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Novel chromium carbonyl complexes of dihydropyridines and their application to the synthesis of dehydrosecodine Ridaura-Sanz, Vincente Ernesto 1979

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9.1 NOVEL CHROMIUM CARBONYL COMPLEXES OF DIHYDROPYRIDINES AND THEIR APPLICATION TO THE SYNTHESIS OF DEHYDROSECODINE BY B.Sc, ITESM, Monterrey, Mexico, 1970 A THESIS SUBMITTED IN PARTIAL FULFILMENT OF THE REQUIREMENTS FOR THE DEGREE OF THE FACULTY OF GRADUATE STUDIES Department of Chemistry University of B r i t i s h Columbia We accept t h i s thesis as conforming to the required standard THE UNIVERSITY OF BRITISH COLUMBIA August, 1979 £c) Vicente Ernesto Ridaura-Sanz, 1979 VICENTE DOCTOR OF PHILOSOPHY IN In present ing t h i s t h e s i s i n p a r t i a l f u l f i l m e n t of the requirements f o r an advanced degree a t the U n i v e r s i t y of B r i t i s h Co lumbia, I agree tha t the L i b r a r y s h a l l make i t f r e e l y a v a i l a b l e f o r re ference and s tudy. I f u r t h e r agree that permiss ion f o r ex tens ive copying of t h i s t h e s i s f o r s c h o l a r l y purposes may be granted by the Head of my Department or by h i s r e p r e s en t a t i v e s . I t i s understood tha t copying or p u b l i c a t i o n of t h i s t h e s i s f o r f i n a n c i a l ga in s h a l l not be a l lowed wi thout my w r i t t e n pe rm iss i on . V icente Ernesto Ridaura-Sanz Department nf Chemistry The U n i v e r s i t y of B r i t i s h Columbia 2075 Wesbrook P lace Vancouver, Canada V6T 1W5 Date August 21 , 1979. E - 6 B P 7 5 - 5 1 I E ABSTRACT The work presented i n t h i s thesis i s aimed at the t o t a l synthesis of 14,21-dehydrosecodine (1). This substance i s an indole derivative with reactive substituents at position 2 (an a c r y l i c ester segment) and 3 (a 1,6-dihydropyridine system). The s t a b i l i z a t i o n of the l a t t e r involved the generation of chromium carbonyl complexes employing trisacetonitriletricarbonylchromium (0) as the reagent with appropriate synthetic indole derivatives. In order to develop the required methodology for the preparation of the above complexes, the i n i t i a l experiments employed simple dihydropyridine systems. Thus, when N-methyl-3-ethyl pyridinium iodide (4_1) was treated with NaBH^ in a two-phase system (ether - water), N-methyl-3-ethyl-1,2-dihydropyridine (46_) was obtained. When t h i s compound was treated with the above complexing agent a mixture (ratio 1:2) of (N-methyl-3-ethyl-l,2-dihydropyridine) tricarbonylchromium (0) (4_3) and (N-methyl-3-ethyl-l, 6-dihydropyridine) tricarbonylchromium (0) (4_4) was obtained. Thermal isomerization of t h i s mixture i n refluxing cyclo-hexane afforded a 1 : 1 r a t i o of (4_3) and (4_4) . Liberation of the organic ligand could be achieved by s t i r r i n g (43) and/or (4_4) with pyridine. - i i i -The above strategy was applied to the indole intermediate, N-(2-carbomethoxymethyltryptophyl)-3-ethylpyridinium per-chlorate (_36) but only a low y i e l d (2%) of the desired chromium complexes was obtained. These r e s u l t s prompted a change i n the o r i g i n a l synthetic strategy and a new approach was i n i t i a t e d by other coworkers i n t h i s laboratory. Some studies with the novel system (4_6) were conducted as they relate to position of a l k y l a t i o n . It was shown that (46) undergoes reaction with benzyl bromide to afford the 5-substituted derivative. / - i v -TABLE OF CONTENTS Page TITLE PAGE i ABSTRACT i i TABLE OF CONTENTS i v LIST OF DIAGRAMS V LIST OF FIGURES ix ACKNOWLEDGEMENTS X INTRODUCTION 1 RESULTS AND DISCUSSION 38 CONCLUSIONS 119 EXPERIMENTAL 121 ADDENDUM 154 APPENDIX 157 REFERENCES 158 - v -LIST OF DIAGRAMS Diagram 1 Diagram 2 Diagram 3 Diagram 4 Diagram 5 Diagram 6 Diagram 7 Diagram 8 Diagram 9 Diagram 10 Diagram 11 Diagram 12 Diagram 13 Diagram 14 Diagram 15 Some Indole A l k a l o i d Families Early Postulations of the Biosynthesis of Indole Alkaloids Wenkert-Thomas Hypothesis for the Bio-synthesis of Indole Alkaloids Loganin Biosynthesis Role of Loganin i n the Biosynthesis of Indole Alkaloids Early Stage i n the Biosynthesis of Indole Alkaloids Biosynthesis of Akuammicine and Stemmadenine Biosynthetical Postulate for the Formation of Aspidosperma-Type Alkaloids Wenkert's Hypothesis for the Bio-synthesis of Aspidosperma and Iboga-Type Alkaloids Kutney's Transannular C y c l i z a t i o n of Indolic Nine-Membered Ring Systems Kutney's Synthesis of Pseudovinca-difformine and Dihydrocatharanthine by a Transannular C y c l i z a t i o n Use of the Transannular C y c l i z a t i o n for the Synthesis of Catharanthine and Pseudocatharanthine Feeding Experiments i n C. roseus Feeding Experiments i n V. minor Proposed Mechanism for the Conversion of Aspidosperma-Type Alkaloids into Iboga-Type Page 2 3 10 12 14 15 16 18 19 21 22 24 - v i -Diagram 16 Diagram 17 Diagram 18 Diagram 19 Diagram 20 Diagram 21 Diagram 22 Diagram 23 Diagram 24 Diagram 25 Diagram 26 Diagram 2 7 Diagram 28 Diagram 2 9 Diagram 30 Diagram 31 Page Role of Dehydrosecodine i n the 25 Biosynthesis of Indole Alkaloids Secodine-Type Compounds Isolated 27 from Natural Sources Presecamine-Type Alkaloids and Their 28 Chemistry Incorporation of Secodine into 29 Vindoline and Catharanthine Scott's Thermal Rearrangement of 32 Indole Alkaloids 14,21-Dehydrosecodine as an Inter- 33 mediate i n the Thermal Rearrangements of Indole Alkaloids Trapping of the Dehydrosecodine 34 Intermediates in the Thermal Rearrange-ments of Indole Alkaloids 14,21-Dehydrosecodine as an Inter- 35 mediate i n the Thermal Rearrangement of Catharanthine Synthesis of Andraginine by Thermal 37 Rearrangement of Indole Alkaloids 14,21-Dehydrosecodine 38 Ziegler's Synthesis of Minovine 40 Secodine Reactions 41 General Method for the Construction of 42 the A c r y l i c Ester Segment Methodology for the Synthesis of 43 a-Methylene Lactones and Ziegler's Synthesis of 2-Indolyl-Acrylic Esters Protection of a-Methylene Lactones 44 Isomeric Dihydropyridines 4 6 Diagram 32 Diagram 33 Diagram 34 Diagram 35 Diagram 36 Diagram 37 Diagram 38 Diagram 3 9 Diagram 4 0 Diagram 41 Diagram 42 Diagram 4 3 Diagram 44 Diagram 45 Diagram 4 6 Diagram 47 Diagram 4 8 Diagram 49 Stable Dihydropyridines Oxidation of Dihydropyridines Some Dihydropyridine Reactions Hantzsch Synthesis of Dihydropyridines 1,2-Dihydropyridines v i a Condensation Reactions NaBH4 Reduction of Pyridinium Salts Orientation of the Nucleophilic Additions to Pyridinium Salts Nucleophilic Reactions with Pyridinium Salts Dihydropyridines from Other Hetero-c y c l i c Systems Page 48 50 52 54 55 56 58 59 61 62 Protection of Dihydropyridines Scheme "A": Synthesis of Dehydrosecodine 64 Scheme "B": Synthesis of Dehydrosecodine 65 Formation of N-Methyl-3-ethyl Dihydro- 76 pyridine Chromium Complexes Overreduction of N-Methyl-3-ethyl- 7 7 pyridinium. with NaBH^ Mass Fragmentation Pattern of N-Methyl- 8 4 -3-ethyl-l,2-dihydropyridine and Its Chromium Complex Alkylation of N-methyl-3-ethyl-l,2- 92 dihydropyridine Al k y l a t i o n of N ,3,5-Trimethyl-l,2- 95 dihydropyridine Scheme for the Synthesis of 2-carbo- 101 methoxymethyltryptophyl Chloride (65) - v i i i -Page Diagram 50 Intramolecular Condensation of N-(2- 103 cyanomethyl-tryptophyl) Pyridinium Diagram 51 Scheme "C" for the Synthesis of 14,21- 106 Dehydrosecodine (1_) Diagram 52 Synthesis of (N-Benzyl-2-carbomethoxy- 108 methylindolyl)-benzyl Ether (72) Diagram 53 Reduction of 2-N,N-Dimethylcarbox- 110 amidoindole Derivatives with LiAlH^ Diagram 54 Homologation Reactions in Acetic Ester 115 Derivatives Diagram 55 Complexation Reaction of N-(2-Carbo- 155 methoxymethyltryptophyl)-3-ethyl-l,2-dihydropyridine (37) Diagram 56 Synthesis of N-Benzyl-3,14-dehydro- 156 secodine Diagram 57 Appendix: Numbering System of Indole 157 Alkaloids - i x -LIST OF FIGURES Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Figure 6 Figure 7 Figure 8 Figure 9 Figure 10 NMR spectrum of (N-methyl-3-ethyl-l,2-dihydropyridine)tricarbonylchromium(0) complex (4_3) (CgDg) NMR spectrum of (N-methyl-3-ethyl-l,6-dihydropyridine)tricarbonylchromium(0) complex (4_4) (CgDg) Double resonance studies of complex 4_4 (C 6D 6) NMR spectrum of (1,6-dihydropyridine) chromium complex 4_4 i n CDCI3 Page 70 72 74 75 NMR spectrum of N-carbomethoxy-3-ethyl- 80 1,2-dihydropyridine (4_9) (CgDg) Double resonance studies of 4_9 81 NMR spectrum of N-methyl-3-ethyl-l,2- 83 dihydropyridine (4_6) (C5D5) NMR spectrum of N-methyl-3-ethyl-l,2- 88 dihydropyr idine (5_1) {CQDQ) NMR spectrum of (N-tryptophyl-3-ethyl- 97 1,6-dihydropyridine)tricarbonyl-chromium(O) complex (59) NMR spectrum of (N-tryptophyl-3-ethyl- 99 1,2-dihydropyridine)tricarbonyl-chromium (0) complex (60) ACKNOWLEDGEMENTS The author wishes to thank Dr. James P. Kutney for his dir e c t i o n and unconditional help during the course of the present work. He would also l i k e to thank other members of the research group for th e i r h e l p f u l suggestions, es p e c i a l l y Drs. R. Greenhouse and E. Jahngen, as well as Professor W.R. Cullen for various discussions during the early phases of t h i s research. Financial aid from CONACYT in 1971-72 i s g r a t e f u l l y acknowledged, as i s further f i n a n c i a l support from the University of B r i t i s h Columbia i n the form of a University Graduate Fellowship from 1974-7 6, and the U.B.C. Chemistry Department for a teaching assistantship. - 1 -INTRODUCTION B i o s y n t h e s i s of n a t u r a l l y o c c u r r i n g compounds i s an area t h a t has i n t r i g u e d s c i e n t i s t s f o r many years, l e a d i n g to the p o s t u l a t i o n of s e v e r a l hypotheses f o r the formation of v a r i o u s f a m i l i e s of compounds found i n l i v i n g systems, mainly i n the p l a n t kingdom. These hypotheses have been formulated to t r y and c o r r e l a t e , i n a l o g i c a l manner, the d i f f e r e n t compounds i s o l a t e d from a p a r t i c u l a r p l a n t t h a t belongs to a s p e c i f i c f a m i l y o f substances ( a l k a l o i d s , terpenes, e t c . ) . T h i s c o r r e l a t i o n i s sometimes based on known chemical r e a c t i o n s and on o t h e r o c c a s i o n s enzymes are i n e x p l i c a b l y bestowed w i t h powerful and magical p r o p e r t i e s . The biosyntheses of a l k a l o i d s 1 b e l o n g i n g t o the Yohimbe, Corynanth^, Strychnos, Aspidosperma and Iboga f a m i l i e s (see Diagram 1), have been s u b j e c t to a g r e a t d e a l of s p e c u l a t i o n and i t was not u n t i l 1965 t h a t some l i g h t was shed on t h i s i n t e r e s t i n g problem. Since 1930 the tryptamine segment o f t h i s type o f a l k a l o i d was thought t o be d e r i v e d from t r y p t o -2-5 phan, but not u n t i l r e c e n t l y was t h i s proven to be c o r r e c t L a b e l l e d tryptamine can a l s o be i n c o r p o r a t e d i n t o the major 5-7 a l k a l o i d s of V i n c a and other s p e c i e s , although i n a l e s s e f f i c i e n t manner than the p r e v i o u s l y mentioned aminoacid^. - 2 -DIAGRAM 1 Some I n d o l e A l k a l o i d F a m i l i e s CH302C CH302C OH YOHIMBINE (Yohimbg Family) AJMALICINE (Corynanthg Family) C0 2CH 3 CH 0 H H C02CH, AKUAMMICINE (Strychnos Family) VINDOLINE (Aspidosperma Family) C0 2CH 3 CATHARANTHINE (Iboga Family) - 3 -E a r l y p o s t u l a t i o n s f o r t h e b i o s y n t h e s i s o f t h e n o n - t r y p t a m i n e 8 9 p o r t i o n o f y o h i m b i n e i n v o k e d p h e n y l a l a n i n e a n d f o r m a l d e h y d e ' a s p r e c u r s o r s . T h i s i d e a was r e i n f o r c e d when Woodward''"^ '"'"''" s u g g e s t e d a r e l a t e d p a t h w a y f o r t h e f o r m a t i o n o f s t r y c h n i n e i n v o l v i n g t h e f i s s i o n o f a 3 , 4 - d i h y d r o x y p h e n y l a l a n i n e - d e r i v e d r i n g E, w i t h t h e i n c o r p o r a t i o n o f an a c e t a t e u n i t ( D i a g r a m 2 ) . DIAGRAM 2 E a r l y P o s t u l a t i o n s o f t h e B i o s y n t h e s i s o f I n d o l e A l k a l o i d s - 4 -With the i s o l a t i o n of new types of i n d o l e a l k a l o i d s p o s s e s s i n g the c o , ~ c i n u n i t f o r the non-tryptamine moeity, Wenkert ' and Thomas noted t h a t the p r e v i o u s h y p o t h e s i s was l i m i t e d as i t d i d not r e a d i l y account f o r the predomin-a n t l y a l i p h a t i c c h a r a c t e r of these compounds, e s p e c i a l l y those c o n t a i n i n g a c a r b o c y c l i c r i n g E. They proposed an a l t e r n a t i v e scheme based mainly on the s i m i l a r i t y of the Cg-C^g segment of the i n d o l e a l k a l o i d s w i t h s e v e r a l new g l y c o s i d e s , i s o l a t e d a t t h a t time, known as i r i d o i d s and s e c o - i r i d o i d s . Rearrangement of these compounds b e f o r e or a f t e r condensation w i t h tryptamine, or the tryptamine p r e c u r s o r , g i v e s the d i f f e r e n t i n d o l e a l k a l o i d s t h a t have a C 9 ~ c i o segment. T h i s p o s t u l a t i o n i s known as the Wenkert-Thomas Hypothesis and i s summarized i n Diagram 3. The t e r p e n o i d c h a r a c t e r of these a l k a l o i d s was proven by the i n c o r p o r a t i o n of l a b e l l e d mevalonic a c i d and/or g e r a n i o l . , , . 15-19 i n t o v i n d o l i n e 20 S c o t t c o n v e n i e n t l y d i v i d e s the b i o s y n t h e s i s of t e r p e n o i d i n d o l e a l k a l o i d s and t h e i r i n t e r c o n v e r s i o n s i n t o t h r e e phases. The e a r l y stage covers the development of a h i g h l y oxygenated and r e a c t i v e g l u c o s i d e (secologanin) and i t s c o n v e r s i o n t o v i n c o s i d e (a). T h i s i s f o l l o w e d by the - 5 -DIAGRAM 3 T-Tenkert-Thomas Hypothesis for the Biosynthesis of Indole Alkaloids IRIDOID 5 + 3 2 t 5 + 6 AJMALICINE ft 3 G02CH3 VINDOLINE '2 3 AKUAMMICIME CH3O2C YOHIMBINE OH CH302C CATHARANTHINE - 6 -tr a n s f o r m a t i o n o f v i n c o s i d e t o Corynanthe" and Strychnos a l k a l o i d s (b), and f i n a l l y the development of the Aspido-sperma and Iboga f a m i l i e s ( c ) . a) FROM MEVALONATE TO VINCOSIDE - Thomas 2 1 suggested i n 1964 t h a t the p a r t i c u l a r monoterpene p r e c u r s o r f o r a s e r i e s of i n d o l e a l k a l o i d s might be the g l u c o s i d e , l o g a n i n (see Diagram 4), which undergoes cleavage t o sec o l o g a n i n (see Diagram 5) as p a r t o f the i n t e r m e d i a r y metabolism. Loganin has been found by r a d i o c h e m i c a l 22 d i l u t i o n i n Catharanthus roseus as w e l l as i n oth e r p l a n t s p e c i e s (Strychnos, Rhazyja, Catharanthus, etc.) , where the t e r p e n o i d i n d o l e a l k a l o i d i s a l s o p r e s e n t . I t s b i o s y n t h e s i s i s shown i n Diagram 4. The pathway between l o g a n i n and v i n c o s i d e was e l u c i d a t e d 23 24 as a r e s u l t of the i s o l a t i o n o f two new g l u c o s i d e s ' , f o l i a m e n t h i n and m e n t h i a f o l i n (Diagram 5). Hydroly-s i s of these two compounds, r i n g opening and m e t h y l a t i o n f u r n i s h e d s e c o l o g a n i n which, i n i t s [o-methyl-^H] -l a b e l l e d form, proved a good p r e c u r s o r f o r the thr e e 25 26 f a m i l i e s o f i n d o l e a l k a l o i d s ' (Corynanth£, A s p i d o -sperma and Iboga). The c o n v e r s i o n from l o g a n i n t o - 7 -DIAGRAM 4 Loganin Biosynthesis OH LOGANIN secologanin was v i s u a l i z e d by Battersby v i a hydroxy-l a t i o n of the former compound to y i e l d the as yet un-isola t e d hydroxyloganin which i s transformed to seco-loganin v i a a 1,3 fragmentation reaction (Diagram 5). Condensation i n v i t r o of secologanin with tryptamine forms a separable mixture of vincoside and i t s three 6 7 27 epimer isovincoside or s t r i c t o s i d i n e ' ' (see Diagram 5). ) - 8 -DIAGRAM 5 Role of Loganin in the Biosynthesis of Indole Alkaloids VINCOSIDE ISOVINCOSIDE - 9 -The presence of secologanin, vincoside and isovincoside in C. roseus ' ' has been shown by radiochemical d i l u t i o n 2 6 27 28 analysis ' . Scott , studying germinating C. roseus seedlings, showed that vincoside i s one of the f i r s t alkaloidal-type materials produced (24 hours). b) FROM VINCOSIDE TO CORYNANTHE AND STRYCHNOS ALKALOIDS -As just mentioned, vincoside was reported as one of the f i r s t alkaloids produced in germinating C. roseus seedlings, however, two other Corynanthe alkaloids are formed at the same time (ajmalicine and corynantheine, see Diagram 6). In order to convert vincoside into the Corynanthe family a hydrolysis of the glucoside i s necessary, followed by a c y c l i z a t i o n of the resultant dialdehyde, as shown i n Diagram 6. As can be see in the Diagram the stereochemistry of C^ must be inverted when vincoside i s transformed into the Corynanthe alkaloids. Feeding experiments using t r i t i u m at C-3 in vincoside and isovincoside showed that only the former 7 29 compound was incorporated i n ajmalicine ' . Any mechanism converting vincoside into the Corynanthe" family must explain inversion at C-3 without loss of the l a b e l . One such 20 p o s s i b i l i t y i s shown at the bottom of Diagram 6. 30 44 50-52 It has been shown recently ' ' by using tissue - 10 -DIAGRAM 6 Early Stage in the Biosynthesis of Indole Alkaloids - 11 -cultures that the previously mentioned feeding experiments are incorrect and that isovincoside i s indeed the precursor for the Corynanthe al k a l o i d s . Following Scott's sequential i s o l a t i o n of alkaloids from C. roseus seedlings i t was found that corynantheine aldehyde, geissoschizine and a series of oxidized derivatives of the l a t t e r compound are i s o l a t e d in a period of between 28 to 40 hours aft e r germination (Diagram 7). Alkaloids belonging to the Strychnos family (preakuammicine, akuammicine, stemmadenine) s t a r t to appear after a germination time of 40 to 50 hours. 29 Feeding experiments in C. roseus have shown geissoschizine to be a good precursor for akuammicine. This, together with the series of oxidized geissoschizine derivatives iso l a t e d i n the same period (40-50 hours), led to the proposal of the sequence, shown in Diagram 7, for the conversion of the Corynanthe-type of alkaloids to the Strychnos family. The sequence i s a r a t i o n a l i z a t i o n of the compound is o l a t e d and has not yet been proven. The only evidence that exists to support t h i s claim at the moment i s the po s i t i v e - 1 2 -DIAGRAM 7 B i o s y n t h e s i s o f A k u a m m i c i n e a n d Stemmadenine - 13 -incorporation of geissoschizine oxyindole into akuammicine 28 c) FORMATION OF ASPIDOSPERMA AND IBOGA-TYPE ALKALOIDS -In the same time i n t e r v a l that preakuammicine, akuammicine and stemmadenine are formed, tabersonine, one of the Aspidosperma-type al k a l o i d s , i s also produced by C. roseus seedlings. If a sequential i s o l a t i o n of compounds, with respect to time, can give an idea of how molecules are formed, that means that tabersonine, could have stemmadenine or preakuammicine (both with a C^g-unit) as a precursor. For t h i s to happen the bonds indicated as dotted l i n e s i n Diagram 8 must be broken to form an intermediate (named "intermediate A" as no f u n c t i o n a l i t y i s shown at t h i s point), which w i l l c y c l i z e as shown to give the Aspido-sperma skeleton. 