UBC Theses and Dissertations

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UBC Theses and Dissertations

Part I. The synthesis of 6-AZA pregnane derivatives : Part II. Studies relating to alkaloid tatl synthesis Gletsos, Constantine 1965

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P a r t I. THE SYNTHESIS OF 6-AZA PREGNANE DERIVATIVES P a r t I I . STUDIES RELATING TO ALKALOID TOTAL SYNTHESIS by CONSTANTINE . GLETSOS Diploma Chem., The U n i v e r s i t y o f Athens - Greece, 1958 A THESIS SUBMITTED I N PARTIAL FULFILMENT OF THE REQUIREMENTS FOR THE DEGREE OF MASTER OF SCIENCE i n t h e Department o f C h e m i s t r y We a c c e p t t h i s t h e s i s as c o n f o r m i n g t o t h e r e q u i r e d s t a n d a r d THE UNIVERSITY OF BRITISH COLUMBIA May, 1965 t In presenting th i s thes i s in p a r t i a l f u l f i lmen t of the requirements for an advanced degree at the Un ivers i ty of B r i t i s h Columbia, I agree that the L ibrary sha l l make i t f r e e l y a va i l ab l e fo r reference and study. I fur ther agree that per-mission for extensive copying of t h i s thes i s for s cho la r l y purposes may be granted by the Head of my Department or by his representatives,, It i s understood that copying or p u b l i -cat ion of t h i s thes i s for f i n a n c i a l gain sha l l not be allowed without my wr i t ten permiss ion. Department The Un ivers i ty of B r i t i s h Columbia Vancouver 8, Canada ABSTRACT O z o n i z a t i o n o f JjJ ,20(3 - d i a c e t o x y - 5 - p r e g n e n e - 7 - o n e ( X I I ) gave m e t h y l 5 (J ,20(3 -diacetoxy-5-oxo-5»7-seco-6-norpregnan-7-oate ( X I I I ) . Treatment o f t h e l a t t s r w i t h sodium h y d r o x i d e y i e l d e d m e t h y l 20(J -acetoxy-5-oxo-5,7 -seco-6-nor-J-pregnen-7-oate (XIV), which upon r e d u c t i o n gave m e t h y l 20$ -acetoxy-5-oxo-5,7 -seco-6-norpregnan-7 _oate (XV) i n h i g h y i e l d ( s e e F i g u r e 20). Upon t r e a t m e n t o f t h e l a t t e r w i t h b e n z y l a m i n e , r i n g c l o s u r e o c c u r r e d and t h e e n o l l a c t a m , 20(5 -acetoxy-N-benzyl-6-aza-4-pregnen-7-one (XVI) was formed. C a t a l y t i c r e d u c t i o n o f t h e d o u b l e bond f o l l o w e d by r e d u c t i o n o f t h e c a r b o n y l w i t h l i t h i u m aluminum h y d r i d e y i e l d e d 20p -hydroxy-N-b e n z y l - 6 - a z a ~ 5 § -pregnane (XVIII) . ABSTRACT The i n d o l e u n i t , 2 - c a r b o m e t h o x y - 3 - c h l o r o a c e t y l i n d o l e ( X X I I I ) was s y n t h e s i z e d by a sequence w h i c h u t i l i z e d t h e R e i s s e r t s y n t h e s i s i n i t s i n i t i a l s t a g e s t o p r e p a r e 2-carbomethoxy i n d o l e . Subsequent i n t r o d u c t i o n o f t h e c h l o r o a c e t y l s u b s t i t u e n t a t t h e 5 p o s i t i o n was a c c o m p l i s h e d by means o f a Hoesch r e a c t i o n e m p l o y i n g c h l o r o a c e t o n i t r i l e as t h e r e a c t a n t . The d e s i r e d p i p e r i d i n e u n i t , ^ - c a r b o m e t h o x y - ^ - e t h y l p i p e r i d i n e ( X X I V ) was s y n t h e s i z e d f r o m a p y r i d i n e d e r i v a t i v e ( X L ) by c a t a l y t i c h y d r o g e n a t i o n s . The n e c e s s a r y p y r i d i n e c a r b o x y l i c a c i d was made a v a i l a b l e f r o m 5 ~ d i m e t h y l -p y r i d i n e a f t e r s e v e r a l r e a c t i o n s a l r e a d y known i n p y r i d i n e c h e m i s t r y . TABLE OP CONTENTS PART I . . Page. t INTRODUCTION t > o » o » « « t i o » , i o « e , a < > u o o w o « « i i > o « t t a a « 9 o u 0 0 » o a « a o a e a a a » t f e < > 0 * o X DISCUSSION o * » a « u * o v » e « < > a » * ^ e w > < * « > B » * » t ( * » « « 9 « » « * a w « 9 a s o * B B a » « « * « » * u a « * • I CONCLUSION ........... ......... • 20 EXPERIMENTAL . 21 BIBLIOGRAPHY -. .... 29 L i s t of Figures 1. C h o l e s t e r o l and-the numbering system of s t e r o i d s 2 2. Some b i o l o g i c a l l y a c t i v e aza s t e r o i d s 5 Metabolic sequence lea d i n g to c h o l e s t e r o l 4 4. Synthesis of 7-aza s t e r o i d s by use of r i n g B expansion 6 5. The Beckmann Rearrangement and i t s use i n the synthesis of 2-aza- !-A-homo s t e r o i d s 6 6. The Schmidt Reaction and i t s use i n the synthesis of aza s t e r o i d s 6 7. Use of the Seco-keto a c i d method f o r the prep a r a t i o n of aza s t e r o i d s 7 8. Prep a r a t i o n of aza s t e r o i d s from the corresponding oxa-steroids 1 9« Pr e p a r a t i o n of l6-aza s t e r o i d s by the imide synthesis 8 10. Mechanism and pr e p a r a t i o n of lJ-aza-D-homo s t e r o i d s by i r r a d i a t i o n 8 11. Synthesis of 11-aza-C-homo s t e r o i d s by use of a Seco-dialdehyde 8 12. Synthesis of 11-aza-C-homo s t e r o i d s by c y c l i z a t i o n of a Saco-dialdehyde ( a l t e r n a t e method) 9 1^ . C u r t i u s or Hofmann rearrangement f o r p r e p a r a t i o n o f * 5 - a z a s t e r o i d s 9 14. C y c l i z a t i o n of a Seco-aminoacid to l6-aza s t e r o i d s 10 15. 3-Aza-5j,4~nor s t e r o i d s from quaternary ammonium s a l t s 10 16. T o t a l synthesis of 11-aza s t e r o i d s 10 17. Synthesis of 6-aza s t e r o i d s i n the cholestane and androstane s e r i e s 12 •±93. y. Page. 18. S y n t h e s i s o f 11-aza s t e r o i d s i n t h e h e c o g e n i n s e r i e s 15 19- S y n t h e s i s o f 5(J ,20)3 -diacetoxy~5-pregnene-7-one ( X I l ) f r o m p r e g n e n o l o n e ( I X ) 14 20. P r e p a r a t i o n o f 20p -hydroxy-N-benzyl-6-aza-51 -pregnane ( X V I I I ) by o z o n o l y s i s and e n o l - l a c t a m f o r m a t i o n 18 PART I I INTRODUCTION J l DISCUSSION 59 CONCLUSION '. 54 EXPERIMENTAL 55 BIBLIOGRAPHY 66 L i s t o f F i g u r e s 1. B i o g e n e t i c d e r i v a t i o n o f s i m p l e i n d o l e a l k a l o i d s 52 2. C o n d e n s a t i o n r e a c t i o n s i n v o l v e d i n t h e a l k a l o i d b i o s y n t h e s i s J4 5. I n t e r c o n v e r s i o n o f 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 r o u g h Wenkert's i o n i c i n t e r m e d i a t e 56 4. I n t e r r e l a t i o n s o f d i f f e r e n t 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 57 5. P r o p o s e d sequence f o r s y n t h e s i s o f nine-membered r i n g i n t e r m e -d i a t e s 59 6. P r e p a r a t i o n o f 2 - c a r b o m e t h o x y - 5 - c h l o r o a c e t y l i n d o l e f r o m o-n i t r o t o l u e n e 40 7. R e a c t i o n mechanism f o r p r e p a r a t i o n o f o - n i t r o p h e n y l p h r u v i c a c i d 4 l 8. R e a c t i o n mechanism f o r p r e p a r a t i o n o f i n d o l e - 2 - c a r b o x y l i c a c i d 41 9. R e a c t i o n mechanism f o r p r e p a r a t i o n o f 2-carbomethoxy-5-chloro-a c e t y l i n d o l e by Houben-Hoesch r e a c t i o n 10. R e a c t i o n sequence, l e a d i n g t o m e t h y l e s t e r o f 5 - s t h y l n i p e c o t i c a c i d 45 11. S h i f t s i n U.V. spectrum o f compound ( X X X V I I I ) because o f t h e e n o l i z a t i o n 47 Page. 12. S t e r e o i s o m e r s o f methyl e s t e r ( XXIV) 51 15. S t e r e o c h e m i c a l c o r r e l a t i o n between compounds ( X L l ) , (XXIV) and some i s o q u i n o l i h e d e r i v a t i v e s 52 v»7 ACKNOWLEDGMENT The a u t h o r l i k e s t o e x p r e s s h i s a p p r e c i a t i o n t o Dr. James Kutney f o r h i s g u i d a n c e , encouragement and h e l p d u r i n g t h e c o u r s e o f t h i s r e s e a r c h . F i n a n c i a l a i d f r o m Smith K l i n e and F r e n c h L a b o r a t o r i e s , P h i l a d e l p h i a , and t h e N a t i o n a l R e s e a r c h C o u n c i l o f Canada i s v e r y g r a t e -f u l l y acknowledged. PART I THE SYNTHESIS OF 6-AZA PREGNANE DERIVATIVES 1 INTRODUCTION A long time ago chemists concerned with work on the chemistry of 4 natural products discovered that the cyclopentanoperhydrophenanthrene skele-ton was widespread i n many substances i s o l a t e d from animal as well as plant sources. The compounds containing t h i s system were named Steroids. The b i o l o g i c a l a c t i v i t i e s of these natural substances (such as sex hormones, adreno-cortical hormones, etc. ) when administered to animals as well as to humans provided a very a t t r a c t i v e stimulus to a great deal of research i n t h i s area. Much of t h i s e f f o r t has been directed toward the syn-thesis of these hormones and other analogues which may have s i m i l a r or improved b i o l o g i c a l properties. In some instances these investigations were f r u i t f u l l y rewarded. For example some 9-halogenated C o r t i s o l d e r ivatives were found to have greater p h y s i o l o g i c a l a c t i v i t y , than the natural compounds ( l ) . Furthermore, i t was found that the smaller the s i z e of the halogen substituent the greater was tie a c t i v i t y and the most i n t e r e s t i n g compounds b i o l o g i c a l l y are the 9-fluoro-compounds (2). Further research led to a combination of several substituents i n the same s t e r o i d residue, r i n g contraction or expansion, el i m i n a t i o n or addition of various f u n c t i o n a l groups and therefore, a great v a r i e t y of s t e r o i d analogues having considerable b i o l o g i c a l a c t i v i t y . Typical examples are provided from the work of Djerassi and co-workers (3>4). Cur own i n t e r e s t i n t h i s area was directed toward the introduction of a hetero atom i n the steroid skeleton (Figure l ) . In p a r t i c u l a r the s u b s t i t u t i o n of a nitrogen atom may provide aza steroids which exhibit new 2 F i g u r e 1. C h o l e s t e r o l and t h e numbering s y s t e m o f s t e r o i d s . t y p e s o f b i o l o g i c a l a c t i v i t y . Dorfman e t a l had r e p o r t e d some i n t e r e s t i n g f i n d i n g s i n t h i s r e g a r d A more d e t a i l e d d i s c u s s i o n by Doorenbos i n -d i c a t e d t h a t a z a s t e r o i d s do i n d e e d p r o v i d e a r i c h s o u r c e of new drugs a g a i n s t c e r t a i n d i s e a s e s (6). F o r example, t h e a c e t a t e d e r i v a t i v e s o f 1 7 - h y d r o x y - 4 - a z a - a n d r o s t - 5 ~ en-J-one (I) and 1 7p-hydroxy - 1 7 o <-methyl—4-aza-androst - 5-en - 5~one ( l i ) ( F i g u r e 2) e x h i b i t e d a n d r o g e n i c a c t i v i t y e q u i v a l e n t t o one s e v e n t h and one f i f t h t h a t of t e s t o s t e r o n e by a c h i c k comb i n j u n c t i o n t e s t , but when t h e dosage was i n c r e a s e d , t h e compounds were i n a c t i v e so t h e p o t e n c y a t t h e h i g h e r dose l e v e l was l e s s t h a n one p e r c e n t of t e s t o s t e r o n e . The compounds, 17B -hydroxy - 4-aza - 1 9-norandrost - 5-en - 5~one ( i l l ) and ( I I ) when i n j u n c t e d on t h e c h i c k ' s comb a t a dose o f 2 mg, i n h i b i t e d t h e a c t i o n o f t e s t o s t e r o n e a d m i n i s t e r e d by subcutaneous i n j e c t i o n (5) . One o f t h e major d i s e a s e s o f t h e modern w o r l d , namely, a t h e r o s c l e r o s i s , i s a s s o c i a t e d w i t h a b n o r m a l l y h i g h serum c h o l e s t e r o l l e v e l s . C l i n i c a l and e x p e r i m e n t a l e v i d e n c e s u g g e s t s t h a t a t h e r o s c l e r o s i s i s t h e r e s u l t o f a m e t a b o l i c d i s o r d e r i n v o l v i n g l i p i d s and l i p o p r o t e i n s , e s p e c i a l l y c h o l e s t e r o l , and t h e r e f o r e s u b s t a n c e s w h i c h b l o c k c h o l e s t e r o l b i o s y n t h e s i s w i l l be o f V I I C S H 5 V I I I F i g u r e 2. Some b i o l o g i c a l l y a c t i v e a z a s t e r o i d s . 4 c l i n i c a l v a l u e (6,1). The i m p o r t a n t i n t e r m e d i a t e s i n t h e b i o s y n t h e s i s o f c h o l e s t e r o l a r e e s t a b l i s h e d and a r e shown i n F i g u r e A c e t y l - c o e n z y m e A w A c e t o a c e t y l - c o e n z y m e A it J - H y d r o x y - J - m e t h y l g l u t a r y l - c o e n z y m e A I M e v a l o n i c a c i d Squalene L a n o s t e r o l i Z y m o s t e r o l I D e s m o s t e r o l 1 C h o l e s t e r o l F i g u r e 3> Scheme showing some o f t h e m e t a b o l i c f u n c t i o n s o f a c e t a t e and i t s c o n v e r s i o n t o c h o l e s t e r o l . Two a c t i v e a z a s t e r o i d s w h i c h b l o c k t h e r e d u c t i o n o f d e s m o s t e r o l t o c h o l e s -t e r o l a r e : N-methyl-4-aza-;5p - m e t h y l - ^ c * - c h o l e s t a n e ( I V ) and N , N - d i m e t h y l --4-aza~5^ -benzyl-5<x - c h o l e s t a n e i o d i d e ( V ) . A n o t h e r i m p o r t a n t d i s c o v e r y i n t h i s f i e l d by C o u n s e l l and co-workers a t S e a r l e was t h a t a group o f d i a z a i s o t e r e s o f c h o l e s t e r o l a p p a r e n t l y b l o c k t h e c o n v e r s i o n o f J - h y d r o x y - J -- m e t h y l g l u t a r y l - c o e n z y m e A i n t o m e v a l o n i c a c i d . The most e f f e c t i v e compound i s 2 0 , 2 5 - d i a z a c h o l e s t e r o l ( V I ) . I n t h i s c a s e , c h o l e s t e r o l i n h i b i t s i t s own b i o s y n t h e s i s a t t h i s s t e p by a f e e d b a c k mechanism. 5 Aza steroids have also caused a marked increase i n cho l e s t e r o l bio-synthesis. The most active of these are 5<* -N-ethanolamino-cholestane (VII) and N-phenyl-4-aza-5-cholesten-5~one (VIII). These derivations could be used i n inducing s c l e r o t i c lesions i n laboratory animals without r e s o r t i n g to high l e v e l s of cholesterol i n the d i e t . Besides these properties aza steroids have been reported to possess anabolic, a n t i b a c t e r i o l o g i c a l , antifungal, hypotensive, coronary artery d i l a t i n g , CNS stimulant, CNS depressant, neuromuscular blocking, a n t i -inflammatory, androgenic and hypocholesterolemic a c t i v i t i e s . In the l a s t case i t was reported that aza steroids blocked the conversion of mevalonate-to digitonide p r e c i p i t a b l e s t e r o l (7)« The great stimulation of research i n t h i s area i s obvious when one r e a l i z e s that publications on aza steroids have been appearing with great frequency-during the past f i v e years. As a r e s u l t of numerous investigations p a r t i c u l a r l y during recent years, nitrogen atoms have been introduced into v i r t u a l l y every p o s i t i o n on the st e r o i d nucleus as well as i n the side-chain. An excellent l i t e r a t u r e survey on the various aza s t e r o i d syntheses i s given by Djorassi (8) and the side-chain introduction i s given i n reference (9)» The methods applied are as follows and one t y p i c a l example i s given for each case: l ) By Beckmann rearrangement of the corresponding oximes. This reaction usually provides homo steroids, but i n a recent paper (10) a p p l i c a t i o n to a five-membered r i n g oxime, gave the desired six-membered system and the f i r s t 7-a'za steroid (Figure 4). Reagents used: R^SO^PCl^, POClj, S0C12, S0Cl 2/Bz, S0Cl 2/Dioxane, S0C12/ Pentane, Polyphosphoric a c i d , TsCl/Py, TsCl/Et 20 and AcNHC5H4S02Cl (Figures 4,5). 