Synthesis of 2-alkylcysteine via phase transfer catalysis

Abstract

Non-natural amino acids such as 2-alkylated amino acids allow for the synthesis of a wider variety of peptidal and non-peptidal pharmaceutically active agents. In one embodiment, the present invention provides methods of preparing 2-alkylcysteine derivatives. In another embodiment, the method comprises forming a 2-alkylcysteine derivative from a cysteine derivative in the presence of a phase transfer catalyst. In particular, the present invention provides methods for preparing 2-methylcysteine derivatives. The present invention also discloses a method of preparing a class of iron chelating agents related to desferrithiocin, all of which contain a thiazoline ring. In one aspect, an aryl nitrile or imidate is condensed with cysteine or a 2-alkyl cysteine. The present invention also relates to the preparation of 4,5-dihydro-2-(2,4-dihydroxyphenyl)-4-alkyl-thiazole-4-carboxylic acids, such as 4,5-dihydro-2-(2,4-dihydroxyphenyl)-4-methyl-thiazole-4-carboxylic acid.

1 . A method of preparing a substituted thiazoline carboxylic acid represented by Structural Formula (VII):  
     
       
         
         
             
             
         
       
       or a salt thereof,  
       the method comprising:  
       (a) reacting, in the presence of a phase transfer catalyst, an (R)-cysteine derivative represented by Structural Formula (VIII):  
       
         
           
           
               
               
           
         
         or a salt thereof, wherein 
 R 20  is —NH 2 ; —N(R 25 )(R 26 ); —NHR 26 ; or —N═R 27 , wherein R 24 , R 25 , R 26 , and R 27  are, independently, a substituted or unsubstituted alkyl group, a substituted or unsubstituted aromatic group, or a substituted or unsubstituted heterocyclic group; and  
 R 21  and R 22  are, independently, —H, a substituted or unsubstituted alkyl group, a substituted or unsubstituted aromatic group, or a substituted or unsubstituted heterocyclic group;  
 
         with a compound having the formula CH 3 -L, wherein L is a leaving group, thereby forming a 2-methylcysteine derivative represented by Structural Formula (IX):  
         
           
             
             
                 
                 
             
           
           or a salt thereof;  
         
       
       (b) optionally, purifying the (S)-isomer of the 2-methylcysteine derivative;  
       (c) reacting the (S)-isomer of the 2-methylcysteine derivative with acid to form (S)-2-methylcysteine represented by Structural Formula (X):  
       
         
           
           
               
               
           
         
       
         
       (d) coupling the (S)-2-methylcysteine with 2,4-dihydroxybenzonitrile thereby forming the substituted thiazoline carboxylic acid represented by Structural Formula (VII).  
     
   
   
       2 . The method of  claim 1  wherein the phase transfer catalyst is a compound represented by Structural Formula (V):  
     
       
         
         
             
             
         
       
     
     wherein 
 R 9  is a substituted or unsubstituted alkyl group, a substituted or unsubstituted aromatic group, or a substituted or unsubstituted heterocyclic group;  
 R 10  and R 11  are, independently, —H, a substituted or unsubstituted alkyl group, a substituted or unsubstituted aromatic group, or a substituted or unsubstituted heterocyclic group; and  
 X is a halogen.  
 
   
   
       3 . The method of  claim 2  wherein R 9  is 9-anthracenylmethyl, represented by the Structural Formula (VI):  
     
       
         
         
             
             
         
       
     
   
   
       4 . The method of  claim 2  wherein R10 is substituted or unsubstituted allyl.  
   
   
       5 . The method of  claim 2  wherein R11 is substituted or unsubstituted ethenyl.  
   
   
       6 . The method of  claim 2  wherein X is chlorine.  
   
   
       7 . The method of  claim 1 , wherein the phase transfer catalyst is selected from the group consisting of benzyl triethyl ammonium chloride, benzyl trimethyl ammonium chloride, benzyl tributyl ammonium chloride, tetrabutyl ammonium bromide, tetraethyl ammonium bromide, tetrabutyl ammonium hydrogen sulfate, tetramethyl ammonium iodide, tetramethyl ammonium chloride, triethylbutyl ammonium bromide, tributyl ethyl ammonium bromide, tributyl methyl ammonium chloride, 2-chloroethylamine chloride HCl, bis(2-chloroethyl)amine HCl, 2-dimethylaminoethyl chloride HCl, 2-ethylaminoethyl chloride HCl, 3-dimethylaminopropyl chloride HCl, methylamine HCl, dimethylamine HCl, trimethylamine HCl, monoethylamine HCl, diethylamine HCl, triethylamine HCl, ethanolamine HCl, diethanolamine HCl, triethanolamine HCl, cyclohexylamine HCl, dicyclohexylamine HCl, cyclohexylamine HCl, diisopropylethylamine HCl, ethylenediamine HCl, aniline HCl, methyl salicylate, ethyl salicylate, butyl salicylate amyl salicylate, isoamyl salicylate, 2-ethylsalicylate, and benzyl salicylate.  
   
