Desymmetrization of difluoromethylene groups by C–F bond activation

Abstract

Tertiary stereogenic centres containing one fluorine atom are valuable for medicinal chemistry because they mimic common tertiary stereogenic centres containing one hydrogen atom, but they possess distinct charge distribution, lipophilicity, conformation and metabolic stability1,2,3. Although tertiary stereogenic centres containing one hydrogen atom are often set by enantioselective desymmetrization reactions at one of the two carbon–hydrogen (C–H) bonds of a methylene group, tertiary stereocentres containing fluorine have not yet been constructed by the analogous desymmetrization reaction at one of the two carbon–fluorine (C–F) bonds of a difluoromethylene group3. Fluorine atoms are similar in size to hydrogen atoms but have distinct electronic properties, causing C–F bonds to be exceptionally strong and geminal C–F bonds to strengthen one another4. Thus, exhaustive defluorination typically dominates over the selective replacement of a single C–F bond, hindering the development of the enantioselective substitution of one fluorine atom to form a stereogenic centre5,6. Here we report the catalytic, enantioselective activation of a single C–F bond in an allylic difluoromethylene group to provide a broad range of products containing a monofluorinated tertiary stereogenic centre. By combining a tailored chiral iridium phosphoramidite catalyst, which controls regioselectivity, chemoselectivity and enantioselectivity, with a fluorophilic activator, which assists the oxidative addition of the C–F bond, these reactions occur in high yield and selectivity. The design principles proposed in this work extend to palladium-catalysed benzylic substitution, demonstrating the generality of the approach.

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Fig. 1: Approaches to the desymmetrization of methylene units.
Fig. 2: Reaction development and mechanistic studies.
Fig. 3: Scope of nucleophiles and electrophiles that participate in defluorinative alkylation reactions and transformations of the products.
Fig. 4: Selective activation of a single benzylic C–F bond.
Fig. 5: Mechanistic studies support a cation-assisted, turnover-limiting, enantiodetermining and irreversible oxidative addition from a rapidly interconverting mixture of diastereomeric olefin complexes under Curtin–Hammett control.

Data availability

The characterization data are available in the Supplementary Information, together with details about the materials and methods, experimental procedures, mechanistic studies, investigations of reaction conditions, and the design of ligands.

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Acknowledgements

We thank the NSF (CHE-1565886) for financial support. T.W.B. gratefully acknowledges the National Science Foundation Graduate Research Fellowship Program and the UC Berkeley Graduate Research Fellowship Program for support. J.L.Y. gratefully acknowledges a Summer Undergraduate Research Fellowship from the University of California, Berkeley and a summer fellowship from the Rose Hills Foundation. N.D.W. thanks the UC Berkeley Amgen Scholars Program for support. We thank the College of Chemistry’s NMR facility for resources and H. Celik for assistance. Instruments in the CoC-NMR facility are supported in part by NIH S10OD024998.

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T.W.B. and J.F.H. initiated and designed the overall project. T.W.B., J.L.Y., W.M.A., N.B.W. and N.D.W. conducted the experiments, and T.W.B., J.L.Y., W.M.A., N.B.W., N.D.W. and J.F.H. interpreted the results. T.W.B. conducted the mechanistic experiments and density functional theory calculations. T.W.B. and J.F.H. prepared the manuscript.

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Correspondence to John F. Hartwig.

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This file contains Materials and Methods, Supplementary Text, and Supplementary Figures S1 to S17.

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Butcher, T.W., Yang, J.L., Amberg, W.M. et al. Desymmetrization of difluoromethylene groups by C–F bond activation. Nature 583, 548–553 (2020). https://doi.org/10.1038/s41586-020-2399-1

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