Stereoselective reduction of substituted oxo-butanes

Abstract

The present invention relates to a process for the stereoselective enzymatic reduction of 1-halo-2-oxo-3-(protected)amino-4-substituted-butanes utilizing certain species of Rhodococcus and Brevibacterium. The product 1-halo-2-hydroxy-3-(protected)amino-4-substituted-butanes, which are useful as intermediates in the synthesis of compounds that are inhibitors of ACE, renin and HIV proteases, are obtained in high yield and, particularly, in very high diastereomeric purity. The process is advantageously highly selective for the 1S,2S enantiomer of the product.

We claim:  
     
         1 . A stereoselective process for the preparation of (1S,2S)-1-halo-2-hydroxy-3-(protected)amino-4-substituted butanes represented by the formula I  
       
         
           
           
               
               
           
         
       
       wherein Hal is halogen, R is selected from the group consisting of alkyl, substituted alkyl, aryl and substituted aryl and R 1  is a protecting group for the amino function comprising contacting a (1S)-1-halo-2-oxo-3-(protected)amino-4-substituted butane represented by formula II  
       
         
           
           
               
               
           
         
       
       wherein Halo, R and R 1  are as defined above with a microorganism capable of catalyzing the stereoselective reduction of the compound represented by formula II wherein said microorganism is selected from the group consisting of  Rhodococcus erythropolis  ATCC 4277,  Rhodococcus erythropolis  DSM 6971 and Rhodococcus sp. ATCC 21227,  Rhodococcus erythropolis  ATCC 27854 and Brevibacterium sp. ATCC19653 under conditions such that said reduction is effected, and recovering said compound represented by formula I.  
     
     
         2 . A process in accordance with  claim 1 , wherein Hal is chloro, R is phenyl and R 1  is t-butoxycarbonyl.  
     
     
         3 . A process in accordance with  claim 1 , wherein said microorganism is  Rhodococcus erythropolis  ATCC 4277.  
     
     
         4 . A process in accordance with  claim 1 , wherein said microorganism is  Rhodococcus erythropolis  DSM 6971.  
     
     
         5 . A process in accordance with  claim 1 , wherein said microorganism is Rhodococcus species ATCC 21227.  
     
     
         6 . A process in accordance with  claim 1 , wherein said microorganism is Rhodococcus species ATCC 27854.  
     
     
         7 . A process in accordance with  claim 1 , wherein said microorganism is Brevibacterium sp. ATCC19653.  
     
     
         8 . A process in accordance with  claim 1  carried out as a one-stage fermentation.  
     
     
         9 . A process in accordance with  claim 1  carried out as a two-stage fermentation.  
     
     
         10 . A process in accordance with  claim 1  carried out in the presence of an inducer.  
     
     
         11 . A process in accordance with  claim 10 , wherein the inducer is a compound represented by formula I that is added during the growth of said microorganism.  
     
     
         12 . A process in accordance with  claim 1 , wherein compound represented by formula I is obtained in at least 70% yield and at least 93% diastereomeric purity.  
     
     
         13 . A process in accordance with  claim 10 , wherein compound represented by formula I is obtained in at least 95% yield and at least 99% diastereomeric purity.  
     
     
         14 . In a process of preparing an epoxy compound represented by the formula  
       
         
           
           
               
               
           
         
       
       wherein R is selected from the group consisting of alkyl, substituted alkyl, aryl and substituted aryl and R 1  is a protecting group for the amino function, comprising reacting an aryl ester represented by the formula  
       
         
           
           
               
               
           
         
       
       wherein R and R 1  are as defined above and R 2  is hydrogen or nitro and may be substituted in the ortho or para position on the phenyl ring with a sulfur ylide compound containing a function represented by the formula  
       
         
           
           
               
               
           
         
       
       wherein R 3  and R 4  are selected from the group consisting of alkyl, substituted alkyl and aryl to produce an intermediate keto ylide compound represented by the formula  
       
         
           
           
               
               
           
         
       
       wherein R, R 1 , R 3  and R 4  are as defined above, treating said compound represented by formula III with a source of chloride and an organic acid to form a 1-substituted-2-amino-3-oxo-4-chloro butane compound represented by the formula  
       
         
           
           
               
               
           
         
       
       wherein R and R 1  are as defined above, reducing said compound to form a 1-chloro-2-hydroxy-3-amino-4-substituted butane compound represented by the formula  
       
         
           
           
               
               
           
         
       
       wherein R and R 1  are as defined above and reacting said hydroxy compound with a base to form said epoxy compound, the improvement wherein the reduction of said 1-chloro-2-oxo-3-amino-4-substituted butane is carried out in accordance with  claim 1  thereby yielding said 1-chloro-2-hydroxy-3-amino-4-substituted butane compound in at least 70% yield and at least 93% diastereomeric purity.  
     
     
         15 . A process in accordance with  claim 14 , wherein compound represented by formula I is obtained in at least 95% yield and at least 99% diastereomeric purity.