13 In 1962 Wenkert proposed a similar sequence for the formation of Aspidosperma and Iboga-type a l k a l o i d s . His sequences started with an oxidized form of stemmadenine to y i e l d a compound that has the same structure as "intermediate A". C y c l i z a t i o n i n the forms indicated i n Diagram 9, w i l l give compounds "B" and "C", which could be the precursors to the - 14 -DIAGRAM 8 Biosynthetical Postulate for the Formation of Aspidosperma-Type Alkaloids ASPIDOSPERMA TYPE "INTERMEDIATE A" quebrachamine and cleavamine-types of alkaloids, respectively. The l a t t e r family of compounds has not yet been i s o l a t e d from any natural source, except i n the form of bisindole a l k a l o i d s . A second c y c l i z a t i o n of the nine-membered rin g intermediates w i l l furnish the Aspidosperma and Iboga al k a l o i d s . Investigating a general entry to the syntheses of Aspidosperma and Iboga-type alk a l o i d s , Kutney studied the transannular c y c l i z a t i o n reaction of i n d o l i c nine-membered r i n g systems, similar to the one proposed by Wenkert for the f i n a l stages of t h i s kind of a l k a l o i d (Diagram 9). DIAGRAM 9 Wenkert's Hypothesis for the Biosynthesis of Aspidosperma and Iboga-Type Alkaloids IBOGA FAMILY ASPIDOSPERMA FAMILY - 16 -Kutney and collaborators started t h e i r study with simple systems using mercuric acetate to oxidize the piperidine r i n g forming an iminium s a l t , which then condensed with the indole. In t h i s manner oxidation of 4g-dihydrocleavamine ("D") followed by a reduction with lithium aluminum hydride (LAH) of the resultant indolenine gave 7B-ethyl-5-desethyl aspidospermidine ("E"), as shown in Diagram 10. A similar reaction using (-) 31 quebrachamine gave (+) aspidospermidine in good y i e l d DIAGRAM 10 Kutney's Transannular C y c l i z a t i o n of Indolic Nine-Membered Ring Systems (-) QUEBRACHAMINE < + > ASPIDOSPERMIDINB - 17 -When 18a-carbomethoxy dihydrocleavamine ("F") was used 32 33 as s t a r t i n g material ' a mixture of three compounds was i s o l a t e d . One of them was a compound with an Aspidosperma skeleton that was named pseudovincadifformine and whose formation follows reactions s i m i l a r to those outlined i n Diagram 10. The other two compounds were i d e n t i f i e d as coronaridine and dihydrocatharanthine, which belong to the Iboga family. These two compounds are obtained by a c y c l i z a t i o n of the carbon a to the carbo-methoxy with the other possible iminium s a l t that can be formed i n the piperidine r i n g . Epimerization of the ethyl side chain can be explained by e q u i l i b r a t i o n of the iminium s a l t with the corresponding enamine, as described i n Diagram 11. The same research group was interested to see i f the i n t r o -duction of a double bond i n the piperidine ring affected the course of t h i s transannular c y c l i z a t i o n . They found that 183-carbomethoxy cleavamine ("G"), when treated with mercuric acetate, gave a mixture of catharanthine plus 32 33 pseudocatharanthine ' , a compound previously reported i n the l i t e r a t u r e (Diagram 12). - 18 -DIAGRAM 11 Kutney 1s Synthesis of Pseudovincadifformine and Dihydro-catharanthine by a Transannular C y c l i z a t i o n C02CH3 Hg (OAc) 2 002CH3 C02CH3 C02CH3H CH302C C02CH3 PSEUDOVINCADIFFORMINE CH302C - 19 -DIAGRAM 12 Use of the Transannular C y c l i z a t i o n for the Synthesis of Catharanthine and Pseudocatharanthine PSEUDOCATHARANTHINE CATHARANTHINE Now that Kutney et a l proved that the transannular c y c l i z a t i o n was a useful synthetic reaction, they wondered whether t h i s reaction had any significance i n the l a t e r stages of Aspidosperma and Iboga biosyntheses and i f not, was there any relati o n s h i p between the nine-membered rin g compounds and the r i g i d c y c l i c systems (Iboga and Aspidosperma), as suggested by Wenkert? To answer t h i s question a series of experiments - 20 -was c a r r i e d o u t where d e r i v a t i v e s o f t h e q u e b r a c h a m i n e a nd c l e a v a m i n e - t y p e a l k a l o i d s w e r e f e d t o C. r o s e u s u n d e r v a r y i n g c o n d i t i o n s . The i s o l a t e d a l k a l o i d s ( v i n d o l i n e and c a t h a r a n t h i n e ) w e re shown t o c o n t a i n l i t t l e o r no a c t i v i t y ( D i a g r a m 1 3 ) . T h i s l a c k o f i n c o r p o r a t i o n c o u l d s i m p l y mean t h a t t h e r e w e r e some d i f f i c u l t i e s w i t h p e r m e a b i l i t y a n d / o r t r a n s p o r t o f t h e s e h i g h m o l e c u l a r w e i g h t s u b s t a n c e s t o t h e s i t e o f b i o -s y n t h e s i s , o r t h a t t h e c y c l i z a t i o n r e a c t i o n was o f l i t t l e b i o s y n t h e t i c s i g n i f i c a n c e . To o v e r c o m e t h e f i r s t d i f f i c u l t y t a b e r s o n i n e was f e d t o C. r o s e u s a nd a p o s i t i v e i n c o r p o r a t i o n was o b s e r v e d i n v i n d o l i n e a n d , most s u r p r i s i n g l y , i n c a t h a r a n t h i n e ( l a s t f e e d i n g e x p e r i m e n t i n D i a g r a m 1 3 ) . W i t h t h i s e x p e r i m e n t i t was d e m o n s t r a t e d t h a t t h e r e was no p r o b l e m o f p e r m e a b i l i t y o r t r a n s p o r t a t i o n o f t h e p r e c u r s o r . To be c e r t a i n o f t h e n e g a t i v e r e s u l t s o b t a i n e d w i t h t h e n i n e - m e m b e r e d r i n g p r e c u r s o r s , b i o s y n t h e t i c s t u d i e s w e r e p e r f o r m e d i n a n o t h e r p l a n t , V i n c a  m i n o r , where a l k a l o i d s b e l o n g i n g t o t h e q u e b r a c h a m i n e a n d o t h e r A s p i d o s p e r m a f a m i l i e s a r e f o u n d . L a b e l l e d t r y p t o p h a n was f e d t o t h i s p l a n t a n d t h e a l k a l o i d s , v i n c a d i n e , v i n c a -m i n o r e i n e ( q u e b r a c h a m i n e - t y p e ) , m i n o v i n e a nd v i n c a d i f f o r m i n e - 21 -DIAGRAM 13 Feeding Experiments i n C. roseus (aspidosperma-type), were is o l a t e d at d i f f e r e n t time i n t e r v a l s . If there was any biosynthetic r e l a t i o n s h i p between these two families of alkaloids the r a t i o between - 22 -them (B/A) should increase or decrease with respect to time. As can be seen i n Diagram 14, the r a t i o B/A remained r e l a t i v e l y constant over a period of fourteen days. DIAGRAM 14 Feeding Experiments i n V. minor TIME TOTAL % INCORPORATION B/A r 4 hours 0.003 0.057 19 1 day 0. 015 0.24 16 2 days 0.01 0.21 21 4 days 0. 01 0.22 22 7 days 0.009 0.13 14 14 days 0. 003 0.06 20 The p o s s i b i l i t y of e q u i l i b r a t i o n of these compounds i n the plant system (which could account for a constant B/A ratio) - 23 -was eliminated when i t was shown"33 that neither vinca-minoreine nor minovine transfer any a c t i v i t y to each other when they are separately incorporated into the plant over a period of one week. The conversion of tabersonine into catharanthine (last experiment i n Diagram 13), demands a considerable number of transformations since the s t r u c t u r a l features of the two a l k a l o i d families are s u b s t a n t i a l l y d i f f e r e n t . A possible pathway could be the one described i n Diagram 15 (no f u n c t i o n a l i t y shown) , where the bonds cleaved by dotted l i n e s break to provide an intermediate which possesses the same structure as "intermediate A!' i n Diagram 8. By c y c l i z a t i o n i n the manner indicated (probably v i a a con-certed mechanism) the Iboga system w i l l be formed. In order to verify the functionality inherent in intermediate "A" i t is 4 20 28 convenient to go back to Scott's feeding experiments ' ' where stemmadenine was p o s i t i v e l y incorporated into vindo-l i n e and catharanthine. Scott explains these conversions (Diagram 16) by an isomerization of stemmadenine to a com-pound that he named isostemmadenine ( s t i l l not i s o l a t e d from natural sources). This compound then rearranges to form "H", which i s the protonated form of a 1,6-dihydro-pyridine, named from t h i s point on as dehydrosecodine. - 24 -DIAGRAM 15 Proposed Mechanism for the Conversion of Aspidosperma-Type Alkaloids into Iboga-Type TYPE IBOGA TYPE The dihydropyridine can react as a diene with the double bond of the a c r y l i c ester v i a an intra-molecular Diels--37 Alder to y i e l d catharanthine, or i t can react as an enamine that adds in a Michael manner to the a c r y l i c ester to form compound " I " . This substance w i l l c y c l i z e to form tabersonine, which i s further transformed into vindoline, or i t could remain i n the ring'-opened nine-membered ring form and be the precursor for the quebrachamine-type a l k a l o i d s . The - 25 -DIAGRAM 16 Role of Dehydrosecodine i n the B i o s y n t h e s i s of Indole A l k a l o i d s CATHARANTHINE TABERSONINE VINCADINE (quebrachamine-type) VINDOLINE - 26 -formation of tabersonine from dehydrosecodine could also 37 be v i s u a l i z e d by an intra-molecular Diels-Alder reaction between the 2,3 double bond of the dihydropyridine and the diene formed by the indole and the a c r y l i c ester. The formation of tabersonine from dehydrosecodine i s a reversible process on the basis of Kutney's biosynthetic work (see Diagram 14). The sequence presented i n Diagram 16 i s 13 very similar to the one proposed by Wenkert i n 1962 , the main difference being that i n the former the nine-membered ring intermediates are eliminated. The i n s t a b i l i t y of the dihydropyridine and the r e a c t i v i t y 1 of the a c r y l i c ester moeity makes the dehydrosecodine almost impossible to i s o l a t e from any plant system. However the following i n vivo evidence and re s u l t s obtained i n the laboratory indicate the certainty of the existence of such intermediates: 1. Compounds with the same skeleton as dehydrosecodine 3 8 have been is o l a t e d from Razhya o r i e n t a l i s by Smith 41 At the same time Battersby reported the i s o l a t i o n of a similar compound from C. roseus shoots: 16,17-dihydro-secodine-17-ol (Diagram 17). Working with the same plant Smith also i s o l a t e d a - 27 -DIAGRAM 17 Secodine-Type Compounds I s o l a t e d from N a t u r a l Sources 002CH3 TETRAHYDROSECODINE C0 2CH 3 TETRAHYDROSECODINOL C0 2CH 3 15,16-DIHYDR0SEC0DINE T J . OH H C0 2CH 3 16,17-DIHYDROSECODINE-17-OL For numbering system of i n d o l e a l k a l o i d s see appendix. s e r i e s of new d i m e r i c a l k a l o i d s t h a t were named p r e -39 secammes . Treatment of these compounds w i t h 2N h y d r o c h l o r i c a c i d gave the p r e v i o u s l y r e p o r t e d secamine 40 a l k a l o i d s . When the presecamines were heated a s e r i e s of secodine d e r i v a t i v e s were obtained which, on sta n d i n g f o r two days at 0°C without s o l v e n t , r e t u r n e d to a mixture of i s o m e r i c presecamines (Diagram 18). 2. P o s i t i v e i n c o r p o r a t i o n of secodine i n t o v i n d o l i n e and c a t h a r a n t h i n e was found by Kutney"^ ^ and S c o t t . - 28 -DIAGRAM 18 Presecamine-Type Alkaloids and Their Chemistry SECAMINES Doubly l a b e l l e d secodine with t r i t i u m i n the ethyl side chain was incorporated i n t a c t , maintaining the same "^C/T r a t i o . However, 62% of t h i s l a b e l was 3 l o s t when H was present i n the piperidine ri n g seg-ment (Diagram 19). - 29 -What t h i s suggested was that the piperidine had gone to a higher oxidation stage p r i o r to forming vindoline and catharanthine, which was consistent with a dihydro-pyridine intermediate. DIAGRAM 19 Incorporation of Secodine into Vindoline and Catharanthine T CATHARANTHINE - 30 -3. In 1968 Scott"*" reported that tabersonine, on heating with AcOH for 16 hours, gave (+) catharanthine and (+) pseudocatharanthine, and that stemmadenine, under the same conditions, gave a mixture of (+) tabersonine, (+) catharanthine and (+) pseudocatharanthine. He invoked the formation of dehydrosecodine as the i n t e r -mediate for the products obtained. The existence of dehydrosecodine as an intermediate formed i n the thermal rearrangement of alkaloids (aspidosperma, strychnos and iboga) was further proved i n the following experiments. a) When 19,20-dihydrostemmadenine acetate or 19,20-dihydrqpreakuammicine were heated over s i l i c a gel at 150°C for 45 minutes a mixture of pseudocatharan-43 thine and dihydropseudocatharanthine was obtained Scott explained t h i s transformation by the series of reactions outlined i n Diagram 20. Oxidation of the dihydrostemmadenine derivative to dihydro-preakuammicine i s an easy reaction and can be performed under several experimental conditions (best y i e l d s are obtained with Pt0 2/02). By heating dihydropreakuammicine, the iminium s a l t " J " i s formed which then transforms to the corres-ponding enamine "K". Via a retro-Michael reaction t h i s substance gives the dihydropyridinium s a l t "L", which i s act u a l l y the protonated form of a 1,2 dihydro-pyridine "M" (3,14 dehydrosecodine). By a Michael reaction and then c y c l i z a t i o n with the indole r i n g , or d i r e c t l y by a Diels-Alder reaction, the dihydropyridine gives (+)pseudocatharanthine. The formation of the dihydro product i s probably due to a disproportionation reaction between "L" and "M", which i s a very common 6 2 reaction for dihydropyridines When 19,20-dihydroprecondylocarpine acetate was treated under the same conditions, a mixture of (+) tabersonine and (+) vincadifformine was obtained as indicated i n Diagram 21. In t h i s case the isomeric dehydrosecodine "N" (14,21 dehydrosecodine) i s formed. i . Treating dihydropreakuammicine with methanol at 80°C for 15 minutes gave 15-methoxy-dihydropseudocatharan-thine. This confirmed the existence of intermediate "L" (Diagram 22). i i . Hydrogenation of stemmadenine acetate with PtC^ as a cat a l y s t gave 75% tetrahydrosecodine (Diagram 22). DIAGRAM 20 Scott's Thermal Rearrangement of Indole Alkaloids 19,20-DIHYDRO- 19,20-DIHYDROPRE-STEMMADENINE ACETATE AKUAMMICINE ACETATE 15,20-DIHYDRO PSEUDO-CATHARANTHINE - 33 -DIAGRAM 21 14,21-Dehydrosecodine as an Intermediate i n the Thermal Rearrangements of Indole Alkaloids CH302C CH2OAc 19,20-DIHYDROPRE-CONDYLOCARPINE ACETATE C02CH3 C02CH3 (+) TABERSONINE H CH302C CH2OAc CH302C CH2QAc C02CH3 C02CH3 (+) VINCADIFFORMINE - 34 -DIAGRAM 22 Trapping of the Dehydrosecodine Intermediates i n the Thermal Rearrangements of Indole A l k a l o i d s C0 2CH 3 C0 2CH 3 15 - JT-METHOXYDIHYDRO-PSEUDOCATHARANTHINE STEMMADENINE ACETATE TETRAHYDROSECODINE - 35 -c) When catharanthine was heated with methanol at 140°C the pyridinium s a l t "0" (Diagram 23) was 48 49 formed i n 50% y i e l d ' . Again, a dehydroseco-dine intermediate was contemplated which, by a disproportionation reaction, produced the pyridinium s a l t . When the s a l t was heated at 175°C a mixture of l-methyl-2-hydroxy-carbazole and 3-ethyl pyridine was formed. The same mixture was obtained when tabersonine was heated with xylene at 205°C. 14,21-Dehydrosecodine as an Intermediate i n the Thermal DIAGRAM 23 Rearrangement of Catharanthine MeOH 140°C CATHARANTHINE ylene II 0 II + - 36 -d) F i n a l l y , when p r e c o n d y l o c a r p i n e was heated i n EtOAc a new p e n t a c y c l i c a l k a l o i d was o b t a i n e d (Diagram 2 4 ) 4 7 . 48 Almost a t the same time P o t i e r r e p o r t e d the i s o l a t i o n of the same p e n t a c y c l i c compound from Craspidospermum v e r t i c i l l a t u m , naming i t a n d r a g i n i n e . I f the thermal rearrangement i s performed u s i n g methanol as s o l v e n t , then methoxy-dihydroandranginine i s formed. Andran-g i n i n e has a l s o been t h e r m a l l y s y n t h e s i z e d from A 1 8 -49 t a b e r s o n i n e As can be seen, dehydrosecodine i s an important i n t e r m e d i a t e i n the l a s t stage of a l k a l o i d b i o s y n t h e s i s as w e l l as i n the thermal rearrangements of some i n d o l i c a l k a l o i d s . Due t o i t s i n s t a b i l i t y i t has not been i s o l a t e d from any p l a n t system or r e a c t i o n mixture and there i s o n l y i n d i r e c t evidence of i t s e x i s t e n c e . I t was thought t h a t the s y n t h e s i s of dehydrosecodine would be h e l p f u l s i n c e i t would a l l o w us t o a s c e r t a i n the c h e m i s t r y of t h i s type of compound and, depending on the r e s u l t s ob-t a i n e d , c o u l d probably be used i n b i o s y n t h e t i c s t u d i e s . P r e l i m i n a r y s t u d i e s towards the s y n t h e s i s of dehydrosecodine c o n s t i t u t e the work r e p o r t e d i n t h i s t h e s i s . DIAGRAM 24 S y n t h e s i s o f A n d r a g i n i n e b y T h e r m a l R e a r r a n g e m e n t o f I n d o l e A l k a l o i d s CH 30 2C CH2GH PRECONDYLOCARPINE CO2CH3 A 1 8-TABERSONINE 15-METHOXY-14,15-DIHYDRO-ANDRAGININE - 38 -RESULTS AND DISCUSSION As mentioned i n the introduction, the object of t h i s work i s the synthesis of 14,21 dehydrosecodine (,1), which w i l l be u t i l i z e d i n further studies of synthesis and biosynthesis of indole a l k a l o i d s . Upon inspection of the molecule to be synthesized (Diagram 25) i t i s found that the 14,21 dehydrosecodine possesses two segments that are very reactive: 1) an a c r y l i c ester derivative (segment A), and 2) an N-substituted 3-ethyl-1,6-dihydropyridine (segment B). DIAGRAM 25 14,21 Dehydrosecodine Due to the fact that these two segments are chemically very d i f f e r e n t , i t i s necessary to analyse them s u f f i c i e n t l y ( i . e . factors a f f e c t i n g s t a b i l i t y , reactions, methods of preparation and protection, i f any), i n order to decide when they w i l l be constructed within a synthetic scheme. - 39 -A c r y l i c E s t e r Segment I n g e n e r a l a c r y l i c e s t e r d e r i v a t i v e s a r e v e r y g o o d M i c h a e l a c c e p t o r s t h a t r e a c t , i n r e l a t i v e l y m i l d c o n d i t i o n s , w i t h a 53 5^ v a r i e t y o f n u c l e o p h i l e s , i n c l u d i n g h y d r i d e s (NaBH^, L i A l H ^ ) t o y i e l d t h e c o r r e s p o n d i n g 1,4 a d d u c t s . Due t o t h e f a c t t h a t t h e y p o s s e s s a p o l a r i z e d d o u b l e b o n d , a c r y l i c e s t e r s h a v e b e e n u t i l i z e d v e r y s u c c e s s f u l l y a s d i e n o p h i l e s i n D i e l s - A l d e r 55 r e a c t i o n s I n t h e c a s e o f a m e t h y l 2 - ( 2 • - i n d o l y l ) - a c r y l a t e d e r i v a t i v e (as i n d e h y d r o s e c o d i n e ) , an e x t r a p r o p e r t y i s a d d e d t o t h e s y s t e m , t h a t i s , t h e d o u b l e b o n d o f t h e a c r y l i c e s t e r , i n c o n j u g a t i o n w i t h t h a t o f t h e i n d o l e ' s p y r r o l e s e g m e n t , makes a good s y s t e m f o r D i e l s - A l d e r - l i k e r e a c t i o n s . T h i s p r o p e r t y 56 57 h a s b e e n u t i l i z e d by Z i e g l e r ' i n t h e t o t a l s y n t h e s i s o f m i n o v i n e (4) ( D i a g r a m 2 6 ) . F o r t h i s p a r t i c u l a r c a s e , t h e r e a c t i o n c o u l d be e x p l a i n e d d i r e c t l y b y a D i e l s - A l d e r r e a c t i o n o r b y an a d d i t i o n o f t h e e n d o c y c l i c e n a m i n e (2) t o t h e 2 - ( 2 ' -i n d o l y l ) - a c r y l i c e s t e r (_3) , f o l l o w e d b y an i n t r a m o l e c u l a r M a n n i c h c o n d e n s a t i o n , a s shown i n t h e D i a g r a m . The d i e n e f o r m e d b e t w e e n t h e i n d o l e a n d t h e a c r y l i c e s t e r i s q u i t e r e a c t i v e a n d , a s d e s c r i b e d i n t h e i n t r o d u c t i o n , d i m e r i z e s 3 8 v e r y e a s i l y y i e l d i n g p r e s e c a m i n e - t y p e a l k a l o i d s ( D i a g r a m 2 7 ) . I n t h e same p a p e r w h e r e t h i s r e a c t i o n i s d e s c r i b e d , S m i t h r e p o r t s t h a t when t h e i n d o l y l - a c r y l a t e s y s t e m i s k e p t i n - 40 -DIAGRAM 26 Z i e g l e r ' s S y n t h e s i s o f M i n o v i n e C H 3 C0 2 CH 3 3 3 COjCHg C H 3 C0 2 CH 3 (*) Minovine 4 - 41 -methanol, the 17-methoxy d e r i v a t i v e (7_ i n Diagram 27) i s formed. DIAGRAM 27 Secodine Reactions A g e n e r a l method f o r c o n s t r u c t i o n o f the a c r y l i c e s t e r segment of the dehydrosecodine might be one i n which a preformed a - i n d o l y l - a c e t i c e s t e r i s converted d i r e c t l y v i a an "a-methylen-a t i o n sequence"into the d e s i r e d 2 - i n d o l y l - a c r y l i c e s t e r (Diagram 28). - 42 -DIAGRAM 28 G e n e r a l M e t h o d f o r t h e C o n s t r u c t i o n o f t h e A c r y l i c E s t e r Segment OgC , • OgC H CO-R* H CO.R The m e t h o d o l o g y f o r t h i s t r a n s f o r m a t i o n i s v e r y s i m i l a r t o t h e one u t i l i z e d f o r t h e s y n t h e s i s o f a - m e t h y l e n e l a c t o n e s , 58 w h i c h h a s b e e n r e v i e w e d b y G r i e c o . A n a l y z i n g h i s p a p e r one c a n s e e t h a t i n g e n e r a l , t h e p r o c e d u r e s u t i l i z e d f o r t h e a^nethylenation o f l a c t o n e s f o l l o w t h e two g e n e r a l r o u t e s o u t -l i n e d i n D i a g r a m 29. • 35-37 I n h i s s y n t h e s i s o f s e c o d i n e K u t n e y u s e d r o u t e A (x = OH) f o r t h e f o r m a t i o n o f t h e 2 - i n d o l y l - a c r y l i c s y s t e m . A d i f f e r e n t a p p r o a c h was t a k e n b y Z i e g l e r i n h i s s y n t h e s i s o f m i n o v i n e . I n t h i s c a s e a n i n d o l e g l y o x y l i c (8_) e s t e r i s c o n v e r t e d v i a a W i t t i g r e a c t i o n i n t o t h e a c r y l i c e s t e r d e r i v a t i v e (9^) a s shown a t t h e b o t t o m o f D i a g r a m 29. - 43 -DIAGRAM 29 Methodology for the Synthesis of a-Methylene Lactones Ziegler's Synthesis of 2-Indolyl-Acrylic Esters CH 3 CO£Hz 3. - 45 -As can be seen i n the p r e v i o u s Diagram, the 1,4 adduct (10) i s the same type of i n t e r m e d i a t e as t h a t o b t a i n e d i n one o f the r o u t e s d e s c r i b e d f o r the p r e p a r a t i o n of a-methylene l a c t o n e s (Route A i n Diagram 29). T h e r e f o r e , a p o s s i b i l i t y i n the s y n t h e s i s of dehydrosecodine c o u l d be the p r e p a r a t i o n of an i n d o l i c compound c o n t a i n i n g the same f e a t u r e s as (3^0) , which would a l l o w us t o b u i l d the other s e n s i t i v e segment of dehydrosecodine without any s i d e r e a c t i o n . F i n a l l y the a c r y l i c segment c o u l d be formed at the l a s t stage of the s y n t h e s i s v i a a r e t r o - M i c h a e l r e a c t i o n , s i m i l a r to the one o u t l i n e d i n Diagram 30. 