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UBC Theses and Dissertations

Transannular cyclisations ot 6-substituted cyclodecynes and attempted synthesis of samanine Rao, R. Balaji 1973

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TRANSANNUL&R CYCLISATIONS OF 6-S0BSTITUTED CYCLODECYNES and ATTEMPTED SYNTHESIS OF SAMANINE by R. BALAJI RAO B . S c , U n i v e r s i t y of Madras, I n d i a , 1962; I . S c , U n i v e r s i t y of Bombay, I n d i a , 1968 ; A THESIS SUBMITTED IN PARTIAL FULFILMENT OF THE REQUIREMENT FOR THE DEGREE OF DOCTOR OF PHILOSOPHY i n the Department of Chemistry He accept t h i s t h e s i s as conforming to the r e q u i r e d standard THE UNIVERSITY OF BRITISH COLUMBIA May, 1973 In presenting t h i s thesis i n p a r t i a l f u l f i l m e n t of the requirements for an advanced degree at the University of B r i t i s h Columbia, I agree that the Library s h a l l make i t f r e e l y available for reference and study. I further agree that permission for extensive copying of t h i s thesis for scholarly purposes may be granted by the Head of my Department or by h i s representatives. It i s understood that copying or publication of t h i s thesis for f i n a n c i a l gain s h a l l not be allowed without my written permission. Department of C VA £ S> "X N The University of B r i t i s h Columbia Vancouver 8 , Canada Date xC^Vn i i i A B S T R A C T Part I The t r a n s a n n u l a r c y c l i s a t i o n r e a c t i o n of c y c l o d e c y n - 6 -one ( ^ 1 ), c y c l o d e c y n - 6 - o l ( 3 8 ) and 6-methyl c y c l o d e c y n - 6 -o l ( 39 ) were i n v e s t i g a t e d , with the view of s y n t h e s i s i n g b i c y c l o £ 5 . 3 . o j decane system ( Jl ) • Compound 2_[ when t r e a t e d with s e v e r a l proton a c i d s i n a v a r i e t y of s o l v e n t s ranging i n p o l a r i t y from hexane to methanol, y i e l d e d only o c t a l i n , which i s a b i c yclo [ < 4 . 4 . 0 ] decane system ( 2 ) . Treatment of 21 with l i t h i u m i n antioonia-THF f o l l o w e d by o x i d a t i o n , y i e l d e d A W 7 b i c y c l o j ~ 5 . 3 . 0 J decane - 2-cne ( 2 9 ) i n only 43? ( 19 ). S i m i l a r l y boron t r i f l u o r i d e e t h e r a t e i n methelene c h l o r i d e reacted with 2± to y i e l d o n l y 1 9 . Compound 3 8 , on treatment with h y d r o c h l o r i c a c i d i n methanol y i e l d e d only decanone - 2 . Treatment of 39 with h y d r o c h l o r i c a c i d i n methanol y i e l d e d a mixture of two compounds having systems 1 and 2 . Again the product having system 2 was the major product. Treatment of 3 8 as w e l l as 3 9 with boron t r i f l u o r i d e e t h e r a t e i n methylene c h l o r i d e y i e l d e d a f l u o r o o l e f i n . Through s p e c t r a l a n a l y s i s and chemical degradation s t u d i e s , the compounds were e s t a b l i s h e d as having system 2. A &r?chanism i s proposed to r a t i o n a l i s e the preponderance of system 2 i n a l l these r e a c t i o n s . y i e l d . The major product was i v Part I I A new route f o r the s y n t h e s i s of salamander a l k a l o i d samanine ( _1_ ) was attempted. Thus testosterone ( _0_ ) was converted to 17 B-acetoxy-2-oxo-2,3-seco-5 B-androstane-3-n i t r i l e ( __8 ) through the method of K. P a i s l e y . Reduction of the aldehyde to the a l c o h o l followed by t o s y l a t i o n y i e l d e d 17 6-acetoxy-3-cyano-2,3-seco-5 6-androstane-2-p-toluenesulphonate ( 5_3 ). The n i t r i l e and the acetate moieties were s e l e c t i v e l y reduced with diborane and the product thus obtained was t r e a t e d with 103? excess of a c e t i c anhydride i n p y r i d i n e to y i e l d 17-hydrcxy samane-N-acetate ( _57 ), i n about 30% y i e l d . A mechanism i s proposed f o r t h i s c y c l i s a t i o n . In a s i m i l a r way, treatment of the diborane r e d u c t i o n product with benzoic anhydride y i e l d e d the corresponding N-benzoate ( 7_2 ). Compound 57 was o x i d i s e d to 17-oxosamanine-N-acetate ( 77 ), which was then converted to the 16-oximino-17-oxcsanianine-N-acetate ( 78 ). Attempts to remove the C-17 oxygen from 78 were uns u c c e s s f u l . O x i d a t i o n of 72, followed by treatment with benzaldehyde and base y i e l d e d the corresponding 16-benzylidene-17-oxosamanine-N-benzoate 7U. Again attempts to remove the 17-oxo group f a i l e d . V TABLE OF CONTENTS F a c e T i t l e Page i A p c l c g i a X Ab s t r a c t i i i Table cf Centsr,ts v Table of Schemes v i i L i s t of T a b l e s v i i i Acknowledgement i x Pa r t I 1 I n t r o d u c t i o n 2 Methods and r e s u l t s 11 D i s c u s s i o n s 29 C o n c l u s i o n 37 Experimental 38 B i b l i o g r a p h y 5 5 P a r t I I 60 I n t r o d u c t i o n I s o l a t i o n and S t r u c t u r e of Samanine 61 S y n t h e t i c Approaches 6 5 Present Approach 71 D i s c u s s i o n and R e s u l t s 78 C o n c l u s i o n Experimenta1 B i b l i o g r a p h y Appendix S p e c t r a l Appendix v i i LIST OF SCHEMES Page Scheme 1 . 1 ; M a r s h a l l ' s S y n t h e s i s of G u a i o l 5 Scheme 1.2; S y n t h e s i s of 2\ 11 Scheme 1.3; S y n t h e s i s of 19 13 Scheme 1.4; S y n t h e s i s of Authentic 4 2 - 4 5 20 Scheme 2 . 1 ; Salamander A l k a l o i d s 6 2 Scheme 2 . 2 ; Habermehl's S y n t h e s i s of J 66 Scheme 2 . 3 ; Oka's S y n t h e s i s of _^  6 8 Scheme 2 . 4 ; Oka's S y n t h e s i s of 3 5 70 v i i i LIST OF TABLES PAGE TABLE 1.1 14 TABLE 1.2 22 TABLE 2.1 64 ACKNOWLEDGEMENT I wish t o e x p r e s s my s i n c e r e t h a n k s t o Dr. L a r r y H e i l e r f o r t h e encouragement and gu i d a n c e he has g i v e n me thr o u g h o u t t h e c o u r s e of t h i s r e s e a r c h and d u r i n g the p r e p a r a t i o n of t h i s m a n u s c r i p t . My t h a n k s are a l s o extended t o John F. K i n g s t o n , S t u a r t N. Huckin and Frank H.B. S k i n n e r f o r t h e i r many h e l p f u l d i s c u s s i o n s and s u g g e s s i o n s d u r i n g t h e c o u r s e o f t h i s work. APOLOGIA " F o r even the most sober s c i e n t i f i c i n v e s t i g a t o r i n s c i e n c e , t h e most thoroughgoing p o s i t i v i s t , c annot d i s p e n s e w i t h f i c t i o n ; he must a t l e a s t make use o f c a t e g o r i e s , and they a r e a l r e a d y f i c t i o n s , a n a l o g i c a l f i c t i o n s or l a b e l s , which g i v e us t h e same p l e a s u r e as c h i l d r e n r e c e i v e when they a r e t o l d t h e 'name' o f t h i n g s . " Havelock E l l i s 'The Dance o f L i f e ' 1 PART I THANSANNULAR CYCLISATI0N5 OP 6-SUBSTITUTED CYCLODECYNES 2 INTRODUCTION S e s q u i t e r p e n e s having b i c y c l o [5.3.0jdecane system a r e w e l l known. 1* 2 T h e i r s t r u c t u r a l c o m p l e x i t y v a r i e s from a -gurjunene 3 ( J ) t o t h e ve r y h i g h l y oxygenated compound e u p a r o t i n a c e t a t e ( _2 ) . 4 S e v e r a l approaches have been made towards the s y n t h e s i s of th e s e compounds h a v i n g a b i c y c l o -5.3.oJdecane s k e l e t o n . I n a d d i t i o n t o the d i f f i c u l t y i n form i n g 7-membered r i n g s , t h i s system a l s o poses the problem a r i s i n g from t h e i n h e r e n t c o n f o r m a t i o n a l c o m p l e x i t i e s of s u b s t i t u t e d c y c l o p e n t a n e and c y c l o h e p t a n e r i n g s . 5 Both systems undergo p s e u d o r o t a t i o n and the v a r i o u s c o n f o r m e r s d i f f e r o n l y s l i g h t l y i n energy. Hence the f a v o u r e d r o u t e b i c y c l o |_5. 3. OJ decane system as d e p i c t e d by e g u a t i o n 1. T h i s approach can be i l l u s t r a t e d by t h e f o l l o w i n g example. Treatment of _3 w i t h potassium t_-butoxide gave through a p i n a c o l - t y p e rearrangement ( e q u a t i o n 2 ) . 6 has been the rearrangement to A c O O O 2 3 A s i m i l a r rearrangement has been e f f e c t e d through the photochemical rearrangement of 5 to _6 ( eguation 3 ). 7 Since the b i c yclo [n. 4. o] systems could be s y n t h e s i s e d s t e r e o s p e c i f i c a l l y and the rearrangements of 6-membered r i n g s are well known, these approaches c o n s t i t u t e a s t e r e o s p e c i f i c s y n t h e s i s of b i c y c l o [5. 3.o] decanes. Another i n t e r e s t i n g approach was in t r o d u c e d by J.A. M a r s h a l l and h i s coworkers i n t h e i r s y n t h e s i s of g u a i o l J_1 by the s o l v o l y s i s of 7. 8 The r e a c t i o n presumably proceeded through the t r i c y c l i c i n t e r m e d i a t e s _8 and J9 ( scheme 1 . 1 ) . Routes i n v o l v i n g c y c l i s a t i o n s i n which the b i c y c l i c system i s formed from monocyclic p r e c u r s o r s have a l s o been r e p o r t e d . J.A. M a r s h a l l and h i s coworkers showed that compound 1_2, on passage through s i l i c a g e l , was smoothly transformed i n t o J_3 ( equation 4 ) A l s o , M. Yamasaki c y c l i s e d JJ± to (-)-daucene ( 15. ) i n moderate y i e l d s ( equation 5 ) . 1 0 12 13 e ^ - 4 Scheme II 6 Another i n t e r e s t i n g approach, which i s somewhat r e l a t e d to the approach d e s c r i b e d i n t h i s t h e s i s , was r e p o r t e d by E.C. Brown and h i s c o w o r k e r s . 1 1 Compound 16, on treatment with a c i d , c y c l i s e d s t e r e o s p e c i f i c a l l y to 17 and 1_8 ( equation 6 ). 14 15 eq.5 7 It was f e l t t h a t another general approach f o r the s y n t h e s i s of b i c y c l o [5. 3 . 0] decanes was a l s o p o s s i b l e . a cyclodecyne r i n g with a s u i t a b l y placed l e a v i n g group c o u l d be a good p r e c u r s o r f o r t h i s g o a l . S i n c e cyclodecyn-6-one ( ) was e a s i l y a v a i l a b l e from the b i c y c l o Q * .4 .0] decenone 19 through the route shown i n equation 7, 1 2 , 1 3 i t was decided to study t h i s as a model compound. 19 20 eq,7 Acetylenes are known to r e a c t with both e l e c t r o p h i l e s and n u c l e o p h i l e s . 1 * On the model compound 2 J , these r e a c t i o n s were envisaged as p o s s i b l y proceeding as d e p i c t e d by the equations 8 and 9. Most t r a n s a n n u l a r c y c l i s a t i o n s i n 10-membered r i n g s appear to favour a t r a n s i t i o n s t a t e i n v o l v i n g 6-membered r i n g s . 1 5 « 1 6 However, the o b s e r v a t i o n made by G. Stork and h i s coworkers was encouraging. 1 7 When the a c e t y l e n i c ketone 8 9 22 was reduced with l i t h i u m i n ammonia-THF, they obtained a mixture c o n t a i n i n g 23 and unreacted s t a r t i n g m a t e r i a l ( eguat ion 10 ). * H Z O ^> i-OH £ 2 23 eq, IO M s o the s o l v o l y s i s of 6 - c c t y n - 2 - y l t o s y l a t e ( 2M_ ) i n t r i f l u o r o a c e t i c a c i d proceeded p r e f e r e n t i a l l y to products c o n t a i n i n g a cyclopentane r i n g ( equation 11 ) . 1 8 These r e s u l t s suggested that i n the case of cyclcdecyne d e r i v a t i v e s the c y c l i s a t i o n c ould lead to r i n g c l o s u r e to 5-membered r i n g . 25t> eq.U 10 Cyclodecyn-6-ones of the type _2_1 could be s y n t h e s i s e d from fcicyclo[u.U.oJdecanes,12>13 which i n turn c o u l d be s y n t h e s i s e d with s u i t a b l e s u b s t i t u e n t s by well known methods. T h i s c y c l i s a t i c n o f f e r s the added advantage of the p o t e n t i a l use of both e l e c t r o p h i l i c and n u c l e o p h i l i c reagents. T h e r e f o r e t h i s system was i n v e s t i g a t e d i n d e t a i l . * o METHODS AND RESULTS S t u d i e s on cyclodecyn-6-one ( 2 J ) Cyclodecyn-6-one ( _2J ) was prepared by the sequence de s c r i b e d below ( Scheme 1.2 ) . 1 9 The 1 - d e c a l o l 26 was dehydrated with 1 0 0 % phosphoric acid. 2° The mixture of o l e f i n s ( 21 ) thus obtained was ozonised i n HQ% a c e t i c a c i d to the diketone ^8. 2 1 The a l d o l condensation of 28 to 29 was e f f e c t e d with 5% sodium carbonate and the product 29 was i s o l a t e d by steam d i s t i l l a t i o n . On treatment of 29 with 3 0 % hydrogen peroxide i n sodium hydroxide, the epoxide 30 Scheme 1.2 26 27 28 29 30 21 Synthesis of 21 12 was o b t a i n e d i n good y i e l d s . T h i s epoxide was converted to cyclodecyn-6-one by treatment with t o s y l h y d r a z i n e under the c o n d i t i o n s of S c h r e i b e r and h i s coworkers. 