Hybrid Chemo-, Bio-, and Electrocatalysis for Atom-Efficient Deuteration of Cofactors in Heavy Water

[Image: see text] Deuterium-labeled nicotinamide cofactors such as [4-(2)H]-NADH can be used as mechanistic probes in biological redox processes and offer a route to the synthesis of selectively [(2)H] labeled chemicals via biocatalytic reductive deuteration. Atom-efficient routes to the formation and recycling of [4-(2)H]-NADH are therefore highly desirable but require careful design in order to alleviate the requirement for [(2)H]-labeled reducing agents. In this work, we explore a suite of electrode or hydrogen gas driven catalyst systems for the generation of [4-(2)H]-NADH and consider their use for driving reductive deuteration reactions. Catalysts are evaluated for their chemoselectivity, stereoselectivity, and isotopic selectivity, and it is shown that inclusion of an electronically coupled NAD(+)-reducing enzyme delivers considerable advantages over purely metal based systems, yielding exclusively [4S-(2)H]-NADH. We further demonstrate the applicability of these types of [4S-(2)H]-NADH recycling systems for driving reductive deuteration reactions, regardless of the facioselectivity of the coupled enzyme.