One-pot photoenzymatic synthesis of β-chiral malononitrile derivatives

Abstract

Chiral malononitrile compounds, as universal modules, are extensively distributed in bioactive molecules (such as insecticides and herbicides). Developing efficient and highly enantioselective methods for synthesizing β-chiral malononitrile derivatives under mild conditions continues to pose a challenge. Here, we report a one-pot two-stage photoenzymatic strategy combining photocatalytic Knoevenagel Condensation with enzymatic C=C asymmetric reduction. In the first step, quantitative reactions are achieved between substituted acetophenones and acetonitrile, with methyl orange (MO) as the photocatalyst under white light irradiation. The next step is asymmetric hydrogenation mediated by ene reductase, which only takes 50 minutes to obtain a series of β-chiral malononitrile derivatives with good yields (43-99%) and excellent enantiomeric excess (ee>99%). The differences in stereoselectivity and reaction activity of several ene reductases are reasonable explained through enzymatic kinetics and computer simulations results. Furthermore, a scale-up reaction gives 4e in good yield (80%) and excellent ee (>99%). This study provides a sustainable and highly enantioselective approach for accessing a series of valuable β-chiral malononitrile derivatives.