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: 
       
         
           
           
               
               
           
         
         wherein Ar is an aryl, R is an acyl, R 1 , and R 2 , identical or different, are independently acyl, hydrogen or a hydroxy protecting group, L is a cleavable linker, Y 1  is hydrogen, a hydroxy or a protected hydroxy group, Y 2  is a hydrogen or a protected hydroxy group or Y 1  and Y 2  taken together form a carbonyl group. 
       
     
     
         2 . A compound as defined in  claim 1 , wherein Ar is phenyl optionally substituted with one or more substituents. 
     
     
         3 . A compound as defined in  claim 1 , wherein Ar is unsubstituted phenyl. 
     
     
         4 . A compound as defined in  claim 1 , wherein Y 1  is a hydroxyl and Y 2  is a hydrogen. 
     
     
         5 . A compound as defined in  claim 4 , wherein Y 1  is a hydroxyl having stereochemistry 
       
         
           
           
               
               
           
         
       
     
     
         6 . A compound as defined in  claim 1 , wherein Y 1  and Y 2  taken together form a carbonyl group. 
     
     
         7 . A compound according to  claim 1 , wherein R is benzoyl, R 1  is acetyl and R 2  is a hydroxy protecting group. 
     
     
         8 . A compound according to  claim 7  wherein R 2  is selected from the group consisting of ethoxyethyl, triethylsilyl, triisopropylsilyl, t-butyldimethylsilyl, t-butyldiphenylsilyl, benzyl and tert-butyloxycarbonyl. 
     
     
         9 . A compound according to  claim 1 , wherein R is benzoyl, R 1  is acetyl and R 2  is a hydrogen. 
     
     
         10 . A compound according to  claim 1 , wherein R is benzoyl and wherein R 1  and R 2  are both hydrogen. 
     
     
         11 . A compound according to  claim 1 , wherein R is benzoyl and wherein R 1  and R 2  are both a hydroxy protecting group. 
     
     
         12 . A compound according to  claim 11 , wherein R 1  and R 2  are selected from the group consisting of ethoxyethyl, triethylsilyl, triisopropylsilyl, t-butyldimethylsilyl, t-butyldiphenylsilyl, benzyl and tert-butyloxycarbonyl. 
     
     
         13 . A compound according to  claim 1 , wherein R is tert-butyloxycarbonyl, R 1  is acetyl and R 2  is a hydroxy protecting group. 
     
     
         14 . A compound according to  claim 13 , wherein R 2  is selected from the group consisting of ethoxyethyl, triethylsilyl, triisopropylsilyl, t-butyldimethylsilyl, t-butyldiphenylsilyl, benzyl and tert-butyloxycarbonyl and R is phenyl or tert-butoxy. 
     
     
         15 . A compound according to  claim 1 , wherein R is tert-butyloxycarbonyl, R 1  is acetyl and R 2  is a hydrogen. 
     
     
         16 . A compound according to  claim 1 , wherein R is tert-butyloxycarbonyl and wherein R 1  and R 2  are both hydrogen. 
     
     
         17 . A compound according to  claim 1 , wherein R is tert-butyloxycarbonyl and wherein R 1  and R 2  are both a hydroxy protecting group. 
     
     
         18 . A compound according to  claim 17 , wherein R 1  and R 2  are selected from the group consisting of ethoxyethyl, triethylsilyl, triisopropylsilyl, t-butyldimethylsilyl, t-butyldiphenylsilyl, benzyl and tert-butyloxycarbonyl. 
     
     
         19 . 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. 
     
     
         20 . 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. 
     
     
         21 . 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. 
     
     
         22 . 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. 
       
     
     
         23 . A compound according to  claim 1 , wherein L is —CH 2 —(C 6 H 5 )—(CH 2 )—. 
     
     
         24 . A process for producing a compound of formula: 
       
         
           
           
               
               
           
         
         comprising treating a taxane precursor compound of formula: 
       
       
         
           
           
               
               
           
         
         with a compound of formula: 
       
       
         
           
           
               
               
           
         
         wherein Ar is an aryl, R is an acyl, R 1 , and R 2 , identical or different, are independently acyl, hydrogen or a hydroxy protecting group, L is a cleavable linker, Y 1  is hydrogen, a hydroxy or a protected hydroxy group, Y 2  is a hydrogen or a protected hydroxy group or Y 1  and Y 2  taken together form a carbonyl group. 
       
