The synthesis of a polypeptide derived from the cancer testis antigen NY-ESO-1 bearing a C-terminal α-thiolester is described. Employing tert-butyloxycarbonyl solid phase peptide synthesis the thiolester moiety was installed on-resin using a mercaptopropionic acid linker, thereby requiring no post synthetic manipulations and delivering the requisite α-thiolester polypeptide after cleavage from the resin with HF. Several 9-fluorenylmethyloxycarbonyl solid phase peptide synthesis approaches whereby the thiolester was required to be introduced in a post synthesis manner were examined concurrently. These comprised syntheses on two different “safety catch” linkers, an N-alkyl-N-acyl sulphonamide and an N-acyl benzimidazolone wherein the thiolester is generated from an activated precursor. The condensation of a mercaptan with the C-terminal carboxylate in a direct thiolesterification reaction was also examined. When using either of the three 9-fluorenylmethyloxycarbonyl-based approaches, the linear polypeptide could be assembled straightforwardly on the solid phase resin; however, a thiolesterification of the C-terminal carboxyl of the fully side chain protected peptide proved to be the most effective post-assembly method for the installation of the C-terminal thiolester. © 2013 Wiley Periodicals, Inc. Biopolymers (Pept Sci) 100: 356–365, 2013.
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