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,ß-Dehydrovaline, E- and Z-α,ß-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.