e t , 4H, C1CH 2CH 20H 2-), 8,80 ( t r i p l e t , 6H, 2xC00CH 2CH 3). Benzenediazonium c h l o r i d e A n i l i n e h y d r o c h l o r i d e (10 g, 0.076 mole) was suspended i n a m i x t u r e of g l a c i a l a c e t i c a c i d (60 ml) and d r y , p e r o x i d e -f r e e d i o x a n (60 m l ) . The m i x t u r e was c o o l e d i n an i c e - s a l t b a t h and i s o a m y l n i t r i t e (10 g, 0.084 mole) was added s l o w l y , the temperature b e i n g h e l d below 5°• A f t e r the a d d i t i o n was complete the m i x t u r e was s t i r r e d f o r 30 min d u r i n g w h i c h the s o l i d s u s p e n s i o n d i s s o l v e d . Dry d i o x a n (300 ml) or dry e t h y l e t h e r (300 ml) was added i n one p o r t i o n and the whit.e p r e c i p i t a t e of benzenediazonium c h l o r i d e was c o l l e c t e d > washed w i t h f r e s h ' 63 s o l v e n t and d r i e d i n a d e s i c c a t o r . ( Y i e l d 9.5 g ) , ( l i t ). 2 - C a r b o e t h o x y - 3 - ( f t - c h l o r o e t h y l ) - i n d o l e (97,a) To a sodium e t h o x i d e s o l u t i o n p r e p a r e d by d i s s o l v i n g sodium (1.65 g, 0.0715 mole) i n dry e t h a n o l (200 m l ) , was added -86-d i e t h y l tf-chloropropylmalonate (17.0 g, 0*0715 mole), and the m i x t u r e s t i r r e d f o r 30 min a t room temperature. A f t e r c o o l i n g t h i s s o l u t i o n i n an i c e - s a l t b a t h the benzenediazonium c h l o r i d e was added i n s m a l l p o r t i o n s i n o r d e r t o keep the temperature below 5°. The r e a c t i o n m i x t u r e was a l l o w e d t o stand i n the r e f r i g e r a t o r f o r 12 h r and t h e n poured i n t o water (200 m l ) . The dark r e d o i l w h i c h s e p a r a t e d was c o l l e c t e d and the aqueous l a y e r e x t r a c t e d w i t h e t h e r . The o i l was combined w i t h the e t h e r e x t r a c t s and the r e s u l t i n g s o l u t i o n was washed w i t h water 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 , 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 under reduced p r e s s u r e . The crude r e a c t i o n p r o duct (19.0 g) was i m m e d i a t e l y s u b j e c t e d t o the F i s c h e r i n d o l e s y n t h e s i s d e s c r i b e d below. The m a t e r i a l o b t a i n e d above was d i s s o l v e d i n dry e t h a n o l (150 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 (20 ml) and the m i x t u r e r e f l u x e d f o r 12 h r . A f t e r c o o l i n g t o room temperature t o r e a c t i o n m i x t u r e was poured onto i c e and the r e s u l t i n g m i x t u r e e x t r a c t e d w i t h c h l o r o f o r m . The c h l o r o f o r m e x t r a c t was washed s e v e r a l t i m e s w i t h water, t h e n w i t h sodium b i c a r b o n a t e s o l u t i o n , and a g a i n w i t h water, 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 under reduced p r e s s u r e . The crude dark o i l (15 g) was p u r i f i e d by chromatography over alumina (750-g). -Unreacted s t a r t i n g m a t e r i a l (108) was e l u t e d w i t h benzene as a c l e a r o i l (6 g ) , w h i l e the d e s i r e d m a t e r i a l was. e l u t e d w i t h c h l o r o f o r m , and o b t a i n e d as a w h i t e s o l i d . R e c r y s t a l l i s a t i o n from c h l o r o f o r m / p e t r o l e u m e t h e r - 8 7 -(60-80°) gave w h i t e n e e d l e s (3.0 g, 2 6 % ) , mp 125-132°. I n f r a r e d ( n u j o l m u l l ) : 3250 (-NH) and 1670 (-COOCE^CH^) cm" 1. U l t r a v i o l e t ; ^max (log£): 229 ( 4 . 4 0 ) , 296 (4.27) mu. NMR s i g n a l s : 0 . 7 5 (broad s i n g l e t , IH,-NH), 2.60 ( m u l t i p l e t , 4H, a r o m a t i c ) , 5.54 ( q u a r t e t , 2H,-COOCH^CH^), 6.50 ( m u l t i p l e t , 4H, -CH 2qH 2Cl) and 8.60 ( t r i p l e t , 3H,-COOCH^H^). Found: C, 62.07; H, 5-53; N, 5.60; 0, 12.64; 0 1 , 14.08. C a l c . f o r C ^ H ^ O g N C l : G, 62.03; H, 5 .57.; N, 5 . 5 7 ; 0, 12 . 7 5 ; 0 1 , 14.12. 2 - C a r b o m e t h o x y - 3 - ( f t ^ c h l o r o e t h y l ) - i n d o l e (97,b) 2 - C a r b o e t h o x y - 3 - ( i S - c h l o r o e t h y l ) - i n d o l e (1.22 g, 4.9 mmole) was d i s s o l v e d i n d r y methanol (300 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 (5 m l ) , and t h e ' m i x t u r e r e f l u x e d f o r 24 nr.. P a r t of the methanol was d i s t i l l e d (100 ml) and the r e s t of the r e a c t i o n m i x t u r e was poured onto crushed i c e (500 g ) . A f t e r c a r e f u l n e u t r a l i s a t i o n w i t h sodium b i c a r b o n a t e the aqueous m i x t u r e was e x t r a c t e d w i t h c h l o r o f o r m . The c h l o r o f o r m e x t r a c t was washed w i t h w ater 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 , d r i e d over anhydrous sodium s u l f a t e and c o n c e n t r a t e d under reduced p r e s s u r e t o g i v e a w h i l e s o l i d * c C r y s t a l l i s a t i o n from l i g h t p e t r o l e u m (60-80°)/ethyl e t h e r gave w h i t e n e e d l e s (1.0 g, 8 7 % ) , mp 125-132°. I n f r a r e d ( n u j o l m u l l ) : 3250 (-NH), 1670 (-COOCH^) cm - 1. U l t r a v i o l e t ; /max ( l o g f ) : 228 ( 4 . 2 6 ) , 296 (4.30) mu. NMR s i g n a l s : 0.75 (broad s i n g l e t , 1H, -NH), 2.60 ( m u l t i p l e t , 4H, a r o m a t i c ) , 6.06 ( s i n g l e t , 3H, -COOCH^) 1 and 6.40 ( m u l t i p l e t , 4H, - G H 2 C H 2 C l ) . -Found: C, 60.64; H, 5.10; N, 5-89; 0, 13.61 and C I , 14.84. C a l c . f o r -88-C 1 2 H 1 2 N 0 2 C 1 : G ' 6 0 * 6 2 5 H ' 5 * 0 4 ; N ' 5 , 8 8 ; °' 1 3 ' 4 4 a n d C I , 14.91-C o u p l i n g r e a c t i o n s (a) C o u p l i n g product ( 9 9 , R°Bt) A s o l u t i o n of 2-carboethoxy-3-(£-chloroethyl)-indole ( 9 7 ,a) 500 mg, 2 mmole) and 3 - c a r b o m e t h o x y p i p e r i d i n e (98) (600 mg, 4.2 mmole) i n f r e s h l y d i s t i l l e d d r y dioxane (15 ml) was s e a l e d i n a C a r i u s tube. The tube was t h e n t r a n s f e r r e d t o a m e t a l c o n t a i n e r and heated a t 160° f o r 14 h r . A f t e r c o o l i n g , the r e a c t i o n m i x t u r e was poured i n t o d i l u t e h y d r o c h l o r i n e a c i d (120 ml) and the a c i d i c s o l u t i o n e x t r a c t e d w i t h e t h e r . The e t h e r e x t r a c t was washed w i t h aqueous sodium b i c a r b o n a t e and water, d r i e d over anhydrous sodium s u l f a t e and c o n c e n t r a t e d under reduced p r e s s u r e . E x a m i n a t i o n by t h i n l a y e r chromoatography ( a l u m i n a , c h l o r o f o r m ) and NMR i n d i c a t e d t h a t t h i s crude product was u n r e a c t e d s t a r t i n g m a t e r i a l ( 9 7 , a ) . The aqueous a c i d i c s o l u t i o n was b a s i f i e d w i t h 15N ammonia and e x t r a c t e d w i t h e t h e r . The e t h e r e x t r a c t was t h o r o u g h l y washed 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 c o n c e n t r a t e d under reduced p r e s s u r e . The crude s o l i d (500 mg) was p u r i f i e d by chromatography on al u m i n a (25; g ) . The d e s i r e d m a t e r i a l was e l u t e d w i t h c h l o r o f o r m and o b t a i n e d as a w h i t e s o l i d ^ w h i c h was r e c r y s t a l l i s e d from p e t r o l e u m e t h e r (60-80°)/ether or pet r o l e u m e t h e r (60-80°)/ c h l o r o f o r m as nee d l e s (250 mg, 60$ based on unr e c o v e r e d s t a r t i n g m a t e r i a l ( 9 7 ,a) , mp 103-5°. I n f r a r e d ( n u j o l m u l l ) : 3250 (-NH), 1710 (-COOCH^) and 1670 (-COOC^CH^) cm - 1. U l t r a v i o l e t ; -89->jnax (log£): 228 (4.41) 296 ( 4 . 