Asymmetric α-benzylation of cyclic ketones enabled by concurrent chemical aldol condensation and biocatalytic reduction

Yunting Liu, Teng Ma, Zhongxu Guo, Liya Zhou, Guanhua Liu, Ying He, Li Ma, Jing Gao, Jing Bai, Frank Hollmann () and Yanjun Jiang ()
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Yunting Liu: Hebei University of Technology
Teng Ma: Hebei University of Technology
Zhongxu Guo: Hebei University of Technology
Liya Zhou: Hebei University of Technology
Guanhua Liu: Hebei University of Technology
Ying He: Hebei University of Technology
Li Ma: Hebei University of Technology
Jing Gao: Hebei University of Technology
Jing Bai: Hebei University of Science & Technology
Frank Hollmann: Delft University of Technology
Yanjun Jiang: Hebei University of Technology

Nature Communications, 2024, vol. 15, issue 1, 1-9

Abstract: Abstract 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.

Date: 2024
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DOI: 10.1038/s41467-023-44452-z

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