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The total syntheses of dregamine and epidregamine : a general route to 2-acylindole alkaloids Sung, Wing Lam 1977

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THE TOTAL SYNTHESES OF DREGAMINE AND EPIDREGAMINE. A GENERAL ROUTE TO 2-ACYLINDOLE ALKALOIDS by WING LAM^SUNG B.Sc, Oregon State University, 1971 M.Sc. , Oregon State University, 1973 A THESIS SUBMITTED IN PARTIAL FULFILMENT OF THE REQUIREMENTS FOR THE DEGREE OF We accept this thesis as conforming to the required standard THE UNIVERSITY OF BRITISH COLUMBIA November, 1977 (~c\ Wing Lam Sung, 1977 DOCTOR OF PHILOSOPHY i n the Department of Chemistry In presenting this thesis in partial fulfilment of the requirements for an advanced degree at the University of British Columbia, I agree that the Library shall make it freely available for reference and study. I further agree that permission for extensive copying of this thesis for scholarly purposes may be granted by the Head of my Department or by his representatives. It is understood that copying or publication of this thesis for financial gain shall not be allowed without my written permission. Department of CHEMISTRY The University of British Columbia 2075 Wesbrook Place Vancouver, Canada V6T 1W5 Date 7» Dec., 1977 - i i -ABSTRACT A general method for the t o t a l synthesis of 2-acylindole a l k a l o i d s i s outlined and i t s a p p l i c a t i o n to the syntheses of dregamlne (34) and epidregamine (181) described. 2(S)-Amino-3(B-indolyl)-propan-l-ol (113), prepared from L-(-)-tryptophan (112) by l i t h i u m aluminum hydride reduction, was converted to i t s d i t o s y l a t e (114). Reaction of the l a t t e r with potassium cyanide afforded 3(S)-tosylamino-4-(g-indolyl)-butanonitrile (115) which was transformed to 3(S)-amino-4((3-indolyl)-butanonitrile (116) by reductive cleavage. Formylation of (116) with methyl formate afforded 3(S)-(N-formylamino)-4-(B-indolyl)-butanonitrile (117) . From t h i s stage, a number of routes directed towards the synthesis of e i t h e r a vobasine or sarpagine system were investigated. The only successful sequence involved i n i t i a l l y a B i s c h l e r - N a p i e r a l s k i type reaction of (117) with polyphosphate ester (PPE) as the reagent where-upon the 3-dihydrocarboline d e r i v a t i v e , 3(S)-cyanomethyl-3,4-dihydro-3-carboline (160) was obtained. The l a t t e r compound was then condensed with 3-methylenepentan-2-one (121) under a c i d i c conditions to afford four isomeric 6(S)-cyanomethyl-3-ethyl-2-oxo-l,2,3,4,6,7,12,12b-octahydroindolo-(2,3-a)-quinolizines (159A-D). These isomers can be interconverted by a c i d i c , basic or thermal methods, and therefore a l l of these compounds are useful for subsequent synthetic reactions. Base catalysed transannular c y c l i z a t i o n of the 3(S), 12b(S)-isomer (159D) - i i i -gave 16(R)- and 16(S)-cyano-16-descarbomethoxy-19,20(S)-dihydro-15(R)-hydroxypericyclivine (164) and (165), the l a t t e r possessing the desired sarpagine skeleton. Both the n i t r i l e s (164) and (165) were u t i l i z e d for the subsequent experiments. Reaction of (164) with cyanogen bromide provided the 3(R) and 3(S)-N-cyano-16(R)-cyano-16-descarbomethoxy-19,20(S)-dihydro-15(R)-hydroxyperivinols (173) and (174), while (165) under these conditions afforded the 3 ( S ) , 16(S)-diol (170). Manganese dioxide oxidation of both (173) and (174) afforded N-Cyano-16(R)-cyano-16-descarbomethoxy-19,20(S)-dihydro-15(R)-hydroxyperivine (175) and the l a t t e r was converted to N-cyano-16 (S)-cyano-14,15-dehydro-16-descarbomethoxy-19,20(S)-dihydroperivine (172) by t h i o n y l chloride dehydration and subsequent treatment with sodium hydroxide. The d i o l (170) i n the other series was converted to the same ketone (172) through the same procedure. Sodium borohydride (pyridine) treatment of (172) accomplished the simultaneous reduction of the unsaturated carbonyl system and removal of the N-CN group to provide 16(S)-cyano-16-descarbomethoxy-19, 20 ( S)-dihydroperivinol (176) which was oxidised by manganese dioxide to give i t s corresponding ketone (177). A l k a l i n e hydrolysis of the l a t t e r and subsequent e s t e r i f i c a t i o n yielded 16-epi-19,20 (S) -dihydroperivine (179). The l a t t e r compound i s i d e n t i c a l with an authentic sample prepared from the a l k a l o i d perivine (23) by hydro-genation and epimerization of the ester group. N-methylation of (179) -iv-b y the Eschweiler-Clarke procedure and in turn, dregamine (34) after (181). provided 16-epidregamine (181) base-catalysed epimerization of -v-TABLE OF CONTENTS Page T i t l e Page i A b s t r a c t i i T a b l e o f C o n t e n t s V L i s t of T a b l e s v i L i s t o f F i g u r e s v i i Acknowledgements < i x I n t r o d u c t i o n 1 D i s c u s s i o n 26 a) Scheme A 27 b) Scheme B 36 c) Scheme C 38 d) Scheme D 40 e) Scheme E 43 E x p e r i m e n t a l • . 77 B i b l i o g r a p h y 107 - v i -LIST OF TABLES Table Page I 2-Acylindole (vobasine type) alk a l o i d s 9 II Sarpagine a l k a l o i d s 10 III Ajmaline a l k a l o i d s 11 IV IR and nmr data of speciogynine (162), m i t r a c i l i a t i n e (128), mitragynine (163) and s p e c i o c i l i a t i n e (161) 50 V IR and nmr data of ketones (159A-D) 51 VI Relative i n t e n s i t y of the molecular ions (M+) and the (M +-CH 2C0 2CH 3) ions i n the ester series 55 VII Relative i n t e n s i t y of the molecular ions (M ) and the (M+-CH0CN) ions i n the n i t r i l e s e r i e s 56 - v i i -LIST OF FIGURES Figure Page 3 1. Incorporation of [0-methyl- H]-loganin (21) into various a l k a l o i d s 5 2. Possible interconversion of the corynanthe skeleton (7) to the aspidosperma (5) and iboga (6) systems 6 3. Possible i n t e r r e l a t i o n between the corynanthe skeleton (24,25) and vobasine (27), sarpagine (28) and ajmaline (29) systems 8 4. Reactions applicable to the conversion of the sarpagine skeleton to the vobasine type a l k a l o i d s 12 5. Reactions applicable to the conversion of the vobasine skeleton to the sarpagine type a l k a l o i d s 13 6. Chemical interconversions of sarpagine and ajmaline systems 14 7. Tautomerization of some vobasine systems 15 8. Buchi's p a r t i a l synthesis of voacamine (72) 17 9. Masamune's t o t a l synthesis of ajmaline (11) 18 10. van Tamelen's biogenetic-type t o t a l synthesis of ajmaline (11) 19 11. Yamada's synthesis of l-methyl-16-descarbomethoxy-20-desethylidenevobasine (94) 20 12. Potier's synthesis of 16-descarbomethoxyvobasine (99) .. 21 - v i i i -LIST OF FIGURES - continued » Figure Page 13. Potier's conversion of tabernaemontanine (35) to ervatamine (105) 24 14. Preparation of the ketoester (141) 36 15. Preparation of the hy d r o x y n i t r i l e s (157,158) 42 16. Interconversion of the ketones (159A-D) 48 17. Preparation of the hydr o x y n i t r i l e s (164 and 165) and d e r i v a t i v e s . 52 18. Mass spectrum of the k e t o n i t r i l e (159D) 57 19. Fragmentation of the k e t o n i t r i l e (159D)' upon electron impact ; . 58 20. Mass spectrum of the h y d r o x y n i t r i l e (164) 60 21. Fragmentation of the h y d r o x y n i t r i l e (164) upon electron impact 61 22. Preparation of the h y d r o x y n i t r i l e (164) from the k e t o n i t r i l e (159A) 62 23. Preparation of the unsaturated ketone (172) 64 24. Preparation of 16-epi-19,20(S)-dihydroperivine (179) 66 25. Mass spectra of 16-epi-19,20(S)-dihydroperivine (179) 69 26. Fragmentation of 16-epi-19,20(S)-dihydroperivine (179) upon electron impact 70 27. Mass spectrum of 19,20(S)-dihydroperivine (180) 72 28. IR spectrum of 16-epi-19,20(S)-dihydroperivine (179) 74 i x ACKNOWLEDGEMENTS I wish t o express my gratitude to Professor James P. Kutney for h i s encouragement and guidance throughout the course of my research. I also wish to thank Drs. B. Worth and T. Honda for t h e i r suggestions concerning t h i s work. A deep sense of gratitude i s directed towards my wife Ann for her support. This thesis i s dedicated to her with love. -1-I. INTRODUCTION Alkaloids are widely d i s t r i b u t e d among flowering plants. It i s estimated that about 25% of these nitrogenous bases have the indole or dihydroindole nucleus"''. The majority of the simple indole 2 al k a l o i d s inhabit the dicotyledon plants . However, some of them, can be found occasionally i n animals, fungi and other plant f a m i l i e s . The simplest of the indole a l k a l o i d s may contain a tryptamine (1) unit with a s l i g h t l y modified structure, such as the hallucinogenic agents N,N-dimethyltryptamine (2, Phalaris tuberosa), p s i l o c i n (3, Psilocybe baeocystine) and the toxic bufotenine (4) secreted by the European toad. H H (3) <4> The complex indole a l k a l o i d s are also confined mainly to the dicotyledons p a r t i c u l a r l y of the Apocynaceae, Loganiaceae and Rubiaceae 3 plant f a m i l i e s . A large majority of them consist of a tryptamine unit 4-6 and a C q-C 1^ unit which i s monoterpene-derived . Examples of these -2-indole alkaloids are vindoline ( 5 ) , catharanthine ( 6 ) , ajmalicine ( 7 ) , ,<ll ) ( 1 2 ) -3-stemmadenine (8), vobasine (9), sarpagine (10), ajmaline (11) and strychnine (12). It is generally agreed that the tryptamine segment is derived from tryptophan (13), because of the successful incorporation of labelled tryptophan (13) into a large variety of indole alkaloids'' Since the carboxylate function of tryptophan (13) is absent in most of the monoterpenoid indole alkaloids. Battersby suggested that tryptamine (1) was derived from the decarboxylation of tryptophan (13) before the condensation with secologanin (14) to produce vincoside (15) as an intermediate in the biosynthetic sequence. H (13) (14) ^OGIu H 3 C O 2 C (15) (16) This hypothesis was justified by the incorporation of labelled tryptamine (I), secologanin (14), and a synthetic mixture of vincoside -4-(15) and isovincoside (16) into several a l k a l o i d s of Vinca rosea 12 More recently Scott reported a high l e v e l of tryptamine incorporation 13 into ajmalicine (7) . However, since 1968, a number of vincoside related compounds possessing the carboxylate group were reported. 14 15 For example, c o r d i f o l i n e (17) and 5a-carboxystrictosidine (18) were i s o l a t e d . Brown^ suggested that (a) the l a t t e r compound (18) can be an a l t e r n a t i v e intermediate to vincoside (15) for some indole a l k a l o i d s and (b) the precursor of some a c i d i c indole a l k a l o i d s which r e t a i n the carboxyl group of tryptophan (13), such as adirubine (19) and 5a-carboxytetrahydroalstonine ( 2 0 ) 1 7 . 16 C 0 2 H ..'OGIu H 3 C 0 2 C (17) H 3 C 0 2 C -(19) (20) * After t h i s section of the Discussion was completed, a new series of investigations by Zenk and coworkers (J. Stockigt and M. H. Zenk, FEBS Let t e r s , 233 (1977), J. Stockigt and M. H. Zenk, Chem. Commun., in press (1977) sent as personal communication to Prof. J. P. Kutney, have revealed that isovincoside (16) and not vincoside (15) i s the key intermediate i n the biosynthesis. _5-The o r i g i n of the remaining C ^ - C ^ Q unit was also investigated with l a b e l l i n g experiments. In i s o t o p i c d i l u t i o n studies i t was shown that the mevalonate-derived^''^ glycoside loganin (21) e x i s t s along with other complex indole a l k a l o i d s i n many a l k a l o i d -containing plants"*'^>^ t and i t s intermediacy was proved by the s p e c i f i c incorporation into catharanthine (6), vindoline (5), ajmalicine (7), serpentine (22) and perivine (23) i n V. rosea (Figure l ) 4 Figure 1. Incorporation of [0-methyl- H]-loganin (21) into various a l k a l o i d s . -6-Also i s o l a t e d from V_. rosea was the cleaved d e r i v a t i v e of loganin (21), secologanin (14) which was shown to be derived from 20 loganin (21) . Secologanin (14) undergoes condensation with tryptamine (1) to give vincoside (15) as indicated by Battersby's 12 experiment . It appeared that the corynanthe (7) skeleton was formed f i r s t i n the conversion of vincoside (15) and was then 21-23 rearranged to the skeletons of the other f a m i l i e s (Figure 2). The sequential formation of these a l k a l o i d s according to the pathway, 24 25 corynanthe-*-strychnos->aspidosperma->-iboga, was established by Scott ' i n studies with germinated V. rosea seedlings. The mechanisms involved i n these various rearrangements are s t i l l completely unknown. (6) (5) Figure 2. Possible interconversion of the corynanthe skeleton (7) to aspidosperma (5) and iboga (6) system. -7-Alkaloids of the vobasine (9), sarpagine (10) and ajmaline (11) type and of d i r e c t i n t e r e s t i n the present study, are probably derived b i o g e n e t i c a l l y from the corynanthe skeleton v i a a common intermediate 26 27 (26) ' (Figure 3). It i s not known whether the carboxylate group of tryptophan (13) i s retained at the intermediary vincoside (18) and 5 27 corynanthe (25) stages ' . It was suggested that such a carboxylic acid group would f a c i l i t a t e an oxidative decarboxylation to generate 4(5) 28 29 s p e c i f i c a l l y the A iminium ion (26) for the ensuing c y c l i z a t i o n ' During the l a s t twenty years, a large v a r i e t y of these three a l k a l o i d types have been i s o l a t e d from natural sources. Some of them 30 31 31 32 are presented i n Tables I ' ,11 and I I I . Considerable e f f o r t s have been directed i n the s t r u c t u r a l e l u c i d a t i o n and chemistry of these 30 systems . Chemical interconversion of these three fa m i l i e s have been achieved. For example, the vobasine (9) type has been i n t e r r e l a t e d with the sarpagine (10) family (Figures 4 and 5) and the l a t t e r to the ajmaline (11) family (Figure 6). Therefore a synthesis