3 1 ) mu. NMR s i g n a l s : 0.80 (broad s i n g l e t , 1H, -NH), 2.60 ( m u l t i p l e t , 4H, a r o m a t i c ) , 5.50 ( q u a r t e t , 2H, -COOCH^CH^), 6 . 3 0 . ( s i n g l e t , 3H, -COOCH^) and 8.60 ( t r i p l e t , 3H, -COOCH^H^). Found: C, 66.89; H, 7.40; N, 7.77; 0, 17,81. C a l c . f o r c 2 o H 2 6 W 2 ° 4 : C f 6 7 - ° ° 5 H , 7.31; N, 7.82; 0, 17.85. (b) C o u p l i n g -product (99. R=Me) The c o u p l i n g r e a c t i o n between (97,b) and (98) was c a r r i e d out as d e s c r i b e d above. C r y s t a l l i s a t i o n from p e t r o l e u m e t h e r (60-80°)/chloroform y i e l d e d w h i t e needles ( 5 0 $ ) , mp 109°. I n f r a r e d ( n u j o l m u l l ) : 3250 (-NH), 1720 (-C00CH 3) and 1670 (-COOCH^) cm"1:. U l t r a v i o l e t ; Xmax ( l o g * ) : 229 ( 4 . 3 4 ) , 296 (4.23) mu. NMR s i g n a l s : 0.80 (broad s i n g l e t , 1H, -NH), 2.60 ( m u l t i p l e t , 4H> a r o m a t i c ) , 6.10 ( s i n g l e t , 3H, -COOCH^), 6.32 ( s i n g l e t , 3H, -COOCH^). Mass spectrum: MW 344, base peak m/e 156.' C a l c . MW: .344. Found: C, 65.88; H, 7.14; N, 8.03; 0,..18.70. C a l c . f o r c 1 g E 2 A B 2 ° A ' ' C ' 6 6 ' 2 6 ; H ' 7 « 0 2 5 N, 8.13; 0, 18.58. I n some i n s t a n c e s the e t h e r e x t r a c t of the aqueous a c i d i c l a y e r c o n t a i n e d , a n . a d d i t i o n a l p r o d u c t , which c o u l d be s e p a r a t e d from t h e u n r e a c t e d s t a r t i n g i n d o l e (97,b) by chromatography on a l u m i n a . T h i s p r o duct (113) was e l u t e d w i t h c h l o r o f o r m c o n t a i n i n g 1$ methanol and o b t a i n e d as a w h i t e s o l i d w h i c h c o u l d be c r y s t a l l i s e d from c h l o r o f o r m as w h i t e n e e d l e s , mp 199-201°. I n f r a r e d ( n u j o l m u l l ) : 3250 (-NH) and 1690 (-CO0CH2-) cm" 1. . U l t r a v i o l e t , 2max ( l o g f ): 230 (4 . 3 6 ) , -90-296 (4.24) mu. NMR s i g n a l s : 0.4 ( s i n g l e t , 1H, -NH), 2,60 ( m u l t i p l e t , 4H, a r o m a t i c ) , 5.36 ( t r i p l e t , 2H,'-C00CH 2CH 2-) and 6.90 ( t r i p l e t , 2H, eC00CH 2CH 2-). Mass spectrum: : MW 187, base peak m/e 187. C a l c . MW: 187. Found: C, 70 . 4 8 ; H, 4.67; N, 7:.39; 0, 17.24. C a l c . f o r C- L 1H gN0 2: C, 70.58; H, 4.85; N, 7.48; 0, 17.09. Attempted A c y l o i n C o n d e n s a t i o n U s i n g I n t e r m e d i a t e 99, R=Me The a c y l o i n c o n d e n s a t i o n s were a l l r u n i n a s p e c i a l a p p a r a t u s . .The r e a c t i o n m i x t u r e was c o n t a i n e d i n a t h r e e -necked 250 ml Morton f l a s k f i t t e d w i t h a h i g h speed s t i r r e r , a n i t r o g e n i n l e t and ,'a h i g h d i l u t i o n a p p a r a t u s , as d e s c r i b e d 86 by Leonard P r i o r t o the s t a r t of the r e a c t i o n , the apparatus was flame d r i e d . w h i l e a stream of p u r i f i e d n i t r o g e n was passed through... Toluene was d i s t i l l e d from sodium i n t o t he r e a c t i o n - f l a s k u n t i l i t was t h r e e - q u a r t e r s f u l l . P a r t of the s o l v e n t was r e d i s t i l l e d from the Morton f l a s k and the condensate removed v i a a condenser a t the t o p of the h i g h d i l u t i o n a p p a r a t u s , Any r e m a i n i n g water was thus removed a z e o t r o p i c a l l y from'the a p p a r a t u s . F o l l o w i n g c o o l i n g , sodium (0..5 g) was i n t r o d u c e d i n t o t he r e a c t i o n f l a s k and the s o l v e n t h e ated t o v i g o r o u s r e f l u x as the m i x t u r e was s t i r r e d at h i g h speed (6000 rpm). The c o u p l i n g product (99, R=Me, 1 g) was d i s s o l v e d i n anhydrous t o l u e n e (25 ml) and i n t r o d u c e d i n t o the d i l u t i o n chamber over a p e r i o d of 4 h r . When a d d i t i o n was completed r e f l u x i n g was c o n t i n u e d f o r an a d d i t i o n a l 2 h r . The f l a s k and i t s c o n t e n t s were c o o l e d and an e q u i v a l e n t amount of g l a c i a l a c e t i c a c i d added. S t i r r i n g was c o n t i n u e d u n t i l a l l the sodium had been d e s t r o y e d . The s o l i d m a t e r i a l was removed by f i l t r a t i o n and washed w i t h t o l u e n e , e t h e r and c h l o r o f o r m . The combined t o l u e n e f i l t r a t e and t o l u e n e washings were c o n c e n t r a t e d under reduced p r e s s u r e t o y i e l d a brown gum (500 mg) which c r y s t a l l i s e d on s t a n d i n g . T h i s m a t e r i a l was. i d e n t i f i e d as 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 (99, R=Me). The e t h e r and c h l o r o f o r m e x t r a c t s upon e x a m i n a t i o n by t h i n l a y e r chromatography ( s i l i c a , c h l o r o f o r m : methanols 4.: l ) . . ] were shown t o c o n t a i n one major p o l a r component and two v e r y i minor components. I n f r a r e d ( C H C l ^ ) : 3220 (-NH), 1700 ( c a r b o n y l ) cm" 1. U l t r a v i o l e t spectrum, X m a x : 228, 296 mu. NMR s i g n a l s : a l t h o u g h the spectrum was p o o r l y r e s o l v e d i t d i d show a s i n g l e t a t 7*1.6 (-NH) and a m u l t i p l e t a t ^2.70 c h a r a c t e r i s t i c of the a r o m a t i c p r o t o n s . Attempted A c y l o i n Oondensation U s i n g I n t e r m e d i a t e 99, R-=Et The i n t e r m e d i a t e (99, R=Et) (500 mg) was s u b j e c t e d t o the a c y l o i n c o n d e n s a t i o n as d e s c r i b e d above. The t o l u e n e s o l u b l e product (340 mg) on e x a m i n a t i o n by t h i n l a y e r chromatography ( s i l i c a , e t h y l ; a c e t a t e ) was found t o c o n t a i n t h r e e components, which we w i l l d e s i g n a t e 1, 2 and 3 i n o r d e r of i n c r e a s i n g p o l a r i t y . 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, e t h y l a c e t a t e ) p r o v i d e d homogeneous samples of these components. Compound 1: I n f r a r e d ( f i l m ) : 3320 (-NH), 1710 ( s a t u r a t e d e s t e r ) , 1680 ( s h , a r o m a t i c e s t e r ) cm 1 . U l t r a v i o l e t spectrum, 7 m a x : 228, 296 mu. NMR s i g n a l s : 0.68 ( s i n g l e t , -NH), 2.65 ( m u l t i p l e t , -92-a r o m a t i c ) , 5.60 (quartet,-COOCH^CH^), 5.86 ( q u a r t e t , -CHCOOCH^CH^ ), 8.75 ( s e x t e t , 2x-0CH 2CH^). T h i s product appeared t o be the d i e t h y l e s t e r . Compound 2: I n f r a r e d ( f i l m ) : 3320 (-NH), 1715 ( s a t u r a t e d e s t e r ) , 1680 ( s h , a r o m a t i c e s t e r ) cm - 1. U l t r a v i o l e t spectrum, Xmax: 228, 296 mu. NMR s i g n a l s : 0.50 ( s i n g l e t , -NH), 2.65 ( m u l t i p l e t , a r o m a t i c ) , 6.08 (singlet,-COOCH^), 6.32 (singlet,-COOCH^). R^ v a l u e by t h i n l a y e r chromatography ( s i l i c a , e t h y l a c e t a t e ) i d e n t i c a l w i t h c o u p l i n g product (99, R=Me). Compound 5: I n f r a r e d ( f i l m ) : 3320 (-NH), 1710 ( s a t u r a t e d e s t e r ) , 1675 ( s h , a r o m a t i c e s t e r ) cm-"1". U l t r a v i o l e t spectrum, )^max: 324, 296 mu. NMR s i g n a l s : 1.0 ( s i n g l e t , -NH), 2.60 ( m u l t i p l e t , a r o m a t i c ) , 5.50 ( q u a r t e t , -COOCH^CH^) 6.30 ( s i n g l e t , -COOCH^), 8.60 ( t