1 3 c y c l o d e c y n - 6 -one ( 2A ) was thus a v a i l a b l e i n l a r g e q u a n t i t i e s f o r the f o l l o w i n g i n v e s t i g a t i o n s . 1) Reactions of _2_1 with proton a c i d s On treatment of cyclodecyn - 6-one ( _2_[ ) with aiethanolic aqueous h y d r o c h l o r i c a c i d , an i s o m e r i c a » 3-unsaturated ketone was obtained i n very high y i e l d . The s p e c t r a l p r o p e r t i e s , t i c and g l c behaviour of t h i s compound were d i f f e r e n t from those of the unsaturated ketone 29. However they were i n complete agreement with A 1 » 6-b i c y c l o [^4. 4. o ] -decanone - 2 ( 19 ) . T h i s was e s t a b l i s h e d by comparing the r e a c t i o n product with an a u t h e n t i c sample of 1_9 prepared by the method of House and Thompson ( Scheme 1.3 ) . 2 2 The d e c a l o l _3J was o x i d i s e d with potassium dichromate to a mixture of c i s - and t r a n s - d e c a l o n e s from which the t r ans-decalone ( 3_2 ) was i s o l a t e d by d i s t i l l a t i o n . 2 3 ' 2 4 T h i s was then c h l o r i n a t e d with s u l f u r y l c h l o r i d e to y i e l d 9 - c h l o r o - t r a ns-1-decalone ( 33 ) . 2 2 D e h y d r o c h l o r i n a t i o n of 33 i n c o l l i d i n e , f o l l o w e d by column chromatography on s i l i c a g e l , gave A 1 > 6 - b i c y c l o [ 4 . 4. 0~) decanone - 2 ( 1_9 ) . 2 2 Synthesis of 1 ^ 1U The ketones 29 and 19 had d i s t i n c t d i f f e r e n c e s i n t h e i r i r s p e c t r a and they were e a s i l y s e p a r a b l e by g l c . The crude r e a c t i o n mixture was c a r e f u l l y s c r u t i n i s e d f o r the ketone 29. No t r a c e of the ketone 29 could be d etected by g l c . Since l e s s than 1% of compound 29 could be e a s i l y d e t e c t e d , i t was concluded that l o s s than 1 % of ketone 2_9 was formed i n the c y c l i s a t i o n . T h i s i n d i c a t e d that o n l y the product r e s u l t i n g from a six-membered r i n g t r a n s i t i o n s t a t e was formed i n t h i s r e a c t i o n . Table 1. 1 Reagent Solvent Product ag. HC1, HDr, HCIO4, CI3CCOOH methanol, dioxane, hexane 19 p-Tolue nesul phonic a c i d benzene 19 The e f f e c t ot s o l v e n t and other a c i d s on t h i s c y c l i s a t i o n was a l s o i n v e s t i g a t e d . The r e s u l t s are 15 summarised i n Table 1.1 . No t r a c e of the ketone 29 c o u l d be detected i n any of these r e a c t i o n s . 2) Reaction of _21 with lithium/aminonia-THF On treatment with l i t h i u m i n ammonia-THF, cyclodecyn-6-one ( ^ 1 ) y i e l d e d a s o l i d with a wide melting range, s u g g e s t i n g t h a t the product was a mixture. A sharp peak at 3580 cm-1 and another at 1605 cm- 1 i n the i r spectrum suggested the presence of a t e r t i a r y a l c o h o l and a C=C groups. A m u l t i p l e t at 6 5.4 i n the nmr spectrum i n t e g r a t e d f o r one proton and was assigned to a v i n y l proton. The mixture was u n s t a b l e to g l c and could not be seperated by t i c or c r y s t a l l i s a t i o n techniques. Hence i t was o x i d i s e d by Brown's p r o c e d u r e . 2 5 The mixture thus o b t a i n e d showed two peaks on g l c i n the r a t i o 25 : 1. By comparing the r e t e n t i o n times with that of the a u t h e n t i c m a t e r i a l s , the major component was i d e n t i f i e d as 19 and the minor component as _29. From these data, s t r u c t u r e J4 was assigned to the major product of the B i r c h r e d u c t i o n . The minor product was assigned the s t r u c t u r e _35. The a l t e r n a t e s t r u c t u r e _36 was r u l e d out f o r the minor product because on o x i d a t i o n t h i s should g i v e _37. S t r u c t u r e _37 was not c o n s i s t e n t with the i r spectrun of the minor ketone obtained 16 17 r e d u c t i o n product was u n l i k e l y on mechanistic grounds. Here agai n the t r a n s a n n u l a r c y c l i s a t i o n gave predominantly the product r e s u l t i n g from a six-membered r i n g t r a n s i t i o n s t a t e . 3) Reactions with Lewis a c i d s When the cyclodecyn-6-one ( _21 ) i n methylene c h l o r i d e was t r e a t e d with boron t r i f l u o r i d e e t h e r a t e at room temperature, the o c t a l o n e 1_9 was again obtained i n 605? y i e l d . On the other hand, on treatment of 2_1 with mercuric c h l o r i d e i n r e f l u x i n g methanol or z i n c i n a c e t i c a c i d at room temperature, no r e a c t i o n was observed. The crude r e a c t i o n mixture showed no t r a c e of 2_9 by g l c a n a l y s i s . Once again the c y c l i s a t i o n had proceeded to give products r e s u l t i n g from a six-membered r i n g t r a n s i t i o n s t a t e . Other Lewis a c i d s l i k e s t a n n i c c h l o r i d e and toron t r i f l u o r i d e a l s o gave only compound 1_9. 4) Reactions of 21 with hydride reducing agents Lithium aluminium h y d r i d e reduced cyclodecyn-6-one ( 2 J ) to the corresponding a l c o h o l , c y c l o d e c y n - 6 - o l ( 38 ) . 2 6 Sodium borohydride a l s o y i e l d e d t h i s compound 18 though i n poorer y i e l d s . These hydride r e d u c i n g agents a t t a c k e d the c a r b o n y l group and not the a c e t y l e n i c bond. 5) Reactions of _2_1 with o r g a n c m e t a l l i c s ttethyllithiuro added to cyclodecyn-b-cne ( 2_1 ) and gave the a c e t y l e n i c a l c o h o l , 6-methylcyclodecyn-6-ol ( 39 ). Here again the reagent d i d not a t t a c k the a c e t y l e n i c bond. With l i t h i u m dimethylcuprate r e a g e n t * 6 cyclcdecyn-6-one ( 2_1 ) was recovered unchanged. 6) Reactions of 21 with bases Compound _2J was found to be very s t a b l e to r e f l u x i n g methanolic sodium hydroxide. However, on treatment with -"• potassium t-butoxide i n DMSO or DMF at. room temperature no i d e n t i f i a b l e product was obtained, but the s t a r t i n g m a t e r i a l disappeared. OH C H 3 OH 38 39 19 Studies on c y c l o d e c y n - 6 - o l ( 38 ) Cyciodecyn-6-ol ( 38 ) was a v a i l a b l e from e a r l i e r i n v e s t i g a t i o n s . Thus r e d u c t i o n of cyclodecyn-6-one ( 2_1 ) with l i t h i u m aluminium hydride gave _38 i n very good y i e l d s . 2 6 T h i s compound was used f o r the f o l l o w i n g i n v e s t i g a t i o n s . 1) Reactions of 3_8 with proton a c i d s On treatment of c y c l o d e c y n - 6 - o l ( _1_8 ) with r e f l u x i n g wet methanolic h y d r o c h l o r i c a c i d , c i s - and t r a n s - d e c a l o n e s ( 4_2 and _43 ) were i s o l a t e d i n good y i e l d s . No trace of b i c y c l o [5.3. o] decalone-2 ( M or |I5 ) could be detected by g l c . While t h i s work was i n progress, Hanach and h i s coworkers r e p o r t e d that the corresponding t o s y l a t e 4_6 on s o l v o l y s i s y i e l d e d a mixture of ,42,43 ,44 and 4_5.26 Since v a r i a t i o n of s o l v e n t p o l a r i t y d i d not a f f e c t the formation of 4_4 and 4j> i n the s o l v o l y s i s experiment, we cannot a s c r i b e the d i f f e r e n c e between the s o l v o l y s i s e x p e r i m e n t 2 6 and the a c i d treatment of _38 to s o l v e n t e f f e c t s . The a u t h e n t i c samples of 4_2,4J ,4_4 and 4j> were prepared by the B i r c h r e d u c t i o n o f the corresponding unsaturated compounds 19 and 29. The a l c o h o l s thus obtained were o x i d i s e d and e q u i l i b r a t e d with base as shown i n Scheme 1.4. The product Scheme I- 4 Syntheses of authentic 4-2-4-5 2 1 obtained on a c i d treatment of _38 was a l s o e q u i l i b r a t e d under the same c o n d i t i o n s as the a u t h e n t i c samples 4 2 - 4 5 to enable proper comparison by g l c . Compounds 4 2 - 4 5 were c l e a r l y separable by g l c . 2) Reaction of 38 with boron t r i f l u o r i d e e t h e r a t e When a s o l u t i o n of .3_8 i n methylene c h l o r i d e was t r e a t e d with boron t r i f l u o r i d e e t h e r a t e at room temperature, a s i n g l e v o l a t i l e product was ob t a i n e d . The compound was homogeneous by g l c and t i c a n a l y s i s . I n i t i a l l y the s p e c t r o s c o p i c data were c o n f u s i n g . High r e s o l u t i o n mass spectrum e v e n t u a l l y e s t a b l i s h e d the molecular formula as C 1 0 H 1 5 F " T n e peak at 1705 cm-1 i n the i r spectrum was assigned to C=C-F. 2 7 The Ml nmr spectrum showed no v i n y l protons i n d i c a t i n g t h a t the double bend was t e t r a s u b s t i t u t e d . The 1 9 F nmr spectrum had a sharp s i n g l e t at 111 ppm u p f i e l d from CC1 3F. The >'F nmr data of some r e l a t e d o l e f i n i c f l u o r i d e s are given i n Table 1 . 2 . 2 8 The data i n d i c a t e that the compound obtained i n the above r e a c t i o n has 1 9 F nmr spectrum c l o s e r to that of 1-fl u o r o c y c l o h e x e n e ( 101.7 ppm ) than that of 1-f l u o r o c y c l o h e p t e n e ( 9 1.1 ppm ). Furthermore the l a t t e r showed a c o u p l i n g constant J H F = 1 1 . 5 Hz, whereas our 22 compound had a sharp singlet at 111 ppm. Hence the structure 47 was assigned for this Compound. The sharp singlet also indicated that the compound was homogeneous. Table 1.2 2 8 Compound F (ppm) J (HZ) CH -CF=C 1-Fluoroc y c l o pen tene 122.7 Small 1 - f l u orocyclohe xene 101.7 - -1-fluorocycloneptene 91.1 11.5 The l 9 F chemical s h i f t s are i n ppm from CCl^F. As a chemical proof f o r the s t r u c t u r e , the compound 47 was ozonised and worked up o x i d a t i v e l y . The k e t o - a c i d 48 thus obtained had i r peaks at 1705 and 1725 cm- 1. Cn e s t e r i f i c a t i o n with diazomethane the i r peaks s h i f t e d to 1705 and 1735 cm-1 ( equation 12 ).. The e s t e r thus obtained was homogeneous by g l c . The k e t o - e s t e r was compared with an a u t h e n t i c sample of 2 - o x o c y c l c h e x y l b u t y r a t o _49, which was prepared by the a l k y l a t i o n of the enamine of cyclohexanone ( 50 ) with Y - i o d o b u t y r a t e ( 51,. equation 13 ) . The two compounds were i d e n t i c a l by t h e i r i r s p e c t r a and g l c r e t e n t i o n times, and the melting p o i n t s and mixed melting point of their 2,4-DNP derivatives. The degradation sequence again supported the assumption that the fluoro-olefin was a single compound. F | + l(CH 2) 3COOCH 3 > 49 eqJ3 Once again the t r a n s a n n u l a r c y c l i s a t i o n had proceeded to g i v e products r e s u l t i n g from a six-membered r i n g t r a n s i t i o n s t a t e . Studies on 6-methyl c y c l o d e c y n - 6 - o l ( 39 ) 6-Methylcyclodecyn-6-one ( 39 ) was a v a i l a b l e i n 27? y i e l d from the a d d i t i o n of m e t h y l l i t h i u m to cyclodecyn-6-one ( 2_1 ) i n TIIF. The compound thus obtained was used f o r the f o l l o w i n g i n v e s t i g a t i o n s . 1) Reaction of _39 with mineral a c i d The t e r t i a r y a l c o h o l 39. on treatment with r e f l u x i n g wet methanolic h y d r o c h l o r i c a c i d y i e l d e d a mixture of four compounds. T h i s mixture was i d e n t i f i e d as _5_2 ( a + b ) and _53 ( a+b ) by comparing with a u t h e n t i c samples using g l c and nmr t e c h n i q u e s . The four isomers were not d i s t i n g u i s h a b l e by g l c alone. The r a t i o s of the c i s - and t r a n s - isomers were perhaps e q u i l i b r i u m values because they d i d not appear to change on prolonged treatment with a c i d . The product at a s h o r t e r r e a c t i o n time was not i n v e s t i g a t e d to determine whether the c y c l i s a t i o n led to a preference of e i t h e r c i s -or t r a n s - isomer. The products i n the mixture were i n the r a t i o 52a : 52b : 53a : 53b = 1.0 : 1.4 : 0.1 : 0.25. T h i s 25 was the only example of a t r a n s a n n u l a r c y c l i s a t i o n of a cyclodecyne i n which we have found a s i g n i f i c a n t amount of the product r e s u l t i n g from c y c l i s a t i o n through a seven-membered r i n g t r a n s i t i o n s t a t e . The a u t h e n t i c samples of 52a and 52b were prepared by the conjugate a d d i t i o n of l i t h i u m d imethylcuprate to the unsaturated ketone V9. 2 9 The conjugate a d d i t i o n y i e l d e d a predominance of the c i s - isomer. The isomers c o u l d be e q u i l i b r a t e d by base and the mixture was s e p a r a b l e by g l c . The nmr s i g n a l at 5 1.02 was assigned tc the angular methyl group of the c i s - isomer and the s i g n a l at § 0.77 to that of the t r a n s - isomer. These assignments are based on the values of C-19 methyl groups of the 5 3- and 5 a-androstan-4-ones, which appear at 6 1.12 and 6 0.74 r e s p e c t i v e l y . 