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Enantioselective remote meta-C–H arylation and alkylation via a chiral transient mediator

Abstract

Enantioselective carbon–hydrogen (C–H) activation reactions by asymmetric metallation could provide new routes for the construction of chiral molecules1,2. However, current methods are typically limited to the formation of five- or six-membered metallacycles, thereby preventing the asymmetric functionalization of C–H bonds at positions remote to existing functional groups. Here we report enantioselective remote C–H activation using a catalytic amount of a chiral norbornene as a transient mediator, which relays initial ortho-C–H activation to the meta position. This was used in the enantioselective meta-C–H arylation of benzylamines, as well as the arylation and alkylation of homobenzylamines. The enantioselectivities obtained using the chiral transient mediator are comparable across different classes of substrates containing either neutral σ-donor or anionic coordinating groups. This relay strategy could provide an alternative means to remote chiral induction, one of the most challenging problems in asymmetric catalysis3,4.

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Fig. 1: Enantioselective C(sp2)–H activation.
Fig. 2: Enantioselective meta-C–H arylation of diarylmethylamines.
Fig. 3: Enantioselective meta-C–H activation of homobenzylamines.

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Acknowledgements

We acknowledge The Scripps Research Institute, the National Institutes of Health (National Institute of General Medical Sciences grant 5R01GM102265) and Shanghai RAAS Blood Products Co. Ltd for their financial support. Y.S. thanks Jiangsu Overseas Research & Training Program for University Prominent Young & Middle-aged Teachers and Presidents.

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Nature thanks M. Catellani, G. Chen and the other anonymous reviewer(s) for their contribution to the peer review of this work.

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Authors and Affiliations

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Contributions

J.-Q.Y. and H.S. conceived the concept. H.S. developed the enantioselective remote C−H activation. H.S. and A.N.H. performed the mechanistic study. H.S., A.N.H., Y.S. and Q.S. prepared reaction substrates. J.-Q.Y. directed the project.

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Correspondence to Jin-Quan Yu.

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This file contains General Information, Experimental Section, X-Ray Crystallographic Data, NMR Spectra, SFC Traces and References

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Shi, H., Herron, A.N., Shao, Y. et al. Enantioselective remote meta-C–H arylation and alkylation via a chiral transient mediator. Nature 558, 581–585 (2018). https://doi.org/10.1038/s41586-018-0220-1

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  • DOI: https://doi.org/10.1038/s41586-018-0220-1

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