30
S e p a r a t u m
H E L V E T I C A C H I M I C A A C T A V o l . 56, F a s c . 8, p . 2882-2884 (1973)
297. Stereospecific Synthesis of a 9,11,12,13,13a, 14- hexahydro-dibenzo(/, h)pyrrolo(l ,2-&)isoquinoline-alkaloid
P r e l i m i n a r y c o m m u n i c a t i o n
b y Ludwig Faber a n d Wolfgang Wiegrebe
P h a r m a z e u t i s c h e s I n s t i t u t , B e r n e' (12. X I . 73)
S e v e r a l syntheses of the t i t l e - t y p e a l k a l o i d s s t a r t i n g f r o m c h i r a l p r o l i n e - d e r i v a t i - ves, are described i n t h e l i t e r a t u r e [1-4]. A l l these routes produce racemates because t h e y i n c l u d e intermediates w i t h a c a r b o n y l - g r o u p a t o the a s y m m e t r i c a l l y s u b s t i t u t e d c a r b o n - a t o m C(13a). W e a v o i d e d r a c e m i s a t i o n b y u s i n g t h e p r o l i n e d e r i v a t i v e I I I [5]
a n d c y c l i s i n g the p h e n a n t h r e n e - m o i e t y at a late stage of o u r s y n t h e t i c route, s h o w n i n the f o l l o w i n g schemes:
Scheme 1
*) diastereomers were isolated + ) m i x t u r e of diastereomers R = O C H ,
W e o b t a i n e d I I I b y L i B H4- r e d u c t i o n of 5 - o x o - p r o l i n e m e t h y l ester to 5 - o x o - p r o - i n o l w h i c h was s u b s e q u e n t l y t o s y l a t e d . T h e o p t i c a l p u r i t y of 5 - o x o - p r o l i n o l was o n l y 5 1 % of t h a t of Hardegger's [5] p r o d u c t , w h o u s e d L i A l H4. T h i s d i s a d v a n t a g e is c o m p e n s a t e d b y a b e t t e r y i e l d of 5 - o x o - p r o l i n o l , as c o m p a r e d w i t h the L i A l H4- r e d u c - t i o n .
A n i s o l e + h o m o v e r a t r o y l c h l o r i d e - > I [6]. - I + 6 5 % H N Oa i n g l a c i a l A c O H - > I I , m . p . 1 9 7 ° ; N M R . (ehem. shift i n d): Hx: 6.80, I s ; H2: 7.83, I s ; H3 a, i , : 8.09, 2dxd, J0 = 7 H z , / m = 1,7 H z ; H4a,i>: 7.03, 2dxd,JQ = 7 H z , /m = 1.7 H z . - II + III i n a c e t o n e / K2C 03, 1 1 0 ° , 4 - 5 a t m - > I V ; y e l l o w o i l ; M + : 428. N M R . : H5: 5.67, It, J = 7.5 H z ; [a]^° = + 2 2 ° ( M e O H ) . - I V + N a B H4 (70%
E t O H ) -> V . V a , l o w R f . , N M R . : H7: 4.74, Id, J = 7 Hz; H8: 3.00, I s . - V b , h i g h R f , N M R . : H7: 4.77, Id, J = 7 H z ; H8: 3.00, I s . - V (a or b) + 1.25% H C l i n g l a c i a l A c O H (20°) -> V I (a or b respectively). V i a (high R f ) ; m . p . 1 5 2 ° ; p h e n y l g r o u p s eis; N M R . : H6: 5.08, Id, J = 8.5 H z ;
