Cluster model study of the mechanism and origins of enantio- and chemoselectivity in non-heme iron enzyme-catalyzed C-H azidation

• Published in: RSC advances Vol. 15; no. 12; pp. 8931 - 8937
• Main Authors: Liu, Hang, Chen, Xiahe, Wu, Hongli, She, Yuanbin, Yang, Yun-Fang
• Format: Journal Article
• Language: English
• Published: England Royal Society of Chemistry 21.03.2025; The Royal Society of Chemistry
• Subjects: Chemistry; Clusters; Density functional theory; Enantiomers; Energy of dissociation; Free energy; Heat of formation; Hydrogen atoms; Iron; Steric effects
• ISSN: 2046-2069; 2046-2069
• DOI: 10.1039/d5ra00632e

The mechanisms and enantio- and chemoselectivities of non-heme iron enzyme-catalyzed C-H azidation were investigated using density functional theory (DFT) calculations. A detailed active site cluster model comprising 337 atoms was constructed, incorporating essential features of the first- and second-coordination spheres and substrate-binding pockets. The catalytic cycle involves N-F bond activation, hydrogen atom transfer (HAT), and radical rebound steps. DFT calculations suggest that the observed enantioselectivity arises from steric effects between the substrate and key active-site residues. Additionally, in the non-heme Fe(N 3 )F complex, the Fe-N 3 bond, which has a lower diabatic bond dissociation energy, preferentially rebounds to form the azidation product. Computational insights reveal the origin of enantio- and chemoselectivity in non-heme iron enzyme-catalyzed C-H azidation.