3 o 26 The conjugate a d d i t i o n of l i t h i u m dimethylcuprate to 29 y i e l d e d the c i s - and t r a n s - isomers cf .53. 3 1 The two isomers c o u l d be separated by g l c . The methyl s i g n a l s of the c i s -and t r a n s - isomers were again c l e a r l y d i s c e r n i b l e by nmr ( 6 1.1b and 0.72 r e s p e c t i v e l y ) and were i n agreement with the values r e p o r t e d . 3 » A mixture of a l l the f o u r isomers was not completely separable by g l c . A combination of g l c and nmr techniques were employed to c h a r a c t e r i s e and determine the r a t i o of a l l the isomers i n the mixture. The a c i d c a t a l y s e d c y c l i s a t i o n of 39 gave the same r a t i o s of 52a : 52b and 53a : 53b as the base e q u i l i b r a t i o n of the a u t h e n t i c conjugate a d d i t i o n products. 2) Reaction of 39 with boron t r i f l u o r i d e e t h e r a t e On treatment of 3_9 i n methylene c h l o r i d e with boron t r i f l u o r i d e e t h e r a t e , a fluoro-compound was i s o l a t e d i n gcod y i e l d . The product was homogeneous cn s e v e r a l g l c columns and t i c systems. The high r e s o l u t i o n mass spectrum suggested a molecular formula of C 1 1 H 1 7 F . The *H nmr spectrum of the f1uoro-compound had one sharp s i n g l e t at 6 1.05 due to angular methyl group and had no v i n y l protons. The 1 9 F nmr spectrum showed a r e l a t i v e l y sharp s i n g l e t at 27 110 ppm u p f i e l d from C C l 3 F . The i r a b s o r p t i o n a t 1700 c m - 1 was a s s i g n e d to a t e t r a s u b s t i t u t e d v i n y l f l u o r i d e ( see page 21 ) . Here a g a i n the l 9 F nmr spectrum f a v o u r s s t r u c t u r e 5J4 and not 55. O z o n o l y s i s of the fluorc-compcund and o x i d a t i v e work-up gave a k e t o - a c i d w i t h a broad i r a b s o r p t i o n a t 1705 cm- 1. E s t e r i f i c a t i o n y i e l d e d methyl 1-methyl-2-oxo-c y c l o h e x y l - l - b u t y r a t e ( J56 ) , which had i r a b s o r p t i o n a t 1700 and 1730 cm- 1 ( e q u a t i o n 14 ) . T h i s compound was c h a r a c t e r i s e d as i t s 2,4-DNP d e r i v a t i v e . No t r a c e of the i s o m e r i c c y c l o p e n t a n o n e c o u l d be d e t e c t e d by the i r spectrum of the a c i d o r the g l c of t h e e s t e r . In summary, t h e r e was a s t r o n g p r e f e r e n c e towards p r o d u c t s r e s u l t i n g from a six-membered r i n g t r a n s i t i o n s t a t e . Only i n two cases were p r o d u c t s r e s u l t i n g from a seven-membered r i n g t r a n s i t i o n s t a t e f o u n d . Here a g a i n t h e r e was a v e r y s t r o n g p r e f e r a n c e f o r a six-membered r i n g t r a n s i t i o n s t a t e . Hanach and h i s coworkers a l s o o b t a i n e d s i m i l a r r e s u l t s i n the s o l v o l y s i s o f c y c l o d e c y n - 6 -t o s y l a t e . 28 COOCH 3 56 eq. 14 DISCUSSION W.D. P f e i f e r and h i s coworkers have s t u d i e d the behaviour of bent v i n y l c a t i o n s . 3 2 T h e i r s t u d i e s on the s o l v o l y s i s of simple c y c l o a l k e n y l t r i f l a t e s showed that 6_0 i s more s t a b l e than 6_1. T h i s was a t t r i b u t e d to the f a c t t h a t the v i v y l c a t i o n 60 would be more l i n e a r than 6_1. I f 61 30 our c y c l i s a t i o n r e a c t i o n s were to proceed through a f r e e carbonium ion 57, then one would expect a preference f o r the formation of _59 ( equation 15 ). However, as demonstrated i n the p r e v i o u s s e c t i o n , products r e s u l t i n g from 58_ appear to be favoured over those r e s u l t i n g from _59. I t co u l d be argued that_59 may be formed i n i t i a l l y and subsequently i t could r e a r r a n g e to .58.. However from the work of OTf eq.l6 31 W.D. Pfeifer and his coworkers i t appears that the reverse may be true. 3 2 The solvolysis of _62_ in b0% aqueous methanol/diet hylamine at 100 y i e l d e d 63 and 64, ( equation 16 ). Those r e a c t i o n s most likely to yield carbonium ions, for example, the s o l v o l y s i s of cyclodecyn-6-tosylate ( M ) 2 6 and the a c i d treatment of 39, did lead to products which can be c o n s i d e r e d to a r i s e from 59. An examination of the molecular models of _2_1 and 738 suggest that C-1 and C-2 are n e a r l y e q u i d i s t a n t from C-b and hence we might expect a f i x t u r e of bicyclo(u.4.ojdecanes and bicyclo[5. J.ojdecanes. However, a s t r o n g preference f o r six-membered ting formation was observed. We f e e l t h a t these r e a c t i o n s are essentially concerted. The acetylene i s simultaneously attacked by the' e l e c t r o p h i l i c C-6 and an e x t e r n a l n u c l e o p h i l e . Assuming that the carbon atoms 1 and 2 approach sp 2 hybridisation in the t r a n s i t i o n s t a t e f o r c y c l i s a t i o n , then i t appears from the models that the t r a n s i t i o n s t a t e l e a d i n g to b i c y c l o -ecane s k e l e t o n has l e s s s t e r i c i n t e r f e r e n c e and t o r s i o n a l s t r a i n than the t r a n s i t i o n s t a t e l e a d i n g to the b i c y c l o ^ 5 . 3 . o j d e c a n e s k e l e t o n . S t r u c t u r e 65 i s the Newman p r o j e c t i o n along C-10, C-1, C-2 and C-3. S t r u c t u r e 66 d e p i c t s the whole molecule i n i t s most s t a b l e ( a l l 32 staggered ) conformation. Planes a and b are p e r p e n d i c u l a r to the plane of the paper. For trans c o p l a n a r a d d i t i o n of C-6 and the n u c l e o p h i l e at the t r i p l e bond, i t can be seen t h a t one of the hydrogens on C-10 w i l l s t e r i c a l l y hinder the a d d i t i o n of the n u c l e o p h i l e at C-1. However the n u c l e o p h i l e could add to C-2 with the two hydrogens s t a g g e r i n g i t . The mechanism d i s c u s s e d above would e x p l a i n the almost e x c l u s i v e formation of b i c y c l o Q * . 4. (f]decanes i n the a c i d and the Lewis a c i d c a t a l y s e d r e a c t i o n s . However t h i s does not e x p l a i n the preponderance of 3_4 i n the B i r c h r e d u c t i o n of 21. G. Stork and h i s coworkers have suggested that the B i r c h r e d u c t i o n of Y - e t h y n y l ketones i n v o l v e a n o n - l i n e a r r a d i c a l anion as an i n t e r m e d i a t e . 1 7 Assuming that the r e d u c t i o n of 2A would i n v o l v e a s i m i l a r i n t e r m e d i a t e , i n s p e c t i o n of the molecular model of _67 shows a p r e f e r e n c e f o r the formation of a six-membered r i n g product. 33 1 U Quite i n d e p e n d e n t l y , H. Hanack and h i s coworkers worked on the same a c e t y l e n i c ketone and i t s d e r i v a t i v e s . " T h e i r work y i e l d e d r e s u l t s s i m i l a r tc c u r s . But they e x p l a i n e d the preponderance of the b i c y c l o ^ U . 4 . O ^ d e c a l i n s as f o l l o w s . In the s o l v o l y s i s of the t o s y l a t e J U b , the bridged c a t i o n 69 was ruled out by Hanach and h i s coworkers because n e i t h e r c y c l o d e c y n - 6 - o l nor b i c y c l o j j S . 3.cQdecane-2-one c o u l d be i s o l a t e d . 3 3 They suggest t h a t the e x c l u s i v e formation of bicyclo[^4.4.0 -J decanes shows that out of the two p o s s i b l e v i n y l c a t i o n s 5_8 and 59, 58 i s more s t a b l e . •The s t a b i l i t y of the c a t i o n _58 i s understandable. Hethylenecyclopentane ( a model for 59 ), owing to i t s higher r i n g s t r a i n has about 5 kcal/f!ole ( enthalpy ) l e s s e r s t a b i l i s a t i o n than 1-methylcyclohexene ( a model f o r 53 ) * . * On the s t a b i l i t y of the two s p e c i e s 58 and 59, a comparison of the s t a b i l i t i e s of 70 and 7J would be more a p p r o p r i a t e than the c o r r e s p o n d i n g ground s t a t e models { the models suggested by Hanach and h i s c o w o r k e r s 3 3 ) . W.D. P f e i f e r and h i s coworkers have pointed out that 70 and 71 do not d i f f e r much i n s t a b i l i t y . 2 6 T h e i r s t u d i e s i n d i c a t e t h a t the r i n g s t r a i n and the v i n y l c a t i o n s t r a i n f a c t o r s seem to • Abstrac ted from the p a p e r , 3 3 35 balance each other. However, i t should be noted that i n our case t h e r e i s the added c o m p l i c a t i o n of the fused r i n g s . W.S. Johnson and h i s coworkers have made some i n t e r e s t i n g o b s e r v a t i o n s i n connection with t h e i r s t u d i e s on the b i o g e n e t i c type c y c l i s a t i o n s . When J72 i n pentane was t r e a t e d with a n u c l e o p h i l e l i k e formic a c i d f o r 15 minutes o at 23 compound 7J was i s o l a t e d i n 90$ y i e l d . 3 * However, on treatment with a poor n u c l e o p h i l e l i k e t r i f l u o r o a c e t i c a c i d i n methylene c h l o r i d e compound 7_U was the p r o d u c t . 3 S The authors suggest the f o l l o w i n g mechanism to e x p l a i n the p r o d u c t s . 3 5 The v i n y l c a t i o n 7_6 i s f i r s t formed. In the presence of a good n u c l e o p h i l e the c a t i o n i s trapped. However, i n the absence of such a n u c l e o p h i l e , 76 rearranges to 7 5 and a b s t r a c t s c h l o r i d e from the s o l v e n t . The s t a b i l i t y of 75 over 76 was a t t r i b u t e d to the r e l i e f of the 36 t o r s i o n a l s t r a i n i n going from 6/5 ti;ans-fused r i n g system to 6/6 t r a n s - f u s e d r i n g system. 74 73 37 C O N C L U S I O N The r e s u l t s of our experiment and t h a t o f Hanach and h i s c o w o r k e r s 3 3 c l e a r l y i n d i c a t e t h a t the c y c l o d e c y n e d e r i v a t i v e s 2 J , 38, 39 and 46 a r e not s u i t a b l e as s y n t h e t i c i n t e r m e d i a t e s f p r h i c y c l o [ 5 . 3 . o J d e c a n e s k e l e t o n . I t appears t h a t the t o r s i o n a l and s t e r i c e f f e c t s around the t r i p l e bond a r e mainly r e s p o n s i b l e f o r t h e e x c l u s i v e f o r m a t i o n of p r o d u c t s , one would be d e a l i n g w i t h s u b s t i t u t e d c y c l p d e c y n e s . Here the s t e r i c e f f e c t s may compete with the t o r s i o n a l s t r a i n . The o v e r a l l p i c t u r e thus becomes more c o m p l i c a t e d and t h e r e f o r e l e s s p r e d i c t a b l e . In the s y n t h e s i s of n a t u r a l o 21 38 OH QTs 39 46 38 EXPERIMENTAL Melting p o i n t s were determined on the K o f l e r hot stage and are uncorrected. The i r s p e c t r a were recorded on a Perkin-Elmer model 700 and were c a l i b r a t e d using 160 1 cm 1 band of p o l y s t y r e n e . The M! nmr s p e c t r a were recorded on e i t h e r a Varian T-60, Varian HA-100 or XL-100 and the » 9F nmr s p e c t r a were recorded on a Varian T-60 equipment with a T-6T18 wide sweep module using C C l 3 F as an i n t e r n a l s tandard. The mass s p e c t r a were obtained using an AEI MS-9 ope r a t i n g a t 70eV. The u l t r a v i o l e t s p e c t r a were run on a Unicam SP 800B instrument using methanol as s o l v e n t . Microanalyses were performed by Mr. Peter Borda, U n i v e r s i t y of B r i t i s h Columbia. The g l c a n a l y s i s were performed with a Varian Aerograph 90-P-3 using column A, 5 f t x 1/U i n column of 3% SE 30 on Chromsorb W; column B, 5 f t x 1/1 i n . column of 10% FFAP on Chromsorb W; or with a Perkin-Elmer Model 900 using column C, 5 f t x 1/8 i n . column of 10% FFAP on Chromsorb K. Unless i t i s s p e c i f i e d otherwise, a l l i r s p e c t r a were recorded i n chloroform s o l u t i o n and the nmr spectra i n C D C l 3 s o l u t i o n with TK3 as i n t e r n a l standard. The chemical s h i f t s are recorded i n 5 ppm t o r *H nmr and 6 ppm u p f i e l d from C C l 3 F f o r l 9 F nmr. 39 A 1 *• * - B i c y c l o 5.3.0 decanone ( 29 ) T h i s compound was prepared from A 9 » 1 °-octalin by the method of Anderson and N e l s o n . 