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Enantioselective Pd-catalysed nucleophilic C(sp3)–H (radio)fluorination

Nature Catalysis volume 8, pages 678–687 (2025)Cite this article

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Abstract

Despite increasing demand for chiral fluorinated organic molecules, enantioselective C–H fluorination remains among the most challenging and sought-after transformations in organic synthesis. Furthermore, utilizing nucleophilic sources of fluorine is especially desirable for 18F-radiolabelling. To date, methods for enantioselective nucleophilic fluorination of inert C(sp3)–H bonds remain unknown. Here we report our design and development of a palladium-based catalytic system bearing bifunctional monoprotected amino sulfonamide ligands which enabled highly regio- and enantioselective nucleophilic β-C(sp3)–H fluorination of synthetically important amides and lactams, commonly present in medicinal targets. The enantioenriched fluorinated products can be rapidly converted to corresponding chiral amines and ketones which are building blocks for a wide range of bioactive scaffolds. Mechanistic studies suggest that the C–F bond formation proceeds via outer-sphere reductive elimination with direct incorporation of fluoride, which was applied to late-stage 18F-radiolabelling of pharmaceutical derivatives using [18F]KF.

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Fig. 1: Catalytic C(sp3)–H fluorination strategies.
Fig. 2: Ligand optimization of the enantioselective C(sp3)–H nucleophilic fluorination.
Fig. 3: Scope of ligand-enabled desymmetrization via nucleophilic C(sp3)–H fluorination.
Fig. 4: Scope of kinetic resolution via ligand-enabled nucleophilic C(sp3)–H fluorination.
Fig. 5: Applications of enantioselective fluorination and radiochemistry studies.
Fig. 6: Mechanistic and computational studies.

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Data availability

Crystallographic data for compound (S)-2b are available in the Supplementary Information files and from the Cambridge Crystallographic Data Centre under deposition number CCDC 2211757. Copies of the data can be obtained free of charge via https://www.ccdc.cam.ac.uk/structures/. Cartesian coordinates (Å) for the computed structures are provided in the xyz file. All other data are available from the authors upon reasonable request.

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Acknowledgements

We gratefully acknowledge The Scripps Research Institute, the NIH (NIGMS, 2R01GM084019) and Bristol Myers Squibb for financial support. We thank D. Strassfeld and Y.-H. Li for proofreading and help with editing the manuscript. We thank T. Sheng and Y.-H. Li for help with spectral data analysis. We thank J. Lee, B. Sanchez, Q. N. Wong, J. Smith and J. Chen of the Scripps Research Automated Synthesis Facility for their assistance with SFC and LC-MS analysis and for help with compound purification. We thank M. Gembicky, J. Bailey and the University of California San Diego Crystallography Facility for X-ray crystallographic analysis and the Scripps Research High Performance Computing facility for computational resources.

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Author notes

  1. These authors contributed equally: Nikita Chekshin, Luo-Yan Liu.

Authors and Affiliations

  1. Department of Chemistry, The Scripps Research Institute, La Jolla, CA, USA

    Nikita Chekshin, Luo-Yan Liu, D. Quang Phan, Yuxin Ouyang & Jin-Quan Yu

  2. Small Molecule Drug Discovery, Bristol-Myers Squibb Research and Development, Princeton, NJ, USA

    David J. Donnelly

  3. Small Molecule Drug Discovery, Bristol-Myers Squibb Research and Development, Cambridge, MA, USA

    Kap-Sun Yeung & Jennifer X. Qiao

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  1. Nikita Chekshin
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Contributions

J.-Q.Y. conceived the concept. N.C. discovered and developed the enantioselective fluorination and L.-Y.L. discovered and developed the nucleophilic fluorination conditions. D.Q.P. designed MPASA ligands and prepared the corresponding library. D.J.D. performed radiochemistry studies. L.-Y.L. and N.C. developed the racemic fluorination substrate scope. N.C. developed the enantioselective fluorination substrate scope and product derivatization. Y.O. assisted with enantioselective fluorination scope development. N.C. performed mechanistic and computational studies. J.X.Q. and K.-S.Y. provided discussions and assistance in substrate screening. N.C. and J.-Q.Y. wrote the manuscript. J.-Q.Y. directed the project.

Corresponding author

Correspondence to Jin-Quan Yu.

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Competing interests

N.C., D.Q.P., Y.O. and J.-Q.Y. are inventors on a patent application related to this work (USSN patent application 63/797,339) filed by The Scripps Research Institute. D.J.D., K.-S.Y. and J.X.Q. are employees of Bristol Myers Squibb. The authors declare no other competing interests.

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Nature Catalysis thanks Hee-Kwon Kim, Biplab Maji, Yun-Dong Wu and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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Supplementary information

Supplementary Information

Supplementary Methods, Supplementary Figs.1–34, Tables 1–31 and References.

Crystallographic Data 1

X-ray structure of 2b.

Computational Data 1

Cartesian coordinates of computed structures.

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Chekshin, N., Liu, LY., Phan, D.Q. et al. Enantioselective Pd-catalysed nucleophilic C(sp3)–H (radio)fluorination. Nat Catal 8, 678–687 (2025). https://doi.org/10.1038/s41929-025-01366-x

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