     
     
         25 . A process according to  claim 24 , wherein R is an acyl that is an aroyl or alkyloxycarbonyl. 
     
     
         26 . A process according to  claim 24 , wherein Ar is phenyl optionally substituted with one or more substituents. 
     
     
         27 . A process according to  claim 24 , wherein Ar is unsubstituted phenyl. 
     
     
         28 . A process according to  claim 24 , wherein Y 1  is a hydroxyl and Y 2  is a hydrogen. 
     
     
         29 . A process according to  claim 28 , wherein Y 1  is a hydroxyl having stereochemistry 
       
         
           
           
               
               
           
         
       
     
     
         30 . A process according to  claim 24 , wherein, Y 1  and Y 2  taken together form a carbonyl group. 
     
     
         31 . A process according to  claim 24 , wherein R is benzoyl, R 1  is acetyl and R 2  is a hydroxy protecting group. 
     
     
         32 . A process according to  claim 31 , wherein R 2  is selected from the group consisting of ethoxyethyl, triethylsilyl, triisopropylsilyl, t-butyldimethylsilyl, t-butyldiphenylsilyl, benzyl and tert-butyloxycarbonyl. 
     
     
         33 . A process according to  claim 24 , wherein R is benzoyl, R 1  is acetyl and R 2  is a hydrogen. 
     
     
         34 . A process according to  claim 24 , wherein R is benzoyl and wherein R 1  and R 2  are both hydrogen. 
     
     
         35 . A process according to  claim 24 , wherein R is benzoyl and wherein R 1  and R 2  are both a hydroxy protecting group. 
     
     
         36 . A process according to  claim 24 , wherein R 1  and R 2  are selected from the group consisting of ethoxyethyl, triethylsilyl, triisopropylsilyl, t-butyldimethylsilyl, t-butyldiphenylsilyl, benzyl and tert-butyloxycarbonyl. 
     
     
         37 . A process according to  claim 24 , wherein R is tert-butyloxycarbonyl, R 1  is acetyl and R 2  is a hydroxy protecting group. 
     
     
         38 . A process according to  claim 37 , wherein R 2  is selected from the group consisting of ethoxyethyl, triethylsilyl, triisopropylsilyl, t-butyldimethylsilyl, t-butyldiphenylsilyl, benzyl and tert-butyloxycarbonyl. 
     
     
         39 . A process according to  claim 24 , wherein R is tert-butyloxycarbonyl, R 1  is acetyl and R 2  is a hydrogen. 
     
     
         40 . A process according to  claim 24 , wherein R is tert-butyloxycarbonyl and wherein R 1  and R 2  are both hydrogen. 
     
     
         41 . A process according to  claim 24 , wherein R is tert-butyloxycarbonyl and wherein R 1  and R 2  are both a hydroxy protecting group. 
     
     
         42 . A process according to  claim 41 , wherein R 1  and R 2  are selected from the group consisting of ethoxyethyl, triethylsilyl, triisopropylsilyl, t-butyldimethylsilyl, t-butyldiphenylsilyl, benzyl and tert-butyloxycarbonyl. 
     
     
         43 . A process according to  claim 24 , wherein L is a cleavable chiral linker. 
     
     
         44 . A process according to  claim 24 , 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. 
     
     
         45 . A process according to  claim 24 , 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. 
     
     
         46 . A process according to  claim 24 , 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. 
     
     
         47 . A process according to  claim 24 , 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. 
       
     
     
         48 . A process according to  claim 24 , wherein L is  —CH   2 —(C 6 H 5 )—(CH 2 )—. 
     
     
         49 . A process for producing a compound of formula: 
       
         
           
           
               
               
           
         
         comprising treating a compound of formula: 
       
       
         
           
           
               
               
           
         
         with an oxidizing agent; wherein Ar is an aryl, R is an acyl, R 1 , and R 2 , identical or different, are independently acyl, hydrogen or a hydroxy protecting group, L is a cleavable linker. 
       
     
     
         50 . The process of  claim 49  wherein the oxidizing agent is selected from the group consisting of o-iodoxybenzoic acid (IBX), Dess-Martin periodinane, iodosobenzene, iodozobenzene diacetate, Jone's reagent, pyridinium dichromate, pyridinium chlorochromate, potassium permanganate and Swern reagent.