Electrochemical deuteration of allylic esters with divergent site-selectivity

Abstract

Deuterium-labelling technology has emerged as a promising new direction for drug discovery. Developing a divergent protocol to incorporate deuterium into different sites of bioactive molecules is highly desirable, as it opens up diverse access for leading compounds. Herein, we developed a site-selective divergent protocol for the deuteration of allylic esters via an electrochemical reduction approach. In the transformation, the reaction solvents and cathodes jointly dictated the reaction mechanism and active intermediates, and led to D₃-incorporation and mono-deuteration products. The synthetic utility of the electrochemical protocol is highlighted in the synthesis of D-labelled ACP synthase inhibitors. Further mechanistic studies involving linear sweep voltammetry (LSV) and gas chromatography (GC) confirmed that the observed selectivity originates from distinct reaction pathways.