r i p l e t , -COOCH^H^). R f v a l u e by t h i n l a y e r chromatography ( s i l i c a , e t h y l a c e t a t e ) was i d e n t i c a l w i t h s t a r t i n g m a t e r i a l (99, R=Et). D i o l (114) The c o u p l i n g product (99, R=Me) (50 mg) was d i s s o l v e d i n anhydrous t e t r a h y d r o f u r a n (5 ml) and added t o a 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 (50 mg) i n t e t r a h y d r o f u r a n (10 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 h r , and the excess l i t h i u m 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 o f moist t e t r a h y d r o f u r a n . The s o l i d m a t e r i a l was removed by f i l t r a t i o n and the r e s i d u e washed 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 sodium s u l f a t e and" the s o l v e n t removed under reduced p r e s s u r e t o g i v e d i o l (35 mg), - 9 3 -w h i c h was one spot on t h i n l a y e r chromatography ( s i l i c a , c h l o r o f methanol, 4:1). I n f r a r e d ( C H C l ^ ) : 3250 (broad, -NH), no c a r b o n y l . U l t r a v i o l e t , ^max: 225, 2 7 6 ( s h ) , 284, 292 mu. NMR s i g n a l s : 0.75 ( s i n g l e t , IH, -NH), 2.60 ( m u l t i p l e t , 4H, ar o m a t i c ) 5.10 (broad, 2H, 2xt-0H - a s s i g n e d on the b a s i s of deu t e r i u m exchange), 5.45 ( s i n g l e t , 2H, indole-CHgOH), 6.70 ( d o u b l e t , 2H, -CHCH 20H). Mass spectrum: MW 288, base peak m/e 128. C a l c . f o r G 1 7 E 2 A ^ 2 0 2 : W 2 8 8 , D i a c e t a t e (115) The d i o l (35 mg) o b t a i n e d above was d i s s o l v e d i n a m i x t u r e of p y r i d i n e (1.5 ml) and a c e t i c a n h y d r i d e (1.5 ml) and 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 sta n d a t room temperature f o r 12 h r . Anhydrous p o t a s s i u m carbonate was added and the r e s u l t i n g m i x t u r e f i l t e r e d . The f i l t r a t e was c o n c e n t r a t e d under reduced p r e s s u r e t o p r o v i d e the d i a c e t a t e (115) as a c l e a r c o l o r l e s s g l a s s (43 mg). E x a m i n a t i o n 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 ) showed t h a t t h i s product was e s s e n t i a l l y one s p o t . I n f r a r e d ( C H C l ^ ) : 3400 (-NH), 1725 ( c a r b o n y l ) cm" 1. U l t r a v i o l e t spectrum, .^max 225, 27 6 ( s h ) , 283, 292 mu. NMR s i g n a l s : 1.5 (broad s i n g l e t , 1H, -NH), 2.60 ( m u l t i p l e t , 4H, a r o m a t i c ) , 4.76 ( s i n g l e t , 2H, i n d o l e - C H 2 0 A c ) , 6.05 ( d o u b l e t , 2H, -CHCH 20Ac), 8.0 ( s i n g l e t , 6H, 2x-0CH 3). D i a c i d (116) The c o u p l i n g product (30 mg) was mixed w i t h 2 ml of 10% aqueous sodium h y d r o x i d e and the r e s u l t i n g m i x t u r e r e f l u x e d -94-f o r 12 h r . .Upon c o o l i n g , an e q u i v a l e n t amount of g l a c i a l a c e t i c a c i d was added and r e s u l t i n g m i x t u r e c o n c e n t r a t e d t o dryness under reduced p r e s s u r e . The s o l i d r e s i d u e was t r e a t e d w i t h warm c h l o r o f o r m (3 m l ) . The c h l o r o f o r m s o l u b l e m a t e r i a l (18 mg) on e x a m i n a t i o n by t h i n l a y e r chromatography ( s i l i c a , c h l o r o f o r m : m e t h a n o l 1:1) was shown t o c o n t a i n one v e r y p o l a r s p o t . U l t r a v i o l e t spectrum, /imax: 2 2 3(sh), 293 mu. NMR s i g n a l s : 2.60 ( m u l t i p l e t , a r o m a t i c ) , no s i g n a l s due t o the m e t h y l e s t e r f u n c t i o n s . The r e s t of the NMR spectrum was i l l - d e f i n e d . Treatment of D i a c i d (116) w i t h Diazomethane The crude d i a c i d (116) (18 mg) o b t a i n e d above was suspended i n d r y e t h y l e t h e r (10 ml) and the r e s u l t i n g m i x t u r e c o o l e d i n an i c e b a t h . E t h e r e a l diazomethane added s l o w l y u n t i l the y e l l o w c o l o r p e r s i s t e d . The r e a c t i o n f l a s k was t h e n removed from the i c e b a t h and h e l d a t room temperature f o r 6 h r . Removal of the s o l v e n t under reduced p r e s s u r e y i e l d e d a p a l e y e l l o w g l a s s (18 mg) which on e x a m i n a t i o n 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 ) was e s s e n t i a l l y one component whose R^ v a l u e was i d e n t i c a l w i t h the c o u p l i n g p r o d u c t i o n (99, R=Me). I n f r a r e d ( n u j o l m u l l ) : 3225 (-NH), 1695 (broad c a r b o n y l ) cm - 1. U l t r a v i o l e t spectrum, fanax: 228, 296 mu. NMR s i g n a l s : 0.75 (broad s i n g l e t , 1H, -NH), 2.60 ( m u l t i p l e t , 4H, a r o m a t i c ) , 6.10 ( s i n g l e t , 3H, -COOCH^), 6.32 ( s i n g l e t , 3H, -C00CH • ) . - 9 5 -Treatment of the A c y l o i n P r o d u c t -with L i t h i u m Aluminum H y d r i d e The p o l a r m a t e r i a l (20 mg) o b t a i n e d from the attempted a c y l o i n c o n d e n s a t i o n of compound ( 9 9 , R=Me) was t r e a t e d w i t h l i t h i u m aluminum h y d r i d e by the procedure d e s c r i b e d above. The crude product (17 mg), which was e s s e n t i a l l y one spot on t h i n l a y e r chromatography, . ( s i l i c a , c h l o r o f o r m : m e t h a n o l 4:1) had an R^ v a l u e i d e n t i c a l w i t h the d i o l (114). I n f r a r e d ( C H C l ^ ) : 3230 (broad,-OH), no c a r b o n y l . U l t r a v i o l e t , Amax: 224, 2 7 6 ( s h ) , 284, 292 mu. NMR s i g n a l s : 0.75 ( s i n g l e t , 1H, -NH), 2.60 ( m u l t i p l e t , 4H, a r o m a t i c ) , 5.42 (broad s i n g l e t , 4H, i n d o l e - C H 2 0 H and -GHC^OH), 6.65 (broad s i n g l e t , 2H, -CH0H 20H). Mass spectrum: MW 288, base peak m/e 128. C a l c f o r G17 H24 W2°2' M : 2 8 8 * Treatment of Reduced A c y l o i n P r o d u c t w i t h A c e t i c A nhydride  i n ' P y r i d i n e The reduced a c y l o i n product (17 mg) was a c e t y l a t e d by the procedure d e s c r i b e d above. .The crude product (21 mg) on e x a m i n a t i o n 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 ) Was e s s e n t i a l l y one s p o t , whose R^ v a l u e was i d e n t i c a l w i t h t h a t of the d i a c e t a t e (115). I n f r a r e d ( C H C l ^ ) : 3350 (-NH), 1725 ( c a r b o n y l ) cm - 1. U l t r a v i o l e t spectrum, 7-max: 225, 2 7 6 ( s h ) , 283, 292 mu. NMR s i g n a l s : 1.50 (broad s i n g l e t , 1H, -NH), 2 . 6 0 . ( m u l t i p l e t , 4H, a r o m a t i c ) , 4.75 ( s i n g l e t , 2H, i n d o l e - C H 2 0 A c ) , 6.05 ( d o u b l e t , 2H, -CHCH_20Ac), 8.00 ( s i n g l e t , 6H, 2x-OCH 3). Diazomethane Treatment of - A c y l o i n P r o d u c t The p o l a r m a t e r i a l (20 mg) o b t a i n e d from the attempted - 9 6 -a c y l o i n c o n d e n s a t i o n of compound ( 9 9 , R=Me) was d i s s o l v e d i n anhydrous e t h e r and t r e a t e d w i t h an excess of diazomethane i n e t h e r a t 0°C. The s o l u t i o n was a l l o w e d t o st a n d a t room temperature f o r 6 h r , and the excess diazomethane d e s t r o y e d by a d d i t i o n of water. 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 c o n c e n t r a t e d under reduced p r e s s u r e . The crude p r o d u c t , on e x a m i n a t i o n by t h i n l a y e r chromatography, c o n t a i n e d t h r e e components, one of whi c h had an R^ v a l u e i d e n t i c a l t o the c o u p l i n g product . 