Isolation, Total Synthesis and the Structure Determination of the Antifungal Macrocyclic Depsipeptide, Tetraselide

Abstract

Macrocyclic peptides and depsipeptides are the emerging class of a new modality in drug discovery research. Tetraselide, an antifungal cyclic peptide isolated from a marine-derived filamentous fungus, possesses the unique amphiphilic structural feature that represents the five consecutive β-hydroxy-amino acid and fatty acid moieties. Because the structure elucidation of the naturally occurring product left six stereocenters ambiguous, we implemented bioinformatic analyses, chemical degradation study and chiral pool fragment synthesis to identify two of the undetermined stereochemistry. Convergent total synthesis of four remaining plausible isomers of tetraselide was accomplished via liquid-phase peptide synthesis using the soluble hydrophobic tag auxiliaries. The key advance involves fragment coupling by the serine/threonine ligation reaction and head-to-tail macrolactamization of the carrier-supported precursors that enabled systematic elaboration of the amphiphilic cyclic peptides. Ultimately, we determined the absolute structure of this natural product.