6 F i g u r e 4. S y n t h e s i s o f 7 - a z a s t e r o i d s by use o f r i n g B e x p a n s i o n by a Beckmann re a r r a n g e m e n t ( 1 0 ) . F i g u r e 5* Use o f Beckmann re a r r a n g e m e n t f o r s y n t h e s i s o f 2-aza-A-homo s t e r o i d s ( l l ) . 2 ) By Schmidt rearrangement of t h e a c i d a z i d e . Reagents u s e d : R V I S C T J / B Z, H ^ S O ^ / C h l , P o l y p h o s p h o r i c a c i d ( s e e F i g u r e 6 ) . F i g u r e 6 . Use o f Schmidt rearrangement f o r s y n t h e s i s o f 2-aza-A-homo s t e r o i d s ( l l ) . 7 5) By c y c l i z a t i o n o f S e c o - k e t o a c i d s w i t h amines o r ammonia (see F i g u r e 7). HOOC 180°, 1 h r . , N 2 Y i e l d 99% F i g u r e 1. Use o f t h e S e c o - k e t o a c i d method t o p r e p a r e N-benzyl-4-aza s t e r o i d s . ( 1 2 ) . 4) From O x a - s t e r o i d s . Ammonium h y d r o x i d e , b u t y l amine, ammonia/Bz, h y d r a z i n e have been u s e d as r e a c t a n t s ( see F i g u r e 8). Y i e l d 94% F i g u r e 8. P r e p a r a t i o n o f 4-aza s t e r o i d s f r o m 4-oxa s t e r o i d s (15)> 5) By an i m i d e s y n t h e s i s w h i c h proceeds v i a c y c l i z a t i o n o f an amido-a c i d , c y a n o - a c i d , or an a m i d o - e s t e r (see F i g u r e 9)> 6) By u l t r a v i o l e t p h o t o l y s i s o f n i t r i t e s i n benzene ( s e e F i g u r e 10). 7) V i a S e c o - d i a l d e h y d e s , w i t h NH^/EtOH (see F i g u r e s 11,12). 8) Use o f C u r t i u s o r Hofmann rearrangement (see F i g u r e l j ) . 9) By c y c l i z a t i o n o f S e c o - a m i d o a c i d s i n t h e p r e s e n c e o f NaOH/MeOH (see F i g u r e 14). 8 Figure 10. P r e p a r a t i o n of lJ-aza-D-homo s t e r o i d s by U.V. i r r a d i a t i o n and the proposed mechanism (15)« Figure 11. Use of a Seco-dialdehyde syn t h e s i s f o r 11-aza-C-homo s t e r o i d s (16). Figure 15. Use of C u r t i u s or Hofmann rearrangement to prepare 5 s t e r o i d s (17)' 10 Figure 14. P r e p a r a t i o n of 16-aza s t e r o i d s by c y c l i z a t i o n of a Seco-aminoacid (18) 10) By c y c l i z a t i o n of quaternary ammonium s a l t s (see Figure 15)-Figure 15. 5~Aza~i^,4-nor s t e r o i d s from quaternary ammonium s a l t c y c l i z a t i o n (19). l l ) By t o t a l s y n t h e s i s (see Figure l 6 ) . O • o Figure 16. 11-aza s t e r o i d d e r i v a t i v e s prepared by t o t a l synthesis (20). 11 I t i s o b v i o u s t h a t t h e above methods p r o v i d e a v a r i e t y o f a z a s t e r o i d s b u t i t i s n o t p o s s i b l e a t t h i s t i m e t o d i s c u s s t h e r e l a t i v e m e r i t s o f each o f t h e s e methods. I t i s s u f f i c i e n t t o i n d i c a t e t h a t most of t h e s e methods a r e s u i t a b l e f o r t h e s y n t h e s i s o f r i n g A and D a z a s t e r o i d s but v e r y o f t e n cannot be used t o p r e p a r e a z a s t e r o i d s p o s s e s s i n g t h e h e t e r o atom i n r i n g s B or C. I n f a c t s e v e r a l y e a r s ago, when r e s e a r c h i n our l a b o r a t o r y was i n i -t i a t e d i n t h i s a r e a t h e r e were no r i n g B o r C a z a s t e r o i d s known i n w h i c h t h e normal s k e l e t o n had been r e t a i n e d . T h e r e f o r e i t was o f i n t e r e s t t o d e v e l o p a s u c c e s s f u l sequence l e a d i n g t o t h e s e n o v e l s u b s t a n c e s . T h i s a i m was f i n a l l y a c c o m p l i s h e d and t h e e s s e n t i a l f e a t u r e s o f t h i s a p p r o a c h a r e g i v e n i n F i g u r e 17- T h i s sequence as w e l l as a s i m i l a r one i n d e p e n d e n t l y c o n c e i v e d by J a c o b s and B r o w n f i e l d (25), p r o v i d e d t h e f i r s t g e n e r a l s y n t h e s i s o f r i n g B a z a s t e r o i d s . L e t t r e * and Knof (24) p r e p a r e d r i n g B a z a s t e r o i d s by u s i n g a m o d i f i e d C u r t i u s r e a c t i o n . A f u r t h e r e x t e n s i o n o f the method i l l u s t r a t e d i n F i g u r e 17 was c a r r i e d o u t i n our l a b o r a t o r y and has p r o v i d e d t h e f i r s t example o f 11-aza pregnane a n a l o g u e s ( s e e F i g u r e 18) (26). The f i r s t p a r t o f t h i s t h e s i s d e s c r i b e s an e x t e n s i o n o f t h e c y c l i z a t i o n r e a c t i o n t o 6-aza pregnane d e r i v a t i v e s . T h i s work p r o v i d e s a n o t h e r n o v e l c l a s s o f a z a s t e r o i d s and e x e m p l i f i e s t h e complete v e r s a t i l i t y o f t h i s s y n t h e t i c a p p r o a c h t o v i r t u a l l y v e r y i m p o r t a n t c l a s s o f s t e r o i d a l hormones. 12 R Figure 17. P r e p a r a t i o n of 6-aza s t e r o i d s u s i n g r i n g cleavage and e n o l -lactam r i n g c l o s u r e , a p p l i e d s u c c e s s f u l l y i n cholestane (above) and androstane s e r i e s as w e l l i n our l a b o r a t o r i e s (21,22). R = H or < ^ C H 2 F i g u r e 18. S y n t h e s i s of l l - a z a s t e r o i d s v i a t h e S e c o - k e t o a c i d method (25). 14 DISCUSSION I n o r d e r t o e x t e n d t h e sequence o u t l i n e d i n F i g u r e 17 t o t h e pregnane s e r i e s , i t was n e c e s s a r y t o f i r s t c o n s i d e r t h e s y n t h e s i s o f t h e oi, p-u n s a t u r a t e d k e t o n e ( X I I ) . T h i s i n t e r m e d i a t e c o u l d be c o n v e r t e d t o t h e d e s i r e d S e c o - k e t o - a c i d f o r t h e subsequent c y c l i z a t i o n s t u d i e s . The s y n t h e s i s of ( X I I ) was a c c o m p l i s h e d by t h e sequence o f r e a c t i o n s as o u t l i n e d i n F i g u r e 19. F i g u r e 19. S y n t h e s i s of J B ,20$ -diacetoxy - 5~pregnene - 7-one ( X I I ) f r o m p r e g n e n o l o n e ( I X ) . P r e g n e n o l o n e ( I X ) was f i r s t s u b j e c t e d t o r e d u c t i o n w i t h l i t h i u m aluminum h y d r i d e and as e x p e c t e d f r o m t h e p u b l i s h e d p r o c e d u r e (27) t h e 5,20-diol (X) was o b t a i n e d . We found t h a t t h e r e p o r t e d y i e l d (63%) o f t h i s r e a c t i o n c o u l d 1 5 be r a i s e d to e s s e n t i a l l y 100% by conducting the r e a c t i o n i n a mixture of t e t r a h y d r o f u r a n , benzene and e t h y l ether ( l : J : 4 r e s p e c t i v e l y ) and a l l o w i n g the hydride to be g r a d u a l l y admitted i n t o the r e a c t i o n mixture from a Soxhlet apparatus. The product, 5 f ,20^ -dihydroxy-pregn - 5-ene (X) showed a l l the c h a r a c t e r i s t i c s ( s p e c t r a , m.p. , r o t a t i o n , e t c . ) reported i n the published work ( 2 7 ) . Subsequent a c e t y l a t i o n to the 5 >20-diacetate (XI) was c a r r i e d out ac-cording t o the published procedure ( 2 7 ) but again the y i e l d was increased, s i g n i f i c a n t l y by employing a higher temperature and a longer time f o r the a c e t y l a t i o n . Spectra, melting p o i n t , r o t a t i o n , e t c . were i d e n t i c a l to the de s i r e d compound, 5 (3 ,20 p -diacetoxy-pregn-5~ene ( X I ) . For the i n t r o d u c t i o n of the k e t o - f u n c t i o n at the 7 - p o s i t i o n we used a s o l u t i o n of t - b u t y l chromate and followed e s s e n t i a l l y a published procedure (28) which had been p r e v i o u s l y u t i l i z e d i n our l a b o r a t o r i e s f o r an analogous o x i d a t i o n (21,22). The y i e l d of t h i s o x i d a t i o n was again very high and the s p e c t r a l p r o p e r t i e s of the r e s u l t i n g product was i n good agreement f o r the de s i r e d compound ( X I I ) (29). Having obtained the <=<, ^ -unsaturated ketone ( X I I ) , we then considered the subsequent o z o n i z a t i o n r e a c t i o n . I t had been observed (22) t h a t ozonoly-s i s i n non-acidic solvents and p a r t i c u l a r l y i n the presence of an a l c o h o l increases the y i e l d of t h i s r e a c t i o n and converts the ozonide d i r e c t l y to the corresponding e s t e r . Furthermore the use of low temperatures a l s o improved the y i e l d of t h i s conversion. Thus o z o n i z a t i o n of 5 ^ >20f> -diacetoxy - 5-pregnen - 7-one(XII)at ~ 7 8°C i n a solvent mixture of methylene chloride-methanol f o l l o w e d by o x i d a t i v e de-composition of the ozonide w i t h hydrogen peroxide and water gave a r e a c t i o n product which was i s o l a t e d on numerous occasions i n q u i t e a pure c r y s t a l l i n e 16 s t a t e . However t r a c e s of i m p u r i t i e s can i n f l u e n c e the s o l i d s t a t e of t h i s product and sometimes i t was obtained as a foamy, very viscous gum. I t was very s u r p r i s i n g that the y i e l d i n t h i s r e a c t i o n was very high (~80%) since i n the cholestane, androstane and hecogenin s e r i e s , studied p r e v i o u s l y these reactions.never proceeded i n b e t t e r than k0% y i e l d (21 ,22,25). Furthermore, i n t h i s instance the compound produced, r e t a i n s the acetoxy f u n c t i o n at C-5, as shown by an es t e r carbonyl band at 1728 cm-"'" (5*79 and a C-0 s t r e t c h i n g band at 1242 cm-"'" (8.05^) i n i t s i n f r a r e d spectrum. There was a l s o no absorption i n the u l t r a v i o l e t spectrum nor any o l e f i n i c a b sorption i n the N.M.R. spectrum of the r e a c t i o n product. We could there-f o r e a s s i g n s t r u c t u r e ( X I I I ) t o t h i s product. The analogous product i n the cholestane and androstane s e r i e s reported p r e v i o u s l y (21,22) could be only i s o l a t e d w i t h considerable d i f f i c u l t y . Subsequent treatment of ( X I I I ) with 5% aqueous NaOH caused r a p i d e l i m i n a t i o n of a c e t i c a c i d to give methyl 20 p> -acetoxy-5-oxo-5 ,7-seco-6-nor-5-pregnen-7-oate (XIV). The i n f r a r e d a b s o r p t i o n maxima at 1727 cm - 1 (5-79 V 1)* 1675 cm - 1 (5*97 and 1665 cm - 1 (6.01 ^ ) are c h a r a c t e r i s t i c of a carbomethoxy and an <* ,^ -unsaturated carbonyl system as demanded by s t r u c t u r e (XIV). The presence of the unsaturated ketone system was f u r t h e r shown.by the u l t r a v i o l e t spectrum of t h i s compound (XIV) which has a maximum at 227 m y (log£ 4.89). The p o s i t i o n of t h i s a bsorption was i n good agreement w i t h the corresponding chromophores i n the s e r i e s studied p r e v i o u s l y , as mentioned above. The expected p o s i t i o n of t h i s maximum as c a l c u l a t e d by Woodward's r u l e s i s a l s o 227 rn u . The N.M.R spectrum a l s o showed the c h a r a c t e r i s t i c lower f i e l d o l e f i n i c s i g n a l s a t 2.72 T and m u l t i p l e t s - a t 4.14 and 4.28 r c . The unsaturated k e t o - e s t e r (XIV) was c a t a l y t i c a l l y hydrogenated {10% Pd on charcoal) and the expected saturated k e t o - e s t e r (XV) was obtained i n 17 e x c e l l e n t y i e l d . The success of the hydrogenation was evidenced by a s h i f t of the ketone carbonyl absorption to 1686 cm-"'' (5*95 p ) i n the i n f r a r e d , and by disappearance of the strong a b s o r p t i o n i n the u l t r a v i o l e t spectrum. Furthermore, the o l e f i n i c proton s i g n a l s i n the N.M.R. spectrum had s i m i l a r l y disappeared. The c y c l i z a t i o n of (XV) to provide the 6-aza pregnane d e r i v a t i v e could be accomplished i n the presence of ammonia or an amine. Since t h i s r e a c t i o n had been thoroughly studied i n the case of benzyl amine and since the r e s u l t a n t aza s t e r o i d s were more s u i t a b l e f o r any subsequent r e - i n t r o d u c t i o n of an oxygen f u n c t i o n at C-3, (XV) was t r e a t e d w i t h benzyl amine and the mixture r e f l u x e d i n a n i t r o g e n atmosphere. The s e m i c r y s t a l l i n e product was chromatographed on a s i l i c a g e l column and a c r y s t a l l i n e compound (87% y i e l d ) was obtained. The i n f r a r e d spectrum of t h i s r e a c t i o n product had a lactam carbonyl band at 1636 cm"-1- (6.11ft) and an o l e f i n i c band at l 6 6 l cm--'- (6.02 Y )• Furthermore, the u l t r a v i o l e t maximum of t h i s compound at 257 my 4.04) was i d e n t i c a l to tha t of analogous enol-lactam chromophores obtained i n the N-benzyl - 6-aza s t e r o i d s p r e v i o u s l y reported (21,22). This evidence e s t a b l i s h e d the expected s t r u c t u r e (XVI) f o r t h i s product. Hydrogenation of the enol-lactam (XVI) with Adam's c a t a l y s t (platinum oxide) i n an a c e t i c a c i d s o l u t i o n gave a s e m i c r y s t a l l i n e m a t e r i a l . This m a t e r i a l when chromatographed on a n e u t r a l s i l i c a g e l column gave 81% of a c r y s t a l l i n e product. I t i s important to note at t h i s p o i n t t h a t the red u c t i o n product as w e l l as the enol-lactam (XVI) upon standing i n the a i r or on a s l i g h t l y a c i d i c s i l i c a g e l column are transformed slowly i n t o some other compound which i s more polar (by T.L.C.). The hydrogenation product, s t i l l showed a lactam carbonyl band i n the 18 i n f r a r e d at 1644 cm--'- (6.08 but now the u l t r a v i o l e t spectrum clearly-i n d i c a t e d t h a t the enol-laotam chromophore was no longer present. I t was c l e a r t h a t s t r u c t u r e (XVII) must be assigned to t h i s product. ( X I I ) P t 0 2 / H 2 Figure 20. Preparation of 20p -hydroxy-N-benzyl - 6-aza - 5 i -pregnane ( X V I I I ) by o z o n o l y s i s and enol-lactam formation. Reduction of the lactam (XVII )with l i t h i u m aluminum hydride i n a con-tinuous Soxhlet e x t r a c t i o n apparatus gave an o i l y product. This o i l c r y s t a l -l i z e d e a s i l y from methanol and was shown to possess no carbonyl absorption i n the i n f r a r e d spectrum. As expected the acetoxy f u n c t i o n was a l s o reduced 19 at C-20 thereby giving r i s e to a secondary alcohol grouping at t h i s p o s i t i o n . The proton attached to C-20 now absorbed at 6.14 x whereas the t e r t i a r y proton at C-5 was assigned to a signal at 6.72 t i n the N.M.R. spectrum of t h i s reduction product. This evidence established the formula (XVIII) f o r t h i s compound. It was now clear that the sequence to the desired aza pregnane deriv-atives had been completed. F i n a l l y i t should be mentioned that these N-benzyl compounds can provide the parent N-H series since hydrogenalysis of the N-benzyl group i s a well-known reaction (JO). However, v/e have not a c t u a l l y c a r r i e d out such a conversion i n our work as yet. 20 CONCLUSION A s y n t h e s i s o f 6-aza s t e r o i d s p o s s e s s i n g t h e t r u e s t e r o i d s k e l e t o n and t h e pregnane s i d e c h a i n has been d e v e l o p e d . T h i s r e p r e s e n t s t h e f i r s t s y n -t h e s i s o f a z a d e r i v a t i v e s i n t h e pregnane s e r i e s i n w h i c h r i n g B c o n t a i n s a h e t e r o atom. The sequence i s p a r t i c u l a r l y a t t r a c t i v e s i n c e a l l t h e r e a c t i o n s i n c l u d i n g the o z o n i z a t i o n s t e p , p r o c e e d i n e x c e l l e n t y i e l d s . S i n c e pregnen-o l o n e i s a v a i l a b l e i n commercial q u a n t i t i e s , t h i s s y n t h e s i s i s a d a p t a b l e t o l a r g e s c a l e p r e p a r a t i o n s i f t h e s e a z a d e r i v a t i v e s s h o u l d p r o v e o f b i o l o g i c a l i n t e r e s t . v-21 EXPERIMENTAL A l l m e l t i n g p o i n t s were d e t e r m i n e d on a F i s h e r - J o h n s a p p a r a t u s and a r e u n c o r r e c t e d . The i n f r a r e d s p e c t r a were d e t e r m i n e d on a P e r k i n - E l m e r Model 21 s p e c t r o p h o t o m e t e r . The u l t r a v i o l e t s p e c t r a were r e c o r d e d i n ab-s o l u t e e t h a n o l on a Cary 11 r e c o r d i n g s p e c t r o p h o t o m e t e r and t h e r o t a t i o n s were t a k e n i n c h l o r o f o r m s o l u t i o n s , u n l e s s o t h e r w i s e i n d i c a t e d . The N.M.R. s p e c t r a were t a k e n a t 60 Mc/s on a V a r i a n A60 i n s t r u m e n t . The v a l u e s a r e g i v e n i n t h e T i e r s X s c a l e w i t h t h e s i g n a l o f t e t r a m e t h y l s i l a n e , w h i c h was used as t h e i n t e r n a l s t a n d a r d , s e t a t 10.0 Hz u n i t s . A n a l y s e s were p e r f o r m e d by A. B e r n h a r d t , Mulheim ( R u h r ) , Germany, and by Mrs. C. J e n k i n s , U n i v e r s i t y o f B r i t i s h Columbia. 