1 9 Cyclodecyn-6-one ( 2J. ) A s o l u t i o n of 1.0g (0.007 mole; ) of enone .29 i n 20 ml o of methanol was cooled i n a water hath at 10 and t r e a t e d with 10 ml of 305? hydrogen peroxide with s t i r r i n g . A s o l u t i o n of 2 ml of 6N sodium hydroxide i n 5 ml of methanol was added dropwise over a period of 0.5 h. The r e s u l t i n g o s o l u t i o n was s t i r r e d at 10 f o r an a d d i t i o n a l 15 h. The methanolic s o l u t i o n was d i l u t e d with 50 ml of water and e x t r a c t e d t h r e e times with methylene c h l o r i d e . The e x t r a c t s were combined, washed with s a t u r a t e d b r i n e s o l u t i o n u n t i l n e u t r a l , d r i e d over anhydrous sodium sul p h a t e , f i l t e r e d and the s o l v e n t was removed under reduced pressure. The r e s i d u e was d i s t i l l e d ( bp 100*/0.6 mm , bath temp. ) to y i e l d 0.82 g ( 74 % ) of A 1i7-oxido-bicyclo 5.3.0 decanone-2 ( 30 ) . A 1.6 1 g (0.0097 mole ) sample of the above epoxide was tr e a t e d with t o s y l h y d r a z i n e under the c o n d i t i o n s of S c h r e i b e r and h i s c o w o r k e r s , 1 3 to y i e l d cyclodecyn-6-one ( 21 ) which was d i s t i l l e d at 55 /0.02mm ( bath temp. ). u o Acid i s o m e r i s a t i o n of cyclodccyn-6-one ( 2 1 ) 1) Methanolic h y d r o c h l o r i c a c i d A 79mg ( 0.53 mmole ) sample of cyclodecyn-6-one was d i s s o l v e d i n 1.5 ml of methane! c o n t a i n i n g one drop of cone, h y d r o c h l o r i c a c i d and the s o l u t i o n was allowed to stand a t room temperature f o r 12 h. Methanol was removed under reduced pressure, the re s i d u e d i s s o l v e d i n ether and washed with s a t u r a t e d sodium carbonate s o l u t i o n . The organic e x t r a c t was d r i e d over anhydrous sodium s u l p h a t e , f i l t e r e d and the s o l v e n t was removed under reduced p r e s s u r e . The r e s i d u e was d i s t i l l e d at 70 - 80 /0.2 mm ( bath temp. ) to y i e l d 75mg ( 95% ) of o c t a l c n e ( 19 ) which was compared by i r and g l c ( column D ) to the a u t h e n t i c sample prepared by the method of House and Thompson. 2 2 Compounds J 9 and 29 were sepa r a b l e by g l c ( column B ) . No t r a c e of _29 could be detected i n the crude r e a c t i o n product or i n the sample obtained by d i s t i l l a t i o n . 2) Boron t r i f l u o r i d e e t h e r a t e i n methylene c h l o r i d e A s o l u t i o n of 225mg ( 1.5 m mole ) of 21 l n 1 ^ m l o f methylene c h l o r i d e was t r e a t e d with ca. 0.5 ml of boron t r i f l u o r i d e e t h e r a t e . The dark green s o l u t i o n thus obtained 41 was s t i r r e d w e l l f o r 10 min. The r e a c t i o n mixture was washed with s a t u r a t e d aqueous sodium bicarbonate u n t i l the organic l a y e r was c o l o u r l e s s . The o r g a n i c e x t r a c t was d r i e d over anhydrous sodium s u l p h a t e , f i l t e r e d and the s o l v e n t was removed under reduced pressure. Glc a n a l y s i s ( column B ) showed only 19 to be present i n the r e a c t i o n mixture. The e residue on d i s t i l l a t i o n at 70 - 80 /0.2 mm ( bath temp. ) y i e l d e d 133 mg ( 59 % ) of pure 19. 3) A d d i t i o n a l c o n d i t i o n s f o r i s o m e r i s a t i c n The f o l l o w i n g c o n d i t i o n s were a l s o found to be e f f e c t i v e i n the i s o m e r i s a t i o n of _21 to 19. H y d r o c h l o r i c a c i d , hydrobromic a c i d or p e r c h l o r i c a c i d i n methanol, dioxane or hexane at room temperature; p - t o l u e n e s u l p h o n i c a c i d i n r e f l u x i n g ben2ene= B i r c h r e d u c t i o n of Cyclodecyn-6-one ( 2 1 ) A s o l u t i o n of 165 mg ( 1.1 mmole ) of _21 i n 1 ml of dry te t r a h y d r o f u r a n was added to 100 ml of l i q u i d ammonia. The s o l u t i o n was s t i r r e d and very small pieces of l i t h i u m wire were added u n t i l a blue c o l o u r p e r s i s t e d . S o l i d ammonium c h l o r i d e was q u i c k l y added to render the s o l u t i o n c o l o u r l e s s and the ammonia was allowed to evaporate. Water was added U2 to the r e s i d u e and the mixture was e x t r a c t e d with ether. The o r g a n i c e x t r a c t was washed with s a t u r a t e d sodium c h l o r i d e s o l u t i o n u n t i l n e u t r a l , d r i e d ever anhydrous sodium s u l p h a t e , f i l t e r e d and the s o l v e n t s removed under reduced p r e s s u r e . The y i e l d of the crude product was 168 mg ( 100% ). T h i s s e m i s o l i d showed no c a r b o n y l a b s o r p t i o n i n the i r . I t was sublimed at 25° /0.005 mm t o g i v e a o q u a n t i t a t i v e y i e l d of a product mp 61 - 69 ; i r , ( CH 2C1 2 ) 3580, 1605 cm-» ; F i g u r e 1; nmr, ( C C l 4 ) 5.4 ( m, 1H ), 1.2 - 2.6 { m, 15H ) ; F i g u r e 1; m/e c a l c d . f o r C i 0 H 1 6 0 152.1201; found 152.1198; 152 ( 15% ), 134 ( 585? ), 119 ( 40* ), 105 ( 52* }, 91 { 100% ); Figure 2. O x i d a t i o n of the a l c o h o l s from the B i r c h r e d u c t i o n of cyclodecyn-6-one ( 2J\ ). ft s o l u t i o n of the above a l c o h o l s ( 10 mg ) i n ether was added to an i c e c o l d s o l u t i o n of 100 mg of chromium t r i o x i d e i n 5 ml of water and 0„5 ml of concentrated s u l p h u r i c a c i d . o The mixture was s t i r r e d f o r 2.5 h. at 0 . The e t h e r l a y e r was then washed with water u n t i l n e u t r a l . The e t h e r s o l u t i o n was d r i e d over anhydrous sodium s u l p h a t e , f i l t e r e d and the s o l v e n t was removed under reduced pressure to g i v e 4 3 an o i l y r e s i d u e : i r , 1650, 1630 cm-». T h i s was analysed by g l c ( column C ) and was found to c o n t a i n 19 and 29 i n the r a t i o 25 : 1. Attempted k e t a l i s a t i o n of 21 1) A s o l u t i o n of 80 mg of 2J» 0*5 ml of ethylene g l y c o l and a few c r y s t a l s of p - t o l u e n e s u l p h o n i c a c i d i n 50 ml of benzene was r e f l u x e d f o r 16 h. The benzene s o l u t i o n was washed with s a t u r a t e d sodium c h l o r i d e s o l u t i o n , d r i e d over anhydrous sodium s u l p h a t e , f i l t e r e d and the s o l v e n t was removed under reduced pressure. Glc ( column B ) and t i c ( s i l i c a g e l - benzene ) a n a l y s i s i n d i c a t e d that the major component of the mixture was 19 and a s m a l l amount of unreacted 21. 2) 36 mg of 2!1 was d i s s o l v e d i n 1.5 ml of the e t h y l e n e k e t a l of methyl e t h y l ketone. A smal l c r y s t a l of p-toluene s u l p h o n i c a c i d was added and the mixture was r e f l u x e d f o r 36 h. The r e a c t i o n mixture was d i s s o l v e d i n 20 ml of ether and washed twice with 20 ml p o r t i o n s of s a t u r a t e d sodium c h l o r i d e s o l u t i o n . The or g a n i c l a y e r was then d r i e d over anhydrous sodium sulphate, f i l t e r e d and the ether and the ket.a.l of methyl e t h y l ketone were removed under reduced 44 pressure ( water pump ) . The r e s i d u e was analysed on g l c and t i c as above. The only product was the s t a r t i n g ketone. Cyclodecyn-6-ol ( 38 ) Fol l o w i n g the procedure of Hanach and Heumann, 2 6 15.2 mg (Q.I01 mmole ) of j H was reduced with 15 mg of l i t h i u m aluminium hydride in 10 ml of r e f l u x i n g ether f o r 0.5 h. The r e a c t i o n mixture was c o o l e d , t r e a t e d with 5 ml of a satur a t e d aqueous s o l u t i o n of potassium sodium t a r t r a t e and the r e s u l t i n g s o l u t i o n was s t i r r e d f o r 5 min. The aqueous l a y e r was e x t r a c t e d with 2 x 20 ml of e t h e r . The e x t r a c t s were combined, d r i e d over anhydrous sodium s u l p h a t e , f i l t e r e d and the s o l v e n t was removed under reduced p r e s s u r e . 9 The residue was d i s t i l l e d at 85 - 90 /0.5mm ( bath temp. ) to y i e l d 145 mg ( 94% ) c f 38; i r , ( CH 2 C l 2 ) 3360 cm-* ; nmr, ( C C I 4 ) 1.2 - 1.9 ( in, 1H ), 1.94 ( br.s, 1H ), exchangeable i n D 2 0 , 4.2 ( m, 1H ). 6-Methylcyclodecyn-6-ol ( 3_9 ) A s o l u t i o n of 1.7 g ( 0.011 mole ) of 21 i n dry THF was t r e a t e d dropwise with 7 ml of 2.3 M s o l u t i o n of m e t h y l l i t h i u m under n i t r o g e n . A f t e r a d d i t i o n of 45 m e t h y l l i t h i u m , the s o l u t i o n was s t i r r e d f o r an a d d i t i o n a l 3.5 h. at room temperature. Excess m e t h y l l i t h i u m was decomposed with water. The mixture was then s a t u r a t e d with sodium c h l o r i d e and e x t r a c t e d with e t h e r . The ether e x t r a c t was d r i e d over anhydrous sodium s u l p h a t e , f i l t e r e d and the s o l v e n t was removed under reduced pressure t o y i e l d an o i l y r e s i d u e . T h i s was p u r i f i e d by column chromatography on s i l i c a g e l using benzene - e t h y l a c e t a t e ( 95 : 5 to 50 : 50 ) as eluent to g i v e 500 mg ( 27% ) of 39. Due to the l a b i l i t y of t h i s compound i t c o u l d not be p u r i f i e d f o r combustion a n a l y s i s . I r , ( f i l m ) 3390 cm->; F i g u r e 3; nmr, 1.04 ( s, 3H ) , 1.27 ( s, 1H ) , exchangeable with D 2 O , 1.2 - 1.8 ( m, 10H ), 1.9 - 2.4 ( m, 4H ) ; F i g u r e 3; mass spectrum, m/e 166 ( 8% ) , 151 ( 30"S ) , 148 ( 26'X ) , 133 ( 50% ), 105 ( 52% ) , 91 ( 100* ) ; F i g u r e 4. A c i d treatment of c y c l o d e c y n - 6 - o l ( 38 ) A s o l u t i o n of 56 mg ( 0-2T17 mmole ) of cyclodecyn- 6 - 0 I and 2 drops of concentrated h y d r o c h l o r i c a c i d i n 2 ml of methanol was r e f l u x e d f o r 3.5 h. The r e a c t i o n mixture was then poured i n t o 30 ml of water and e x t r a c t e d with 30 ml of benzene - e t h e r ( 1 : 1 ) . The e x t r a c t s were washed with 20 ml o f s a t u r a t e d sodium bicarbonate s o l u t i o n and 20 ml of sa t u r a t e d sodium c h l o r i d e and then d r i e d over anhydrous sodium s u l p h a t e . The s o l u t i o n was then f i l t e r e d and the s o l v e n t s removed under reduced pressure. The r e s i d u a l o i l was p u r i f i e d by p r e p a r a t i v e t i c { s i l i c a g e l - benzene : e t h y l a c e t a t e 9 : 1 ) to y i e l d 8 mg of c y c l o d e c y n - 6 - o l and 42 mg ( 87% based on the recovery of the s t a r t i n g m a t e r i a l ) of the decalones _U_2 and 4_3. These were shown to be i d e n t i c a l with a u t h e n t i c m a t e r i a l by g l c ( column C ). C i s - and trans-deca lone-1 ( U2 and 4 J ) Compound 19 ( 29 mg ) was d i s s o l v e d i n 10 ml of dry l i q u i d ammonia. Small p i e c e s of l i t h i u m metal were s l o w l y added to the well s t i r r e d mixture u n t i l a permanent blue c o l o u r p e r s i s t e d . S o l i d ammonium c h l o r i d e was q u i c k l y added u n t i l the s o l u t i o n became c o l o u r l e s s . A f t e r removing a l l the ammonia, the o r g a n i c m a t e r i a l was e x t r a c t e d i n t o 2 x 20 ml of ether and washed with s a t u r a t e d sodium c h l o r i d e s o l u t i o n u n t i l the washings were n e u t r a l to l i t m u s . The combined ether e x t r a c t s were then evaporated to dryness on the water pump and the r e s i d u a l o i l was d i s s o l v e d i n 10 ml of acetone. T i t r a t i o n with Jones' reagent and the usual workup gave 29 mg of o i l . 3 7 The mixture was e q u i l i b r a t e d as 47 f o l l o w s . A 15 my sample of the above mixture from the Birch reduction was dissolved in 15 ml of methanol and 2 drops of IN sodium hydroxide was added. The solution was heated cn a steam bath for 5 minutes and then diluted with 20 ml of water. The organic m a t e r i a l was e x t r a c t e d with 20 ml of e t h y l a c e t a t e and the e x t r a c t s were washed with saturated aqueous sodium c h l o r i d e s o l u t i o n u n t i l the washings were neutral to l i t m u s . These ketones j£2_ and 43 were clearly separable by g l c on columns B and C. C i s - and t r a n s - b i c y c l o [ 5 . 