title: Total synthesis and complete structural assignment of yaku'amide A.
abstract: Here we report the first total synthesis and the complete stereochemical assignment of yaku'amide A. Yaku'amide A (1) was isolated from a sponge Ceratopsion sp. as an extremely potent cytotoxin. Its structure was determined except for the C4-stereochemistry in the N-terminal acyl group (NTA). This tridecapeptide consists of 2 proteinogenic and 11 nonproteinogenic amino acid residues and is capped with NTA and a C-terminal amine (CTA). α,β-Dehydrovaline, E- and Z-α,β-dehydroisoleucines are the most unusual nonproteinogenic residues of 1 and necessitated development of new methodologies for their assembly. Consequently, Cu-mediated cross-coupling reactions were efficiently employed for E/Z-selective syntheses of the three dipeptides with the dehydroisoleucines and for construction of the tetrapeptide with the dehydrovaline. The peptide was then elongated from the tetrapeptide in a stepwise fashion to deliver the two possible C4-epimers of 1. Extensive NMR studies revealed that the natural 1 possessed the C4S-stereochemistry, and biological assays using P388 mouse leukemia cells demonstrated that both C4-epimers possessed comparable toxicities. The present synthetic methodologies for construction of the highly unsaturated peptide sequence of 1 will allow studies of the relationships between the conformational properties of dehydro amino acid residues and cytotoxicity.
authors.affiliation: Graduate School of Pharmaceutical Sciences, The University of Tokyo, Hongo, Bunkyo-ku, Tokyo 113-0033, Japan.
authors.forename: Takefumi
authors.initials: T
authors.lastname: Kuranaga
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Sesoko
authors.forename: Komei
authors.initials: K
authors.lastname: Sakata
authors.forename: Naoya
authors.initials: N
authors.lastname: Maeda
authors.forename: Atsushi
authors.initials: A
authors.lastname: Hayata
authors.forename: Masayuki
authors.initials: M
authors.lastname: Inoue
mesh_terms: D015394:Molecular Structure; D009842:Oligopeptides / Q000138:chemical synthesis* / Q000737:chemistry*
chemical_list: D009842:Oligopeptides; C556702:yaku'amide A