Imine Reductase-Catalyzed Synthesis of a Key Intermediate of Avacopan: Enzymatic Oxidative Kinetic Resolution with <i>Ex Situ</i> Recovery and Dynamic Kinetic Reduction Strategies toward 2,3-Disubstituted Piperidine

Imine reductase (IRED) enzymes catalyze the asymmetric reduction of cyclic imines and have recently gained attention due to their reductive aminase (RedAm) activity. Herein, we demonstrated their ability to control the two vicinal stereogenic centers in an N-heterocyclic system. By reversing their usual mode of action, the oxidative kinetic resolution (KR) of the rac-cis-1 piperidine intermediate of avacopan was used to leave the (2R,3S)-1 desired enantiomer untouched, whereas the undesired enantiomer was oxidized and tautomerized to enamine 4. The synthesis was improved by using alcohol dehydrogenase (ADH) for cofactor regeneration, and 4 was recycled by catalytic hydrogenation to rac-cis-1. Hence, KR was carried out on a 1 kg scale with 99.5% ee and 37.2 g/L/d space-time yield (STY). One cycle of recycling of 4 enamine was confirmed at the kg scale in 83.7% yield, which resulted after the bioconversion of (2R,3S)-1 with a total yield of 57.8% (theoretical maximum KR of 50%). Repetitive sequences of KR with ex situ recycling of 4 afforded an overall theoretical yield of 72%. Moreover, an enantiocomplementary enzyme was utilized for the dynamic kinetic reduction of 4 to (2R,3S)-1 with excellent diastereoselectivity.