Preparation of epothilone intermediates

Abstract

The present invention relates to a process for the preparation of intermediates useful in the synthesis of epothilone analogs by initially enzymatically degrading certain epothilone compounds to form ring-open structures containing a carboxyl group which is esterified, the hydroxyl groups on the moiety protected and the resulting compound oxidized by, e.g. ozone, to form a first intermediate. The first intermediate can be reacted with a triphenylphosphine adduct to yield a compound containing an ester group at position 1 which is subsequently hydrolyzed to form a second intermediate.

What is claimed is:  
     
         1 . A process for preparing a compound represented by formula I:  
       
         
           
           
               
               
           
         
       
       wherein: 
 X is selected from the group consisting of hydrogen, alkyl, substituted alkyl, aryl and substituted aryl;  
 R 1  is selected from the group consisting of hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, and heterocyclo; and  
 P 1  and P 2  are independently selected from the group consisting of hydrogen, aralkyl, substituted aralkyl, trialkylsilyl, triarylsilyl, dialkylarylsilyl, diarylalkylsilylalkoxyalkyl, and aralkyloxyalkyl;  
 comprising treating an epothilone compound of formula III or formula IV:  
                     
  wherein: 
 X, R 1 , P 1  and P 2  are as defined above;  
 R 2  is hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, heterocyclo or  
                     
  and  
 R 3  and R 4  are selected from the group consisting of hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, cycloalkyl and heterocyclo;  
 with an enzyme to form a compound represented by formula VI:  
                     
  wherein R 1  and R 2  are as defined above; 
 optionally esterifying the carboxyl group of said compound;  
 optionally reacting the resulting esterified compound to form protecting groups on the hydroxyl groups of said compound; and  
 reacting the resulting compound with a suitable oxidizing agent to form said compound of formula I.  
 
 
 
     
     
         2 . A process for preparing a compound represented by formula II:  
       
         
           
           
               
               
           
         
       
       wherein: 
 X is selected from the group consisting of hydrogen, alkyl, substituted alkyl, aryl and substituted aryl;  
 R 1  is selected from the group consisting of hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, and heterocyclo;  
 R 2  is hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, heterocyclo or  
                     
  and  
 R 3  and R 4  are selected from the group consisting of hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, cycloalkyl and heterocyclo; and  
 P 1 , P 2 , and P 3  are independently selected from the group consisting of hydrogen, aralkyl, substituted aralkyl, trialkylsilyl, triarylsilyl, dialkylarylsilyl, diarylalkylsilylalkoxyalkyl, and aralkyloxyalkyl;  
 comprising reacting a compound represented by formula I:  
                     
  wherein X, R 1 , P 1  and P 2  are as defined above; 
 with a compound represented by formula IX:  
                     
  wherein R 2  and P 3  are as defined above, to form a compound represented by formula X:  
                     
  and  
  hydrolyzing the ester group on said compound in the presence of a suitable base to form said compound represented by formula II.  
 
 
     
     
         3 . A process for preparing a compound represented by formula II:  
       
         
           
           
               
               
           
         
       
       wherein: 
 X is selected from the group consisting of hydrogen, alkyl, substituted alkyl, aryl and substituted aryl;  
 R 1  is selected from the group consisting of hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, and heterocyclo;  
 R 2  is hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, heterocyclo or  
                     
 R 3  and R 4  are selected from the group consisting of hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, cycloalkyl and heterocyclo; and  
 P 1 , P 2 , and P 3  are independently selected from the group consisting of hydrogen, aralkyl, substituted aralkyl, trialkylsilyl, triarylsilyl, dialkylarylsilyl, diarylalkylsilylalkoxyalkyl, and aralkyloxyalkyl;  
 comprising treating an epothilone compound of formula III or formula IV:  
                     
  with an enzyme to form a compound represented by formula VI:  
                     
 esterifying the carboxyl group of said compound;  
 reacting the resulting esterified compound to form protecting groups on the hydroxyl groups of said compound;  
 reacting the resulting compound with a suitable oxidizing agent to form a compound represented by formula I:  
                     
 reacting said compound with a compound represented by formula IX:  
                     
 to form a compound represented by formula X:  
                     
  and  
 hydrolyzing the ester group on said compound in the presence of a suitable base to form said compound represented by formula II.  
 
     
     
         4 . A process for preparing a compound represented by formula I:  
       
         
           
           
               
               
           
         
       
       wherein: 
 X is selected from the group consisting of hydrogen, alkyl, substituted alkyl, aryl and substituted aryl;  
 R 1  is selected from the group consisting of hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, and heterocyclo; and  
 each P 1  and P 2  is, independently, selected from the group consisting of hydrogen, aralkyl, substituted aralkyl, trialkylsilyl, triarylsilyl, dialkylarylsilyl, diarylalkylsilylalkoxyalkyl, and aralkyloxyalkyl;  
 comprising treating an epothilone compound represented by formula XV:  
                     
  wherein: 
 R 1 , P 1  and P 2  are as defined above;  
 R 2  is hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, heterocyclo or  
                     
  and  
 R 3  and R 4  are selected from the group consisting of hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, cycloalkyl and heterocyclo;  
 with an enzyme to form a compound represented by formula XVI:  
                     
  wherein: 
 R 1 , R 2 , P 1  and P 2  are as defined above; and  
 P 3  is selected from the group consisting of hydrogen, aralkyl, substituted aralkyl, trialkylsilyl, triarylsilyl, dialkylarylsilyl, diarylalkylsilylalkoxyalkyl, and aralkyloxyalkyl;  
 esterifying the carboxyl group of compound of formula XVI to form an ester compound represented by formula XVII:  
                     
  wherein X, R 1 , R 2 , P 1 , P 2  and P 3  are as defined above; 
 hydrolyzing the ester compound to form a diol compound of formula XVIII:  
                     
  wherein X, R 1 , R 2 , P 1 , P 2  and P 3  are as defined above; and  
  reacting the diol compound with a suitable oxidizing agent to form said compound of formula I.