Solid-Phase Synthesis of Oxathiocoraline by a Key Intermolecular Disulfide Dimer

Abstract

Oxathiocoraline, a member of the quinoxaline antibiotic family, has been synthesized on solid-phase. The depsipeptide exhibits high synthetic complexity owing to the presence of consecutive NMe amino acids, two ester moieties, a disulfide bridge, and two SMe Cys residues. Because of internal diketopiperazine formation, standard stepwise or convergent approaches failed to deliver the linear octadepsipeptide precursor. Therefore, an alternative methodology where an intermolecular disulfide dimer is formed on solid-phase was developed. Cleavage of the dimer from the solid-phase and subsequent bismacrolactamization followed by incorporation of the heterocyclic unit afforded the target compound. Oxathiocoraline showed antitumoral activity in three tumor cell lines.