Imine Reductase-Catalyzed, Radical-Mediated Asymmetric Cyano Group Migration

Functional group migration (FGM) reactions represent a fundamental class of transformations in organic chemistry, enabling the repositioning of functional moieties in non-obvious ways. However, catalytic asymmetric radical-mediated FGMs re-main rare, due to the inherent challenges of achieving catalyst-controlled enantioselectivity over free radical intermediates. Herein, we repurpose imine reductases (IREDs), a class of biotechnologically important enzymes known for their substrate promiscuity, to enable the first examples of catalytic asymmetric cyano group migration via a radical mechanism. An orthog-onal set of radical enzymes, including PbaIREDCym and SmiIREDCym, were engineered, allowing both 1,4- and 1,5-cyano group migrations reactions to occur in an enantiodivergent fashion. The use of nonionic surfactant TPGS-1000 was found to improve both the yield and enantioselectivity of these cyano migration reactions. This biocatalytic process exhibited a broad substrate scope and is readily scalable, affording a rare example of chiral non-amine product assembly with imine reductases. More broadly, stereoselective radical biocatalysis with engineered IREDs and other versatile enzymes provide a potentially general solution to challenging asymmetric FGM reactions.