= + 8 9 ° ( C H C 13) . - V I b (low R f ) ; m . p . 1 9 4 ° ; p h e n y l g r o u p s trans; N M R . : H6: 4.83, Id, J = 1.7 H z ; [a]?? = + 4 3 , 5 ° ( C H C 13) . - V I (a or b) + H2 (Raney-mfEtOH) -> V I I (a or b respec- t i v e l y ) . M S . : M+: 382, d o m i n a t i n g peaks at 203 a n d 175. - V I I ( m i x t u r e of diastereomers) + N a N 02/ 2 . 5 % aqueous H C l , followed b y 3 0 % H3P 02- » V I I I . M S . of b o t h diastereomers: M+:
367, d o m i n a t i n g peaks 203 a n d 175. - V I I I ( m i x t u r e of diastereomers) + L i A l H4/ T H F I X ; diastereomers (colourless oils) were separated. I X a (low R f ) , [a]f> = - 2 1 4 ° ( M e O H ) ; I X b (high
Scheme 2
R R
XI R' = CN
XII R = H
R=OCH3
Rf), [a]25 = - 1 7 3 ° ( M e O H ) . M S . (both diastereomers): M+ 353, base p e a k : 189. - I X ( m i x t u r e of a a n d b) + B r C N i n abs. C6H6^ X . I R . ( C H C 13) : 2200/cm. M S . : M+: 378, d o m i n a t i n g peaks 283 a n d 95. - X (4.6 x 1 0_ 5M i n C6H1 2, s a t u r a t e d w i t h air) was i r r a d i a t e d (254 n m ) - » X I ; m . p . 1 5 1 - 2 ° ; U V . : Amax ( l o g e ) : 257 (4.73), 285 (4.44), 311 (3.90), 342 (2.89), 359 n m (2.31); M®\ 376; [a]ff =
+ 74.7 (CHC13). - X I + L i A l H4 i n T H F - > X I I (viscous o i l ) . M+: 351, s m a l l i n t e n s i t y [7], d o m i - n a t i n g peaks 349, 282 a n d 7 0 ; [a]g = + 8 . 1 ° . - X I I + 9 8 % H C O O H / 1 8 0 ° - > X I I I ; c y c l i s a t i o n (without further purification) w i t h P O C l3/ t o l u e n e -> X I V ; U V . : Am a x: 259; 268; 282; 320; 420 n m . X I V + N a B H4/ M e O H -> X V , m . p . 2 0 6 - 1 1 ° . [a]f)2 = + 6 6 ° ( C H C 13) ; antofine: [a]f? = - 1 3 1 ° (CHC13). X V was i d e n t i c a l w i t h n a t u r a l antofine [8] ( T L C , U V . , M S . , I R . ) b u t shows opposite o p t i c a l r o t a t i o n , 5 0 % i n m a g n i t u d e for the reason stated. Because X V has 5-configuration, antofine is of the jR-configuration. T h i s is i n a c c o r d w i t h o u r d e g r a d a t i o n of antofine to D-proline [9].
R E F E R E N C E S
[1] B. Chauncy, E. Geliert & K. N. Trivedi, A u s t r a l . J . C h e m i s t r y , 22, 427 (1969).
[2] R. B. Herbert & C. J. Moody, C h e m . C o m m u n . 1970, 121.
[3] T. R. Govindachari, B. R. Pai, S. Prahabhakar & T. S. Savitri, T e t r a h e d r o n 21, 2573 (1965).
[4] B. Chauncy & E. Geliert, A u s t r a l . J . C h e m i s t r y , 23, 2503 (1970).
[5] E. Hardegger & H. Ott, H e l v . 38, 313 (1955).
[6] A. Novelli 8cA.de Santis, B o l . Soc. Q u i r n . P e r u 30, (4) 155 (1964); C h e m . A b s t r . 64, 5 0 6 9 a . [7] W. Wiegrebe, L. Faber & H. Budzikiewicz, L i e b i g s A n n . C h e m . 733, 125 (1970).
[8] W. Wiegrebe, L. Faber, H. Brochmann jr., H. Budzikiewicz & U. Krüger, L i e b i g s A n n . C h e m . 721, 154 (1969).
[9] W. Wiegrebe, L. Faber & Th. Breyhan, A r c h . P h a r m a z . 304, 188 (1971).