3 ft ,20ft - D i h y d r o x y - p r e g n - ^ - e n e ( X ) A s o l u t i o n o f p r e g n e n o l o n e ( I X ) (JO.O g) i n t e t r a h y d r o f u r a n (250 m l ) , benzene (75^ m l ) a n d . e t h y l e t h e r (1000 ml) was r e f l u x e d w i t h s t i r r i n g f o r 2§- h o u r s w i t h l i t h i u m aluminum h y d r i d e (25.77 g)> w h i c h was i n i t i a l l y p l a c e d i n a S o x h l e t e x t r a c t o r and g r a d u a l l y b r o u g h t i n t o t h e v e s s e l by t h e r e f l u x i n g s o l v e n t . A f t e r t h i s t i m e t h e r e a c t i o n m i x t u r e was a l l o w e d t o come t o room t e m p e r a t u r e and t h e n a m i x t u r e o f wet e t h y l e t h e r (^>0G ml) and a c e t o n e (240 m l ) was added w i t h c a u t i o n t o decompose t h e e x c e s s h y d r i d e . A t t h i s p o i n i e t h y l e t h e r (1000 ml) was added and t h e e t h e r l a y e r was e x t r a c t e d t w i c e w i t h aqueous 2 N s u l f u r i c a c i d (2 x ^>0Q m l ) . The aqueous l a y e r was washed w i t h e t h e r (2 x ^500 ml) and t h e washings combined w i t h t h e main e t h e r e a l e x t r a c t . The e t h e r s o l u t i o n was t h e n washed w i t h aqueous 2 N sodium c a r b o n a t e (500 ml) and w a t e r (2 x 7^0 ml) s u c c e s s i v e l y , u n t i l t h e washings were n e u t r a l t o l i t m u s paper. A f t e r d r y i n g over anhydrous magnesium s u l f a t e , t h e 22 solvent was removed to y i e l d a white c r y s t a l l i n e product (20.25 g ) , m.p. 185-187°. C r y s t a l l i z a t i o n of t h i s m a t e r i a l from acetone gave an a n a l y t i c a l sample-. [ot] J j i o x a n e -67 .5°(C , 1 .92) ; i n f r a r e d i n CHClj : 2 . 8 2 ^ and 2.98y» ,6.90p ; no absorption i n u l t r a v i o l e t . Lit. ( 2 7 ) : [o 'ln"" 0^ 5°J m , P * 196-199° ( c o n t a i n i n g acetone of c r y s t a l l i z a t i o n ) . 5ft ,20ft -Diacetoxy-pregn -5-ene (XI) A s t i r r e d s o l u t i o n of the d i o l (X) (50.25 g) i n a c e t i c anhydride (700 ml) was r e f l u x e d gently f o r 2§ hours. A f t e r a l l o w i n g t o come to room tem-perature, water {JOO ml) was added with caution u n t i l no f u r t h e r r e a c t i o n was evident. The r e a c t i o n mixture was f u r t h e r d i l u t e d w i t h water (1000 ml) and washed with e t h y l ether (5 x 1500 ml). The combined e t h e r e a l s o l u t i o n was washed again with water (2 x 250 m l ) , then d r i e d over anhydrous mag-nesium s u l f a t e . F i l t r a t i o n , evaporation of the solvent and complete removal of t r a c e s of a c e t i c a c i d ( i n vacuo) which remained, y i e l d e d a white c r y s t a l -l i n e m a t e r i a l (58.25 g ) . C r y s t a l l i z a t i o n of t h i s product from a mixture of mathanol-water (4:1) gave an a n a l y t i c a l sample, m.p. 128-1510; i n f r a r e d i n CHCl^: 5*82^ , 8.00|x; u l t r a v i o l e t : no absorption; N.M.R. s i g n a l s i n CDCl^: 4.60 t (CH=C), 5.50 ( m u l t i p l e t ) , 8.00 ^ (CHj-S-O), doublet centered at 8.86 t (CH^-CH-), 8.98 and 9-55T. (angular methyl groups); Mn-39-7 0 (0,1.67). Lit. ( 2 7 ) : m.p. 150-151° and M r r 5 9°i 2. 5 ft,20 p -Diacetoxy-5-pregnen-7-one ( X I I ) To a s o l u t i o n of d i a c e t a t e (XI) (58.25 g) i n carbon t e t r a c h l o r i d e (200 ml), a f r e s h l y prepared s o l u t i o n of t - b u t y l chromate i n carbon t e t r a -c h l o r i d e (250 ml), a c e t i c anhydride (50 ml) and g l a c i a l a c e t i c a c i d (80 ml) 25 were added. The t-butyl chromate solution was prepared as described in reference (28). The latter was added dropwise and under stirring to the diacetate (XI) solution. After addition was complete the reaction mixture was refluxed with stirring over a period of 10 hours. After this time the mixture was cooled to 0°C and treated cautiously with a solution of oxalic acid (52 g) in water (600 ml). Another portion of solid oxalic acid (59 g) was added carefully and the entire reaction mixture was allowed to come to room temperature (~2 hours). At this point water (7>0 ml) was added and the mixture extracted with carbon tetrachloride (5 x 2000 ml). The organic layer was washed twice with water (2 x J000 ml) and then dried over anhydrous magnesium sulfate. Evapo-ration of the solvent, left a pale yellow semi-crystalline material (59.6 g)« Crystallization of this product from ethyl ether gave flat, trans-parent, long crystals, m.p. 199.5-201.5°; [©0 D - 8 5 « 2 5 ° (°> 5-^9); infrared in CHCly 5.80p , 6.00yt ; u l t r a v i o l e t : ^ ^ StOH 2 ^ mp ( l o g £ 4. J l ) ; N.M.R. signals in CDCl^: 4. J2 i t (CrCH-g- ), 6 . 5 4 x (CHj-g-O-CH) 8.00 x(CH^-C-0- ), double centered at 8.861: (CH^-CH-), 8.98T.and 9« 55 rt-( angular methyl groups). Lit. (29):m.p. 198-200° (Kofler); [ o f ] D -87° ; ultraviolet: j\ 2j6m^ (log 6 4 .24). Methyl 5$ >20p -diacetoxy-5-oxo-5,7-seco-6-norpregnan-7-oate (XIII) The conjugated ketone (XII) (2-709 g) was dissolved in methylene chloride (80 ml) and absolute methanol ( l j ml) was then added. This solution was ozonized at -78°C using the following settings on the Welsbach ozonizer: pressure of oxygen, 5.5 lbs/sq.in-5 voltage, 100; rotameter, 0.4; time, 20 minutes. After this time the reaction mixture had attained a deep blue colour. After allowing the reaction mixture to come to room temperature, a solution of 50% hydrogen peroxide (O.55 ml) in water (l.O ml) was added and 24 the mixture was l e f t f o r 12 hours at room temperature. The r e a c t i o n mixture was then t r e a t e d w i t h methylene c h l o r i d e ( 2 0 0 ml) and water (400 ml) and the organic l a y e r was separated. The aqueous l a y e r was washed with methylene c h l o r i d e (5 x 200 ml) and the combined methylene c h l o r i d e e x t r a c t was d r i e d over anhydrous magnesium s u l f a t e . Evaporation of the solvent l e f t a y e l l o w viscous o i l (5.278 g) which was then taken up i n e t h y l ether ( 2 0 0 ml) and the ether s o l u t i o n washed with 2.5% aqueous sodium hydroxide ( 2 0 ml) to remove the a c i d i c m a t e r i a l . A f t e r washing the ether l a y e r w i t h water u n t i l the washings were n e u t r a l to l i t m u s , i t was f i n a l l y d r i e d over anhydrous magnesium s u l f a t e . Removal of the ether gave a pale y e l l o w foamy gum (2.577 g)« I t was noted t h a t small amounts of i m p u r i t i e s can i n f l u e n c e the s t a t e of the f i n a l product and i n many cases t h i s m a t e r i a l was obtained as a white c r y s -t a l l i n e substance. C r y s t a l l i z a t i o n of t h i s m a t e r i a l from methanol-ethyl ether ( 1 :l) gave an a n a l y t i c a l sample, m.p." I 8 5 - I 8 5 0 ; [o<2 D+8°.5° (C ,0.25); i n f r a r e d i n KBr: 5«79[A and 5.85 V* ( s h o u l d e r ) , 8.05y\(C-0 s t r e t c h i n g ) ; N.M.R. s i g n a l s i n 0 ODGly. 4 . 7 0 T L ( C H - O A C ) , 6.48T.(-C-0CH^), 8.00x (CH^C - O -), doublet centered at 8.86t (CH^-CH-), 8.98t: and 9»55t (angular methyl groups); no absorption i n u l t r a v i o l e t ; Found: C, 66.85; H, 8.54; 0 , 24.65 . Calc. f o r C^HjQOy: C, 66.64; H, 8.5O; 0, 24.86 . Methyl 20ft -acetoxy - 5~oxo - 5,7~seco - 6-nor-5-P r eg n e n-7-oate (XIV) The saturated keto e s t e r ( X I I I ) (2.577 g ) , was taken up i n dioxane ( 1 0 0 ml) and t r e a t e d f o r 15 minutes w i t h 5% aqueous sodium hydroxide ( 2 0 ml) under constant s t i r r i n g . Water (500 ml) was then added and e x t r a c t i o n w i t h e t h y l ether (5 x 400 ml) followed. S o l i d sodium c h l o r i d e was used as an a i d to separate the two l a y e r s . The combined e t h e r e a l e x t r a c t was d r i e d over anhydrous magnesium 25 s u l f a t e . The d r y i n g agent was f i l t e r e d o f f and t h e e t h e r e v a p o r a t e d t o y i e l d a l i g h t y e l l o w , t r a n s p a r e n t o i l - w h i c h s l o w l y c r y s t a l l i z e d on s t a n d i n g (1.878 g ) . T h i s m a t e r i a l was chromatographed on n e u t r a l s i l i c a g e l (94 g) t o p r o v i d e a l i g h t y e l l o w c r y s t a l l i n e m a t e r i a l ( l . 5 0 g) a f t e r e l u t i o n w i t h b e n z e n e - c h l o r o f o r m (5 : 7). Two r e c r y s t a l l i z a t i o n s f r o m m e t h a n o l - e t h y l e t h e r ( J : l ) and p e t r o l e u m e t h e r - e t h y l e t h e r (1:2) p r o v i d e d a w h i t e c r y s t a l l i n e m a t e r i a l , m.p. 151-1550; [ « * ] D -t-77.4° ( C , 1.0J); i n f r a r e d i n ICBr: 5-79 f\ (-OAc), 5« 97 y\ ( oi, ft - u n s a t u r a t e d k e t o n e ) and 6.01 ( s h o u l d e r ) , 8.07 y> (CH ^ C-OR)i u l t r a v i o l e t : ^ 2JE t 0 H 227 m^ ( l o g f i J . 8 9 ) j N.M.R. s i g n a l s i n ODCl^: m u l t i p l e t s c e n t e r e d a t 4.2ncand 5. .18 <X., 6.46 Z. ( - C-OCH^), 8.02T. (CH^C-O-), d o u b l e t c e n t e r e d a t 8.88.T. (CH5-CH-), 8.98x. and 9. 57x ( a n g u l a r m e t h y l g r o u p s ) . Found: C , 70.24; H, 8.66; 0, 21.10 . C a l c . f o r C ^ j H ^ O ^ : C , 70.74; H, 8.78; 0, 20.49 • M e t h y l 20ft -acetoxy - 5-oxo - 5 ,7-seco-6-norpregnan-7-oate (XV) The u n s a t u r a t e d k e t o e s t e r (XIV ) (9.586" g ) , was h y d r o g e n a t e d over 10% p a l l a d i u m on c h a r c o a l (5.725 g) i n e t h a n o l a t room t e m p e r a t u r e and atmos-p h e r i c p r e s s u r e . A f t e r t r e a t m e n t f o r 1 hour t h e r e a c t i o n s t o p p e d , t h e c a t a l y s t was removed by f i l t r a t i o n . I t was n e c e s s a r y t o wash t h e f i l t e r e d c a t a l y s t s e v e r a l t i m e s w i t h h o t e t h a n o l t o a v o i d c o n s i d e r a b l e l o s s o f m a t e r i a l . The s o l v e n t was removed t o y i e l d a w h i t e semi c r y s t a l l i n e m a t e r i a l (8.908 g ) . T h i s s o l i d was t a k e n u p - i n benzene and chromatographed on a n e u t r a l s i l i c a g e l column (490 g ) . E l u t i o n w i t h b e n z e n e - c h l o r o f o r m (5 :7) gave a w h i t e - s e m i c r y s t a l l i n e m a t e r i a l (6.952 g) (18%). C r y s t a l l i z a t i o n o f t h i s m a t e r i a l f r o m e t h y l e t h e r - p e t r o l e u m e t h e r ( l : 5 ) gave an a n a l y t i c a l sample, m.p. 146-147°; [pCn + ? 8» 7° ( C , 1.95); i n f r a r e d 0 i n KBr: 5 .82 p (-OAc), 5 . 95LA(>C=0), 8.05 p (CHz5-0R); u l t r a v i o l e t : no ab-0 q s o r p t i o n ; N.M.R. s i g n a l s i n C D O l j : 6.50x(CH^0-C-), 8 . O J x ( C H j C - O - ) , d o u b l e t 26 centered at 8 . 8 7 ^ C H ^ - C H - ) , 9 » 0 9 p r _ a n d 9 . 5 5 ^ a n g u l a r methyl groups). Found: 0 , 7 0 . 0 6 ; H , 9 . 0 1 ; 0 , 2 0 . 6 1 . Calc. f o r CgjH^gO^: 0 , 7 0 . 5 7 ; H , 9 « 2 4 ; 0 , 2 0 . 5 8 . 20ft -Acetoxy-N-benzyl-6-aza-4-pregnen-7-one (XVI) The saturated keto e s t e r (XV) ( 6 . 9 5 2 g ) , Was r e f l u x e d w i t h s t i r r i n g i n benzyl-amine ( 5 0 ml) f o r 18 hours i n a n i t r o g e n atmosphere. A f t e r t h i s time the r e a c t i o n mixture was allowed t o come t o room temperature, taken up i n e t h y l ether (1000 ml) and the e t h e r e a l s o l u t i o n was washed with d i l u t e 2N h y d r o c h l o r i c a c i d ( 5 0 0 ml) to remove any unreacted benzylamine. The ether e x t r a c t was then washed w i t h water (2 x 250 ml), t i l l the aqueous washings were n e u t r a l to l i t m u s , and then d r i e d over anhydrous magnesium s u l f a t e . The dr y i n g agent was f i l t r a t e d o f f and the ether evaporated t o provide a pale y e l l o w s e m i - c r y s t a l l i n e m a t e r i a l ( 7 . 6 5 0 g ) . This m a t e r i a l was chromatographed on a n e u t r a l s i l i c a g e l (575 g) column and gave a pale y e l l o w c r y s t a l l i n e m a t e r i a l (6.684 g) (87%) upon e l u t i o n w i t h benzene-chloroform (1:1). C r y s t a l l i z a t i o n of t h i s m a t e r i a l from-ethyl ether gave a n i c e l y c r y s t a l l i n e compound, m.p. 190-191°; ' j j 0 1 ^ + 1 0 0 .5°(C,0.784); i n f r a r e d i n KBr: 5 . 8 0 ^ (-OAc), 6 .02 y*(-CsC- ), 6. 1 1 (-6-N- ), 8.06 LA (>C -0-) ; u l t r a v i o l e t : ! X m a x 257 m^ (lo g € 4 . 0 4 ) ; N.M.R. s i g n a l s i n CDClj': 2 . 8 7 t (aromatic H), 5 . J 2 x ( o l e f i n i c H), 6 . 8 5 x(;N - C H 2-Ph),- 8.05 t^-CHgCHsC), doublet centered at 8.86 t.(CHj-CH-), 8 . 9 9 'X. and 9 . 2 7 < X ( a n g u l a r methyl groups). Found: C, 7 7 * 7 4 ; H, 8.80j 0, 10.25; N, 5 . 2 1 , Calc. f o r C29H59O5W: C, 7 7 . 4 6 ; H, 8.74; 0, 10.68; N, 5 . 1 2 . 