Emulating nature to design multienzyme cascade systems for the given synthetic targets is fascinating but highly challenging. Here, we established a three-enzyme nanoreactor (TENR) for stereodivergent synthesis of α-substituted cyclohexanols, in which the two contiguous chiral centers are created by old yellow enzyme (OYE)- and alcohol dehydrogenase (ADH)-catalyzed asymmetric reductions, coupled with glucose dehydrogenase (GDH)-catalyzed cofactor regeneration. To achieve this goal, enantio-complementary OYEs and ADHs were identified, in which an (S)-stereoselective OYE variant toward α-methyl cyclohexenone was obtained by site-directed mutagenesis based on the rational enzyme design. The TENR with high compositional and spatial controls was fabricated by coimmobilizing the three enzymes on amphiphilic core–shell polydopamine-encapsulated dendritic organosilica nanoparticles. A customized microenvironment for the rate-limiting enzyme and the rationally arranged locations of enzymes that match the reaction sequence was designed to improve the cascade catalytic performance. Moreover, the TENR displayed much higher stability, reusability, and cofactor recycling efficiency than that of the free multienzyme system.

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The synthesis of enantiopure chiral cyclic amines is of critical importance but highly challenging. In this study, a metal‐enzyme hybrid catalyst was fabricated by the co‐immobilization of palladium nanoparticles and monoamine oxidases on dendritic organosilica nanoparticles (DONs) for chemoenzymatic deracemization, furnishing a panel of chiral cyclic amines in high enantioselectivities (96–98 % ee). Catalyst optimization revealed that the ultra‐high specific surface area, mesoporous channels and hydrophobic microenvironment of the DONs are responsible for the improved catalyst stability, activity and catalytic efficiency.

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