Synthesis of substituted thiazoline carboxylic acids

A method of preparing an alkylated thiazoline carboxylic acid or a derivative thereof represented by Structural Formula (I):

• or a salt thereof,
• wherein R1 is a substituted or unsubstituted alkyl group;
• each R2 is, independently, —H or a substituted or unsubstituted alkyl group;
• R3 is —H, a substituted or unsubstituted alkyl group or a carboxylprotecting group;
• and
• n is an integer from 1 to 5,
• the method comprising:
• (a) coupling a compound represented by Structural Formula (II):
• wherein each R4 is, independently, a substituted or unsubstituted alkyl group
• and n is an integer from 1 to 5,
• with a cysteine ester represented by Structural Formula (III):
• wherein A is an anion and R5 is a substituted or unsubstituted alkyl group,
• thereby forming a substituted thiazoline carboxylic acid ester represented by Structural Formula (IV):
• (b) optionally, hydrolyzing the substituted thiazoline carboxylic acid ester to form a substituted thiazoline carboxylic acid represented by Structural Formula (V):
• (c) optionally, protecting the carboxyl group of the substituted thiazoline carboxylic acid to form a protected thiazoline carboxylic acid represented by Structural Formula (VI):
• wherein R6 is a carboxylprotecting group;
• (d) alkylating the optionally protected thiazoline carboxylic acid represented by Structural Formula (VII):
• wherein R4 and n are as defined above and R7 is —H, R5 or R6, with a compound having the formula R1-L, wherein R1 is defined as above and L is a leaving group, in the presence of a chiral phase transfer catalyst to produce an enantiomeric excess of either the (R)- or (S)-isomer of an alkylated optionally protected thiazoline carboxylic acid represented by Structural Formula (VIII):
• (e) optionally, hydrolyzing the optionally protected alkylated thiazoline carboxylic acid and cleaving ether groups,
• thereby forming the compound represented by Structural Formula (I).