20ft -Acetoxy-N-benzy-l-6-aza-5 |-pregnen-7-one (XVII) A s o l u t i o n of the enol lactam (XVI) ( 5 5 5 » g ) i n g l a c i a l a c e t i c a c i d (50 ml) was hydrogenated over platinum oxide (100 mg) (Adam's c a t a l y s t ) at room temperature and atmospheric pressure f o r 5 hours. The c a t a l y s t was f i l -t e r e d o f f ( " c e l i t e " f i l t e r a i d was used ) and the f i l t r a t e was taken up i n 27 e t h y l e t h e r (l>0 ml) and t h e n t r e a t e d w i t h i c e - c o l d 10% aqueous sodium c a r -bonate (125 ml) t o remove t h e e x c e s s a c e t i c a c i d . The e t h e r e a l l a y e r was s e p a r a t e d and d r i e d over anhydrous magnesium s u l f a t e . F i l t r a t i o n and removal o f t h e s o l v e n t y i e l d e d a l i g h t y e l l o w semi c r y s t a l 1 i n e m a t e r i a l (3*56 mg). T h i s crude m a t e r i a l was t a k e n up i n benzene and chromatographed on a n e u t r a l s i l i c a g e l (56 g) column. E l u t i o n w i t h b e n z e n e - c h l o r o f o r m (5*2) p r o v i d e d a m e t e r i a l , 268 mg. In t h i s c a s e , as a l r e a d y n o t e d above t h e r e a c t i o n p r o d u c t a p p ears s e n s i t i v e t o h y d r o l y s i s and the a c e t o x y group a t C-20 i s c o n v e r t e d t o t h e c o r r e s p o n d i n g a l c o h o l (T.L.C. i n f o r m a t i o n ) . C r y s t a l l i z a t i o n o f t h i s m a t e r i a l f r o m e t h y l e t h e r gave an a n a l y t i c a l sample, m.p. 211-212°; [~©^J D + 51»^° (C, 2.16); i n f r a r e d i n KBr: 5.79|A (-OAc), 6 .08 y\ (-N-C-); u l t r a v i o l e t : R 6 no a b s o r p t i o n ; N.M.R. s i g n a l s i n CDCl^: 2.8l x.( a r o m a t i c H ) , 5'21xand 5 . J 7 x (>CH-0Ac), 6.56x()-M-CH2-Ph), 8 . 0 1 x(CH C-0-), d o u b l e t c e n t e r e d a t 8.G ! 5x(CH 5CH-), 9 - 0 8 x and 9-27x ( a n g u l a r m e t h y l g r o u p s ) . Found: C, 76.49; H, 8.98; 0, 10.99; N, 5.54. C a l c . f o r Q2^1Q^:U C, 77-12; H, 9.15; 0, 10 . 6 J ; ri, 5.10 . 20 ft-Hydroxy-N-benzyl-6-aza-5§-pregnane (XVIII) The s a t u r a t e d l a c t a m (XVII) (2.780 g) was d i s s o l v e d i n anhydrous e t h e r (2^0 ml ) and r e f l u x e d f o r 24 h o u r s w i t h l i t h i u m aluminum h y d r i d e (5-4 g)> which was i n i t i a l l y p l a c e d i n a S o x h l e t e x t r a c t o r and g r a d u a l l y b r o u g h t i n t o t h e r e a c t i o n v e s s e l by t h e r s f l u x i n g e t h e r . A f t e r t h i s t i m e , t h e r e a c t i o n m i x t u r e was t h e n a l l o w e d t o come t o room t e m p e r a t u r e and t h e e x c e s s h y d r i d e was decomposed by t h e d r o p w i s e a d d i t i o n o f wet e t h e r . The i n o r g a n i c s a l t s were f i l t e r e d o f f , washed w i t h e t h y l e t h e r and t h e combined e t h e r s o l u t i o n was d r i e d over anhydrous mag-nesium s u l f a t e . F i l t r a t i o n and e v a p o r a t i o n o f t h e s o l v e n t gave a p a l e 28 yellow transparent o i l (2.486 g). Crystallization of this o i l from methanol yielded an analytical sample, m.p. 108-109°; Ly"]D-*-58.50 (C, 1.745); infrared in KBr: 2.86 J A ( - O H ) ; ultraviolet: no absorption; N . M . R . signals in C D C l y 2. 71 T.(aromatic H ) , 6. 14T ( - C H - 0H ) , 6 .72t . (>N -CH2-^), doublet centered at 8. 92 n ( O H ^ - C H - ), 9 . 0 8 ^ and 9.25 ^ (angular methyl groups ). Found: C, 81.90; H, 10.54; 0, 5.66; N, 5.90. Calc. for C ^ H ^ O N : C, 81.97; H , 10.45; 0, 4.04; N , 5.54 . 29 BIBLIOGRAPHY 1. FRIED, J . and SABO,E.F. : J.Am. Chem. Soc. ,7J>,2275 (1955) 2. FRIED,J.and SABO,E.F.; I b i d . , 7 6 , 1455(1954). J . DJSRASSIjC.,MIRAMONTES,L.and ROSENKRANZ,G.:Ibid.7^,444o(1955) 4. DJERASSI,C.,MIRAMONTES,L.,ROSENKRANZ,G.and SONDHEIMER,F.:Ibid.,76,4092 (1954) • 5. D0RFMAN,R.I.,USK0K0VIC,M.and GUT,M.:157th M e e t i n g o f t h e Am.Chem.Soc., p . l 9 N , A p r i l (1960);PAPP0,R.: l47th,Ibid.,p.17M,April(1964). 6. D00RENB0S,N.: 6th Drug Trade News Survey,Sept.(1962 ) 7. HOLMES,W.L.: "Drugs A f f e c t i n g L i p i d S y n t h e s i s " , S m ith K l i n e and F r e n c h Lab., P h i l a d e l p h i a , Penn.( l964). 8. D J E R A S S I , C . : " S t e r o i d R e a c t i o n s " , Holden-Day,Inc.,San F r a n c i s c o (1965) 9- ALAUDDIN,M.and MARTIN-SMITH,M.:J.Pharm.Pharmacol.,14,525,469(1962) 10. MORISAWA,Y. ,KISHIDA,Y. and TANABA, K. -.Chem.andPharm. B u l l . (Japan),5,686(1965) 11. D00RENB0S,N.J.and WU,M.T.:J.Org.Chem.26,2548(1961) 12. WOODWARD,R.B.,SONDHEIMER,F.,TAUD,D.,HEUSLER,K. and McLAMORE,W.M.: J.Am.Chem.Soc.,74,4225(1952) 15. GUT,M.and USK0K0VIC,M.:J.Org.Chem.,26,1945(196l) 14. 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R0M0,J.^0SEMRANZ,G.and CJERASSI,C. :J.Org.Chem.17,l4l5(1952) JO. ADAMS,R. ( e d . ){'Organic R e a c t i o n s * J . W i l e y and Sons,pp 265-526,New York( l955) PART I I STUDIES RELATING TO ALKALOID TOTAL SYNTHESIS 51 INTRODUCTION Of a l a r g e number of n i t r o g e n bases o c c u r r i n g i n N a t u r e , a c o n s i d e r a b l e p o r t i o n c o n t a i n the i n d o l e n u c l e u s , A wide c a t e g o r y o f t h e s e compounds i s t h e w e l l known and v e r y i m p o r t a n t f a m i l y o f so c a l l e d " I n d o l e a l k a l o i d s " , w hich have so f a r been i s o l a t e d f r o m upwards o f twenty f i v e g e n e ra o f p l a n t s and t r e e s . They i n c l u d e many i m p o r t a n t and w i d e l y used a l k a l o i d s , such as the e r g o t b a s e s , v a l u a b l e as o x y t o c i c drugs i n c h i l d b i r t h ; s t r y c h n i n e , v a l u a b l e as a g e n e r a l t o n i c and a l s o employed as a v e r m i n k i l l e r ; yohim-b i n e , used i n v e t e r i n a r y m e d i c i n e as an a p h r o d i s i a c ; t h e e x t r a c t s o f Rau-w o l f i a s e r p e n t i n a B e n t h . , used i n I n d i a f o r s e v e r a l p u r p o s e s , c h i e f l y as a s e d a t i v e , e t c . .The p h a r m a c o l o g i c a l p r o p e r t i e s o f a l l t h e s e p l a n t e x t r a c t s have s t i m -u l a t e d c h e m i c a l i n v e s t i g a t i o n s i n t o - t h e s t r u c t u r e s o f t h e a l k a l o i d a l con-s t i t u e n t s , and so f a r t h e s t r u c t u r e s o f a p p r o x i m a t e l y t h r e e hundred i n d o l e a l k a l o i d s have been c o m p l e t e l y e l u c i d a t e d ( l ) . B e s i d e s t h e i s o l a t i o n o f a l k a l o i d s and t h e c h e m i c a l e l u c i d a t i o n of t h e i r s t r u c t u r e a c o n s i d e r a b l e e f f o r t has been c o n t r i b u t e d t o t h e t o t a l or p a r t i a l s y n t h e s i s o f t h e s e s u b s t a n c e s . I n many o f t h e s e i n s t a n c e s i n v e s t i -g a t o r s have even t r i e d t o f o l l o w s y n t h e t i c schemes i n t h e l a b o r a t o r y w h i c h c o u l d p o s s i b l y b e a r some r e l a t i o n s h i p t o t h e pathways u t i l i z e d by N a t u r e . A l t h o u g h a good d e a l o f work s t i l l r e mains t o be c a r r i e d out i n the a r e a o f a l k a l o i d b i o s y n t h e s i s , a. c o n s i d e r a b l e amount of i n f o r m a t i o n i s a l r e a d y a v a i l a b l e f r o m e x p e r i m e n t s w i t h r a d i o a c t i v e t r a c e r s (2). I t has l o n g been s u s p e c t e d t h a t t r y p t o p h a n ( I ! i s t h e i m p o r t a n t amino a c i d w h i c h s e r v e s as t h e b u i l d i n g u n i t f o r t h e i n d o l e a l k a l o i d s (5). Recent t r a c e r e x p e r i m e n t s have p r o v i d e d c o n f o r m a t i o n o f t h i s p o s t u l a t e . T r y p t o p h a n , a f t e r d e c a r b o x y l a t i o n , i s c o n v e r t e d i n t o t r y p t a m i n e ( I I ) , w h i c h j u s t l i k e p h e n e t h y l a m i n e , i s c a p a b l e o f u n d e r g o i n g a whole s e r i e s o f con-d e n s a t i o n s r e a c t i o n s ( s e e F i g u r e l ) . CONDENSATION PRODUCTS F i g u r e 1. B i o g e n e t i c d e r i v a t i o n o f s i m p l e i n d o l e a l k a l o i d s . F o r example, s e r o t o n i n ( 5 - h y d r o x y t r y p t a m i n e ) ( I V ) , one o f t h e more i m p o r t a n t n a t u r a l l y o c c u r r i n g i n d o l y 1 - a l k y l a m i n e s i s produced by h y d r o x y l a t i o n o f t r y p t o p h a n ( i ) t o 5 - h y d r o x y t r y p t o p h a n ( i l l ) and subsequent d e c a r b o x y l a t i o n . T r y p t a m i n e i t s e l f cannot be h y d r o x y l a t e d . P s i l o c y b i n e ( V ) , a p h o s p h o r i c e s t e r o f N , N - d i m e t h y l - 4 - h y d r o x y t r y p t a m i n e , a n o t h e r t r y p h a m i n e d e r i v a t i v e , i s t h e a c t i v e c o n s t i t u e n t of t h e M e x i c a n h a l l u c i n o g e n i c f u n g i o f t h e genus 55 " P s i l o c y b e " ( F i g u r e l ) . I t i s i n t e r e s t i n g t o n o t e t h a t i t i s one o f t h e few 4-hydroxy i n d o l e a n a l o g u e s a c t u a l l y i s o l a t e d i n N a t u r e . I n d o l e i t s e l f o c c u r s i n c e r t a i n p l a n t s and has been o b t a i n e d f r o m t h e d i s t i l l e d o i l of j a s m i n e f l o w e r s and f r o m t h e d e c a y i n g wood of " C e l t i s r e t i c u l o s a " . However, i t i s not a t r u e a l k a l o i d , and p r o b a b l y a r i s e s f r o m d e g r a d a t i o n o f more complex i n d o l e d e r i v a t i v e s , e.g. t r y p t o p h a n ( I ) . F o u r comparably s i m p l e , m o n o s u b s t i t u t e d i n d o l e bases have been i s o l a t e d f r o m n a t u r a l s o u r c e s . They a r e : a b r i n e ( V I ) f r o m t h e seeds o f "Abrus p r e c a t o r i u s " L., h y p a p h o r i n e ( V I I ) f r o m t h e seeds of v a r i o u s " E r y t h r i n a " s p e c i e s , gramine ( V I I I ) f r o m b a r l e y l e a v e s and "Arundo donax", and d o n a x a r i n e , C l j H i g C v , ^ , a l s o f r o m the same p l a n t ( F i g u r e l ) . As L e e t e has shown, th e p i p e r i d i n e m o i e t y of a l k a l o i d s i s d e r i v e d f r o m l y s i n e (4) and/or c a d a v e r i n e (5)> I t i s p o s t u l a t e d t h a t t h e more complex a l k a l o i d s t r u c t u r e s a r e d e r i v e d f r o m t h e s i m p l e r c o u n t e r p a r t s by v a r i o u s t y p e s of c o n d e n s a t i o n r e a c t i o n s and some o f t h e more i m p o r t a n t ones a r e i l l u s t r a t e d i n F i g u r e 2 and mentioned b r i e f l y below: 1) C o n d e n s a t i o n o f a c a r b i n o l a m i n e w i t h t h e a c t i v e methylene groups o f k e t o n e s or ^ - k e t o a c i d s ( R e a c t i o n l ) . 2 ) A l d o l c o n d e n s a t i o n between a l d e h y d e s and ft - k e t o a c i d s ( R e a c t i o n 2 ) . I t i s b e l i e v e d t h a t subsequent d e c a r b o x y l a t i o n o c c u r s w i t h t h e f o r m a t i o n o f a (3 - h y d r o x y k e t o n e , e t c . 5) C o n d e n s a t i o n s of - s u b s t i t u t e d e t h y l a m i n e s ' w i t h a l d e h y d e s ( R e a c t i o n 5)' T h i s r e a c t i o n i s p a r t i c u l a r l y i m p o r t a n t f o r t h e s y n t h e s i s o f N - h e t e r o c y c l i c r i n g s . 4) A l d o l - t y p e c o n d e n s a t i o n s between r e a c t i v e d o u b l e bonds i s shown i n t h e c a s e o f a A ^ - p i p e r i d e i n e ( R e a c t i o n 4). 54 O H C - H li o © • N -•CH-OH - M -. C O O H H p - C - R •CO, O R —CL—O COOH O H,0 N — 0 -^-[^-CHOH-CH2-C-R + C 0 Z © © OHO4  H k 4-^ R H H F i g u r e 2. Some c o n d e n s a t i o n r e a c t i o n s w h i c h a r e b e l i e v e d i m p o r t a n t i n a l k a l o i d b i o s y n t h e s i s . I t s t i l l r emains u n c l e a r whether the above " i n v i t r o " , " p h y s i o l o g i c a l -t y p e " r e a c t i o n s , r e p r e s e n t t h e t r u e b i o s y n t h e t i o pathways i n p l a n t s and f u r t h e r . r e s e a r c h on t h e a c t u a l b i o l o g i c a l systems i s an a b s o l u t e n e c e s s i t y . The tremendous i n t e r e s t i n a l k a l o i d b i o s y n t h e s i s has led,,a number .of r e s e a r c h e r s t o propose v a r i o u s h y p o t h e s i s t o t r y and r a t i o n a l i z e t h e f o r -m a t i o n of t h e s e p l a n t p r o d u c t s . We w i l l c o n c e r n o u r s e l v e s h e r e w i t h o n l y t h o s e p o s t u l a t e s which a r e r e l e v a n t t o t h i s t h e s i s . Wenkert ( 6 ) , i n 1962, c o n s i d e r e d and proposed an i n t e r e s t i n g scheme f o r t h e i n d o l e . b a s e s and our d i s c u s s i o n w i l l emphasize t h e Asp i d o s p e r m a and Iboga f a m i l i e s . F or example he proposed t h a t i o n i c i n t e r m e d i a t e s such as 55 ( I X ) can proc e e d v i a a p p r o p r i a t e t r a n s a n n u l a r c y c l i z a t i o n s t o t h e s e s e r i e s . There a r e v a r i o u s p o s s i b i l i t i e s f o r t h i s c y c l i z a t i o n depending on t h e p o s i t i o n o f t h e i m i n i u m ( >C=N<) bond and t h i s i n t u r n can l e a d t o d i f -f e r e n t c l a s s e s o f a l k a l o i d s . A l t h o u g h t h e s e s p e c u l a t i o n s were o f i n t e r e s t , e x p e r i m e n t a l v e r i f i c a t i o n was u n a v a i l a b l e u n t i l r e c e n t l y when a s e r i e s o f i n v e s t i g a t i o n s by Kutney e t a l . ( 7 - 1 2 ) p r o v i d e d t h e f i r s t l a b o r a t o r y r e a l i z a t i o n o f such a t r a n s a n -f. n u l a r c y c l i z a t i o n p r o c e s s . I t i s a p p r o p r i a t e a t t h i s , p o i n t t o d i s c u s s t h i s work b r i e f l y s i n c e i t has a d i r e c t b e a r i n g on t h e r e a s o n s o f t h e s y n t h e s e s w h i c h were c a r r i e d o ut and d e s c r i b e d i n t h i s t h e s i s . I n 1965 i t was f o u n d t h a t c l e a v a m i n e ( X I ) , F i g u r e 5, (7) was i n d e e d one o f .the main p r o d u c t s o f a c i d i c h y d r o l y s i s o f c a n t h a r a n t h i n e ( X ) , as w e l l as o f v i n c a l e u k o b l a s t i n e and l e u r o s i n e . D i h y d r o c l e a v a m i n e ( X I I ) p r e p a r e d by c a t a l y t i c h y d r o g e n a t i o n o f c l e a v a -mine ( X I ) , was c o n v e r t e d t o an A s p i d o s p e r m a - s k e l e t o n ( X I V ) as i n d i c a t e d i n F i g u r e 5* I n subsequent work (10), a n o t h e r s u c c e s s f u l s e r i e s o f r e a c t i o n s was c a r r i e d out i n w h i c h c a r b o m e t h o x y d i h y d r o c l e a v a m i n e (XV) r e a c t e d as above w i t h m e r c u r i c a c e t a t e t o p r o v i d e an i m i n i u m i n t e r m e d i a t e . C y c l i z a t i o n o f the l a t t e r gave a V i n c a d i f f o r m i n e - t y p e s k e l e t o n ( X I X ) as t h e major p r o d u c t ( F i g u r e 4 ) . The l a t t e r ( X I X ) by r e d u c t i o n w i t h z i n c i n s u l f u r i c a c i d gave (XX).. Treatment o f ( X X ) w i t h 2 N h y d r o c h l o r i c a c i d and t h e n r e d u c t i o n w i t h l i t h i u m aluminum h y d r i d e , gave an As p i d o s p e r m a - t y p e s k e l e t o n ( X X I ) t h e r e b y c o r r e l a t i n g t h e s e t h r e e f a m i l i e s o f a l k a l o i d s . ( F i g u r e s 5 and 4) ; I t i s a l s o i m p o r t a n t t h a t t h e p r e p a r e d v i n c a d i f f o r m i n e - t y p e a l k a l o i d p r o v i d e s t h e con-n e c t i n g b i o g e n e t i c l i n k s between a s p i d o s p e r m i n e - and akuammicine-type b a s e s . I n t h e most r e c e n t paper (12) i t i s d e m o n s t r a t e d t h a t a f u r t h e r pos-36 F i g u r e J . Wenkert's i o n i c i n t e r m e d i a t e and i n t e r c o n v e r s i o n o f one i n d o l e - a l k a l o i d family'-4.0 a n o t h e r . 