of an appropriate member of the vobasine (9) or sarpagine (10) serie s would allow subsequent elaboration of the other f a m i l i e s by means of the known interconversions. -8-Figure 3. P o s s i b l e i n t e r c o n v e r s i o n of the corynanthe s k e l e t o n (24,25) and vobasine (27), sarpagine (28) and ajmaline (29) systems. Table I. (A) Substituents on (A) Alkaloids R l R2 Others A f f i n i n e (30) CH20H H 4-Me Perivine (23) C0 2CH 3 H Periformyline (31) C0 2CH 3 H 4-CHO Ochropamine (32) C0 2CH 3 H 1-Me,4-Me Ochropine (33) C0 2CH 3 H l-Me,4-Me,ll-OMe Dregamine (34) C0 2CH 3 H 4-Me,20-a-ethyl Tabernaemontanine (35) C0 2CH 3 H 4-Me,20-B-ethyl N-Demethyl-16-epiaccedine (36) CH20H H V i n c a d i f f i n e (37) C0 2CH 3 CH20H 4-Me -10-Table I I . Sarpagine a l k a l o i d s Substituents on (B) Alkaloids R2 Others A f f i n i s i n e (38) Vellosimine (39) P e r i c y c l i v i n e (40) Polyneuridine (41) Akuammidine (42) Macusine-B (43) Macusine-C (44) Voacoline (45) Gardnutine (46) H CH20H 1-Me H CHO C0 2CH 3 H CH20H C0 2CH 3 C0 2CH 3 CH20H H CH20H 4-Me C0 2CH 3 CH20H 4-Me -11-T a b l e I I I . A j m a l i n e a l k a l o i d s A l k a l o i d s R l S u b s t i t u e n t s R 2 R 3 on (C) O t h e r s M a u i e n s i n e (47) a-OH H H T e t r a p h y l l i c i n e (48) 3-OH H H Vincamaj i n e (49) 6-0H 6- •C0 2CH 3 H 1-H A j m a l i n e (11) 6-0H H a-OH 2 0 - B - e t h y l I s o a j m a l i n e (50) 3-0H H B-OH 2 0 - 6 - e t h y l A j m a l i d i n e (51) = 0 H a-OH 2 0 - B - e t h y l -12-F i g u r e 4. R e a c t i o n s a p p l i c a b l e t o the c o n v e r s i o n o f the s a r p a g i n e s k e l e t o n t o the v o b a s i n e t y p e a l k a l o i d s . -13-Figure 5. Reactions applicable to the conversion of the vobasine skeleton to the sarpagine type a l k a l o i d s . -14-Figure 6. Chemical interconversion of sarpagine and ajmaline systems. One of the most i n t e r e s t i n g aspects which occurs i n the 2-acyl indole (vobasine) s e r i e s concerns the transannular reactions which may occur. Thus these a l k a l o i d s can e x i s t e x c l u s i v e l y i n any of the two tautomeric forms, namely, the carbinolamine (23a) and 2-acylindole 36 40 41 (23) systems or as equilibrium mixtures of both ' ' (Figure 7). -15-The preferred tautomeric form depends on the functional groups, stereochemistry, solvent and other fa c t o r s , and can be determined e a s i l y by uv, i r and mass s p e c t r a l data ' ' . Figure 7. Tautomerization of some vobasine systems. -16-Many of the 2-acylindole a l k a l o i d s are s t r u c t u r a l units of some n a t u r a l l y occurring b i s i n d o l e a l k a l o i d s . Among them are 44 voacamine (72) , tabernaelegentines A,B,C,D(73,74,75,76 respectively) 46 and tabernamine (77) . The l a t t e r was shown recently to possess s i g n i f i c a n t i n h i b i t o r y a c t i v i t y against lymphocytic leukemia and against human carcinoma of the nasopharynx. (72) linkage at C (73) linkage at C (74) linkage at C (75) linkage at C. (76) linkage at C. (77) linkage at C KT-OMe ll'-OMe, 20 - B-ethyl ll'-OMe, 20 - B-ethyl ll'-OMe, 20-a-ethyl ll'-OMe, 20-a-ethyl 16'-H Several p a r t i a l syntheses of these dimers were developed The synthetic route involves b a s i c a l l y an a c i d i c condensation of the alcohol (78) of an appropriate 2-acylindole intermediate with an indole unit of the iboga a l k a l o i d family (80). This method, f i r s t introduced by Buchi jit a l , was employed i n the p a r t i a l synthesis of voacamine (72) 44 46 (Figure 8) and more recently, by Kingston i n the p a r t i a l synthesis of tabernamine (77) 4^. -17-C0 2 CH 3 (81) + VOACAMINE (72) Figure 8. Biichi's p a r t i a l synthesis of voacamine C72) . -18-The syntheses of these various a l k a l o i d f a m i l i e s provide a considerable challenge to the synthetic chemists. The f i r s t t o t a l 47 synthesis of ajmaline (11) was reported by Masamune et^ al_ and a b r i e f o u t l i n e i s provided i n Figure 9. The route involves con-s t r u c t i o n of a t e t r a c y c l i c aldehyde (84) with the C^-C,. bridge already formed at an early stage. Figure 9. Masamune's t o t a l synthesis of ajmaline (11). -19-A b i o g e n e t i c a l l y patterned t o t a l synthesis of deoxyajmalal B 27 (89) was reported by van Tamelen et_ a l (Figure 10) . The scheme r e l i e s on the oxidative decarboxylation of the t e t r a c y c l i c acid (87) to provide an intermediate that activates the formation of the C..-C, ,-C„ 5 16 15 bridge of deoxyajmalal B (89). The l a t t e r could be converted to ajmaline 37 (11) by an established procedure C H 2 0 C H 2 C 6 H 5 (86) N0.IO4 H CHO r (88) Figure 10. von Tamelen's biogenetic-type t o t a l synthesis of ajmaline (11). -20-Besides ajmaline (11) and the c l o s e l y related isoajmaline 49 (50) , a few attempts were made to synthesize the vobasine skeleton. 42 The f i r s t was reported by Yamada and S h i o i r i and i s outlined i n Figure 11. The carboxylic acid (90) was c y c l i s e d , upon treatment with polyphosphoric a c i d (PPA) to give the 2 - a c y l i n d o l l c structure (91). The skeleton was further elaborated by reduction with l i t h i u m aluminum hydride, chromic acid oxidation and methylation to afford the f i n a l product (94). H (90) (91) ,003 (92) '-CH-(94) Figure 11. Yamada's synthesis of l-methyl-16-desearbomethoxy-20-desethylidenevobasine (94). -21-i A synthesis of 16-descarbomethoxyvobasine (99) was reported by Potier and Langlois"^ (Figure 12). This scheme, l i k e that of the Japanese group, r e l i e d upon the same a c i d i c c y c l i z a t i o n of ester (98) for assembly of the 2-acylindole r i n g system i n the f i n a l steps of the sequence. In summary, up to the present time, synthetic studies have only led to either synthesis of ajmaline (11) or models of the natural vobasine system (94,99), and no sucessful t o t a l synthesis of any n a t u r a l l y occurring vobasine type a l k a l o i d has been reported. C H 3 PPA 4r Figure 12. Potier's synthesis of 16-descarbomethoxyvobasine (99). -22-In considering our synthetic strategy for t h i s system we were attracted to a new approach for the synthesis of the vobasine-sarpagine-ajmaline skeleton v i a a 2-acylindole intermediate exemplified by the general structure (100). There were several reasons for t h i s choice. Among them are (a) the p o s s i b i l i t y of subsequent elaboration to the sarpagine (10) and ajmaline (11) s e r i e s with already established procedures (Figures 5 and 6), (b) convenient entry into the b i s i n d o l e 44 system by the use of Buchi's method of coupling (Figure 8 ) , and (c) the prospect of introducing the appropriate functional groups at the secondary amine and thereby extending the syntheses of other natural products and t h e i r analogs. As our immediate goal for t h i s new approach, the a l k a l o i d dregamine (34) was chosen as the target compound. It was f i r s t i s o l a t e d from the bark of Voacanga dregei plants of the Apocynaceae -23-family^^". It constitutes a monomeric unit of the n a t u r a l l y occurring 45 tabernaelegentines C,D(75,76) and 16-demethoxycarbonyldihydrovoacamine 52 (101) . It i s c l o s e l y related to vobasine (9) and can be prepared by 53 the c a t a l y t i c hydrogenation of vobasine (9) . Other r e l a t i v e s of dregamine (34) are known, for example, tabernaemontanine (35) which 54 i s simply an isomer . These l a t t e r two a l k a l o i d s both show a s i m i l a r i t y to vobasine (9) with regard to t h e i r i r and uv data. Their nmr spectra 54 show that t h e i r carbomethoxy groups orient towards the aromatic system However the stereochemistry of t h e i r e t h y l groups at C ^ Q had been a subject of c o n t r o v e r s y 4 ^ ' . The a-ethyl assignment for dregamine (34) and the 3-orientation for tabernaemontanine (35) were l a t e r v e r i f i e d by X-ray d i f f r a c t i o n studies of the structure and r e l a t i v e configuration 56 57 of ervatamine (105) ' . The l a t t e r a l k a l o i d could be i n t e r r e l a t e d with tabernaemontanine (35) i n the manner indicated i n Figure 13. According to t h i s sequence of reactions, dregamine (34) provided 20-epiervatamine. -24-(104) (105) Figure 13. Potier's conversion of tabernaemontanine (35) to ervatamine (105). -25-i In conclusion, the above inv e s t i g a t i o n s afforded various possible extensions to the synthetic sequence once the synthesis of dregamine (34) was completed. Our studies r e l a t i n g to t h i s general area are presented i n the following discussion. I I . DISCUSSION At the outset of t h i s study a synthetic scheme was envisaged i n which a t e t r a c y c l i c system (106), v i a a transannular c y c l i z a t i o n reaction, affords a sarpagine system (107) and the l a t t e r , i n turn, can be converted into the vobasine (100) and ajmaline (110) systems by established procedures (Figures 4 and 6). If the t e t r a c y c l i c system (106) i s too r i g i d , the C/D r i n g j unction can be cleaved (106-5-108) with the established methods as outlined i n Figure 4, p r i o r to the c y c l i z a t i o n reaction. -27-To achieve the transannular c y c l i z a t i o n process, the following synthetic approaches were considered and are b r i e f l y described i n terms of the type of reaction used i n the c r u c i a l bridging stage: A) Nucleophilic displacement i n the t e t r a c y c l i c n i t r i l e (106, R^CN) seri e s (106+107). B) Nucleophilic displacement i n the t e t r a c y c l i c ester (106, R 1=C0 2CH 3) series (106+107). C) Nucleophilic displacement i n the ring-opened n i t r i l e (108, R1=CN) series (108+111). D) Michael addition i n the conjugated acylindole n i t r i l e (109, R =CN) s e r i e s (109+100). E) Aldol type c y c l i z a t i o n i n the t e t r a c y c l i c k e t o - n i t r i l e To form the t e t r a c y c l i c system (106), L-(-)-tryptophan (112) was selected as the s t a r t i n g material since i t contains the desired tryptamine u n i t , and the carboxylate side chain that can be developed for the l a t e r transannular c y c l i z a t i o n process. Scheme A R (106) , R|=C0 2 CH 3 or CN -28-Our i n i t i a l approach was to extend the side chain of the tryptophan system. To t h i s end, L-(-)-tryptophan (112) was re-duced to the alcohol (113) by means of l i t h i u m aluminium hydride (82% y i e l d ) . The alcohol (113) was allowed to react with a large excess of p_-toluenesulfonyl chloride to y i e l d the d i t o s y l a t e (114) (2xCH 3, 2s, 62.27 and 2.39) i n 90% y i e l d . Reaction of (114) with potassium cyanide afforded the n i t r i l e (115)(C=N absorption at 2280 -1 . * cm ; CH^, s, 62.28, 81%) . Thus the development of the side chain of tryptophan (112) was achieved. (116). 9 5 % (117), 7 5 % * The sequence ((112)->-(115)) had been c a r r i e d out previously by Dr. G. Eigendorf i n our laboratory. - 2 9 -The N-tosyl n i t r i l e (115) was converted to the n i t r i l e - a m i n e (116) i n a reductive cleavage with sodium i n l i q u i d ammonia i n almost quantitative y i e l d " ^ Formylation of (116) with methyl formate afforded the N-formyl n i t r i l e (117) (-CO-NH-absorption at 1680 cm""1) i n 75% y i e l d . Since the proton of the i n d o l i c nitrogen atom can be e a s i l y removed by basic reagents, i t was f e l t at t h i s time that the nitrogen p o s i t i o n (N ) should be protected to avoid the formation of the i n d o l i c anion i n the l a t e r stage where strong basic media were to be employed. Therefore the N-formyl n i t r i l e (117) was transformed into the N -benzyl cl d e r i v a t i v e (118) i n 84% y i e l d . The dibenzyl d e r i v a t i v e (119) was i s o l a t e d i n 14% y i e l d as a byproduct i n t h i s reaction. B i s c h l e r - N a p i e r a l s k i reaction of (117) with the polyphosphate 61 ester (PPE) developed by Ban e_t a l furnished the 3-dihydrocarboline 62 d e r i v a t i v e (120) (A = 323 nm) i n 84% y i e l d . Condensation of (120) max with 3-methylenepentan-2-one ' (121) under a c i d i c conditions gave the 65 * desirable t e t r a c y c l i c ketone (122) (49% y i e l d ) . It should be noted at t h i s point i n the discussion that the' numbering system employed here i s as shown i n (122) i n order to make f a c i l e comparison with the natural series (see for example, (127) and Table 1). An a l t e r n a t i v e * This sequence (115)+(122)) had been ca r r i e d out previously by Dr. A. Murai i n our laboratory. -30-as shown in ( 1 2 2 a ) and consistent for the quinolizine series can be employed and is utilized in the experimental portion when systematic nomenclature is provided for the various intermediates. (122 a) (122), 4 9 % - 31 -0 (123) NaH •OCpHe • 2 5 C2H5I OC 2 H 5 DKOH 0 2)HCHO( (CH.kNH ( I 2 4 ) . 8 5 % HCl ' (125). 4 6 % N(CH-,) 3V2 CH, 0 NaOH N(CH3)3 (120.60% (126).96% It was very d i f f i c u l t to determine the stereochemistry of (122) at t h i s stage because of the u n a v a i l a b i l i t y of the other three possible stereoisomers ( C ^ , C ^ Q ) for a comparative study. However, some i n -formation concerning the configuration could s t i l l be obtained from i r and nmr studies. I t has been f o u n d ^ ^ from studies with indole a l k a l o i d s (eq.