Bridging the Gap between Bioreduction and Ullmann Homocoupling for Continuous-Flow Chemoenzymatic Cascades

The development of chemoenzymatic cascades has gained much attention in synthetic chemistry but is highly restricted by the big gap between chemo- and biocatalysis. Herein, we report the sequential combination of enzymatic ketoreduction and metal-catalyzed Ullmann homocoupling reaction for the enantiocomplementary synthesis of C2-symmetric chiral biaryldiols. Key to this achievement lies in the synthesis of a phenylene-bridged mesoporous organosilica nanoflower (PMON)-immobilized palladium–copper (PdCu) bimetallic catalyst and the construction of a continuous-flow synthesis system, which lowers the Ullmann reaction temperature (typically >100 °C) to 40 °C. The sequential enzyme-metal cascade sequence improves the stereoselectivity and significantly expands the substrate scope due to the higher enzyme performance for small starting substrates (aryl ketones) than for their bulky dimers (biaryl diketones). In addition, the catalytic mechanism and the rate-determining step of the Ullmann homocoupling reaction were elucidated by density functional theory (DFT) calculations.