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Enantioselective radical C–H amination for the synthesis of β-amino alcohols

Nature Chemistry volume 12, pages 697–704 (2020)Cite this article

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Abstract

Asymmetric, radical C–H functionalizations are rare but powerful tools for solving modern synthetic challenges. Specifically, the enantio- and regioselective C–H amination of alcohols to access medicinally valuable chiral β-amino alcohols remains elusive. To solve this challenge, a radical relay chaperone strategy was designed, wherein an alcohol was transiently converted to an imidate radical that underwent intramolecular H-atom transfer (HAT). This regioselective HAT was also rendered enantioselective by harnessing energy transfer catalysis to mediate selective radical generation and interception by a chiral copper catalyst. The successful development of this multi-catalytic, asymmetric, radical C–H amination enabled broad access to chiral β-amino alcohols from a variety of alcohols containing alkyl, allyl, benzyl and propargyl C–H bonds. Mechanistic experiments revealed that triplet energy sensitization of a Cu-bound radical precursor facilitates catalyst-mediated HAT stereoselectivity, enabling the synthesis of several important classes of chiral β-amines by enantioselective, radical C–H amination.

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Fig. 1: Design of a selective, radical C–H amination for the synthesis of β-amino alcohols.
Fig. 2: Mechanistic experiments.
Fig. 3: Synthetic applications.

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The data that support the findings of this study are available within the article and its Supplementary Information files.

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Acknowledgements

Financial support was provided by the National Institutes of Health (NIH R35 GM119812) and National Science Foundation (NSF CAREER 1654656). L.M.S. is supported by an NSF graduate fellowship. Calculations were performed using resources at the Ohio Supercomputer Center.

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Author notes

  1. These authors contributed equally: Kohki M. Nakafuku, Zuxiao Zhang, Ethan A. Wappes.

Authors and Affiliations

  1. Department of Chemistry and Biochemistry, The Ohio State University, Columbus, OH, USA

    Kohki M. Nakafuku, Zuxiao Zhang, Ethan A. Wappes, Leah M. Stateman, Andrew D. Chen & David A. Nagib

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Contributions

K.M.N. designed and discovered the enantioselective C–H amination. K.M.N., E.A.W. and Z.Z. developed the optimized method. Z.Z. evaluated the synthetic scope. Z.Z. and L.M.S. performed the mechanistic experiments and derivatizations. A.D.C. performed the calculations. All authors contributed to writing the manuscript.

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Correspondence to David A. Nagib.

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Supplementary Information

Supplementary Figs. 1–3, Tables 1–7, new compound characterization, and mechanistic and density functional theory experiments.

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Nakafuku, K.M., Zhang, Z., Wappes, E.A. et al. Enantioselective radical C–H amination for the synthesis of β-amino alcohols. Nat. Chem. 12, 697–704 (2020). https://doi.org/10.1038/s41557-020-0482-8

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