9 9 , R=Me. Scheme B E x p e r i m e n t a l S e c t i o n  ^ - B e n z y l o x y propand (142) Sodium (50 g, 2.18 mole) was added i n s m a l l p o r t i o n s t o a hot (115°-120°), v i g o r o u s l y s t i r r e d s o l u t i o n of t r i m e t h y l e n e g l y c o l (500 g, 6.6 mole) i n dry x y l e n e (200 m l ) . A f t e r a l l the sodium had d i s s o l v e d , b e n z y l c h l o r i d e (300 g, 2.38 mole) was s l o w l y added w i t h s t i r r i n g the hot (120°) s o l u t i o n over a . p e r i o d of 2 h r . The r e a c t i o n m i x t u r e was heated f o r an a d d i t i o n a l 1 h r and the n c o o l e d t o room temperature. The p r e c i p i t a t e d sodium c h l o r i d e was removed by f i l t r a t i o n and washed w i t h benzene. 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 under reduced p r e s s u r e t o p r o v i d e a c l e a r l i q u i d (600 g ) , which was f r a c t i o n a t e d t h r o u g h a 1 f t . Y i g r e u s column. A f t e r a f o r e - r u n of t r i m e t h y l e n e g l y c o l (345 g ) , bp 80-85°/2 mm, the jf- b e n z y l o x y p r o p a n o l (243 g, 65$) d i s t i l l e d o 77 as a c l e a r c o l o r l e s s o i l , bp 95-100 / l - 2 mm, ( l i t , 145-150°/13 mm), NMR s i g n a l s ( n e a t ) : 2.76 ( s i n g l e t , 5H, a r o m a t i c ) , -97-5.59 ( s i n g l e t , 1H, - O H ) , 5.65 ( s i n g l e t , 2H, CgH^H^O-), 6.35 ( t r i p l e t , 2H, -CH 2 O H ) , 6.51 ( t r i p l e t , 2H, C g H ^ H ^ C i y m ^ ) , 8.21 ( q u i n t e t , 2H, -0CH 2 C H 2 C H 20H). B e n z y l X-chloropropyl e t h e r (143) T h i o n y l c h l o r i d e (190 g, 1.5 mole) was added t o a m i x t u r e tf-benzyloxypropanol (234 g, 1.4 mole) and d i m e t h y l a n i l i n e (200 g) at such a r a t e as t o keep the temperature below 60°. A f t e r c o m p l e t i n g the a d d i t i o n , w hich took 3 h r , the r e a c t i o n was a l l o w e d t o proceed f o r an a d d i t i o n a l hour. The m i x t u r e was t h e n poured i n t o h y d r o c h l o r i c a c i d (10$, 500 ml) and e x t r a c t e d w i t h c h l o r o f o r m . The c h l o r o f o r m e x t r a c t was washed w i t h w ater, sodium b i c a r b o n a t e s o l u t i o n , and 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 , d r i e d over anhydrous sodium s u l f a t e and c o n c e n t r a t e d under reduced p r e s s u r e . The r e s u l t i n g dark o i l was d i s t i l l e d t h r o u g h a 1 f t . V i g r e u x column t o p r o v i d e the d e s i r e d m a t e r i a l (200 g, 80$) as a c o l o r l e s s o i l , bp 95-100°/l mm, ( l i t 7 8 , 129°/l6 mm). NMR s i g n a l s ( n e a t ) : 2.72 ( s i n g l e t , 5H, a r o m a t i c ) , 5.72 ( s i n g l e t , 2H, C g H^ H ^ O - ) , 6.57 ( t r i p l e t , 2H, CgH^H^CHgCHg-), 6,65 ( t r i p l e t , 2H, - C H 2 C H 2 C 1 ) , 8.30 ( q u i n t e t , 2H, - C H 2 C H 2 C H 2 C l ) . D i e t h y l X-benzyloxypropylethyl malonate (144). To a s o l u t i o n of sodium e t h o x i d e (70 g, 1 mole) i n a b s o l u t e e t h a n o l (500 ml) was added e t h y l d i e t h y l malonate (190 g, 1 mole). The s o l u t i o n was heated t o r e f l u x and b e n z y l y - c h l o r o p r o p y l e t h e r (185 g., 1 mole) added over a p e r i o d of l / 2 h r . R e f l u x i n g -98-was c o n t i n u e d f o r 10 hr and the r e a c t i o n m i x t u r e was th e n s t i r r e d a t room temperature f o r a f u r t h e r 10 h r . 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 , and water added t o d i s s o l v e the i n o r g a n i c s a l t s . The l a y e r s were a c i d i f i e d w i t h g l a c i a l a c e t i c a c i d and 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 w i t h e t h e r . The o i l and e t h e r e x t r a c t s were combined, washed w i t h w a t e r , sodium b i c a r b o n a t e s o l u t i o n , 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 , 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 under reduced p r e s s u r e . The crude l i q u i d (320 g) was d i s t i l l e d t o g i v e the d e s i r e d m a t e r i a l (163 g, 46%) as a c l e a r c o l o r l e s s o i l , bp 140-150°/0.1 mm. NMR s i g n a l s : 2.75 ( s i n g l e t , 5H, a r o m a t i c ) , 5.56 ( s i n g l e t , 2H C 6H 5CH 20-), 5.86 ( q u a r t e t , 4H, 2x-0CH. 2CH 5), 6.58 ( t r i p l e t , 2H, C 6H 50H 20CH 2-), 8.00 ( m u l t i p l e t , 6H, -OCHgCHgCH^CCH^CH^), 8.82 ( t r i p l e t , 6H, 2x-OCH 2CH 5), 9.20 ( t r i p l e t , 3H, -CH^CH^). ( c f . l i t 5 4 ' a ) . ( f - B e n x y l o x y p r o p y l e t h y l m a l o n i c a c i d (145) A m i x t u r e of i n t e r m e d i a t e (144) (163 g, 0.5 mole), p o t a s s i u m h y d r o x i d e (108 g ) , water (200 ml) and e t h a n o l (50 ml) was warmed t o 40° f o r 10 hr and t h e n a l l o w e d t o s t i r f o r a f u r t h e r 10 h r a t room temperature. The a l k a l i n e s o l u t i o n was e x t r a c t e d w i t h e t h e r t o remove any s t a r t i n g m a t e r i a l (5.0 g ) . The aqueous l a y e r was a c i d i f i e d w i t h 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 u s i n g Congo r e d as i n d i c a t o r and the o i l t h a t s e p a r a t e d was c o l l e c t e d . The aqueous l a y e r was e x t r a c t e d -99-w i t h e t h e r and the combined e t h e r e x t r a c t s and o i l washed w i t h water 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 , 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 under reduced p r e s s u r e . .The r e s u l t i n g o i l was d i l u t e d w i t h warm e t h e r and hexane added u n t i l the s o l u t i o n was o p a l e s c e n t . Upon c o o l i n g the d e s i r e d . a c i d (145) s e p a r a t e d as a w h i t e c r y s t a l l i n e s o l i d (70 g, 50$), mp 117-120°, NMR s i g n a l s : -1.5 ( s i n g l e t , 2H, 2x-C00H), 2.70 ( s i n g l e t , 5H, a r o m a t i c ) , 5-47 ( s i n g l e t , 2H, 0 6 H 5 C H 2 0 - ) , 6.50 ( t r i p l e t , 2H, C 6H 5CH 20CH 2-), 7.8-8.8 ( m u l t i p l e t , 6H, -OCH 2CH 2CH 2CCH 2CH 3), 9.12 ( t r i p l e t , 3H, -CH 2CH 3). ( c f . l i t 5 4 ' a ) . E x a m i n a t i o n of the mother l i q u o r s by t h i n l a y e r chromatography ( s i l i c a , c h l o r o f o r m ) i n d i c a t e d the presence of another compound i n a d d i t i o n t o the f o r e g o i n g d i a c i d (145). The NMR spectrum showed the presence of an e t h y l e s t e r f u n c t i o n ( q u a r t e t a t 75.95 and t r i p l e t a t 7*8.85) and a c a r b o x y l i c a c i d p r o t o n ( s i n g l e t a t 7-1.6). The s t r u c t u r e (149) was a s s i g n e d on t h i s b a s i s , and was c o n f i r m e d by d e c a r b o x y l a t i o n t o y i e l d e t h y l 2-( ^ f - b e n z y l o x y p r o p y l ) - b u t a n o a t e ( 1 4 7 ) , see below experiment ( b ) . 2 - ( l f - B e n z y l o x y p r o p y l ) - b u t a n o i c a c i d (146) E t h y l ^ - b e n z y l o x y p r o p y l m a l o n i c a c i d (67 g, 0 . 