Azathiocoraline synthesis has been developed and optimized by using the solid-phase approach. This convenient solid-phase methodology, which involves more steps on solid-phase, has been successfully applied for generating Azathiocoraline analogues. The solid-phase approach consolidates a rapid and efficient way to explore synthetic strategies for new bioactive, highly non-proteinogenic complex depsipeptides and is an essential tool to shorten the development time required for new therapeutic compounds.