(127)^) that i f , i n t h e i r preferred conformation, these compounds possess the C^H (ie a) and at l e a s t one more C-H proton adjacent to the nitrogen atom, i n a t r a n s - d i a x i a l o r i e n t a t i o n to the unshared electrons on t h i s nitrogen, a series of complex i n f r a r e d signals (Bohlmann b a n d s ) ^ between 2700-2850 cm ^ would appear. A l k a l o i d s , such 69 as m i t r a c i l i a t i n e (128) , possessing C^H c i s to the nitrogen electrons would not show these absorptions. -32-(128) An independent study of the chemical s h i f t of C^H i n the nmr 66 69 71 spectrum can a l s o be u t i l i z e d ' ' . The s i g n a l of C^H (64.5-4.0) c i s to the e l e c t r o n p a i r of the n i t r o g e n atom w i l l appear downfield r e l a t i v e to that of the trans o r i e n t a t i o n (above 63.8). In our case, ketone(122) showed a set of i r absorption at 2854 and 2797 cm \ i n d i c a t i n g probably an a o r i e n t a t i o n f o r C^H. This was f u r t h e r confirmed by the absence of a C^H nmr s i g n a l below 63.8. With the t e t r a c y c l i c k e t o - n i t r i l e (122) i n hand, i t appeared reasonable to envisage that (122) can be converted to the sarpagine -33-system (107) v i a a n u c l e o p h i l i c displacement of an appropriate leaving group at C^ ,. by the carbanion generated at the carbon s i t e adjacent to the n i t r i l e group (106+107). However such a reaction required an a-orientation of the leaving group (R^ i n (106)), so a series of experiments with various reducing agents were c a r r i e d out with ketone (122) as substrate. Sodium borohydride reduction provided the 3 (equatorial) alcohol (129), while reduction with a bulky reagent, isobornyloxyaluminum d i c h l o r i d e , 72 afforded the desirable a ( a x i a l ) alcohol (130) . This compound was acetylated and the a-acetate (131) was obtained . (130) , 5 6 % ( l3 l ) ,72°/o *This sequence ((122)+(129), (122)->(131)) was i n i t i a l l y c a r r i e d out by Dr. A. Murai i n our laboratory. -34-Conversion of the a-hydroxyl group i n (130) into a su i t a b l e leaving group would then provide the required f u n c t i o n a l i t y for the c y c l i z a t i o n v i a n u c l e o p h i l i c displacement. Thus the a x i a l alcohol (130) was treated with 3,5-dinitrobenzoyl chloride to y i e l d the dinitrobenzoate (132)(C=0 absorption at 1727 cm ^ ) . Attempts at c y c l i z a t i o n of (132) with sodium hydride or l i t h i u m diisopropylamide met with f a i l u r e . Alcohol (130) was then converted into the mesylate (133) but reaction of (133) with sodium hydride led to the i s o l a t i o n of the o l e f i n i c compound (134)(1 o l e f i n i c H i n nmr, 65.31). This l a t t e r compound proved to be i d e n t i c a l with that obtained from the dehydration of alcohol (130). The mesylate (133) was also converted to o l e f i n (134) by simply r e f l u x i n g i n pyridine. V a r i a t i o n of base (lithium diisopropylamide) brought no reward i n terms of the desired c y c l i z a t i o n . H H OH CN R — C II 0 RCI (130) (132), 5 3 % Now that the o l e f i n (134) was a v a i l a b l e i t was appropriate to -35-determine whether i t could be employed for the purpose of introducing a C2Q~ethylidene side chain, a feature present i n many natural products. Consequently, (134) was allowed to react with osmium tetroxide, to give two c i s d i o l s (135,136) which could, i n turn, be u t i l i z e d i n subsequent studies to be discussed l a t e r . (135,136), 73°/o (134) - 3 6 -Scheme B In addition to the various i n v e s t i g a t i o n s i n the n i t r i l e s e r i e s , a p a r a l l e l series of experiments were ca r r i e d out with an ester function i n the side chain. An analogous synthesis of the t e t r a c y c l i c ester (141) was devised along the l i n e s shown i n Figure 14. H C N DNaOH (115) NH 2) Na, NH 3 3) CH 30H,H I C0 2 CH 3 (137) . 8 6 % HC0 2CH 3 0 2 C H 3 C0 2 CH 3 (140). 9 3 % (141),18% Figure 14. Preparation of the ketoester (141). *This sequence (Scheme B) was developed by Drs. K. Wada and G. Eigendorf i n our laboratory. In this study, the nitrile group was converted into an ester group at an early stage in the sequence by means of a basic hydrolysis and subsequent esterification. The individual steps leading to the tetracyclic ketone (141) are basically similar to those discussed earlier in the nitrile series. The keto-ester (141) was then converted to the mesylate (142) in the previously described manner but as indicated below, i t also failed to undergo the desired cyclization. -38-F a i l u r e of the transannular c y c l i z a t i o n i n both t e t r a c y c l i c n i t r i l e and ester series prompted consideration of another approach. Scheme C Examination of the molecular models reveals that i n the compounds (133) and (142), the geometry of the basic nitrogen atom has to be inverted from i t s most stable form (the nonbonded electron p a i r i n a 3-orientation) to a l e s s stable one (the non-bonded electron pair i n an a-orientation) i n order to allow the two reaction centers to achieve the required proximity. F a i l u r e of such a nitrogen inversion may have consequently led to the sole occurrence of the elimination reaction observed. A possible s o l u t i o n to this problem i s to increase the f l e x i b i l i t y of the system by eliminating the C/D r i n g junction thereby providing a ten-membered r i n g system. Various r i n g opening reaction i n the a l k a l o i d s e r i e s were already outlined i n Figure 4. Among them, the von Braun reaction using cyanogen bromide and water appeared to be most applicable i n our case, since i t s product with the newly formed C^-hydroxyl and N-CN groups provides the options of e i t h e r 3 A 36 r e c y c l i z a t i o n by established procedures ' , or oxidation of the 34 35 C^-hydroxyl group into the 2-acylindole series ' Studies of t h i s reaction i n model systems such as o l e f i n (134), alcohol (130) and acetate (131) were undertaken and desirable r i n g opening products were obtained. The reaction could be conveniently monitored by i r spectroscopy (N-CN reveals a strong band at -2200 cm "^). -39-(130) , R = H (146),R = H . 4 0 % (131) . R = A c (|47) . R = A c . 2 9 % The 3,5-dinitrobenzoate (132) was subjected to the same c o n d i t i o n , the ring-opened benzoate (148) was formed. However, c y c l i z a t i o n attempts using (148) as substrate and employing various b a s i c c o n d i t i o n s (diisopropylamide etc.) f a i l e d to y i e l d any d e s i r a b l e compound. In each instance only s t a r t i n g m a t e r i a l was recovered or extensive decomposition occurs i f f o r c i n g con-d i t i o n s are u t i l i z e d . -40-Scheme D With f a i l u r e i n the l a s t three series of in v e s t i g a t i o n s , the approach using n u c l e o p h i l i c displacement was abandoned i n favor of another approach inv o l v i n g a Michael reaction of a 2-acylindole intermediate as shown in the sequence, (149)^(150). This o v e r a l l strategy appeared a t t r a c t i v e for the following reasons, a) no competition of elimination reaction, b) rapid analysis of the reaction course by uv spectroscopy since (149) and (150) have d i f f e r e n t conjugated systems and c) a v a i l a b i l i t y of the e s s e n t i a l s t a r t i n g materials from the previously studies. *This sequence (Scheme D) was developed previously by Drs. K. Tanaka and H. Matsue i n our laboratory. -41-The synthesis of the desirable 2-acylindole intermediate i s outlined i n Figure 15. For the purpose of removing the s t e r i c hindrance of the N -benzyl group i n the von Braun reaction, the a previously prepared alcohol (130) was f i r s t converted to i t s parent NH analog (151) by reaction with sodium i n l i q u i d ammonia"*^ ^®. Treatment of (151) with a c e t i c anhydride afforded the acetate (152) and the l a t t e r upon reaction under von Braun conditions provided (153) -1 35 73 (N-CN absorption at 2210 cm ) i n high y i e l d ' Oxidation of (153) with manganese oxide produced a mixture of the 2-acylindole acetate (155)(2-acylindole uv absorption at 312 nm) and the unexpected a,3-unsaturated ketone (154)(uv absorption at 316 nm). Treatment of (155) with r e f l u x i n g triethylamine i n benzene completed the conversion to (154). It was f e l t that the i n d o l i c nitrogen p o s i t i o n should be protected, to avoid the interference of an i n d o l i c anion generated otherwise i n the basic conditions to be employed l a t e r . Towards t h i s end, (154) was reacted with methyl chloroformate and sodium hydride to give (156). With the completion of the synthesis of (156), attempts at c y c l i z a t i o n under basic conditions were made i n the hope of a Michael ad d i t i o n to the conjugated ketone system. Treatment of (156) with l i t h i u m diisopropylamide led to 1,2-addition, hence a mixture of the wrongly c y c l i z e d products (157,158)(indolic uv absorption and disappearance of the unsaturated carbonyl i r absorption) were obtained. Although the desirable c y c l i z a t i o n had not been achieved, the syntheses of (157,158) indicated the formation of the carbanion centre that i s required for any further c y c l i z a t i o n attempts. -42-N*,NH 2-* (130) BrCN H 2 0 (153). 9 1 % n n o 2 OAc (152). 8 4 % OAc ( W 3 N * Y. 9 5 % v + (15 4 ) , 5 4 % KH,CIC0 2CH 3 (155), 2 7 % OAc U N - K ^ N-CN H 3 C0 2 C 0 (157) , 1 5 % (158) . 1 2 % Figure 15. Preparation of the hyd r o x y n i t r i l e s (157,158). - 4 3 -Scheme E It was f e l t that for the ongoing research program, a more appropriate intermediate, such as (159), had to be prepared. This intermediate would provide a more e f f i c i e n t route to (156), the l a t t e r being required for a further study of 1,4 vs 1,2-addition as presented i n Scheme D. It would also allow another system for anionic c y c l i z a t i o n s of the a l d o l type (106, R^=CN; R^ = 0 + 1 0 7 , R1=CN; R2=0H). H (159) The following reactions were c a r r i e d out for the synthesis of (159). The N-formyl compound (117) was treated with PPE, as i n the N -benzyl series discussed e a r l i e r (Scheme A), to y i e l d the cl 8-dihydrocarboline d e r i v a t i v e (160), which, without thorough p u r i -f i c a t i o n , was reacted with 3-methylenepentan-2-one (121) to provide a mixture of four t e t r a c y c l i c ketones (159A, D, B and C, designated i n order of decreasing R^ values) i n a r a t i o of 5:4:3:3. Separation of these compounds was accomplished by means of column chromatography and f r a c t i o n a l r e c r y s t a l l i z a t i o n . Data from i r , uv and mass spectra -44-indicated that they are compounds of the same chemical structure but d i f f e r from each other i n terms of stereochemistry at several c h i r a l centers. ( I 59A-D ) 75% f r . (U7 ) A:D'B>C = 5;4--3=3 Considering the sequence (160)->-(159) i t i s cl e a r that two new c h i r a l centers ( C ^ and C 2 Q ) were created thereby providing four possible stereoisomers. The terms normal, a l i o , pseudo and e p i a l l o , commonly employed i n the indole a l k a l o i d area, w i l l be -45-u t i l i z e d here as well to portray the stereochemical differences i n the ketone (159 A-D) Configuration C 3 H C20 normal a e pseudo B B a l i o a a e p i a l l o B a The stereochemistry of these isomeric ketones (159A-D) was studied with same physical ( i r , nmr) c r i t e r i a applied i n the case 69 of the N -benzyl n i t r i l e (122) a Of the four ketones (159A-D), ketones A, B and D exhibit Bohlmann bands i n t h e i r i r spectra which i s evidence of a trans r e l a t i o n s h i p between C^H and the unshared electrons on N^, as mentioned e a r l i e r . Ketone C did not exhibit s i g n i f i c a n t absorption at 2850-2700 cm 1 and was therefore assigned an B-orientation for the C^ proton. However, the appearance of Bohlmann bands i n three rather than two of the isomeric ketones seemed puzzling. Those data tend to i n d i c a t e that one of these three ketones (159A, B and D), possessing either the pseudo or e p i a l l o configuration, might e x i s t i n a state of equilibrium between the two c l a s s i c a l forms (E) and (F). The l a t t e r conformation (F) i s expected to reveal Bohlmann bands i n the i r spectrum. Indeed l i t e r a t u r e precedent e x i s t s for t h i s s i t u a t i o n , 69 as seen i n the a l k a l o i d s p e c i o c i l i a t i n e (161, e p i a l l o ) , which e x i s t s 25% i n the trans configuration (H) and 75% i n c i s conformation (G) i n s o l u t i o n . (E) (F) The stereochemistry of C^H i n these various ketones can a l s o be determined by a c a r e f u l a n a l y s i s of t h i s proton chemical s h i f t i n the nmr s p e c t r a ^ ' ^ ' ^ . The c r i t e r i o n , which was stat e d e a r l i e r i n Scheme A, i s that the proton s i g n a l when C~H i s c i s to the N, e l e c t r o n s -47-w i l l appear downfield r e l a t i v e to that of the trans r e l a t i o n s h i p . The nmr si g n a l of the proton with a c i s r e l a t i o n s h i p generally appears at 64.0-4.5, whereas that of the trans r e l a t i o n s h i p occurs above 63.8. In our case, the chemical s h i f t s of C^H of ketones (159A, 63.77), (159B, 64.00), (159C, 64.46) and (159D, 63.95) indicate that ketones B and C possess the c i s r e l a t i o n s h i p , that i s 33H stereochemistry while A and D belong to the 3a se r i e s . With the sterochemistry of t e n t a t i v e l y assigned i n ketones A-D, a series of experiments directed at epimerization of the ethyl group and hence the determination of the C^Q stereochemistry was i n i t i a t e d (Figure 16). I t was found that ketone B could be transformed into ketone A as a major component i n an equilibrium mixture (2:1), when the former was treated with diethylamine, hydrochloric acid, or simply heated. Ketone C could be converted into ketone D i n the same manner. However, interconversion between either (159A) and (159D), or (159B) and (159C) f a i l e d under the same conditions. This r e s u l t i n -dicated that epimerization of only one c h i r a l center was occurring during these studies, (either or . The u p - f i e l d s h i f t i n the C 3 proton s i g n a l B(64.00) + A(53.