Total Synthesis and Structural Revision of Keenamide A

Stereochemical assignments of thiazoline-containing cyanobactins, a family of ribosomally synthesized and post-translationally modified peptides, are often complicated due to the propensity of the exomethine and C-4 chiral centers of thiazolines to epimerize under basic and acidic conditions. In this work, we re-evaluate the proposed configuration of the leucine-thiazoline moiety of the cyanobactin-like cyclopeptide keenamide A. Using a fast and adaptable strategy for the synthesis of thiazoline-containing cyclopeptides, we synthesized four possible keenamide A stereoisomers, one of which was oxidized to mollamide C, the thiazole analogue of keenamide A. Comparison of the NMR spectra of synthetic keenamide A stereoisomers with that of natural keenamide A combined with X-ray crystallographic analysis indicates that the originally proposed (R)-configuration of the thiazoline ring of keenamide A must be revised to (S)-configuration. This work highlights the power of synthetic methods to inform the structure elucidation and structural revision of natural products, especially in cases where isolation and purification of natural material are not readily achieved.