Quaternary stereocentres via an enantioconvergent catalytic SN1 reaction

Abstract

The unimolecular nucleophilic substitution (SN1) mechanism features prominently in every introductory organic chemistry course. In principle, stepwise displacement of a leaving group by a nucleophile via a carbocationic intermediate enables the construction of highly congested carbon centres. However, the intrinsic instability and high reactivity of the carbocationic intermediates make it very difficult to control product distributions and stereoselectivity in reactions that proceed via SN1 pathways. Here we report asymmetric catalysis of an SN1-type reaction mechanism that results in the enantioselective construction of quaternary stereocentres from racemic precursors. The transformation relies on the synergistic action of a chiral hydrogen-bond-donor catalyst with a strong Lewis-acid promoter to mediate the formation of tertiary carbocationic intermediates at low temperature and to achieve high levels of control over reaction enantioselectivity and product distribution. This work provides a foundation for the enantioconvergent synthesis of other fully substituted carbon stereocentres.

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Fig. 1: Approaches to the enantiocontrolled construction of quaternary stereocentres.
Fig. 2: Asymmetric allylation of propargyl acetates.
Fig. 3: Kinetic data and catalytic cycle.
Fig. 4: Mechanistic studies to probe the post-rate-limiting steps of the allylation reaction.

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Acknowledgements

Financial support for this work was provided by the NIH through GM043214 and a postdoctoral fellowship to A.E.W. We thank S. McCann and C. Fry for assistance with NMR experiments, E. E. Kwan for discussions regarding the KIE studies, and S.-L. Zheng for X-ray structure determination.

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Nature thanks R. Gilmour and the other anonymous reviewer(s) for their contribution to the peer review of this work.

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A.E.W. and E.N.J. conceived the work, A.E.W. and P.V. conducted the experiments, E.N.J. directed the research, and A.E.W., P.V. and E.N.J. wrote the manuscript.

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Correspondence to Eric N. Jacobsen.

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This file contains Supplementary Text 1-15, with Supplementary Figures S1-S9 and Supplementary Tables S1-S3

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Wendlandt, A.E., Vangal, P. & Jacobsen, E.N. Quaternary stereocentres via an enantioconvergent catalytic SN1 reaction. Nature 556, 447–451 (2018). https://doi.org/10.1038/s41586-018-0042-1

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