Investigating Substrate Scope and Enantioselectivity of a Defluorinase by a 
Stereochemical Probe

Wang, Jianbo; Ilie, Adriana; Yuan, Shuguang; Reetz, Manfred T.

doi:10.1021/jacs.7b06019

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Investigating Substrate Scope and Enantioselectivity of a Defluorinase by a Stereochemical Probe

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Wang, Jianbo
Research Department Reetz, Max-Planck-Institut für Kohlenforschung, Max Planck Society;
Philipps-Universität Marburg, Fachbereich Chemie;

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Ilie, Adriana
Research Department Reetz, Max-Planck-Institut für Kohlenforschung, Max Planck Society;
Philipps-Universität Marburg, Fachbereich Chemie;

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Reetz, Manfred T.
Research Department Reetz, Max-Planck-Institut für Kohlenforschung, Max Planck Society;
Philipps-Universität Marburg, Fachbereich Chemie;

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Citation

Wang, J., Ilie, A., Yuan, S., & Reetz, M. T. (2017). Investigating Substrate Scope and Enantioselectivity of a Defluorinase by a Stereochemical Probe. Journal of the American Chemical Society, 139(32), 11241-11247. doi: 10.1021/jacs.7b06019.

Cite as: https://hdl.handle.net/11858/00-001M-0000-002E-80D3-F

Abstract

The possibility of a double Walden inversion mechanism of the fluoracetate dehalogenase FAcD (RPA1163) has been studied by subjecting rac-2-fluoro-2-phenyl acetic acid to the defluorination process. This stereochemical probe led to inversion of configuration in a kinetic resolution with an extremely high selectivity factor (E > 500), showing that the classical mechanism involving SN2 reaction by Asp110 pertains. The high preference for the (S)-substrate is of synthetic value. Wide substrate scope of RPA1163 in such hydrolytic kinetic resolutions can be expected because the reaction of the even more sterically demanding rac-2-fluoro-2-benzyl acetic acid proceeded similarly. Substrate acceptance and stereoselectivity were explained by extensive molecular modeling (MM) and molecular dynamics (MD) computations. These computations were also applied to fluoroacetic acid itself, leading to further insights.