β-Sultams II: Synthesis of tri-, tetra- and pentamethylene- 1,2-thiazetidine 1,1-dioxides

Tetrahedron Letters,Vol.23,No.51,pp Printed in Great Britain

5389-5390,1982

0040-4039/B2/515389-02503.00/0 ©1982

P e r g a m o n Press Ltd.

8-SULTAMS II: SYNTHESIS OF T R I - , T E T R A - AND P E N T A M E T H Y L E N E 1,2-THIAZETIDINE 1,1 -DIOXIDES

H a n s - H a r t w i g Otto* and P e t e r Schwenkkraus P h a r m a z e u t i s c h e s Institut, L e h r s t u h l P h a r m a z e u t i s c h e C h e m i e , A l b e r t - L u d w i g s - U n i v e r s i t ~ i t , D-78oo F r e i b u r g , Germany

A b s t r a c t : The unsubstituted p a r e n t s t r u c t u r e of sulfone analogs of penicillin and its h i g h e r homologs a r e obtained by b a s e p r o m o t e d c y c l i z a t i o n of cyclic 8 - a m i n o - e t h anes ulf ony 1 c h l o r i d e s •

C h e m i c a l r e a c t i v i t y and m o l e c u l a r g e o m e t r y a r e two fundamental f a c t o r s con= t r i b u t i n g to the a n t i m i c r o b i a l potency of B-laetam a n t i b i o t i c s . Substitution of the 1 c a r b o n y l group of the 8-1actam ring by sulfone group r e s u l t s in 8 - s u l t a m s which a r e s o m e t i m e s m o r e r e a c t i v e than c o r r e s p o n d i n g B - l a c t a m s . The syn= t h e s i s of biologically not active sulfone analog of p e n i c i l l i n is r e c e n t l y pub= •

lished by Koller et al.

2

. This p r o m p t s us to r e p o r t in this c o m m u n i c a t i o n on

the s y n t h e s i s of the p a r e n t s t r u c t u r e 3 of sulfone analog penicillin and of its =

h i g h e r h o m o l o g s 6 and 9. ( S ) - 2 - P y r r o l i d i n y l m e t h a n e t h i o l (1) was p r e p a r e d f r o m (S)-proline by reduction with LiA1H4, b r o m i n a t i o n with P B r 3 / H B r

and r e a c t i o n with t h i o u r e a 3 ' 4 .

T r e a t m e n t of its h y d r o c h l o r i d e with an e x c e s s of c h l o r i n e in c a r b o n t e t r a c h l o r i d e / e t h a n o l / w a t e r gave r i s e to a high y i e l d ( 84% ) of c r y s t a l l i n e ( S ) - 2 - p y r r o l i d i = n y l m e t h a n e s u l f o n y l c h l o r i d e h y d r o c h l o r i d e (2) ( m . p . 126°C, acetone ). The s t r u c t u r e of 2 was a s s i g n e d on the b a s i s of its s p e c t r a l data as w e l l as by its c y c l i z a t i o n with a m m o n i a in c h l o r o f o r m at O°C producing c r y s t a l l i n e ( S ) - 2 , 3 o t r i m e t h y l e n e - 1 , 2 - t h i a z e t i d i n e 1 , 1 - d i o x i d e (3) ( m . p . 56 C, c a r b o n t e t r a c h l o = r i d e ) in 6o% yield. The s t r u c t u r e of this m a t e r i a l was unambiguously c o n f i r m e d by h y d r o l y s i s to the p a r e n t sulfonic acid and by its e l e m e n t a r y a n a l y s i s and s p e c t r o s c o p i c data ~ . Reaction of (R, S ) - 2 - p i p e r i d y l m e t h a n e t h i o l (4) 4 with c h l o r i n e under s i m i l a r conditions gave the c r y s t a l l i n e (R, S ) - 2 - p i p e r i d y l m e t h a n e s u l f o n y l c h l o r i d e

5389

5390

hydrochloride (5) ( m . p . 134-135°C, acetone; yield 98% ). T r e a t m e n t of 5 with ammonia in c h l o r o f o r m resulted in f o r m a t i o n of the expected (R, S ) - 2 , 3 - t e t r a = m e t h y l e n e - l , 2-thiazetidine 1,1-dioxide (6) ( m . p . 57°C, carbon t e t r a c h l o r i d e )5 in 82% yield. We also p r e p a r e d ( R , S ) - 2 - p e r h y d r o a z e p i n y l m e t h a n e t h i o l (7) ( m . p . 6o°C, subl. ; yield 63% ) f r o m (R, S)-2-perhydroazepinylmethanol 6 in t h r e e steps by a s i m i l a r p r o c e d u r e as used for the synthesis of 1. It was converted into the =

parent sulfonyl chloride hydrochloride 8_ ( m . p . 121°C, acetone; yield 83% ) which could be c y c l i s i z e d in c h l o r o f o r m with ammonia at O°C yielding (R, S ) - 2 , 3 p e n t a m e t h y l e n e - 1 , 2 - t h i a z e t i d i n e 1,1-dioxide (9) 5 ( m . p . 49-5o°C, carbon tetra= chloride; yield 76% ) as c o l o u r l e s s c r y s t a l s .

~_~:H2

SH

H2 .CH2SO2CI CI-

~SO2

('2\~ , , H

H 1

2

=

3

=

CH2SH

~

=

~'CH 2SO2El

n=l

4 =

----

5

6

n=2

7

8

9

=

=

=

--.7.

Acknowledgments: Support of this work f r o m Deutsche F o r s c h u n g s g e m e i n s c h a f t and Fonds der C h e m i s c h e n Industrie, Frankfurt, is gratefully acknowledged.

R e f e r e n c e s and Notes: 1

E. Meyle and H. -H.Otto, J. Org. C h e m . , submitted.

2

F . C a v a g n a , W . K o l l e r , A . L i n k i e s , H.Rehling, and D.Reuschling, Angew. Chem. 9._44, 549 (1982); Int. Ed. Engh 2_.1, 548 (1982).

3

O.Vogl, and M. PShm, Monatsh. Chem. 83, 541 (1952).

4

S . S e a r l e s J r . , G . E . R o e l o f s , M . T a m r e s , and R.N. McDonald, J . O r g . Chem. 3_.~o, 3443 (1965).

5

all new compounds gave c o r r e c t e l e m e n t a l analyses; 3: [~]2l = _ 8", 1 (CHCI3), S O 2 : 1 3 2 o , 1 1 9 5 cm -1. 6: SO2: 131o,118o cm -1. 9: SO2: 131o,119o c m - l ( K B r )

6

C . J . Lu, and F . F . B l i c k e , - Hua Hsueh Hsueh Pao 2_~2, 513 (1956), C . A . 5_..22, 11o86a (1958). (Received in Germany 1 September

1982)