Harnessing Photoenzymatic Systems for Intermolecular C-H Fluorination
Yu Zhou1, Danielle Lawson2, Zihan Zhang1
1Department of Chemistry, The University of Texas at Austin, Austin, TX, 78712, USA.
Angewandte Chemie (International Ed. in English)
|December 22, 2025
Summary
Scientists developed a novel radical photoenzymatic system for direct C-H fluorination. This breakthrough enables precise, selective enzymatic fluorination of organic compounds, crucial for pharmaceutical development.
Area of Science:
- Biocatalysis and Organic Chemistry
- Enzyme Engineering and Protein Design
Background:
- Organofluorine compounds are essential in pharmaceuticals, yet efficient enzymatic fluorination methods are limited.
- Nature's enzymes offer precise catalysis, but enzymatic intermolecular C-H fluorination remained an unmet challenge.
Purpose of the Study:
- To develop the first enzymatic strategy for intermolecular C-H fluorination.
- To engineer a novel radical photoenzymatic system for selective fluorination.
Main Methods:
- Designed a de novo protein scaffold incorporating an unnatural amino acid.
- Utilized a radical photoenzymatic approach driven by photoexcited amino acid hydrogen atom transfer.
- Employed Selectfluor as the fluorinating agent in aqueous solutions.
Main Results:
- Achieved chemoselective benzylic monofluorination of various aromatic compounds.
- Demonstrated successful biosynthesis of fluorinated polyketides.
- Enabled the synthesis of chiral fluorinated alcohols.
Conclusions:
- Established the first radical photoenzymatic system for intermolecular C-H fluorination.
- This biocatalytic approach offers efficient and selective fluorination relevant to pharmaceutical synthesis.
- The developed system opens new avenues for enzymatic synthesis of organofluorine compounds.
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