2 5 mole) was heated a t 160°. The e v o l u t i o n of carbon d i o x i d e ceased a f t e r 6 h r . The p r o d u c t , a y e l l o w v i s c o u s o i l (54 g) was used f o r subsequent r e a c t i o n w i t h o u t f u r t h e r p u r i f i c a t i o n . NMR s i g n a l s : -1.6 ( s i n g l e t , 1H, -C00H), 2.71 ( s i n g l e t , 5H, -IOC-a r o m a t i c ) , 5.55 ( s i n g l e t , 2H, CgH^CH^O-), 6.56 ( t r i p l e t , 2H, C 6H 5CH 2OCH 2CH 2-), 7.65 ( m u l t i p l e t , 1H, - 6 H C 0 2 H ) , 8.45 ( m u l t i p l e t , 6H, -OCH 2CH 2CH 2CCH 2CH 3), 9.11 ( t r i p l e t , 3H,-CHgCH^). ( c f . l i t 5 4 ' a ) E t h y l 2 -(df-benzyloxypropyl) -butanoate (147) (a) A s o l u t i o n of 2 - ( # - b e n z y l o x y p r o p y l ) - b u t a n o i c a c i d (146) (54 g, 0.23 mole) i n a b s o l u t e e t h a n o l ( l l i t r e ) and c o n c e n t r a t e d s u l f u r i c a c i d (8 ml) was r e f l u x e d f o r 10 h r . P a r t of the e t h a n o l (800 ml) was removed by d i s t i l l a t i o n and the r e s t of the r e a c t i o n m i x t u r e was poured i n t o i c e water. The r e s u l t i n g m i x t u r e was e x t r a c t e d w i t h e t h e r . The e t h e r e x t r a c t was washed w i t h w a t e r , 5% sodium carbonate s o l u t i o n , and w i t h water a g a i n , 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 under reduced p r e s s u r e . The r e s u l t i n g l i q u i d was d i s t i l l e d under reduced p r e s s u r e t o a f f o r d the d e s i r e d m a t e r i a l (50 g, 81%) as a c l e a r o i l , bp 135°/l.5 mm. Gas chromatography, performed on a W i l k i n s Aerograph Autoprep, Model A-700, u s i n g , a 20% SE 30 a n a l y t i c a l column (60/80 Chrom W, 10' x t " column temperature 260, h e l i u m f l o w r a t e 100 ml/min), r e t e n t i o n time 5 mins. NMR s i g n a l s : 2.75 ( s i n g l e t , 5H, a r o m a t i c ) , 5-58 ( s i n g l e t , 2H, CgH^CH^O-), 5.95 ( q u a r t e t , 2H, -OCH^CH^), 6.61 ( t r i p l e t , 2H, C 6H 5CH 2OCH 2CH 2-), 7.75 ( m u l t i p l e t , 1H, -CHCOOC^), 8.40 ( m u l t i p l e t , 6H, -OCH 2CH 2CH 2CCH 2CH 3), 8.85 ( t r i p l e t , 3H, -OCH^H^), 9.15 ( t r i p l e t , 3H, -CR^CH^). ( c f . l i t 5 4 ' a ) . -101-(b) The mother l i q u o r s (60 g) o b t a i n e d from the c r y s t a l l i s a t i o n of the d i a c i d (145) were d e c a r b o x y l a t e d as d e s c r i b e d above. The crude p r o d u c t , by t h i n l a y e r chromatography ( s i l i c a , c h l o r o f o r m ) , c o n t a i n e d a h i g h l y p o l a r component and a n o n - p o l a r component whose R^ v a l u e was i d e n t i c a l w i t h t h a t of (147). W i t h o u t f u r t h e r p u r i f i c a t i o n the crude product was e s t e r i f i e d by the above proc e d u r e . The f i n a l p roduct of r e a c t i o n (40 g) was 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 (147). P r e p a r a t i o n of t r i p h e n y l ; m e t h y l sodium Sodium (3 g) was p l a c e d i n a 250 ml ground g l a s s s t o p p e r e d b o t t l e and covered w i t h x y l e n e (10 m l ) . The x y l e n e was heated on an open flame u n t i l the sodium melted. The flame was e x t i n g u i s h e d and w h i l e a steady stream of n i t r o g e n was passed t h r o u g h the b o t t l e , mercury (200 g) was s l o w l y added. A f t e r c o o l i n g the amalgam t o room temperature the excess x y l e n e was removed by means of a p i p e t t e and t r i p h e n y l m e t h y l c h l o r i d e ( 1 1 'g) and anhydrous e t h e r (50 ml) added. The b o t t l e was s t o p p e r e d w i t h a w e l l greased s t o p p e r which i n t u r n was s e c u r e l y w i r e d t o the b o t t l e . A f t e r v i g o r o u s s h a k i n g f o r 6 hr the s o l u t i o n a t t a i n e d the dark r e d c o l o r of t r i p h e n y l m e t h y l sodium. A f u r t h e r 80 ml of anhydrous e t h e r was added and s h a k i n g c o n t i n u e d f o r l / 2 h r . The c o n c e n t r a t i o n of t r i p h e n y l m e t h y l sodium (approximate 0.2 m o l e / l i t r e ) was determined by t i t r a t i o n w i t h 0.1N s u l f u r i c -102-a c i d u s i n g m e t h y l orange as i n d i c a t o r . E t h y l <-( tf-benzyloxypropylV^-ethylsuccinate (148) (a) U s i n g T r i p h e n y l M e t h y l Sodium An e t h e r e a l s o l u t i o n (200 ml, 0.0485 mole) of t r i p h e n y l m e t h y l sodium was added t o a 500 ml f l a s k w hich had been f i l l e d w i t h n i t r o g e n and f i t t e d w i t h a d r o p p i n g f u n n e l c o n t a i n i n g the monoester (147). The monoester was added over a p e r i o d of 15 mins and the s o l u t i o n a l l o w e d t o s t i r a t room temperature f o r 1.5 h r . E t h y l bromoacetate (12.8 g, 0.0485 mole) was s l o w l y added t h r o u g h the d r o p p i n g f u n n e l a t such a r a t e as t o keep the e t h e r from r e f l u x i n g . A f t e r the a d d i t i o n was completed (15 mins) the m i x t u r e was s t i r r e d f o r 30 mins a t room temperature. The r e a c t i o n m i x t u r e was t h e n t r e a t e d w i t h water (100 ml) and the e t h e r l a y e r c o l l e c t e d , washed w i t h f r e s h w a t e r , 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 . ' The r e s u l t i n g o i l was d i l u t e d w i t h a s m a l l q u a n t i t y of benzene and a l l o w e d t o s t a n d u n t i l most of the t r i p h e n y l methane had c r y s t a l l i s e d . The t r i p h e n y l methane was removed by f i l t r a t i o n and•the f i l t r a t e chromatographed t h r o u g h a l u m i n a (1100 g ) . The t r i p h e n y l methane which remained i n the f i l t r a t e was e l u t e d w i t h p e t r o l e u m e t h e r (65-110°), w h i l e the u n r e a c t e d s t a r t i n g monoester (147) was e l u t e d w i t h p e t r o l e u m e t h e r (65-110)/ benzene ( l : l ) (7.8 g ) . The d e s i r e d s u c c i n a t e d e r i v a t i v e (148) was e l u t e d w i t h benzene as a y e l l o w o i l , w h ich was -103-s u b s e q u e n t l y p u r i f i e d by m o l e c u l a r d i s t i l l a t i o n (2.80 g, 42$-based on unrecovered s t a r t i n g m a t e r i a l ) t o p r o v i d e a c l e a r v i s c o u s o i l , bp 180-200°/0.1 mm. Gas chromatography, performed on a W i l k i n s Aerograph Autoprep, Model A-700, u s i n g a 20$ SE 30 a n a l y t i c a l column (60/80 Ghrom W, 10' x {" column temperature 260, h e l i u m f l o w r a t e 100 ml/min), r e t e n t i o n time 15 mins. NMR s i g n a l s : 2.72 ( s i n g l e t , 5H, . a r o m a t i c ) , 5.56 ( s i n g l e t , 2H, CgH^CH^O-), 5-92 ( o c t e t , 4H, 2x-0CH 2CH 3), 6.60 ( t r i p l e t , 2H, CgH^CB^OCE^CE^-), 7.4 ( s i n g l e t , 2H, -CH 2C00Et), 8.32 ( m u l t i p l e t , 6H, -OCH^CH^CH^CH^), 8.82 ( s e x t e t , 6H, 2x-CH 2CH 5), 9:. 