59 D i h y d r o p y r i d i n e Segment The r e d u c t i o n of the aromatic h e t e r o c y c l e p y r i d i n e can l e a d to s e v e r a l i s o m e r i c dihydro-and t e t r a h y d r o - p y r i d i n e s , depending on the c o n d i t i o n s used i n the r e a c t i o n . Dihydro-p y r i d i n e s p l a y an important r o l e as r e a c t i o n i n t e r m e d i a t e s i n the r e a c t i o n of p y r i d i n e , e.g. i n n u c l e o p h i l i c s u b s t i t u -t i o n s . They a l s o r e p r e s e n t r i n g systems of t h e o r e t i c a l and b i o l o g i c a l importance. In theory t h e r e can be f i v e i s o m e r i c d i h y d r o p y r i d i n e s ( s t r u c t u r e s 11^  - 15 i n Diagram 31), but i n f a c t most of the known d i h y d r o p y r i d i n e s have e i t h e r the 1,2 d i h y d r o (11) or the - 44 -On the basis of the r e a c t i v i t y reported for the i n d o l y l -a c r y l i c segment, i t i s adviseable to form t h i s at the l a s t stage of the planned synthesis of dehydrosecodine. Other-wise, t h i s segment could create several problems that would be d i f f i c u l t to overcome unless a way to protect t h i s portion were u t i l i z e d . In his review Grieco points out that there have been several methods reported for the protection of a-methylene lactones. A l l of them u t i l i z e the high r e a c t i v i t y of t h i s system towards nucleophiles, to form the corresponding 1,4 adducts (10). By a "retro-Michael" reaction the a-methylene unit i s reestablished from the adduct, v i a a type of intermediate that depends on the nucleophile u t i l i z e d (Diagram 30). DIAGRAM 30 Protection of a-Methylene Lactones if X=NorS R-XH - 46 -1,4 dihydro structure (12^). When a substituent (R) , i s present at p o s i t i o n 2 or 3 of the pyridine r i n g , two isomeric dihydro structures (11) can a r i s e , named 2-R (or 3-R)-l,2-dihydropyridine and 2-R (or 3-R)-1,6-dihydropyridine (structures 16 and 1/7, respectively, i n Diagram 31) . DIAGRAM 31 Isomeric Dihydropyridines o '1ST I H 11 1,2 Dihydro O 13 0 1± o i 1,4 Dihydro o N' Or' I 3-R-1,2-Dihydro H JZ 3-R-1,6-Dihydro - 47 -There are scattered data available that indicate that the 1,4 dihydropyridine system i s more stable than the 1,2 isomer. One example i s the work by Traber and K a r r e r ^ , which reports that 1,2 dihydropyridines are oxidized by s i l v e r ion at a faster rate than the 1,4 d e r i v a t i v e . From e q u i l i b r a t i o n studies of N-methyl-1,2-dihydropyridine, Fowler^"*" estimates that the 1,4 isomer of t h i s system i s more stable by a difference of 2.3 kcal/mole. 6 2 In general electron withdrawing substituents, capable of resonance i n t e r a c t i o n (COR, C02R, CN, N0 2) i n the 3 and/or 5 p o s i t i o n , s t a b i l i z e dihydropyridines by extending the con-jugation. Substituents i n the same positions but that donate electrons by resonance (SCgH,-, OCgH^) have a d e s t a b i l i z i n g e f f e c t . A l k y l substitution on nitrogen as well as i n the 3 and 5 positions have the same d e s t a b i l i z i n g e f f e c t . A glucosyl substituent on the nitrogen appears to have a remarkable s t a b i l i z i n g influence. P o l y c y c l i c or otherwise highly substituted dihydropyridines seem to be less reactive, probably due to s t e r i c factors. 6 3 There are several patents that claim the use of stable, low t o x i c i t y dihydropyridines as antihypertensives and i n the treatment of c i r c u l a t o r y and cardiac disorders. The compounds - 48 -used consist of hindered 1,4 dihydropyridines with electron withdrawing groups on nitrogen as well as i n the 3 and 5 positions (L8 i n Diagram 32). Another example of a stable dihydropyridine i s the NADPH enzyme which i s involved i n 64 several important b i o l o g i c a l oxido-reduction reactions A part of t h i s enzyme i s constituted by an N-ribofuranosyl-1,4-dihydropyridine with an amide group at the 3 position (19 i n Diagram 32). DIAGRAM 32 Stable Dihydropyridines - 49 -In g e n e r a l d i h y d r o p y r i d i n e s are very r e a c t i v e i n t e r m e d i a t e s which o x i d i z e very e a s i l y . E i s n e r and Kuthan c l a s s i f y the o x i d a t i o n of t h i s type of compounds i n three ways: 1) Dehydrogenation, where a one or two e l e c t r o n t r a n s f e r takes p l a c e . There are a wide v a r i e t y of o x i d i z i n g reagents t h a t can cause t h i s type of r e a c t i o n : 0 2 , Sg, N0 2, HN0 3, H 2 0 2 / AgN0 3, I 2 , Hg(OAc) 2, e t c . A g a i n , l i t t l e work has been r e p o r t e d on the c o r r e l a t i o n between s t r u c t u r e and ease o f o x i d a t i o n . The r e l a t i v e r a t e s of dehydrogenation decrease w i t h the s u b s t i t u e n t s i n the 3 p o s i t i o n i n the o r d e r : CONH 2 > C 0 2 E t > COCH 3, and w i t h s u b s t i t u e n t s a t N i n the order 0CH2 > C1 20CH 2 > 0OCH2. 2) Hydrogen T r a n s f e r , where a hydrogen i s t r a n s f e r r e d from a d i h y d r o p y r i d i n e to an a c c e p t o r , as a f r e e r a d i c a l or a h y d r i d e , the l a t t e r b e i n g the more common. For t h i s r e a c t i o n , s e v e r a l h y d r i d e acceptors have been u t i l i z e d , f o r example: m a l e i c a c i d , p y r u v i c a c i d , hexachloroacetone, a,3-unsaturated ketones, e t c . 3) D i s p r o p o r t i o n a t i o n , where the d i h y d r o p y r i d i n e , i n a c i d i c media, i s both a donor and an a c c e p t o r of hydrogen. These three modes of d i h y d r o p y r i d i n e o x i d a t i o n are e x e m p l i f i e d i n Diagram 33. - 50 -DIAGRAM 33 O x i d a t i o n o f D i h y d r o p y r i d i n e s 1) Dehydrogenation II 1 AgN03-^ l\ I^CH 2 -CH 3 C H 3 CH: I CH 3 CH2—CH3 Ref.65 2) Hydrogen T r a n s f e r & i NH2 9 + C L C - C - C C U ST fl C ^ N H 2 HO +Cl C-CH-CCL Ref.66 3) D i s p r o p o r t i o n a t i o n Nud. R I R' + cr R .k Tars - 51 -Besides the d i s p r o p o r t i o n a t i o n r e a c t i o n , the p r o t o n a t e d d i h y d r o p y r i d i n e (20) can be a t t a c k e d by a v a r i e t y o f n u c l e o p h i l e s (Nucl.= HO~, C l ~ , MeO~, CN~, 05), or polymerized (see bottom of Diagram 33). T h i s i s one of the reasons why r e a c t i o n s u s i n g these s e n s i t i v e compounds, y i e l d , i n g e n e r a l , s e v e r a l products and a f a i r amount of t a r s . However, t h e r e are examples where t h i s r e a c t i o n between d e r i v a t i v e s of (20) and n u c l e o p h i l e s has been s u c c e s s f u l l y u t i l i z e d i n the s y n t h e s i s of i n d o l e a l k a l o i d s (see example i n the upper p a r t of Diagram 34). Although d i h y d r o p y r i d i n e s c o u l d be c o n s i d e r e d as diene-amines (homoannular t y p e ) , and t h e r e f o r e should behave as such i n f u n c t i o n a l i t y , there have not been any r e p o r t s on C - a l k y l a t i o n 67 (a t y p i c a l r e a c t i o n o f diene-amines ) of these p y r i d i n e 6 8 d e r i v a t i v e s . However, N - l i t h i a t e d - 1 , 2 - d i h y d r o p y r i d i n e (21) has been s u c c e s s f u l l y a l k y l a t e d and f u n c t i o n a l i z e d w i t h a wide v a r i e t y of reagents (see bottom p a r t of Diagram 34). The C versus N f u n c t i o n a l i z a t i o n of these d i h y d r o p y r i d i n e s depends upon the type of reagents used. Some examples of D i e l s - A l d e r r e a c t i o n s between 1,2 d i h y d r o -73 p y r i d i n e s and s e v e r a l d i e n o p h i l e s (maleic anhydride , N-p h e n y l m a l e i m i d e ^ , methyl v i n y l k e t o n e 7 ^ ' a n d a c r y l o -7 6 n i t r i l e ) have been r e p o r t e d . In a l l cases, the d i h y d r o -- 52 -DIAGRAM 34 Some D i h y d r o p y r i d i n e Reactions Ref. 69 0 +• RL i XX X = - C H 2 - Ref. 70 X = ) c = 0 Ref. 71 X = - S - Ref. 7 2 C03 - 53 -pyridine has been s t a b i l i z e d by electron-withdrawing groups (-CN, -C0 2 R or -CONH2). 77 Apart from one unsupported statement that N-phenyl-1,2-dihydropyridine adds to dimethyl acetylene dicarboxylate i n a Michael fashion, there are no reports of th i s type of reaction by dihydropyridines i n the l i t e r a t u r e . There are three main general synthetic routes for the pre^ paration of dihydropyridines: a) c y c l i z a t i o n of a c y c l i c s t a r t i n g materials (Hantzsch synthesis); b) nucleophilic additions to pyridine and pyridinium s a l t s and c ) , thermal rearrangement of other r i n g systems. The o r i g i n a l Hantzsch dihydropyridine synthesis consisted of the reaction between ethyl acetoacetate and an aldehyde i n the presence of ammonia (or ammonium s a l t ) , y i e l d i n g the 1,4 dihydropyridine (22) shown i n Diagram 35. The aldehyde reacts with two molecules of the enamine formed between the 3-keto ester and ammonia. C y c l i z a t i o n of the r e s u l t i n g molecule with elimination of ammonia gives the 1,4 dihydro-pyridine . Several modifications to the Hantzsch synthesis have been reported (the use of B-diketone, 8 - k e t o n i t r i l e s , t h e i r enamine - 54 -DIAGRAM 35 Hantzsch Synthesis of Dihydropyridines derivatives; 1,5 diketones, e t c . ) , r e s u l t i n g i n better-y i e l d i n g reactions with easy work-up. Hantzsch's synthesis i s a very v e r s a t i l e and high-yielding reaction, used mainly for the preparation of 1,4 dihydro-pyridines. There are few examples where a 1,2 dihydro-pyridine i s formed instead. In general these compounds are produced when the aldehyde i s substituted by a ketone or when the nitrogen source i s a primary amine (Diagram 36). In these cases, i t i s more l i k e l y that a d i f f e r e n t mechanism p r e v a i l s . i Nucleophilic attack on the pyridine r i n g i s another e f f i c i e n t method of preparing dihydropyridines, e s p e c i a l l y i f the more e l e c t r o p h i l i c pyridinium s a l t i s employed. This last compound has e l e c t r o p h i l i c positions at the 2-, 4-, and 6- carbon - 55 -DIAGRAM 36 1,2-Dihydropyridines v i a Condensation Reactions 9 NHt."OAc Ref.78 R '-CH 2 -NH 2 R + rr R R-CH 2 -CHO R-CHf^N Ref-79 CH2-R' atoms. Of these, the 2- and 6- p o s i t i o n s are the more p o s i t i v e ones, because of t h e i r p r o x i m i t y to the q uaternary n i t r o g e n , t h e r e f o r e a n u c l e o p h i l e should a t t a c k p r e f e r e n t i a l l y a t these two p o s i t i o n s . However, the s t e r i c and e l e c t r o n i c f a c t o r s r e s u l t i n g from the type and l o c a t i o n of s u b s t i t u e n t s , as w e l l as the nature of the n u c l e o p h i l e , are the r e a l f a c t o r s t h a t govern the o r i e n t a t i o n of a n u c l e o p h i l i c a t t a c k on a p y r i d i n i u m s a l t . Borohydride r e d u c t i o n of p y r i d i n i u m s a l t s y i e l d s u n s t a b l e d i h y d r o p y r i d i n e s which have been d e t e c t e d s p e c t r o s c o p i c a l l y . - 56 -These dihydropyridines are usually reduced further to t e t r a -hydropyridine, since the solvent protonates them and the re s u l t i n g iminium s a l t i s reduced to the tetrahydro derivative (Diagram 37). In order to stop the reaction at the dihydro-pyridine stage, large concentrations of a l k a l i have to be used. DIAGRAM 37 NaBH^ Reduction of Pyridinium Salts Ref. 80 Lyle and Anderson 0" established that i n the reduction of pyridinium s a l t s with NaBH^: a) the attack of the hydride ion w i l l occur p r e f e r e n t i a l l y at the carbon adjacent to the nitrogen (positions 2 and 6) i f s t e r i c interference does not occur; b) t h i s attack w i l l not take place i f these positions are substituted or, at least, the rate w i l l be greatly reduced; and c) large substituents near the point of poten-t i a l attack w i l l d i r e c t attack towards more distant positions ( i . e . : sugar residues attached at the 1-position favor hydride addition at the 4-position). The influence of the type of pyridine substituents on the ^ N s i t e of attack of a p a r t i c u l a r nucleophile, i s exemplified i n Diagram 38. Thus, reduction of N-tryptophyl-3-ethyl-pyridinium bromide (23), with NaBH^ yi e l d s the 1,2-dihydro 81 derivative (24) exclusively, but when an electron with-drawing group i s i n the 3-position, a mixture of 1,2 and 1,6 dihydropyridines (2_5, 26) r e s u l t s , the l a t t e r being the more 75 76 predominant ' . Two additional examples are given i n 8 2 Diagram 38, where a d i f f e r e n t nucleophile i s u t i l i z e d 8 3 The reaction between pyridinium s a l t s and Grignard reagents 84 or lithium dialkylcuprates i s a good i l l u s t r a t i o n of the influence of nature on the nucleophile. In the case of Grignard reagents, a 1,2-addition occurs, whereas i n the case - 58 -DIAGRAM 38 Orientation of the Nucleophilic Additions to Pyridinium Salts - 59 -of the cuprate d e r i v a t i v e , a 1 , 4 - a d d i t i o n i s observed (Diagram 30). The behavior of these two reagents i s the same as t h a t r e p o r t e d f o r a,B-unsaturated c a r b o n y l compounds, 85 which are t y p i c a l analogs f o r p y r i d i n e s o r p y r i d i n i u m s a l t s DIAGRAM 39 N u c l e o p h i l i c Reactions w i t h P y r i d i n i u m S a l t s Solvent: THF -Me OH, mixture of 2§_ and 29 *-only ___ - 60 -Another f a c t o r t h a t has a d e f i n i t i v e i n f l u e n c e on the o r i e n t a t i o n o f the n u c l e o p h i l i c a t t a c k i s the s o l v e n t used 73 i n the r e a c t i o n . For i n s t a n c e , Fowler r e p o r t s t h a t when (27) (Diagram 39) i s t r e a t e d w i t h NaBH 4 i n THF, a mixture o f 1,2- and 1, 4 - d i h y d r o p y r i d i n e s i s formed but, i f the r e a c t i o n i s performed i n dry methanol, on l y the 1,2-isomer i s formed. The s y n t h e s i s of d i h y d r o p y r i d i n e s v i a the thermal r e a r r a n g e -ment of oth e r h e t e r o c y c l i c systems i s not as v e r s a t i l e as the methods p r e v i o u s l y d i s c u s s e d , but has the g r e a t advantage t h a t i t leads to a s p e c i f i c d i h y d r o p y r i d i n e (1,2- or 1-4-isomer), as shown i n Diagram 40. The main problem w i t h t h i s method i s the d i f f i c u l t y o f s y n t h e s i z i n g the a p p r o p r i a t e r i n g systems. There i s o n l y one r e p o r t concerning the p r o t e c t i o n o f d i h y d r o -8 8 p y r i d i n e s . In t h a t study i t was observed t h a t when a p y r i d i n i u m s a l t was reduced w i t h NaBH^ i n the presence o f hydrogen cyanide, s u b s t i t u t e d 6-cyano-l,2,5,6-tetrahydro-p y r i d i n e s (3_0) are formed i n h i g h y i e l d . Treatment of these compounds w i t h base regenerates the d i h y d r o p y r i d i n e , probably v i a the mechanism o u t l i n e d i n Diagram 41. *• 89 In 1967 O f e l e r e p o r t e d the p r e p a r a t i o n o f s t a b l e (dihydro-p y r i d i n e ) chromium t r i c a r b o n y l complexes from the u n s t a b l e DIAGRAM 40 Dihydropyridines from Other Heterocyclic Systems Ret 87 dihydropyridine and chromium hexacarbonyl (31^  and 32 i n Diagram 41). This type of reaction could be a good way to trap and protect these reactive intermediates i f the chromium complexes are r e a l l y stable under a wide variety of reaction conditions and , i f there i s a mild method available to d i s -engage the dihydropyridine as a ligand. A l l these questions need answers i n order to claim that the formation of the dihydropyridine chromium complexes i s a good way to protect these compounds. - 62 -DIAGRAM 41 Protection of Dihydropyridines - 63 -Another stable dihydropyridine metal complex (3_3 i n Diagram 90 41) has been reported , where a method for decomplexation i s given. However, t h i s type of compounds have l i t t l e synthetic use since the dihydropyridine employed i s already stable. This b r i e f introduction to a c r y l i c ester and dihydropyridine chemistry provides a basis for o u t l i n i n g the possible synthetic strategies for the preparation of 14,21-dehydrosecodine (__) . As already mentioned, th i s substance, possesses a 1,6-dihydro-pyridine with two a l k y l substituents at p o s i t i o n 1 and 3 of the pyridine ri n g (besides the a c r y l i c ester moiety). These a l k y l substituents do not s t a b i l i z e the dihydropyridine system, which means that the molecule w i l l be very reactive and un-stable . Two schemes were envisioned for the synthesis of 14,21-dihydro-pyridine: A) construction of a protected a c r y l i c ester, followed by the generation of the dihydropyridine and f i n a l l y the removal of the a c r y l i c ester protection (Diagram 42), or a l t e r n a t i v e l y B) formation of a protected or trapped dihydro-pyridine and subsequent generation of the a c r y l i c ester function, and l i b e r a t i o n of the pyridine d e r i v a t i v e (Diagram 43). The two schemes shown i n the Diagrams r e l y on the reduction 88 of a pyridinium s a l t with NaBH4. I t has been reported that - 64 -DIAGRAM 42 Scheme "A": Synthesis of Dehydrosecodine 3 5 3,14 - Dehyd rosecod ine i n these conditions N-indolyl-3-alkylpyridinium s a l t s give exclusively 1,2-dihydropyridines (see Diagram 38). If t h i s i s the case for the system being studied, following scheme "A", or route "a" of Scheme "B", w i l l lead d i r e c t l y to the preparation of the isomeric 3,14-dehydrosecodine (35). - 65 -DIAGRAM 43 Scheme "B": S y n t h e s i s of Dehydrosecodine R o u t e a Route b 35 - 66 -Since there are no r e p o r t s on the d i r e c t p r e p a r a t i o n of N , 3 - d i a l k y l - l , 6 - d i h y d r o p y r i d i n e s , the o n l y a l t e r n a t i v e i s to use the thermal i s o m e r i z a t i o n of d i h y d r o p y r i d i n e chromium 89 complexes (route "b" i n Diagram 43) r e p o r t e d by O f e l e (see Diagram 41), w i t h the hope of f i n d i n g an e f f i c i e n t and m i l d method f o r removing the l i g a n d from these s t a b l e and novel complexes. I f the chromium complexes are to be used w i t h the d u a l purpose of p r o t e c t i o n of d i h y d r o p y r i d i n e s and a method f o r p r e p a r i n g the 1,6-isomer, the f o l l o w i n g q u e s t i o n s have to be answered: 1) Can the ( d i h y d r o p y r i d i n e ) t r i c a r b o n y l chromium complex be formed? 