   
       8 . A method of preparing a 2-alkylcysteine derivative represented by Structural Formula (I):  
     
       
         
         
             
             
         
       
     
     or a salt thereof, wherein 
 R 1  is —NH 2 ; —N(R 5 )(R 6 ); —NHR 7 ; or —N═R 8 ; wherein R 5 , R 6 , R 7 , and R 8  are, independently, a substituted or unsubstituted alkyl group, a substituted or unsubstituted aromatic group, or a substituted or unsubstituted heterocyclic group;  
 R 2  and R 3  are, independently, —H, a substituted or unsubstituted alkyl group, a substituted or unsubstituted aromatic group, or a substituted or unsubstituted heterocyclic group; and  
 R 4  is a substituted or unsubstituted alkyl group;  
 the method comprising,  
 reacting, in the presence of a phase transfer catalyst, a cysteine derivative represented by Structural Formula (II):  
                     or a salt thereof, wherein R 1 , R 2  and R 3  are defined as above, with a compound having the formula R 4 -L, wherein R 4  is defined as above and L is a leaving group thereby forming the 2-alkylcysteine derivative represented by Structural Formula (I),    
 wherein the phase transfer catalyst is selected from the group consisting of benzyl triethyl ammonium chloride, benzyl trimethyl ammonium chloride, benzyl tributyl ammonium chloride, tetrabutyl ammonium bromide, tetraethyl ammonium bromide, tetrabutyl ammonium hydrogen sulfate, tetramethyl ammonium iodide, tetramethyl ammonium chloride, triethylbutyl ammonium bromide, tributyl ethyl ammonium bromide, tributyl methyl ammonium chloride, 2-chloroethylamine chloride HCl, bis(2-chloroethyl)amine HCl, 2-dimethylaminoethyl chloride HCl, 2-ethylaminoethyl chloride HCl, 3-dimethylaminopropyl chloride HCl, methylamine HCl, dimethylamine HCl, trimethylamine HCl, monoethylamine HCl, diethylamine HCl, triethylamine HCl, ethanolamine HCl, diethanolamine HCl, triethanolamine HCl, cyclohexylamine HCl, dicyclohexylamine HCl, cyclohexylamine HCl, diisopropylethylamine HCl, ethylenediamine HCl, aniline HCl, methyl salicylate, ethyl salicylate, butyl salicylate amyl salicylate, isoamyl salicylate, 2-ethylsalicylate, and benzyl salicylate.  
 
   
   
       9 . The method of  claim 8 , wherein R 1  is —N═C(Ar) 2  wherein each Ar is, independently, a substituted or unsubstituted aryl group.  
   
   
       10 . The method of  claim 9 , wherein R 1  is a benzophenone imine represented by Structural Formula (III):  
     
       
         
         
             
             
         
       
     
   
   
       11 . The method of  claim 8 , wherein R 2  is —C(Ar) 3  wherein each Ar is, independently, a substituted or unsubstituted aryl group.  
   
   
       12 . The method of  claim 11 , wherein R 2  is trityl.  
   
   
       13 . The method of  claim 8 , wherein R 3  is a substituted or unsubstituted C1 to C10 alkyl group.  
   
   
       14 . The method of  claim 13 , wherein R 3  is t-butyl.  
   
   
       15 . The method of  claim 8 , wherein the cysteine derivative is the (R) isomer, represented by Structural Formula (IV):  
     
       
         
         
             
             
         
       
     
   
   
       16 . The method of  claim 8 , wherein R 4  is a substituted or unsubstituted C1 to C4 alkyl group.  
   
   
       17 . The method of  claim 16 , wherein R 4  is methyl.  
   
   
       18 . The method of  claim 8 , wherein the cysteine derivative is protected at any acidic nitrogen, oxygen, or sulfur atoms.  
   
   
       19 . The method of  claim 8 , further comprising the step of resolving the enantiomers of the 2-alkylcysteine derivative.  
   
   
       20 . The method of  claim 19 , wherein the (S)-isomer of the 2-alkylcysteine derivative is isolated.