Syntheses of deuterium-labeled dihydroartemisinic acid (DHAA) isotopologues and mechanistic studies focused on elucidating the conversion of DHAA to artemisinin

Abstract

Dihydroartemisinic acid (DHAA), a sesquiterpenoid natural product from Artemisia annua, converts to artemisinin, an anti-malarial natural product that contains an endoperoxide bridge. The endoperoxide moiety is responsible for the biological activity of artemisinin. Therefore, understanding the biosynthesis of this functional group could lead to the optimization of the process to produce this medicine. DHAA converts to artemisinin through the incorporation of two molecules of oxygen in a four-step process. The reaction is a spontaneous cascade process that involves (i) the initial incorporation of a molecule of oxygen through the reaction of an allylic C–H bond of DHAA, (ii) followed by the cleavage of a C–C bond, (iii) the incorporation of a second molecule of oxygen, and (iv) polycyclization to yield artemisinin. This manuscript is focused on describing the chemical syntheses of regioselectively polydeuterated DHAA isotopologues at C3 and C15, in addition to research efforts related to clarifying how the endoperoxide-forming process of artemisinin occurs.