One-pot photoenzymatic synthesis of β-chiral malononitrile derivatives

• Published in: Organic chemistry frontiers an international journal of organic chemistry Vol. 11; no. 18; pp. 5179 - 5187
• Main Authors: Xin-Yue, Fan, Yu, Yuan, Ru-De, Lin, Yao, Yao, Ming-Liang, Shi, Li, Kun, Xiao-Qi, Yu, Yan-Hong, Liu, Wang, Na
• Format: Journal Article
• Language: English
• Published: London Royal Society of Chemistry 10.09.2024
• Subjects: Chemical synthesis; Dyes; Enantiomers; Herbicides; Insecticides; Irradiation; Light irradiation; Malononitrile; Molecular docking; Molecular dynamics; Photocatalysis; Reductases; Stereoselectivity; White light
• ISSN: 2052-4110; 2052-4110
• DOI: 10.1039/d4qo00859f

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 Knoevenagel reactions are achieved between substituted acetophenones and malononitrile, 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 reasonably explained through enzymatic kinetics, molecular docking and molecular dynamic simulation. 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.