18 ( t r i p l e t , 3H, -CB^CH^). ( c f . l i t 5 4 ' 2 ) . (b) U s i n g M e t h y l s u f i n y l C a r b a n i o n Sodium h y d r i d e ( l . O g, 0.20 mole, 50$ m i n e r a l o i l d i s p e r s i o n : M e t a l H y d r i d e s , I n c . ) was p l a c e d i n a 2-necked f l a s k and washed w i t h d r y pe t r o l e u m e t h e r (3x) and decanted t o remove the m i n e r a l o i l . D i m e t h y l s u l f o x i d e ( d i s t i l l e d from c a l c i u m h y d r i d e , bp 64°/4 mm) was added and the m i x t u r e heated t o 70-75° u n t i l t he e v o l u t i o n of hydrogen ceased. The monoester (5.28 g, 0.02 mole) (147) and a s m a l l amount of t r i p h e n y l methane as i n d i c a t o r were d i s s o l v e d i n anhydrous e t h e r (250 ml) and p l a c e d i n a 3-necked f l a s k f i t t e d w i t h a n i t r o g e n i n l e t , d r y i n g tube and a s y r i n g e cap. The m e t h y l s u l f i n y l c a r b a n i o n was i n t r o d u c e d i n t o t h i s m i x t u r e t h r o u g h the s y r i n g e cap u s i n g a hypodermic s y r i n g e u n t i l the -104-r e d c o l o r of t r i p h e n y l m e t h y l sodium p e r s i s t e d . E t h y l bromoacetate (3.24 g, 0.02 mole) was added over a p e r i o d of 15 mins and the m i x t u r e s t i r r e d f o r a f u r t h e r 15 mins. A f t e r t h i s time a t h i c k p r e c i p i t a t e had formed. The r e a c t i o n m i x t u r e was t h e n poured i n t o water and the e t h e r l a y e r s e p a r a t e d , washed w i t h water, 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 under reduced p r e s s u r e . The crude product c o n t a i n e d a q u a n t i t a t i v e y i e l d of u n r e a c t e d monoester (147). N - [ & - ( 3 - I n d o l y l ) - e t h y l l -JL-(8-benzyloxypropyl)-o<-ethylsuccinimide  (123) A s u s p e n s i o n of t r y p t a m i n e h y d r o c h l o r i d e (6.1 g, 0.0312 mole) i n a m i x t u r e of water (100 ml) and e t h e r (200 ml) was b a s i f i e d w i t h 10% sodium h y d r o x i d e s o l u t i o n . The e t h e r e x t r a c t , w h i c h c o n t a i n e d the f r e e base, was washed w i t h water, d r i e d over anhydrous sodium s u l f a t e and c o n c e n t r a t e d under reduced p r e s s u r e . A s o l u t i o n of the s u c c i n a t e d e r i v a t i v e (2.5 g, 0.00715 mole) and t r y p t a m i n e h y d r o c h l o r i d e (152 mg) i n f r e s h l y d i s t i l l e d 2 - ( 2 - e t h o x y e t h o x y e t h a n o l ) (75 ml) was added t o the t r y p t a m i n e r e s i d u e . The m i x t u r e was heated t o r e f l u x and 10 ml of the s o l v e n t was d i s t i l l e d t o remove the l a s t t r a c e s of water. R e f l u x i n g was c o n t i n u e d f o r 48 h r under an atmosphere of p u r i f i e d n i t r o g e n . A f t e r c o o l i n g , the r e a c t i o n m i x t u r e was poured i n t o water and the aqueous s o l u t i o n e x t r a c t e d w i t h e t h e r . The e t h e r e x t r a c t was washed w i t h -105-water, 10$ a c e t i c a c i d s o l u t i o n , w a t e r , 5$ 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 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 , d r i e d over anhydrous sodium s u l f a t e and c o n c e n t r a t e d under reduced p r e s s u r e . The crude r e a c t i o n p r o d u c t , a dark brown o i l (4.1 g ) , was p u r i f i e d by chromatography on al u m i n a (300 g ) . The d e s i r e d i m i d e (123) was e l u t e d w i t h b e n z e n e / c h l o r o f o r m (1:1) as a c l e a r s l i g h t l y brown gum (2.5 g, 86$). An a n a l y t i c a l sample was prepared by m o l e c u l a r d i s t a l l a t i o n (290°/0.05 mm). I n f r a r e d ( f i l m ) : 3325 (-NH), 1760 (weak) and 1690 ( s t r o n g ) ( i m i d e ) > 7 5 0 and 700 ( a r o m a t i c ) cm - 1. U l t r a v i o l e t , M a x ( l o g f ) : 224 ( 4 . 2 3 ) , 275 ( s h , 3.64), 282 (3 . 6 8 ) , 290 (3.62) mu. NMR s i g n a l s : 1.48 (broad s i n g l e t , 1H, -NH), 2.70 ( m u l t i p l e t , 9H, a r o m a t i c ) , 3.06 ( d o u b l e t , 1H, <<-proton of the i n d o l e ) , 5.60 ( s i n g l e t , 2H, C ^ C H ^ O - ) , 6.13 ( t r i p l e t , 2H, -CH 2CH 2N-), 6.66 ( t r i p l e t , 2H, C 6H 5CH 2OCH 2CH 2-), 7.00 ( t r i p l e t , 2H, -CH 2CH 2N-), 7.60 ( s i n g l e t , 2H, - C H J J W - ) , 8.55 ( m u l t i p l e t , 6H, -OCH 2CH 2CH 2CCH 2CH 3), 9-26 ( t r i p l e t , 3H, -CH^H^). Mass spectrum: MW 418; main peaks: m/e 144, 143, 130, 91. Found: C, 74.45; H, 7.17; N, 7.07. C a l c . f o r C 2 6 H 3 0 N 2 ° 3 : C, 74.61; H, 7.01; N, 6 . 6 9 . B i s c h l e r - N a p i e r a l s k i C y c l i s a t i o n of.Imide (123) A s o l u t i o n of the imide (118 mg) i n dry t o l u e n e (75 ml) was p l a c e d i n a 3-necked f l a s k f i t t e d w i t h a n i t r o g e n i n l e t and condenser. The t o l u e n e was heated t o r e f l u x and a p p r o x i m a t e l y 10 ml d i s t i l l e d t o remove the l a s t t r a c e s of - 1 0 6 -m o i s t u r e . W i t h a steady stream of n i t r o g e n p a s s i n g t h r o u g h ' . the a p p a r a t u s phosphorus p e n t o x i d e ( a p p r o x i m a t e l y 0.9 g) was added i n t h r e e e q u a l p o r t i o n s over a p e r i o d of 45 mins. A f t e r r e f l u x i n g f o r a f u r t h e r 30 mins, the r e a c t i o n was c o o l e d t o room temperature and the t o l u e n e decanted. The brown p r e c i p i t a t e was t r e a t e d w i t h i c e - w a t e r and the n made s t r o n g l y a l k a l i n e w i t h c o n c e n t r a t e d p o t a s s i u m h y d r o x i d e . The b a s i c s o l u t i o n was e x t r a c t e d 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 e x t r a c t washed w i t h water 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 , d r i e d over anhydrous sodium s u l f a t e and c o n c e n t r a t e d under reduced p r e s s u r e t o a f f o r d a brown gum (49 mg). P u r i f i c a t i o n by chromatography on alumina p r o v i d e d a y e l l o w amorphous s o l i d (15 mg). F u r t h e r p u r i f i c a t i o n 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 ) a f f o r d e d a y e l l o w amorphous s o l i d (10 mg), t o which we a s s i g n e d s t r u c t u r e (155). HC1 U l t r a v i o l e t , Ama*.: 224, 313 , 326 mu, Amax 395 mu. Mass spectrum: MW 310; main peaks: m/e 282 (M-18), 263, 251, 143 and 130. N-Lft - ( 3 - I n d o l y l ) - e t h y l - 3 - ( y - h y d r o x y p r o p y l ) - 3 - e t h y l - p y r r o l i d i n e (161) To a s o l u t i o n of the imide (110 mg, 0.262 mmole) i n dry t e t r a h y d r o f u r a n (20 ml) was added l i t h i u m aluminum h y d r i d e (400 mg) and 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 10 h r and th e n a l l o w e d t o s t a n d a t room temperature f o r 12 h r . The exces s l i t h i u m aluminum h y d r i d e was d e s t r o y e d by a d d i t i o n of mo i s t t e t r a h y d r o f u r a n and the s o l i d h y d r o x i d e s a l t s removed by f i l t r a t i o n and the r e s i d u e washed w i t h f r e s h t e t r a h y d r o f u r a n . -107-The combined f i l t r a t e and washings were poured i n t o water and the r e s u l t i n g m i x t u r e was e x t r a c t e d w i t h c h l o r o f o r m . The c h l o r o f o r m e x t r a c t was washed w i t h water, d r i e d over anhydrous sodium s u l f a t e and c o n c e n t r a t e d under reduced p r e s s u r e . The r e s i d u e (90 mg) was chromatographed on al u m i n a (10 g ) . The d e s i r e d m a t e r i a l was e l u t e d w i t h b e n z e n e / c h l o r o f o r m (1:4) as a c l e a r g r e e n i s h gum (64 mg, 8 2 % ) . An a n a l y t i c a l sample was prepared by m o l e c u l a r d i s t i l l a t i o n (220/0.1 mm). I n f r a r e d ( f i l m ) : 3222 (-0H), 750 ( a r o m a t i c ) cm - 1. U l t r a v i o l e t , ^max (log £); 221 ( 4 - 3 0 ) , 274 ( s h , 3.56), 282 (3 . 5 9 ) , 290 (3 . 5 3 ) . NMR s i g n a l s (100 Mc/s), 1.75 (broad s i n g l e t , 1H, -kg), 2.70 ( m u l t i p l e t , 4H, a r o m a t i c ) , 3.05 ( d o u b l e t , 1H, o<-proton on i n d o l e n u c l e u s ) , 6.40 ( t r i p l e t , 2H, -CH 2CH 20H), 6.60.(broad s i n g l e t , 1H, -CH 20H - d i s a p p e a r s on t r e a t m e n t w i t h D 2 0 ) , 7.35 ( m u l t i p l e t , 8H, -CH^H^N^p), 8.52 ( m u l t i p l e t , 8H, -CH^ ^ - ^ - 2 C H 2 0 H ) , 9.16 ( t r i p l e t , 3H, —2 3 -CHgCH^). Mass spectrum: MW 300; main peaks: m/e 170 (base peak), 156, 144, 130. Pound: C, 75.96; H, 9.34; N, 9 . 