3 .o3decalone-2 ( 44, and 45 ) B i r c h r e d u c t i o n f o l l o w e d by o x i d a t i o n of A * «7-bicyclo«» [5,3.o3decenone-2 ( 29 ) gave a mixture of isomers which were e q u i l i b r a t e d as d e s c r i b e d above. Again the isomers were separable by g l c on columns B and C . Treatment of 3 8 with boron t r i f l u o r i d e e t h e r a t e A s o l u t i o n of 190 mg ( 1.26 mmole ) of cyclodecyn-6-cl ( .38 ) i n 20 ml of dry methylene c h l o r i d e was tr e a t e d with 0.5 ml of boron t r i f l u o r i d e e t h e r a t e and s t i r r e d at room temperature f o r 15 minutes. The brown s o l u t i o n was washed with s a t u r a t e d aqueous sodium bicarbonate u n t i l the o r g a n i c l a y e r became c o l o u r l e s s . T h e methylene c h l o r i d e s o l u t i o n was 4 8 dried over anhydrous sodium s u l p h a t e , filtered and the s o l v e n t removed under reduced p r e s s u r e . The volatile r e s i d u e was p u r i f i e d by p r e p a r a t i v e tic ( silica gel -benzene ) to y i e l d 163 mg ( 85% ) of f l u o r o a l k e n e 47 which was homogeneous by g l c ( columns B and C ). i r , ( f i l m ) 1705 cm- 1; F i g u r e 5; »H nmr, 1 - 3 ( m ); 1 9 F nmr ( CC14 , reference CC13 F ) 111; F i g u r e 5; m/e c a l c d . f o r C ^ ^ H F:154.1158; found: 154.1102; 154 ( 10X' ) ,• 1 35 ( 100* ) ; F i g u r e 6. O Z o n o l y s i s of 47 A s o l u t i o n of 100 mg of j4_7 was d i s s o l v e d in 2 ml of methanol. The s o l u t i o n was cooled i n a dry i c e / acetone bath and ozone was passed through the s o l u t i o n u n t i l a light blue colour appeared. The excess ozone was removed under reduced pressure. The ozonide s o l u t i o n was t r e a t e d with 0.5 ml of 30% hydrogen peroxide and r e f l u x e d en a steam bath for 15 minutes. The r e a c t i o n mixture was poured i n t o 25 ml of water and e x t r a c t e d with 3 x 20 ml of ether. The combined e x t r a c t s were d r i e d over sodium s u l p h a t e , f i l t e r e d and the s o l v e n t s removed under reduced pressure to y i e l d crude 2 - o x o c y c l o h e x y l b u t y r i c a c i d . 49 I r , 1705, 1725 c i - ' . The crude a c i d was e s t e r i f i e d with diazometbane and the r e s u l t i n g keto e s t e r 4J} was p u r i f i e d by tic ( silica gel • c h l o r o f o r m ) . Ir, 1705, 1735 cm-1; Fi g u r e 7. T h i s was converted to i t s 2,4-DNP d e r i v a t i v e ( rap 109 * 111 ). Mixed mp with a u t h e n t i c sample, prepared as d i s c r i b e d below showed no d e p r e s s i o n . For superimposed i f see F i g u r e 8. Methyl 4-iodobutyrate ( 5^ ) A s o l u t i o n of 13.65 g { 100 mmole } of methyl 4 - c h l o r o b u t y r a t e i n 100 ml of dry acetone was refluxed with 44.94 g ( 300 mmole ) of sodium i o d i d e , under n i t r o g e n atmosphere f o r 16 h. The brown s o l u t i o n was then cooled to room temperature. The s o l i d was f i l t e r e d and washed with ether. The combined f i l t r a t e s were d i s t i l l e d under reduced pressure to remove a l l s o l v e n t . About 50 ml of water was added to the r e s i d u e and the org a n i c m a t e r i a l was e x t r a c t e d with 150 ml of ether. The brown ether l a y e r was then washed with 2 x 50 ml of satu r a t e d aqueous sodium b i s u l p h i t e s o l u t i o n t o render i t c o l o u r l e s s . The ether e x t r a c t was then d r i e d over anhydrous sodium sulphate, f i l t e r e d and the 50 s o l v e n t was removed under reduced pressure. The methyl 4-i o d o t u t y r a t e thus obtained was used d i r e c t l y i n the enamine o a l k y l a t i o n ; bp 75 - 80 /8 mm. I r , ( f i l m ) 1740 cm-»; nmr, 1.8 - 2.6 ( m, 4H ) 3.2 ( t , 2H ) , 3.66 ( s, 3 H ) ; Methyl 2 - o x o c y c l o h e x y l b u t y r a t e ( 49 j A s o l u t i o n of 10.6 g ( 70 mmcle ) of the p y r r o l i d i n e enamine of c y c l o h e x a n o n e 3 8 i n 100 ml of dry methanol was t r e a t e d with 7.6 g ( 33.6 mmole ) of methyl 4-iodobutyrate« The mixture was r e f l u x e d under n i t r o g e n f o r 20 h. Then the s o l v e n t was removed under reduced p r e s s u t e . The r e s i d u e was s r i r r e d with 20 ml of water f o r 5 minutes and e x t r a c t e d with 50 ml of e t h e r . The ether s o l u t i o n was washed with 3 x 10 ml of sa t u r a t e d sodium c h l o r i d e s o l u t i o n u n t i l n e u t r a l t o l i t m u s , d r i e d over anhydrous sodium s l u p h a t e , f i l t e r e d and the s o l v e n t was removed under reduced p r e s s u r e . The r e s i d u e on d i s t i l l a t i o n y i e l d e d 4 g ( b0% ) of _49 ( bp 60*/ 0.2mm ) . Ir 1710, 1730 c i i t - i . A small p o r t i o n was converted to i t s 2,4-DNP d e r i v a t i v e ; mp 1 1 0 - 113' { l i t . mp 1 12° 3*» ) . 51 Acid treatment of ( 39 ) A 20 mg sample of 6-methyl c y c l o d e c y n - 6 - o l ( 39 ) was d i s s o l v e d i n 2 ml of methanol c o n t a i n i n g one drop of concentrated h y d r o c h l o r i c a c i d and r e f l u x e d f o r 3.5 h. The mixture was d i l u t e d with 20 ml of water and e x t r a c t e d with 3 x 10 ml of ethe r . The e x t r a c t s were combined, washed with 20 ml of s a t u r a t e d sodium bicarbonate s o l u t i o n and 20 ml of sat u r a t e d sodium c h l o r i d e s o l u t i o n , d r i e d over anhydrous sodium s u l p h a t e , f i l t e r e d and the s o l v e n t was removed under reduced p r e s s u r e . The r e s i d u e was d i s t i l l e d a t a bath 0 temperature of 85 /0.2 mm, to y i e l d 13 mg ( 65% ) of a mixture of ketones _52 and 53_ ( g l c , columns B and C ) . I r , 1705 cm- 1, no -OH s t r e t c h ; nmr, ( C C 1 4 ) 0.72 ( s ), 0.77 ( s ), 1.03 ( s ) and 1.20 ( s ). C i s - and trans-7-methy 1 b i c y c l o [_5 .3 . oj deca none-2 { 53a and 53b ) Lithium dimethylcuprate was prepared from 571 mg ( 3 . 0 mmole ) of dry cuprous i o d i d e and ca. 4 ml of 2.3 M 0 m e t h y l l i t h i u m i n 100 ml of ether at 0 . 3 6 A s o l u t i o n of 450 mg ( 3 . 0 mmole ) of A 1' 7 b i c y c l o ^ 5 . 3.0Jdecanone-2 ( _29 ) i n 2 ml of dry ether was added dropwise under n i t r o g e n to the 52 c o o l e d s o l u t i o n of l i t h i u m d i m e t h y l c u p r a t e . A f t e r the a d d i t i o n was complete, the s o l u t i o n was s t i r r e d at 0° f o r an a d d i t i o n a l 2 h. The copper complex was decomposed with a s a t u r a t e d ammonium c h l o r i d e s o l u t i o n and the mixture was s t i r r e d at room temperature f o r 1 h. The ether l a y e r was separated, washed with s a t u r a t e d sodium c h l o r i d e s o l u t i o n , d r i e d over anhydrous sodium sulphate, f i l t e r e d and the s o l v e n t was removed under reduced pressure. The r e s i d u e was p u r i f i e d by p i c ( s i l i c a g e l - benzene ) to y i e l d 350 mg ( 70% ) of 53a and 53b. The mixture of isomers was separated by g l c ( column B ) . C i s - m e t h y l b i c yclo[_5. 3. o3decanone-2 ( 53A ) bp 80 /0.2 raui ( bath temperature ) ; i r , 1695 cm-M Figure 9; nmr, ( CCI4 ) 1.18 ( s, 3H ); Figure 9; elemental a n a l y s i s : c a l c d . f o r C-)-|H180: C, 79.17; H, 10.91, found C: 79.48; H, 10.83 . Tr ans-7-methy1 b i c y c l o [ 5 . 3 . o l d e c a none-2 ( 53b ) bp 82 /0.2 mm ( bath temperature ) ; i r , 1695 era- 1; Figure 10; nmr, ( CC1 4 ) 0.72 ( s, 3H ); F i g u r e 10; elemental a n a l y s i s : c a l c d . f o r C^H-^O: C, 79*47; H 10.91 . Found: C, 79.43; H, 10.80 . 53 Treatment of 39 with boron t r i f l u o r i d e e t h e r a t e A s o l u t i o n of 222 mg ( 1.34 mmole ) of 6-methylcyclodecyn-6-ol ( 3 9 ) and 0.5 ml of boron t r i f l u o r i d e e therate i n 20 ml of dry methylene c h l o r i d e was s t i r r e d at room temperature f o r 15 minutes. The r e s u l t i n g brown s o l u t i o n was washed with s a t u r a t e d aqueous sodium bi c a r b o n a t e s o l u t i o n u n t i l the o r g a n i c l a y e r became c o l o u r l e s s . Then the o r g a n i c l a y e r was d r i e d over anhydrous sodium s u l p h a t e , f i l t e r e d and the s o l v e n t was removed under reduced pressure. The v o l a t i l e r e s i d u e was p u r i f i e d by p r e p a r a t i v e t i c ( s i l i c a g e l - benzene ) to y i e l d 191 mg ( 8 6 % ) of the f l u o r o a l k e n e 54. I r , ( f i l m ) 1700 cm- 1; F i g u r e 11; »B nmr ( C C l 4 ) 1.05 ( s, 31! ) , 1.2 - 2.0 ( m, 12H ), 2.05 ( d, J = 6 Hz, 1H ), 2.7 ( d, J = 12 Hz, 1H ); Figure 11; *9p nmr, ( C C I 4 , C C l 3 F ) 110; Figure 11; m/e c a l c d . for C n H 1 7 F : 168.1314; found: 168.1314; 168 ( 35% ) , 153 ( 100* ), 149 ( 40" ); Figure 12. O z o n o l y s i s of _54 A s o l u t i o n of 100 mg of _5U was ozonised under the same c o n d i t i o n s as f o r 4J to y i e l d crude 1-methyl-2-o x o c y c l o h e x y j b u t y r i c a c i d . 54 I r , 1705 cm-i ( broad ). The crude a c i d was e s t e r i f i e d with diazomethane and p u r i f i e d by p r e p a r a t i v e t i c ( s i l i c a g e l - chloroform ) to y i e l d pure 56. I r , 1700, 1730 cm-»; Figure 13; nmr, 1.0 ( s, 3H ) , 1.1- 1.9 ( m, 10H j . 2.3 ( m, 4H ) , 3.6 ( s, 3H ) ; Figure 13 ; m/e 212 ( 5% ), 181 ( b% ), 152( 5% ), 112 ( 90% ), 55 ( 100% ) ; F i g u r e 14. A small p o r t i o n of the e s t e r was converted to i t s 2,4-DNP d e r i v a t i v e , mp 99 -100 ; f o r i r see F i g u r e 15; elemental a n a l y s i s : c a l c u l a t e d f o r C -| g II j 4 N 4 0 g : C # 55.10; H, 6.16; N , 14.28 . Found: C, 54.93; H, 6.11; H, 14.56 . 55 BIBLIOGRAPHY 1. D.H.R. Barton and P. deMayc, Qua r ter l_y Re v e i ws» X_L. 189(1957). 2. J.A M a r s h a l l , S v n t h e s i s , 517 (1972). 3. J . S t r e i t h and G. O u r i s s o n , Bu 1 1 S o c . Chem^ France, 1960(1963). U. A.T. McPhail and G.A. Sim, J.. Ainer^. Chera : S o c i ( .89, U65( 1967) . 5. E.L. E l i e l , N.L. A l l i n g e r , 5.J. Angyal and G.A. Morrison, "Conformational A n a l y s i s " , I n t e r s c i e n c e P u b l i s h e r s , Mew York, 1965, p. 200-210. 6. G. Buchi, W. Hofheinz and J.V. P a u k s t e l i s , J . Anier. Chenu S o c t ( 88, 41 13 (1966). 7. D.H.R. Barton, P. deMayo and M. S h a f i g , J . Cheou Soc., 929 (1957) . 8. J.A. M a r s h a l l and A.E. Greene, Tetrahedron L e t t e r s t 859 (197 1) . 9. J.A. M a r s h a l l , N.H. Andersen and P.C. Johnson, i i i Org.. Chenu, 3_5, 186 (1970). 10. M. Yamasaki, Chemical Communications, 6 06( 1 972). 11. F. D. Brown and J. K. S u t h e r l a n d , Chemical Communications, 1060 (1968). 12. M. Tanabe, D.F. Crowe and B.L. Dehn, Tetrahedron 56 L e t t e r s , 3943 (1967). 13. J . S c h r e i b e r , D. F e l i x , A. Eschenmoser, F. Gau t s c h i , K.H. S c h u l t e - E l t e , E. Sundt, G. O h l o f f , J , Kalvoda, H. Kaufinann, P. Wieland and G. Anner, Helv.. Chem.. Acta, 50 , 210 1 (1967). A. Eschenmoser, D. F e l i x and G. O h l o f f , Helv,. Chem.. Acta, 50 , 708 (1967). 14. E. W i n t e r f e i d t i n "Chemistry of Acetylenes", e d i t e d by H.G. vieke and M. Dekker, New York, Chapter 4. T.F. Rutledge, "Acetylenes and A l l e n e s " , Van Nostrand-Reinhold, Uev York, 1969, Chapter 5. S.I. M i l l e r and l\. Tanaka i n " S e l e c t i v e Organic T r a n s f o r m a t i o n s " . Edited by S. Thyagarajan. Wiley-Int.erscience, New York, 1970,Volume 1, p. 143. 15. A.C. Cope, M.M. Martin and M.A. McKervey. £uar t.. K e V i , 20, 1 19(1966) . 16. V. Prelog and J.G. Traynham i n "Molecular Rearrangements". E d i t e d by P. deMayo. Wiley-I n t e r s c i e n c e , New York, 1963 , Vcluiue 1, Chapter 9. 17. G. Stork, S. Malhotra, H. Thompson and M. Uchibayashi J.. Am£Et. Ghem^ S o c 1 ( 87, 1 148 ( 1965). 18. P.E. Peterson and R.J. Kamat, ^ Ainer. Chenu Soc. t 9J , 4521 (1969) . 19. A.G. Anderson, J r . and J.A. Nelson, J . Amer. Chem_. 57 Soc., 73 , 232 ( 1 9 5 1 ) . 20. W.P. Campbell and G. C. H a r r i s , J . Amer. Chem.. Soc.., 6 3 , 2721 ( 1 9 4 1 ) . 2 1 . PI.A. P l a t t n e r and J. Hulstkamp, Helv.. Chenu Acta, 27 , 2 1 1 (1944) . 22. H.O. House and H.W. Thompson, J± ®L3.± Chem : y 26, 3729 (1961) . The author i s t h a n k f u l to J . B a l f f o r p r o v i d i n g some sample of 1J f o r t h i s i n v e s t i g a t i o n . 2 3 . W.G. Dauben, R.C. Twait and C. Mannerskantz, J . Amer. Chem,. Soc. ( 7 6 , 4420 ( 1 9 5 4 ) . 24. H.E. Zimmerman and A. Mais, J± Amer. Chem.. Soc^^ 8 J , 3644 ( 1959) . 25. H.C. Brown, C. P. Garg and Kwang-Ting L i u , J.. Org.. Chem.., 36 , 387 (1971 ) . 2 6 . M. Hanack and A. Heumann, Tetrahedron L e t t e r s , 51 17 (1969) . 2 7 . L . J . Bellamy, "Advances i n I n f r a r e d Group Fr e q u e n c i e s " , Metheun and Co., 1968, p. 2 6 . 2 8 . D.R. Strobach and G.A. Boswell, J r . , J_. Org.^ Chem^, J 6 , 818 (197 1 ) . S.F. Cambell, A. G. Hudson, E. F. Mooney, A.E. Pe d l e r , R. Stephen and K.N. Wood, Sj-ectrochimica Acta, _23_A, 21 19 (1967) . 58 29. The author i s t h a n k f u l to Dr.W.M. P h i l l i p s f o r c a r r y i n g out t h i s experiment. 30. E. Gotter and D. L a v i e , J.. Chenu Soc. C, 2298 (1967) . 31. H.o. House, W. L. Pespess and G. M. Whitesides, J . Org.. Chem.., 31 , 3128 (1966). 32. W.D. P f e i f e r , C. A. Bahn, P. v. R. S c h l e y e r , S . Bocher, C.E. Harding, K. Hummel, M. Hanack and P.J. Stang, J.. Amer., Chem.. S o c i ( 93, 1513 (1971 ). 