Preparation of ß,ß-Dialkyl Analogues of Cysteine Suitable for Peptide Synthesis

A general method is described for the preparation of cysteine derivatives that are substituted with one or two alkyl groups at the 0-carbon. The synthesis is based on the sulfenylation of N^α-formyl-α,ß-dehydro amino acid esters. The protected dehydro esters were synthesized by the condensation of ethyl isocyanoacetate with a ketone. The sulfenylation of these compounds was accomplished by refluxing with phosphorus pentasulfide to form the intermediate thiazoline, which can be hydrolyzed to the hydrochloride salt of the free sulfhydryl amino acid by heating in acid. The free sulfhydryl amino acid salt was protected as the S-p-methylbenzyl thioether, isolated as the zwitterion. The S-protected amino acids were then protected as the N^α-tert-butyloxycarbonyl derivatives and are suitable for use in solution- or solid-phase peptide synthesis.