New methods for the preparation of taxanes using chiral auxiliaries

Abstract

A stereoselective synthesis of novel β-lactam dimers as useful precursors for the preparation of paclitaxel, docetaxel, and analogues thereof. More particularly, the new β-lactams are prepared from readily available and enantiomerically pure chiral auxiliaries. The β-lactams are then reacted with a suitably protected taxane to produce diastereomerically enriched side chain-bearing taxanes. Finally, the chiral auxiliary is cleaved and protecting groups are removed to provide the desired taxane.

What is claimed is: 
     
         1 . A compound of formula: 
       
         
           
           
               
               
           
         
         in racemic or in either isomerically pure form, wherein R is hydrogen, aryl or acyl, Ar is aryl, and L is a cleavable linker, chiral or non chiral. 
       
     
     
         2 . A compound according to  claim 1 , wherein R is hydrogen. 
     
     
         3 . A compound according to  claim 1 , wherein R is p-methoxyphenyl. 
     
     
         4 . A compound according to  claim 1 , wherein R is benzoyl. 
     
     
         5 . A compound according to  claim 1 , wherein R is tert-butyloxycarbonyl. 
     
     
         6 . A compound according to  claim 1 , wherein L is a chiral tartaric diester acetonide having enantiomerically enriched or substantially pure (R,R) or (S,S) stereochemistry, or a mixture of (R,R) and (S,S) enantiomers including racemic mixtures. 
     
     
         7 . A compound according to  claim 1 , wherein L is a chiral trans-1,2-cyclohexane di(carboxylate ester) having enantiomerically enriched or substantially pure (R,R) or (S,S) stereochemistry or a mixture of (R,R) and (S,S) enantiomers including racemic mixtures. 
     
     
         8 . A compound according to  claim 1 , wherein L is a chiral 1,1′-binaphthyl-2,2′-di(carboxylate ester) having enantiomerically enriched or substantially pure (R) or (S) stereochemistry or a mixture of (R) and (S) enantiomers including racemic mixtures. 
     
     
         9 . A compound according to  claim 1 , wherein L is of formula: 
       
         
           
           
               
               
           
         
         wherein Rc and R′c, identical or different are alkyl, aryl or hydrogen, Rd and R′d, identical or different are alkyl, aryl or hydrogen, Rf and R′f, identical or different are alkyl, aryl or hydrogen, Rg and R′g, identical or different are alkyl, aryl or hydrogen; W is an alkyl. 
       
     
     
         10 . A compound according to  claim 1 , wherein L is —CH 2 —(C 6 H 5 )—(CH 2 )—. 
     
     
         11 . A compound as defined in  claim 1 , wherein Ar is phenyl optionally substituted with one or more substituents. 
     
     
         12 . A compound as defined in  claim 1 , wherein Ar is unsubstituted phenyl. 
     
     
         13 . The compound according to  claim 1 , wherein said cleavable linker L is selected from the group consisting of hydrolysable ketals, acetals, silyl, esters, diesters, and hydrogenolyzable benzyl group. 
     
     
         14 . A process for producing a compound of formula 5″: 
       
         
           
           
               
               
           
         
         wherein Ar is an aryl group and L is a cleavable linker, chiral or non chiral, R is an acyl group; 
         comprising: 
         preparing a compound of formula 3′: 
       
       
         
           
           
               
               
           
         
         wherein L is as defined previously and Rb is an alkoxy group; and reacting said compound of formula 3′ with a compound of formula: 
       
       
         
           
           
               
               
           
         
         wherein Ar is as defined previously and Ra is a group cleaveable in situ from the reaction condition or from an isolation process; to produce a compound of formula 5″: 
         wherein Ar and L are as defined previously: 
       
       
         
           
           
               
               
           
         
         wherein Ar and L are as described above, 
         or 
         preparing a compound of formula 3′: 
       
       
         
           
           
               
               
           
         
         wherein L is as defined previously and Rb is a leaving group; and reacting said compound of formula 3′ with a compound of formula: 
       
       
         
           
           
               
               
           
         
         wherein Ar is as defined previously and Ra is a group cleavable under oxidative condition; to produce a compound of formula 5′: 
       
       
         
           
           
               
               
           
         
         wherein Ar, Ra and L are as defined previously; and reacting said compound of formula 5′ with an oxidizing agent to produce a compound of formula 5″ 
       
       
         
           
           
               
               
           
         
         wherein Ar and L are as described above; 
         and reacting said compound of formula 5″ with an acylating agent to produce said compound of formula 5″. 
       
     
     
         15 . A process according to  claim 14  wherein R is benzoyl or tert-butyloxycarbonyl. 
     
     
         16 . The process according to  claim 14 , wherein said cleavable linker L is selected from the group consisting of hydrolysable ketals, acetals, silyl, esters, diesters, and hydrogenolyzable benzyl group.