Oxathiocoraline: Lessons to be Learned from the Synthesis of ComplexN‐Methylated Depsipeptides

Abstract

AbstractInvestigations into the synthesis of oxathiocoraline, a bicyclic depsipeptide withC2symmetry, revealed a number of unexpected side‐reactions that could not be circumvented by classical or standard means. This cyclodepsipeptide has a large number ofN‐methyl amino acids coexisting with two ester bonds and also shows a branched structure; these features hinder its synthesis. In addition, complexity is further increased because of the presence of a large number of non‐commercially available cysteines and heterocyclic moieties. Here we describe the general points that should be addressed when attempting the synthesis of a cyclodepsipeptide, such as strategies to prevent or minimize diketopiperazine formation, β‐elimination, and oxidation byproducts. The optimum design includes a suitable solid support, the choice of the best starting point for the synthesis (first amino acid to anchor to the resin) and a set of compatible and/or protecting groups and coupling reagents.(© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2009)