33. M. Hanack, C.E. Harding and Jean-Luc Derocque, Chem. Ber., 105, 421 ( 1972) . We are t h a n k f u l to Dr. M. Hanack f o r sending us a copy of t h i s work p r i o r to p u b l i c a t i o n . 34. w.S. Johnson M. B. Gravestock, R.J. P a r r y , R.F. Myers, T.A. Bryson and D.H. M i l e s , Jx Amer : Chem.. §oc.., 9_3, 4330 (1971) . 35. W.S.Johnson, M.B. Gravestock R.J. Parry and E.A Okorie, J.. Aiuar^ Chenu 5 o c i ( 94, 8604 (1972). 36. H.O. House, W. L. Pespess and G. M. Whitesides, J . 2£2i. ChemA, 3_1 , 3128 (1966). H.O. House and W. F. F i s c h e r , J r . , J t 0 r <]_. Chem.., 3 3, 949(1968). G. Posner, Org. React., 1_9, 1(1 972). Organic Syntheses, _52, 109 (1972). 59 37. K. Bowden, I. M. H e i l b r o n , E.H.R. Jones a n d B.C.L. Weedon, J± Chem.. Socu, 39(1946). C. D j e t a s s i , R.R. Engle and A. Dowers, J . Org... Chem. # _2J ' 1547 (1956) . 38. G. Stork, A. B r i z z o l a r c e H. Landesman, J. Szmuszkovicz and R. T e r r e l l , Amer.. Chem.. Soc_. 85, 2 07 (1963). 39. A. C h a t t e r j e e , Tetrahedron L e t t e r s , 959(1965). 40. B a l a j i Rao and L. Weiler, Tetrahedron L e t t e r s , 927 ( 1971) . R. J. B a l f , B a l a j i Rao and L. Weiler, Can,. J . Chenu, 49 , 3 135 (197 1) . PART I I ATTEMPTED SYNTHESIS OF SAMANINE 61 INTRODUCTION I s o l a t i o n and s t r u c t u r e of samanine The i s o l a t i o n of the a z a s t e r o i d samanine ( J_ ) was f i r s t r e p o r t e d by G. Habermehl i n h i s review e n t i t l e d 'Salamandra A l k a l o i d s ' i n 1968. 1 I t was found as a very minor c o n s t i t u e n t i n a mixture of a l k a l o i d s i s o l a t e d from the skin.gland s e c r e t i o n of Salamandra maculosa t a e n i a t a . Later i n 1969 G. [Jatermehl and h i s coworkers publ i s h e d a f u l l paper on the i s o l a t i o n and t o t a l s y n t h e s i s of t h i s a z a s t e r o i d . 2 Since the amount of the n a t u r a l m a t e r i a l a v a i l a b l e was very s m a l l , the s t r u c t u r a l evidence was mainly based on the i r and the mass s p e c t r a o r i g i n a l l y . However, the complete s t r u c t u r e with i t s ster e o c h e m i c a l d e t a i l was e s t a b l i s h e d by s y n t h e s i s of samanine. S e v e r a l a l k a l o i d s were a l s o i s o l a t e d from the same s o u r c e . 1 The s t r u c t u r e s of these compounds are shown i n Scheme 2.1 and l i s t e d i n Table 2.1. Samanine i s unique i n th a t i t i s the only member of group 1 a l k a l o i d s found i n _S._m._t. or jS.m.m. I t i s a simple r i n g A homo s t e r o i d . 62 Scheme 2.1 Salamander A l k a l o i d s 63 7 Salamander Alkaloids (continued) 6 U Table 2.1 Salaniandra A l k a l o i d s G roup Name mp° C Occurence 1 Samanine (1) 197 S. m.t. 2 Samandarine (2) 188 _S. J D . _t. Sama ndarone ({£) 190 S.m.t.; S.m.m. Samandar id ine (5) 290 _S.jn»_t, ; S »jn . . 0-Ace t yl-samandarine (1) 159 S.jn._t. ; 5.m.m. Samandenone (6) 191 S. nut. ; S. m. Samandinine (7) 170 _S • nu m. 3 Cycloneosamandione (8] 1 19 S. m. t. ; S. m.m. Cycloneosamandaridine (2) 282 j>. m. t . ; S . J R . nt. S.nut. = Sa l a ma nd ra maculosa taen i a t a S. m. in. = Salamandra maculoso maculosa 65 SYNTHETIC APPROACHES Samanine ( J_ ) could be looked upon as a modified t e s t o s t e r o n e . In that case the f o l l o w i n g t r a n s f o r m a t i o n s need be e f f e c t e d on t e s t o s t e r o n e ( 1 0 ). 1) S t e r e o s p e c i f i c r e d u c t i o n of C-4-C-5 double bond to a 5 8 - s t e r o i d , 2) i n t r o d u c t i o n of n i t r o g e n between C-2 and C-3 and 3) conve r s i o n of C-17 hydroxy 1 to C-16 hydroxyl. OH 10 While r e p o r t i n g the d e t a i l s of the i s o l a t i o n of samanine, G. Habermehl and h i s coworkers a l s o r e p o r t e d the t o t a l s y n t h e s i s of t h i s compound. 2 T h i s scheme i s shown i n Scheme 2.2. Compound V\_* was converted to 1_2 i n f o u r steps. Oppenauor-oxida t i o n of 1_1 gave the corresponding diketone. The carbonyl group i n the A r i n g was p r o t e c t e d as i t s p y r r o l i d i n e enamine and the c a r b o n y l group i n the D r i n g was Scheme 2-2 67 reduced to the corresponding a l c o h o l . H y d r o l y s i s of t h i s compound gave VI. Compound ]2_ was c a t a l y t i c a l l y reduced to 1_3. The a l c o h o l i n the D r i n g was p r o t e c t e d as i t s a c e t a t e 14. Conversion of t h i s ketone to i t s cxime IS y i e l d e d a mixture of both syn- and anti-oximes. oeckmann rearrangement of t h i s mixture gave two compounds which c c u l d be separated by chromatography. On r e d u c t i o n with l i t h i u m aluminium hydride compound 1J> y i e l d e d 18. and 17 y i e l d e d samanine ( J_ ) . Around the same time, K. Oka and h i s coworkers published another s y n t h e s i s of samanine.* On the b a s i s of the s t r u c t u r a l r e l a t i o n of t h i s a l k a l o i d with the other salamandra a l k a l o i d s and b i o g e n e t i c c o n s i d e r a t i o n s , they presumed that samanine would have 5 6-A/B c i s - r i n g f u s i o n and 1 6 B - h y d r o x y l c o n f i g u r a t i o n as does samandarine and i t s d e r i v a t i v e s ( c f . Scheme 2.1, pp. 62 ). T h i s assumption turned out to be c o r r e c t . T h e i r key intermediate* 1_3 was same as that of G. Fiabermehl and h i s coworkers. 2 T h i s scheme i s shown in Scheme 2.3. The a l c o h o l _1_9 was a c e t y l a t e d to 20 and the ketone i n the D r i n g was reduced to the corresponding a l c o h o l 2_1. The D r i n g a l c o h o l was then p r o t e c t e d as i t s benzoate _22 and the ace t a t e i n the A r i n g was hydrolysed to give compound 2 3. 68 Scheme 2-3 Oka's Synthesis of 1 69 Compound 23 was then o x i d i s e d to 24 followed by the h y d r o l y s i s o f the benzoate to y i e l d 25. C a t a l y t i c r e d u c t i o n of 25 gave 1_3. Treatment of 13 with hydroxylamine h y d r o c h l o r i d e gave a mixture of oximes which they could separate by column chromatography. Since the two isomers were i n e q u i l i b r i u m i n p o l a r s o l v e n t s , by repeated e q u i l i b r a t i o n and chromatography, they could c o n v e r t the mixture completely to the isomer 2b. Beckmann rearrangement of 26 y i e l d e d 2H which on r e d u c t i o n with l i t h i u m aluminium hydride gave samanine ( _1_ ) . K. Oka and h i s coworkers a l s o r e p o r t e d a s y n t h e s i s of samane ( 3_5 ), which i s desoxy sama ni ne. * T h i s scheme i s shown i n Scheme 2.4. The compound Z9 w a s converted t o 3_0 i n thr e e steps by a procedure rep o r t e d e a r l i e r by the same group. 5 Formylation followed by p a r t i a l h y d r o l y s i s gave the compound 3_1. Oxi d a t i o n of _3_[ gave _32. The acid-amide 32, on treatment with methanol and dry h y d r o c h l o r i c a c i d , gave 3 3. The aminoester _33 was then c y c l i s e d to 34. l i t h i u m aluminium hydride r e d u c t i o n of _3_4 gave samane ( 3_5 ). Scheme 2-4 71 PRESENT APPROACH Our approach f o r 'the s y n t h e s i s of samanine ( _1_ ) was again based on the m o d i f i c a t i o n of t e s t o s t e r o n e ( T_0 ) • We decided to postpone the m o d i f i c a t i o n of the D r i n g to the l a s t stage of the s y n t h e s i s . Hence the m o d i f i c a t i o n of the A r i n g was f i r s t attempted. Reduction of t o s t o s t e r o n e ( 1_0 ) to d i h y d r o t e s t o s t e r o n e ( 37 ) was r e p o r t e d by L i s t o n . 6 The 5 a- and the 5 3 -isomers were separated by c r y s t a l l i s a t i o n of the a c e t a t e 38. The 5 8 - isomer which was needed f o r t h i s work co u l d thus be obtained i n 3ti% y i e l d . The mother l i g u o r was an i n s e p a r a b l e mixture of both the i s o m e r s . 6 OH OR Now the next problem was the r e g i o s p e c i f i c i n t r o d u c t i o n of n i t r o g e n i n the A r i n g . The six-membered A r i n g had to 72 be expanded t o a seven-membered ring with the nitrogen a t C-3. The classical methods for the rimj expansion are the Beckmann rearrangement and the Baeyer-Villiget rearrangement. As shown i n the previous chapter ( p.69)* the 5 B-dihydro-3-oxosteroid 13 gave a mixture of two cximes in the r a t i o 1 : 1.* K. Oka and his coworkers could s e p a r a t e these isomers and through repeated equilibration and chromatography c o u l d convert the mixture to one isomer.* In c o n n e c t i o n with the s y n t h e s i s of sanandarine { 2 )# the above work was repeated i n our laboratory on the t d i h y d r o t e s t o s t e r o n e - W - a c e t a t e ( _4_5 ), and on a large scale the s e p a r a t i o n was found to be i n e f f i c i e n t . 6 P. Catsoulacos succeeded i n r e a r r a n g i n g the oxime of t e s t o s t e r o n e a c e t a t e _39. 7 However the r e d u c t i o n of the amide 40 has not been r e p o r t e d so f a r . The Baeyer^-V i l l i g e r o x i d a t i o n of 44. has also been attempted i n t h i s l a b o r a t o r y . The r e a c t i o n gave a mixture of l a c t o n e s J4_1 and 42. 8 Compound 42 was the major product. Hence the c l a s s i c a l methods of e f f e c t i n g the r i n g fission were not of much use. A f t e r s e v e r a l attempts, a method to c l e a v e C-2, C-3 bond was developed as shown i n Scheme 2.5. 8» 9 73 Scheme 2-5 75 Testost e r o n e { J_0 ) was hydrogenated and the d i h y d r o -compound J4_3 thus obtained was a c e t y l a t e d . The 5 8 - isomer c o u l d be f r a c t i o n a l l y c r y s t a l l i s e d at t h i s stage. The pure 5 p - isomer was then brominated. The bromo compound j_5 was converted to the acetoxy compound _4_6. Conversion of j__6 to the hydroxyoxime __T7 f o l l o w e d by Beckmann fragmentation gave __48. T h i s sequence was i n t e r e s t i n g f o r the f o l l o w i n g reasons. I t achieved a very r e g i o s p e c i f i c r i n g f i s s i o n . I t a l s o achieved an unsymmetric cleavage of the C-2, C-3 bond. F i n a l l y , the product _4_B had a n i t r o g e n i n the molecule which was needed f o r f u r t h e r e l a b o r a t i o n to samanine ( ). In an attempt to s y n t h e s i s e samanine, J . B a l s e v i c h c a r r i e d out the f o l l o w i n g sequence i n t h i s l a b o r a t o r y . 1 0 The cyanoa ldeh yde J48 was reduced to the aminodiol 5_0 through __9. Mesylation of ___) gave the t r i m e s y l a t e 5J. i n good y i e l d s . Treatment of _____ with sodium hydride gave 5_2. Though the d e s i r e d c y c l i s a t i o n c ould be e f f e c t e d i n good y i e l d s , the s e l e c t i v e cleavage of the C-17 mesylate to the a l c o h o l c o u l d not be r e a d i l y e f f e c t e d . However, A d e t a i l e d study of t h i s cleavage was not made. 77 In view of t h i s d i f f i c u l t y , i t was f e l t t h a t a d i f f e r e n t approach i n which C-2, C-3 and C-17 c o u l d be e a s i l y d i f f e r e n t i a t e d was d e s i r a b l e . To e f f e c t the c y c l i s a t i o n i t was necessary to convert the oxygen at C-2 i n t o a good l e a v i n g group. S i n c e the d i c l a m i n e .50 demanded s e l e c t i v e t o s y l a t i o n or inesyiation at C-2, t h i s approach through _50 was c l e a r l y l e s s d e s i r a b l e . The d i f f e r e n t i a t i o n had to be in t r o d u c e d at an e a r l y stage of the s y n t h e s i s . In connection with the s y n t h e s i s cf samandarine, K. P a i s l e y had converted JJ9 to *>3 i n good y i e l d s . 8 We hoped that t h i s could be a b e t t e r candidate f o r cur purpose. 7 8 DISCUSSION AND RESULTS In a d e t a i l e d study of the reducing a b i l i t y of diborane H.C. Brown and h i s coworkers have shown t h a t n i t r i l e s are more e a s i l y reduced than t c s y l a t e s with diborane.