Total Synthesis of JBIR-141 and Its Analogues: Potent Inhibitors of Forkhead Box O3 (FOXO3).

The total synthesis of JBIR-141 and its analogues was achieved through a convergent assembly of three fragments. This synthesis successfully addressed several challenges arising from a highly acid-sensitive oxazoline, a reactive nitrosohydroxyamino group, and an epimerization-prone tetramic acid. The developed synthetic route enabled access to 25-methyl/17-methyl derivatives as potent/stabilized FOXO3 inhibitors. This study provides a robust platform for structure-activity relationship studies and future target identification in chronic myelogenous leukemia therapeutics.