Enantioselective Synthesis of y-amino-a, B-unsuturated carboxylic acid derivatives

Abstract

Provided is an enantioselective, palladium-catalyzed method for the preparation of γ-amino-α,β-unsaturated carboxylic acid derivatives having the formulas II, III, VII and VIII:

1 . A process for palladium-catalyzed enantioselective allylic amination of α,β-unsaturated carboxylic acid derivatives, said process comprising reacting a racemic mixture of a carboxylic acid derivative having the structural formula I: 
       
         
           
           
               
               
           
         
       
       with a chiral ligand and a palladium catalyst in the presence of a nucleophile, to yield enantiometrically enriched α,β-unsaturated carboxylic acid derivatives having the formulas II and III: 
       
         
           
           
               
               
           
         
       
       wherein in formulas I, II and III, R1 is a benzyl group, an n-butyl group, or a cyclohexyl group; R2 is a benzyl group or hydrogen; XR3 is an ethoxy group, an amide, or a tert-butoxy group; or formulas I and III are as recited above and in formula II, NR1R2 is a phtalimidyl-substituent. 
     
     
         2 . A process according to  claim 1  wherein said palladium catalyst is [Pd(allyl)Cl] 2 . 
     
     
         3 . A process according to  claim 1  wherein the chiral ligand has the structural formula IV: 
       
         
           
           
               
               
           
         
       
     
     
         4 . A process according to  claim 1  wherein the chiral ligand has the structural formula V: 
       
         
           
           
               
               
           
         
       
     
     
         5 . A process according to  claim 1  wherein the nucleophile is potassium-phtalimide or wherein the nucleophile has the formula R1R2NH, wherein R1 is selected from the group consisting of a benzyl group, an n-butyl group, and a cyclohexyl group; R2 is selected from the group consisting of a benzyl group and hydrogen. 
     
     
         6 . A process according to  claim 1  further comprising reducing the double bond of the α,β-unsaturated carboxylic acid derivatives having the formulas II and III to yield the corresponding γ-amino-acid derivatives. 
     
     
         7 . A process according to  claim 1  further comprising separating the β-unsaturated carboxylic acid derivatives having the formulas II and III. 
     
     
         8 . A process for palladium-catalyzed enantioselective allylic amination of α,β-unsaturated carboxylic acid derivatives, said process comprising reacting a racemic mixture of a carboxylic acid derivative having the formula VI 
       
         
           
           
               
               
           
         
       
       with a chiral ligand and a palladium catalyst in the presence of a nucleophile, to yield enantiometrically enriched α,β-unsaturated carboxylic acid derivatives having the formulas VII and VIII: 
       
         
           
           
               
               
           
         
       
       wherein in formulas VI, and VII, R2 is an alkyl group and in formula VIII, R1 is a benzyl group or PMP. 
     
     
         9 . A process according to  claim 8  wherein said palladium catalyst is [Pd(allyl)Cl] 2 . 
     
     
         10 . A process according to  claim 8  wherein the chiral ligand has the structural formula IV: 
       
         
           
           
               
               
           
         
       
     
     
         11 . A process according to  claim 8  wherein the chiral ligand has the structural formula V: 
       
         
           
           
               
               
           
         
       
     
     
         12 . A process according to  claim 8  wherein the nucleophile is potassium-phtalimide or wherein the nucleophile has the formula R1R2NH, wherein R1 is selected from the group consisting of a benzyl group, an n-butyl group, and a cyclohexyl group; wherein R2 is selected from the group consisting of a benzyl group or hydrogen. 
     
     
         13 . A process according to  claim 8  wherein R2 is ethyl or methyl. 
     
     
         14 . A process according to  claim 8  further comprising reducing the double bond of the α,β-unsaturated carboxylic acid derivatives having the formula VII and VIII to yield the corresponding γ-amino-acid derivatives. 
     
     
         15 . A process according to  claim 8  further comprising separating the β-unsaturated carboxylic acid derivatives having the formula VII and VIII. 
     
     
         16 . A composition comprising an enantiometrically enriched α,β-unsaturated carboxylic acid derivative, said α,β-unsaturated carboxylic acid derivative having the structural formulas II, III, VII or VIII: 
       
         
           
           
               
               
           
         
       
       wherein in formulas II and III, R1 is selected from the group consisting of a benzyl group, an n-butyl group, and a cyclohexyl group; R2 is selected from a benzyl group and hydrogen; XR3 is selected from the group consisting of an ethoxy group, an amide, and a tert-butoxy group, or in formula II, NR1R2 is a phtalimidyl-substituent; in formula VII, R2 is an alkyl group and in formula VIII, R1 is a benzyl group or PMP. 
     
     
         17 . A γ-amino-acid derivative corresponding to an enriched α,β-unsaturated carboxylic acid derivative of  claim 16 . 
     
     
         18 . A process according to  claim 1  further comprising reducing the double bond of the α,β-unsaturated carboxylic acid derivatives having the formulas II and III to yield the corresponding γ-amino-acid derivatives. 
     
     
         19 . A process according to  claim 1  wherein said palladium catalyst is [Pd(allyl)Cl] 2 .