\7JO, C(64.46) -»- D(63.95) i n both transformations showed that the c h i r a l i t y at was being a l t e r e d during these conversions. Examples of the epimerization at by 24 a c i d i c , basic or thermal methods had been reported i n the past These r e s u l t s suggested that both ketones A and B have the same C^Q stereochemistry, while C and D would belong to the antipodal series -48-(159B) ( I59A) ,A:B=2:I Figure 16. Interconversion of the ketones (159A-D). -49-In a conformational analysis study of the corynantheidine system, Trager, Lee and Beckett had established a set of phy s i c a l c r i t e r i a for the four possible absolute c o n f i g u r a t i o n s ^ , and had subsequently applied these i n assigning the absolute configurations of speciogynine (162, normal), m i t r a c i l i a t i n e (128, pseudo), mitragynine (163, a l i o ) and s p e c i o c i l i a t i n e (161, e p i a l l o ) (Table 69 IV) . In conclusion, they suggested that both the chemical s h i f t and the bandwidth of the C^H multiplet i n the nmr spectra can be used as c r i t e r i a f o r d i s t i n g u i s h i n g between the pseudo and the e p i a l l o configuration i n the corynantheidine-type a l k a l o i d s , with the l a t t e r showing the proton s i g n a l at the higher end of the 64.5-4.0 l i m i t and also appearing as a broader band. -50-Table IV. IR and nmr data of speciogynine (162), m i t r a c i l i a t i n e (128), mitragynine (163) and s p e c i o c i l i a t i n e (161). Alkaloids Absolute Bohlmann Configuration Bands Speciogynine (162) normal M i t r a c i l i a t i n e (128) pseudo Mitragynine (163) a l i o S p e c i o c i l i a t i n e (161) e p i a l l o G/H + + weak band at 2856 cm"1 Chemical Shift,C 3H Bandwidth c i s C^H above 63.8 ca 64.5 8 Hz above 63.8 ca 64.1 10 Hz + present, - absent. -51-Table V. IR and nmr data of ketones (159A-D) Ketones(159) Absolute Configuration Bohlmann Bands Chemical Shift,C 3H Bandwidth c i s C 3H D normal + 63.95 C pseudo - 64.46 10 Hz A a l i o + ca 63.7 B e p i a l l o 64.00 12 Hz + present, - absent When the i r and nmr data of ketones (159A-D)(Table V) were compared with Beckett's data (Table IV), a good c o r r e l a t i o n could be noted. On t h i s basis the stereochemical assignments shown i n Figure 16 appeared reasonable although some s t r u c t u r a l differences between our system and that studied by the Beckett group require some caution on our part. Confirmation of these assignments was obtained at a l a t e r date i n our studies. Now that the four ketones A-D were s t r u c t u r a l l y defined, an e f f o r t was directed towards to the c y c l i z a t i o n of these compounds to the sarpagine s e r i e s . In view of the persistent f a i l u r e i n the studies involving c y c l i -zation v i a n u c l e o p h i l i c displacement reactions mentioned e a r l i e r , an approach involving a l d o l type reactions was considered. -52-Towards t h i s end, c y c l i z a t i o n of ketone (159D), using l i t h i u m d i e t h y l a m i d e ^ as base at 0°, was attempted (Figure 17). Two comparatively polar products (164, y i e l d 57%) and (165, y i e l d 25%) of the anticipated c y c l i z a t i o n were formed r e a d i l y (30 min). Both samples indicated disappearance of the carbonyl group and retention of the C=N group (ca 2250 cm "*"), i n t h e i r i r spectra. NaOH I—\ (167) , 4 5 % ( 1 6 6 ) , 3 5 % Figure 17. Preparation of the hy d r o x y n i t r i l e s (164 and 165) and d e r i v a t i v e s . -53-In order to obtain more information about the c y c l i z e d products (164) and (165), a series of chemical reactions were performed. Acetylation of (164) with a c e t i c anhydride yielded an acetate (166, C=0 absorption at 1710 cm 1 CH^ s i n g l e t at 62.05), thus confirming the formation of the t e r t i a r y hydroxyl group i n the c y c l i z a t i o n process. It was suspected that both n i t r i l e s (164) and (165) are of epimeric r e l a t i o n s h i p at Studies of epimerization i n other sarpagine systems 29 (eq. deoxyajmalal A (168)) show that epimerization favors the epimer with the C^g functional group o r i e n t i n g opposite to the i n d o l i c nucleus (168+89). DEOXYAJMALAL A DEOXYAJMALAL B (168) < 8 9 > Treatment of n i t r i l e (165) i n a r e f l u x i n g methanolic s o l u t i o n of sodium hydroxide yielded n i t r i l e (164), and thus confirmed the epimeric r e l a t i o n s h i p of both compounds. Furthermore, f a i l u r e of a reverse conversion of n i t r i l e (164) into (165) under the same condition showed that n i t r i l e (164) i s the thermodynamically more stable isomer, probably possessing the n i t r i l e group i n an o r i e n t a t i o n away from the aromatic system. - 5 4 -Differences i n the C^^ c h i r a l i t y can also be determined by evaluating the chemical s h i f t of the methyl s i g n a l of eit h e r a C-^ -carbomethoxy or acetoxy group i n the nmr spectra. The c r i t e r i o n used i s that the nmr signal of the ester methyl group o r i e n t i n g towards 36 the i n d o l i c nucleus (eg. p e r i c y c l i v i n e (40), 63.05) w i l l appear u p f i e l d r e l a t i v e to that (eg. e p i p e r i c y c l i v i n e (169), 63.78) pointing away from the aromatic system. H 3 C 0 2 C V / H P E R I C Y C L I V I N E ( 4 0 ) N F T Q C H 3 H C 0 2 C H 3 E P I P E R I C Y C L I V I N E ( 1 6 9 ) In order to apply t h i s nmr c r i t e r i o n f o r our compounds, n i t r i l e (164) was heated with hydrochloric acid i n methanol^, y i e l d i n g the ester (167, C=0 absorption at 1720 cm"1, 1 CH 3 s i n g l e t at 63.76). A s i m i l a r attempt to convert the epimeric n i t r i l e (165) into the ester f a i l e d . The lack of a sh i e l d i n g e f f e c t on the ester methyl s i n g l e t by the i n d o l i c nucleus indicated that the carbomethoxy group of ester (167), and thereby, the n i t r i l e group of (164), are i n the o r i e n t a t i o n shown, While the i r and nmr data confirm the presence, absence and or i e n t a t i o n of c e r t a i n f u n c t i o n a l groups, information regarding the carbon skeleton can be obtained by mass spectrometry. Mass sp e c t r a l 78—80 studies of various corynanthe and sarpagine seri e s i n the past -55-had established the fragmentation pattern i n both systems, therefore such investigations are d i r e c t l y applicable i n our s e r i e s . However, the t e t r a c y c l i c compounds prepared i n our i n v e s t i g a t i o n possess an a d d i t i o n a l side chain at C<- when compared to most corynanthe a l k a l o i d s , and t h i s proved to be advantageous for the mass sp e c t r a l study. One of the prominent fragments i n most of the t e t r a c y c l i c compounds prepared was found to be the molecular ion minus the side chain (M+-CH2R where R=CN or C0 2CH 3)(Table VI and VII) ' - C H 2 R , Table VI. Relative i n t e n s i t y of the moelcular ions (M ) and the (M +-CH 2C0 2CH 3) ions i n the ester s e r i e s . Esters % Intensity of (M+) ion % Intensity of (I^-CH^O^H^ ions (141) (142) (143) 50 21 11 72 42 20 -56-Table VII. Relative i n t e n s i t y of the molecular ion (M ) and the (M +-CH„CN) ions i n the n i t r i l e s e r i e s N i t r i l e s % Intensity of % Intensity of (M+) ion (M+-CH2CN) ions (122) 44 100 (129) 61 100 (130) 35 100 (131) 44 100 (159A) 61 100 (159B) 100 90 (159C) 100 95 (159D) 100 95 Upon inspection of the mass spectrum of ketone (159D) (Figure 18), the fragmentation scheme, outlined i n Figure 19, i s suggested. One observes the intense (M^-CR^CN) ion a_ (m/e 267) along with the charac-t e r i s t i c a l l y strong fragment _b (m/e 156) and the weaker fragments c_ and d (m/e 169, 168). However the a l d o l c y c l i z a t i o n of ketone (159D) has obviously al t e r e d the nature of the C,. side chain and i t i s no longer a v a i l a b l e for the formation of ion a (m/e 267). But a possible reverse a l d o l - 5 7 --58-Figure 19. Fragmentation of the ketonitrile C159D) upon electron impact. -59-reaction of the c y c l i s e d products (164 and 165) to regenerate ketone (159D) can o f f e r an a l t e r n a t i v e source of fragment a_. Thus a decrease i n the i n t e n s i t y of ion a_ i s expected, and i n fact i s observed in the mass spectra of n i t r i l e s (164 and 165) (Figure 20) and ester (167). A minor fragment (M -17), possibly the (M -OH) ion, confirmed the existence of a C^ ,. hydroxyl group. This loss of a functional group i s more evident i n the case of the acetate d e r i v a t i v e (166) ((M +-0Ac)ion, m/e 290, 100%). Other evidence of the successful c y c l i -zation i s the presence of two very s i g n i f i c a n t fragments c_ (m/e 169) 78—80 and e_ (m/e 223), c h a r a c t e r i s t i c of a sarpagine system . Thus a fragmentation scheme of n i t r i l e (164) i s outlined i n Figure 21. With the c y c l i z a t i o n of ketone (159D) accomplished, i t was intended at t h i s point to commit the other ketones (159A-C) to c y c l i -zation studies. Since (159B-C) could be converted to (159A and D) respectively, the only task l e f t was to commit ketone (159A) to the a l d o l c y c l i z a t i o n . However, treatment of (159A) with l i t h i u m d i e t h y l -amide at 0°, produced neither any c y c l i z e d product nor i t s C2Q-epimer (159D). Perhaps the g-ethyl group of (159A) has s t e r i c a l l y prevented the carbanionic center to come into close proximity of the carbonyl group thereby prevent reaction. Thus a more vigorous condition was applied. After being heated i n a saturated sodium methoxide-methanol solu t i o n for two days, ketone (159A) was converted into n i t r i l e (164) i n 13% y i e l d , apparently through i n i t i a l epimerization into ketone (159D) -09--61-£ , m/e 169 Figure 21. Fragmentation of the h y d r o x y n i t r i l e 0-64) upon electron impact. -62-which subsequently c y c l i z e d to the thermodynamlcally more stable isomer (164)(Figure 22). Figure 22. Preparation of the h y d r o x y n i t r i l e (164) from the k e t o n i t r i l e (159A). -63-Success o f t h e a l d o l c y c l i z a t i o n o f k e t o n e s (159A-D) l e d t o the f o r m a t i o n o f a t e r t i a r y h y d r o x y l group a t the C^ ,. p o s i t i o n w h i c h i s u s u a l l y o c c u p i e d by hydrogen i n t h e v a b a s i n e - s a r p a g i n e - a j m a l i n e system. However t h e g e n e r a l method o f e l i m i n a t i o n and subsequent h y d r o g e n a t i o n a t t h i s b r i d g e h e a d p o s i t i o n i s f o r b i d d e n because o f t h e l i m i t a t i o n s o u t l i n e d i n the B r e d t ' s r u l e . To overcome t h i s d i f f i c u l t y , a r e a c t i o n i n v o l v i n g a r i n g o p e n i n g o f the r i g i d system was p l a n n e d so t h a t t h e r e s u l t i n g s t r u c t u r e was s u f f i c i e n t l y f l e x i b l e t o p e r m i t a d e h y d r a t i o n r e a c t i o n a t C ^ . Thus n i t r i l e (165) was t r e a t e d w i t h cyanogen bromide t o y i e l d t h e r i n g - o p e n e d —1 ^35 73 p r o d u c t ( 1 7 0 ) ( s t r o n g N-CN a b s o r p t i o n a t 2210 cm ) ' Manganese d i o x i d e o x i d a t i o n o f (170) f u r n i s h e d t h e 2 - a c y l i n d o l e system (171) ( u n s a t u r a t e d c a r b o n y l a b s o r p t i o n a t 1628 cm \ 2 - a c y l i n d o l e uv a b s o r p t i o n 8 1 a t 316 nm) ( F i g u r e 2 3 ) . The same r e a c t i o n sequence was a p p l i e d t o the o t h e r i s o m e r i c s e r i e s ( 1 6 4 ) . The von Braun r e a c t i o n w i t h cyanogen bromide c o n v e r t e d n i t r i l e (164) i n t o two p r o d u c t s ( 1 7 3 , 1 7 4 ) ( s t r o n g N-CN a b s o r p t i o n a t --1 73 2220 cm ) . T h e i r s u s p e c t e d i s o m e r i c r e l a t i o n s h i p a t C^ was i n d i c a t e d by t h e i r subsequent o x i d a t i o n i n t o t he same 2 - a c y l i n d o l e system (175) ( u n s a t u r a t e d c a r b o n y l a b s o r p t i o n a t 1613 cm \ 2 - a c y l i n d o l e uv a b s o r p t i o n * T h i s sequence ((165) -> (172)) had been c a r r i e d out p r e v i o u s l y by Dr. H. Matsue i n our l a b o r a t o r y . -64-at 1613 cm , 2-acylindole uv absorption at 315 nm) by manganese A- -A 81 d i o x i d e OH I (165) B T C N . H 2 0 MCv M OHL (171), 8 5 % D S O C I 2 2) NaOH Y. 9 1 % (164) B T C N . H 20 ( I73),6I%-,(I74),26% M n 0 2 Hv •CN 1) S 0 C I 2 2) NaOH Y . 8 6 % Figure 23. (172) Preparation of the unsaturated ketone (172) . -65-Thionyl chloride dehydration"^" and treatment with sodium hydroxide (0°) of both hydroxyl-ketones (171,175) afforded a common product, the a, (3-unsaturated ketone (172)(1 o l e f i n i c proton at 66.42, uv absorption of the highly conjugated system at 336 nm), thus the C.