Total synthesis of chaiyaphumines A-D: A case study comparing macrolactonization and macrolactamization approaches

Abstract

A comparison of macrolactonization and macrolactamization approaches to the synthesis of the pentadepsipeptide chaiyaphumines is outlined. Fmoc-based solid-phase synthesis approaches were used for the synthesis of the requisite precursors. Attempted solution-phase macrolactonization of a seco-acid precursor using Yamaguchi, pivaloyl chloride, or MNBA activation did not give cyclized products. The use of an MNBA / lanthanide(III) triflate mediated macrolactonization protocol led to an isomeric macrocycle. However, the use of a solution-phase macrolactamization approach using EDC·HCl / HOBt was achieved without detectable epimerization. This strategy was successfully applied to the total synthesis of the antimalarial compound chaiyaphumine A, as well as the natural products chaiyaphumine B, C, and D, by using a late-stage acylation of the threonine amino group. An X-ray crystal structure analysis of synthetic chaiyaphumine D reveals the presence of a type II’ beta turn and a type IV4 beta turn motif embedded in the 16-membered depsipeptide ring. This study illustrates potential challenge associated with macrolactonization approaches to depsipeptides compared to macrolactamization.