57 Q 2N HC1 2) L i A l H ^ F i g u r e 4. I n t e r r e l a t i o n s o f d i f f e r e n t 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 by c l e a v a g e , r e a r r a n g e m e n t s and t r a n s a n n u l a r c y c l i z a t i o h s . 58 s i b i l i t y e x i s t s f o r the transannular c y c l i z a t i o n process. The intermediate r e a c t i o n product with the _>NsC«^ between N-6 and C-5 leads to the Iboga skeleton and i n t h i s manner, coronaridine and dihydrocatharanthine were synthesized. Since a l l of these transannular c y c l i z a t i o n s made p o s s i b l e the i n t e r -conversion and i n t e r - r e l a t i o n of the important and widespread groups of Vinca, Aspidosperma, and Iboga a l k a l o i d s , considerable s t i m u l a t i o n i n our research program was d i r e c t e d toward the pr e p a r a t i o n of dihydrocleavamine, carbomethoxydihydrocleavamine and quebrachamine since these "key" compounds provide the route to the t o t a l synthesis of these v a r i o u s c l a s s e s of a l k a l o i d s . 59 DISCUSSION As a l r e a d y mentioned i n t h e I n t r o d u c t i o n t h e t r a n s a n n u l a r c y c l i z a t i o n o f t h e a p p r o p r i a t e nine-membered r i n g i n t e r m e d i a t e p r o v i d e d an a t t r a c t i v e s y n t h e t i c e n t r y i n t o a wide v a r i e t y o f i n d o l e , and d i h y d r o i n d o l e a l k a l o i d s . C o n s e q u e n t l y i t was now d e s i r a b l e t o d e v e l o p a s y n t h e t i c pathway t o t h e "key" i n t e r m e d i a t e s f o r t h e proposed t o t a l s y n t h e s e s of t h e s e n a t u r a l p r o d u c t s . A p r o j e c t e d p l a n f o r t h e s y n t h e t i c approach i s o u t l i n e d i n F i g u r e 5-Q N - ^ C o o c H , H ^ X X I I I XV COOCH^ C O O C H ^ XXIV ^ H \ ; XXV .OOCH, X I I F i g u r e 5* Proposed s e q u e n c e . f o r s y n t h e s i s o f nine-membered r i n g i n t e r -m e d i a t e s In i t s most g e n e r a l sense t h e i n i t i a l s t e p s r e q u i r e t h e f o r m a t i o n o f an a p p r o p r i a t e d i e s t e r (XXV) w h i c h t h r o u g h subsequent c y c l i z a t i o n c o u l d g e n e r a t e t h e d e s i r e d nine-membered r i n g . T h i s p a r t o f t h e t h e s i s o u t l i n e s our i n -v e s t i g a t i o n s d i r e c t e d a t t h e s y n t h e s i s o f t h e n e c e s s a r y i n d o l e - a n d .-.piper-i d i n e u n i t s which were r e q u i r e d f o r t h i s work. 40 Ths Indole Moiety There are many well-known r e a c t i o n s which provide a s y n t h e t i c entry i n t o the in d o l e nucleus (15-17)' Of the various a l t e r n a t i v e s we chose t o u t i l i z e the R e i s s e r t synthesis which i s w e l l s u i t e d f o r the prep a r a t i o n of indole d e r i v a t i v e s possessing a carboxyl or carbomethoxy group at the op-p o s i t i o n of the indole system (18). From st u d i e s on the va r i o u s methods of in d o l e preparations, i t has been found that the R e i s s e r t ' s method gave op-timum r e s u l t s (19)' The R e i s s e r t synthesis employs o_-nitrotoluene . . as i t s s t a r t i n g m a t e r i a l and the p e r t i n e n t steps f o r the synthesis of i n d o l e - 2 - c a r b o x y l i c a c i d (XXX) are o u t l i n e d i n Figure 6. XXVIII XXXI Hoesch Rx. COOEt COOEt NaOEt Me OH COOCV - i -CH*CN CH2C1CN Hoesch Rx. H - O O C H 3 XXXII XXIX C O O H 1) FeS04/NH4.0H 2) HC1 XXIII COOH Figure 6 . P r e p a r a t i o n of 2~carbomethoxy - 5-chloroacetylindole ( X X I I l ) from o-nitrotol.uene . 4l The p o s t u l a t e d mechanisms f o r t h e f o r m a t i o n o f t h e p y r u v i c a c i d d e r i v a t i v e and i t s subsequent e l a b o r a t i o n t o t h e i n d o l e a r e g i v e n i n F i g u r e 7 and F i g u r e 8. c - o e t NaOEt O O H H 20 -NO, - C H , - C - O E t C O O E t XXIX C O O E t F i g u r e 7* Proposed mechanism f o r p r e p a r a t i o n o f o - n i t r o p h e n y l p y r u v i c a c i d (XXIX) f r o m o - n i t r o t o l u e n e ( X X V I I I ) . .COOH FeS04 + NH4OH -Ha0 XXIX -H 20 C^OOH XXX COOH C O O H F i g u r e 8. Proposed mechanism f o r p r e p a r a t i o n o f i n d o l e - 2 - c a r b o x y l i c a c i d (XXX) f r o m o - n i t r o p h e n y l p y r u v i c a c i d ( X X I X ) . F o l l o w i n g , t h e r e f o r e , t h i s method as d e s c r i b e d i n r e f e r e n c e ( 1 8 ) and u s i n g s l i g h t l y ' s t r o n g e r c o n d i t i o n s we o b t a i n a c r y s t a l l i n e p r o d u c t . The u l t r a v i o l e t s p e c t r u m of t h i s compound showed maxima a t 262, 2°0 ( s h o u l d e r ) and. a b r o a d maximum a t ~ 215 mjx. The i n f r a r e d s p e c t r u m showed a b s o r p t i o n a t 5» 75 p- and 5.86JA f o r t h e c a r b o x y l and ke t o n e f u n c t i o n s and a t 6.25ycdue t o 42 a r o m a t i c system. The s p e c t r a l i n f o r m a t i o n and t h e m e l t i n g p o i n t b e i n g i d e n -t i c a l t o t h e l i t e r a t u r e v a l u e (18) e s t a b l i s h e d s t r u c t u r e ( X X I X ) f o r t h i s p r o d u c t . The n i t r o group i n (XX I X ) r e d u c e d t o t h e amino f u n c t i o n and t h i s l a t t e r compound was s u b s e q u e n t l y c y c l i z e d t o t h e c o r r e s p o n d i n g i n d o l e d e r i v -a t i v e (XXX) by use of f e r r o u s s u l f a t e i n c o n c e n t r a t e d ammonium h y d r o x i d e . Other c y c l i z a t i o n c o n d i t i o n s f o r t h i s c o n v e r s i o n have been r e p o r t e d (20-22), but were n o t used i n t h i s work. The r e a c t i o n p r o d u c t e x h i b i t e d an u l t r a -v i o l e t s p e c t r u m c h a r a c t e r i s t i c f o r i n d o l e s p o s s e s s i n g a c a r b o x y l f u n c t i o n i n t h e o c - p o s i t i o n C^Xmax 217.5 and 292.5 m ^ ) . The i n f r a r e d s p e c t r u m showed t h e s t r o n g c a r b o x y l a b s o r p t i o n a t 5«86y\, and t h e a r o m a t i c bands a t 6 . 0 2 ^ . The m e l t i n g p o i n t o f t h i s compound (XXX) was a l s o i n agreement w i t h t h a t r e p o r t e d i n t h e l i t e r a t u r e ( 2 0 ) . The c a r b o x y l i c a c i d (XXX) was t h e n e s t e r i f i e d w i t h methanol f o l l o w i n g t h e p u b l i s h e d p r o c e d u r e (25). The c r y s t a l l i n e e s t e r (XXXI) w i t h u l t r a v i o l e t a b s o r p t i o n a t 218 and 294 myi and a s t r o n g i n f r a r e d band a t 5»84yi was t h u s o b t a i n e d as e x p e c t e d . I n o r d e r ot i n t r o d u c e a c a r b o n - c h a i n at t h e ^ - p o s i t i o n o f t h e m e t h y l -e s t e r (XXXI) w i t h a s u i t a b l e r e a c t i v e group, n e c e s s a r y f o r a subsequent c o u p l i n g r e a c t i o n w i t h t h e p i p e r i d i n e m o i e t y ( X X I V ) , we c o n s i d e r e d t h e Hoesch s y n t h e s i s (24). T h i s r e a c t i o n i s w e l l s u i t e d f o r p r e p a r i n g ' i n d o l e d e r i v a t i v e s b e a r i n g a c a r b o x y l f u n c t i o n a t the ( 2>-position of t h e i n d o l e n u c l e u s (25). T h e r e f o r e we t r e a t e d t he e s t e r ( X X X I ) w i t h a c e t o n i t r i l e i n a c h l o r o f o r m - e t h y l e t h e r m i x t u r e i n a s e a l e d tube at ^>0°C. The more common Hoesch c o n d i t i o n s employ a b s o l u t e e t h e r as s o l v e n t ! b u t our compound (XXXI) was o n l y s l i g h t l y s o l u b l e i n t h i s s o l v e n t . The e x p e c t e d 2-carbomethoxy~ 5 -a c e t y l i n d o l e ( X X X I I ) was i n d e e d o b t a i n e d , but o n l y i n poor y i e l d . F u r t h e r 45 i n v e s t i g a t i o n s would be n e c e s s a r y i n o r d e r t o f i n d t he optimum e x p e r i m e n t a l c o n d i t i o n s f o r t h i s r e a c t i o n . However t h i s was n o t done s i n c e we fo u n d t h a t a Hoesch r e a c t i o n under t h e same c o n d i t i o n s i n a b s o l u t e c h l o r o f o r m | but u s i n g c h l o r o a c e t o n i t r i l e worked much b e t t e r t o p r o v i d e t h e 5 - c h l o r a c e t y l i n d o l e d e r i v a t i v e as d e s c r i b e d below. See r e a c t i o n mechanism i n F i g u r e 9-XXXI sy H C E E N C = N H _|_ | S e a l e d tube H 2 0 H X X I I I -NH. F i g u r e 9> Proposed mechanism o f Houben-Hoesch r e a c t i o n f o r p r e p a r a t i o n o f 2 - c a r b o m e t h o x y - 5 - c h l o r o a c e t y l i n d o l e ( X X I I I ) P u r i f i c a t i o n o f the l a t t e r by chromatography y i e l d e d a b e a u t i f u l l y c o l o u r -l e s s c r y s t a l l i n e compound w i t h a sharp m e l t i n g p o i n t (l47»5-l48.5°) w h i c h a n a l y z e d f o r C ^ H ^ O j . N C l . The s p e c t r a l p r o p e r t i e s o f t h i s s u b s t a n c e were v e r y i n s t r u c t i v e and s e r v e d t o e s t a b l i s h t h e e x p e c t e d s t r u c t u r e ( X X I I I ) f o r t h i s compound. For example t h e N.M.R. sp e c t r u m i n d i c a t e d t h e normal m u l t i p l e t c e n t e r e d a t 2.65 ^ for t h e a r o m a t i c p r o t o n s o f t h e i n d o l e n u c l e u s , a t w o - p r o t o n s i n g l e t a t 4.98rc (-C-CH2CI) and a t h r e e - p r o t o n s i n g l e t a t 5»98T: f o r t h e e s t e r m e t h y l p r o t o n s . The i n f r a r e d s p e c t r u m o f th e Hoesch p r o d u c t showed a v e r y s h a r p band a t 2.98u (^NH) and two c a r b o n y l bands a t 5*82 y. and 6.0 y i n complete agreement w i t h t h e a s s i g n e d s t r u c t u r e . F i n a l l y t h e u l t r a v i o l e t a b s o r p t i o n a t 2 2 0 , 249 and 518 mJA. was d i s t i n c t l y d i f f e r e n t f r o m t h a t o f t h e s t a r t i n g i n d o l e . 44 The above e x p e r i m e n t s t h e r e f o r e p r o v i d e d us w i t h a d e s i r a b l e i n d o l e u n i t f o r the subsequent r e a c t i o n w i t h t h e p i p e r i d i n e u n i t , t o be d i s c u s s e d below. The P i p e r i d i n e M o i e t y I n o r d e r f o r one t o p r e p a r e a p i p e r i d i n e d e r i v a t i v e s u i t a b l e f o r ' r e a c t i o n w i t h the i n d o l e m o i e t y p r e p a r e d a b o v e , i t was r e a s o n a b l e t o s t a r t f r o m a p y r i d i n e d e r i v a t i v e . We chose 5 > 5~dimethylpyridine ( o r 5 - l u t i d i n e ) v ( X X X I V ) , a c o m m e r c i a l l y r e ady a v a i l a b l e compound and proposed t o p r e p a r e t h e p i p e r i d i n e u n i t (XXIV)as i n d i c a t e d i n F i g u r e 10. The f i r s t s t e p c o n s i s t e d i n c a r r y i n g out an o x i d a t i o n t o y i e l d t h e c o r -r e s p o n d i n g 3> 5-dicarboxylic a c i d ( d i n i c o t i n i c a c i d ) ( X X X V ) i n q u i t e good y i e l d (79%). The r e a c t i o n p r o d u c t had t h e same m e l t i n g p o i n t as r e p o r t e d i n t h e l i t e r a t u r e (26). To p r e p a r e t h e c o r r e s p o n d i n g m e t h y l e s t e r o f d i -n i c o t i n i c a c i d ( X L I I l ) we f i r s t t r i e d an e s t e r i f i c a t i o n u s i n g an e t h e r e a l s o l u t i o n o f diazomethane, w h i c h was added t o a methanol s o l u t i o n of t h e d i a c i d . The y i e l d o f t h e r e a c t i o n was r e a s o n a b l e (6l%, c r u d e ) , but t h e i n -s t a b i l i t y o f t h i s e s t e r t o subsequent p u r i f i c a t i o n ( s u b l i m a t i o n under h i g h vacuum, column chromatography, c r y s t a l l i z a t i o n ) a l l o w e d o n l y a poor r e c o v e r y (»v 15%) o f t h e d e s i r e d p r o d u c t , m.p. 81-84°. The c h a r a c t e r i s t i c s p e c t r a o f t h i s compound and t h e m e l t i n g p o i n t w h i c h was i n agreement w i t h t h e one r e p o r t e d i n t h e l i t e r a t u r e (26) was s u f f i c i e n t e v i d e n c e t o i n d i c a t e t h a t t h e d i m e t h y l e s t e r ( X L I I l ) had been o b t a i n e d . Due t o t h e poor y i e l d i n t h e above e s t e r i f i c a t i o n , we t r i e d t o p r e p a r e t h e d i e t h y l e s t e r (XXXVI$ by t h e u s u a l e s t e r i f i c a t i o n w i t h a b s o l u t e e t h a n o l , and h y d r o g e n c h l o r i d e gas. The r e a c t i o n p r o d u c t had t h e same m e l t i n g p o i n t r e p o r t e d i n t h e l i t e r a t u r e (46-47°C) (27) and t h e s p e c t r a were a g a i n i n agreement w i t h e x p e c t a t i o n s f o r compound ( X X X V I I ) , but t h e y i e l d was a g a i n 45 XXXIV HCOOC^. coocH X L I I l • CH 2 N 2 Me OAc U C C D c ^ \ r OC M£OOCH X L I V 2N H s C P a ^ T C 0 0 C 2 H 5 EtOH HgSO^ H C O C C ^ . C O C H XLV HfpOC X X X V I I EtOAc COCH^COOC^Hs W oIff-K i s h n e r COOH X X X V I I I 2N o l f f - K i s h n e r H f O C H 2 S 0 4 XL H 2 R h / A l 2 0 j XXXIX X C 0 C 2 H 5 X L I I C O O H ' CK 2N2 X L I H X X I V K^yJ £-Br^COCl H F i g u r e 10. R e a c t i o n sequence f o l l o w e d , l e a d i n g t o - t h e f o r m a t i o n o f 5 - e t h y l n i p e c o t i c a c i d m e t h y l e s t e r (XXIV ). 