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

Macrocyclic peptides, including depsipeptides, are an emerging new modality in drug discovery research. Tetraselide, an antifungal cyclic peptide isolated from a marine-derived filamentous fungus, possesses a unique amphiphilic structural feature consisting of five consecutive β-hydroxy-amino acid residues and fatty acid moieties. Because the structure elucidation of the naturally occurring product left six stereocenters ambiguous, we implemented bioinformatic analyses, chemical degradation studies and chiral pool fragment synthesis to identify two of the undetermined stereocenters. Convergent total synthesis of the four remaining plausible isomers of tetraselide was accomplished via liquid-phase peptide synthesis (LPPS) using soluble hydrophobic tag auxiliaries. The key advances involve fragment coupling by the serine/threonine ligation (STL) 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.