Keto reductases are crucial NAD(P)H-dependent enzymes used for the enantioselective synthesis of alcohols from prochiral ketones. Typically, the NADPH cofactor is regenerated through a second enzyme and/or substrate. However, photocatalytic cofactor regeneration using water as a sacrificial electron and hydrogen donor presents a promising alternative, albeit a challenging one. Herein we fabricated several nitrogen-doped carbon dots (CDs) with visible light absorption properties, good water solubility and biocompatibility for photocatalytic regeneration of NADPH. The CD with a smaller size and suitable redox potential gave the highest NADPH yield (55.7 %). Based on this, NADPH-dependent aldo-keto reductase crosslinked aggregates (AKR-CLEs) were initially applied as a stable biocatalyst to reduce the prochiral ketone. (S)-1-(2-Chlorophenyl) ethanol, an intermediate for LPA1R antagonists, was obtained in 65.3 % yield and 99.99 % enantiomeric excess (ee) under visible light irradiation. The isotope tracer experiment confirmed that water is the hydrogen donor in this light-driven, photo-enzymatic asymmetric hydrogenation system. This method is useful for the sustainable synthesis of chiral alcohols. Moreover, the general principle of utilizing water as the sacrificial hydrogen and electron donor holds potential for application in other redox cofactor regeneration systems.

Enzymatic reductions catalyzed by reductases generally depend on reduced nicotinamide cofactors as a hydride source. However, for industrial viability, it is more cost-effective to use water as the hydrogen source, bypassing the requirement for the cofactor. Here we report a hybrid photo-biocatalyst system based on infrared (IR) light and responsive reductive graphene quantum dots (rGQDs), for performing the direct transfer of hydrogen from water to prochiral substrates. The photo-biocatalyst, assembled from rGQDs and cross-linked aldo-keto reductase (AKR), mediates the synthesis of the pharmaceutical intermediate, (R)−1-[3,5-bis(trifluoromethyl)-phenyl] ethanol ((R)−3,5-BTPE), in 82% yield and >99.99% ee under IR illumination. Our photo-enzymatic systems can also be effectively used to drive the enzymatic reduction of imines and alkenes. Since the hybrid photo-biocatalysts are insoluble, they can be readily recovered and recycled. This work opens new avenues to create artificial photo-biocatalyst systems, enabling the facile coupling of renewable solar energy and sustainable chemical production.