46 low (40%). Meanwhile, we had f o u n d i n t h e l i t e r a t u r e a n o t h e r way t o overcome t h i s p r o b l e m and t h e r e f o r e c o n s i d e r e d t h i s a l t e r n a t i v e . Friedman and L e e t e (2 8) r e c e n t l y p r e p a r e d t h e e s t e r o f n i c o t i n i c a c i d by f i r s t c o n v e r s i o n t o th e a c i d c h l o r i d e and subsequent e s t e r i f i c a t i o n w i t h a b s o l u t e e t h a n o l . When we f o l l o w e d t h i s p r o c e d u r e w i t h s l i g h t m o d i f i c a t i o n s t o s u i t our c a s e , we o b t a i n e d a much b e t t e r y i e l d (10%, pure a f t e r d i s t i l l a t i o n under r e d u c e d p r e s s u r e ) o f the d e s i r e d d i e t h y l e s t e r (XXXVII).. I n t h e meantime we were c o n s i d e r i n g a C l a i s e n - t y p e c o n d e n s a t i o n on th e d i m e t h y l e s t e r ( X L I I l ) which was a l r e a d y a v a i l a b l e f r o m our i n i t i a l s t u d i e s mentioned above. T h i s compound was t r e a t e d w i t h m e t h y l a c e t a t e and sodium m e t h c x i d e under anhydrous c o n d i t i o n s and t h e r e a c t i o n p r o d u c t (74%, c r u d e ) showed t h e e x p e c t e d s p e c t r a l p r o p e r t i e s . F o r example t h e u l t r a v i o l e t s p e c t r u m showed maxima a t 228, 26j ( s h o u l d e r ) , 269 and 275 m ^ t ( s h o u l d e r ) , whereas t h e i n f r a r e d was a l s o i n agreement w i t h t h e p o s t u l a t e d s t r u c t u r e ( X L I V ) . However, t h i s r e a c t i o n p r o d u c t was nev e r c h a r a c t e r i s e d c o m p l e t e l y , b u t s u b j e c t e d t o a d e c a r b o x y l a t i o n r e a c t i o n w i t h 2N s u l f u r i c a c i d t o p r o v i d e t h e c o r r e s p o n d i n g 5 - c a r b o m e t h o x y - 5 ~ a c e t y l p y r i d i n e ( X L V ) . A p p l i c a t i o n o f a m o d i f i e d W o l f f - K i ' s h n e r r e d u c t i o n , y i e l d e d t h e known J - e t h y l n i c o t i n i c a c i d ( X L ) . The r e a c t i o n p r o d u c t (XLV) was a l s o n e v e r c h a r a c t e r i z e d c o m p l e t e l y , s i n c e we abandoned t h i s sequence, because we fo u n d t h e pathway t h r o u g h t h e c o r r e s p o n d i n g d i e t h y l e s t e r ( X X X V I I ) t o be more e f f e c t i v e (see F i g u r e 10). N e v e r t h e l e s s t h e s p e c t r a l d a t a i s mentioned h e r e t o i n d i c a t e t h a t i t i s c o n s i s t a n t w i t h t h i s f o r m u l a t i o n . The u l t r a v i o l e t s p e c t r u m shows two maxima, a t 225 my. and 268 my , w i t h % m ^ n a t 252 my.. The i n f r a r e d s p e c t r u m had a sh a r p peak a t 5.76u. ( f o r -COOCHj), 5.91 ( f o r -CCHj) and 6.5O ( f o r t h e a r o m a t i c r i n g ) . H a v i n g d e v e l o p e d a more s a t i s f a c t o r y sequence t o the d i e t h y l ester., we 47 tried, as above, the same Claisen condensation ( 2 7 ) , on the latter but utilizing ethyl acetate and sodium ethoxide. The expected Claisen product (XXXVIII) was obtained, but the yield wa-a very poor because of the possibi-li t y that the reaction proceeded further with the second ester group. After a series of experiments we found the optimum conditions for this reaction which utilized the molar ratio of diester: NaOBt ; EtOAc Of 1:2:4 respectively. The optimum yield was 53% and this product was sufficiently purs and had a sharp melting point without any further purification, which was in agreement with the literature value ( 2 7 ) . The £-keto ester ( X X X V I I I ) exhibited some interesting changes in the ultraviolet spectrum and'these are mentioned briefly. The ini t i a l spectrum taken in methanol showed maxima at 228 and 282 mu,, but i f the solution was allowed to stand for a few minutes the spectrum slowly shifted exhibiting an hypsochromic shift (^-max 282 mu.-—*-278 m|JL ) and an hypochromic shift (optical density from 0.44 >-O.JO). See Figure 11. Curves in 1 ) - 2 8 2 ( 0 . 4 4 ), 248( 0 . 1 7 ) , 228( 0 . 6 8 ) 2)~ 2 7 9 ( 0 . 5 4 ) , 2 5 0 ( 0.17),228 ( 0.68) 5 ) " 2 7 8 ( 0 . 5 0 ) , 2 5 2 ( 0 . l 6 ) , 2 2 8 ( 0 . 6 8 ) WAVELENGTH (in 8 ) Figure 11. Hypochromic and hypsochromic shifts in U.V. spectrum of compound (XXXVIIl)-because of the enolization; 48 T h i s happened w i t h i n 10 m i n u t e s . These s p e c t r a l s h i f t s a r e e x p l a i n a b l e when one c o n s i d e r s t h a t t h e (2-keto e s t e r i s i n e q u i l i b r i u m w i t h i t s e n o l i c f o r m i . e . (-C-CHg-COOEt-s. T-CsOH-COOEt) and t h a t t h i s e q u i l i b r i u m i s 0 OH s l o w l y a t t a i n e d on s t a n d i n g i n methanol. B e s i d e s t h e U.V. d a t a t h i s compound showed an i n f r a r e d s p e c t r u m w i t h a v e r y s t r o n g peak a t 5-80yn, f o r t h e two -COOEt g r o u p s , a weaker ketone peak a t 6.08 y_ and a weak peak a t 6.15 y. (C=C). From t h i s i n f o r m a t i o n and w i t h t h e c h e m i c a l e v i d e n c e f r o m t h e f o l l o w -i n g r e a c t i o n sequence we assumed s t r u c t u r e ( X X X V I I I ) f o r t h i s compound. The C l a i s e n p r o d u c t was now h e a t e d m i l d l y w i t h 2N s u l f u r i c a c i d ; whereupon e v o l u t i o n o f c a r b o n d i o x i d e t o o k p l a c e and t h e i s o l a t e d compound (62% y i e l d ) was a n i c e l y c r y s t a l l i n e m a t e r i a l h a v i n g t h e same m e l t i n g p o i n t as i n t h e l i t e r a t u r e (27). I t s u l t r a v i o l e t s p e c t r u m (\ m a x 224 and 268 my. ) and i n f r a -r e d s p e c t r u m a t 5« 95 yp c o n f i r m e d t h e s t r u c t u r e (XXXIX) a s s i g n e d t o t h i s p r o d u c t . I t was now n e c e s s a r y t o reduce t h e k e t o n i c c a r b o n y l t o a methylene group and t h i s was b e s t a c c o m p l i s h e d by means o f t h e W o l f f - K i s h n e r method (29)). C o n s e q u e n t l y t h e compound (XXXIX) was t r a n s f o r m e d by r e a c t i o n w i t h h y d r a z i n e h y d r a t e i n t o t h e d i f f i c u l t l y s e p a r a t i n g h y d r a z o n e , and t h e l a t t e r w i t h o u t i s o l a t i o n was t h e n r e f l u x e d w i t h c o n c e n t r a t e d p o t a s s i u m h y d r o x i d e (see r e f e r e n c e 50 ). A c i d i f i c a t i o n o f t h e r e a c t i o n m i x t u r e t o l i b e r a t e t h e f r e e a c i d ( s o l u b l e i n w a t e r ) f o l l o w e d by f o r m a t i o n o f t h e copper s a l t ( a d j u s t m e n t o f pH i n i t i a l l y between 2«5 -2.9 and t h e n a d d i t i o n o f copper a c e t a t e i n s m a l l e x c e s s and r e a d j u s t m e n t o f pH t o 5.6-5.9) a l l o w e d i s o l a t i o n o f t h e r e a c t i o n p r o d u c t (see r e f e r e n c e 51•)• D e c o m p o s i t i o n o f t h e l a t t e r w i t h h y d r o g e n s u l f i d e gave t h e crude n i c o t i n i c a c i d d e r i v a t i v e w h i c h was p u r i -f i e d by c r y s t a l l i z a t i o n ( y i e l d 67%), and had t h e d e s i r e d m e l t i n g p o i n t (27) and s p e c t r a . Most n o t e w o r t h y i n t h e i n f r a r e d s p e c t r u m was t h e d i s a p p e a r a n c e 49 of the ketone abs o r p t i o n at 5'95^ and a s h i f t of the carbonyl band from 5.78|A. (COOEt) to 5.83LA, (COOH). The N.M.R. spectrum of t h i s compound when taken i n B^O i n d i c a t e d that some deuterium exchange was oc c u r r i n g w i t h the aromatic protons, but a t r i p l e t at 8.8x and a quartet at 7.5^ e s t a b l i s h e d the presence of an e t h y l group. F i n a l l y a n a l y s i s confirmed beyond any doubt that we had ob-tai n e d the desired 5-ethyl n i c o t i n i c a c i d (XL). The next step i n the sequence in v o l v e d the r e d u c t i o n of the p y r i d i n e r i n g to a saturated p i p e r i d i n e nucleus. The hydrogenation of the aromatic system has been studied i n some d e t a i l and var i o u s c a t a l y s t s have been u t i l i z e d . In some instances h i g h y i e l d s are obtainable w i t h P t 0 2 , 5% Rh/C (52) as w e l l as with Ru0 2 (about 85% y i e l d ) (55) and 5% Rh/AlgOj (about 88% y i e l d ) (54 )• THe reduction of p y r i d i n e c a r b o x y l i c a c i d s provides exper-imental d i f f i c u l t i e s because serious side r e a c t i o n s such as reduction to the primary a l c o h o l , hydrogenolysis, e t c . , set i n and the y i e l d s are poor. Quite r e c e n t l y F r e i f e l d e r (24) Has reported s u c c e s s f u l r e s u l t s w i t h 5% R h / A l 2 0 j . This l a t t e r method was ap p l i e d i n our case to y i e l d 5-ethyl nipe-c o t i c a c i d ( X L l ) . This compound showed no absorption i n the U.V. spectrum and e x h i b i t e d an i n f r a r e d spectrum c h a r a c t e r i s t i c of an amino-acid. I t i s well.known (35) t h a t i n a l l types of amino-acids and t h e i r s a l t s (except h y d r o c h l o r i d e s ) we have a strong hydrogen-bonding (-N-H OsC-) 1 6H because of the i o n i c nature of the ca r b o x y l , which normally absorbs between 6.25 and 6 .4lu,.In our case compound (XL) i s f5>- and o"-amino-acid as w e l l , and indeed has the strong carboxyl absorption i n t h a t region ( 6 . 3 8 U . ) . In a d d i t i o n absorptions at 3«52)^ (sharp) and a broad band around 5* 98|A. (again c h a r a c t e r i s t i c f o r amino-acids) are a l s o present. The N.M.R. spectrum of t h i s compound with m u l t i p l e t s centered at 6.65^ : , 50 7.6j and l.Jl'X. ( c h a r a c t e r i s t i c o f methylene p r o t o n s i n a p i p e r i d i n e r i n g ) and a broad q u a r t e t a t 8.75^ a-3 w e l l as a m e t h y l t r i p l e t a t 9 - 0 8 ^ p r o v i d e d c o n c l u s i v e e v i d e n c e f o r t h e s t r u c t u r e ( X L l ) . I n s p i t e o f numerous a t t e m p t s we were n o t a b l e t o o b t a i n a s a t i s f a c t o r y e l e m e n t a l a n a l y s i s s i n c e t h e a m i n o - a c i d was d i f f i c u l t t o c r y s t a l l i z e and v e r y d i f f i c u l t t o f r e e f r o m s o l v e n t s . I t was. c o n v e r t e d t o t h e e s t e r as d e s c r i b e d below. The ^-ethyl n i p e c o t i c a c i d ( X L l ) upon e s t e r i f i c a t i o n w i t h an e t h e r e a l s o l u t i o n o f diazomethane was c o n v e r t e d t o t h e crude m e t h y l e s t e r ( X X I V ) . T h i s m a t e r i a l was p u r i f i e d by d i s t i l l a t i o n u nder reduced p r e s s u r e t o y i e l d a y e l l o w i s h v i s c o u s o i l i n an o v e r a l l y i e l d o f 75%* F u r t h e r i n v e s t i g a t i o n s of t h i s o i l by v a p o r phase chromatography i n d i c a t e d t h a t t h i s m a t e r i a l was a m i x t u r e o f two components w h i c h had s i m i l a r b u t s t i l l d i s t i n g u i s h a b l e r e t e n t i o n t i m e s on t h e v.p.c. column. The r e l a t i v e r a t i o s o f t h e s e components as i n d i c a t e d by t h e a r e a s under t h e peaks v a r i e d f r o m 1:1 t o 1:4 f o r d i f -f e r e n t r e a c t i o n s . A l t h o u g h v.p.c. seemed i d e a l , a t f i r s t , f o r p u r i f i c a t i o n and s e p a r a t i o n o f t h e s e compounds, we were n o t a b l e t o a c c o m p l i s h t h i s s u c c e s s f u l l y s i n c e t h e r e c o v e r y f r o m t h e column was v e r y poor and t h e com-pounds seemed t o decompose d u r i n g s e p a r a t i o n . Due t o t h e - d i f f i c u l t y o f p r e p a r i n g pure l i q u i d samples we t u r n e d t o t h e p r e p a r a t i o n o f d e r i v a t i v e s w h i c h may be c r y s t a l l i n e . I n t h i s r e g a r d we t r e a t e d t h e n i p e c o t i c e s t e r w i t h p_-bromobenzoyl c h l o r i d e i n p y r i d i n e a t room t e m p e r a t u r e and were a b l e t o p r e p a r e t h e c o r r e s p o n d i n g d e r i v a t i v e as a crude o i l y m a t e r i a l . C r y s t a l -l i z a t i o n o f t h i s o i l f r o m a m i x t u r e o f methano l - w a t e r ( l : l ) p r o v i d e d a n i c e l y c r y s t e l l i n e m a t e r i a l (m.p. 91.5 - 95°C) w h i c h on t h e b a s i s o f i t s a n a l y s i s and s p e c t r a l i n f o r m a t i o n was c o n c l u s i v e l y e s t a b l i s h e d as t h e K-broraobenzoyl d e r i v a t i v e o f 5 _ c a r b o m e t h o x y - 5 - e t h y l p i p e r i d i n e ( X L I l ) . The i n f r a r e d s p e c t r u m o f t h i s compound had t h e carbomethoxy a b s o r p t i o n a t 5-81^, 51 t h e amide a b s o r p t i o n ( p - B r ^ - J J - N ) a t 6«15p-, and t h e a r o m a t i c a b s o r p t i o n 0 a t 6.33)-<- « The u l t r a v i o l e t s p e c t r u m showed one a b s o r p t i o n a t 228mu, o n l y . The N.M.R spec t r u m was most c o n c l u s i v e i n p r o v i d i n g e v i d e n c e f o r t h i s s t r u c -t u r e . An a r o m a t i c m u l t i p l e t c e n t e r e d a t 2.60 T. ( 4 - p r o t o n s ) , a s i n g l e t a t 6.33t (COOCH^ ), and a t r i p l e t c e n t e r e d a t 9«llrx. (CH^CH^) were t h e most s i g n i f i c a n t s i g n a l s t o be mentioned h e r e . E l e m e n t a l a n a l y s i s c o n f i r m e d com-p l e t e l y t h e s t r u c t u r e o f t h i s m a t e r i a l * F i n a l l y i t may be o f i n t e r e s t t o s p e c u l a t e on t h e c o n f o r m a t i o n a l s t r u c t u r e s o f t h e f i n a l p r o d u c t ( X X I V ) . I t i s c l e a r t h a t t h e c a t a l y t i c r e -d u c t i o n o f t h e p y r i d i n e r i n g does g e n e r a t e two asymmetric c e n t r e s i n t h e n i p e c o t i c a c i d , d e r i v a t i v e ( X L I ) and i t s e s t e r ( X X I V ) t h e r e f o r e two d l p a i r s ( c i s or t r a n s ) a r e t h e o r e t i c a l l y p o s s i b l e . L e t us npw c o n s i d e r t h e s e i s o m e r s i n terms o f t h e i r c o n f o r m a t i o n s . I t i s , o f c o u r s e , o b v i o u s t h a t t h e c i s compounds can e x i s t i n c o n f o r m a t i o n s A and B (see F i g u r e 12') F i g u r e 12. Trans and c i S j t h e o r e t i c a l l y p o s s i b l e ) i s o m e r s of methyl e s t e r ( X X I V ) . 52 and that conformation A with both groups e q u a t o r i a l w i l l be by f a r the most s t a b l e one. On the other hand the trans s e r i e s (C and D) must have one of the s u b s t i t u e n t s i n an a x i a l o r i e n t a t i o n and i t i s more d i f f i c u l t t o pre-t u a l d i f f e r e n c e i n s i z e of the s u b s t i t u e n t s i s not s u f f i c i e n t l y great to favor one very much over the other. However, the p o s s i b i l i t y of hydrogen bonding between the >^NH and the e s t e r group might be expected t o be more s i g n i f i c a n t i n conformation C than i n D and t h i s may play some r o l e i n t h i s s i t u a t i o n . I f hydrogen bonding was prominent then the carbonyl frequency i n the i n f r a r e d spectrum would be a f f e c t e d . In t h i s connection, Omoto (J6) i n a very nice s e r i e s of s p e c t r a l i n f o r m a t i o n u s i n g 2-methyl-4-anisoyl - 1 0-hydroxyquinoline and i t s isomers Figure 1J. Stereochemical s i m i l a r i t i e s and conformation'features between compounds ( X L l ) , (XXIV) and some i s o q u i n o l i n e d e r i v a t i v e s . detected the stereochemistry of these compounds, e x h i b i t i n g the same con-f o r m a t i o n a l problem with our compounds ( X L l ) and (XXIV). He observed t h a t d i e t which of these i s the most p r e f e r r e d purely on s t e r i c reasons. The ac-( X L I ) , R - H ( X X I V ) , R=Me 53 the ketone band of the deacetylated product F is at 6.08JA. with a shoulder at 6.04^ (in GHCl^). The first absorption contributed to intramolecular H-bond as in F and the second to dimeric intermolecular H-bond. The shape (sharp) and position (2»89yO of the yOH of F (but without intramolecular H-bond) corresponds to dimeric association, which occurs when steric hin-drance is fairly large. So, F is in equilibrium with the same isomer, but without intramolecular H-bond. The yOH absorption of F is not clear because of the intramolecular H-bond. The hydrochloride of this compound had v> CsO absorption at 6.10yv, while the free form (in CHClj) had v CrO at 5»98^. This implies that a strong H-bond was involved in the 6.10^band; the only structure satisfying i t is E, where l,J-diaxial H-bonds are formed. In the free form, the H-bond is , of course, absent and the vCsO band is shifted higher. The absence of the strong "t-ammonium band" is due again to the intramolecular H-bond-The hydrochloride of F which cannot form such a bond absorbs broadly at 4.29^. Coming back to our case, i t is obvious that in the case of the com-pound ( X L l ) we have very strong intramolecular H-bond ( vCrO at 6.