** Hence the t o s y l a t e _53 was t r e a t e d with a l a r g e excess of diborane i n THF. The product obtained showed nc n i t r i l e or a c e t a t e i n the i r spectrum. The str o n g doublet at 1190 cm-* f o r the t o s y l a t e was s t i l l present. T h i s m a t e r i a l was very d i f f i c u l t to p u r i f y . The a c i d s o l u b l e m a t e r i a l i n the crude r e a c t i o n mixture was estimated as 28% by e x t r a c t i n g i n t o d i l u t e a c i d and r e g e n e r a t i n g with base. However even t h i s m a t e r i a l was impure. No c r y s t a l l i n e d e r i v a t i v e of _5__ co u l d be obtained from t h i s mixture. on the b a s i s of the above mentioned s p e c t r a l evidence and the f a c t that n i t r i l e s and a c e t a t e s are more e a s i l y reduced than t o s y l a t e s by diborane, 1 1 the s t r u c t u r e ____ was t e n t a t i v e l y assigned to the Compound present i n the i n s e p a r a b l e mixture. OAc OH 79 Treatment of 54 with a l a r g e excess of a c e t i c anhydride i n a few drops of p y r i d i n e gave a crude product which appeared to be a mixture of 5b and 56. The i r spectrum of the crude product showed peaks at 1730, 1680, 1625 and 1190 cm- 1. On c a r e f u l examination, the peak at 1625 cm—1 appeared t o be unusually strong f o r an amide IT band, corres p o n d i n g to .56. The t o s y l a t e peak a t 1190 cm- 1 was not very s t r o n g . Since the amide I band of the c y c l i s e d product was expected to be at 1625 cm-1 a l s o , i t was concluded t h a t some c y c l i s a t i o n had occured. On treatment of the crude r e a c t i o n mixture with sodium hydride i n THF, the product o b t a i n e d showed peaks at 1730 and 1640 cm-1 o n l y , as expected f o r 5_5. A f t e r much experimentation i t was found t h a t the. a d d i t i o n of 1. 1 e q u i v a l e n c e ( based on the amount of j>4 used ) of a c e t i c anhydride with p y r i d i n e as s o l v e n t e f f e c t e d a smooth c y c l i s a t i o n of 54 to 57 i n 25-30% y i e l d . K. Oka and h i s coworkers had prepared the compound 57 through another route.s The two compounds were compared by Dr. K. Oka i n h i s l a b o r a t o r y . The i r s p e c t r a of these compounds were superimposable and the mixed melting poi n t showed no d e p r e s s i o n . 1 2 80 In one experiment, the p r e p a r a t i o n of 57 was attempted without p u r i f i c a t i o n of the i n t e r m e d i a t e s . The oxime __7 was c r y s t a l l i s e d a c c o r d i n g to the method of K. P a i s l e y . V From that stage on, the v a r i o u s i n t e r m e d i a t e s were not p u r i f i e d . The crude 57 thus obtained was c r y s t a l l i s e d from e t h e r . The o v e r a l l y i e l d of pure __7 from pure _47 was about 27%. Two mechanisms are c o n c e i v a b l e f o r the c o n v e r s i o n of 5_4 to 57. A c e t i c anhydride could f i r s t a c y l a t e the amine 81 82 to givG_58. T h i s amide co u l d then undergo c y c l i s a t i o n to g i v e 57. On the other hand, the c y c l i s a t i o n of 54 to 59 could be the f i r s t step f o l l o w e d by the a c y l a t i o n of the c y c l i c amine to give_57. Of these two p o s s i b i l i t i e s , the l a t t e r route was p r e f e r e d f o r the f o l l o w i n g reasons. As pointed out e a r l i e r , when the c y c l i s a t i o n was attempted with a l a r g e excess of a c e t i c anhydride and only a small amount of p y r i d i n e , a mixture c o n t a i n i n g a secondary amide and a t e r t i a r y amide was obtained, as judged by the i r spectrum of the crude product. The amount of the c y c l i s e d t e r t i a r y amide did not improve on s t i r r i n g f o r longer p e r i o d s . However, when the mixture thus obtained was s t i r r e d with sodium hydride i n dry THF, the peak f o r the secondary amide at 1680 cm-* and the peak f o r the t o s y l a t e at 1190 c i r 1 disappeared and the peak f o r the t e r t i a r y amide a t 1640 cm- 1 became s t r o n g e r . The f a c t t h at the secondary amide d i d not c y c l i s e on s t i r r i n g i n p y r i d i n e i n d i c a t e d that such a c y c l i s a t i o n needed a s t r o n g e r base. However, when 54 was trea t e d with 1 : 1 e q u i v a l e n c e of a c e t i c anhydride and p y r i d i n e as s o l v e n t , the product showed no secondary amide as judged by the i r spectrum. In l i g h t of these experiments we f e l t that the amine f i r s t c y c l i s e d to 5_9. However, when c y c l i s a t i o n was attempted with only p y r i d i n e and no a c e t i c 83 anhydride, the t o s y l a t e peak a t 1190 cm-1 i n the i r spectrum d i d not d i m i n i s h . In view of these f a c t s , the f o l l o w i n g mechanism i s proposed f o r the c y c l i s a t i o n of 54 to _57 i n the presence of a c e t i c anhydride and p y r i d i n e as s o l v e n t . The acylium i o n formed by the complexation of p y r i d i n e and a c e t i c anhydride, complexes with the t o s y l group ( see 59a ) thus making the C-2 oxygen very l a b i l e . The primary amine then c y c l i s e s i n t e r n a l l y forming the c y c l i c aoine 5__ and i n t h a t process generating a mixed anhydride. T h i s mixed anhydride could then a c y l a t e the c y c l i c amine i n the presence of p y r i d i n e ( see 60 ) to g i v e 57. Since K. Oka and h i s coworkers have converted __7 to samane ( 35 ) , 5 t h i s c o n s t i t u t e s a formal t o t a l s y n t h e s i s of sa ma ne ( 35 ) . Now i t remained to t r a n s f e r the oxygen moiety from C-17 to C-16. S e v e r a l methods are a v a i l a b l e f o r t h i s purpose. J.E. bridgeman and h i s coworkers prepared 5 a-androstan-16-one through the f o l l o w i n g s e q u e n c e . 1 3 Compound 61 was converted to the bonzylidene d e r i v a t i v e 6_2. The C-17 ketone was removed using dichloroaluminium hydride. Compound 6_3 Thus obtained was ozonised to 6JJ. The o v e r a l l y i e l d 82X. RN .0 RN ,0 6 9 a . R=EhCH2; X=0; X'=H2 b. R=H; X=0; X'=H2 C. R=CH0 d. R=CH0 e. R=CH0 f . R=CH0 g. R=CH0 h. R=H: X=0; X»=H 2 X=0; X'.CHOH X=0; X'=CHO-i-Pr X=<Q H; X^CHO-i-Pr X=H2; X'=CHOAc X=H2; X»*0 21a. R=CHOj X = < < £ ] b. R=CHO; X=0 86 To e l i m i n a t e the o x i d a t i o n i n v o l v e d i n the above sequence, G. J u s t and h i s coworkers developed the f o l l o w i n g r o u t e . 1 * Compound ___> was converted to i t s oximino-d e r i v a t i v e 66, which on r e d u c t i o n with hydrazine hydrate and potassium hydroxide gave j_7. Conversion of 67 to 68 was e f f e c t e d i n very high y i e l d s . The o v e r a l l y i e l d i n t h i s sequence was ."5 4%. In a more complex system, K. Oka and h i s coworkers e f f e c t e d the same t r a n s f o r m a t i o n through the f o l l o w i n g s e q u e n c e . 1 5 The compound 6 9a was debenzylated to 69b and then formylatod to 69c. This was then converted to 69d through the e t h y l formate method. A f t e r c o n v e r t i n g 69d to 69e, the 17-ketone was reduced to the a l c o h o l . The compound 69f thus obtained, on treatment with a c i d , gave 70a. P r o t e c t i o n of the aldehyde as i t s ethylene k o t a l , f o l l o w e d by c a t a l y t i c hydrogenation gave 71 a which was hydrolysed t o 71b. T h i s compound was then e n o l - a c e t y l a t e d t o 69g, which was then ozonised and hydrolysed to the 16-oxo- compound 69h. We decided to f i r s t t r y the method of J . E . Bridgeman and hi:: c o w o r k e r s . 1 3 Since t h i s method i n v o l v e d r e d u c t i o n of the ketone using hydride reducing agent, i t was f e l t that a benzamide d e r i v a t i v e 72 would be p r e f e r a b l e to the acetamide 87 d e r i v a t i v e _ 5 J . Hence 54 was c y c l i s e d with benzoic anhydride in p y r i d i n e . T h i s y i e l d e d 7_2 i n 2 5 to 30% y i e l d . O x i d a t i o n of 7 2 gave 7 3 , which was converted to the benzylidene d e r i v a t i v e 74 with excess base and benzaldehyde. T h i s compound was then reduced with l i t h i u m aluminium h y d r i d e -aluminium c h l o r i d e i n ether f o l l o w i n g the procedure of J.H, Brewster and h i s coworkers. 1 6 The expected benzylidene d e r i v a t i v e 75. or 7_6 could not be detected i n the product. The method of G. J u s t and h i s coworkers was next i n v e s t i g a t e d . 1 4 The a l c o h o l J57 was o x i d i s e d to the corresponding ketone 77. 4 The oximincketone 78_ was prepared according to the method of A. Hassner and h i s c o w o r k e r s . 1 7 Reduction of the c a r b o n y l moiety with hydrazine hydrate d i d not give the expected oxi.ne 79. 88 CONCLUSION It i s not c l e a r as to why a s l i g h t l y modified A r i n g would a l t e r the r e a c t i o n s i n the D r i n g so d r a s t i c a l l y i n s t e r o i d s . S e v e r a l other methods could he t r i e d f o r the t r a n s f e r of the oxygen mciety. F u r t h e r work, i n t h i s d i r e c t i o n i s now i n progress. 90 EXPERIMENTAL For e x p e r i m e n t a l d e t a i l s see page 38. S y n t h e s i s of 17 3- a c t o x y - 2 - o x o - 2 , 3 - s e c c - 5 g - a n d r o s t a n e - 3 - n i t r i l e ( 08 ) Compound _48 was prepared a c c o r d i n g to t h e procedure of K. P a i s l e y . 8 * 9 The o v e r a l l y i e l d of j4j_ from t e s t o s t e r o n e ( 1_0 ) was 5%. S i n c e 48 was very u n s t a b l e i t was i m m e d i a t e l y reduced as d e s c r i b e d below. S y n t h e s i s of 17g - a c e t c x y - 2 - h y d r c x y - 2 , 3 - s e c o - 5 g - a n d r o s t a n e - 3 - n i t r i l e ( 09 ) The procedure of K. P a i s l e y was s l i g h t l y m o d i f i e d t o improve the y i e l d s . 8 To a s o l u t i o n of 190 mg f 0.55 ramole ) of 4_8 i n 20 ml of methanol 74 mg ( 1.98 mmole ) of sodium b o r o h y d r i d e was c a r e f u l l y added w i t h s t i r r i n g . The temperature was m a i n t a i n e d a t room temperature u s i n g a water b a t h . A f t e r s t i r r i n g at room . temp e r a t u r e f o r 4.5 h. the s o l u t i o n was c a r e f u l l y a c i d i f i e d w i t h IN h y d r o c h l o r i c a c i d u n t i l the s o l u t i o n was a c i d i c . The mix t u r e was then poured i n t o 50 ml of s a t u r a t e d sodium c h l o r i d e s o l u t i o n and t r a n s f e r e d t o a s e p a r a t o r y f u n n e l . The o r g a n i c m a t e r i a l was 91 e x t r a c t e d with 2 x 50 ml of e t h e r . The combined ether l a y e r was washed with 4 x 40 ml of s a t u r a t e d sodium c h l o r i d e s o l u t i o n u n t i l the washings were n e u t r a l t c l i t m u s . The eth e r l a y e r was then d r i e d over anhydrous sodium s u l p h a t e , f i l t e r e d and the s o l v e n t was completely removed at the pump. The s o l i d thus obtained weighed 188 mg ( y i e l d 100? ) . T h i s compound showed one spot on t i c ( s i l i c a g e l - e t h y l a c e t a t e : chloroform = 5 : 1 ) . The compound was r e c r y s t a l l i s e d o a from e t h e r f o r a n a l y s i s , mp 138-40 ( r e p o r t e d a 138-40 ). I r , 3450, 2250, 1720 e n - 1 ; Figure 16; nmr, 9.25 ( s, 3H ), 8.97 ( s, 3H ) , 5.47 ( t(j=9Hz) 1H ) , 6.30 ( m, 2H ) ; Figure 16; m/e 349 ( b% ), 3t>7 ( 23% ), 329 ( 6£ ) , 322 { 5* J , 303 • { 10% ) , 302 ( 39* ) , 288 ( 9% ) , 287 ( 24S } , 270 ( 31* ) , 240 { 14X ) , 4 3 ( 1002 ) ; Fi g u r e 17; Elemental a n a l y s i s : c a l c d . f o r C 2 1 H 3 3 O 3 N : C, 72. 58; fj, 9.57; * N , 4.03. Found: C , 72.43; H, 9.56; N, 3.88. Sy n t h e s i s of 17 g-acetoxy-3-cyano-2 ,3-seco-5 B-andrcstane-2-p-tcluenesulphonate ( 53 ) Compound 5_3 was prepared according to the procedure of K. P a i s l e y . 