^ hydroxyl group was removed su c c e s s f u l l y . The or i e n t a t i o n of the C-^ g n i t r i l e group was established i n the l a t e r stage of t h i s i n v e s t i -gation. Nevertheless i t was clear at th i s point that both isomeric series represented by (164) and (165) were a v a i l a b l e for the subsequent experiments. Sodium borohydride (pyridine) treatment of (172) accomplished the simultaneous reduction of the unsaturated carbonyl system and the 83—84 removal of the N - n i t r i l e group to provide the saturated alcohol (176) (Figure 24). The l a t t e r compound upon oxidation with manganese dioxide 81 —1 afforded the saturated ketone (177) (carbonyl absorption at 1640 cm , 2-acylindole uv absorption at 315 nm). Since none of the natural systems possess a nitrogen-containing f u n c t i o n a l i t y at C^^, i t was decided to convert the n i t r i l e group into a methyl ester, so that a comparison with a natural system would become possible. Towards t h i s end, the n i t r i l e (177) was hydrolysed with 77 hydrochloric acid i n methanol . The r e s u l t i n g reaction mixture consisted of n i t r i l e (178)(CHN absorption at 2230 cm \ weak unsaturated carbonyl absorption at 1635 cm \ and strong i n d o l i c uv absorption) as a major component and only a trace of the desired ester (179)(ester carbonyl i r absorption at 1725 cm \ 1 CH^ s i n g l e t at 63.65). -66-Figure 24. Preparation of 16-epi-19,20(S)-dihydroperivine (179). - 6 7 -Th e s p e c t r a l d a t a o f n i t r i l e (178) s u g g e s t e d t h a t t h i s compound e x i s t s l a r g e l y i n the c a r b i n o l a m i n e form as shown w h i l e (177) e x i s t s as t u • J O i • J i 36,42-43 the r i n g - o p e n e d 2 - a c y l m d o l e S i n c e a c i d i c h y d r o l y s i s was not an e f f i c i e n t r e a c t i o n i n p r o v i d i n g the d e s i r e d e s t e r ( 1 7 9 ) , the n i t r i l e (178) was s u b j e c t e d t o a l k a l i n e h y d r o l y s i s ( r e f l u x , sodium h y d r o x i d e ) and subsequent e s t e r i f i c a t i o n w i t h methanol and h y d r o c h l o r i c a c i d . I n t h i s manner, t h e e s t e r (179) was o b t a i n e d i n 68% y i e l d . When the i s o m e r i c n i t r i l e (177) was t r e a t e d under the same r e a c t i o n c o n d i t i o n s , the d e s i r a b l e e s t e r (179) c o u l d be o b t a i n e d d i r e c t l y i n 70% y i e l d . I n t h e nmr spec t r u m of t h e s y n t h e t i c e s t e r (.179) , the m e t h y l p r o t o n s i n g l e t (63.68) o c c u r s i n t h e n o r m a l range and c o n s e q u e n t l y t h e s e p r o t o n s a r e n o t e l e c t r o n i c a l l y s h i e l d e d by t h e a r o m a t i c r i n g . T h i s r e s u l t 30 36 i n d i c a t e s t h a t the C^g e s t e r group p o i n t s away from the a r o m a t i c n u c l e u s ' The weak a b s o r p t i o n o f the u n s a t u r a t e d c a r b o n y l system i n the i r spec t r u m showed t h a t the e s t e r (179) e x i s t s i n the two t a u t o m e r i c c a r b i n o l a m i n e 36 42-43 and 2 - a c y l i n d o l e forms ' . T h i s s i t u a t i o n was c o n f i r m e d by the uv spect r u m w h i c h r e v e a l e d b o t h i n d o l e and 2 - a c y l i n d o l e chromophores. Hs/CC^CHj (179) -68-On electron impact the ester (179) showed patterns of f r a g -42-43 80 mentation c h a r a c t e r i s t i c of the two forms ' (Figure 25) and a possible pathway i s outlined i n Figure 26. For the carbinolamine form, which usually fragments as a sarpagine-type a l k a l o i d structure, the diagnostic .fragment i s the ion at m/e 323 (M+-0H). The other i n d i c a t i v e fragments at m/e 184 and 185, correspond to the 3-carboline unit i n the sarpagine s e r i e s . On the other hand, the mass spectrum of (179) also reveals a peak at m/e 168, corresponding to the p i p e r i d i n e r i n g residue, r e s u l t i n g from a cleavage s p e c i f i c to the vobasine (2-acylindole) system. Since t h i s peak i s rather weak compared with those assigned to the carbinolamine structure, i t appears that the l a t t e r form i s the predominant tautomer i n the equilibrium. Since the ester (179) was suspected to be the dihydro-derivative of perivine (23), i t was of i n t e r e s t to prepare dihydroperivine from 36 perivine (23) for the sake of comparison. It was reported by Gorman and Sweeny that the c a t a l y t i c hydro-genation of the ethylidene double bond of perivine (23) with Raney n i c k e l would a f f o r d a dihydro-derivative (180) with the ethyl group i n the a-o r i e n t a t i o n as shown Hydrogenation of perivine (23) with a c a t a l y t i c amount of 36 platinum oxide gave the expected ester (180) (1 CH^ s i n g l e t at 62.67, 1 CH^ t r i p l e t at 61.05). The uv and i r data unambiguously showed that t h i s substance exists e n t i r e l y i n the 2-acylindole form, a s i t u a t i o n also indicated by the s i g n i f i c a n t appearance of the m/e 168 ion (base peak) -69-0.0 50.0 100.0 150.0 200.0 250.0 300.0 3S0.0 M/E a o M/E Figure 25. Mass spectra of 16-epi-19,20(S)-dihydroperivine (179) (top) synthetic sample (below) sample derived from perivine -70-m/e 340 m/e 323 H X 0 C H 3 -CH P=C=0 1 CO 2 CH 3 m^e 168 CH3CH=CHC02CH3 H V C O 2 C H O 7 + •C0 2CH 3 ^ N.-r OH ' -CH3'CH=CHC02CH3 OH m/e185 OH m/e 184 Figure 26. Fragmentation of 16-epi-19,20(S)-dihydroperivine (179) upon electron impact. and the r e l a t i v e l y weak ions at m/e 323, 185 and 184 i n the mass 42-43 80 spectrum ' (Figure 27). Epimerization of (180) with sodium methoxide"^ led to the formation of the expected ester ( 1 7 9 ) ^ . (179) , 6 0 % -ZL--73-H3CP?C\/H ^ H 3 C 0 2 C N / H (180) t. Both the synthetic sample and the authentic sample of ester (179) derived d i r e c t l y from perivine (23) showed i d e n t i c a l nmr, i r (Figure 28), uv, mass spectra and s i m i l a r t i c behavior. Thus the i d e n t i t y of the synthetic ester (179) was confirmed. i t was.able to reinvestigate the s t a r t i n g n i t r i l e s (177) and (178). Since the ester (179) was obtained as the common product from the hydrolysis of both n i t r i l e s , i t i s therefore the thermodynamically more stable isomer compared with (180), that i s also evident i n the e a r l i e r epimerization of the l a t t e r . It thus proved that the favorable o r i e n t a t i o n of the function group i s to point away from the indole n u c l e u s ^ ' > ^ Of the two n i t r i l e s (177) and (178) , the l a t t e r appeared to be the more stable isomer, as indicated i n the epimerization of the former under a c i d i c condition. The o r i e n t a t i o n of the n i t r i l e group i n (178) i s thus t e n t a t i v e l y assigned as pointing away from aromatic system. The fact that both ester (179) and n i t r i l e (178) e x i s t mainly i n form of carbinolamine may be due to the o r i e n t a t i o n of t h e i r f u n c t i o n a l i t y , as i t was found e a r l i e r i n the isomeric n i t r i l e s (164-5) of s i m i l a r pentacyclic structure that the C 1 £ n i t r i l e 16 29 36 group accommodates i t s e l f favourably above the terminal r i n g ' With the stereochemistry of ester (179) f i r m l y established, I I i&r axe Figure 28. IR spectrum of 16-epi-19,20(S)-dihydroperivine (179). -75-( 178) , R = C N (179) . R = C 0 2 C H 3 This c o r r e l a t i o n allowed the assignment of stereochemistry at C^g for the n i t r i l e (177), and, i n turn for (176) and (172) as indicated previously. The f i n a l step i n the synthesis of epidregamine (181) involved an N-methylation and t h i s was accomplished by the Eschweiler-Clarke procedure of treating ester (179) with formaldehyde and platinum oxide 3 6 under an atmosphere of hydrogen DREGAMINE(34) -76-To confirm the C ^ Q stereochemistry of t h i s synthetic material (181) , both epidregamine (181) and epitabernaemontanine (182) were prepared by established procedure, ie_. r e f l u x of their natural 53 epimers (34) and (35) with sodium methoxide . Comparison showed that the synthetic product (181) i s epidregamine. To obtain the a l k a l o i d dregamine (34), an epimerization of epidregamine (181) under s i m i l a r conditions was investigated. Reflux of (181) i n a sodium methoxide s o l u t i o n afforded a mixture of (181) 53 and (34) i n a r a t i o of 4:1 , and thereby completed the syntheses of both dregamine (34) and epidregamine (181). In conclusion, the above i n v e s t i g a t i o n has provided not only a general synthetic route to the 2-acylindole a l k a l o i d s , but also l a i d down the groundwork for entry to the sarpagine and ajmaline a l k a l o i d s e r i e s . -77-III EXPERIMENTAL General Uncorrected melting points were determined on a Reichert micro hot stage. Infrared spectra ( i r ) were recorded on either a Perkin-Elmer 21 or 137 spectraphotometer. U l t r a v i o l e t spectra (uv) were recorded on a Cary 15 spectrophotometer. Mass spectra were recorded on an Atlas CH-4B or AEI MS-902 spectrometer. Nuclear magnetic re-sonance spectra (nmr) were recorded on a Varian HA-100 or XL-100 instrument with tetramethylsilane as i n t e r n a l standard. O p t i c a l rotations were measured on pyridine or chloroform solutions using a Perkin Elmer 141 polarimeteri Elemental analyses were ca r r i e d out by Mr. P. Borda at the Department of Chemistry, University of B r i t i s h Columbia. Merck reagent GF 254 s i l i c a gel was used for preparative th i n layer chromatography ( t i c ) . ; Merck s i l i c a g el 60 ( a c t i v i t y 2-3) was used for column chromatography. Unless otherwise indicated a l l reactions were carried out i n an atmosphere of dry nitrogen. A number of experiments i n the early phases of this project were o r i g i n a l l y i n -vestigated by previous coworkers i n our group. References to t h e i r work are made below. In many instances improvements i n y i e l d s and further characterization data obtained i n my recent studies are also included. 2(S)-Amino-3-(3-indolyl)-propan-l-ol(113) This compound (113) was prepared, according to the l i t e r a t u r e 85 method , i n 82% y i e l d ; mp 76° ( l i t . mp 76.5°). -78-Q c N,O-Ditosyl-2(S)-amino-3-(g-indolyl)-propan-l-ol(114) This compound (114) was prepared, according to the l i t e r a t u r e 85 method , i n 90% y i e l d ( l i t . y i e l d 83%), nmr i d e n t i c a l with the 85 reported spectra . Additional data:[a] D~29°(C, 0.4, C5H,.N) ; i r (CHCJ>3)3478(NH) ,1325,1150 cm"1 (-S020-) ; uv(MeOH) 289(e6590), 280(7760), 272 nm (7950); mass spectrum m/e 171(100%), 155(85), 130(20). 85 3(S)-Tosylamino-4-(g-indolyl)-butanonitrile(115) This compound (115) was prepared, according to the l i t e r a t u r e Q r method , i n 92% y i e l d ; mp 190°(lit. mp 191-192°). Additional data: [a] D-49°(C, 0.5, C 5H 5N); mass spectrum m/e 353(M +, 10%), 130(100%). Q C 3(S)-Amino-4 - ( B-indolyl)-butanonitrile(116) This compound (116) was prepared, according to the l i t e r a t u r e method 8 5, i n 95% y i e l d ; nmr and i r i d e n t i c a l with the reported s p e c t r a 8 5 . 85 3(S)-(N-Formylamino)-4 - ( B-indolyl)-butanonitrile(117) This compound (117) was prepared, according to the l i t e r a t u r e 8 5 method , i n 75% y i e l d ; mp 147° ( l i t . y i e l d 58%; mp 150-151.5°). A d d i t i o n a l data: [ct]D-20°(C, 0.5, C ^ N ) . o tr 3(S)-(N-Formylamino)-4 - ( B-N-benzylindolyl)-butanonitrile(118) and 3(S)-85 (N-benzyl-N-formylamino)-4 - (B-N-benzylindolyl)-butanOriitrile(119) . This compound (118) was prepared, according to the l i t e r a t u r e 8 5 method , i n 84% y i e l d ; mp 135° ( l i t . y i e l d 58%; mp 139-140°). A d d i t i o n a l -79-data: [aJp-4.5 0 (C, 0.5, C 5H N) . The dibenzyl compound (119) was obtained at 14%. Additional data: [a] -36° (C, 1.1, C rH rN). D 5 5 63 85 3-(N,N-Dimethylaminomethyl)-pentan-2-one(125) ' This compound (125) was prepared, according to the l i t e r a t u r e method 8 5, i n 46% y i e l d ; bp 65-70°/17 nm ( l i t . y i e l d 40%, bp 67-70°/17 nm) . 3-(N,N,N-Trimethylaminomethyl)-pentan-2-one i o d i d e ( 1 2 6 ) ^ ' 8 5 This compound (126) was prepared, according to the l i t e r a t u r e method 8 5, i n 96% y i e l d ; mp 145-150° ( l i t . mp 146-151°). 3-Methylenepentan-2-one(121) 6 4» 8 5' 8 6 This compound (121) was prepared, according to the l i t e r a t u r e method 8 5, i n 60% y i e l d , bp 115-121° ( l i t . y i e l d 58%, bp 115-123°). 61 Polyphosphoric Ester (PPE) Phosphorus pentoxide (lOOg) was added to a s o l u t i o n of anhydrous chloroform (100 ml) and ethyl ether (200 ml), and was s t i r r e d at r e f l u x for 48 hr. The residue was removed by f i l t r a t i o n . The f i l t r a t e was concentrated i n vacuo below 70° to give a l i g h t brown viscus s o l u t i o n (PPE)(120g). 87 N(a)-Benzyl-3(S)-cyanomethyl-3 >4-dihydro -B-carboline(120) 61 The sol u t i o n of polyphosphoric ester (PPE)(50g) i n anhydrous chloroform (60 ml) was added to a suspension of n i t r i l e (118) (3.Og, 9".6 -80-mmol) i n chloroform (100 ml), and the mixture was s t i r r e d for 63 hr. Water (100 ml) was added and s t i r r i n g continued for 5 hr. The solut i o n was b a s i f i e d with 10N ammonium hydroxide sol u t i o n and extracted with chloroform. The chloroform extract was washed with brine and dried over anhydrous sodium s u l f a t e . Removal of the solvent i n vacuo yielded 5.5 g of crude product. P u r i f i c a t i o n by column chromatography on s i l i c a gel gave dihydrocarboline (120)(2.4 g, 84%) as a foamy substance: ir(CHC£ 3) 2249(C=N), 1618 cm" 1(conjugated C=N); uv(meOH) 323(e8390), 246(10150), 240 nm (10230), nmr (CDC^) 67.6-6.9 (10H, m, aromatic H and CH=N) , 5.33(2H, s, N-CH_2-C6H5) , 3.94(1H, m, C 3H), 3.30-2.40(4H, m, C 4H and CH_2CN) ; mass spectrum m/e 299.1391 (parent, calcd for C 2 Q H 1 7 N 3 299.1422, 39%), 259(76), 91(100). 12-Benzyl-6(S)-cyanomethyl-3-ethyl-2-oxo-12b(S)-1,2,3,4,6,7,12,12b-87 octahydroindolo—(2,3-a)-quinolizine(122) The dihydrocarboline (120)(2.4 g, 8.0 mmol) was dissolved i n a sol u t i o n of 3-methylene-pentan-2-one(121)(13 g) and methanol(26 ml). Methanol(1 ml) saturated with hydrogen chloride was added. The so l u t i o n was s t i r r e d at 80° for 72 hr. The solvent was removed i n vacuo and the residue was dissolved i n 50 ml of acetone-water (10:1). The s o l u t i o n was treated with jj-toluenesulfonic acid (0.3 g) and s t i r r e d at r e f l u x for 15 hr. The solvent was removed i n vacuo. The residue was taken up with chloroform and 5% sodium bicarbonate s o l u t i o n . The aqueous phase was extracted twice with chloroform. The chloroform extract was dried over anhydrous sodium s u l f a t e . Removal of the solvent i n vacuo gave a -81-residue (3.5 g). P u r i f i c a t i o n by column chromatography on s i l i c a gel afforded the k e t o n i t r i l e (122)(1.57 g, 49%) as an o i l y material: ir(CHC£ 3) 2854, 2797(Bohlmann bands), 2244(C=N), 1708 cm _ 1(C=0); uv(MeOH) 292(e7150), 282(8480), 276 nm (8080); nmr(CDC^)67 .80-6. 