2) W i l l the i n d o l e moiety i n t e r f e r e w i t h the complex formation? 3) Does the thermal i s o m e r i z a t i o n occur i n the system without too much decomposition? 4) Are the chromium complexes s t a b l e i n the r e a c t i o n c o n d i t i o n s used f o r the formation of the a c r y l i c e s t e r segment? 5) F i n a l l y , and most important, i s there a m i l d method f o r l i b e r a t i n g the d i h y d r o p y r i d i n e s t h a t w i l l not d e s t r o y them? In order t o answer a l l these q u e s t i o n s and to develop the r e q u i r e d methodology, i t was decided to s t a r t the i n v e s t i g a t i o n - 67 -using a simple model, before going into more complicated systems. The model had to resemble the dehydrosecodine structure, that i s , i t had to have two a l k y l substituents at positions 1 and 3 of the pyridine and, in order to simplify the spectroscopic i d e n t i f i c a t i o n of the products (especially NMR), they had to be d i f f e r e n t . On t h i s basis the N-methyl-3-ethylpyridinium system (4_1) was chosen as our model. As mentioned previously, the use of a strong basic medium i n the reaction of pyridinium s a l t s with NaBH^ retards the over-reduction of the dihydropyridines, enhancing t h e i r s t a b i l i t y 8 8 and allowing t h e i r i s o l a t i o n i n some cases. Moreover, the use of a two-phase system (ether - water), i n which the pyridinium s a l t i s reduced i n a basic aqueous layer and then extracted from the reducing medium into an organic layer as soon as the dihydropyridine i s formed, further lessens the chances of overreduction. I n i t i a l work performed by A. Zanarotti* concentrated on the generation of the dihydropyridine with no attempt at i s o l a t i o n and characterization of the reactive intermediates. After several experiments with negative r e s u l t s , i t was found that when N-methyl-3-ethylpyridinium iodide (4_1) i s reduced with NaBH. i n a vigorously s t i r r e d mixture of ethyl ether, *1971-1972 Postdoctoral Fellow with Dr. James P. Kutney - 68 -methanol and 2.IN sodium hydroxide solution under an i n e r t atmosphere, the U.V. absorption of the s t a r t i n g material at 266 nm. disappears i n f i v e minutes and then shows a new maximum at 327 nm. (that decreases with time), which corresponds to a dihydropyridine. Treatment of a benzene solution of crude dihydropyridine (obtained i n the manner described), with Cr(CO)g, did not y i e l d any of the expected chromium complexes. However when added to dry, freshly prepared t r i s a c e t o n i t r i l e - t r i -carbonylchromium(0), (42) , under an oxygen-free atmosphere of dry nitrogen, a deep red solution was formed. After 30 minutes of s t i r r i n g at room temperature, the U.V. spectrum of the reaction mixture showed no dihydropyridine absorption (327 nm.) and only a new maximum at 400 nm. was observed. By TLC the reaction mixture showed three coloured spots. The less polar one had a yellow coloration and was i d e n t i c a l to the a c e t o n i t r i l e chromium complex; the other two spots were red and very close together. By r e p e t i t i v e TLC these two compounds were separated, showing that the predominant one was the least polar. Preparative TLC followed by c r y s t a l l i z a t i o n from benzene - hexane allowed the i s o l a t i o n of these two red compounds. The minor component (43) of the mixture presented a U.V. - 69 -maximum at 403 nm. and three carbonyl absorptions at 1830, 1860 and 1942 cm ^ i n the I.R. spectrum. Elemental analysis and the low resolution mass spectrum (m/e 259 (M+)) were consistent for a (dihydropyridine) tricarbonylchromium complex. NMR* signals at 0.7 ( t r i p l e t for 3H; J = 7Hz), 1.74 (quartet for 2H; J = 7Hz) and 1.44 (singlet for 3H), revealed the presence of an ethyl side-chain and an N-methyl group, respectively. The NMR spectrum showed a pair of doublets at 2.28 and 2.36 for two hydrogens forming an AB system (J = 10Hz), as well as a series of o l e f i n i c protons i n the form of a doublet at 4.47 for two hydrogens (J = 5Hz) and a t r i p l e t fc>r doublet of doublets) at 4.98 for one hydrogen (J = 5Hz), (Figure 1). The signals i n the o l e f i n i c region form a t y p i c a l AX 2 pattern 92 for a j / V A - V B ~0.1 • I n t h i s p a r t i c u l a r case, two o l e f i n i c protons (X) have the same chemical s h i f t and the same coupling constant ( J A X ) to the t h i r d o l e f i n i c proton (A), and become 93 "accidentally equivalent" . In general, because of low symmetry, compounds whose spectra exhibit "accidental equiv-alence" would not generally preserve t h i s i n d i f f e r e n t solvents. In the case described compound 43_ could not be run i n any solvent other than benzene, because of severe sample decom-pos i t i o n . *A11 chemical s h i f t values w i l l be given from here on i n the 6 scale, which refers to tetramethylsilane as the i n t e r n a l standard. FIGURE 1 NMR spectrum of (N-methyl-3-ethyl-l,2-dihydropyridine) tricarbonylchromium(0) complex (4 3) (CrDr) - 7 1 -This information leads to the conclusion that 4_3 i s the (N-methyl-3-ethyl-l,2-dihydropyridine)tricarbonylchromium complex, where protons at 4,5 and 6 (see Diagram 44) form the described AX 2 system (A = H^; X 2 = H 4, Hg) and the two hydrogens at position 2 give the AB quartet centered at 62.32. The major constituent (44) of the mixture of the two red compounds obtained i n the complexation reaction has a maximum of 399 nm. by U.V. It also portrays three c h a r a c t e r i s t i c carbonyl signals by I.R., at 1825, 1860 and 1942 cm - 1. Again, elemental analysis and low resolution mass spectrum (m/e 259 (M +)), are consistant for a dihydropyridine chromium complex. 89 Ofele reported that 1,4-dihydropyridines do not form complexes with chromium and the complexed 1,2-isomer has already been i d e n t i f i e d , therefore, compound 4_4 has to be the t r i c a r b o n y l -chromium complex, which possesses an N-methyl-4-ethyl-l, 6-dihydropyridine as ligand. If t h i s i s true, then a downfield si n g l e t i n the NMR spectrum due to the o l e f i n i c proton at 2 (see Diagram 44), could be expected. The NMR spectrum of 44_ i n deuterobenzene (Figure 2) showed a t r i p l e t at 1.12 (J = 7Hz) for three protons (-CH2CH3); and a s i n g l e t at 1.45 also for three protons (N-CH-J . A complex FIGURE 2 -NCH-C(2)H C(4)H CHo 44 i i i -1 -i i i i i i i i i i i - i i i i i i i i i i i i i i i i • L I | 1 I J I I I I I .1 I I I I. I I, I I I I I I I I I I I I I I III 1 I I I J I. I I I | I I I I I I I I I I I I - I I I I I I I I I i I I I I I I I ' l I I l ~ NMR spectrum of (N-methyl-3-ethyl-l,6-dihydropyridine) tricarbonylchromium(0) complex (4_4) (C^Dg) - 73 -pattern i s observed between 2.0 and 2.7, integrating for four . hydrogens. The spectrum also shows a s p l i t t r i p l e t at 3.09, the expected s i n g l e t at 4.53 and a doublet (J = 7Hz) at 4.83, a l l of which are integrated for one proton each. The downfield doublet was assigned to and when doubly ir r a d i a t e d , only the t r i p l e t at 3.09 was affected (see Figure 3), allowing the assignation of t h i s l a s t signal to the hydrogen at position 5. Ir r a d i a t i o n of t h i s t r i p l e t caused to become a sing l e t . In any of these decoupling studies, the signals be-tween 2.0 and 2.7 (which correspond to Hg g and -C^CH^) had a recognizable pattern, even when the methyl group at 1.12 was irr a d i a t e d . When the NMR spectrum was run using deuterochloroform as solvent (Figure 4), the methylene of the ethyl chain can be recognized as two quartets. When th i s solvent i s used the H 2 and H^ signals are reversed. The t r i p l e t due to H^ i s rapidl y recog-nized but now forms what i s probably an ABC system with Hg and Hg' ( s l i g h t l y s i m p l i f i e d when the extra coupling with H^ i s eliminated) that has not been studied further. The structures assigned to compounds 4_4 and 4_5 were confirmed 94 95 by X-ray analysis ' . 8 9 Although i t has been reported that some isomerization of FIGURE 3 -CH, C(5)H -0-C(4)H T I I ,1 I i • , "I . 1 i i i n—.—i I I i i i i ' ' 1 i i i i i i 1 1 I M I I | I I | I | | | M | | | | | | ! | | , , I 1 I 1 ' I I 1 .1 1 I 1 I I Double resonance s t u d i e s of complex 44_ (CgDg) FIGURE 4 -NCH3 ' " 1 M ' ' i u i i|i i i i i i i i i | i M i i i i i i | i i i i | i i i i i i in i | NMR spectrum of (1,6-dihydropyridine) chromium complex 44 in CDC10 - 76 -DIAGRAM 44 Formation of N-Methyl-3-ethyl Dihydropyridine Chromium Complexes the dihydropyridines occurs during the complexation reaction, the fact that the predominant isomer obtained i n t h i s type of reaction was the 1,6-dihydropyridine, led to the conclusion that t h i s pyridine derivative was also the predominant one i n the reduction of the 3-ethyl pyridinium s a l t (430 with NaBH^, which i s contrary to expectations. The only way to est a b l i s h the degree of isomerization taking place i n the system was to i s o l a t e and i d e n t i f y the products obtained i n the reduction of the pyridinium s a l t or t r y to get some i n d i r e c t information on the type of compounds formed. - 77 -This l a s t a lternative could be the overreduction of the N-methyl-3-ethyl pyridinium s a l t (41), since every isomeric dihydropyridine would lead to a d i f f e r e n t overreduced product (Diagram 45). DIAGRAM 45 Overreduction of N-Methyl-3-ethylpyridinium with NaBH, 4 CH 3 41 & 3 4§ C H3 4 2 C H 3 4a - 78 -Treatment of s a l t 41. with NaBH^ i n methanol gave a mixture of three compounds i n a r a t i o of 15:2:1 by gas chromatography (G.C.). Using preparative G.C. p u r i f i c a t i o n the mixture's major component was iso l a t e d and i d e n t i f i e d as tetrahydro-pyridine 47_, based on comparison of i t s spectroscopical data 96 with data reported for that compound The i s o l a t i o n of N-methyl-3-ethyl-3-piperideine (47_) as the predominant product i n the overreduction of the pyridinium s a l t 4_1 indicated that, contrary to expectations but i n 8 8 agreement with previously reported r e s u l t s , the N-methyl-3-ethyl-l, 2-dihydropyridine (46_) i s indeed formed during the reaction of s a l t 4_1 with NaBH^, unless the tetrahydropyridine 48 rearranges during the reaction or the work-up, to form compound 47. Since the fact that i n the complexation reaction the predominant product contained a 1,6-dihydropyridine, but there was some evidence that the st a r t i n g material for that p a r t i c u l a r reaction consisted mainly of the 1,2-isomer, was rather confusing, i t was decided that a stable dihydropyridine would be prepared which, once p u r i f i e d and i d e n t i f i e d , could be transformed into the model system and l a t e r on be submitted to the complexation reaction. In order to do t h i s , N-carbomethoxy-3rethyl 73 dihydropyridines were prepared, since i t has been reported - 79 -that t h i s type of substances are very stable, can be p u r i f i e d by column chromatography and when treated with LiAlH^, give N-methyl dihydropyridines i n high y i e l d . When 3-ethyl pyridine was treated i n methanol with methyl chloroformate and NaBH^ at -78°C, a single compound was obtained which, based on spectroscopic properties, was i d e n t i f i e d as N-carbomethoxy-3-ethyl-l,2-dihydropyridine (49). Compound £9_ has a U.V. maximum at 298 nm. and i n the I.R. spectrum shows an absorption at 1700 cm ^, that corresponds to the N-carbomethoxy group. The NMR spectrum shows t y p i c a l signals for the ethyl chain, 1.07 t r i p l e t (J = 7); 2.03 quartet (J = 7); and a s i n g l e t at 3.75, due to the methoxy group. Signals at 4.21 (quartet; 2H; J = 1Hz); 5.02 (doublet of doublets; IH; J = 6Hz); 5.52 (doublet; IH; J = 6Hz) and 6.53 (broad doublet; IH; J = 6Hz) were attributed to H 2 2 » ' H,-, H^ and Hg, respectively, based on double resonance studies done with the molecule (Figures 5 and 6). Around that time Dr. R. Greenhouse* was studying the reduction of the pyridinium s a l t 41_ with NaBH^ i n the two-phase system. He found that i f some precautions were taken (especially no 1973-1974 Postdoctoral Fellow for Dr. James P. Kutney FIGURE 5 FIGURE 6 - 82 -exposure to a i r ) , a transparent, thick o i l could be iso l a t e d from the organic layer a f t e r 5 minutes of reaction. This o i l had a U.V. absorption maximum at 327 nm., that corresponds to a dihydropyridine. This was confirmed by mass spectroscopy, since t h i s o i l has a parent peak at 123 that corresponds to a molecular formula of CgH^N. The compound is o l a t e d i n the reduction reaction was i d e n t i f i e d as N^methyl-3-ethyl-l,2-dihydropyridine (46) based on the NMR spectrum (Figure 7) and double resonance studies. As can be seen i n the Figure, the NMR resembles the spectrum of N-carbomethoxy-3-ethyl-l,2-dihydropyridine (4_9_) , with the difference that the signals for H2 and Hg are higher f i e l d , which i s to be expected when going from an N-carbomethoxy to an N-methyl group. Further con-firmation of compound 4_6*s structure was obtained when N-carbomethoxy-3-ethyl-l,2-dihydropyridine was treated with 73 LiAlH^ to y i e l d a compound that has the same spectroscopic properties as compound 4j6 (see Diagram 46) . It i s i n t e r e s t i n g to note that the 1,2- and 1,6-dihydropyridine chromium complexes have the same fragmentation pattern as the N-methyl-3-ethyl-l,2-dihydropyridine, once the elements of Cr(CO)^ have been eliminated i n the i o n i z a t i o n chamber (Diagram 46). Knowing that the reduction of N-methyl-3-ethyl-pyridinium iodide with NaBH4 yielded only the 1,2-dihydropyridine isomer, i t was NMR spectrum of N-methyl-3-ethyl-l,2-dihydropyridine (46) (C 6D 6) - 84 -DIAGRAM 46 Mass Fragmentation Pattern of N-Methyl-3-ethyl-1,2-dihydropyridine and Its Chromium Complex m/e =107 u _ , 3 m/e = 94 - 85 -obvious that the isomerization to the 1,6-derivative was occurring only during the complexation reaction. This reaction was repeated several times and i t was observed that the r a t i o of the two isomers was not constant. This indicated that the degree of isomerization must depend on some experimental conditions that were not properly c o n t r o l l e d . When a solution of the 1,2- or 1,6- dihydropyridine chromium complex i n cyclohexane was refluxed under i n e r t atmosphere, a 1:1 mixture of the two isomers was obtained. The thermal isomerization was followed by NMR ( i t e r a t i v e integration of the t r i p l e t at 4.98 due to of the 1,2 isomer, and the t r i p l e t at 3.98 for of the 1,6-derivative), and i t was observed that the 1:1 r a t i o i s obtained a f t e r r e f l u x i n g the solution for 7 hours. Using t h i s thermal isomerization of the chromium complexes, the r a t i o of isomer obtained i n the complexation reaction becomes a minor problem since, independently of which of the isomers predominates, i t can always be converted into a 1:1 mixture. The two chromium complexes decompose very slowly on exposure to a i r at room temperature (up to two weeks for t o t a l decomposition). They are soluble i n most organic solvents but i n pyridine or DMSO, they decompose very r a p i d l y . The - 86 -same thing happens only to the 1,2-dihydropyridine complex when i t i s dissolved i n halogenated solvents. They are very stable to basic media, decomposing rapidly i n a c i d i c ones. The dihydropyridine complexes do not react with NaBH^ or sodium hydride, which are the reagents used i n one 5 8 of the methods for preparing a c r y l i c esters Once the preparation of the dihydropyridine chromium complexes was achieved and their' chemical and physical properties were known, the studies related to the l i b e r a t i o n of the dihydro-pyridine from the complexes were i n i t i a t e d . There are two general methods for disengagement of organic 97 ligands from metal complexes : 1) oxidation of the complex or 2) substitution of the ligand for another one. For the dihydropyridine complexes, the f i r s t method has the disadvan-tage that the oxidant used for the metal w i l l also oxidize the free dihydropyridine. The second method w i l l not destroy i t although the p o s s i b i l i t y exists that the dihydropyridine w i l l isomerize whilst being freed. When the (N-methyl-3-ethyl- 1, 2-dihydropyridine) t r i s c a r b o n y l chromium complex was treated with triphenylphosphine or triphenylphosphite i n cyclohexane, i t was recovered i n t a c t after 24 hours of s t i r r i n g at room temperature. When more - 87 -vigorous conditions were used (reflux), a 1:1 mixture of the two isomeric complexes was obtained. The U.V. spectrum of the reaction mixture did not show any absorption for the free dihydropyridine (327 nm.). However, when t h i s complex was treated with pyridine i n cyclohexane or N-pentane under nitrogen atmosphere, an orange compound pre c i p i t a t e d out of the solution. After four hours of reaction the U.V. spectrum of the reaction mixture showed that some dihydropyridine was being liberated but a f a i r amount of s t a r t i n g material (400 nm.) was s t i l l present. Afte r 24 hours of reaction the s t a r t i n g chromium complex was completely consumed. At t h i s time, the reaction mixture was f i l t e r e d and the solvent evaporated under reduced pressure, y i e l d i n g an o i l that, by NMR, was i d e n t i c a l to N-methyl-3-ethyl-l,2-dihydropyridine ( 4 6 ), without contamination of any other compound except for some pyridine. When the corresponding 1,6-dihydropyridine chromium complex was treated with pyridine i n the manner described, N-methyl-3-ethy 1-1,6-dihydropyridine (5_1) was obtained i n high y i e l d . This compound has a U.V. maximum at 332 nm.; the NMR (Figure 8) shows the t r i p l e t and quartet of the e t h y l group at 1.02 and 1.98 respectively; the N-methyl group appears as a s i n g l e t at 1.98. Based on s p l i t t i n g patterns of the signals as well as on double resonance studies, the r e s t of the 8 annoi^ - 89 -s i g n a l s were assig n e d as f o l l o w s : the doublet a t 3.50 (J = 4Hz) corresponds to Hg g,; appears