8 Thus 444 mg ( 1.17 mmole ) of 49 and 24 1 mg ( 1.27 mmole ) of p - t o l u e n e s u l p h o n y l c h l o r i d e i n 3 ml of 92 p y r i d i n e y i e l d e d 567 try ( 89% y i e l d ) c f 53 nif 128-130 ( r e p o r t e d 8 inp 128-130* }. Reduction of 53 with diborane A s o l u t i o n of 161 mg ( 0.52 mmole ) ot 53 i n 53 ml cf dry THF, 15 ml of a s o l u t i o n of diborane i n THF ( 21.7 mmole ) was added c a r e f u l l y with s t i r r i n g under a stream of n i t r o g e n . The mixture was s t i r r e d at room temperature f o r th r e e days. At the end cf that p e r i o d , 1N h y d r o c h l o r i c a c i d was added drop by drop u n t i l the diborane was completely destroyed. The s l i g h t l y a c i d i c s o l u t i o n was s t i r r e d a t room temperature f o r f i v e more minutes and then c a r e f u l l y t r a n s f e r r e d to a s e p a r a t c r y f u n n e l c o n t a i n i n g 100 ml of saturated sodium bicar b o n a t e s o l u t i o n . The o r q a n i c m a t e r i a l was then e x t r a c t e d i n t o 2 x 50 ml of ether and washed with 2 x 30 ml of s a t u r a t e d bicarbonate s o l u t i o n and 2 x 20 ml of saturated sodium c h l o r i d e s o l u t i o n . The ether l a y e r was then d r i e d over anhydrous sodium sulphate, f i l t e r e d and the s o l v e n t was removed under vacuum. The residue weighed 243 mg. The i r of t h i s crude m a t e r i a l showed that the n i t r i l e and the ac e t a t e groups were completely reduced. The peaks at 2295 and 1730 c i - 1 had completely disappeared. The t o s y l a t e peak at 1190 cm-1 was s t i l l present. S e v e r a l attempts were made tc p u r i f y t h i s mixture. We could not o b t a i n pure 54 f o r complete c h a r a c t e r i s a t i o n and 93 a n a l y s i s . No s o l i d d e r i v a t i v e of the amine c c u l d te prepared ( p i c r a t a or p e r c h l o r a t e ). In one experiment, the a c i d s o l u b l e p o r t i o n was e x t r a c t e d . Thus 55 mq of the crude amine was d i s s o l v e d i n 10 ml cf chloroform and the b a s i c m a t e r i a l was e x t r a c t e d i n t o 2 x 20 ml of 1N h y d r o c h l o r i c a c i d . The a c i d s o l u b l e p o r t i o n was b a s i f i e d with s o l i d sodium bicarbonate and the organic compound was e x t r a c t e d i n 2 x 20 ml of ether. The ether l a y e r was d r i e d over anhydrous sodium s u l p h a t e , f i l t e r e d and the s o l v e n t was removed under vacuum. The r e s i d u e weighed 14 mg. T h i s was again a mixture as judged by the spurious peaks i n the i r spectrum and could net be f u r t h e r p u r i f i e d nor c o u l d a c r y s t a l l i n e d e r i v a t i v e be obtained. Synthesis of 17-hydroxy samane-N-acetate ( _57 } To a s o l u t i o n of 243 mg of j_4 i n 3 ml of p y r i d i n e d r i e d over sodium hydroxide p e l l e t s , 58.7 mg of a c e t i c anhydride i n 0.5 ml of p y r i d i n e was added with s t i r r i n g . The temperature of the r e a c t i o n mixture was maintained at room temperature using a water bath. The mixture was s t i r r e d at room temperature for about 24 h. At the end cf t h i s p e r i o d , the mixture was poured i n t o 40 ml of water and e x t r a c t e d i n t o 2 x 40 ml of ether. The ether e x t r a c t was washed 94 s e v e r a l times with s a t u r a t e d sodium c h l o r i d e s o l u t i o n u n t i l the ether l a y e r was f r e e of the smell c f p y r i d i n e . The ether l a y e r was then d r i e d over anhydrous sodium s u l p h a t e , f i l t e r e d and the s o l v e n t was removed under vacuum. The residue weighed 165 mg. A f t e r c r y s t a l l i s a t i o n from e t h e r , compound .57 was obtained as a white c r y s t a l l i n e s o l i d ( 5_5 mg, 33% y i e l d based on 53 ). H e c r y s t a l l i s a t i o n from ether gave pure Y7, mp 188-191* ( r e p o r t e d s mp 18o-188° ). T h i s compound was sent to Dr. K. Oka f O L comparison.* 2 The i r spectrum of our compound was superimposdble with that of t h e i r compound and the mixed melting p o i n t showed no de p r e s s i o n . Report of Dr. K. Oka: mp, our compound, 189-190*; t h e i r compound, 186-187*; mixed mp, 186-187 . The d i f f e r e n c e i n mp could be due to the f a c t t h a t we c r y s t a l l i s e d our compound from e t h e r , whereas t h e i r compound was c r y s t a l l i s e d from acetone. I r , ( KBr ) 3750, 3450, 1625 cro-»; F i g u r e 18; nmr, 0.75 ( s, 3H ), 1.03 ( s, 3H ), 2.1 ( s, 3H ), 2.33 ( s, 1H, exchangable with D 20 ) ; Figure 18; mass spectrum, m/e 334 ( 28% ), 333 ( 1C0% ) , 319 ( 15^ ) , 318 ( 62* ), 290 ( 12% ) , 246 ( 16If ), 101 ( 14* ), 100 ( 19% ), 99 ( 12% ), 95 ( 10% ), 93 ( 10? ), 88 ( 12* ), 81 ( 12% J 8 8b ( 12X ) , 81 ( 12% ) , 70 ( 12"?, ) , 69 ( 12* ), 57 ( 18% ), 56 ( 24% ) , 55 ( 26% ) , 54 ( 203 ), 44 ( 327c ), 43 9 5 ( 4 6 % ) , 4 2 { 2 0 % ) , 4 1 ( 1 8 % ). F i g u r e 1 9 . O x i d a t i o n of 5 7 to 17-oxcsamane-N-acetate { 77 ) To a s o l u t i o n of 33 mq ( 0 . 1 mmcle ) of 57 i n 5 ml of acetone, standard Jones' o x i d i s i n g a g e n t 1 8 was added drop b y drop with s t i r r i n g u n t i l a d e f i n i t e brown c o l o u r p e r s i s t e d . The mixture was s t i r r e d at room tempetature f o r 15 minutes. At the end of t h i s p e r i o d , i s o - p r o p y l a l c o h o l was added drop by drop to destroy the excess o x i d i s i n g agent. When the brown colour completely disappeared the r e a c t i o n mixture was d i l u t e d with 40 ml of water. The mixture was then t r a n s f e r e d to a, sep a r a t o r y f u n n e l and e x t r a c t e d with 2 x 50 ml of e t h e r . The combined ether l a y e r was washed with 2 X 2 0 ml of saturated sodium c h l o r i d e s o l u t i o n , d r i e d over anhydrous sodium s u l p h a t e , f i l t e r e d and the s o l v e n t was removed a t the pump. The r e s i d u e weighed 3 0 mg ( 9 1 % y i e l d ). It showed only one spot on t i c ( s i l i c a g e l , 5 f l methanol in chloroform ) . The i r spectrum of compound J77 thus obtained showed the c a r b o n y l s t r e t c h at 1 7 4 0 cm-1 as re p o r t e d for t h i s compound. 5 i r , 1740, 1635 Fi g u r e 20. Syn t h e s i s of 16-oximino-17-oxosamane-N-acetate ( 78 ) Th i s compound was prepared according to the procedure 96 of A. Hassner and h i s c o w o r k e r s . 1 7 A s o l u t i o n of 14 mg ( 0.047 inmole ) of 77 and 13 mg ( 0.18 minole ) of potassium t - b u t o x i d e i n 2 ml of t - b u t a n c l was s t i r r e d under n i t r o g e n atmosphere f o r 5 minutes. To t h i s mixture, 0.5 ml of i s c -amyl n i t r i t e was added a l l at once and the mixture was s t i r r e d f o r 2 h. On l a r g e r s c a l e s , longer r e a c t i o n times up to 4 h. were necessary f o r the completion of the r e a c t i o n . At the end of t h i s p e r i o d 3 ml of c o l d water at 0 was added, f o l l o w e d by 10 nil cf 1N sodium hydroxide. The c o n t e n t s were transferred to a s e p a r a t o r y f u n n e l . A f t e r e x t r a c t i n g with 2 x 10 ml cf e t h y l a c e t a t e , the aqueous l a y e r was a c i d i f i e d with 1N h y d r o c h l o r i c a c i d and e x t r a c t e d with 2 x 20 ml of e t h y l a c e t a t e . The o r g a n i c e x t r a c t was washed with s a t u r a t e d sodium c h l o r i d e s o l u t i o n u n t i l the washings were n e u t r a l , d r i e d over anhydrous sodium s u l p h a t e , f i l t e r e d and the s o l v e n t was removed a t the pump. The re s i d u e weighed 11 mg. Th i s compound was an o i l and c o u l d not be induced to c r y s t a l l i s e . I r , 1735 ( br. ), 1635 cm- 1; F i g u r e 21; uv, ( q u a l i t a t i v e ) 230 my. On a d d i t i o n of sodium hydroxide s o l u t i o n the peak s h i f t e d t o 385 my. Reported v a l u e s f o r t h i s cbrcmopbcre X ( HeOH ) 238 m y , and on a d d i t i o n of base the peak s h i f t e d to 388 m y . 1 7 97 S y n t h e s i s o f 17-hydrcxy samane-N-ben?cate ( 72 ) T h i s compound was prepared by the same procedure as f o r 57. Thus 94 my of 54 with 46 mg of benzoic anhydride i n p y r i d i n e for 18 h. y i e l d e d 38 mg cf 1_2 a f t e r p u r i f i c a t i o n by p r e p a r a t i v e t i c ( s i l i c a g e l , 5% methanol i n chloroform ) . i r , 3400, 1620, 1610 (sh), 1580 cm-i; F i g u r e 22; nmr, ( 100WI!z, F o u r i e r Transform ) 0.77 ( s ), 1.0 ( br.d ), 3.4 ( m ),3.8 ( n ), 7.18 ( s ); F i g u r e 22; mass spectrum, m/e c a l c d . f o r 0 2 6 ^ 3 7 ^ 2 , 395.2823; found, 395.2829; O x i d a t i o n of 72 to 1 7-oxcsamane-N-benzoate( 7_3 ) The procedure was same as that f o r 77. Thus 38 mg of 72 y i e l d e d 3 3 mg ( 88% y i e l d ) of 73. Hp 162-164.5° ( ether ). F i g u r e 23; i r , 1740, 1620, 1580 cm* 1i F i g u r e 2 3 ». nmr, 0.71 ( s, 3d ), 1.0 ( b r . s , 3H ), 3.3 ( m, 4H ), 7.3 ( s, 5 H ); Figure 23; mass spectrum, c a l c d . f o r C 2 6 I I 3 5 ? g o 2 : 393.2667 ; found: 3 93.264 9; 395 ( b? ), 394 ( 42% ), 393 ( 67% ), 392 ( 481 ), 379 ( 20% ), 378 ( 501? ) , 288 ( 15* ), 174 ( 22% ), 163 ( 14% ), 98 162 ( 48% ), 161 ( }H% ), 160 ( 12% ), 150 ( 19% ) , 148 ( 17% ), 147 ( 10% ) , 146 ( 10% ) , 134 ( 1 3 % ), 122 ( 14% ), 107 ( 10% ), 106 ( 37% ), 105 ( 100% ), 93 ( 11% ), 79 ( 10% ), 77 ( 67% ), 58 ( 20% ), 56 ( 33% }, 43 ( 10% ), 42 ( 15% ) , Figure 24 ; S y n t h e s i s of 16-beuzylidene-17-oxosamane-N-benzoate ( 74 ) To a s o l u t i o n of 10 mg ( 0.025 mmole ) of 73 i n 2 ml of methanol, 97 mg ( 0.86 mmcle ) of benza ldehydc? was added. The f l a s k was f l u s h e d with n i t r o g e n and 0.4 ml of 6N sodium hydroxide was added. The mixture was s t i r r e d at room temperature under nitrogen.atmosphere f o r 18 h. The s o l u t i o n was then poured i n t o 50 ml of water and e x t r a c t e d with 2 x 30 ml of ether. The combined ether e x t r a c t s was washed with 5 x 20 ml of s a t u r a t e d sodium c h l o r i d e s o l u t i o n u n t i l the washings were n e u t r a l to l i t m u s . The ether l a y e r was then d r i e d over anhydrous sodium sulphate, f i l t e r e d and •F the s o l v e n t was removed under reduced pressure. The r e s i d u e ( 13 mg ) was p u r i f i e d by p r e p a r a t i v e t i c ( s i l i c a g e l , e t h y l a c e t a t e ). The compound with Rf 0.8 was e x t r a c t e d ( y i e l d 10 mg,80% ) . I r , 1715, 1620. 1605, 1580 cm-J; Figure 25; nmr, 0.96 ( s, 3H ), 1.08 ( br. 3K ), 3.3 ( m, 48 ) , 7.3 ( m, 11H ) ; Fig u r e 25; uv, { q u a l i t a t i v e ) 296 m u ; mass spectrum, c a l c d . f o r C 3 3 H 3 9 N 0 2 » 481.2979; found, 481. 2902; 100 BIBLIOGRAPHY 1. Progress i n o r g a n i c Chemistry, Butterworth and Co., London(1968). Volume 7, p. 35, 2. G. Habermehl and A. Haaf, l i e b i c j s A n n : Chem. f 722, 155 ( 1969) . 3. A. Butenandt, J. Schmidt-Thome and J . Weiss, Ber.., 72, 4 17 (1939). 4. K. Oka and S. Hara, Tetrahedron L e t t e r s , 1 193(1969) 5. K. Oka and S. Hara, Tetrahedron L e t t e r s , 1 189 (1969), S. Hara and N. Matsumoto, Yakugaku Zasshi, 85, 48 (1965) . 6. A.J. L i s t o n , J.. Org.. Chem.., 3J, 2105 (1966). 7. P. Cat s o u l a c o s , C h i j i k a Chrcnika t 1, 147( 1972). 8. J.K. P a i s l e y , Ph.D. T h e s i s (1973) , Univ. of B r i t i s h Columbia, Vancouver, Canada. 9. J.K. P a i s l e y and L. Weiler, Tetrahedron L e t t e r s ^ 261 (1972) . 10. J . B a l s e v i c h , This l a b o r a t o r y , Unpublished R e s u l t s . 11. H.C. Brown and W. Korytnyk, J A m e i r Chem.. Soc^., 82, 3866 (1960). 12. We are t h a n k f u l to Dr.K. Oka f c r the copy of the i r spectrum of _57 and checking the i d e n t i t y of our compound with t h e i r s . 101 13. J . E . B r i d g e m a n , E.R.H. J o n e s , G.D. M e a k i n s and J . W i c h a , C h e m i c a l C o m m u n i c a t i o n s 898(1067). 14. G. L u s t and Y. C. L i n , C h e m j i c a l C o m m u n i c a t i o n 1 350 (1 968) . 15. S. Hara and K. Oka, J_. Amer.. S:_!=i!!i 522i 89, 104 1 ( 1967) . 16. J.H. B r e w s t e r and J . E . P r i v e t t , J A Amer. Chem. _ o c . 88, 1419 (1966). 17. A. K a s s n e r and T..F. P c m w r a n t z , J«_ Or___ Chem,. 27 17t>0(1962). 18. K. Bowde-n, I.M. H e i l b r c n , F..H.R. J o n e s and E.C.L. Weed o n , J . Chem_ S o c . 39 (1946). C. D j e r a s s i , R. R. E n g l e and A. P o w e r s , ____ Orcj_, Chem.. 2_1 , 1>'4 7 (195o) . SPECTRAL APPENDIX 103 FIGURE 1 RELRTIVE INTENSITY D .0 , 25.0 50.0 75 .0 [00.0 en •91 Ln ~"| 152 c z TO r n I m o o (V) U V O I V ) CD — o o U l RELRTIVE INTENSITY 0.0 25.0 50.0 75 .0 [00.D J I J _ _ J I 90 L FIGURE 5 107 , -v 100at>m Ml P^M 0.0 RELATIVE 25.0 INTENSITY so. a 75.0 LOO.O o CD LSI CD ' C D -CD • CD 135 CD •154 3 m c r M CD " CD C D CD IVl a ? " C D UJ CD " CD LO CD CD" CD 801 109 t no FIGURE 8-A. A u t h e n t i c B. D e g r a d a t i o n P k t . | FREQUENCY (CM') 4000 3600 3200 2800 2400 2000 1800 1600 1400 . 1200 1000 800 650 112 FIGURE 10 FIGURE 11 1 1 3 CD CD CD CD CD M (_n CD CD LO CD CD CD LO LO 115 FIGURE 13 FIGURE 14 CD CD __, LD . if) CD LU i—y~> -| c r _ j LU ro CD CD 'P. in -i—i—r F3 T — r — i — I — r — ^ i — r — i — i — r — i — i — i — i — i — i — i — i — i — i — i — r O.D 50.0 100.0 150.0 200.0 M/E r 250.0 300.0 1 I 1 350.0 i — r 400 117 FIGURE 15 | FREQUENCY tCM'l 4000 3600 3200 2800 2400 2000 1800 1600 1400 1200 1000 800 650 118 FIGURE 16 RELRTIVE INTENSITY 0 Q 25.0 50.0 75.0 100.0 CD { | I I . 1 en CD " CD CD " CD CD m <V) CD • CD CD •43 Gl CZ TO m CD CD U3 Ul CD CD 611 120 FIGURE 18 CO LU _J LU F I G U R E 1 9 0 .0 T 1 1 1 1 1 1 1 r "J 1 1 1 1 1 — R i — i r 1 — i — I — i 1 — i — p 50 .0 iOD.O 150.0 200.D 250 .0 300.0 350 0 400 M/E 122 123 FIGURE 21 FREQUENCY (CM') 4000 3600 3200 1800 3400 2000 1600 1600 1400 1200 1000 800 650 1ZA FIGURE 22 125 FIGURE 23 0 .0 RELRTIVE 25.0 INTENSITY 50.0 75.0 [00.0 a CD LP CD • CD • CD 105 CD CD m (V) CD • CD CD CD cz m 4^  CD • 2 8 8 CD -CD ( J V CD CD' CD CD •393 92 L 127 FIGURE 25 

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