2 9 . C a l c . f o r C i g H 2 8 N 2 0 : C, 76.00; H, 9.33; N , 9.33. N-[P - ( 3 - I n d o l y l ) - e t h y l - 3 - ( f l - b e n z y l o x y p r o T ) y l ) - 3 - e t h y l p y r r r o I i d i n e  (124) To a s o l u t i o n of the imide (4.6 g, 11 mmole) i n dry t e t r a h y d r o f u r a n (500 ml) was added l i t h i u m aluminum h y d r i d e (4.6 g, 120 mmole) and 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 at room temperature f o r 12 hr and t h e n r e f l u x e d f o r 4 h r . The -108-r e a c t i o n m i x t u r e was worked up as d e s c r i b e d above. The crude r e a c t i o n product (4 . 5 g) was p u r i f i e d by chromatography on alum i n a (300 g ) . The d e s i r e d b e n z y l e t h e r amine (124) was e l u t e d w i t h b e n z e n e - c h l o r o f o r m (9:1) as a l i g h t brown v i s c o u s o i l (3.50 g, 81$). The a n a l y t i c a l sample was prepare d by m o l e c u l a r d i s t i l l a t i o n 280°/0.05 mm. I n f r a r e d ( n e a t ) : 3200 (-RH), 740 and 695 ( a r o m a t i c ) cm . U l t r a v i o l e t spectrum, >max ( l o g £):' 224 ( 4 . 2 7 ) , 275 ( s h , 3.63), 282 ( 3 . 6 6 ) , 290 (3.61) mu. NMR s i g n a l s (100 Mc/s): 1.6 (broad s i n g l e t , 1H, -NH), 2.68 ( m u l t i p l e t , 8H, a r o m a t i c ) , 3.22 ( d o u b l e t , 1H, ^ - p r o t o n on i n d o l e n u c l e u s ) , 5.58 ( s i n g l e t , 2H, CgHj-CH_20-), . 6.50 ( t r i p l e t , 2H, C 6H 5CH 2OCH 2CH 2-), 7.25 ( m u l t i p l e t , 6H, -CH 2CH 2NQH 2-CH-), 7 .59 ( s i n g l e t , 2H, - N C H ^ ) , 8.50 ( m u l t i p l e t , 8H, - CS 2 * p CS2 C-2-), 9.20 ( t r i p l e t , 3H, -CH QCH,). Mass spectrum: CHpCH- • d D base peak m/'e 260, s t r o n g m/e 91. Found: C, 79.76; H, 8.97; N, 7.02. C a l c . f o r C ^ H ^ ^ O : C, 79-96; H, 8.77; N., 7.17. M o l e c u l a r wt. 390.269. ( C a l c . 390.267). 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 B e n z y l E t h e r Amine (124) The b e n z y l e t h e r amine (124) ( l . O g, 2.5 mmole) was d i s s o l v e d i n anhydrous methanol (400 ml) c o n t a i n i n g m e r c u r i c a c e t a t e (8.0 g, 25 mmole) and g l a c i a l a c e t i c a c i d (15 m l ) . The m i x t u r e was s t i r r e d , under an atmosphere of n i t r o g e n a t room temperature f o r 12 hr.and t h e n r e f l u x e d f o r a p p r o x i m a t e l y 4 h r . The p r o g r e s s of the r e a c t i o n was f o l l o w e d by removing s m a l l a l i q u o t s of the r e a c t i o n m i x t u r e , b u b b l i n g hydrogen s u l f i d e -109-t h r o u g h as d e s c r i b e d l a t e r , and o b s e r v i n g the development of the l i g h t a b s o r p t i o n maximum a t 353 mu. The r e a c t i o n m i x t u r e was a l l o w e d t o c o o l and the mercurous a c e t a t e (2.7 g, 5.2 mmoles) was f i l t e r e d o f f . The f i l t r a t e was warmed t o 50° and hydrogen s u l f i d e was bubled t h r o u g h f o r 10 min t o d e s t r o y the mercury complex. The p r e c i p i t a t e d mercury s u l f i d e s were f i l t e r e d o f f j a n d the f i l t r a t e i m m e d i a t e l y t r e a t e d w i t h sodium b o r o h y d r i d e u n t i l t he l i g h t a b s o r p t i o n maximum a t 353 mu had c o m p l e t e l y d i s a p p e a r e d . P a r t of the methanol (200 ml) was d i s t i l l e d and the r e s t of the, r e a c t i o n m i x t u r e poured i n t o w ater. The aqueous s o l u t i o n was extracted:., 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 e x t r a c t washed w i t h water, d r i e d over anhydrous sodium s u l f a t e and c o n c e n t r a t e d under reduced p r e s s u r e t o p r o v i d e a brown v i s c o u s o i l (836 mg). Complete r e s o l u t i o n of a l l the p r o d u c t s of the r e a c t i o n by chromatography on alu m i n a was not s u c c e s s f u l . The major f r a c t i o n s , e l u t e d w i t h b e n z e n e / c h l o r o f o r m ( 1 : 1 ) , c o n t a i n e d t h r e e components (125) (300 mg) whose R.^  v a l u e s , as shown 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 : c h l o r o f o r m 2:1) were v e r y s i m i l a r t o each o t h e r and t o t h a t of the s t a r t i n g m a t e r i a l (124). By r e p e a t e d chromatography on alu m i n a the l e a s t p o l a r component c o u l d be p a r t i a l l y removed from t h e o t h e r s . The f o l l o w i n g s p e c t r a l d a t a were r e c o r d e d on a m i x t u r e of the two more p o l a r components. I n f r a r e d ( n e a t ) : 3220 (-NH), 735 and 695 ( a r o m a t i c ) cm""*". U l t r a v i o l e t spectrum, /'max: 224, 275 ( s h ) , 283, 291 mu. NMR s i g n a l s (100 Mc/s): 2.75 ( m u l t i p l e t , -110-9H, a r o m a t i c ) , 5.58 ( s i n g l e t , 2H, CgH^CH^O-), 5.90 ( m u l t i p l e t , C^-H), 6.60 ( t r i p l e t , 2H, CgH^^OCB^CH^-), 8.04 ( s i n g l e t , -kcR2-((-), 9.20 ( m u l t i p l e t , T C H 2 C H 5 ) . Ma ss spectrum; main peaks: m/e 198, 184, 170, 169, 156, 154, 140. M o l e c u l a r wt. 388.251. G a l e , f o r 02^11^2^20.' 388.251. Attempts t o o b t a i n a sample f o r combustion a n a l y s i s by m o l e c u l a r d i s t i l l a t i o n l e d t o e x t e n s i v e d e c o m p o s i t i o n , as shown by UV s p e c t r a and t h i n l a y e r chromatography. D e b e n z y l a t i o n of the C y c l i s e d B e n z y l E t h e r Amines (125) (a) U s i n g Boron T r i b r o m i d e A m i x t u r e of the c y c l i s e d b e n z y l e t h e r amines o b t a i n e d as ^described' above (90 mg) was d i s s o l v e d i n d i c h l o r o m e t h a n e (5 ml) and the s o l u t i o n c o o l e d t o 0 ° . Boron t r i b r o m i d e (10 drops) was added s l o w l y , the temperature b e i n g h e l d a t 0°C. The r e a c t i o n was s t i r r e d v i g o r o u s l y f o r 10 min and t h e n poured i n t o 20$ p o t a s s i u m h y d r o x i d e s o l u t i o n (15 m l ) . The r e s u l t i n g m i x t u r e was t h p r o u g h l y e x t r a c t e d w i t h d i c h l o r o m e t h a n e . The d i c h l o r o m e t h a n e e x t r a c t was washed w i t h water 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 , d r i e d over anhydrous sodium s u l f a t e , and c o n c e n t r a t e d under reduced p r e s s u r e t o p r o v i d e a y e l l o w -g r een g l a s s (70 mg). Chromatography on alumina (50 g) and e l u t i o n w i t h c h l o r o f o r m / m e t h a n o l (20:1) p r o v i d e d an amorphous ye l l o w ' s o l i d (50 mg) w h i c h a c c o r d i n g t o 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 : m e t h a n o l 20:1) was a m i x t u r e of p r o d u c t s . U l t r a v i o l e t spectrum, }jnax: 225, 283, 292 mu. NMR s i g n a l s : 2.80 ( m u l t i p l e t , a r o m a t i c ) , no o^-protori a b s o r p t i o n a t 3-10, 9.20 ( t r i p l e t , -GHpCH~). A s m a l l sample of t h i s m i x t u r e was - I l l -s e p a r a t e d by t h i n l a y e r chromatography on alumina to-.provide a pure sample of the major component. Mass spectrum; main peaks: m/e 184, 170, I 6 9 , 156. M o l e c u l a r weight: 298.204. C a l c . f o r C i g H 2 6 N 2 0 : 298.205. (b) By_ C a t a l y t i c H y d r o g e n o l y s i s The m i x t u r e of c y c l i s e d b e n z y l e t h e r amines (125) (110 mg) o b t a i n e d as d e s c r i b e d above and 10% p a l l a d i u m on c h a r c o