Solid-Phase Total Synthesis of Daptomycin and Analogs

An entirely solid-phase synthesis of daptomycin, a cyclic lipodepsipeptide antibiotic currently in clinical use, was achieved using a combination of a-azido and Fmoc amino acids. This methodology was applied to the synthesis of several daptomycin analogs, one of which did not contain kynurenine or the synthetically challenging amino acid (2S,3R)-methylglutamate yet exhibited an MIC approaching that of daptomycin.