Synthesis of 2-alkyl amino acids

Abstract

A method of preparing a 2-alkyl amino acid involves the aziridination of an alkylacrylate and the opening of the aziridine ring by addition of a side chain. This method can result in the preparation of enantiomeric excess of a 2-alkyl amino acid. The invention also discloses a method of preparing a class of iron chelating agents related to desferrithiocin, all of which contain a thiazoline ring. In this method, an aryl nitrile or imidate is condensed with cysteine, a 2-alkyl cysteine, or a cysteine ester.

1 - 17 . (canceled)  
   
   
       18 . A method of preparing a compound represented by Structural Formula (VI):  
     
       
         
         
             
             
         
       
       or a salt thereof;  
       wherein:  
       R 6  and R 7  are, independently, —H or a substituted or unsubstituted alkyl group; comprising the steps of: 
 a.) aziridinating a compound represented by Structural Formula (VII):  
                     
  by reacting said compound with a source of nitrogen and an aziridination catalyst, thereby forming a compound represented by Structural Formula (VIII):  
                     wherein:    L is a bond, sulfoxide (—S(O)—), or sulfone (—S(O)(O)—);    R 9  is a substituted or unsubstituted alkyl group or a substituted or unsubstituted aryl group; and    R 6  and R 7  are as defined above;    
 b.) reacting the compound represented by Structural Formula (VIII) with a nucleophile, A-S-Z, wherein A is —H; and Z is —H or a protecting group; thereby forming a compound represented by Structural Formula (IX):  
                     
 c.) cleaving Z and L-R 9  from the compound represented by Structural Formula (IX), thereby forming the compound represented by Structural Formula (VI).  
 
     
   
   
       19 . The method of  claim 18 , wherein the source of nitrogen is represented by Structural Formula (X):  
     
       
         
         
             
             
         
       
     
     wherein M is an alkali metal, X is a halide, and R 10  is a substituted or unsubstituted alkyl group or a substituted or unsubstituted aryl group.  
   
   
       20 . The method of  claim 19 , wherein M is sodium and X is chloride or bromide.  
   
   
       21 . The method of  claim 20 , wherein the aziridination catalyst is a copper halide.  
   
   
       22 . The method of  claim 21 , wherein the nucleophile is CH 3 COSH or C 6 H 5 C(O)SH.  
   
   
       23 . The method of  claim 22 , further comprising the step of resolving enantiomers of the product of step (c.).  
   
   
       24 . The method of  claim 23 , wherein a (S)-2-amino acid is isolated from the enantiomers.  
   
   
       25 . The method of  claim 23 , wherein R 6  and R 7  are each methyl.  
   
   
       26 . A method of preparing a compound represented by Structural Formula (XI):  
     
       
         
         
             
             
         
       
       or a salt thereof;  
       wherein:  
       R 11  and R 12  are, independently, —H or a substituted or unsubstituted alkyl group;  
       R 13  is —H, —(CH 2 ) n SH, —(CH 2 ) n OH, —(CH 2 ) n NH 2 , —COOH, —CONH 2 , a substituted or unsubstituted alkyl group, a substituted or unsubstituted aromatic group, or a substituted or unsubstituted heteroaromatic group; and  
       x is an integer from 0-12;  
       comprising the steps of: 
 a.) aziridinating a compound represented by Structural Formula (XII):  
                     
  by reacting said compound with a source of nitrogen and a stereospecific aziridination catalyst, thereby forming a compound represented by Structural Formula (XIII):  
                     wherein:    L is a bond, sulfoxide (—S(O)—), or sulfone (—S(O)(O)—);    R 14  is a substituted or unsubstituted alkyl group or a substituted or unsubstituted aryl group; and    R 11  and R 12  are as defined above;    
 b.) reacting the compound represented by Structural Formula (XIII) with a nucleophile, A-R 13 , wherein A is —H, —Li, —MgCl, —MgBr, or —MgI, provided that A and R 13  are not each —H; and R 13  is as defined above; thereby forming a compound represented by Structural Formula (XIV):  
                     
 c.) cleaving L-R 14  and optionally the protecting group of R 13  from the compound represented by Structural Formula (XIV), thereby forming the compound represented by Structural Formula (XI).  
 
     
   
   
       27 . The method of  claim 26 , wherein the stereospecific aziridination catalyst is a copper 4,4′-disubstituted bis(oxazoline).  
   
   
       28 . The method of  claim 26 , wherein the stereospecific azridination catalyst is a copper-exchanged zeolite.  
   
   
       29 . The method of  claim 26 , wherein R 11  and R 12  are each methyl.  
   
   
       30 . The method of  claim 29 , wherein the source of nitrogen is represented by Structural Formula (XV):  
     
       
         
         
             
             
         
       
     
     wherein M is an alkali metal, X is a halide, and R 15  is a substituted or unsubstituted alkyl group or a substituted or unsubstituted aryl group.  
   
   
       31 . The method of  claim 30 , wherein M is sodium and X is chloride or bromide.  
   
   
       32 . The method of  claim 31 , wherein R 13  is —SH.  
   
   
       33 . The method of  claim 32 , wherein the nucleophile is CH 3 COSH or C 6 H 5 C(O)SH.  
   
   
       34 . A method of preparing a compound represented by Structural Formula (XVI):  
     
       
         
         
             
             
         
       
     
     comprising the steps of: 
 a) reacting the compound represented by Structural Formula (XVIII):  
                     
 wherein: 
 L is a bond, sulfoxide (—S(O)—), or sulfone (—S(O)(O)—); and  
 R 17  is a substituted or unsubstituted alkyl group or a substituted or unsubstituted aryl group;  
 
 with a nucleophile, A-S-Z, wherein A is —H; and Z is —H or a protecting group; thereby forming a compound represented by Structural Formula (XIX):  
                     
 b) cleaving R 16 , Z, and L-R 17  from the compound represented by Structural Formula (XIX), thereby forming 2-methylcysteine or a salt thereof;  
 c) resolving the enantiomers of 2-methylcysteine or salts thereof;  
 d) isolating (S)-2-methylcysteine or a salt thereof, and neutralizing the salt, if present; and  
 e) coupling (S)-2-methylcysteine with 2,4-dihydroxybenzonitrile, thereby forming the compound represented by Structural Formula (XVI)  
 
   
   
       35 . The method of  claim 34 , wherein the aziridine represented by Structural Formula (XVIII) is prepared by aziridinating a compound represented by Structural Formula (XVII):  
     
       
         
         
             
             
         
       
     
     by reacting said compound with a source of nitrogen and an aziridination catalyst, thereby forming a compound represented by Structural Formula (XVIII):