as a d o u b l e t of t r i p l e t s a t 5.18 ( J 4 5 = 8Hz, J 5 g = 4Hz); the s i g n a l s f o r H 2 and H^ are shown as a broad s i n g l e t and a d o u b l e t (J = 8Hz) a t 5.52 and 5.58, r e s p e c t i v e l y . Once the necessary methodology f o r p r e p a r i n g and h a n d l i n g u n s t a b l e d i h y d r o p y r i d i n e s was known and, g i v e n the s c a t t e r e d i n f o r m a t i o n of the r e a c t i o n s of t h i s type of compounds, i t was important to study some of t h e i r chemical p r o p e r t i e s , e s p e c i a l l y those r e a c t i o n s t h a t supposedly occur w i t h dehydro-secodine (1_) d u r i n g the b i o s y n t h e s i s of i n d o l e a l k a l o i d s . Attempts to a l k y l a t e N - m e t h y l - 3 - e t h y l - l , 2 - d i h y d r o p y r i d i n e w i t h a l l y l or b e n z y l bromide i n benzene, f o l l o w e d by r e d u c t i v e work up (NaBH^), y i e l d e d v e r y complex r e a c t i o n m i x t u r e s t h a t c o u l d not be separated. One reason t h a t so many prod u c t s were encountered i n these r e a c t i o n s i s t h a t the iminium s a l t (52) i n i t i a l l y produced on a l k y l a t i o n (see Diagram 47) i s i t s e l f an e l e c t r o p h i l e , capable of a l k y l a t i n g another d i h y d r o -p y r i d i n e . M o d i f i c a t i o n of the r e a c t i o n c o n d i t i o n s such as a d d i t i o n of a d i l u t e d s o l u t i o n of d i h y d r o p y r i d i n e to a l a r g e excess of b e n z y l bromide, d i d not improve the r e s u l t s o f the a l k y l a t i o n r e a c t i o n . In order to e l i m i n a t e a l l u n d e s i r e d products i t i s necessary - 90 -f ) to trap the iminium s a l t formed upon a l k y l a t i o n before i t has a chance to react further. A sim i l a r system to the one used for the reduction of pyridinium s a l t s to tetrahydro-pyridines could be used, where a large excess of NaBH^ i s added to the reaction mixture i n order to reduce the pyridinium s a l t as well as the iminium s a l t produced by protonation of the re s u l t i n g dihydropyridine (see Diagram 37). If these conditions were to be used there i s a p o s s i b i l i t y of competition between al k y l a t i o n versus protonation of the reactive diene-amine system. However t h i s l a s t process can be reduced i f a large excess of al k y l a t i n g reagent (benzyl bromide) and a two-phase system (ether - water) i s used, given that the dihydropyridine w i l l be present primarily i n the organic phase, that i s where the benzyl bromide i s dissolved. Furthermore the same conditions (benzyl bromide added) used for the generation of dihydropyridines can be u t i l i z e d (two-phase system consisting of aqueous sodium hydroxide, methanol, ether and NaBH4 to which the pyridinium s a l t i s added), eliminating the need for the i s o l a t i o n of these intermediates since the following sequence of events takes place (Diagram 47): 1. The pyridinium s a l t (4_1) enters the aqueous layer and i s reduced to the corresponding dihydropyridine which i s transferred to the organic layer. 2. The dihydropyridine i s alkylated to give a water-soluble iminium s a l t (5_2) which leaves the ether layer. - 91 -3. In the water layer the s a l t 5_2 i s reduced with borohydride, afte r which the tetrahydropyridine 54_ thus formed i s extracted into the ether. 4. The tetrahydropyridine 5_4 w i l l either remain i n the upper phase or be alkylated a second time with the remaining benzyl bromide to form a water soluble quaternary ammonium s a l t (53_) which i s then transferred to the lower aqueous phase. When N-methyl-3-ethyl-pyridinium iodide was added to the two-phase system mentioned (ten-fold excess of benzyl bromide) a salt-type material (5_3) was isola t e d a f t e r three hours of reaction from the aqueous layer. This compound came from the 3-ethyl pyridine system since the ethyl chain could be recognized very e a s i l y in the NMR spectrum. Moreover, the presence of an o l e f i n i c proton at 5.71 and two sets of aromatic protons at 7.2 6 and 7.41 suggested a doubly benzylated t e t r a -hydropyridine. The presence of a s i n g l e t at 4.53 for two hydrogens, as well as a downfield N-methyl signal (3.08) was the reason for a l l o c a t i n g one of the benzyls to the nitrogen, forming a quaternary ammonium s a l t with the methyl group. When the s a l t material obtained i n the reaction described 9 8 was treated with lithium propyl mercaptide in HMPA a - 92 -DIAGRAM 47 Alky l a t i o n of N-methyl-3-ethyl-l,2-dihydropyridine Ether layer • ( i : H 3 C H 3 k 5 2 | X 1 c 1 : H 3 c h 3 1 c 1 c 4 Water r layer i 1 c 5 ( H 3 CH 3 N 1 C , 1 H 3 C H 3 r N 1 Cl 5 J 1 CH 3 1 5 j R = f^CHg-£ R=H - 93 -s e l e c t i v e N-debenzylation took place y i e l d i n g an N-methyl tetrahydropyridine with a benzyl group s t i l l attached to the ring . If dihydropyridines behaved as normal diene-amines a B-benzylation should take place which, afte r reduction, would give compound 5_4_ (Diagram 47) but, being a homoannular system i t may happen that a 6-attack i s preferred, in which case tetrahydropyridine 5_5 (Diagram 47) w i l l be formed. The fact that the compound obtained i n the debenzylation reaction shows only one o l e f i n i c proton i n the NMR, rules out the p o s s i b i l i t y of a 6-attack, i n which case two o l e f i n i c hydrogens should be present. When the al k y l a t i o n reaction was done using only a two-fold excess of benzyl bromide a mixture of N-methyl -3-ethyl -5-benzyl-1,2 , 5 , 6-tetrahydropyridine (5_4; 10%) and i t s correspond-ing N-benzylated s a l t 5_3 (R = 0CH2~; 20%) was obtained, plus a second quaternary ammonium s a l t that was i d e n t i f i e d as N-methyl-N-benzyl-4-ethyl-l,2,5,6-tetrahydro pyridinium s a l t ( 53, R = H; 50%), by d i r e c t comparison with an authentic sample obtained from the reaction between the tetrahydro-pyridine 4J7 and benzyl bromide. The y i e l d of s a l t 5_3 (R = H) could be as high as 80% i f a less reactive a l k y l a t i n g reagent - 94 -(benzyl chloride) was used. It can be argued that the p o s s i b i l i t y of a 6-attack on the diene-amine system cannot be ruled out completely under the circumstances that i n the p a r t i c u l a r model system used (N-methyl-3-ethyl), there i s a substituent i n that same pos i t i o n i n h i b i t i n g (for, s t e r i c reasons) the chance of such an al k y l a t i o n . To observe the influence that a substituent at the a l k y l a t i o n s i t e could have on the a l k y l a t i o n of dihydropyridines, the reaction was repeated, using N-methyl-3,5 - lutidinium iodide (56). In t h i s case the only product i s o l a t e d from the reaction mixture was N-methyl-3-5-dimethyl-5-benzyl-l,2,5,6-tetrahydro-pyridine (57_ in Diagram 48) i n about the same y i e l d (48%) as the previous a l k y l a t i o n reaction. The method described for the a l k y l a t i o n of dihydropyridines y i e l d s very clean, easy to work-up reaction mixtures, demon-str a t i n g that t h i s type of system i s . a l k y l a t e d in the 0 position even i f there i s an a l k y l substituent at that . . 99 position . . A l l t h i s indicates that the homoannularity of diene-amine does not induce abnormal behaviour for the al k y l a t i o n of t h i s f u n c t i o n a l i t y . - 95 -DIAGRAM 48 Alky l a t i o n of N-3,5-Trimethyl-l,2-dihydropyridine 56 Some preliminary work on the Diels-Alder reaction of Dihydro-pyridines with a c r y l i c derivatives was done by Dr. Greenhouse. He found that when N-methyl-3-ethyl-l,2-dihydropyridine was refluxed in the acrytonitrile the predominant product obtained was a 1:2 adduct of the dihydropyridine with two molecules of a c r y l o n i t r i l e . Small amounts of a 1:1 adduct that could correspond to the Diels-Alder product were also i s o l a t e d . Neither of these two products were f u l l y characterized since i t was decided at t h i s time to put aside the model system and continue with the research related to the synthesis of dehydrosecodine. The next problem was to see i f an indole side chain in the pyridine r i n g , interfered with the complexation reaction. To resolve t h i s , N-tryptophyl-3-ethyl-pyridinium bromide (58) , prepared from 3-ethyl-pyridine and tryptophyl bromide"*"^ - 96 -was reduced with NaBH^ in the same manner as the model compound. The UV spectrum of the ether layer a f t e r f i v e minutes of reaction showed a maximum at 336 nm. that corresponded to the dihydropyridine, as well as the t y p i c a l signals for the indole system (290, 283 and 220 nm.). When t h i s ether solution was added to the dry t r i s a c e t o n i t r i l e t r i c a r b o n y l chromium(0) complex, a red gum was i s o l a t e d i n 20% y i e l d , by preparative TLC. This gum had UV (402,290,283 and 220 nm.), IR (1945, 1865 and 1830 cm - 1) and MS spectra (388 (M+) for ('20H20N2<^>3<"r^ t h a t were consistant for (N-tryptophyl-dihydro-pyridine)tricarbonylchromium complex. Although t h i s compound showed only one spot by TLC, the NMR spectrum indicated that i t consisted of a mixture of the two dihydropyridine isomers. Separation of the two isomers was achieved by preparative TLC using a solvent mixture of low p o l a r i t y and r e p e t i t i v e developments at the cost of losing a l o t of the material, due to sample decomposition. By NMR (Figure 9) the less polar dihydropyridine complex (59) of the N-tryptophyl series was i d e n t i f i e d as the 1,6-isomer since i t presented the same signal pattern between 6 3 and 5 for the protons at 2, 4 and 5 of the pyridine r i n g as the same isomer (4_3) of the N-methyl series (compare Figures 2 and 9) . As in t h i s l a s t compound, compound 5_9 also presented FIGURE 9 i i i i i i i i i i I J ^ I i i i I i i i i I i i i i I TTT 1 1 1 1 1 T 1 1 1 i i i i i n i i i i i i i i i i i i i i i i i i i i i i i i i i i i i i i ,i i i i i i i NMR spectrum of (N-tryptophyl-3-ethyl-l,6-dihydropyridine) tricarbonyl-chromium(O) complex (59) - 98 -a complex pattern for the two hydrogens at p o s i t i o n 6 and the methylene of the ethyl side chain, that was even more d i f f i c u l t to recognize because of the presence of signals for the ethylene part of the tryptophyl group. The NMR spectrum of the (N-tryptophyl-3-ethyl-l,2-dihydro-pyridine) tricarbonylchromium complex (6_0) (Figure 10). shows some d i s s i m i l a r i t i e s when compared with the spectrum of the 1,2-dihydropyridine complex (4_4) obtained from the N-methyl pyridinium s a l t . These differences are: 1. H2 and are no longer "accidentally equivalent" as with the N-methyl derivatives; they appear now as a di s t o r t e d t r i p l e t at 4.68. 2. The AB quartet present i n the N-methyl series for the two protons at p o s i t i o n 2 of the pyridine ri n g , becomes a broad s i n g l e t at. 2.68 in the N-tryptophyl de r i v a t i v e . This l a s t change i s an indica t i o n that the conformation of the tryptophyl moeity of t h i s complex i s such that the indole part, together with the chromium, forms a type of "sandwich" with the dihydropyridine located between the two parts. The same phenomenum must occur with the N-FIGURE 10 NMR spectrum of (N-tryptophyl-3-ethyl-l, 2-dihydropyridine) tricarbonyl-chromium(0) complex (60) - 100 -tryptophyl-1,6-dihydropyridine chromium complex, although the evidence i s not as clear as i n the case just discussed. The r e s u l t s obtained up to now answer p o s i t i v e l y a l l the questions related to the use of the chromium complexes as a method for traping and protecting dihydropyridines. In spite of not having optimized the complexation reactions, i t was decided to move on to the synthesis of dehydrosecodine, as outlined i n Diagram 43 (route b), and t r y to increase the y i e l d of the complexation reaction i n t h i s series. In order to obtain the pyridinium s a l t 3_6, the i n d o l y l chloride 6_5 (Diagram 49) or tosylate 6_7 must be prepared. There are several methods reported i n the literature"'"^"''' ^ ~®2 for the preparation of t h i s type of compounds, however the one 103 reported by Wenkert i s the most convenient because i t i s a high y i e l d i n g sequence of reactions (Diagram 49) that can e a s i l y be scaled up without too many complications. The required s t a r t i n g material (2-carboxytryptophol lactone 61) used for the synthesis of chloride 65_, was prepared from 104 6-butyrolactone following the work reported by Plieninger The lactone 6_1 was opened with dimethylamine i n methanol at room temperature to give the corresponding carboxyamido-tryptophol derivative 6_2. By reduction of t h i s amide - 101 -DIAGRAM 49 Scheme f o r t h e S y n t h e s i s o f 2 - C a r b o m e t h o x y -m e t h y l t r y p t o p h y l C h l o r i d e (65) 0 6Z R =OTs - 102 -with LiAlH^, followed by treatment with methyl iodide, the quaternary ammonium s a l t 6^ was obtained i n 67% o v e r a l l y i e l d from lactone 6_1. Reaction of the methiodide 6_3 with potassium cyanide i n reflux i n g a c e t o n i t r i l e gave a high y i e l d (90%) of the n i t r i l e 6_4. Treatment of t h i s material with a saturated solution of hydrogen chloride i n methanol converts the n i t r i l e f u n c t i o n a l i t y into a carbomethoxy group and the alcohol into the chloride 65_, afte r s t i r r i n g the solution at room temperature for three days. To t r y to speed up t h i s reaction the solution was heated, but t h i s resulted i n a mixture of compounds 65_ and 66. Condensation of 6_5 at 80°C with 3-ethyl pyridine gave the corresponding N-tryptophyl pyridinium s a l t 3_6, i s o l a t e d as the perchlorate s a l t a f t e r a quick p u r i f i c a t i o n by column chromatography (Alumina grade V) . Salt 3_6 can also be obtained from the spiro-compound 6_6 and a mixture of 3-ethyl pyridine and i t s hydrochloride s a l t . In t h i s case, the hydrogen chloride present i n the reaction mixture opens the cyclopropyl r i n g to y i e l d the tryptophyl derivative 65, which then reacts with the pyridine to form the s a l t . Before proceeding with the sequence of reactions portrayed in Diagram 43, some studies had to be done i n r e l a t i o n to the - 103 -reaction conditions to be used for the generation of the dihydropyridine 3_7 (Diagram 43) since there were l i t e r a t u r e precedents'*"^ that established that similar pyridinium s a l t s under mild a l k a l i n e conditions (NaHCO^) form dihydropyridines v i a an intramolecular condensation (Diagram 50). DIAGRAM 50 Intramolecular Condensation of N-(2-cyanomethyl-tryptophyl) pyridinium The p o s s i b i l i t y of a similar condensation to the one just described had to be studied for the pyridinium derivative 36_ because in the two-phase system used for the generation of the dihydropyridine, strong a l k a l i n e conditions are employed i n order to prevent the formation of tetrahydropyridines. The U.V. spectrum of the pyridinium s a l t 36_ shows the absorption maxima corresponding to the indole moiety (219, 280 and 289 nm.) plus the absorption for the pyridinium part - 104 -at 265 nm. Upon a d d i t i o n of a 2N s o l u t i o n of sodium hydroxide to the U.V. c e l l , the spectrum remained unchanged even a f t e r a p e r i o d of 30 minutes. However, when some c r y s t a l s of NaBH^ were added, the maximum due to the p y r i d i n i u m segment disappeared i n about ten minutes and a new a b s o r p t i o n a t 327 nm. ( d i h y d r o p y r i d i n e ) was then observed. T h i s q u a l i t a t i v e experiment q u i c k l y g i v e s an i n d i c a t i o n t h a t , i f the i n t r a m o l e c u l a r condensation takes p l a c e , i t occurs a t a slower r a t e than the r e d u c t i o n of the p y r i d i n i u m system. With t h i s i n f o r m a t i o n on hand a complexation experiment was set using the two-phase system f o r the g e n e r a t i o n of the d i h y d r o p y r i d i n e and then the normal procedure f o r the formation of the chromium complexes. The r e s u l t s o b t a i n e d were not very good s i n c e , b e s i d e s the expected red c o l o u r e d compounds, the TLC showed s e v e r a l spots as w e l l as a f a i r amount of base l i n e m a t e r i a l . The p u r i f i c a t i o n of the r e a c t i o n mixture was aimed at the i s o l a t i o n of the d i h y d r o -p y r i d i n e complexes o n l y . A f t e r s e v e r a l s e p a r a t i o n s by column chromatography and p r e p a r a t i v e TLC, a few m i l l i g r a m s of the d e s i r e d red m a t e r i a l were i s o l a t e d . The NMR spectrum of t h i s m a t e r i a l was complex, i n d i c a t i n g a mixture of a t l e a s t two i s o m e r i c d i h y d r o p y r i d i n e complexes. The IR and low r e s o l u t i o n mass s p e c t r a were c o n s i s t a n t with the d e s i r e d type of d i h y d r o p y r i d i n e chromium complexes. - 105 -Several modifications to the complexation technique were t r i e d with e s s e n t i a l l y the same r e s u l t s . The mixture of dihydropyridine complexes is o l a t e d from a l l these experiments were combined and the separation of the two isomers was done using preparative TLC. As i n the case of the N-tryptophyl dihydropyridine series, there was severe decomposition of the sample and no clean separation of the complexes was achieved. S t i l l , the less polar component of the mixture was pure enough to i d e n t i f y i t as the 1,6-dihydropyridine complex (4_0 in Diagram 43) based on the c h a r a c t e r i s t i c s p l i t t i n g pattern that t h i s kind of isomer presents i n the NMR spectrum: doublet and a s i n g l e t i n the region between 6 4.5 and 5.00 for the hydrogen at position 2 and 4 and a t r i p l e t around 4.2 for the hydrogen at 5. The U.V. spectrum of the other red compound is o l a t e d from the mixture had the indole absorption, plus one at 401 nm. that corresponded to a dihydropyridine chromium complex. It was assumed that t h i s complex had the 1,2-dihydropyridine as ligand (39, Diagram 43) although a p o s i t i v e i d e n t i f i c a t i o n could not be done due to the small amount is o l a t e d (less than 2 mg.). The low y i e l d obtained i n the complexation reaction, consider-ing that the a c r y l i c segment s t i l l had to be b u i l t , was one of the reasons for which the synthetic scheme was changed. The new scheme chosen was a combination of the one outlined - 106 -in Diagram 42 and the one followed up to now, that i s , hal f construction of the a c r y l i c ester (34) moiety followed by the preparation o f the dihydropyridine chromium complexes and f i n a l l y formation of the a c r y l i c ester and l i b e r a t i o n of the dihydropyridine from the chromium complex. These l a s t two reactions could be done stepwise or perhaps be performed at the same time. In t h i s way, even.if the complexation reaction y i e l d i s s t i l l low i t i s almost at the end of the synthesis (Diagram 51). DIAGRAM 51 Scheme "C" for the Synthesis of 14,21-Dehydrosecodine (1) - 107 -For t h i s new approach to the synthesis of 14,21-dehydro-secodine i t was necessary to answer two questions: 1. Which substrate i s the most appropriate to do the homologation reaction of the acetic ester derivative (introduction of a -CI^-X unit, r e f e r to Diagram 24, route A), and 2. What kind of building unit (nature of X) was most useful for the p a r t i a l synthesis of the a c r y l i c ester. From the compounds already synthesized, three of them could be u t i l i z e d as substrates for the homologation: 2-cyano-methyl tryptophol (64_) , 2-carbomethoxymethyl tryptophyl chloride (65) , and the pyridinium s a l t 3_6. This l a s t compound was disregarded because of s o l u b i l i t y problems. The possible use of the chloro-ester 65_ was also eliminated 102 because previous experience with t h i s compound has shown that under strong basic conditions i t i s converted into the spiro-cyclopropyl-indole derivative 66. The cyano derivative 6j4, besides the active methylene group, has two ac i d i c hydrogens (^ NH, -OH) that perhaps could i n t e r f e r e with the homologation reaction. To eliminate t h i s p o s s i b i l i t y , these two positions were protected as the benzyl - 108 -derivatives, as shown i n Diagram 52. When the indole lactone 6_1 was treated with potassium hydride in HMPA, the N-benzyl derivative 6_8 was obtained i n 70% y i e l d a f t e r p u r i f i c a t i o n by column chromatography. Opening the lactone with dimethylamine yielded the amide 6_9, which, upon treatment with benzyl bromide i n the same conditions mentioned before, gave the dibenzyl amide 7Q_. This compound can also be obtained from N,N-dimethyl-2-carboxamido-tryptophol (62 in Diagram 49) using two equivalents of potassium hydride and benzyl bromide, however, the product obtained i n t h i s way i s not as pure as when the method described e a r l i e r i s employed. DIAGRAM 52 Synthesis of (N-Benzyl-2-carbomethoxymethyl-indolyl)-benzyl Ether (72) - 109 -Treatment of compound 70^  with LiAlH^ followed by d i r e c t treatment, without p u r i f i c a t i o n , of the r e s u l t i n g dimethyl amine derivative (7_3 i n Diagram 53) , with a large excess of methyl iodide gave the corresponding methiodide s a l t i n only 40% y i e l d . Reaction of t h i s s a l t with potassium cyanide in r e f l u x i n g a c e t o n i t r i l e gave a high y i e l d of the n i t r i l e 71_ which was solvolysed to the methyl ester 7_2 in 70% y i e l d . Reinvestigation of reduction of the amide group with LiAlH^ indicated that a mixture of two compounds was obtained possessing the same p o l a r i t y on the TLC plate. One of them reacted with methyl iodide to give the methiodide s a l t previously described but the other remained i n the reaction mixture. After removal of the s a l t , t h i s compound was iso l a t e d and i d e n t i f i e d as (N-benzyl-2-carbinol-tryptophyl)-benzyl ether 7_4 (Diagram 53). Contrary to what happened in the reduction of the amide 6_2 (Diagram 49) , that yielded only the amine derivative, the amide in 7^0_ was reduced to the corresponding alcohol and amine. These two compounds were separated by preparative TLC and f u l l y characterized. By i t e r a t i v e integration of the NMR spectrum signals for the methylene of the benzyl groups attached to the indole nitrogen, i t was found that the alcohol 7_4 was the predominant product of t h i s reduction reaction by a r a t i o of 6:1. - 110 -DIAGRAM 53 Reduction of 2-N,N-Dimethylcarboxamidoindole Derivatives with LiAlH. 