Studies on amino acids and peptides. Part 6. Methods for introducing thioamide bonds into the peptide backbone: synthesis of the four monothio analogues of leucine enkephalin

Abstract

A methodology for preparing peptide analogues in which a thioamide bond replaces the normal amide bond is described. Thus, the synthesis of the three leucine enkephalin analogues [Phet⁴]-, [Glyt²]-, and [Tyrt¹]-leucine enkephalin and the attempted synthesis of [Glyt³]-leucine enkephalin is reported. The replacement of an amide group in position 4 is most conveniently achieved by thionation of Boc–Phe–Leu–OBzl using Lawesson's Reagent (LR), followed by deprotection of the Boc-group and segment coupling with Boc–Tyr(Bzl)–Gly–Gly–OH. Final deprotection is accomplished by using liquid HF–anisole. Single thioamino acid residues are introduced in positions 1, 2, and 3, respectively, by using protected amino acid dithio esters, which are prepared in high yields in a four-step reaction sequence starting from the N-protected amino acids.