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

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

Liu, Yunting (Hebei University of Technology)
Ma, Teng (Hebei University of Technology)
Guo, Zhongxu (Hebei University of Technology)
Zhou, Liya (Hebei University of Technology)
Liu, Guanhua (Hebei University of Technology)
He, Ying (Hebei University of Technology)
Ma, Li (Hebei University of Technology)
Gao, Jing (Hebei University of Technology)
Hollmann, F. (TU Delft BT/Biocatalysis)

2024

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.

http://resolver.tudelft.nl/uuid:13c09c8b-40b2-4f3e-9f26-5c47ca308010

https://doi.org/10.1038/s41467-023-44452-z

2041-1723

Nature Communications, 15 (1)

Institutional Repository

journal article

© 2024 Yunting Liu, Teng Ma, Zhongxu Guo, Liya Zhou, Guanhua Liu, Ying He, Li Ma, Jing Gao, F. Hollmann, More Authors