70 R = CH2<£ 7_3 R=CH2</> R' = N ( C H ^ 69_ R=H T4 . R = CH2^ > R' = 0H 75 R=H R' = N(CH 3) 2 76 R' = CH2^ R' = H O x o R N(CH3)2 R N(CH 3) 2 77 R=H or CH <f> 78 0 N(Et)2 7_a SQ R = N(Et)2 81 R = OH - I l l -It has been reported in the l i t e r a t u r e that the reduction of amideswith LiAlH^ p r e f e r e n t i a l l y y i e l d s the corresponding amine but, depending on s t e r i c and e l e c t r o n i c factors, as well as on the nature of the reducing agent, the alcohol or a mixture of t h i s and the amine, i s obtained instead. For the case under discussion, there i s an amide that behaves normally (6_2) but when the hydroxy group and the nitrogen of the indole of t h i s molecule are benzylated (70) , the amide f u n c t i o n a l i t y behaves d i f f e r e n t l y . Of the two modifications done with compound 6_2_ the one most l i k e l y to be responsible for the abnormal behaviour of the amide group in 70, i s the one that a f f e c t s the indole nucleus (N-benzyl-ation) . If t h i s assumption i s correct the amide 6_9 (Diagram 53) would give a mixture of alcohol and amine. Treatment of t h i s amide in the same manner as the two previous compounds resulted in a high y i e l d conversion to the amine 7_5 exclusively. With a l l these r e s u l t s on hand i t was clear, although not understood, that what was a f f e c t i n g the reduction of the amide was whether a free alcohol was present i n the molecule or not. It was r e a l i z e d that i f the free alcohol was present i t would react very rapidly with LiAlH^ forming an aluminate derivative that could be considered as changing the nature of the reducing agent, reacting with the amide group i n an i n t e r - or intra-molecular fashion. If t h i s i s what r e a l l y - 112 -occurs i n the reduction of t h i s type of amides, then there i s a p o s s i b i l i t y that when the dibenzylated amide 70^  i s treated with a s i m i l a r type of reducing agent, the dibenzylated amine 73 w i l l be formed p r e f e r e n t i a l l y . When 7_0 was added to a solution of LiAlH^ i n anhydrous THF, previously treated with one equivalent of n-butanol, a mixture of alcohol 7_4 and the amine 7_3 was again obtained but now, t h i s l a s t compound was the predominant one by an 3:1 r a t i o . To complete the studies of the reduction of t h i s type of amide i t was necessary to prepare a derivative of 6_2 (Diagram 42 ) where the nitrogen of the indole i s free and the alcohol i s protected as the benzyl ether (2-(N,N-dimethyl carboxamido)-tryptophyl-benzyl ether). This compound was more d i f f i c u l t to synthesize than expected, since when 6_2 was treated with only one equivalent of benzyl bromide in basic conditions, the N-benzyl, free alcohol, dimethyl amide (59_ was formed exclusively. No other type of approach for the preparation of the desired benzyl ether was attempted and the synthesis of t h i s compound was eventually abandoned. Searching for another amide that would f a i l to give the normal reduction product, i t was thought that perhaps compound 7_7 would give a mixture of alcohol and amine, when treated with LiAlH^. However, t h i s was not the case, since i n both series - 113 -(R = H or. R = benzyl) , the N,N-dimethyl amine 78_ was the only product i s o l a t e d from the reaction mixture. The only t e r t i a r y amide that has been reported in the l i t e r a t u r e that has an abnormal behaviour when reduced with t h i s type of 107 hydride i s the N,N-diethylbenzamide (79_) that y i e l d s a 1:1 mixture of benzyl alcohol (8.1) and diethylbenzyl amine (80) . This amide was converted exclusively to the amine 8_0 when treated with LiAlH^-n-BuOH (one equivalent) in the same conditions. A type of amide (7_0)was accidentally found that has very peculiar chemical properties, not only in the reduction with LiAlH 4 but also when i t i s reduced with diborane 1^^. In t h i s case a mixture of the dimethyl amine derivative 73_ and the f u l l y reduced product 7_6 was obtained in a 3:1 r a t i o . Once the problem in the reduction of amide 7_0 was solved, the y i e l d in the formation of the amine 73-methiodide s a l t was increased up to 80%, just by treating the crude product from the reduction with an excess of methyl iodide. Attempts to incorporate the reduction by-product, alcohol 74, into the synthesis of the dibenzyl n i t r i l e 71. by treating the corresponding benzoate or p-bitrobenzoate with potassium cyanide f a i l e d , mainly due to the formation of - 114 -several reaction products that made t h i s approach unattractive Coming back to the o r i g i n a l problem of forming a p a r t i a l l y synthesized a c r y l i c ester, two methods were studied where the ester 7_2 was used as the substrate, instead of the n i t r i l e 71, as o r i g i n a l l y planned. The f i r s t method was the synthesi of the enamine 8_5 (Diagram 54) which could be converted to a protected a c r y l i c ester-type substance, upon reduction with cyanoborohydride, to the corresponding amine, or i t could remain as such and be transformed into the a c r y l i c ester segment, once the chromium complexes were formed. The other method investigated was the formylation of 72_ to form the enol 87_. In t h i s case the enol f u n c t i o n a l i t y must remain as such and be protected as methyl enol ether (or some other type of protection), because: 1. the free enol i s reduced with NaBH^ and t h i s w i l l i n t e r -fere with the reduction of the pyridinium s a l t ; 2. the reduction of the enol to the corresponding alcohol w i l l i n t e r f e r e with the formation of the pyridinium s a l t since, once the benzyl groups are removed, a molecule with two primary alcohols w i l l be obtained and i t w i l l be d i f f i c u l t to functionalize only one of them. - 115 -DIAGRAM 54 Homologation Reactions i n Acetic Ester Derivatives 82 83 84 C0 2 CH 3 ^ C 0 z C H 3 ^ C 0 Z C H 3 8§ X=(Z)N(CH 3 ) 2 83 X=R=0H 86 X=H 8 9 X = ( Z ) 0 C H 3 R = 0H 87 X=0H 90X=(Z )0CH 3 R = OTs 91 X =(E)0CH 3 R=0H 9 2 X =(E)0CH 3 R = OTs 93 X =(EJ0CH3 R = - 116 -In the l i t e r a t u r e i t was reported that active methylene could be transformed into enamine derivatives when treated with the complex formed between dimethyl formamide and dimethyl 10 8 sulphate (DMF-DMS complex), under strongly basic conditions To check i f t h i s method could be used for the preparation of the enamine 8_5, the methyl ester of 2-phenyl-acetic acid (82) was chosen as the model compound. When 8_2 was treated f i r s t with lithium or potassium di-isopropyl amide and l a t e r with the DMF-DMS complex, the enamine 8_3 was formed i n high y i e l d . Treatment of t h i s compound with sodium cyanoborohydride under s l i g h t l y a c i d i c conditions, gave the dimethyl amine deriv a t i v e which, once converted into the corresponding methiodide, was treated with sodium bicarbonate to y i e l d methyl atropate (84) in almost quantitative y i e l d . When the methyl ester 72_ (Diagram 52) was treated with the DMF-DMS complex i n the manner described i n the previous paragraph, enamine 8_5 was formed i n 30% y i e l d (78% based on 123 recovered s t a r t i n g material ). The v i n y l i c hydrogen of the compound 8_5 enamine system was at 109 7.71, which compares very c l o s e l y to the reported value (7.69) for the (Z)-configuration of a very si m i l a r compound: methyl (Z)-2(2-(3-methyl)indolyl)-3-N,N-dimethylaminoacrylate The v i n y l i c proton for the (E) isomer of t h i s derivative appears at 6 7.9. - 117 -Treatment of 8_5 with cyanoborohydride gave a mixture of two compounds that had very d i f f e r e n t Rf values by TLC. The most polar compound was d i f f i c u l t to i s o l a t e i n a pure form since, on standing at room temperature, i t i s converted into the other component present i n the reaction mixture. This l a s t substance was i d e n t i f i e d as the a c r y l i c ester 86, which was s u r p r i s i n g l y very stable. Once t h i s compound was f u l l y characterized i t was possible, from the NMR of the crude reaction mixture, to determine the structure of the polar component as the corresponding amine derivative (85 with no double bond i n the a c r y l i c segment), by subtracting the signals due to 8_6. This amine derivative spontaneously loses the elements of dimethyl amine to form the a c r y l i c derivative 86. The s t a b i l i t y observed i n 8_6 was the main factor for deciding to r e t a i n the N-benzyl group in the indole r i n g as t h i s would be b e n e f i c i a l during the synthesis of dehydrosecodine. The anion prepared from ester 7^2 and potassium d i - i s o p r o p y l -amide was allowed to react with methyl formate at room temper-ature to furnish the enol 8_7, which on hydrogenolysis gave 88. Methylation of t h i s compound with diazomethane produced a mixture of two methylated substances (89 and 91) i n a 2:1 - 118 -r a t i o , that were separated by preparative TLC. By calculations using the substituent c o e f f i c i e n t s for the chemical s h i f t of o l e f i n i c protons"*""^, the v i n y l i c proton i n the (Z)-isomer 8_9 was expected to be at higher f i e l d s (calculated value: 7.16) than the same proton i n the (E)-isomer (calculated value: 7.38). The minor component of the mixture was i d e n t i f i e d as the (Z)-isomer 8_9_, since the o l e f i n i c proton in t h i s product was at higher f i e l d (6.52) than i n the major component (7.69) to which an (E)-configur-ation was assigned. CONCLUSIONS Due to time l i m i t a t i o n s the synthesis of 14,21-dehydrosecodine was not completed, however, the following r e s u l t s obtained from the work presented here, provided a l t e r n a t i v e s and a basis for further research. 1. The dihydropyridine chromium complexes provided a good method for protecting t h i s sensitive type of substances. 2. The thermal isomerization of the dihydropyridine complexes, in conjunction with the mild method found for the l i b e r a t i o n of the dihydropyridine ligand, makes t h i s type of compounds syn t h e t i c a l l y useful because i t f a c i l i t a t e s the preparation of dihydropyridine isomers, which would otherwise be d i f f i c u l t to prepare. 3. Although the y i e l d s were from low to moderate, the complexation reaction took place when more elaborate dihydropyridines were used ( i . e . N-tryptophyl dihydro-pyridine d e r i v a t i v e s ) . 4. Based on the low y i e l d s obtained i n the complexation of the dihydropyridine 3_7 (Diagram 43) a new approach for the synthesis of 14,21 dehydrosecodine was begun (Diagram 51). Although the sequence of reactions outlined i n Diagram 51 was not finished, three important r e s u l t s were obtained: A) A method was found to correct the problem i n the LiAlH^ reduction of t e r t i a r y amides when they f a i l e d to give the corresponding amine. B) An e f f i c i e n t method for the preparation of a c r y l i c esters was found v i a the homologation of an acetic ester segment, using the complex formed between dimethyl formamide and dimethyl sulphate. C) Based on the remarkable s t a b i l i t y found for the 2-(N-benzyl-indolyl)-acrylic derivative 8_6 (Diagram 54), the goal of t h i s work has changed and i s now aimed at preparing the N-benzyl-14,21-dehydrosecodine, since the s t a b i l i t y added when the nitrogen of the indole r i n g i s protected w i l l help i n the synthesis and chemical behaviour studies of t h i s important b i o l o g i c a l intermediate. - 121 -EXPERIMENTAL Melting points were determined on a Kofler block and are uncorrected. U l t r a v i o l e t (UV) spectra were recorded on a Cary 15 spectrophotometer i n ethanol solution. The wave-lengths of absorption maxima are reported i n nanometers (nm) with log e values i n parentheses. Infrared (IR) spectra were measured on a Perkin Elmer model 710 or 457 spectro-photometer in chloroform solution. The absorption maxima are reported i n wavenumbers (cm "*") , c a l i b r a t e d with respect to the absorption band of polystyrene at 1601 cm Proton magnetic resonance (^ "Hmr) spectra were measured i n deutero-chloroform (CDCl^) solution at ambient temperature on either a Varian HA-100 or XL-100 spectrometer. Chemical s h i f t values are given i n the 6 (ppm) scale r e l a t i v e to t e t r a -methylsilane (TMS) used as i n t e r n a l standard. The integrated peak areas, signal m u l t i p l i c i t i e s and proton assignments are given i n parentheses. Low resolution mass spectra (MS) were determined on either an AEI-MS-902 or an Atlas CH-4B spectrometer. High resolution mass spectra were measured on an AEI-MS-902 instrument. Microanalyses were c a r r i e d out by Mr. P. Borda of the Microanalytical Laboratory, University of B r i t i s h Columbia. Thin-layer chromatography (TLC) u t i l i z e d Merck s i l i c a gel G - 122 -(according to Stahl) containing 2% fluorescent indicator. For preparative layer chromatography (PLC), plates (20 x 20 or 20 x 60 cm) of 1 mm thickness were used. V i s u a l i z a t i o n was effected by viewing under u l t r a v i o l e t l i g h t and/or by colour reaction with eerie sulphate spray reagent. Column chromatography u t i l i z e d Merck s i l i c a gel 60 (70-230 mesh) or Merck aluminum oxide 90 (neutral). As a matter of routine, a l l reagents and solvents were r e c r y s t a l l i z e d or d i s t i l l e d before use. A l l the indole derivatives were named as derived from tryptophol (2-(3-indolyl)-ethanol) following Wenkert's . 100,103 system A l l the work presented i n t h i s section was done by the author unless otherwise stated. N-Methyl-3-ethyl-pyridinium Iodide (41) (From Greenhouse's 1974 research report) 64 g of 3-ethylpyridine and 90 g of methyl iodide are each dissolved i n dry iso-propanol and then mixed at room temper-ature. The solution, protected from moisture, i s allowed - 123 " to stand at room temperature overnight. The alcohol i s removed under reduced pressure and the s o l i d residue washed well with ether to remove any excess methyl iodide. The s a l t i s then r e c r y s t a l l i z e d from acetone to give 130 g of the methiodide 41 i n 88% y i e l d ; mp: 91-92°C; UV X : — u max 219 (4.24), 266 (3.72); 1Hmr 6: 1.4 (3H, t, J= 7.5 Hz, -CH2CH3) , 3.00 (2H, q, J = 7.5 Hz, -CH_2CH3), 4.68 (3H, s, N-CH3), 8.15 (IH, dd, J = 6 Hz, J = 7 Hz, C(5)-H), 8.54 (IH, d, J = 7 Hz, C(4)-H), 9.2 (IH, d, J = 6 Hz, C(6)-H), 9.35 (IH, s, C(2)-H). Analysis calculated for CgH^NI: C 38.58, H 4.86, N 5.62; found: C 38.39, H 5.00, N 5.83. (N-Methyl-3-ethyl-l,2-dihydropyridine)tricarbonylchromium(0)  and (N-Methyl-3-ethyl-l,6-dihydropyridine)tricarbonylchromium(O)  Complexes (43 and 44) 91 1. Formation of trisacetonitriletricarbonylchromium(0) (42) : A solution of 15 g of Cr(CO) g i n 250 ml of f r e s h l y d i s t i l l e d a c e t o n i t r i l e i s refluxed under an i n e r t atmosphere for two to three days u n t i l no carbonyl absorption, due to st a r t i n g material, i s observed i n the IR spectrum (19 90 cm" 1). The excess a c e t o n i t r i l e i s eliminated under reduced pressure and the yellow p r e c i p i t a t e obtained i s immediately used i n the complexation reaction. IR v : 1940, 1895, 1835. Caution: XTlcLX • - 124 -i t has been reported that t h i s complex i g n i t e s on exposure to a i r . 2. Generation of N-methyl-3-ethyl-l,2-dihydropyridine (46) (From Greenhouse's report): To a mixture of 20 ml of a 2.1 N solution of sodium hydroxide i n water and 80 ml Et 2 0 , 2.5 g of NaBH^ were added. The mixture was vigorously s t i r r e d under a nitrogen atmosphere for 10 min and then a solution of 15 g of the methiodide 4_1 i n 20 ml of methanol was added. After 5 min of reaction, the aqueous layer was removed with a syringe and the ether solution was b r i e f l y washed with 10 ml of 2.1 N sodium hydroxide by vigorous s t i r r i n g . The water layer was removed and the ether layer dried under nitrogen on anhydrous sodium sulphate with a p e l l e t or two of sodium hydroxide added. The ether was f i l t e r e d and the drying agent washed well with ether. The combined ether solutions were evaporated at room temperature under reduced pressure to give 6.2 g of a nearly colourless o i l (82% y i e l d ) . UV X : 327; 1Hmr (C^D,) 6: 1.00 (3H, t, J = 7 Hz, -CH 2CH 3), 1.88 (2H, q, J = 7 Hz, -CH 2CH 3), 2.27 (3H, s, N-CH3), 3.58 (2H, s, C(2)-H 2), 4.74 (IH, dd, J = 7 Hz, J ca 7 Hz, C(5)-H), 5.73 (2H, m, superimposed doublets, one of them with J = 7 Hz, C(6)-H and C(4)-H); MS m/e: 67, 94, 96, 107, 108, 122 (100%), 123 (M +). High resolution - 125 -molecular weight determination, calculated for CgH-^N: . . . 123.1047; found: 123.1041. 