Method of Synthesizing Acetonide-Protected Catechol-Containing Compounds and Intermediates Produced Therein

Abstract

The inventors disclose here a novel, facile approach to the synthesis of acetonide-protected catechol-containing compounds having at least one amine group. In specific embodiments, the invention provides novel methods of synthesizing 3,4-dihydroxyphenylalanine (H-DOPA(acetonide)-OH (6)), Fmoc-protected H-DOPA(acetonide)-OH (Fmoc-DOPA(acetonide)-OH (7)), Fmoc-protected dopamine (Fmoc-dopamine(acetonide) (10)), TFA-protected dopamine (TFA-dopamine(acetonide) (13)) and acetonide-protected 4-(2-aminoethyl)benzene-1,2-diol (acetonide-protected dopamine (14)).

1 . An optically pure preparation of acetonide-protected 3,4-dihydroxyphenylalanine (H-DOPA(acetonide)-OH) having the structure 
       
         
           
           
               
               
           
         
       
       prepared by a method of providing optically pure acetonide-protected 3,4-dihydroxyphenylalanine (H-DOPA(acetonide)-OH), the method comprising:
 a. protecting the amine group of L-DOPA with a phthaloyl group to yield Phth-DOPA-OH, the Phth-DOPA-OH comprising a carboxyl group; 
 b. protecting the carboxyl group of Phth-DOPA-OH with a methyl ester to yield Phth-DOPA-OMe; 
 c. converting Phth-DOPA-OMe via acetonide cyclization to yield Phth-DOPA(acetonide)-OMe; and 
 d. deprotecting Phth-DOPA(acetonide)-OMe to yield optically pure H-DOPA(acetonide)-OH. 
 
     
     
         2 . An optically pure preparation of Fmoc-protected H-DOPA(acetonide)-OH having the structure: 
       
         
           
           
               
               
           
         
       
       prepared according to a method of providing optically pure Fmoc-protected 3,4-dihydroxyphenylalanine (Fmoc-DOPA(acetonide)-OH), the method comprising:
 a. protecting the amine group of L-DOPA with a phthaloyl group to yield Phth-DOPA-OH, the Phth-DOPA-OH comprising a carboxyl group; 
 b. protecting the carboxyl group of Phth-DOPA-OH with a methyl ester to yield Phth-DOPA-OMe; 
 c. converting Phth-DOPA-OMe via acetonide cyclization to yield Phth-DOPA(acetonide)-OMe; 
 d. deprotecting Phth-DOPA(acetonide)-OMe to yield H-DOPA(acetonide)-OH; and 
 e. reacting H-DOPA(acetonide)-OH with Fmoc-OSu to yield optically pure Fmoc-DOPA(acetonide)-OH. 
 
     
     
         3 . An intermediate useful in the synthesis of H-DOPA(acetonide)-OH having the structure: 
       
         
           
           
               
               
           
         
       
     
     
         4 . A preparation of acetonide-protected dopamine prepared according to a method of providing acetonide-protected 4-(2-aminoethyl)benzene-1,2-diol (dopamine), the method comprising:
 a. preprotecting the amino group of dopamine with a protecting group selected from the group consisting of a phthalimide, a carbamate and an amide to yield a protected dopamine product;   b. converting the protected dopamine product of step (a) via acetonide cyclization to yield an acetonide-protected product;   c. deprotecting the amine group of the acetonide-protected product of step (b) to yield acetonide-protected dopamine.   
     
     
         5 . An intermediate useful in the synthesis of acetonide-protected dopamine(acetonide) having the structure selected from the group consisting of: 
       
         
           
           
               
               
           
         
       
     
     
         6 . A method of providing an acetonide-protected catechol-containing molecule bearing at least one amine group, the method comprising:
 a. preprotecting the amine group of the catechol-containing molecule bearing the amine group with a protecting group to yield a protected catechol-containing molecule;   b. converting the protected catechol-containing molecule of step (a) via acetonide cyclization to yield an acetonide-protected molecule, wherein the acetonide cyclization is carried out in the presence of paratoluene sulfonic acid under polar aprotic conditions;   c. deprotecting the amine group of the acetonide-protected molecule of step (b) to yield an acetonide-protected catechol-containing molecule bearing at least one amine group.