Bringing biocatalytic deuteration into the toolbox of asymmetric isotopic labelling techniques

Enzymes dependent on nicotinamide cofactors are important components of the expanding range of asymmetric synthetic techniques. New challenges in asymmetric catalysis are arising in the field of deuterium labelling, where compounds bearing deuterium (²H) atoms at chiral centres are becoming increasingly desirable targets for pharmaceutical and analytical chemists. However, utilisation of NADH-dependent enzymes for ²H-labelling is not straightforward, owing to difficulties in supplying a suitably isotopically-labelled cofactor ([4-²H]-NADH). Here we report on a strategy that combines a clean reductant (H₂) with a cheap source of ²H-atoms (²H₂O) to generate and recycle [4-²H]-NADH. By coupling [4-²H]-NADH-recycling to an array of C=O, C=N, and C=C bond reductases, we demonstrate asymmetric deuteration across a range of organic molecules under ambient conditions with near-perfect chemo-, stereo- and isotopic selectivity. We demonstrate the synthetic utility of the system by applying it in the isolation of the heavy drug (1S,3'R)-[2',2',3'-²H₃]-solifenacin fumarate on a preparative scale.