Ternary catalytic α-deuteration of carboxylic acids

Efficient and practical construction of deuterated molecules has been a long-standing challenge. Although α-deutero carboxylic acids are ubiquitous structural components that serve as a wide array of synthons, and are thus in high demand, α-selective and mild methods for the deuteration of carboxylic acids have remained unexplored. Here we report the development of a ternary catalytic system for the α-deuteration of carboxylic acids in high yields with excellent levels of α-deuteration. The method shows wide functional group tolerance, including the late-stage deuteration of complex molecules, pharmaceuticals and natural products. Mechanistic studies and pKa calculations indicate that the reaction proceeds through the enolization of an acyl pyridinium species. The process was applied to the synthesis of a deuterated EP3 receptor antagonist, with the deutero analogue showing increased metabolic stability in human microsomes compared with the proto compound.