78 (9H, m, aromatic H) , 5.20(2H, s, N-CH„-C,H C) , 3.82(1H, m, C.„,H), — z o 5 Izb 0.95(3H, t, J=7Hz, CH^CH^) ; mass spectrum m/e 397.2186 (parent, calcd for C„,H o^N o0 397.2153, 44%), 357(100), 259(15), 246(10). 12-Benzyl-6(S)-cyanomethyl-3-ethyl-2(R)-hydroxy-12b(S)-1,2,3,4,6,7,12, 87 12b-octahydroindolo-(2,3-a)-quinolizine(129) The t e t r a c y c l i c ketone (122) (52 mg, 0.13 mmol) i n dry methanol (1 ml) was s t i r r e d with sodium borohydride (20 mg, 0.53 mmol) at 0° for 30 min. Brine was added and the solu t i o n was extracted with chloroform. The extract was dried over anhydrous sodium s u l f a t e . Removal of the solvent i n vacuo yielded an o i l y residue which was p u r i f i e d by preparative t i c on s i l i c a gel afforded the alcohol (129)(28 mg, 54%) as a foamy sub-stance: ir(CHC£ 3) 3596, 3380(0H), 2853, 2791(Bohlmann bands), 2243 cm _ 1(CN); uv(MeOH) 291(e7530), 283(8830), 275 nm(8310); nmr(CDC&3)67.58-6.87 (9H, m, aromatic H), 5.27(2H, q, J=16.5 and 13.8 Hz, N-CH^-CgH^, 3.58 (IH, q, J=10 and 4Hz, C 2H), 0.93 (3H,t,J=5Hz, CH_3CH2-); mass spectrum m/e 399.2265 (parent, calcd for C ^ H ^ ^ O 399.2309, 61%), 359(100). 12-Benzyl-6(S)-cyanomethyl-3-ethyl-2(S)-hydroxy —12b(S)-1,2,3,4,6,7,12,12b-octahydroindolo-(2,3-a)-quinolizine(130) Aluminum chloride (1.0 g, 7.5 mmol) i n anhydrous ether (20 ml) was -82-treated with l i t h i u m aluminum hydride (88 mg, 2.3 mmol) at 0°. A solut i o n of D,L-isoborneol (1.2 mg, 8.0 mmol) i n dry ether (13 ml) was added. After the solu t i o n was s t i r r e d for 20 min, the excess l i t h i u m aluminum hydride was destroyed by addition of t^butanol (0.2 ml). The k e t o n i t r i l e (122)(400 mg, 1.0 mmol) i n anhydrous t e t r a -hydrofuran (1 ml) was added at 0°. The so l u t i o n was s t i r r e d at room temperature for 30 min and then at r e f l u x for 2 hr, before being added to a 2N hydrochloric acid s o l u t i o n . After being washed with ethyl ether, the aqueous phase and the s o l i d residue were b a s i f i e d with a 5% sodium hydroxide s o l u t i o n and extracted with chloroform. The chloroform was washed with water and dried over anhydrous sodium s u l f a t e . Removal of the solvent i n vacuo provided a residue (0.3 g). P u r i f i c a t i o n by preparative t i c on s i l i c a gel yielded the k e t o n i t r i l e (122)(27 mg) and the alcohol (130) (224 mg, 56%) as a foamy substances: i r (CHC&.J 3613, 3483(OH); 2815, 2780 (Bohlmann bands), 2242 cm _ 1(CiN); uv(MeOH) 292(e9180), 283(10260), 276 nm(9660); nmr (CDC^) 67 .57-6.91 (9H, m, aromatic H), 5.25(2H, q, J=18 and 13Hz, N-CH^-C^) , 3.92(1H, broad s i n g l e t , C2H) , 3.86(1H, q, J=12 and 3Hz, C H), 0.90(3H, t, J=7Hz, CH-jCH^-) ; mass spectrum m/e 399.2305 (parent, calcd for C ^ H ^ ^ O 399.2309, 35%), 359(100). 12-Benzyl-2(S)-acetoxy-6(S)-cyanomethyl-3-ethyl-12b(S)-1,2,3,4,6,7,12,12b-8 7 octahydroindolo-(2,3-a)-quinolizine(131) The alcohol (130)(639 mg, 1.6 mmol) was dissolved i n pyridine (6.5 ml) and a c e t i c anhydride (6.5 ml), and s t i r r e d at 80° for one hr. The solvent -83-was removed tn vacuo. The residue was taken up with water and chloroform. The so l u t i o n was b a s i f i e d with 2N ammonium hydroxide so l u t i o n and extracted with chloroform. The combined chloroform extract was washed with brine and dried over anhydrous sodium s u l f a t e . Removal of the solvent gave a foamy residue. P u r i f i c a t i o n by preparative t i c with s i l i c a gel yielded the acetate (131) (513 mg, 72%) as a brown o i l : ir(CHCX,3) 2811 (Bohlmann band), 2243(CEN), 1728 cm - 1(C=0); uv(MeOH) 291(e6650), 282(7810), 275 nm (7480); nmr(CDC£ 3)67.58-6.75(9H, m, aromatic H), 5.23(2H, q, J=17 and 23 Hz, N-CH 2~C 6H 5), 5.08(1H, q, J-3, C 2H), 3.47(1H, q, J = l l and 3Hz, C 1 2 bH) , 2.00(3H, s, CH 3C0 2-) 0.88(3H, t, J=7Hz, CH_3CH2-) ; mass spectrum m/e 441.2435 (calcd for C O Q H o l N o 0 o 441.2416, 44%), 401(100). 12-Benzyl-6(S)-cyanomethyl-2(S)-(3',5'-dinitrobenzoyloxy)-3-ethyl-12b(S)- l,2,3,4,6,7,12,12b-octahydroindolo-(2,3-a)-quinolizine(132). 3,5-Dinitrobenzoyl chloride (35 mg, 0.13 mmol) was added to a sol u t i o n of the t e t r a c y c l i c alcohol (130)(40 mg, 0.099 mmol) i n pyridine (1 ml), and s t i r r e d at 0° for 1 hr and then at room temperature for 18 hr. Brine was added. The s o l u t i o n was extracted with methylene c h l o r i d e . The extract was washed with aqueous sodium bicarbonate s o l u t i o n and water, and then dried over sodium s u l f a t e . Removal of methylene chloride i n  vacuo gave an o i l y residue. P u r i f i c a t i o n by preparative t i c with s i l i c a gel afforded the alcohol (130)(12 mg) and the 3',5'-dinitrobenzoate(132) (22 mg, 53%) as an o i l y material: i r (CHC&.J : 2810, 2780(Bohlmann bands) 2250(C=N), 1724 cm _ 1(C=0); uv(MeOH) 290(e9220) , 279(11770), 222 nm (71230); nmr(CDC£ 3)69.20(lH, t, J=2Hz, C^'H), 8.96(2H, d, J=2Hz, and -84-C,'H), 7.56(9H, m, aromatic H), 5.41(1H, m, C„H) , 5.16(2H, q, J=17 D / and 24 Hz, N-CH„-C,H C), 0.92(3H, t, J=7Hz, CH„CH„-); mass spectrum m/e 593.2284 (parent, calcd for C 3 3 H 3 1 N 5 0 6 593.2272). .12-Benzyl-6(S)-cyanomethyl-3-ethyl-2(S)-mesyloxy-12b(S)-l,2,3,4,6,7,12, 12b-octahydroindolo-—(2,3-a)-quinolizine(133) Methanesulfonyl chloride (2 ml) was added to a s o l u t i o n of the t e t r a c y c l i c alcohol (130)(350 mg, 0.21 mmol) i n pyridine (4 ml) at 0°. The s o l u t i o n was kept at the same temperature for 20 hr. Brine was added and the s o l u t i o n was extracted with methylene chloride. The extract was dried over anhydrous sodium s u l f a t e . Removal of the solvent i n vacuo yielded an o i l y residue which was p u r i f i e d by preparative t i c on s i l i c a gel to a f f o r d the mesylate (133)(267 mg, 64%) as a foamy substance: ir(CHC£ 3) 2810, 2780(Bohlmann bands), 2245(C=N), 1335, 1175 cm _ 1(-S0 2-); uv(MeOH) 275(e7490), 282(7860), 291 nm (6690); nmr(CDC£ 3)67.58-6.84(9H, m, aromatic H), 5.29(2H, s, N-CH^-C^) , 4.91 (IH, m, C 2H), 3.85(1H, q, J=16 and 5Hz, C ^ H ) , 0.93(3H, t, J=7Hz, CH_3CH2-); mass spectrum m/e 477.2098 (parent, calcd for C ^ H ^ N ^ S 477.2085) . 12-Benzyl-6(S)-cyanomethyl-3-ethyl-12b(S)-1,4,6., 7,12,12b-hexahydroindolo- (2,3-a)-quinolizine(134) a) The mesylate (133)(66 mg, 0.14 mmol) was s t i r r e d i n pyridine (1.5 ml) at r e f l u x for 1 hr. The solvent was removed i n vacuo. The residue was taken up with water and chloroform. The aqueous phase was -85-extracted with chloroform. The combined chloroform extract was dried with anhydrous sodium s u l f a t e . Removal of the solvent i n vacuo l e f t a residue which was p u r i f i e d by preparative t i c on s i l i c a gel to give the o l e f i n i c n i t r i l e (134) (22 mg, 45%) as a yellow o i l : ir(CHC«.3) 2775 (Bohlmann band), 2247 cm _ 1(C=N); uv(MeOH) 292(e6900), 283 (7880), 276 nm (7330); nmr(CDC&3)67.62-6.83 (9H, m, aromatic H), 5.31(1H, broad s i n g l e t , C 2H), 5.24(2H, s, N-CH^-C^) , 3.62(1H, q, J=10 and 5Hz, C 1 2 b H ) , 0.99(3H, t, J=8Hz, CH^CR^-) ; mass spectrum m/e 381.2204 (parent, calcd for C^H^N., 381.2204). Zo 11 5 b) The mesylate (133)(28 mg, 0.059 mmol) i n anhydrous dimethyl-sulfoxide (0.1 ml) was added to a suspension of sodium hydride (15 mg, 0.62 mmol) i n the same solvent (1 ml). The mixture was s t i r r e d at room temperature for 4 hr, and treated with 2N hydrochloric acid s o l u t i o n (0.4 ml). The so l u t i o n was b a s i f i e d with 2N ammonium hydroxide s o l u t i o n and extracted with methylene chl o r i d e . The extract was washed with brine and dried over anhydrous sodium s u l f a t e . Removal of the solvent gave a residue which was p u r i f i e d by preparative t i c on s i l i c a gel to give the mesylate (133)(13 mg) and the o l e f i n i c n i t r i l e (134)(4.6 mg, 39%) i d e n t i c a l with that prepared above. c) The t e t r a c y c l i c alcohol (130)(30 mg, 0.076 mmol) i n pyridine (0.5 ml) was treated with phosphorus oxychloride (0.1 ml) at 0°, and was s t i r r e d at room temperature for 15 hr. Ice was added. The s o l u t i o n was b a s i f i e d with 2N ammonium hydroxide s o l u t i o n and extracted with methylene c h l o r i d e . Removal of the solvent i n vacuo provided- an o i l y residue which was p u r i f i e d by preparative t i c on s i l i c a gel to afford the o l e f i n i c n i t r i l e (134)(10 mg, 34%) i d e n t i c a l with that prepared above. -86-12-Benzyl-6(S)-cyanomethyl-2,3-dihydroxy-3-ethyl-12b(S)-1,2,3,4,6,7,12, 12b-octahydroindolo-(2,3-a)-quinolizines(135) and (136) A so l u t i o n of osmium tetroxide (8.5 mg, 0.035 mmol) i n t e t r a -hydrofuran (0.34 ml) was added dropwise to the o l e f i n i c n i t r i l e (134) (12 mg, 0.031 mmol) i n tetrahydrofuran-pyridine (2:1, 6 ml) at -78° during 10 min. The so l u t i o n was s t i r r e d at -78° for 10 min, and then at room temperature for 1.5 hr, and poured into ethanol-methylene chloride (1:1, 16 ml). Hydrogen sulphide was bubbled into the solu t i o n for 5 min. The residue was removed by f i l t r a t i o n through c e l i t e and washed with ethanol-methylene chloride (1:1). Removal of the solvent i n the combined f i l t r a t e i n vacuo gave a black residue which was p u r i f i e d by preparative t i c on s i l i c a gel to afford the d i o l s (135)(4.2 mg, 32%) and (136) (5.5 mg, 41%), both as brown o i l . The d i o l (135): ir(CHC£ 3) 3680, 3560(OH), 2780(Bohlmann band), 2242 cm _ 1(CHN); uv(MeOH) 289(e6l48), 282(7010), 276 nm (6665); nmr(CDCJ!,3) 67.54-6.78(9H, m, aromatic H) , 5.26(2H, d, J=8Hz, N-CH^-C^) , 0.85(3H, t, J=8Hz, CtLjC^-) ; mass spectrum m/e 415.2237 (parent, calcd for C26 H29 N3°2 4 1 5 - 2 2 5 9 > -The d i o l (136): ir(CHC2-3) 3670, 3530 (OH), 2780 (Bohlmann band), 2240 cm _ 1(C=N); uv(MeOH) 291(e 5970), 283(6890), 277 nm (6570); nmr(CDCJL3) 67.53-6.86(9H, m, aromatic H), 5.25 (2H, d, J=4Hz, N-CH^-C^) , 0.85 (3H, t, J=8Hz, CH^C^-) ; mass spectrum m/e 415.2226 (parent, calcd for C 2 6 H 2 9 N 3 ° 2 4 1 5 - 2 2 5 9 ) -12-Benzyl-5-cyano-6(S)-cyanomethyl-3-ethyl-12b-hydroxy-5,12b-seco-l,4,6, 7,12,12b-hexahydroindolo—(2,3-a)-quinolizines (144) ahd (145) - 8 7 -Th e o l e f i n i c n i t r i l e (134)(22 mg, 0.058 mmol) was added to a suspension of cyanogen bromide (51 mg, 0.48 mmol) and magnesium oxide (35 mg) i n tetrahydrofuran-water (2:1, 1.5 ml). The mixture was heated i n a sealed tube at 110° for 6 days. Brine was added and the solu t i o n was extracted with chloroform. The extract was dried over anhydrous sodium s u l f a t e . Removal of the solvent l e f t a residue which was p u r i f i e d by preparative t i c on s i l i c a g el to give the alcohols (144)(5.5 mg, 22%) and (145)(11.3 mg, 46%), both as brown o i l . The alcohol (144): ir(CHC£ 3) 3600(OH), 2210 cm - 1(CEN and N-CN); uv(MeOH) 294(E6070), 286(6750), 28lnm (6410); nmr (CDC2..J67 . 54-6.85 (9H, m, aromatic H), 5.41 (2H, s, N-CH--C,HC), 5.08(2H, m, C„ and —Z O J Z C 1 2 bH) , 0.77(3H, t, J=8Hz, CH^CR^-) ; mass spectrum m/e 424.2270 (parent, calcd f or C o,H„ oN.0 424.2262). Z I / O H The alcohol (145): ir(CHC£ 3) 3595(0H), 2208 cm _ 1(CEN and N-CN); uv(MeOH) 292(e6230), 284(6945), 279 nm (6420); nmr(CDCJI.J67.52-6.89 (9H, m, aromatic H), 5.61(2H, s, N-CH -C,H C), 5.38(2H, m, C„ and C, 0, H), —Z b -> Z LZb 0.71(3H, t, J=8Hz, CH_3CH2-); mass spectrum m/e 424.2262 (parent, calcd for C 2 ?H 2 8N 40 424.2262). 12-Benzyl-5-cyano-6(S)-cyanomethyl-2,12b-dihydroxy-3-ethyl-5,12b-seco- 1,2,3,4,6,7,12,12b-octahydroindolo-(2,3-a)-quinolizine(146) The t e t r a c y c l i c alcohol (130)(90 mg, 0.23 mmol) was added to a suspension of cyanogen bromide (280 mg, 2.6 mmol) and magnesium oxide (200 mg) i n tetrahydrofuran-water (2:1, 1.5 ml). The mixture was heated -88-i n a sealed tube at 107° for 60 hr. Brine was added and the so l u t i o n was extracted with chloroform. The extract was dried over anhydrous sodium s u l f a t e . Removal of the solvent l e f t a residue which was p u r i f i e d by preparative t i c on s i l i c a gel to give the alcohol (130) (4 mg) and d i o l (146)(42 mg, 44%) as a yellow o i l : ir(CHC£ 3) 3680, 3600(OH), 2250(C=N), 2210 cm _ 1(CEN and N-CN); uv(MeOH) 292(e5890), 284(6195), 278 nm (6135); nmr(CDC£ 3) 7.69-6.99(9H, m, aromatic H), 5.46(2H, s, N-CH 2-C 6H 5), 5.25(1H, q, J = l l and 6Hz, C ^ H ) , 4.10(1H, m, C2H) , 0.92(1H, t, J=7Hz, CH^CK^-) ; mass spectrum m/e 442.2395 (parent, calcd for c 27 H3o N4°2 4 4 2 - 2 3 6 8 ) -12-Benzyl-2(S)-acetoxy-5-cyano-6(S)-cyanomethyl-3-ethyl-12b-hydroxy-5, 12b-seco-l,2,3,4,6,7,12,12b-octahydroindolo-(2,3-a)-quinolizine(147) The t e t r a c y c l i c acetate (131)(16 mg, 0.036 mmol) was added to a suspension of cyanogen bromide (40 mg, 0.38 mmol) and magnesium oxide (20 mg) i n tetrahydrofuran-water (2:1, 1 ml). The mixture was heated i n a sealed tube at 107° for 60 hr. Brine was added and the s o l u t i o n was extracted with chloroform. The extract was dried over anhydrous sodium s u l f a t e . Removal of the solvent l e f t a residue which was p u r i f i e d by preparative t i c on s i l i c a gel to give the hydroxyacetate (147)(5.0 mg, 29%) as a brown o i l : ir(CHC£ 3) 3580(OH), 2220(C=N and C-CN), 1720 cm"1 (C=0); uv(MeOH) 292(e6215), 285(6830), 279 nm (6550); nmr (CDC^) 67.52-6.88(9H, m, aromatic H), 4.86(1H, m, C 2H), 0.77(3H, t, J=8Hz, CH^CR^-); mass spectrum m/e 484.2446 (parent, calcd for C„ QH„„N,0„ 484.2473). -89-12-Benzyl-5-cyano-6(S)-cyanomethyl-2(S)-(3',5'-dinitrobenzoyloxy)-3- ethyl-12b-hydroxy-5,12b-seco-l,2,3,4,6,7,12,12b-octahydroindolo-(2, 3-a)-quinolizine(148) The ester (132)(22 mg, 0.038 mmol) was added to a suspension of cyanogen bromide (60 mg, 0.56 mmol) and magnesium oxide (30 mg) i n t e t r a -hydrofuran-water (2:1, 1.1 ml). The mixture was heated i n a sealed tube at 97° for 40 hr. Brine was added and the so l u t i o n was extracted with chloroform. The extract was dried over anhydrous sodium s u l f a t e . Re-moval of the solvent l e f t a residue which was p u r i f i e d by preparative t i c on s i l i c a gel to give the ester (132)(3 mg) and hydroxyester (148) (13 mg, 64%) as an o i l y material: ir(CHC£ 3) 3580(OH), 2220(C=N and N-CN), 1729 cm - 1(C=0); uv(MeOH) 292(e6250), 282(8000), 220 nm(48100); nmr(CDC£ 3) 69.18(1H, t, J=2Hz, C.'H), 8.94(2H, d, J=2Hz C ' and C,'H), 7.60-6.88 H Z D (9H, m, aromatic H) , 5.42(2H, s, N-CH^-C^) , 5.21(2H, m, C 2 and C ^ H ) , 0.87(3H, t, J=7.5Hz, CH_3CH2-) ; mass spectrum m/e 636.2358 (parent, calcd for C 3 4 H 3 2 N 6 0 ? 