^&\K.) of type E, which is supported from the lack of s-amine absorption. In other words ( X L l ) exists in the form C. For the compound (XXIV) (oil itself) we observed that v CrO is quite high (5> 78 (A,), being in the regular place for esters and i f any inter- or intramolecular H-bonding (CrO H-NC ) occurs i t must be negligible. So, compound (XXIV) must exist in form A. Thus, for the isomers of (XXIV) (never purely isolated) the only' possibility for the ethyl group is to be axial (as in D) or equatorial (as in A), with the latter being in favour. 54 CONCLUSION The s y n t h e s e s o f t h e n e c e s s a r y i n d o l e ( X X I I I ) and p i p e r i d i n e (XX TV) u n i t s has been com p l e t e d . These compounds p r o v i d e t h e i n t e r m e d i a t e s r e -q u i r e d f o r t h e proposed scheme as o u t l i n e d i n F i g u r e 5- A l t h o u g h n o t d i s -c ussed i n t h i s t h e s i s , we would l i k e t o m e n t i o n h e r e t h a t t h e r e a c t i o n between t h e s e two u n i t s t o p r o v i d e XXV has been s u c c e s s f u l l y a c c o m p l i s h e d i n some v e r y r e c e n t s t u d i e s i n our l a b o r a t o r i e s . I t t h e r e f o r e appears t h a t t h e s y n t h e t i c scheme proposed i s w e l l underway. 55 EXPERIMENTAL A l l m e l t i n g p o i n t s were d e t e r m i n e d on a F i s c h e r - J o h n s a p p a r a t u s and a r e u n c o r r e c t e d . The u l t r a v i o l e t s p e c t r a were r e c o r d e d i n a b s o l u t e methanol on a Gary 11 r e c o r d i n g s p e c t r o p h o t o m e t e r , u n l e s s o t h e r w i s e i n d i c a t e d . The i n f r a r e d s p e c t r a were d e t e r m i n e d on a P e r k i n - E l m e r model 21 s p e c t r o p h o t o -meter. The N.M.R. s p e c t r a were t a k e n a t 60 Mc/s on a V a r i a n A60 i n s t r u m e n t . The v a l u e s a r e g i v e n i n t h e T i e r s <*t s c a l e , w i t h t h e s i g n a l o f t e t r a m e t h y l -s i l a n e , w h i c h was used .as t h e i n t e r n a l s t a n d a r d ^ s e t a t 10.0 T. u n i t s . The s o l v e n t s used were d e u t e r i o c h l o r o f o r m , d e u t e r i o a c e t o n e o r heavy w a t e r . Vapor phase chromatography ( v . p . c . ) was c a r r i e d o u t on an A e r o g r a p h Model A-90-P i n s t r u m e n t w i t h h e l i u m as c a r r i e r g as. A column 5' x i " °f A p i e z o n J was used and t h e c a r r i e r gas p r e s s u r e was 50 l b s / s q . i n . Temperatures o f column used were between l40-210°C. S i l i c a g e l G p l a t e s were used f o r t h i n -l a y e r chromatography ( T . L . C . ) . A n a l y s e s were performed by A . B e r n h a r d t and h i s a s s o c i a t e s , Mulheim ( R u h r ) , Germany, and by M r s . C . J e n k i n s , U n i v e r s i t y o f B r i t i s h C o l u mbia. o _ - N i t r o p h e n y l p y r u v i c a c i d ( XXIX) Sodium m e t a l (~ 28 g, 1.2 mole) was d i s s o l v e d i n 200 ml a b s o l u t e e t h -a n o l under s t i r r i n g and t h e m i x t u r e was d i l u t e d w i t h a b s o l u t e e t h y l e t h e r (1000 ml) whereupon a m i l k y s u s p e n s i o n r e s u l t e d . To t h i s s u s p e n s i o n e t h y l o x a l a t e (.175 g* d = 1.08, 1.2 mole) was f i r s t added, f o l l o w e d f i v e m i n u t e s l a t e r by b - n i t r o t o l u e n e ( X X V I I I ) (1J7 g, d = 1.16, 1 m o l e ) . The r e a c t i o n m i x t u r e w h i c h s l o w l y t u r n e d r e d was t h e n r e f l u x e d under a d r y n i t r o g e n atmosphere f o r two days. A p o r t i o n (500 ml) o f e t h y l e t h e r was removed by d i s t i l l a t i o n , t h e r e a c t i o n m i x t u r e c o o l e d and c o l d w a t e r (1000 m l ) was added. The m i x t u r e was s t i r r e d f o r h a l f an hour and t h e n a c i d i f i e d w i t h h y d r o c h l o r i c a c i d ( \/60 m l , 12N). The l a y e r s were s e p a r a t e d and t h e w a t e r l a y e r was e x t r a c t e d w i t h e t h y l e t h e r (2 x 1000 m l ) . The 56 combined e t h e r e a l e x t r a c t was washed w i t h w a t e r ( l x 1000 ml) and f i n a l l y -washed w i t h d i l u t e ammonium h y d r o x i d e (5 x 1000 m l , I N ) . The combined aqueous s o l u t i o n was washed w i t h e t h y l e t h e r (2x750 m l ) . Then the aqueous s o l u t i o n was c o o l e d ( ~5~"10°C) and poured c a r e f u l l y i n t o a s t i r r e d i c e - c o l d c o n c e n t r a t e d h y d r o c h l o r i c ' a c i d s o l u t i o n (110 m l , 12N). A y e l l o w s o l i d was p r e c i p i t a t e d i m m e d i a t e l y f r o m t h e r e d d i s h r e a c t i o n m i x t u r e . More c o l d c o n c e n t r a t e d h y d r o c h l o r i c a c i d was added (200 m l , 12N) d r o p w i s e , t i l l no f u r t h e r p r e c i p i t a t i o n was n o t e d . Oare must be t a k e n a t t h i s p o i n t , because sometimes the y e l l o w p r e c i p i t a t e was s l o w l y c o n v e r t e d i n t o a v i s c o u s r e d o i l . F i l t r a t i o n o f the s o l i d o r e x t r a c t i o n o f t h e o i l w i t h e t h y l e t h e r (5 l i t r e s ) was t h e n c a r r i e d o u t . A f t e r d r y i n g t h e e t h e r l a y e r o v e r anhydrous magnesium s u l f a t e , and removal o f t h e s o l v e n t , a crude mater-i a l (158 g j 76%) r e s u l t e d w h i c h upon c r y s t a l l i z a t i o n f r o m benzene gave a r e d - y e l l o w s o l e d (l06 g, y i e l d ^>1%), m.p. 115-120°. R e c r y s t a l l i z a t i o n o f t h e l a t t e r gave an a n a l y t i c a l sample, m.p. 120-122°. L i t . (l8):121°. U l t r a -v i o l e t i n a b s o l u t e ethano 1: ^ m a x 262 m|/>-; i n f r a r e d i n N u j o l : 5.75pc, 5.86JA.. I n d o l e - 2 - c a r b o x y l i c a c i d (XXX) A s o l u t i o n o f o - n i t r o p h e n y l p y r u v i c a c i d ( XXIX) (100 g, 0.48 mole) i n h o t (~80°C) 4N ammonium h y d r o x i d e (600 ml) was added s l o w l y , w i t h s t i r r i n g t o a s u s p e n s i o n o f f e r r o u s h y d r o x i d e i n b o i l i n g w a t e r . The l a t t e r was ob-t a i n e d by t h e a d d i t i o n o f c o n c e n t r a t e d ammonium h y d r o x i d e (500 m l , 15N), t o a b o i l i n g s o l u t i o n o f f e r r o u s s u l f a t e (FeSO^^R^O) (900 g) i n wa t e r (1500ml). The r e s u l t i n g m i x t u r e was k e p t near i t s b o i l i n g p o i n t f o r 2 h o u r s and th e n f i l t e r e d c a r e f u l l y (~5 h o u r s ) . Care must be t a k e n d u r i n g t h i s p r o c e d u r e ! because t h e r e a c t i o n m i x t u r e foams b a d l y and good s t i r r i n g i s n e c e s s a r y . The r e s u l t a n t s l u d g e was r e p e a t e d l y e x t r a c t e d w i t h b o i l i n g 2N ammonium 57 h y d r o x i d e (2250 ml) and t h e combined f i l t r a t e and e x t r a c t s were f i l t e r e d a g a i n . The c l e a r f i l t r a t e was poured i n t o i c e - c o l d (0-5°C) c o n c e n t r a t e d h y d r o c h l o r i c a c i d ( 5 5 ° ml, 12N). The p r e c i p i t a t e w h i c h formed was removed and washed w i t h a s m a l l amount o f w a t e r . I t was t h e n d r i e d o v e r n i g h t i n a vacuum d e s s i c a t o r o ver sodium h y d r o x i d e t o p r o v i d e a y e l l o w powder, m.p. 188-192°. L i t . ( 1 8 ) : 205-204°. T h i s crude m a t e r i a l was never p u r i f i e d f u r t h e r but used i n t h e subsequent r e a c t i o n . U l t r a v i o l e t i n a b s o l u t e e t h a n o l : % m a x 217.5 and 292.5 myv; i n f r a r e d i n N u j a l : 5.86y» , 6 . 0 2 y u 2 - C a r b o m e t h o x y - i n d o l e ( X X X I ) I n d o l e - 2 - c a r b o x y l i c a c i d (XXX) (24.5 g> 0.15 mole) was d i s s o l v e d i n a b s o l u t e methanol (JOO ml) and c o n c e n t r a t e d s u l f u r i c a c i d (4 ml) was added c a r e f u l l y w i t h s t i r r i n g . The r e s u l t i n g s o l u t i o n was r e f l u x e d f o r 4 h o u r s t h e n c o o l e d and poured i n t o i c e - w a t e r (JOO m l ) . The l i g h t y e l l o w p r e c i p i t a t e w h i c h formed was f i l t e r e d and d r i e d i n a vacuum d e s s i c a t o r o ver anhydrous c a l c i u m c h l o r i d e t o y i e l d a crude p r o d u c t (20 g ? 75%)« C r y s t a l l i z a t i o n f r o m benzene p r o v i d e d a pure sample , m.p. 150-151.5°' L i t . ( 2 J ) ' , 1 5 1 - 1 5 2 °• U l t r a -v i o l e t i n a b s o l u t e e t h a n o l : % ' 218 miA and 294 mi* : i n f r a r e d i n C h l o r o -max ' 1 f o r m : 2 . 9 5 ^ (>NH), 5.84j i . 2 ~ C a r b o m e t h o x y - 5 - c h l o r a c e t y l i n d o l e ( X X I I I ) Pure d r y 2 - c a r b o m e t h o x y i n d o l e (XXXI) (5»644g, 0.00^2 mole) was p l a c e d i n a t h i c k - w a l l e d g l a s s tube and t r e a t e d , w i t h d r y c h l o r o f o r m (200 m l ) , and dr y c h l o r o a c e t o n i t r i l e (50 ml, 0.756" m o l e ) . The d r y c h l o r o f o r m was p r e p a r e d by d i s t i l l a t i o n " a n a l y t i c a l " grade s o l v e n t s and t h e n passed s u c c e s s i v e l y t h r o u g h a chromatography column com-posed f r o m a t h i c k l a y e r o f A l u m i n a Woelm and t h e n a t h i c k l a y e r o f anhydrous sodium s u l f a t e . The a b s o l u t e c h l o r o a c e t o n i t r i l e was p r e p a r e d f r o m " a n a l y t i c a l " r e a g e n t 58 by r e f l u x i n g f o r •§- hour o v e r anhydrous c a l c i u m s u l f a t e , f o l l o w e d by d i s -t i l l a t i o n and s t o r a g e o v e r f r e s h anhydrous c a l c i u m s u l f a t e . Dry hydrogen c h l o r i d e gas ( p a s s i n g t h r o u g h a c o n c e n t r a t e d s u l f u r i c a c i d t r a p ) was bubbl e d i n t o t h e m i x t u r e w h i c h had been c o o l e d t o 0°C o v e r a p e r i o d o f 2 h o u r s . A f t e r t h i s t i m e t h e r e a c t i o n was c o o l e d t o -78°C ( d r y i c e - a c e t o n e ) and hydrogen c h l o r i d e passed i n f o r a f u r t h e r 10 m i n u t e s a t whi c h p o i n t a y e l l o w s o l i d had formed i n t h e r e a c t i o n m i x t u r e . The tube was t h e n s e a l e d and t h e r e a c t i o n m i x t u r e was k e p t a t 50°C f o r 11 h o u r s . A f t e r t h i s p e r i o d t h e tube was removed, s l o w l y c o o l e d t o -78°C u n t i l t h e r e a c t i o n m i x t u r e had s o l i d i f i e d and t h e n opened c a r e f u l l y as soon as i t came t o room t e m p e r a t u r e . The p r e c i p i t a t e was f i l t e r e d and washed w i t h i c e - c o l d c h l o r o f o r m (2 x 25 ml) t o remove any s t a r t i n g m a t e r i a l , and t h e combined f i l t r a t e and washings were k e p t a s i d e as t h e y c o n t a i n e d m a i n l y s t a r t i n g m a t e r i a l . The deep y e l l o w amorphous s o l i d r e m a i n i n g on t h e f u n n e l was d r i e d under vacuum t o remove any c h l o r o f o r m and t h e n t r e a t e d w i t h water (50 ml) t o a f f e c t h y d r o l y s i s o f t h e i m i n i u m s a l t . The s a l t d i s s o l v e d i n s t a n t l y , but on h y d r o l y s i s t o t h e c o r r e s p o n d i n g k e t o n e y i e l d e d an i n s o l u b l e s o l i d - c o m p o u n d . T h e - r e a c t i o n m i x t u r e was f i l t e r e d and t h e l i g h t y e l l o w s o l i d w h i c h remained was d r i e d under vacuum t o remove any wa t e r and t h e n t r e e t e d s e v e r a l t i m e s w i t h b o i l i n g c h l o r o f o r m . A s m a l l amount o f i n o r g a n i c m a t e r i a l w h i c h remained u n d i s s o l v e d was removed by f i l t r a t i o n and t h e c l e a r y e l l o w f i l t r a t e was d r i e d o ver anhydrous magnesium s u l f a t e . Removal o f t h e s o l v e n t l e f t a l i g h t y e l l o w s e m i c r y s t a l l i n e ( c r u d e ) p r o d u c t (5*278-g). Ah a d d i t i o n a l O.596 g' o f t h i s p r o d u c t was o b t a i n e d f r o m t r e a t m e n t o f t h e aqueous f i l t r a t e w i t h ammonia gas f o r 1 hour and removing t h e y e l l o w s o l i d w h i c h was p r e c i p i t a t e d d u r i n g t h i s t r e a t m e n t . The crude p r o d u c t (5.674 g) was d i s s o l v e d i n a s m a l l amount o f c h l o r o f o r m and p l a c e d on a n e u t r a l a l u m i n a 59 column (285 g) ( S h a w i n i g a n , d e a c t i v a t e d w i t h 1 .5 ml 10% a c e t i c a c i d , a c t i v i t y I I - I I I ) . I n i t i a l e l u t i o n w i t h b e n z e n e - c h l o r o f o r m (1:1) gave s t a r t i n g m a t e r i a l (1.025 g), but f u r t h e r e l u t i o n w i t h t h e same s o l v e n t gave t h e d e s i r e d pure compound (I .766 g, J l % y i e l d ) , m.p. l47>5-148.5°. U l t r a v i o l e t i n a b s o l u t e e t h a n o l : X m a x 249 m \\ (loge 4 .11 ),\- x 518 myt ( l o g € 4.10); i n f r a r e d i n c h l o -r o f o r m : 2 , 9 8 ^ ( > N H ) , 5.80^ (-COOCHj), 6.00 yi (OsC-CHg-), 6.58 ft ( a r o m a t i c ); N.M.R. i n (CD^) 2C0: m u l t i p l e t c e n t e r e d a t 2 . 6 5 < t ( a r o m a t i c - H ) , 4 . 9 8 ^ . s i n g l e t (-CH2C1), . 5 . 9 8 T . s i n g l e t (CHjOCO-R). Found: C, 57.10; H, 4.11; 0, 18.97; N, 5.75; C l , 14.07. C a l c . f o r C 1 2 H 1 0 0 5 N C 1 : C, 57.24; H, 4.01; 0, 19 .07; N, 5.56; C l , 14.11 . P y r i d i n e - 5 , 5 - d i c a r b o x y l i c a c i d (XXXV) or D i n i c o t i n i c a c i d A m i x t u r e o f 5 ^ 5-dimethyl p y r i d i n e (XXXIV) (85 g, 0.8 m o l e ) , p o t a s -s i u m permanganate (260 g, I .65 mole) and sodium h y d r o x i d e (50 g, 1.25 mole) i n w a t e r (5«5 l i t r e s ) was c a r e f u l l y h e a t e d by means o f a h e a t i n g m a n t l e and m e c h a n i c a l s t i r r i n g , u n t i l a v i g o r o u s r e a c t i o n t o o k p l a c e . H e a t i n g was c o n t i n u e d , u n t i l t h e permanganate c o l o u r had d i s s a p p e a r e d (~-45 m i n u t e s ) , whereupon an a d d i t i o n a l (260 g, I .65 mole) o f p o t a s s i u m permanganate was added. The r e s u l t i n g m i x t u r e was r e f l u x e d f o r . t w o hours, and t h e n f i l t e r e d . The brown manganese d i o x i d e was washed w i t h p o r t i o n s o f b o i l i n g w a t e r (2 x 500 m l ) . The f i l t r a t e and washings were combined and c o n c e n t r a t e d t o about 1 l i t r e by vacuum d i s t i l l a t i o n . The r e a c t i o n m i x t u r e was t h e n c o o l e d i n i c e and c o n c e n t r a t e d h y d r o c h l o r i c a c i d (180 m l , 12N) was s l o w l y added w i t h s t i r r i n g u n t i l t h e m i x t u r e was a c i d i c t o Congo r e d paper. The w h i t e p r e c i p i t a t e w h i c h formed a t t h i s p o i n t was f i l t e r e d and t h e n d r i e d f o r 2 days i n a vacuum d e s s i c a t o r o v e r anhydrous c a l c i u m c h l o r i d e and sodium h y d r o x i d e . The w e i g h t o f t h e d r i e d p r o d u c t was 105 g ( y i e l d 79%)^  m.p. 60 J22-325 0; L d t . (26): 323°. U l t r a v i o l e t i n m e t h a n o l : X m B V 26$ m u . ( s h o u l d e r ) , !Xmax 2 ( 5 8 mY^' a n d ^  max 2 7 ^ ( s h o u l d e r ) ; i n f r a r e d i n K u j o l : 5.80^, 6.02y* and 6 . 