Chemoenzymatic cascade catalysis has emerged as a revolutionary tool for streamlining traditional retrosynthetic disconnections, creating new possibilities for the asymmetric synthesis of valuable chiral compounds. Here we construct a one-pot concurrent chemoenzymatic cascade by integrating organobismuth-catalyzed aldol condensation with ene-reductase (ER)-catalyzed enantioselective reduction, enabling the formal asymmetric α-benzylation of cyclic ketones. To achieve this, we develop a pair of enantiocomplementary ERs capable of reducing α-arylidene cyclic ketones, lactams, and lactones. Our engineered mutants exhibit significantly higher activity, up to 37-fold, and broader substrate specificity compared to the parent enzyme. The key to success is due to the well-tuned hydride attack distance/angle and, more importantly, to the synergistic proton-delivery triade of Tyr28-Tyr69-Tyr169. Molecular docking and density functional theory (DFT) studies provide important insights into the bioreduction mechanisms. Furthermore, we demonstrate the synthetic utility of the best mutants in the asymmetric synthesis of several key chiral synthons.

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We report the synthesis and characterization of an artificial peroxygenase (CoN4SA-POase) with CoN4 active sites by supporting single-atom cobalt on polymeric carbon nitrogen, which exhibits high activity, selectivity, stability, and reusability in the oxidation of aromatic alkanes to ketones. Density functional theory calculations reveal a different catalytic mechanism for the artificial peroxygenase from that of natural peroxygenases. In addition, continuous-flow systems are employed to combine CoN4SA-POase with enantiocomplementary ketoreductases as well as an amine dehydrogenase, enabling the enantioselective synthesis of chiral alcohols and amines from hydrocarbons with significantly improved productivity. This work, emulating nature and beyond nature, provides a promising design concept for heme enzyme-based transformations.@en

An aqueous chemoenzymatic cascade reaction combining Pd-catalyzed C-C formation and enzymatic C=C asymmetric hydrogenation (AH) was developed for enantioselective synthesis of tertiary α-aryl cycloketones in good yields and excellent enantioselectivities. The stereopreference of the enzyme in AH of α-aryl cyclohexenones was studied. An enantiocomplementary enzyme was obtained by site-directed mutation.

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