636.2331, 2%), 618(2), 424(8), 91(100). 3(S)-Cyanomethyl-3,4-dihydro-B-carboline(160) The s o l u t i o n of PPE (80 g) i n anhydrous chloroform (100 ml) was added to a suspension of n i t r i l e (117)(5.0 g, 22 mmol) i n chloroform (120 ml), and s t i r r e d at room temperature for 14 hr. Water (100 ml) was added. The solu t i o n was s t i r r e d for 5 hr., b a s i f i e d with 10N ammonium hydroxide so l u t i o n and extracted with ethyl acetate. The extract was washed with brine and dried over anhydrous sodium s u l f a t e . Removal of the solvent i n vacuo yielded a residue (6.1 g). P u r i f i c a t i o n by preparative t i c on s i l i c a gel afforded a sample of dihydrocarboline (160) as a foamy -90-material: [a] + 35°(C, 0.3, CHC£ 3) , ir(CHC£ 3) 3462(NH), 2250 cm (C=N) ; uv(MeOH) 318(E9646), 240(9600), 235 nm (10105); nmr(CDC£3)6 9.04(IH, s, -CH=N), 8.33(1H, s, NH), 7.60-7.05(4H, m, aromatic H), 3.92(1H, m, C^H), 3.2-2.7(4H, m, -CH^-CN and C^H); mass spectrum m/e 209.0947 (parent, calcd for C 1 3H 1 ] LN 3 209.0952, 18%), 169(100). The isomeric 6(S)-Cyanomethyl-3-ethyl-2-oxo-l,2,3,4,6,7,12,12b-octahydro- indolo-(2,3-a)-quinolizines(159A-D) The crude dihydrocarboline (160)(6.1 g) and 3-methylene-pentan-2-one(121)(30 g) were added into a methanolic s o l u t i o n (100 ml) saturated with hydrogen chl o r i d e , and s t i r r e d at 70° for 18 hr. The solvent was removed i n vacuo and the residue was s t i r r e d at r e f l u x with p-toluene-s u l f o n i c acid (0.3 g) i n acetone-water (10:1, 100 ml) for 15 hr. The solvent was removed in. vacuo. The residue was taken up with e t h y l acetate and 5% sodium bicarbonate s o l u t i o n . The ethyl acetate extract was washed with water and dried over anhydrous sodium s u l f a t e . Removal of the solvent yielded a residue (10.1 g) which was p u r i f i e d by column chromatography on s i l i c a gel and f r a c t i o n a l r e c r y s t a l l i z a t i o n from ether-chloroform (1:1). 6(S)-Cyanomethyl-3(R)-ethyl-2-oxo-12b(S)-1,2,3,4,6,7,12,12b-octahydroindolo-(2,3-a)-quinolizine(159A), (1.65 g, 25% from (117)) as c o l o r l e s s prisms; mp 171°; [ a ] D + 39°(C, 0.5, C ^ N ) ; ir(CHC£ 3) 3465(NH), 2805 (Bohlmann band), 2245(CEN), 1705 cm _ 1(C=0); uv(MeOH) 288(e6000), 278(7395), 273 nm (7186); nmr(CDC£ 3)68.48(lH, s, NH), 7.65-7.09(4H, m, aromatic H), 3.77(2H, m, and C 1 9,H), 0.98(3H, t, J=7.0 Hz, CH„CH - ) ; mass spectrum m/e 307(M +, 61%), -91-267(100)', 169(37), 156(60). Anal Calcd for ketone A C, QH 0 1N„0:C, 74.24; H, 6.89; N, 13.67. i y AL j Found: C, 74.46; H, 6.97; N, 13.70. 6(S)-Cyanomethyl-3(S)-ethyl-2-oxo-12b(S)-1,2,3,4,6,7,12,12b-octahydroindolo- (2,3-a)-guinolizine(159D), (1.44 g, 21% from (117)) as c o l o r l e s s needles; mp 188-189°; [a] D-73° (C, 1.0, C ^ N ) ; ir(CHC£ 3) 3478(NH), 2835, 2795 (Bohlmann bands), 2250(C=N), 1718 cm _ 1(C=0); uv(MeOH) 288(e5928), 279 (6986), 273 nm (6722); nmr(CDCX,3)67.98(1H, s, NH) , 7.6-7.1(4H, m, aromatic H), 3.95(1H, q, J=4 and 10 Hz, C 1 2 t )H) , 3.42(1H, q, J=4 and 10 Hz, CgH) , 0.97(3H, t, J=7.5 Hz, CH 3CH 2-); mass spectrum m/e 307(M +, 100%), 267(95), 169(35), 156(70). Anal Calcd for ketone D C i gH 2 1N 30:C, 74.24., H, 6.89; N, 13.67, Found: C, 73.99; H, 6.67; N, 13.79. 6(S)-Cyanomethyl-3(R)-ethyl-2-oxo-12b(R)-1,2,3,4,6,7,12,12b-octahydroindolo-(2,3-a)-quinolizine(159B), (0.94 g, 14% from (117)) as c o l o r l e s s needles; mp 179-180°; [a] D+92°(C, 0.8, C ^ N ) ; ir(CHCJ>3) 3470(NH), 2770, 2820 (Bohlmann bands), 2250(C=N), 1708 cm _ 1(C=0); uv(MeOH) 288(e6140), 279(7265), 273 nm (6958); nmr(CDCJ^)68.05(IH, s, NH), 7.7-7.1(4H, m, aromatic H), 4.00 (IH, m, C ^ H ) , 3.74(1H, m, C,H), 0.92(3H, t, J=7Hz, CH„CH„-); mass spectrum 1 2 b o — J 2. m/e 307(M+, 100%), 267(90), 169(37), 156(70). Anal Calcd for ketone B C i gH 2 1N 30:C, 74.24; H, 6.89; N, 13.67. Found: C, 74.40; H, 6.76; N, 13.64. -92-6(S)-Cyanomethyl-3(S)-ethyl-2-oxo-12b(R)-1,2,3,4,6,7,12,12b-octahydro- indolo-(2,3-a)-quinolizine(159C), (1.08 g, 16% from (117)) as an o i l ; [a] D-34°(C, 0.3, C 5H 5N); ir(CHCS>3) 3475(NH), 2252(CEN), 1710 cm~1(C=0); uv(MeOH) 288(e6101), 278(7194), 273 nm (6966); nmr(CDCi>3) 68.39(IH, s, NH), 7.5-7.1 (4H, m, aromatic H), 4.46(1H, t, J=5Hz, C 0, H), 3.34(1H, Lib m, C6H) , 0.89(3H, t, J=7.5 Hz, CH_3CH2-) ; mass sp e c t r a l data. m/e measured ion composition calcd r e l . i n t . % mass C H N 0 mass 307 100 307.1690 19 21 3 1 307.1684 267 95 267.1486 17 19 2 1 267.1497 169 30 169.0774 11 9 2 169.0766 156 70 156.0815 11 10 1 156.0814 Epimerization of the Ketone(159B) a) With Diethylamine The ketone (159B)(30 mg, 0.098 mmol) i n diethylamine (2 ml) was s t i r r e d at room temperature for 2 hr. Removal of the solvent i n vacuo gave a residue which was p u r i f i e d by preparative t i c on s i l i c a g el to give the ketones (159B)(7 mg) and (159A)(15 mg, 65%) i d e n t i c a l with an authentic sample. b) With p-Toluenesulfonic Acid The ketone (159B)(28 mg, 0.091 mmol) was s t i r r e d at r e f l u x with jj-toluenesulfonic acid (10 mg) i n acetone (5 ml) for 2 hr. Removal of acetone yielded a residue which was p u r i f i e d by preparative t i c to give the ketones (159B)(8 mg) and (159A)(7 mg, 35%) i d e n t i c a l with an authentic sample. c) At 210° The ketone (159B)(21 mg, 0.068 mmol) was heated i n a glass c a p i l l a r y -93-at 210° for 2 min. P u r i f i c a t i o n by preparative t i c yielded (159B) (8 mg) and (159A)(4 mg, 30%) i d e n t i c a l with an authentic sample. ) Epimerization of the Ketone (159C) a) With Diethylamine The ketone (159C)(2.60 g, 0.084 mol) i n diethylamine (15 ml) was s t i r r e d at room temperature for 14 hr. Removal of the solvent i n  vacuo gave a residue which was p u r i f i e d by preparative t i c on s i l i c a gel to give (159C)(0.65 g) and (159D)(1.15 g, 58%) i d e n t i c a l with an authentic sample. b) With p-Toluenesulfonic Acid The ketone (159C)(50 mg, 0.16 mmol) was s t i r r e d at r e f l u x with p_-toluene s u l f onic acid (10 mg) i n acetone (5 ml) for 10 hr. Removal of acetone yielded a residue which was p u r i f i e d by preparative t i c to give (159C)(11 mg) and (159D)(17 mg, 43%) i d e n t i c a l with an authentic sample. c) At 220° The ketone (159C)(27 mg, 0.083 mmol) was heated i n a glass c a p i l l a r y at 220° for 1 min. P u r i f i c a t i o n by preparative t i c yielded (159C)(9 mg) and (159D)(7 mg, 39%) i d e n t i c a l with an authentic sample. 16(R) and 16(S)-Cyano-16-descarbomethoxy-19,20(S)-dihydro-15(R)-hydroxy- pericyclivines(164) and (165) The k e t o n i t r i l e (159D)(320 mg, 1.04 mmol) was added to a s o l u t i o n of lit h i u m diethylamide, prepared from 16 mmol (8 ml of 2.0M hexane solution) of n-butyllithium and diethylamine (0.96 g, 20 mmol) i n tetrahydrofuran (120 ml), precooled i n an ice-water bath. The solu t i o n was s t i r r e d f o r 30 min, and brine was added. The mixture was extracted with ethyl acetate. The ethyl acetate extract was dried over anhydrous sodium s u l f a t e . Removal -94-of the solvent i n vacuo yielded a red residue (0.4 g). P u r i f i c a t i o n by preparative t i c on s i l i c a gel afforded the ketone (159D)(63 mg), the hyd r o x y n i t r i l e s (164)(147 mg, 57%) and (165)(64 mg, 25%). A n a l y t i c a l samples of (164) and (165) were obtained by r e c r y s t a l l i z a t i o n from acetone-chloroform (1:1). The 16(R) der i v a t i v e (164): c o l o r l e s s needles; mp 250°; [a] D+137° (C, 0.1, C 5H 5N); i r ( n u j o l ) 2245 cm _ 1(CEN), uv(MeOH) 288(e6501), 277(8186), 272 nm (8065); nmr(CDC£ 3)67.79(1H, s, NH), 7.5-7.1(4H, m, aromatic H), 4.16 (IH, q, J=10 and 2 Hz, C3H) , 0.93(3H, t, J=6 Hz, CH_3CH2-) , mass spectra data: measured ion composition calcd m/e r e l . i n t . % mass C H N 0 mass 307 85 307, .1684 19 21 3 1 307.1684 290 35 290, .1651 19 20 3 290.1657 267 30 267, ,1509 17 19 2 1 267.1497 223 47 223, ,1242 15 15 2 223.1235 169 100 169, ,0767 11 9 2 169.0766 168 45 168, .0713 11 8 2 168.0692 156 34 156, .0808 11 10 1 156.0814 Anal Calcd for (164) C 1 9H 2 1N 30: :C, 74 • 24; H, 6 .89; N, 13.67. Found: C, 74.25; H, 6.90; N, 13.69. The 16(S) de r i v a t i v e (165): c o l o r l e s s needles; mp 278°; [ct] D + 158° (C, 0.05, C 5H 5N), i r ( n u j o l ) 2245 cm - 1(C=N); uv(MeOH) 288 (e5117), 277 (6528), 272 nm (6395), nmr(CDC^ 3)67.94(IH, s, NH), 7.6-7.1(4H, m, aromatic H), 4.08(1H, q, J=9 and 2Hz, C 3H), 0.93(3H, t, J=6Hz, CH 3CH 2-); mass spectrum m/e 307(M +, 100%), 290(39), 267(46), 223(30), 169(75), 156(25). Anal Calcd for (165) C ^ H ^ N ^ C , 74.24; H, 6.89; N, 13.67. Found: -95-C, 74.13; H, 6.99; N, 13.46. Alkoxide Treatment of the Ketonitrile(159A) The k e t o n i t r i l e (159A)(50 mg, 0.16 mmol) was added to a so l u t i o n of sodium methoxide, prepared from sodium (50 mg, 2.2 mmol) i n methanol (5 ml), and the mixture was s t i r r e d at reflux for 48 hr. Brine was added and the so l u t i o n was extracted twice with ethyl acetate. The extract was dried over anhydrous sodium s u l f a t e . The solvent was re-moved i n vacuo. P u r i f i c a t i o n of the crude product by preparative t i c on s i l i c a gel afforded the ketones (159A)(11 mg), (159B)(5 mg, 13%), (159C)(2 mg, 5%) and the n i t r i l e (164)(5 mg, 13%) i d e n t i c a l with an authentic sample. 15(R)-Acetoxy-16(R)-cyano-16-descarbomethoxy-19,20(S)-dihydropericyclivine(166) The h y d r o x y n i t r i l e (164)(20 mg, 0.065 mmol) was dissolved i n anhydrous ac e t i c anhydride. The solu t i o n was s t i r r e d at r e f l u x for 14 hr. Acetic anhydride was removed In vacuo. P u r i f i c a t i o n of the crude product by pre-parative t i c on s i l i c a gel yielded the acetate (166)(8 mg, 35%) as a yellow o i l : ir(CHC£ 3) 3450(NH), 2218(CEN), 1700 cm - 1(C=0); uv(MeOH) 286(e6530), 279(8230), 270 nm (8240); nmr(CDC£3)<57.97(lH, s, NH) , 7.7-7.1(4H, m, aromatic H), 4.24(1H, d, J=9Hz, C 3H), 2.09(3H, s, CH 3C0 2-), 1.08(3H, t, J=6.5 Hz, CH^CH9-); mass spe c t r a l data: -96-measured ion composition calcd m/e r e l . i n t . % mass C H. N 0 mass 349 41 349.1765 21 23 3 2 349.1790 290 100 290.1661 19 20 3 290.1657 223 11 223.1205 15 15 2 223.1235 169 25 169.0772 11 9 2 169.0762 168 17 168.0672 11 8 2 168.0688 Base Treatment of the Hydroxynitrile(165) The h y d r o x y n i t r i l e (165)(15 mg, 0.049 mmol) was added to a mixture of aqueous concentrated sodium hydroxide s o l u t i o n (0.1 ml) and methanol (1 ml), and s t i r r e d at r e f l u x for 1 hr. Brine was added, and the solut i o n was extracted with ethyl acetate. The extract was dried over anhydrous sodium s u l f a t e . Removal of ethyl acetate i n vacuo yielded a residue which was p u r i f i e d by preparative t i c to give the h y d r o x y n i t r i l e (164)(14 mg, 93%) i d e n t i c a l with an authentic sample. 19,20(S)-Dihydro-16(S)-epi- 15(R)-hydroxypericyclivine(167) The h y d r o x y n i t r i l e (164)(90 mg, 0.26 mmol) was added to a so l u t i o n of concentrated hydrochloric acid (2 ml) i n methanol (4 ml). The s o l u t i o n was s t i r r e d at r e f l u x for 16 hr. The solvent was evaporated and the residue was taken up with 2N ammonium hydroxide and eth y l acetate. The ethyl acetate extract was washed with brine and dried over anhydrous sodium s u l f a t e . Removal of the solvent i n vacuo gave a residue (0.1 g) which was p u r i f i e d by preparative t i c on s i l i c a gel to give the n i t r i l e (164)(24 mg) and the ester (167)(32 mg, 45%). An a n a l y t i c a l sample of -97-(167) was obtained by r e c r y s t a l l i z a t i o n from chloroform: needles; m P225-227°, [a] + 98°(C, 0.03, C ^ N ) ; ir(CHC£ 3) 3470(OH and NH) , 1720 cm - 1(C=0); uv(MeOH) 287(e6600), 282(8300), 272 nm (8250); nmr (CDC£ 3)68.10(1H, m, NH) , 7.55(4H, m, aromatic H) , 3.76(3H, s, C02CH_3), 0.99(3H, m,CH^CH0-); mass s p e c t r a l data: m/e r e l . i n t . % measured mass ion C composition H N 0 calcd mass 340 100 340.1773 20 24 2 3 340.1787 323 14 323.1725 20 23 2 2 323.1767 223 38 223.1246 15 15 2 223.1235 169 81 169.0781 11 9 2 169.0766 168 55 168.0737 11 8 2 168.0692 Anal Calcd for ( 167)C 2 QH 2 4N 2 0 3:C, 70 .57; H, 7 .11; N, 8.23. Found: C, 70.45; H, 7.14; N, 8.21. 