Ca2+-mediated thiolysis of peptide–resin linkage as an option for preparing protected peptide thioesters

A mild new procedure for preparing protected peptide thioesters, based on Ca2+-assisted thiolysis of peptide–Kaiser oxime resin (KOR) linkage, is described. Ac-Ile-Ser(Bzl)-Asp(OcHx)-SR (Ac: acetyl; Bzl: benzyl; cHx: cyclohexyl), model peptide, was readily released from the resin by incubating the peptide–KOR at 60 °C in mixtures of DMF with n-butanethiol [R = (CH2)3CH3] or ethyl 3-mercaptopropionate [R = (CH2)2COOCH2CH3] containing Ca(CH3COO)2. After serine and aspartic acid side-chain deprotection under acid conditions, Ac-Ile-Ser-Asp-S(CH2)2COOCH2CH3 was successfully obtained with good quality and high yield. This type of C-terminal modified peptide may act as an excellent acyl donor in peptide segment condensation by the thioester method, native chemical ligation and enzymatic methods.