Total Synthesis, Antibacterial Activity, and Structural Analysis of Atratumycin and Its Analogues

Solid-phase total synthesis of atratumycin (<b>1</b>) and its analogues is described. The linear depsipeptide was synthesized by the standard Fmoc solid-phase peptide synthesis, on-resin esterification, and epimerization-free macrolactamization. A structure-activity relationship study of <b>1</b> led to the identification of the amino acid residue that preserves its antituberculosis activity. Conformational analyses of <b>1</b> and its analogues revealed that the solution structure of <b>1</b> closely resembles the crystal structure of <b>1</b>, suggesting the structural rigidity of its unique conformation.