Balgacyclamide A: Structural Revision of the First Reported Total Synthesis and Evaluation of Oxazoline Synthesis via β-Hydroxy Amides Dehydrative Cyclization Conditions.

Abstract

A total synthesis of balgacyclamide A was reported for the first time in 2020, however, after multiple epimerization studies of β-hydroxy amides dehydrative cyclization to access oxazolines, we proposed a configurational reassignment from the previous synthetic pathway. Balgacyclamide A is a macrocyclic hexapeptide with antiparasitic activity against Plasmodium falciparum and Trypanosoma brucei rhodesiense. Chemically, its core contains six amino acids that undergo heterocyclization to form one thiazole and two oxazoline rings. Two of the six amino acids are L-threonines that play an important role in their synthetic pathway to achieve oxazolines with the right configuration upon epimerization at the β-carbon. Thus, we investigated the effect of L-threonine and L-allothreonine β-carbon epimerization via the Burgess reagent, diethylaminosulfur trifluoride (DAST), and (NH₄)₆Mo₇O₂₄•4H₂O catalyst to support previous oxazoline synthetic studies. Furthermore, the first total synthesis of balgacyclamide A and an epimer is reported via multiple synthetic key steps that involve a tandem sulfur incorporation, cyclization, and aromatization of the thiazole, and a late-stage β-hydroxy amide Walden inversion to access both oxazolines.