Work

Engineered Flavin-Dependent Halogenases Catalyze C–C Bond Formation via Enantioselective Semipinacol Rearrangement

Year: 2026

Type: article

Abstract: The semipinacol rearrangement comprises a valuable class of synthetic organic transformations that provides access to useful molecular scaffolds via C–C bond cleavage and formation. Biocatalytic semipinacol rearrangements are rare, however, and the only naturally occurring semipinacolase catalyzes a reaction that proceeds via chirality transfer on a complex natural product substrate. Herein, we report that flavin-dependent halogenases (FDHs) can catalyze enantioselective halogenative semipinacol rearrangement of pro-chiral allylic alcohols. This biocatalytic platform exhibits a broad substrate scope, affording chiral ketones bearing all-carbon quaternary stereocenters with high enantioselectivity. The reaction system displays a kcat value of 16.86 ± 0.97 min-1, representing the highest reported to date for FDH catalysis, and the T52G mutation was found to play a key role in reshaping the enzyme active site to enable this non-native transformation. This first example of asymmetric C−C bond construction using an FDH highlights the catalytic flexibility of these enzymes and provides access to a diverse range of enantioenriched carbocycles and heterocycles.

Source: Journal of the American Chemical Society

DOI: 10.1021/jacs.5c20091

Authors: Xuzhong Shen, Paras Gupta, Pratibha Gandhi, IanGustavo Ramirez, Dibyendu Mondal, Jared C. Lewis

Institution: Indiana University

Language: English

Topic: Enzyme Catalysis and Immobilization

Subfield: Molecular Biology

Field: Biochemistry, Genetics and Molecular Biology

Domain: Life Sciences

Open Access status: green

Funders: Indiana Clinical and Translational Sciences Institute, National Institute of General Medical Sciences, Division of Chemistry

Awards: G415980670, G4412226944