Total Synthesis of Gelsemoxonine through a Spirocyclopropane Isoxazolidine Ring Contraction

Abstract

Plants of the species Gelsemium have found application in traditional Asian medicine for over a thousand years. Gelsemoxonine represents a novel constituent of this plant incorporating a highly functionalized azetidine at its core. We herein report a full account of our studies directed toward the total synthesis of gelsemoxonine that relies on a conceptually new approach for the construction of the central azacyclobutane. A spirocyclopropane isoxazolidine ring contraction was employed to access a key β-lactam intermediate, which could be further elaborated to the azetidine of the natural product. In the course of our studies, we have gained detailed insight into this intriguing transformation. Furthermore, we report on previously unnoticed oligomerization chemistry of gelsemoxonine. We also document an enantioselective synthesis of a key precursor en route to gelsemoxonine.