3. Complexation reaction (from Zanarotti's report): The dihydropyridine obtained i n the previous experiment, was taken up i n 30 ml of benzene and added to the a c e t o n i t r i l e complex 4_2 prepared as described e a r l i e r , a l l t h i s under an in e r t atmosphere. The addition immediately produced a deep red coloured solution which did not show dihydropyridine absorption (* m a x = 327) a f t e r 30 min of s t i r r i n g at room temperature, but a maximum was observed at 400 nm. At t h i s time the TLC (benzene - hexane, 1:1) showed three coloured spots. The less polar one was yellow, decomposed very rapid l y on exposure to a i r , and was i d e n t i f i e d as the aceto-n i t r i l e complex. The other two spots were red and very close together. The complexation reaction mixture was concentrated to a small volume and chromatographed on s i l i c a gel (1.5 Kg). After the yellow band of the unreacted aceto-n i t r i l e chromium complex was eluted with a mixture of benzene-petroleum ether (1:1), 5.3 g of the two red compounds were eluted with benzene. A small portion of t h i s mixture (70 mg) was separated by preparative TLC (benzene - petroleum ether, 1:1; developed twice), y i e l d i n g 15 mg of the less polar component and 9 mg of the other one. This l a s t compound was - 126 " r e c r y s t a l l i z e d from benzene - hexane and i d e n t i f i e d as the (N-methyl-3-ethyl-l,2-dihydropyridine)tricarbonylchromium (0) complex (4_3) based on i t s spectroscopic properties. mp: 97-98°C; UV X : 403 (3.64); IR v : 1942, 1860, 1830; max max 1Hmr (CgDg) 6 : 0.70 (3H, t, J = 7 Hz, -CH2CH_3) , 1.45 (3H, s, N-CH_3), 1.60 (2H, q, J = 7 Hz, -CH 2CH 3), 2.34 (2H, AB system, J = 10 Hz, ((2)-H 2), . 4.50 (2H, br.d. J = 5 Hz, C(4)-H and C(6)-H), 5.00 (IH, t, J = 5 Hz, C(5)-H); MS m/e: 94, 107, 122 (100%), 123, 259 (M+) . Analysis calculated for C ^ H ^ N0 3Cr: C 50.90, H 5.05, N 5.40; found: C 51.04, H 4.95, N 5.46. The major component of the reaction mixture obtained in the complexation reaction was i d e n t i f i e d as a chromiumtricarbonyl complex but now possessed an N-methyl-3-ethyl-l,6-dihydro-pyridine as ligand (4_4) . R e c r y s t a l l i z a t i o n of 4_4_ from benzene-hexane gave red prisms that had mp: 68°C; UV ^ m a x ^ 399 (3.67); IR v : 1942, 1860, 1825; 1Hmr (C £D C) <5 : 1.12 (3H, t, J = max D o 7 Hz, -CH 2CH 3), 1.45 (3H, s, N-CH_3), 2.0-2.7 (4H, m, -CH2CH3 and C(6)-H_2), 3.09 (IH, di s t o r t e d t, J = 7 Hz, C(5)-H), 4.58 (IH, s, C(2)-H), 4.83 (IH, br.d. J = 7 Hz, C(4)-H); (CDC13) 6 : 1.40 (3H, t, J = 7 Hz, -CH2CH3) , 2.39 (3H, s, N-CH_3) , 2.73 (2H, m, -CH2CH3) , 3.7-3.45 (2H, m C(6)-H_2), 6.29 (IH, br.d. J = 7 Hz, C(4)-H), (5.40 (IH, hr.s. C(2)-H); MS m/e: 94, 107, - 127 -122 (100%), 123, 259 (M+) . Analysis calculated for C l l H 1 3 N 0 2 C r : C 5 0 - 9 0 ' H 5-°5, N 5.40; found: C 50.81, H 5.26, N 5.16. 4. Thermal isomerization of the dihydropyridine chromium complexes: 70 mg of a mixture of complexes 4_3 and 4_4 (this l a s t one being predominant) were dissolved i n 15 ml of cyclohexane and refluxed for 6 h under a nitrogen atmosphere. In t h i s manner a 1:1 r a t i o was obtained based on the integration of the signal in the NMR for the hydrogen at position 5 ((C^Dg) 5.01 in 4_3 and 3.02 for complex 44) . N-Methyl-3-ethyl-l,2,5,6-tetrahydropyridine (47) (From Greenhouse's research report) N-Methyl-3-ethylpyridinium iodide (0.250 g) was dissolved i n methanol (15 ml) and treated with sodium- borohydride (0.250 g) added i n small portions with s t i r r i n g . After 20 min the solution was di l u t e d with 3N solution of HC1 and extracted with ether. The aqueous layer was b a s i f i e d with s o l i d sodium hydroxide and extracted with methylene chloride. The organic layer was dried with anhydrous sodium sulphate and evaporated to y i e l d 0.036 g (29%) of a nearly colourless o i l . Gas l i q u i d chromatography (GLC) using a 30% carbowax (10 f t long, - 128 -at a temperature of 120°C with a flow of 10 ml/7 sec) i n d i c -ated that t h i s o i l consisted of a mixture of three substances in a 15:2:1 r a t i o . By preparative VPC the major component of t h i s mixture was is o l a t e d . IR v : 2960, 2780, 1460, max ' ' 840; 1Hmr 6: 0.95 (3H, t, J = 7 Hz, -CH2CH_3) ; 2.20 (3H, s, -N-CH_3) , 2.5-1.7 (6H, m, C(5)-H, C(6)-H and -CH_2CH3) , 2.65 (2H, bs, C(2)-H 2), 5.33 (IH, m, C(4)-H); MS m/e: 67, 81, 82, 94, 96 (100%), 110, 124, 125(M +). High resolution molecular weight determination, calculated for CgH^N: 125.1204; found: 125.1225. N-Carbomethoxy-3-ethyl-l,2-dihydropyridine (49) Methyl chloroformate (1.89 g) i n 3 ml of anhydrous ether was added at -78°C to a mixture of 0.8 g of NaBH^ and 2.14 g of 3-ethylpyridine i n 20 ml of absolute methanol. The rate of addition was controlled so that the reaction temperature did not exceed -69°C. Two hours aft e r the addition was completed, the reaction mixture was poured into ice-water and extracted with ether. The ether layer was worked up i n the usual manner and concentrated. The l i g h t yellow o i l obtained was f i l t e r e d over a column containing 100 g of basic alumina to y i e l d 1.6 g of the dihydropyridine 49; UV A : 2 98; IR v : ITlclX IHclX 1700; 1Hmr 6: 1.07 (3H, t, J = 6.5 Hz, -CH2CH_3) , 2.03 (2H, q, - 129 -J = 6.5 Hz, -CH2CH3) , 3.75 (3H, s, N-CH_3) , 4.21 (2H, d, J = 1 Hz, C(2)-H_2), 5.02 (IH, dd, J = 6 Hz, J = 6.5 Hz, C(5)-H), 5.52 (IH, bd, J = 6 Hz, C(4)-H). N-Methyl-3-ethyl-l,6-dihydropyridine (51) 0.18 5 ml of pyridine were added to a solution of 150 mg of chromium complex 4_4 i n 12.5 ml of n-pentane (ratio 4_4 to pyridine, 1:4). The reaction was s t i r r e d at room temperature and followed by UV. After 24 h of reaction an abundant pr e c i p i t a t e had formed and the UV spectrum showed very small amounts of complex 4_4 (399 nm) . The p r e c i p i t a t e was f i l t e r e d and the solvent evaporated under.reduced pressure to give a pale orange o i l (72%) y i e l d ) ; UV * m a x : 332; "'"Hmr 6 : 1.02 (3H, t, J = 7 Hz, -CH2CH3) , 1.98 (2H, q, J = 7 Hz, -CH_2CH3) , 2.24 (3H, s, N-CH3), 3.50 (IH, d, J = 4 Hz, C(6)-H_2), 5.18 (IH, dt, J = 4 Hz, J = 8 Hz, C(5)-H), 5.52 (IH, s, C(2)-H). N-Methyl-3-ethyl-5-benzyl-l,2,5,6-tetrahydropyridine (54) (From Greenhouse's research report) Pyridinium s a l t 41^  (1.00 g) was added a l l at once to a mixture of sodium borohydride (0.385 g) and benzyl bromide (4.75 ml) in 2.IN sodium hydroxide (6 ml), methanol (6 ml) and ether - 130 ~ (40 ml), and vigorously s t i r r e d for 20 h. Ether (100 ml) was added and the mixture was a c i d i f i e d with 2.5N hydrochloric acid. The two layers were separated and the aqueous one was further extracted with two portions of ether and evaporated to dryness, to give 1.316 g of a l i g h t yellow s o l i d (5_3, R = CH20) . 1Hmr (CDCl3-DMSO-d5) : 1.10 (3H, t, J = 8 Hz, -CH2CH_3), 2.11 (2H, q, J = 8 Hz, -CH 2CH 3), 2.79 (2H, apparent t r i p l e t , C(5)-CH_ 20), 3. 08 (3H, s, N-CH_3) , 3.20-2.85 (IH, m, C(5)-H), 3.44 (2H, apparent t r i p l e t , C(6)-H_2), 3.86 (2H, "AB quartet", J A B 16 Hz, C(2)-H 2), 4.53 (2H, s, N-CH20), 5.71 (IH, br.s., C(4)-H), 7.41 and 7.26 (10H, two si n g l e t s , aromatic). Dry HMPA (10 ml) and lithium hydride (0.25 g) were added to the s a l t 5_3. The suspension was deoxygenated at water aspirator pressure and placed under nitrogen while cooling to 0°C. Propane t h i o l (1.15 ml) was added a l l at once with s t i r r i n g . The reaction mixture was brought to room temperature and s t i r r e d for 20 h and poured onto a mixture of ice and 2.5 HC1 solution and extracted with ether. The aqueous layer was b a s i f i e d and extracted with ether to y i e l d 0.75 g of 54_ as the hydrochloride s a l t . P u r i f i c a t i o n of the free s a l t by column chromatography gave 0.4 9 g of 5_4 (48% from 41) ; 1Hmr (C gD 6) 6: 0.91 (3H, t, J = 7 Hz, -CH2CH_3) , 1.83 (2H, q, J = 7 Hz, -CH 2CH 3), 2.10 (3H, s, N-CH3), 2.90-1.95 (7H, m proton at C(2), C(5) and C(6)), 5.34 (IH, br.s. C(4)-H), - 131 -7.09 (5H, s, aromatic); MS m/e: 42, 44, 91, 115, 123, 124, 128, 129, 138, 143 (100%), 144, 157, 186, 200, 215 (M +). High resolution molecular weight determination, calculated for C 1 5H 2 1N: 215.1673; found: 215.1673. N,3,5-Trimethyl-5-benzyl-l,2,5,6-tetrahydropyridine (57) When 3 g of N-methyl-3,5-lutidinium iodide (5_6_) was treated with benzyl bromide i n the same way as described i n the previous experiment, 1.92 g of the hydrochloride s a l t of 5_7 were iso l a t e d . P u r i f i c a t i o n by column chromatography yielded 1.1 g of 5J7 (48%); bp: 79-81°C (hot box d i s t i l l a t i o n ) ; IR v : 1600, 1500, 1465, 1455, 740, 705; 1Hmr 6: 0.86 (3H, max ' ' ' s, C(5)-CH 3), 1.61 (3H, s, C(3)-CH 3), 2.11 (2H, "AB quartet", J = 11 Hz, C(6)-H 2), 2.28 (3H, s, N-CH3), 2.63 (2H, s, C(5)-CH 2 0 ) , 2.71 (2H, "AB quartet", J = 12 Hz, C(2)-H_2), 5.11 (IH, s, C(4)-H), 7.15 (5H, m, aromatic); MS m/e: 157 (100%), 172, 215 (M +). Analysis calculated for C 1 5H 2 1N: C 83.67, H 9.83; found: C 83.90, H 9.95. (N-Tryptophyl-3-ethyl-l,6-dihydropyridine)tricarbonylchromium(0)  and (N-Tryptophyl-3-ethyl-l,2-dihydropyridine)tricarbonyl- chromium(O) Complexes (59 and 60) - 132 " N-Tryptophyl-3-ethylpyridinium bromide (58) (0.5 g) was added to a mixture of ether (25 ml), 2.IN solution of sodium hydroxide (3 ml), methanol (1 ml) and sodium borohydride (60 mg), and s t i r r e d for 20 min. At t h i s time, besides the indole absorption (220, 274, 282, 289), the UV spectrum showed the t y p i c a l band for a dihydropyridine (336). The ether layer was separated, washed with 2.1 N sodium hydroxide and added to dry trisacetonitriletricarbonylchromium(0) (42) (-2 g), and s t i r r e d under a nitrogen atmosphere for 12 h. The reaction mixture was f i l t e r e d and evaporated to dryness under reduced pressure and the product obtained was p u r i f i e d by preparative TLC(petroleum ether - ethyl acetate, 6:4), to give 109 mg (20%) of red compound that showed a single spot on the TLC (same system as before). The NMR spectrum i n d i c -ated that t h i s compound was a mixture of at le a s t two compounds Using a less polar solvent (petroleum ether - ethyl acetate, 85:15) and r e p e t i t i v e development of the plates (four times) two red compounds were i s o l a t e d . The less polar compound (7 mg) was i d e n t i f i e d as the dihydropyridine chromium complex 59_ based on i t s spectroscopical properties; UV ^ m a x : 219, 272, 278, 288, 397; IR v : 3480, 1950, 1870, 1835; 1Hmr ' ' ' max ' ' ' (CgDg) 6 : 1.04 (3H, t, J = 7 Hz, -CH2CH_3) , 3.19 (IH, br. distorted t, apparent J = 7 Hz, C(5)-H), 4.86 (IH, br.s. C(2)-H), 4.90 (IH, d, J = 7 Hz, C(4).-H), 6.31 (IH, br.s., - 133 -indole-C(2)-H), 7.1-7.6 (4H, m, aromatic-H 4); MS m/e: 52, 122 (100%), 130, 144, 252, 304, 388 (M +). The other compound obtained from the TLC plates (4 mg) was i d e n t i f i e d as N-tryptophyl-3-ethyl-l,2-dihydropyridine chromium complex 60; UV X : 220,285, 290, 400; IR v : r — max ' ' max 3480, 1945, 1855, 1830; 1Hmr (CgDg) 6: 0.77 (3H, t, J = 7 Hz, -CH 2CH 3), 1.83 (2H, q, J = 7 Hz, -CH 2CH 3), 2.38 (4H, br.s. -CH 2CH 2-), 2.62 (2H, s, C(2)-H 2), 4.0-4.8 (2H, m, C(4)-H and C(6)-H), 4.90 (IH, t, J * 5.0 Hz, C(5)-H), 6.24 (IH, br.s. indole-C(2)-H), 7.0-7.6 (4H, m, aromatic-H_4) . 103 2-Carboxytryptophol Lactone (61) 1. a-Ethoxalyl - y-butyrolactone: In a 3 l i t e r round-bottomed flas k , equipped with an e f f i c i e n t condenser, a mixture of 69 g of f i n e l y cut sodium, 2 1 of anhydrous ether, and one t h i r d of a mixture of 258 g of y-butyrolactone and 438 g of diethyloxalate, was s t i r r e d mechanically. The reaction started upon addition of 1 ml of methanol and warming the reaction mixture. After a short time the reaction became viol e n t and the warm bath was removed and replaced by an i c e -water bath. The remaining two thi r d s of the y-butyrolactone/ diethyloxalate mixture was added over a two hour period, and - 134 -the mixture s t i r r e d u n t i l no more sodium was l e f t . The ether was then d i s t i l l e d and the pr e c i p i t a t e obtained was dissolved i n 1 1 of ice-water. Upon a c i d i f i c a t i o n with sulphuric acid, a thick o i l separated out of solution. The mixture was then extracted with ether (3 x 1 1) and the combined ether layers were dried over anhydrous sodium sulphate, The ether was eliminated under reduced pressure, leaving approximately 300 ml of a very dense, brownish o i l . This o i l was d i s t i l l e d to y i e l d 190 g (34%) of a colourless o i l . Bp: 119-120°C at 10~ 2 mm of Hg; UV X : 280 (3.77), 315 ^ ^ max (3.59); IR v m .(neat o i l ) : 3400, 1770, 1740, 1700, 1640; in 3.x 1Hmr <5: 1.39 (3H, t, J = 7 Hz, -CH2CH_3), 3.23 (2H, t, J = 7.5 Hz, C(3)-H 2), 4.38 (2H, q, J = 7 Hz, -CH_2CH3) , 4.5 (2H, t, J = 7.5 Hz, C ( y ) - H 2 ) ; MS m/e: 95, 113 (100%), 186 (M+) Analysis calculated for c 8 H i o ° 5 : C 5 1 * 6 1 ' H 5« 41» found: C 51.53, H 5.60. 2. a-Phenylhydrazono - S-valerolactone: 191.4 g of a-ethoxalyl - y-butyrolactone were suspended i n 500 ml of a 2N solution of HC1 and refluxed u n t i l no more C0 2 came out of the condenser (3 h). After cooling the solution at room temperature 85 g of sodium acetate and a solution of 115 g of phenylhydrazine i n 16 ml of g l a c i a l acetic acid were added. The reaction mixture was heated at 80°C for half an hour and - 135 -di l u t e d with 1 1 of a 7M solution of HC1 to y i e l d a yellow p r e c i p i t a t e , which was f i l t e r e d o f f and r e c r y s t a l l i z e d from hot methyl alcohol to y i e l d 70 g (28%) of pure yellow c r y s t a l s . 12 0 g of brownish c r y s t a l s were obtained when the mother liquo r s were evaporated to dryness; mp: 189-190°C; UV X m = : 230 (4.29), 284 (3.98), 292 (4.10), 333 (4.62); IuciX IR v : 3250, 1690, 1500, 750; 1Hmr (DMSO-dc) 6: 2.00 (2H, max 6 m, C(y)-H 2), 2.63 (2H, t, J = 7 Hz, C ( B ) - H 2 ) , 3.32 (IH, s, NH), 4.30 (2H, t, J = 5 Hz, C( )-H 2), 6.8-7.5 (5H, m, aromatic protons); MS m/e: 65, 91, 93, 205 (M+, 100%). Analysis calculated for c 1 i H 1 2 N 2 ° 2 : c 64.69, H 5.92, N. 13.72; found: C 64.95, H 5.83, N 13.71. 3. Indole lactone 61^ : The phenylhydrazone obtained i n the previous experiment (50 g) was suspended i n 250 ml of g l a c i a l acetic acid and a stream of hydrogen chloride was bubbled over a period of 20 min. The reaction mixture was then refluxed for 10 min and d i l u t e d with 1.2 1 of water. The white p r e c i p i t a t e formed was f i l t e r e d o f f , washed with water and r e c r y s t a l l i z e d from methanol - acetone to y i e l d 39 g (85%) of the lactone 6_1 as long white needles. Mp: 194-196°C; UV X ' : 227 (4.31), 296 (4.25); IR v,,, : IuciX IUclX 3460, 1700; 1Hmr <5 : 3.16 (2H, t, J = 6 Hz, -CH 2CH 20-), 4.72 (2H, t, J = 6 Hz, -CH 9CH 90-), 6.9-7.8 (4H, m, aromatic-- 136 -H 4), 9.48 (IH, br.s, N-H); MS m/e: 129, 187 (M+, 100%). Analysis calculated for C^HgNC^: C 70.58, H 4.85, N 7.48; found: C 70.44, H 4.7, N 7.54. N,N-Dimethyl-2-carboxamidotryptophol (62) The indole lactone 6JL (30 g) and excess dimethyl amine were s t i r r e d i n dry methanol at room temperature u n t i l no absorption at 1700 cm"''' (lactone) was observed i n the IR spectrum (= 48 h) . The solvent was removed under reduced pressure and the residue c r y s t a l l i z e d from acetone - benzene to give 32 g of the amide 62 (87.5%). Mp: 125-126°C; UV X : 218 (4.75), 289 (4.31); ' m.ci.x IR v : 3460, 3200, 1600; 1Hmr 6 : 3.04 (6H, s, -N(CH,),) r 3.11 (2H, t, J = 6 Hz, -CH_2CH2OH) , 4.0 (2H, t, J = 6 Hz, -CH2CH2OH), 5.92 (IH, s, D 20 exchangeable, -CH2CH2OH), 6.6-7.8 (4H, m, aromatic-H 4), 9.6 (IH, br. s, N-H); MS m/e: 128, 158, 202 (100%), 232 (M +). High resolution molecular weight determination, calculated for c i 3 H x 5 N 2 ° 2 : 232.1211; found: 232.1214. 2-Dimethylaminomethyltryptophol-methiodide (63) 1. 2-Dimethylaminomethyltryptophol: A solution of the amide 62 (32 g) i n dry tetrahydrofuran (200 ml) was added slowly to a suspension of lithium aluminum hydride (30 g) i n - 137 -dry tetrahydrofuran (750 ml) at 0°C under a nitrogen atmos-phere. The mixture was heated under r e f l u x for about 5 h, cooled, and quenched with saturated sodium sulphate solution. The mixture was f i l t e r e d and the sol i d s were washed with hot ethyl acetate (ca 2 1). The f i l t r a t e was evaporated to dryness and the residue r e c r y s t a l l i z e d from ethyl acetate to give 2-dimethylaminomethyltryptophol (24.3 g, 84%). Mp: 140-142°C; UV X : 222 (4.61), 274 (3.91), 281 (3.95), 290 (3.88); HlclX IR v : 3470, 3400-3000; 1Hmr 6 : 2.2 (6H, s, -N(CH,) 0), 3.01 max ' —3' 2' (2H, t, J = 6 Hz, -CH2CH2OH) , 3.49 (2H, s, -CH_2N (CH3) 2 ) , 3.84 (2H, t, J = 6 Hz, -CH2CH2OH), 4.29 (IH, br.s. -CH2CH2OH), 6.9-7.7 (4H, m, aromatic-H^), 8.7 (IH, br.s, N-H) ; MS m/e: 115, 130, 132, 143, 144 (100%), 173, 174, 218 (M +). Analysis calculated for C 1 3H 1 8N 20: C 71.53, H 8.31, N 12.83; found: C 71.39, H 8.15, N 12.79. 2. Methiodide 6_3: Iodomethane (27.2 g) i n ethyl acetate (40 ml) was added to an ethyl acetate solution (700 ml) of the dimethyl amine obtained i n the previous section (24 g). The mixture was s t i r r e d at ambient temperature for 45 min then at 50°C for 1 h. The mixture was cooled and the prec i p i t a t e c o l l e c t e d by f i l t r a t i o n . R e c r y s t a l l i z a t i o n from ethanol yielded 35.7 g of the methiodide 6_3 (90.2%). Mp: 162-165°C; UV X m = v : 218 (4.72), 273 (4.02, 286 (3.93), 296 (3.68); - 138 " IR v : 3410, 3280; 1Hmr (CDCl-,-DMSO-dc) 6: 3.13 (2H, t, max J o J = 6 Hz, -CH2CH2OH), 3.28 (9H, s, -N(CH 3) 3), 3.80 (2H, m, -CH2CH_2OH) , 4.20 (IH, t, J = 6 Hz, -CH2CH2OH), 4.96 (2H, s, -CH2N(CH3) 3) , 6.9-7.8 (4H, m, aromatic-H^), 10.84 (IH, s, N-H). 2-Cyanomethyltryptophol (64) A mixture of 40 g of the methiodide 6_3 and 30 g of potassium cyanide was heated i n refluxing a c e t o n i t r i l e (1 1) for 18 h under a nitrogen atmosphere. The reaction mixture was cooled and f i l t e r e d . The f i l t r a t e was evaporated and the residue f i l t e r e d through a short column of alumina (grade III) with dichloromethane (500 ml) and then with ethyl acetate (1. 1), to y i e l d 20 g of a pale yellow gum that s o l i d i f i e d with time. R e c r y s t a l l i z a t i o n from benzene gave 18.5 g of 2-cyanomethyl-tryptophol (64) (87%). Mp: 106-107°C; UV A : 220 (4.58), 272 (3.89), 279 (3.90), 289 (3.79). I R v : 3680, 3620, 3460, 2400; 1Hmr <5 : 1.66 (IH, s, -CH2CH2OH), 2.90 (2H, t, J = 6 Hz, -CH2CH2OH) , 3.81 (2H, t, J = 6 Hz, -CH2CH_2OH) , 3.84 (2H, s, -CH2CN), 6.9-7.7 (4H, aromatic-H^), 8.29 (IH, br.s, N-H). MS m/e: 64, 77, 115, 142, 169 (100%), 182, 200 (M +). Analysis calculated for C 1 2H 1 2N 20: C 71.98, H 6.04, N 13.99; found: C 72.10, H 6.20, N 13.74. - 139 -A l l inorganic s a l t s (KI and KCN) obtained i n t h i s reaction were dissolved i n water and treated with saturated solution of ferrous sulphate (with a small amount of f e r r i c sulphate) to destroy excess potassium cyanide. 2-Carbomethoxymethyltryptophyl Chloride (65) An ice-cold solution of 20 g of hydroxynitrile 64_ and 4 ml of water i n 400 ml of methanol was saturated with hydrogen chloride gas. After s t i r r i n g at room temperature for 48 h the solution was taken to dryness under vacuum and the residue treated with a saturated solution of sodium bicarbonate (250 ml) and extracted with methylene chloride. The extracts were washed with water, brine and dried over anhydrous sodium sulphate. The solvent was removed and the residual o i l obtained (19.4 g) was p u r i f i e d by column chromatography (600 g of s i l i c a gel, petroleum ether - ethyl acetate) to y i e l d 8.