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

Solid-phase total synthesis of atratumycin (1) 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 1 led to the identification of the amino acid residue that preserves its antituberculosis activity. Conformational analyses of 1 and its analogues revealed that the solution structure of 1 closely resembles the crystal structure of 1, suggesting the structural rigidity of its unique conformation.