Rational enzyme design for enabling biocatalytic Baldwin cyclization and 
asymmetric synthesis of chiral heterocycles

Li, Jun-Kuan; Qu, Ge; Li, Xu; Tian, Yuchen; Cui, Chengsen; Zhang, Fa-Guang; Zhang, Wuyuan; Ma, Jun-An; Reetz, Manfred T.; Sun, Zhoutong

doi:10.1038/s41467-022-35468-y

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Rational enzyme design for enabling biocatalytic Baldwin cyclization and asymmetric synthesis of chiral heterocycles

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Reetz, Manfred T.
Tianjin Institute of Industrial Biotechnology, Chinese Academy of Sciences;
Research Department Reetz, Max-Planck-Institut für Kohlenforschung, Max Planck Society;

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Citation

Li, J.-K., Qu, G., Li, X., Tian, Y., Cui, C., Zhang, F.-G., et al. (2022). Rational enzyme design for enabling biocatalytic Baldwin cyclization and asymmetric synthesis of chiral heterocycles. Nature Communications, 13: 7813. doi:10.1038/s41467-022-35468-y.

Cite as: https://hdl.handle.net/21.11116/0000-000C-BA62-4

Abstract

Chiral heterocyclic compounds are needed for important medicinal applications. We report an in silico strategy for the biocatalytic synthesis of chiral N- and O-heterocycles via Baldwin cyclization modes of hydroxy- and amino-substituted epoxides and oxetanes using the limonene epoxide hydrolase from Rhodococcus erythropolis. This enzyme normally catalyzes hydrolysis with formation of vicinal diols. Firstly, the required shutdown of the undesired natural water-mediated ring-opening is achieved by rational mutagenesis of the active site. In silico enzyme design is then continued with generation of the improved mutants. These variants prove to be versatile catalysts for preparing chiral N- and O-heterocycles with up to 99% conversion, and enantiomeric ratios up to 99:1. Crystal structural data and computational modeling reveal that Baldwin-type cyclizations, catalyzed by the reprogrammed enzyme, are enabled by reshaping the active-site environment that directs the distal RHN and HO-substituents to be intramolecular nucleophiles.