a l (110 mg) i n g l a c i a l a c e t i c a c i d (10 ml) were s t i r r e d i n an atmosphere of hydrogen u n t i l the uptake of hydrogen ceased. The c a t a l y s t was removed by f i l t r a t i o n t h r o u g h C e l i t e and the f i l t r a t e d i l u t e d w i t h water (50 ml) and n e u t r a l i s e d w i t h • s o l i d sodium c a r b o n a t e . The r e s u l t i n g m i x t u r e was e x t r a c t e d 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 e x t r a c t was washed w i t h water and 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 , d r i e d over anhydrous sodium s u l f a t e and c o n c e n t r a t e d under reduced p r e s s u r e t o p r o v i d e the crude a l c o h o l s (164) as a green v i s c o u s g l a s s (65 mg). The crude product was p u r i f i e d by chromatography on a l u m i n a (10 g ) . E l u t i o n w i t h c h l o r o f o r m / methanol (99:1) p r o v i d e d t h r e e pure a l c o h o l s which w i l l be d e s i g n a t e d A, B, and C i n o r d e r of i n c r e a s i n g p o l a r i t y . A l c o h o l A', .10 mg, 14% !j on a d d i t i o n of d i c h l o r o m e t h a n e c r y s t a l l i s e d as w h i t e p l a t e s , mp 168-170°. U l t r a v i o l e t s p e c t r a , ^max (log£):. 225 ( 4 . 3 2 ) , 275 ( s h , 3.68), 283 ( 3 . 7 0 ) , 290 ( 3 . 6 l ) mu. NMR s i g n a l s (100 Mc/s): 2.05 (broad s i n g l e t , 1H, -NH), 2.75 ( m u l t i p l e t , 4H, a r o m a t i c ) , 5.90 ( m u l t i p l e t , 1H, C^.-H), 6.55 -112-( t r i p l e t , -CH 20H), 9.18 ( t r i p l e t , 3 H , -CHgCH^). Mass spectrum; main peaks: m/e 297 ( M - l ) , 184, 170, 169, 156. M o l e c u l a r w e i g h t : 298.204. C a l c . f o r C^qH^^O: 298.205. A l c o h o l 33: 20 mg, 24$, on a d d i t i o n of dic h l o r o m e t h a n e c r y s t a l l i s e d as w h i t e n e e d l e s , mp 1 8 0 - 5 ° . U l t r a v i o l e t , ^max (log£): 223 ( 4 . 2 6 ) , 274 ( s h , 3-65), 283 ( 3 . 6 8 ) , 291 (3.62) mu. NMR s i g n a l s (100 Mc/s): 1.80 (broad s i n g l e t , 1H, -NH), 2.75 ( m u l t i p l e t , 4H, a r o m a t i c ) , 6.40 ( t r i p l e t , -CH 20H), 8.00 ( s i n g l e t , 2H, -NCH^-), 9.16 ( t r i p l e t , 3H, -CH^H^). Mass spectrum; main peaks: 297 ( M - l ) , 199, 170, 169, 156, 140. M o l e c u l a r w e i g h t : 298.205. C a l c . f o r C i g H 2 6 N 2 0 : 298.205. A l c o h o l C: green amorphous s o l i d (14 mg, 17$). U l t r a v i o l e t spectrum, J-max (log£):' 225 ( 4 . 3 3 ) , 275 ( s h , 3.67), 283 ( 3 . 7 0 ) , 291.(3.63) mu. NMR s i g n a l s (100 Mc/s): 1.60 (broad s i n g l e t , 1H, -NH), 2.75 ( m u l t i p l e t , 4H, a r o m a t i c ) , 5.80 ( m u l t i p l e t , 1H, C^-H), 6.40 ( t r i p l e t , -CH_20H) ^ Mass spectrum; main peaks: •m/e 297 ( M - l ) , 199, 184, 170, 169, 156, 140, 139. M o l e c u l a r w e i g h t : 298.206. C a l c . f o r C i g H 2 6 N 2 0 : 298.205. M e s y l a t i o n iof the C y c l i s e d A m i n o a l c o h o l s (164) (a) The m i x t u r e of c y c l i s e d a m i n o a l c o h o l s (164) (100 mg) o b t a i n e d from the d e b e n z y l a t i o n experiment (a) (see above) was d i s s o l v e d i n dry p y r i d i n e (2 ml) and the s o l u t i o n c o o l e d t o 0°. M e t h a n e s u l f o n y l c h l o r i d e (200 mg) was added s l o w l y and the r e s u l t i n g m i x t u r e was a l l o w e d t o st a n d i n the r e f r i g e r a t o r f o r 24 h r s , a f t e r w h i c h time the s o l u t i o n was dark wine r e d . -113-The r e a c t i o n m i x t u r e was poured i n t o 2N ammonia (20 ml) and the r e s u l t i n g m i x t u r e was e x t r a c t e d w i t h e t h e r . The e t h e r e x t r a c t was washed w i t h water, d r i e d over anhydrous sodium s u l f a t e , and c o n c e n t r a t e d under reduced p r e s s u r e t o p r o v i d e a l i g h t brown foam (12 mg). The u l t r a v i o l e t spectrum ()jnax: 258, 262, 268 mu) l a c k e d the c h a r a c t e r i s t i c a b s o r p t i o n s of an i n d o l e but showed the presence of a p y r i d i n e . The aqueous l a y e r was c o n c e n t r a t e d t o d r y n e s s , and the l a s t t r a c e s of water removed by a z e o t r o p i c d i s t i l l a t i o n w i t h benzene and x y l e n e . The r e s u l t i n g powdery w h i t e r e s i d u e (126) had an i n d o l i c u l t r a v i o l e t spectrum (Amax: 220, 280, 289 mu) w i t h a s h o u l d e r a t 270 mu p r o b a b l y due t o p y r i d i n e s a l t s . (b) The c y c l i s e d a m i n o a l c o h o l B (34 mg) was m e s y l a t e d by the above procedure, and the d e s i r e d m a t e r i a l (126) was o b t a i n e d from the water e x t r a c t . U l t r a v i o l e t spectrum, max: ^220, 280, 289 mu - w i t h a s h o u l d e r a t 270 mu a s c r i b e d t o 1 p y r i d i n e s a l t s . R e d u c t i v e R i n g Cleavage R e a c t i o n (a) The q u a t e r n a r y s a l t (126) o b t a i n e d from the m e s y l a t i o n experiment (a) was d i s s o l v e d i n anhydrous e t h a n o l (2 ml) and t r a n s f e r r e d t o a 3-necked f l a s k f i t t e d w i t h a dry i c e condenser and an ammonia i n l e t . A f t e r condensing a p p r o x i m a t e l y 30 ml of l i q u i d ammonia i n t o the f l a s k , s m a l l q u a n t i t i e s (50 mg each) of f r e s h l y cut sodium were added • -114-u n t i l a f t e r the f i n a l a d d i t i o n the b l u e c o l o r p e r s i s t e d f o r 20 mins. Ammonium c h l o r i d e was added and the ammonia a l l o w e d t o e v a p o r a t e . The r e s i d u e was t r e a t e d w i t h water and e x t r a c t e d w i t h e t h e r . The e t h e r e x t r a c t was washed w i t h water 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 , d r i e d over anhydrous sodium s u l f a t e and c o n c e n t r a t e d under reduced p r e s s u r e . The r e s i d u e , a l i g h t g r een gum (32 mg) was chromatographed on a lumina (Woelm, a c t i v i t y I , 3 g ) • (dl)-Quebrachamine ( l ) (5 mg, 6% - based on m i x t u r e of c y c l i s e d a m i n o a l c o h o l s ) was e l u t e d w i t h d i c h l o r o m e t h a n e : e t h e r 20:1. The i n f r a r e d spectrum ( P e r k i n Elmer Double Beam Model 21, c h l o r o f o r m ) of t h i s m a t e r i a l was superimposable on t h a t of n a t u r a l (-)-quebrachamine. U l t r a v i o l e t spectrum, ^max ( l o g f ) : 228 ( 4 . 4 0 ) , 285 ( 3 . 8 3 ) , 292 (3.81) mu. Mass spectrum: MW 282; main peaks: m/e 253, 210, 156, 144, 143, 138, 124, 110. These p r o p e r t i e s were i d e n t i c a l w i t h those of an a u t h e n t i c sample of (-)-quebrachamine. A d d i t i o n a l e v i d e n c e came from t h i n l a y e r chromatography u s i n g 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; a l u m i n a , benzene. Spray reagent: antimony p e n t a c h l o r i d e - p u r p l e s p o t , e e r i e s u l f a t e - green-grey s p o t . (b) The q u a t e r n a r y s a l t o b t a i n e d from m e s y l a t i o n experiment (b) was reduced by a procedure i d e n t i c a l w i t h t h a t described^: above t o p r o v i d e (dl)-quebrachamine (1.5 mg, 5% - based on u n c y c l i s e d a m i n o a l c o h o l B ) . -115-B i b l i o g r a n h y 1. M. Hesse, " I n d o l a l k a l o i d e " , S p r i n g e r - V e r l a g , B e r l i n - G o t t i n g e n -H e i d e l b e r g , 1964. 2. 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