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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 againstPlasmodium falciparumandTrypanosoma 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 areL‐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 ofL‐threonine andL‐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. 

Balgacyclamide A−C are a family of cyanobactin natural products isolated from freshwater cyanobacteriaMicrocystis aeruginosa. These macrocyclic peptides are characterized by their oxazoline‐thiazole core, their 7 or 8 stereocenters, and their antiparasitic activities. Balgacyclamide B is known for its activity towardsPlasmodium falciparumchloroquine‐resistant strain K1,Trypanosoma brucei rhodesiense, andLeishmania donovani. In this report, the first total synthesis of Balgacyclamide B is described in a 17‐steps pathway and a 2 % overall yield. The synthetic pathway toward balgacyclamide B can be adapted for the future syntheses of balgacyclamide A and C. In addition, a brief history background of oxazolines syntheses is shown to emphasize the importance of the cyclization conditions used to interconvert or retain configuration of β‐hydroxy amides via dehydrative cyclization.