biostudies-literatureNakahara HJapan Agency for Medical Research and DevelopmentMinistry of Education, Culture, Sports, Science and TechnologyJapan Society for the Promotion of Science6060-6069https://www.ebi.ac.uk/biostudies/studies/S-EPMC11892018biostudies-literatureUnknown16(14)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 <i>via</i> 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.Chemical scienceIsolation, total synthesis and structure determination of antifungal macrocyclic depsipeptide, tetraselide.PMC11892018JP24H0178924K18256JP24ama12103522K0653523K0605321K05293Tsutsumi HAzami HWatanabe YNakahara HInahashi YNoguchi YSennari GHirose TIwatsuki MSunazuka TfalseIsolation, 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 <i>via</i> 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.2025-01-01T00:00:00Z2025 Apr2026-06-02T00:02:47.949Z2025-04-04T13:11:22.392ZS-EPMC118920184007046710.1039/d5sc00566c