Ground-state flavin-dependent enzymes catalyzed enantioselective radical trifluoromethylation
Abstract The introduction of fluoroalkyl groups into pharmaceutical compounds has the potential to enhance their therapeutic properties. Nevertheless, the synthesis of enantiomerically pure C(sp³)–CF₃ compounds poses a significant challenge. Biocatalysis offers precise stereochemical control, howeve...
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| Format: | Article |
| Language: | English |
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Nature Portfolio
2025-01-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-025-56437-1 |
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| author | Xinyu Duan Dong Cui Mengdi Wang Chenlu Jin Xiaochen Cai Zhiguo Wang Jian Xu |
| author_facet | Xinyu Duan Dong Cui Mengdi Wang Chenlu Jin Xiaochen Cai Zhiguo Wang Jian Xu |
| author_sort | Xinyu Duan |
| collection | DOAJ |
| description | Abstract The introduction of fluoroalkyl groups into pharmaceutical compounds has the potential to enhance their therapeutic properties. Nevertheless, the synthesis of enantiomerically pure C(sp³)–CF₃ compounds poses a significant challenge. Biocatalysis offers precise stereochemical control, however, the scarcity of fluorine-containing natural products makes it difficult to find enzymes capable of incorporating fluoroalkyl groups. Herein, we develop a ground-state flavin-dependent enzyme-catalyzed strategy for the radical-mediated enantioselective trifluoromethylation. Two engineered flavin-dependent enzymes are successfully developed to catalyze stereoselective hydrotrifluoromethylation and trifluoromethyl-alkyl cross-electrophile coupling reactions using trifluoromethyl thianthrenium triflate as a radical donor. Experimental investigations and computational simulations demonstrate that the reaction is initiated through single-electron transfer from the ground state flavin hydroquinone (FMNhq) and quenched through hydrogen atom transfer by flavin semiquinone (FMNsq). This strategy provides an opportunity to bridge the gap between biocatalysis and organic fluorides but also introduces an alternative approach to address challenging stereoselective fluoroalkylation reactions in organic synthesis. |
| format | Article |
| id | doaj-art-ba1b3eb2a9794119bc4b3886d750123c |
| institution | Kabale University |
| issn | 2041-1723 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj-art-ba1b3eb2a9794119bc4b3886d750123c2025-02-02T12:31:43ZengNature PortfolioNature Communications2041-17232025-01-0116111010.1038/s41467-025-56437-1Ground-state flavin-dependent enzymes catalyzed enantioselective radical trifluoromethylationXinyu Duan0Dong Cui1Mengdi Wang2Chenlu Jin3Xiaochen Cai4Zhiguo Wang5Jian Xu6College of Biotechnology and Bioengineering, Zhejiang University of TechnologyCollege of Biotechnology and Bioengineering, Zhejiang University of TechnologyCollege of Biotechnology and Bioengineering, Zhejiang University of TechnologyCollege of Biotechnology and Bioengineering, Zhejiang University of TechnologyCollege of Biotechnology and Bioengineering, Zhejiang University of TechnologyInstitute of Ageing Research, School of Basic Medical Sciences, Hangzhou Normal UniversityCollege of Biotechnology and Bioengineering, Zhejiang University of TechnologyAbstract The introduction of fluoroalkyl groups into pharmaceutical compounds has the potential to enhance their therapeutic properties. Nevertheless, the synthesis of enantiomerically pure C(sp³)–CF₃ compounds poses a significant challenge. Biocatalysis offers precise stereochemical control, however, the scarcity of fluorine-containing natural products makes it difficult to find enzymes capable of incorporating fluoroalkyl groups. Herein, we develop a ground-state flavin-dependent enzyme-catalyzed strategy for the radical-mediated enantioselective trifluoromethylation. Two engineered flavin-dependent enzymes are successfully developed to catalyze stereoselective hydrotrifluoromethylation and trifluoromethyl-alkyl cross-electrophile coupling reactions using trifluoromethyl thianthrenium triflate as a radical donor. Experimental investigations and computational simulations demonstrate that the reaction is initiated through single-electron transfer from the ground state flavin hydroquinone (FMNhq) and quenched through hydrogen atom transfer by flavin semiquinone (FMNsq). This strategy provides an opportunity to bridge the gap between biocatalysis and organic fluorides but also introduces an alternative approach to address challenging stereoselective fluoroalkylation reactions in organic synthesis.https://doi.org/10.1038/s41467-025-56437-1 |
| spellingShingle | Xinyu Duan Dong Cui Mengdi Wang Chenlu Jin Xiaochen Cai Zhiguo Wang Jian Xu Ground-state flavin-dependent enzymes catalyzed enantioselective radical trifluoromethylation Nature Communications |
| title | Ground-state flavin-dependent enzymes catalyzed enantioselective radical trifluoromethylation |
| title_full | Ground-state flavin-dependent enzymes catalyzed enantioselective radical trifluoromethylation |
| title_fullStr | Ground-state flavin-dependent enzymes catalyzed enantioselective radical trifluoromethylation |
| title_full_unstemmed | Ground-state flavin-dependent enzymes catalyzed enantioselective radical trifluoromethylation |
| title_short | Ground-state flavin-dependent enzymes catalyzed enantioselective radical trifluoromethylation |
| title_sort | ground state flavin dependent enzymes catalyzed enantioselective radical trifluoromethylation |
| url | https://doi.org/10.1038/s41467-025-56437-1 |
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