^ 8 g of 6_5 as a pale yellow gum that s o l i d i f i e d when kept overnight in the freezer. The a n a l y t i c a l sample was prepared by sublimation at 80°C and 10~ 2 mm of Hg. Mp: 59-60°C; UV A : 3 c max 221 (4.58), 274 (3.90), 281 (3.91), 289 (3.86); I R v : 3480, r r i c i x 1730; W 3.19 (2H, t, J = 7.5 Hz, -CH 2CH 2C1), 3.72 (2H, t, J = 7.5 Hz, -CH2CH2C1) , 3.77 (3H, s, -OCH_3) , 3.85 (2H, s, -CH 2C0 2CH 3), 7.0-7.7 (4H, m, aromatic-H 4), 8.61 (IH, br.s, N-H); MS m/e: 142, 143, 156, 192, 202 (100%), 251 (M +), 253 - 140 -(M++2). Analysis calculated for C 1 3H 1 3N0 2C1: C 62.03, H 5.61, N 5.56; found: C 62.11, H 5.78, N 5.57. N-(2-Carbomethoxymethyltryptophyl)-3-ethyl-pyridinium  Perchlorate (36) The chloroester 6_5 (5.14 g) and freshly d i s t i l l e d 3-ethyl-pyridine (15 ml) were heated at 82°C for 18 h. The solution was cooled and d i l u t e d with ether. The ether was decanted and the residula o i l chromatographed on alumina (grade V) with ethyl acetate. Evaporation of the eluate gave 4.5 g of a thick o i l which was dissolved i n water (100 ml). A saturated solution of sodium perchlorate (25 ml) was added and the p r e c i p i t a t e formed c o l l e c t e d by f i l t r a t i o n . R e c r y s t a l l -i z a t i o n from methanol gave 3.85g(44%) of the perchlorate s a l t 36. Mp: 140-141.5°C; UV \ : 219 (4.56), 265 (4.01), 271 (3.98), m 3.x 280 (3.91), 289 (3.83); IR v : 3350, 1740; 1Hmr (CDC1,,-max ' 3 DMSO-dg) 6: 1.01 (3H, t, J = 8 Hz, -CH 2CH 3), 2.60 (2H, q, J = 8 Hz, -CH 2CH 3), 3.40 (2H, t, J = 6.5 Hz, -CH 2CH 2Py +), 3.74 (3H, s, -0CH 3), 3.83 (2H, s, -CH 2C0 2CH 3), 4.81 (2H, t, J = 6.5 Hz, - CH 2CH 2Py +), 6.7-7.5 (4H, m, aromatic-H 4), 7.79 (IH, dd, J = 8 Hz, J = 6 Hz, pyridine-C(5)-H), 8.19 (IH, d, J = 8 Hz, pyridine-C(4)-H), 8.46 (IH, s, pyridine-C(2)-H), 8.70 (IH, d, J = 6Hz, pyridine-C(6)-H), 10.77 (IH, br.s, N-H). - 141 " Analysis calculated for C 2 ( )H 2 3N 20 6C1: C 56.81, H 5.48, N 6.65; found: C 56.61, H 5.30, N 6.63. {N-(2-Carbomethoxymethyltryptophyl)-3-ethyl-l,6-dihydro- pyridine }tricarbonylchromium(0) Complex (40) Using the procedure described for the formation of the chromium complexes 5_9 and 6_0_, 1.2 g of the s a l t 3_6 gave 35 mg of a mixture of 3_9 and 4_0 (2.6%). The mixture was separated by preparative TLC to y i e l d 6 mg of the less polar component that was i d e n t i f i e d as chromium complex 40; UV A : 220, 273, 281, 290, 398; 1Hmr 6 : 1.02 (t, J = 8 Hz, -CH2CH_3) , 3.1 (distorted t, J = 6 Hz, pyridine-C(5)-H), 3.24 (s, -CH 2C0 2CH 3), 3.37 (s, -OCH3), 4.84 (br.s, pyridine-C(2)-H), 4.86 (d, J = 6 Hz, pyridine-C(4)-H); MS m/e: 52, 122 (100%), 202, 220, 324, 344, 460 (M +). The other component (2 mg) of the mixture obtained i n the complexation reaction was s t i l l impure and i t was assumed that i t corresponded to complex 39. N-Benzyl-2-carboxytryptophol Lactone (68) A solution of the lactone 6_1 (18.7 g) i n HMPA (40 ml) and - 142 " tetrahydrofuran (30 ml) was added slowly to a suspension of potassium hydride (40 ml of 23% suspension) i n HMPA (40 ml) and tetrahydrofuran (500 ml) at 0-5°C and s t i r r i n g maintained at t h i s temperature for 30 min then at ambient temperature for 2 h. The mixture was cooled i n ice and excess hydride destroyed by the addition of alumina (grade I I I , 200 g) and the mixture s t i r r e d for 4 5 min. The so l i d s were removed by f i l t r a t i o n and the f i l t r a t e concentrated i n vacuo. The o i l obtained i n t h i s way was p u r i f i e d by column chromatography (800 g s i l i c a gel) to y i e l d 22.6 g of a s o l i d which upon c r y s t a l l i z a t i o n from ethyl acetate-hexane gave 19.9 g of the lactone 68 (67%). Mp: 109-109.5°C; UV X : 232 (4.64), — ^ max 297 (4.55); IR v : 1710; 1Hmr 6 : 3.08 (2H, t, J = 6 Hz, max -CH2CH20-) , 4.56 (2H, t, J = 6 Hz, -CH2CH_20-) , 5.76 (2H, s, NCH 20), 7.0-7.7 (9H, m, aromatic-Hg); MS m/e: 91 (10 0%), 277 (M +). Analysis calculated for C 1 8H 1 5N0 2: C 77.96, H 5.45, N 5.05; found: C 77.92, H 5.56, N 5.00. N-Benzyl-2-dimethylcarboxamido-tryptophol (69) As described before for the preparation of the amide 6_2, 68_ gave a 91% y i e l d of amide 69_ which was r e c r y s t a l l i z e d from methanol - hexane. Mp: 93.5-94°C; UV X : 215 (4.91), r ' max ' 287 (4.31); IR v : 3280, 1630, 740-710; 1Hmr 6 : 2.52 (3H, -143 -br. s, -N(CH 3) 2), 2.93 (5H, Br. s, -N(CH_3)2 and -CH2CH2OH), 3.78 (2H, t, J = 6 Hz, -CH2CH2OH), 5.28 (2H, s, NCH20), 6.8-7.8 (9H, m, aromatic-Hg); MS m/e: 91, 247, 248, 277, 278, 291, 292 (100%), 322 (M +). High resolution molecular weight determination calculated for C 2 Q H 2 4 N 2 0 2 : 322.168; found: 322.1651. Analysis calculated for c 2 Q H 2 2 N 2 ° 2 : C 74.51, H 6.88, N 8.69; found: C 74.35, H 6.79, N 8.522. (N-Benzyl-2-dimethylcarboxamido-tryptophyl)-benzyl Ether (70) As described for the preparation of 6_8, 6_9 gave a 91% y i e l d of the amide 70 as a thick gum. UV X : 215 (4.55), 287 (3.97); IR v : 1630, 745, 700; 1Bxar 6: 2.44 (3H, br. s, IT13.2C -N(CH_ 3) 2), 2.89 (3H, br. s, -N(CH 3) 2), 3.04 (2H, t, J = 7 Hz, -CH2CH20) , 3.69 (2H, t, J = 7 Hz, -CH2CH_20) , 4.47 (2H, s, -OCH_20) , 5.28 (2H, s, NCH_20) , 6.9-7.7 (17H, m, aromatic-H 1 7); MS m/e: 91 (100%), 149, 291, 412 (M +). High resolution molecular weight determination, calculated for C 2 7 H 2 8 N 2 ° 2 : 4 1 2 - 2 1 5 1 ' * found: 412.2159. Reduction of Amide 70 1. A solution of the amide (70_) (1.65 g) i n dry tetrahydro-furan (10 ml) was added slowly to a suspension of lithium - 144 -aluminum hydride (230 mg) i n dry tetrahydrofuran (10 ml) at 0°C under nitrogen. The mixture was s t i r r e d at ambient temperature for 4 h, cooled, and excess hydride destroyed with Na 2S0 4•10H 2O. The so l i d s were removed by f i l t r a t i o n and the f i l t r a t e concentrated i n vacuo. Chromatography on s i l i c a gel afforded: N-benzyl-2-dimethylaminomethyl-tryptophyl-benzyl ether (73) (150 mg, 9.5%); UV X m : 225, 277, 285 and 296; IR v : 1470, 1450, 1360, 740, 700; 1Hmr 6: 2.11 (6H, max ' ' s, -N(CH 3) 2), 3.09 (2.H, t, H = 8 Hz, -CH2CH20-) , 3.19 (2H, s, -CH 2N(CH 3) 2), 3.67 (2H, t, J = 8 Hz, -CH 2CH 20-), 4.48 (2H, s, -OCH20) , 5.5 (2H, s, -NCH_20) , 6.8-7.7 (14H, m, aromatic-H 1 4); MS m/e: 91 (100%), 232, 262, 352, 353, 354, 398 (M +). High resolution molecular weight determination, calculated for C 2 7H 3 QN 20: 398.2358; found: 398.2387; and (N-benzyl-2-carbinol-tryptophyl)-benzyl ether (74_) (850 mg, 67%); UV X : 225 (4.52), 279 (3.87), 286 (3.88), 297 (3.81); IT13.X IR 1 max : 3400, 740, 700; Hmr 6: 2.82 (. H, br. s, -CH2OH) 3.06 (2H, t, J = 6 Hz, -CH 2CH 20), 3.66 (2H, t, J = 6 Hz, -CH 2CH 20-), 4.38 (2H, s, -OCH 20), 4.54 (2H, s, -CH2OH), 5.35 (2H, s, NCH_20) , . 6.8=7.6 (14H, m, aromatic-H 1 4) ; MS m/e: 91, 250 (100%), 371 (M +). High resolution molecular weight determination calculated for C 2 4H 2^N0 2: 371.1885; found: 371.1906. 2. n-Butanol (8.4 ml) was added, over a period of 15 min - 1 4 5 -to a suspension of lithium aluminum hydride (3.5 g ) i n dry tetrahydrofuran (60 ml) at 0-5°C under nitrogen and the mixture s t i r r e d at ambient temperature for 1 h. A solution of the amide 7_0 (7.4 g) i n dry tetrahydrof uran (100 ml) was added and the mixture s t i r r e d at ambient temperature for 4 h. Work-up as described above gave a mixture of 7_3 and 74^  (6.5 g, r a t i o 8:1 by "'"Hmr) . 3. A solution of borane-tetrahydrofuran (1.5 ml of IN solution) was added to the amide 7^0_ (2 50 mg) i n dry tetrahydrof uran (50 ml) at 0-5°C under a nitrogen atmosphere. The solution was refluxed for 1 h, d i l u t e d with triethylamine (1 ml), and reflux continued for 2 h. The mixture was cooled and concentrated i n vacuo. The residue was dissolved i n ethyl acetate, washed with IN ammonium hydroxide solution, water, brine, dried (Na 2S0 4), and concentrated i n vacuo. Chromato-graphy on s i l i c a gel gave the amine 7_3 (14 0 mg, 58%) and a less polar compound (50 mg, 23%) that was i d e n t i f i e d as (N-benzyl-2-methyl-tryptophyl)-benzyl ether (76); UV A : 225, 276, 284, 292; IR v : 1470, 1460, 1365, 740, 700; ' ' ' max ' ' I I I 1Hmr 6: 2.24 (3H, s, indole-C (2)-CH_3) , 3.07 (2H, t, J = 7.5 Hz, -CH 2CH 20-), 3.67 (2H, t, J = 7.5 Hz, -CH2CH_20-) , 4.10 (2H, s, -OCH20) , 5.22 (2H, s, -NCH_20) , 6.7-7.6 (14H, m, aromatic—H,.); MS m/e: 91, 234 (100%), 355 (M +). High - 146 -resolution molecular weight determination, calculated for C 2 5 H 2 5 N O : 3 5 5 - 1 9 3 6 ? found: 355.1941. (N-Benzyl-2-cyanomethyl-tryptophyl)-benzyl Ether (71) 1. Methiodide of 73_: The crude product obtained i n the reduction of 70^  with LiAlH^-nBuOH was s t i r r e d i n ethyl acetate with iodomethane for 18 h. The s o l i d was co l l e c t e d by f i l t r a t i o n and r e c r y s t a l l i z e d from methanol - ethyl acetate to give the methiodide of 7_3 in 82% y i e l d . Mp: 143-145.5°C (decomposition); UV X : 220 (4.68), 276 (4.01), c max 292 (3.89), 304 (3.71); IR v : 1400, 1200, 1100, 1030, 860, in 3.x 730, 690; -""Hiiir (CDCl3-DMSO-dg) 6: 3.24 (11H, br. s, -N(CH_3)3 and CH2CH20-) , 3.81 (2H, t, J = 6.5 Hz, -CH2CH_20-) , 4.46 (2H, s, -OCH20) , 5.01 (wH, s, -CH_2N (CH3) 3) , 5.67 (2H, s, NCH_20) , 6.7=7.8 (14H, m, aromatic-H^) . Analysis calculated for C 2 gH 3 3N 2OI: C 62.22, H 6.15, N 5.18; found: C 62.21, H 6.30, N 5.12. 2. N i t r i l e 7JL: The methiodide of 7J3 (18.5 g) and potassium cyanide (10 g) were s t i r r e d i n refluxing a c e t o n i t r i l e (500 ml) for ca. 40 h. The mixture was cooled and f i l t e r e d . The f i l t r a t e was washed with water (twice), brine (twice), dried, and concentrated i n vacuo. Chromatography of the residue provided the n i t r i l e 7_1 (10.6 g, 82%) as a thick gum. - 147 -UV X : 222 (4.59), 275 (3.93), 283 (3.93), 295 (3.84); IR v : 2250, 740, 700; 1Hmr <5: 3.04 (2H, t, J = 6.5 Hz, in 3.x -CH 2CH 20-), 3.66 (2H, t, J = 6.5 Hz, -CH 2CH 2C~), 3.69 (2H, s, -CH2CN) , 4.44 (2H, s, -OCH_20) , 5.40 (2H, s, NCH 20) 6.8-7.7 (14H, m, aromatic-H_ 1 4) ; MS m/e: 91 (100%), 289, 380 (M +). High resolution molecular weight determination calculated for C 2 6H 2 4N 20: 380.1887; found: 380.1909. (N-Benzyl-2-carbomethoxymethyl-tryptophyl)-benzyl Ether (72) A solution of the n i t r i l e 7JL (14.4 g) i n dry methanol (400 ml) and water (4 ml), cooled to ca. 0°C, was saturated with hydro-gen chloride and then s t i r r e d for 72 h at room temperature. The solvent was partitioned between saturated sodium bicarbonate and dichloromethane. The organic layer was washed with water, brine, dried over sodium sulphate and evaporated. P u r i f i c a t i o n of the residue by column chromatography afforded the ester 72^  (10.5 g, 67%). UV X : 224 (4.53), 277 (3.87), 287 (3.90), 295 (3. 81); IR v : 1735, 740, 700; 1Hmr <5 : 3.09 (2H, t, max I I I J = 7 Hz, -CH 2CH 20-), 3.43 (3H, s, -OCH3), 3.68 (2H, t, J = 7 Hz, -CH2CH_20-), 3.71 (2H, s, -CH 2C0 2CH 3) , 4.48 (2H, s, -OCH20) , 5.38 (2H, s, NCH_20) , 6.8-7.7 (14H, m, aromatic-H 1 4 ) _ MS m/e: 91 (100%), 292, 312, 413 (M +). High resolution molecular weight determination calculated for C^H^NO.^: - 148 -413.1989; found: 413.1950. Enamine 85 A solution of the ester 7_2 (160 mg) i n dry tetrahydrof uran (2 ml) was added to a solution of lithium diisopropylamide (0.84 mmol) i n tetrahydrofuran (10 ml) and HMPA (0.13 ml) at -7 8°C under a nitrogen atmosphere. The solution was s t i r r e d at -78°C for 15 min then allowed to a t t a i n 0°C. The adduct of dimethylformamide and dimethyl sulphate (1:1, 108 1 g) was added and the mixture s t i r r e d at 0°C for 2 h. The mixture was d i l u t e d with water and extracted with ethyl acetate. The extract was washed with water, brine, dried (Na 2S0 4), and evaporated. Chromatography on s i l i c a gel gave 72 (68 mg) together with the enamine (8_5) (30%) , which can be r e c r y s t a l l i z e d from methanol. Mp: 112-113°C; UV X : 224, 281; IR v : 1665, 1600; 1Hmr 6 : 2.42 (6H, max max br.s, -N(CH 3) 2), 2.92 (2H, m, -CH 2CH 20-), 3.33 (3H, s, -C0 2CH 3) , 3.64 (2H, m, -CH2CH_20-) , 4.48 (2H, s, -OCH20) , 5.12 (2H, AB system, J = 16 Hz, NCH 2 0), 7.0-7.7 (14H, m, aromatic-H 1 4)/ 7.71 (IH, s, C = C(H)N(CH 3) 2; MS m/e: 91, 256, 316, 347, 468 (M+, 100%). Analysis calculated for C 3 0 H 3 2 N 2 ° 3 : C 7 6 * 9 0 ' H 6.88, N 5.98; found: C 76.69, H 6.97, N 6.25. - 149 -A c r y l i c Ester 86 G l a c i a l acetic acid (8 drops) was added to a solution of the enamine 8_5 (50 mg) and sodium cyanoborohydride (50 mg) i n methanol and tetrahydrofuran (1:1, 8 ml) and the mixture s t i r r e d under a nitrogen atmosphere for 18 h. The mixture was evaporated and the residue partitioned between saturated sodium bicarbonate solution and ethyl acetate. The extract was washed with water, brine, dried (Na 2S0 4), and concentrated in vacuo. The residue consisted of a mixture of two compounds that were separated by preparative TLC ( s i l i c a g e l ; petroleum ether - ethyl acetate 1:4). The less polar compound (16 mg, 37%) was i d e n t i f i e d as the a c r y l i c ester 8_6_; Mp: 87-89°C; UV X : 223, 276; IR v : 1720, 1615; 1Hmr 6: 3.05 max ' max ' (2H, t, J = 7.5 Hz, CH 2CH 20-), 3.52 (3H, s, -C0 2CH 3), 3.72 (2H, t, J = 7.5 Hz, -CH 2CH 20-), 4.53 (2H, s, -OCH 20), 5.20 (2H s, NCH 20) , 5.89 (IH, d, J = 2 Hz, C = CH_3) , 6.75 (IH, d, J = 2 Hz, C = CH 2), 7.0-7.8 (14H, m, aromatic-H_ 1 4; MS m/e: 91, 304 (100%), 425 (M +). Analysis calculated for C 2gH 2 7N0 3: C 79.03, H 6,50, N 3.29; found: C 78.21, H 6.50, N 3.21. The other component of the mixture (8 mg) was not f u l l y characterized due to i t s i n s t a b i l i t y . The structure corres-ponding to the reduced enamine was t e n t a t i v e l y assigned. 1Hmr 6: 2.03 (s, -N(CH_ 3) 2), 3.41 (s, -C02CH_3) , 4.52 (s, -OCH 20), 5.38 (s, NCH 20), 6.8-7.6 (aromatic protons). - 150 -Enol 87 Potassium diisopropylamide was prepared at -30 to 0°C from potassium hydride (5.5 ml of 20% dispersion i n o i l ) and d i -isopropylamine (10 ml) i n dry tetrahydrofuran (50 ml) and dry HMPA (5 ml). A solution of 32_ (3.0 g) i n dry t e t r a -hydrofuran (10 ml) was added at -30°C. The mixture was s t i r r e d at t h i s temperature for 15 min, at ambient temperature for 1 h, then cooled to -3 0°C. Dry methyl formate (50 ml) was added and the mixture s t i r r e d at ambient temperature for 18 h and d i l u t e d with water (100 ml), ethyl acetate (250 ml), and IN HC1 (100 ml). The organic layer was washed with (Na 2S0 4), and concentrated i n vacuo. Chromatography on s i l i c a gel gave the crude enol 87_ (2.6 g) as a pale yellow c r y s t a l l i n e s o l i d , s a t i s f a c t o r y for use i n further reactions. R e c r y s t a l l i z a t i o n from methanol gave pure 87_ (2.1 g, 65%); mp: 88-90°C; UV X : 225 (4.45), 275 (4.17), 286 (4.12), 295 (4.01); IR v : 3500-3000, 1665, 1605; 1Hmr 6 : 2.95 iricLX (2H, t, J = 7 Hz, pCH 2CH 20-), 3.35 (3H, s, -OCH3), 3.64 (2H, t, J - 7 Hz, -CH 2CH 20-), 4.46 (2H, s, -OCH 20), 5.11 (2H, s, NCH 20), 6.8-7.8 (16H, m, aromatic protons); MS m/e: 91 (100%), 288, 289, 290, 320, 441 (M +). Analysis calculated for C 2 8H 2 7N0 4: C 76.17, H 6.16, N 3.17; found: C 76.16, H 6.0, N 3.35. - 151 -Enol 88 The enol 8J7_ (52 mg) and 10% Pd/C cat a l y s t (11 mg) were s t i r r e d i n methanol (5 ml) under one atmosphere of hydrogen at ambient temperature for 9 h. The mixture was f i l t e r e d through C e l i t e and the f i l t r a t e concentrated i n vacuo. Chromatography on s i l i c a gel gave 8_7 (12 mg) and 8_8 (28 mg, 67%) as a clear gum. UV X : 225, 276; IR v : 3700-^ max ' max 3200, 1665, 1610; ^mr 6 : 2.88 (2H, poorly resolved t r i p l e t , -CH 2CH 20-), 3.36 (3H, br. s, -0CH 3), 3.72 (2H, poorly resolved t r i p l e t , -CH2CH_20-) , 5.11 (2H, br. s, NCH_20) , 6.4-7.7 (aromatic protons); MS m/e: 91 (100%), 288, 289, 292, 319, 320, 251 (M +). Methyl Enol Ethers 89 and 91 Excess ethereal diazomethane was added at 0-5°C to a solution of 8_8 (55 mg) i n ethyl acetate (2 ml) . The solution was kept at t h i s temperature for 12 h. Excess reagent and solvent were removed by passage of nitrogen. Chromatography of the residue provided 8_8 (16 mg) together with ethers 89 and 9_1. These two compounds were separated by preparative TLC ( s i l i c a g e l , petroleum ether - ethyl acetate 3:2, developed four times). The least polar was the major component of the mixture and was i d e n t i f i e d (E) enol ether 91, based on the - 152 -calculated chemical s h i f t for the v i n y l i c proton (vide i n f r a ) . UV X : 226 (4.56), 288 (3.86); IR v : 3660, 3600, 3560, max max 1700, 1630; 1Hmr <5: 1.85 (IH, br. s, -CH20H), 2.93 (2H, t, J = 6 Hz, -CH2CH2OH), 3.57 (3H, s, -C0 2CH 3), 3.69 (3H, s, =C(H)0CH3), 4.86 (2H, t, J = 6 Hz, -CH2CH2OH), 5.16 (2H, s, NCH 20), 7.0-7.6 (9H, m, aromatic-Hg), 7.69 (IH, s, =C(H)0CH3); MS m/e: 91, 334 (100%), 365 (M +). High resolution molecular weight determination calculated for C 2 2 H 2 3 N 0 4 : 365.1627; found: 365.1627. The other compound isol a t e d (6 mg, 10.5%) was i d e n t i f i e d as the Z-isomer of the methyl enol ether (89). UV X : 226 (4.56), 289 (3.89); IR v : 3550, 1710, 1630; 1Hmr 6: max 1.7 (IH, br. s, -CH2OH) , 3.05 (2H, t, J = 6 Hz, -CH_2CH2OH) , 3.51 (3H, s, -C0 2CH 3), 3.79 (3H, s, =C(H)0CH_3), 3.88 (2H, t, J = 6 Hz, -CH2CH2OH), 5.24 (2H, s, NCH 20), 6.52 (IH, s, =C(H)OCH3), 6.9-7.8 (9H, m, aromatic-Hg); MS m/e: 91, 334 (100%)? 365 (M +). High resolution molecular weight determination calculated for C^H^NO^: 365.1627; found: 365.1628. Chemical s h i f t c a l c u l a t i o n for the v i n y l proton i n 89 and 91 1 1 0: (Z)isomer: (E)isomer: Aromatic H Aromatic OCH, c = c c = c CH 30 2C OCH3 CH 30 2C H 153 -Base: 5 28 gem OR: 1.18 c i s Aromatic 0.37 trans C0 2R(conj.) 0.33 7.16 Base: 5.28 gem OR: 1.18 trans Aromatic -0.1 c i s C0 2R(conj.) 1.02 7.38 ADDENDUM The work presented i n t h i s thesis was fi n i s h e d i n May 1976. Since that time, several important advances have been obtained by Dr. Kutney's group, based on the findings presented here: The use of enol ethers 8_9 and 9_1 was not as hel p f u l as was thought, since with time, t h i s compound dimerizes to a substance not yet i d e n t i f i e d . These compounds are also very r e s i s t a n t to h y d r o l y s i s 1 1 1 . This led to the reinvest-igation of the complexation reaction, and i t was found that f l a s h chromatography of the reaction mixture obtained in the complexation reaction, using degassed f l o r i s i l and degassed solvents (methylene chloride and THF), d e f i n i t e l y 112 improved the y i e l d of the dihydropyridine complexes It was also found that when the dihydropyridine 3J7 was used 112 a mixture of three chromium complexes was formed (Diagram 55) . F i n a l l y , the synthesis of N-benzyl 3,14-dehydrosecodine has already been completed, using the sequence of reactions described in Diagram 56. DIAGRAM 55 Complexation Reaction of N-(2-Carbomethoxymethyl-tryptophyl ) -3-e t h y l - l , 2-dihydropyridine (37) DIAGRAM 56 Synthesis of N-Benzyl-3,14-dehydrosecodine R C0 2CH 3 - 157 -APPENDIX DIAGRAM 57 Numbering Systen of Indole A l k a l o i d s 1 1 " * - 158 -REFERENCES 1. For excellent reviews of the biosyntheses of indole alkaloids see: a) I. Kompis, M. Hesse, H. Schmid, Lloydia, 34, 269 (1971). b) G.A. Cor d e l l , Lloydia, 37_, 219 (1974). 2. D. Groger, K. S t o l l e , K. Mothes, Tet. Letters, 2579 (1964). 3. E. Leete, A. Ahmad, I. Kompis, J . Am. Chem. S o c , 87, 4168 (1965). 4. A.A. Qureshi, A.I. Scott, Chem. Commun., 948 (1968). 5. J.P. Kutney, W.J. Cretney, J.R. Hadfield, E.S. H a l l , V.R. Nelson, D.C. Wigfield, J . Am. Chem. S o c , 90, 3566 (1968). 6. A.R. Battersby, A.R. Burnett, P.G. Parsons, Chem. Commun., 1282 (1968). 7. A.R. Battersby, A.R. Burnett, P.G. Parsons, J . Chem. Soc. C., 1193 (1969). 8. G. Barger, C. Sholz, Helv. Chim. Acta., 16, 1343 (1933). 9. 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