2 6 y x ( s h o u l d e r s ) . T h i s p r o d u c t was s u b s e q u e n t l y compared w i t h an a u t h e n t i c sample s u p p l i e d by t h e A l d r i c h C h e m i c a l Co. and fou n d t o be i d e n -t i c a l . D i e t h y l 5 j 5 ~ P y r i d i n e d i c a r b o x y l a t e ( X X X V I I ) D i n i c o t i n i c a c i d (XXXV) (20 g, 0.12 mole) was suspended i n an e x c e s s o f t h i o n y l c h l o r i d e (180 ml) and r e f l u x e d f o r f i v e h o urs i n a w a t e r - b a t h under anhydrous c o n d i t i o n s . A f t e r ~2§- h o u r s o f r e f l u x i n g , t h e m i l k y suspen-s i o n became a homogeneous v i s c o u s c l e a r o i l and o n l y a minute amount o f s o l i d m a t e r i a l remained u n d i s s o l v e d . The e x c e s s t h i o n y l c h l o r i d e was r e -moved by vacuum d i s t i l l a t i o n , l e a v i n g an amorphous deep y e l l o w m a t e r i a l w h i c h was t h e - c r u d e a c i d c h l o r i d e . A b s o l u t e e t h a n o l (220 ml) was added w i t h c a u t i o n t o t h i s m a t e r i a l and t h e m i x t u r e was r e f l u x e d f o r 30 m i n u t e s on a water b a t h . T h e n ( t h e e x c e s s e t h a n o l was removed by vacuum d i s t i l l a t i o n and t h e r e s i d u e was t a k e n up i n w a t e r and made b a s i c w i t h sodium c a r b o n a t e (~ pH 9) and e x t r a c t e d s e v e r a l t i m e s w i t h e t h y l e t h e r . The e t h e r e a l e x t r a c t was d r i e d o v e r anhydrous magnesium s u l f a t e an.' the s o l v e n t removed t o p r o v i d e a r e d d i s h v i s c o u s o i l . T h i s o i l , when l e f t o v e r n i g h t , c r y s t a l l i z e d s l o w l y i n t o l o n g y e l l o w n e e d l e s (19-1 g ) . T h i s crude m a t e r i a l was p u r i f i e d by s u b l i m a t i o n a t 110-160° ( b a t h t e m p e r a t u r e ) /0.2 mm Hg and gave a l m o s t pure l i g h t y e l l o w c r y s t a l l i n e m a t e r i a l , m.p. 48-50° (70%) L i t . (2J): 46-47° (KgO). U l t r a v i o l e t :!> m a x 263 m^ ( s h o u l d e r ) , 268 my, , 274 mu, (shoulder); i n f r a r e d i n N u j o l : 5«76y*., 6.22yt, 8.08yc, 9.10 JJI and 9-71^. 3 1 a i s e n C o n d e n s a t i o n o f d i e t h y l 5 p y r i d i n e d i c a r b o x y l a t e w i t h e t h y l  a c e t a t e ( X X X V I I I ) 61 Sodium metal (l0.2g, 0.44 mole) was reacted under anhydrous c o n d i t i o n s and under a n i t r o g e n atmosphere with an excess of absolute ethanol. When the r e a c t i o n was completed the excess ethanol was removed • under high vacuum, l e a v i n g a white dry powder (sodium ethoxide). A s o l u t i o n of the c r y s t a l l i n e d i e t h y l e s t e r (XXXVII) (49-4 g,.0.222 mole) i n a mixture of dry toluene (157 ml, 156 g, 1.48 mole ) and dry e t h y l a c e t a t e (86 ml, 77-5 g, 0.88 mole) was then added to the ethoxide. The r e a c t i o n mixture was s t i r r e d at room temperature f o r 64 hours. A f t e r t h i s time an i c e - c o l d mixture of water (280 ml) and chloroform (l40 ml) was added to the r e a c t i o n mixture. The mixture was c a r e f u l l y n e u t r a l i z e d (pH 7) by a d d i t i o n of 6N h y d r o c h l o r i c a c i d and ext r a c t e d w i t h chloroform ( t o t a l volume of chloroform ^2 .5 l i t r e s ) . The chloroform e x t r a c t was washed once with water, then d r i e d over anhydrous magnesium s u l f a t e . Removal of the solvent l e f t a red.viscous o i l which slowly c r y s t a l l i z e d upon standing i n the re-f r i g e r a t o r (50.9 g, 55% y i e l d ) . Thin-layer chromatography on the product showed only one spot (methanol), m.p. 68-69°; L i t . (27): 67-5-68.5° (EtOH). U l t r a v i o l e t : 'X m a x 228 m^and 280 my , ^ ^ 250 mJA ; i n f r a r e d as a f i l m : 5.80|A_, 6.08|A. and 6.15yt. 5-Carboethoxy , 5-acetyl p y r i d i n e (XXXIX) •The C l a i s e n product (XXXVIII) (4l g, 0.157 mole) was taken up i n d i l u t e s u l f u r i c a c i d (520 ml, 2N) and heated slowly on a water-bath (~80°C) u n t i l e v o l u t i o n of carbon d i o x i d e ceased. The hot r e a c t i o n mixture was made a l k a l i n e by a d d i t i o n of s o l i d potassium carbonate and the cooled r e a c t i o n mixture was ex t r a c t e d with e t h y l ether (2 x 75^ ml)."" The ether e x t r a c t was d r i e d over anhydrous magnesium s u l f a t e and the solvent removed to y i e l d a vis c o u s l i g h t y e l l o w o i l (55 g)* This o i l slowly c r y s t a l l i z e d on standing and by c o o l i n g (0°C). C r y s t a l l i z a t i o n from a mixture of petroleum ether 62 ( 5 0 - 6 0 °)-ethyl e t h e r gave, a pure c r y s t a l l i n e m a t e r i a l (18 .6 g, 62%), m.p. 67-70°. L i t . (27): 69.5~70.5°. U l t r a v i o l e t : [> m a x 224 my.5 26$ m^. ( s h o u l d e r ) , 268 m^ , and 274 my. ( s h o u l d e r ) ; X m i n 252 myt; i n f r a r e d i n N u j o l : 5.78^, 5.95^ > 6 - 2 7 ^ • 5 ~ E t h y l n i c o t i n i c a c i d ( X L ) The e s t e r (XXXIX) (8.2 g, 0.042 mole m o l e ) , was t a k e n up i n e x c e s s o f h y d r a z i n e h y d r a t e (NgH^'h^O, 120 m l ) and t h e s t i r r e d m i x t u r e was r e f l u x e d f o r 1 h o u r . The e x c e s s h y d r a z i n e , w a t e r , e t c . , was removed by vacuum d i s -t i l l a t i o n ( w a t e r - b a t h u s e d ) and t h e r e s u l t i n g y e l l o w s o l i d r e s i d u e was t r e a -t e d w i t h a s o l u t i o n o f aqueous 90% p o t a s s i u m h y d r o x i d e (20 m l ) . The r e a c t i o n m i x t u r e was s l o w l y b rought up t o t h e b o i l i n g p o i n t and l e f t t o r e f l u x f o r two h o u r s . A f t e r t h i s r e f l u x p e r i o d t h e c o o l e d m i x t u r e was poured i n t o w a t e r (120 ml) and t h e m i x t u r e t h e n a d j u s t e d t o pH 7> A t t h i s p o i n t a w h i t e p r e c i -p i t a t e formed. The p r e c i p i t a t e was f i l t e r e d and d i s c a r d e d . The f i l t r a t e was a d j u s t e d t o pH 2.5 - 2.9, and i f c o l o u r e d (as i s sometimes t h e c a s e ) i t was t r e a t e d w i t h a s m a l l amount o f N o r i t e and b r o u g h t t o b o i l i n g . Removal o f t h e c h a r c o a l by f i l t r a t i o n t h e n p r o v i d e d a c l e a r f i l t r a t e w i c h was t r e a t e d w i t h s o l i d c u p r i c a c e t a t e by slow a d d i t i o n and c o n t i n u o u s s t i r r i n g a t room tempe-r a t u r e . A s m a l l e x c e s s o f c u p r i c a c e t a t e was f i n a l l y added and t h e pH was f i n a l l y a d j u s t e d t o between 5*6 - 5-9. I t was o b s e r v e d t h a t i n t h i s pH r e g i o n th e p u r i t y o f t h e r e a c t i o n p r o d u c t was alwa y s h i g h e r . A t t h i s p o i n t a t h i c k , h eavy, l i g h t - g r e e n i s h p r e c i p i t a t e had s e t t l e d out and t h e m i x t u r e was l e f t o v e r n i g h t f o r c o m p l e t i o n . The copper s a l t was removed by f i l t r a t i o n , t h e n suspended i n h o t wat e r (200 ml) and f i n a l l y decomposed by p a s s i n g h y d r o g e n s u l f i d e gas t h r o u g h t h i s h o t s u s p e n s i o n . The b l a c k " p r e c i p i t a t e o f c u p r i c s u l f i d e was removed by f i l t r a t i o n and t h e y e l l o w i s h c l e a r f i l t r a t e was eva-p o r a t e d t o d r y n e s s i n vacuo ( w a t e r - b a t h t e m p e r a t u r e ) . The y e l l o w s o l i d p r o d u c t w h i c h remained weighed l4 g. P u r i f i c a t i o n o f t h i s m a t e r i a l was 63 accomplished by heating i t successively with ethyl ether and methanol. Some insoluble inorganic material (7 g) remained behind, while the clear v organic filtrates were evaporated to provide 4.28 g (yield 67%) of the desired product in quite a pure state (one spot in T . L . C . , in methanol). Further purification of this material gave a crystalline white material, m.p. 170-171°. Lit. (27): 170-171°. Ultraviolet in absolute ethanol: ^max 2 1 8 m ^ U ° g € 3«97), 270 mj\ . ( log£ 3-55), 266 and 276 mjA.(broad shoulders), y m i n 242 mLA . ( l o g £ 2.12); infrared in KBr (pellet): 5.83 6.29p.; N.M.R. peaks in D 2 O : 7.3"E.> 8 . 8 t , multiplet lower than 2 ^ as expected for pyridines. Found: C, 63.28; H, 6.15; N, 9-87. Calc. for CgH^OgN: C, 65.56; H, 6.00; N, 9-27. 5-Carboxy-5~ethyl piperidine (XLl) (5~Ethyl nipecotic acid). The substituted nicotinic acid (XL) (4.28 g, O.285 mole) dissolved in a mixture of water (200 ml) and concentrated ammonium hydroxide (20 ml, 15N). Catalyst, 5% rhodium on alumina (8.56 g) was added. The reaction mixture was hydrogenated for sixteen hours in a Parr low pressure hydro-genation apparatus at room temperature (~22°C) with mechanical shaking and in i t ia l hydrogen pressure at 29 l'bs/sq.in. In subsequent experiments i t was found that the time necessary for complete reduction was less (about 8 hours). The reduction was easily followed by the disappearance of the ultra-violet absorption due to the pyridine nucleus. The catalyst was filtered off, and the solvent removed in vacuo. The solid residue was treated with absolute benzene and the remaining traces of water removed by benzene-water azeotrope, to yield a glassy, colourless solid (4.26 g). This material showed one spot on T.L.C. (methanol) and was quite pure. It was observed that exposure of this material to air can quickly transform this compound into a gummy, plastic material,and for this reason 64 we were n o t a b l e t o o b t a i n a s a t i s f a c t o r y e l e m e n t a l a n a l y s i s i n s p i t e o f numerous a t t e m p t s . The compound i s s o l u b l e i n w a t e r , s l i g h t l y s o l u b l e i n m e t h a n o l , v e r y s l i g h t l y s o l u b l e i n a c e t o n e , and i n s o l u b l e i n c h l o r o f o r m . U l t r a v i o l e t : no a b s o r p t i o n ; i n f r a r e d i n K u j o l and as f i l m ; 5.05|A(>NH), 5.98 (A (ammonium band), 6.58 (COOH, bonded); N . M . R . peaks i n DgO: 6.6$~c ( m u l t i p l e t , -CH^N^ ), 7 .26<^and 7«51 x ( m u l t i p l e t s , c h a r a c t e r i s t i c o f p i p e r i d i n e H), 8 . 7 5 X(quartet, CH^CHg-CH-), 9»08rc. ( t r i p l e t , CH^CHg-). 5-Carbomethoxy - 5-ethyl p i p e r i d i n e (XXIV) The a c i d ( X L l ) (1.66 g, 10,6mmole) was d i s s o l v e d i n methanol (50 ml) and t h e s o l u t i o n c o o l e d t o 5°C« An i c e - c o l d e t h e r e a l s o l u t i o n o f diazomethane, was added v e r y s l o w l y w i t h s t i r r i n g . The slow a d d i t i o n o f t h i s diazomethane s o l u t i o n c o n t i n u e d u n t i l t h e r e a c t i o n m i x t u r e m a i n t a i n e d t h e y e l l o w c o l o u r of diazomethane s o l u t i o n . D u r i n g t h e a d d i t i o n , n i t r o g e n gas was e v o l v e d . The r e a c t i o n m i x t u r e was l e f t t o s t a n d o v e r n i g h t d u r i n g w h i c h t i m e i t was a l l o w e d t o come t o room tem-p e r a t u r e . A w h i t e amorphous p r e c i p i t a t e formed d u r i n g , t h i s p e r i o d . T h i s w h i t e s o l i d was f i l t e r e d o f f . The s o l v e n t was removed f r o m t h e c l e a r f i l t r a t e and t h e r e m a i n i n g r e s i d u e w a s ' a g a i n t a k e n up i n e t h e r . A s m a l l amount o f i n s o l u b l e m a t e r i a l , w h i c h remained a t t h i s p o i n t , was a g a i n removed by f i l t r a t i o n . E v a p o r a t i o n o f t h e e t h e r p r o v i d e d a v i s c o u s l i g h t y e l l o w o i l . D i s t i l l a t i o n o f t h i s o i l under r e d u c e d p r e s s u r e , 90-l80°C ( b a t h t e m p e r a t u r e ) /0.01 mm Hg, gave t h e p r o d u c t (l»55 g)« T h i n - l a y e r chromatography ( m e t h a n o l ) and v a p o r phase chromatography ( A p i e z o n J , 5' x i " a t 150°C and h e l i u m p r e s s u r e o f 50 I b s / s q . i n . ) i n d i c a t e d two components ( r e t e n t i o n t i m e s , 17-22 m i n u t e s and 22-27 m i n u t e s r e s p e c t i v e l y ) . U l t r a v i o l e t : no a b s o r p t i o n ; i n f r a -r e d as a f i l m : 5.78 ^(-COOCH^), 6.00 ^(-CsO HN< ); N . M . R . peaks i n CDCl^: 6.59 T- and 6.41^ ( v e r y s h a r p s i n g l e t s , c o r r e s p o n d i n g t o two -C00CH* g r o u p s , 65 a r e a — 5H), t r i p l e t c e n t e r e d a t 9.12 ^.(--Ch^CH^, a r e a = 5H). C o n s e q u e n t l y we proceeded t o p r e p a r e a c r y s t a l l i n e d e r i v a t i v e o f t h i s p r o d u c t f o r complete c h a r a c t e r i z a t i o n . N-(£-Bromobenzoyl ) - 5-carbomethoxy - 5-ethyl p i p e r i d i n e ( X L I I ) A s o l u t i o n o f t h e me t h y l e s t e r (XXIV) (210 mg, 1.22 mmole) and p_-bromobenzoyl c h l o r i d e (400 mg, 1.82 mmole) i n p y r i d i n e (6.0 m l ) , was a l l o w e d t o s t a n d a t room t e m p e r a t u r e f o r 22 h o u r s . A f t e r most o f the p y r i d i n e had been removed under vacuum, t h e r e s i d u e was t r e a t e d w i t h c o l d d i l u t e am-monium h y d r o x i d e , and the r e s u l t i n g m i x t u r e was e x t r a c t e d t w i c e w i t h c h l o r o -form. The combined c h l o r o f o r m e x t r a c t was t r e a t e d a g a i n w i t h i c e - c o l d d i l u t e h y d r o c h l o r i c a c i d , t h e n washed w i t h w a t e r , and f i n a l l y d r i e d o v e r anhydrous p o t a s s i u m c a r b o n a t e . The d r y i n g agent was removed and t h e s o l v e n t e v a p o r a t e d t o y i e l d a v i s c o u s o i l (178 mg). T h i s o i l showed one s p o t on T.L.C ( m e t h a n o l ) . C r y s t a l l i z a t i o n o f t h i s o i l f r o m a m i x t u r e o f methanol-water ( l : l ) , gave t h e f i r s t c r o p (84 mg) o f a c r y s t a l l i n e m a t e r i a l , m.p. 91.5 - 95°. I n f r a r e d i n q N u j o l : 5.81^(0001^), 6.15^ (c^ ), 6.55 u. ( f o r -C*CH); u l t r a v i o l e t : ! X m a x 228 my. ; N.M.R. s i g n a l s i n CDCl^: m u l t i p l e t c e n t e r e d a t 2.62 T ( a r o -m a t i c p r o t o n , area= 4 p r o t o n s ) , s i n g l e t a t 6.55rC-(COOCH^, area= 3 p r o t o n s ) , t r i p l e t c e n t e r e d a t 9-lit(CH^CH2-). Found: C, 54,53 ; H, 5-69; 0, 12.21; N, 3.-78; B r , 21.91. C a l c . f o r C-^H^O^NBr: C, 54.25; H, 5.69; 0, 12-56; N, 2-95; B r , 22.57. 66 BIBLIOGRAPHY 1. HESSE,M. : " I n d o l a l k a l o i d e " , S p r i n g e r - V e r l a g , B e r l i n - G o t t i n g e n - H e i d e l b e r g (1964) 2. M0THES,K.and SCHUTTE,H.R".:Angew.ChemJ ( i n t . E d . ),2,44l(1963) 5. ROBINSON,R.:"The S t r u c t u r a l R e l a t i o n s of the Nat u r a l Products",Clarenton Press,Oxford(1955) 4. LEETE,E.:J.Am.Chem.Soc.78,3520(1956) 5» LEETE,E.:Ibid.80,4393(1958) 6 . WENKERT,E.:Ibid.84,98(1962) 7. KUTNEY,J.P.,TROTTER,J.,TABATA,T. KERIGAN,A.and CAMERMAN,N.:Chem.and Ind,648(1963) 8. 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