Chemical peptide macrolactonization via intramolecular S‐to‐S‐to‐O acyl transfer

Abstract

Cyclic depsipeptides (CDPs) are a family of macrocyclic peptides containing an ester bond(s), generally found as secondary metabolites with bioactivities. Despite the interest of CDPs in drug development, de novo discovery of bioactive CDPs from artificial libraries had been yet challenging due to the lack of their efficient chemical preparation. Our recent report involving ribosomal synthesis of CDPs by means of genetic code reprogramming and S‐to‐O acyl shift chemistry has provided a unique approach for the preparation of CDP libraries and significant potentials that enable for screening of target‐binding species using an in vitro display system. However, even if the selection of binding‐active CDPs were successfully executed, it is unavoidable to chemically prepare a sufficient amount of CDPs for downstream bioassays. Prior to the selection, therefore, it is crucial for us to establish a synthetic methodology of various CDPs using standard solid‐phase chemical synthesis and the S‐to‐O acyl shift as the same key chemistry. Here we report a method of chemical macrolactonization via the S‐to‐S‐to‐O acyl shift, affording CDPs in high yields (~91%). This work links the ribosomal synthesis of CDPs to the chemical synthesis of their active species available from campaigns of the affinity‐based selection, enabling downstream bioassays.