3(S)-N--Cyano-16(S)-•cyano-16-descarbomethoxy- 19,20(S)-dihydro-15(R) hydroxyperivinol(170) The n i t r i l e (165)(75 mg, 0.243 mmol) was added to a suspension of cyanogen bromide (40 mg, 0.37 mmol) and magnesium oxide (21 mg) i n t e t r a -hydrofuran-water (2:1, 15 ml). The mixture was heated i n a sealed tube at 110° for 6 days. Brine was added and the solu t i o n was extracted with ethyl acetate. The extract was dried over anhydrous sodium s u l f a t e . Removal of the solvent i n vacuo l e f t a residue which was p u r i f i e d by preparative t i c on s i l i c a gel to give the n i t r i l e (165)(9 mg) and the hyd r o x y n i t r i l e (170)(36 mg, 52%). An a n a l y t i c a l sample of (170) was obtained by r e c r y s t a l l i z a t i o n from dioxane-ether: mp 230° [a] +84°(C, 0.04, -98-C 5H 5N); i r ( n u j o l ) 3380(NH and OH), 2210 cm"1(N-CN and C=N); uv(MeOH) 292(e5040), 283(6300), 275 nm (5980); nmr (acetone-dg)67.59-6.90 (4H, m, aromatic H), 5.34(1H, d, J=12 and 3 Hz, C 3H), 1.80(2H, m, CH3CH_2-) , 0.92(3H, t, J=7.0 Hz, CH_3CH2-) ; mass spectrum m/e 350 (M +, 100%), 332(45). Anal Calcd for (165) C ^ H ^ N ^ :C, 68.55; H, 6.33; N, 15.99. Found: C, 68.50; H, 6.41; N, 15.74. N-Cyano-16(S)-cyano-16-descarbomethoxy-19,20(S)-dihydro-15(R)-88 hydroxyperivine(171) The d i o l (170)(110 mg 0.36 mmol) was s t i r r e d with manganese dioxide (1.5 g) i n tetrahydrofuran (15 ml) for 14 hr. The solu t i o n was f i l t e r e d and the solvent removed i n vacuo to give the ketoalcohol (171)(93 mg, 85%) i n white amorphous form. An a n a l y t i c a l sample was obtained by re-c r y s t a l l i z a t i o n from dioxane-ether: m.p. 273° i r (nujol) 3640, 3468(NH and OH), 2225(N-CN and C=N), 1628 cm"1(C=C-C=0); uv(MeOH) 316(el6000), 240 nm (8850); nmr (pyridine-d ) 68.67 (IH, s, NH) , 7.83(4H, m, aromatic H) , 2.03(2H, m, CH 3CH 2~), 0.85(3H, m, CH 3CH 2"); mass spectrum m/e 348(M +, 100%), 330(4), 157(55). Anal Calcd for ( 1 7 1 ) c 2 o H 2 0 N 4 ° 2 : C ' 6 8 - 9 5 ' H> 5- 7 9> N> 1 6 - 0 8 - Found: C, 68.91; H, 5.71; N, 16.17. 3(R)-and 3(S)-N-Cyano-16(R)-cyano-16-descarbomethoxy-19,20(S)-dihydro- 15 (R)-hydroxyperivinols(173) and (174). a) The n i t r i l e (164)(160 mg, 0.54 mmol) was added to a suspension of cyanogen bromide (1.0 g, 9.0 mmol) and magnesium oxide (1.0 g) i n t e t r a --99-hydrofuran-water (2:1, 90 ml). The mixture was s t i r r e d at 45° for 6 hr. Brine was added and the so l u t i o n was extracted with ethyl acetate. The extract was dried over anhydrous sodium s u l f a t e . Removal of the solvent i n vacuo l e f t a residue which was p u r i f i e d by preparative t i c on s i l i c a gel to give the d i o l s (173)(120 mg, 66%) and (174)(38 mg, 21%). A n a l y t i c a l samples of the d i o l s (173) and (174) were obtained by r e -c r y s t a l l i z a t i o n from dioxane-ether. The 3(S)-derivative(173): c o l o r l e s s needles, mp 233°; [a] D+38° (C, 0.2, C 5H 5N); i r ( n u j o l ) 3380(NH and OH), 2219 cm"1(N-CN and C=N) ; uv(MeOH) 292(e4640), 283(5800), 273 nm (5500); nmr(acetone-dg)67.69-6.95 (4H, m, aromatic H), 5.09(1H, d, J = l l and 3 Hz, C 3H), 0.95(3H, t, J=6 Hz, CH_3CH2-) ; mass spectrum m/e 350(M +, 100%). Anal Calcd for ( 1 7 3 ) C ^ H ^ N ^ :C, 68.55; H, 6.33; N, 15.99, Found: C, 68.31; H, 6.31; N, 15.91. The 3(R)-derivative(174): c o l o r l e s s needles; mp 295° [a] D+29° (C, 0.03, C 5H 5N); i r ( n u j o l ) 3400(NH and OH), 2220 cm""1(N-CN and C=N) ; uv(MeOH) 292(e4560), 283(5600), 274 nm (5300); nmr ( p y r i d i n e ^ ) 68. 70 (IH, s, NH), 7.70-7.25(4H, m, aromatic H), 0.75(3H, t, J=7Hz, -CH 2CH 3); mass spectrum m/e 350(M +, 100%), 332(7). Anal Calcd for (174)C 2 0H 2 2N 40 2:C, 68.55; H, 6.33; N, 15.99. Found: C, 68.49; H, 6.35; 15.99. b) The n i t r i l e (164)(120 mg, 0.40 mmol) was added to a suspension of cyanogen bromide (100 mg, 0.90 mmol) and magnesium oxide (50 mg) i n t e t r a -hydrofuran-water (2:1, 20 ml). The mixture was heated i n a sealed tube at 100-110° for 50 hr. Extraction and p u r i f i c a t i o n as described i n (a) yielded -100-the n i t r i l e (164)(8 mg) , the d i o l s (173)(80 mg, 61%) and (174)(33 mg, 26%) i d e n t i c a l with those samples prepared above. N-Cyano-16(R)-cyano-16-descarbomethoxy-19,20(S)-dihydro-15(R)- hydroxyperivine(175) a) The d i o l (173)(40 mg, 0.11 mmol) was s t i r r e d with manganese dioxide (0.7 g) i n tetrahydrofuran (10 ml) for 16 hr. The so l u t i o n was f i l t e r e d and the solvent was removed i n vacuo to give the ketone (175)(35 mg, 88%) i n white amorphous form. An a n a l y t i c a l sample was obtained by r e c r y s t a l l i z a t i o n from dioxane-ether: mp 295-297°; [ct]D+54°(C, 0.04, C 5H 5N); i r ( n u j o l ) 3400, 3330(NH and OH), 2215(N-CN and CHN), 1613 cm"1 (C=c-C=0); uv(MeOH) 315(el4000), 230 nm (8400); nmr (pyridine-d 5)67.83-7.22(4H, m, aromatic H), 0.85(3H, t, J=7.0 Hz, CH CH„-); mass spectrum m/e 348(M +, 42%), 330(8), 157(100). Anal Calcd f o r (175) C 2 0 H 2 0 N 4 ° 2 : C ' 6 8 > 9 5 ; H ' 5 > 7 9 ; H ' 1 6 - 0 8 -Found: C, 68.71; H, 5.74; N, 16.13. b) The d i o l (174)(35 mg, 0.10 mmol) was s t i r r e d with manganese dioxide (0.5 g) i n tetrahydrofuran (15 ml) for 20 hr. The so l u t i o n was f i l t e r e d and the solvent was removed i n vacuo to give the ketone (175)(27 mg, 78%) i n amorphous form i d e n t i c a l with an authentic sample. N-Cyano-16(S)-cyano-14,15-dehydro-16-descarbomethoxy-19,20(S)-dihydro- perivine(172) a) The ketoalcohol (175)(75 mg, 0.21 mmol) i n pyridine (2 ml) was treated -101-with th i o n y l chloride (0.35 ml) at -10°. The so l u t i o n was s t i r r e d for 20 min, and i c e was added. The so l u t i o n was b a s i f i e d with sodium hydroxide (1 g) and extracted with ethyl acetate. The extract was dried over anhydrous sodium s u l f a t e and removal of solvent i n vacuo gave a residue which was p u r i f i e d by preparative t i c on s i l i c a gel to give the a,8-unsaturated ketone (172)(63 mg, 86%) i n white amorphous form. An a n a l y t i c a l sample was obtained by r e c r y s t a l l i z a t i o n from dioxane-ether: mp 264°; [a] D+42°(C, 0.06, C ^ N ) ; i r ( n u j o l ) 3320(NH), 2230(N-CN and C^N) , 1610 cm"1(C=C-C=0); uv(MeOH)336(el7000), 245 nm (9600); nmr(pyridine-d 5)<S7.86-7.19(4H, m, aromatic H), 6.42(1H, s, C=CH-), 1.40(2H, m, CH 3CH 2~), 0.84(3H, t, J=7.0 Hz, CH_3CH2-) ; mass spectrum m/e 330(M +, 88%), 130(100). Anal Calcd for (172)C_~H., oN.0:C, 72.71 H, 5.49; N, 16.96. Found: ~ " Zl) l o H C, 72.89; H, 5.49; N, 16.97. b) The ketoalcohol (171)(40 mg, 0.12 mmol) was treated i n the same manner as for (175), to give the a,g-unsaturated ketone (172)(34 mg, 91%) i d e n t i c a l with that obtained above. 16(S)-Cyano-16-descarbomethoxy-19,20(S)-dihydroperivinol(176) Sodium borohydride (32 mg, 0.097 mmol) was added to a s o l u t i o n of the k e t o n i t r i l e (172)(39 mg, 0.12 mmol) i n pyridine (4 ml). The sol u t i o n was s t i r r e d at room temperature for 48 hr. Triethylamine (3 ml) was added, and the so l u t i o n was s t i r r e d for a further 30 min before being f i l t e r e d . Removal of the solvent in vacuo gave a residue which was p u r i f i e d by preparative t i c on s i l i c a gel to afford the alcohol (176) -102-(23 mg, 77%) i n white amorphous form. An a n a l y t i c a l sample was obtained by r e c r y s t a l l i z a t i o n from chloroform-ethyl acetate: mp 170°, i r ( n u j o l ) 3365(NH and OH), 2240 cm _ 1(C=N); uv(MeOH) 292(e6480), 282(7400), 274 nm (7100); nmr(acetone-d,)67.85-6.85(4H, m, aromatic H), 5.47(1H, m, C„H), fa -J 1.02(3H, t, J=7.0 Hz, CH_3CH2-) ; mass spectrum m/e 309(M +, 10%), 291(100), 223(25), 169(68), 168(78), 156(48). Anal Calcd for (176)C. QH o 1N,0:C, 73.76; H, 7.49; N, 13.58. Found: C, 73.71; H, 7.35; N, 13.54. 16(S)-Cyano-16-descarbomethoxy-19,20(S)-dihydroperivine(177) The h y d r o x y n i t r i l e (176)(50 mg, 1.6 mmol) was s t i r r e d with manganese dioxide (0.8 g) i n tetrahydrofuran (5 ml). The solu t i o n was f i l t e r e d and solvent was removed jin vacuo to give a yellow residue. P u r i f i c a t i o n by preparative t i c on s i l i c a gel afforded the k e t o n i t r i l e (177) (44 mg, 89%) i n white amorphous form. An a n a l y t i c a l sample of (177) was obtained by r e c r y s t a l l i z a t i o n from chloroform-ethyl acetate: c o l o r l e s s needle, mp 184°; [<x] -67°(C, 0.02, C ^ N ) ; i r (nujol) 3460(NH), 2240(C=N), 1640 cm"1 (C=C-C=0); uv(MeOH) 315(el6400), 238 nm(11700); nmr(pyridine-d 5)68.0-7.0 (4H, m, aromatic H) , 1.12(3H, t, J=7.0 Hz, CH_3CH2-) . Mass spectrum m/e 307(M +, 52%), 290(20), 185(65), 184(50), 172(100), 135(9). Anal Calcd for (177)C. „H 0 1N„0:C, 74.24; H, 6.89; N, 13.67. Found: C, 74.17; H, 6.77; N, 13.82. 16(R)-Cyano-16-descarbomethoxy-19,20(S)-dihydro-3(R)-hydroxypericyclivine(178) The k e t o n i t r i l e (177) (45 mg, 0.15 mmol) was s t i r r e d at r e f l u x with -103-concentrated hydrochloric acid (2 ml) and methanol (2 ml). Brine was added. The s o l u t i o n was b a s i f i e d with ammonium hydroxide and extracted with ethyl acetate. The extract was dried over anhydrous sodium s u l f a t e . Removal of the solvent yielded a residue which was p u r i f i e d with pre-parative t i c on s i l i c a gel to give the n i t r i l e s (177)(4 mg), (178)(27 mg, 60%) and the ketoester (179)(4 mg, 6%). The n i t r i l e (178): yellow o i l ; ir(CHC£ 3): 3450(NH), 2230(C=N), 1635 cm"1 (C=C-C=0, weak); uv(MeOH) 312(e2520), 288(5830), 282(6589), 272 nm (6405); nmr(CDC£ 3)68.17(lH, s, N(a)-H), 7.8-7.0(4H, m, aromatic H), 0.93(3H, t, J=7.0 Hz, CH^CH0-); mass s p e c t r a l data: measured ion composition calcd m/e r e l . i n t . % mass C H N 0 mass 307 90 307.1694 19 21 3 1 307.1685 290 30 290.1649 19 20 3 290.1658 185 65 • 185.0704 11 9 2 1 185.0714 184 57 184.0632 11 8 2 1 184.0637 172 100 172.0759 11 10 1 1 172.0763 135 9 135.0922 8 11 2 135.0923 19,20(S)-Dihydroperivine(180)""' Perivine (23)(50 mg, 0.15 mmol) i n ethanol (5 ml) with a c a t a l y t i c amount of platinum oxide (Adam's catalyst) was hydrogenated at room temperature and atmospheric pressure for 4 hr. The c a t a l y s t was removed by f i l t r a t i o n , and washed with ethanol. Solvent was removed i n vacuo from the combined f i l t r a t e . P u r i f i c a t i o n of the crude product by preparative 3 6 t i c on s i l i c a gel gave dihydroperivine (180) (40 mg, 81%), i r , nmr and , 40 mass spectra i d e n t i c a l with the reported spectra. -104-40 16-Epi-39, 20(S)-dihydroperivine(179) a) The k e t o n i t r i l e (177)(30 mg, 0.098 mmol) was added to s o l u t i o n of sodium hydroxide (40 mg) i n water-methanol (1:2, 5 ml), and s t i r r e d at r e f l u x for 24 hr. Concentrated hydrochloric acid (2 ml) was' added, and the s o l u t i o n was s t i r r e d for a further 6 hr. Brine was added. The s o l u t i o n was b a s i f i e d with 2N ammonium hydroxide and extracted with ethyl acetate. The extract was dried over anhydrous sodium s u l f a t e . Removal of ethyl acetate i n vacuo yielded a residue which was p u r i f i e d by preparative t i c on s i l i c a gel to give (179)(23 mg, 70%) as a glassy s o l i d . R e c r y s t a l l i z a t i o n from ether-chloroform yielded an a n a l y t i c a l sample of (179):mp 157-159°; [a] D+51°(C, 0.06, MeOH); i r (CHC£ 3)3465(N-H), 1725(C=0), 1637 cm"1(C=C-C=0, weak); uv(MeOH) 312 (e3475), 288(4350), 280(4580), 274 nm (4420); nmr(CDC&3)68.32 (IH, s, NH) , 7.40-6 .85(4H, m, aromatic H), 3.65(3H, s, C0 2CH 3), 0.85(3H, t, J=6.5 Hz, CH_3CH2 -) mass spec t r a l data: measured ion composition calcd m/e r e l . i n t . % mass C H N 0 mass 340 93 340.1797 20 24 2 3 340.1787 323 42 323.1767 20 23 2 2 323.1767 185 71 185.0710 11 9 2 1 185.0715 184 100 184.0644 11 8 2 1 184.0636 168 35 168.0998 9 4 1 2 168.1024 Anal Calcd for (179)C 2 Q H 2 4N 20 3: c, 70.57; H, 7.11; N, 8.23. Found C, 70. 60; H, 7.12; N, 8.30. -105-b) The k e t o n i t r i l e ( 1 7 8 ) ( 2 0 mg, 0.065 mmol) was t r e a t e d i n t h e same manner as f o r t h e n i t r i l e (177) t o a f f o r d t h e k e t o e s t e r (179) (15 mg, 68%) i d e n t i c a l w i t h t h a t o b t a i n e d above. c) The e s t e r ( 1 8 0 ) ( 2 4 mg, 0.070 mmol) was added t o a s o l u t i o n o f sodium m e t h o x i d e , p r e p a r e d f r o m 30 mg (1.3 mmol) o f sodium i n m e t h a n o l (5 m l ) , and t h e m i x t u r e was s t i r r e d a t r e f l u x f o r 20 m i n . B r i n e was added and t h e s o l u t i o n was e x t r a c t e d t w i c e w i t h e t h y l a c e t a t e . The e t h y l a c e t a t e e x t r a c t was d r i e d o v e r anhydrous sodium s u l f a t e . The s o l v e n t was removed i n va c u o . P u r i f i c a t i o n o f t h e c r u d e p r o d u c t by p r e p a r a t i v e t i c on s i l i c a g e l a f f o r d e d e s t e r ( 1 7 9 ) ( 1 4 mg, 58%) i d e n t i c a l w i t h t h a t o b t a i n e d i n ( a ) ; [ct]D+61°(C, 0.2, C ^ N ) , + 53°(C, 0.2, MeOH) ( l i t . 4 0 [ a ] D + 56°(MeOH)). 53 1 6 - E p i t a b e r n a e m o n t a n i n e ( 1 8 2 ) Tabernaemontanine ( 3 5 ) ( 2 4 mg, 0.068 mmol) was t r e a t e d w i t h sodium 53 m e t h o x i d e as d e s c r i b e d by Knox and S l o b b e . t o g i v e e p i t a b e r n a e m o n t a n i n e ( 1 8 2 ) ( 3 mg, 1 2 % ) ; nmr and mass s p e c t r u m i d e n t i c a l w i t h t h e r e p o r t e d s p e c t r a . 1 6 - E p i d r e g a m i n e ( 1 8 1 ) 4 ^ ' a) The e s t e r ( 1 7 9 ) ( 2 8 mg, 0.082 mmol) i n 5 ml o f f o r m a l i n - d i o x a n e (1:20) c o n t a i n i n g a c a t a l y t i c amount o f f o r m i c a c i d and p a l l a d i u m / c a r b o n was h y d r o g e n a t e d a t room t e m p e r a t u r e and p r e s s u r e f o r 24 h r . The c a t a l y s t was removed by f i l t r a t i o n . B r i n e was added. The 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 y l a c e t a t e . The e t h y l a c e t a t e e x t r a c t was d r i e d o v e r anhydrous sodium s u l f a t e . Removal o f t h e s o l v e n t i n vacuo l e f t a r e s i d u e w h i c h - 1 0 6 -was purified by preparative tic on silica gel to give the 16-epidregamine (181)(19 mg, 65%), identical with an authentic sample. b) Dregamine (34)(30 mg, 0.085 mmol) was treated with sodium methoxide 53 as described by Knox and Slobbe to give dregamine (34)(7 mg) and 16-epidregamine (181)(14 mg, 47%); i r and nmr of (181) identical with the 53 reported spectra. Dregamine(34) 16-Epidregamine (181)(19 mg, 0.054 mmol) was added to a solution of sodium methoxide, prepared from sodium (24 mg, 1.1 mmol) in methanol (5 ml), and the mixture was stirred at reflux for 16 hr. The work-up procedure was similar to that in the base treatment of dihydroperivine (180). 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