Thioesters of amino acid derivatives as thioacylating agents in thiopeptide synthesis

Abstract

Thioesters, mainly of N-substituted glycine, have been synthesized and examined for their ability to thioacylate amino acids, peptides, and esters and amides of amino acids and peptides. Methyl, ethyl, and benzyl thioesters have been obtained in high yield by thiohydrolysis of the corresponding imino esters. All were found to be excellent thioacylating agents for amino acids, though under the conditions used, they reacted much less readily with amino acid esters and amides including peptides, except where the reacting nucleophile was the amino group of Gly or the imino group of Pro. Attempts to improve the leaving properties of the alkoxy group (OR′) in O-alkyl thioesters (RCSOR′) by introduction of a 2-nitro substituent result in poorer yields of the thioester, probably because of competing elimination between the iminium group and OR′ on treatment of the imino ester with H₂S, although the nitro substituted thioesters are slightly more reactive than simple alkyl derivatives. The reaction of N-benzyloxycarbonylaminoacetonitrile with phenol gives a 30% yield of a product which failed to yield any thioester on reaction with H₂S.