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Catalytic enantiocontrol over a non-classical carbocation

Nature Chemistry volume 12, pages 1174–1179 (2020)Cite this article

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Abstract

Carbocations can be categorized into classical carbenium ions and non-classical carbonium ions. These intermediates are ubiquitous in reactions of both fundamental and practical relevance, finding application in the petroleum industry as well as the discovery of new drugs and materials. Conveying stereochemical information to carbocations is therefore of interest to a range of chemical fields. While previous studies targeted systems proceeding through classical ions, enantiocontrol over their non-classical counterparts has remained unprecedented. Here we show that strong and confined chiral acids catalyse enantioselective reactions via the non-classical 2-norbornyl cation. This reactive intermediate is generated from structurally different precursors by leveraging the reactivity of various functional groups to ultimately deliver the same enantioenriched product. Our work demonstrates that tailored catalysts can act as suitable hosts for simple, non-functionalized carbocations via a network of non-covalent interactions. We anticipate that the methods described herein will provide catalytic accessibility to valuable carbocation systems.

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Fig. 1: The non-classical cation challenge.
Fig. 2: IDPi-catalysed enantioconvergent process from exo-norbornyl derivatives.
Fig. 3: IDPi-catalysed synthesis of enantioenriched product from various substrates.
Fig. 4: Mechanistic investigations.

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Data availability

The experimental procedures and analytical data supporting the findings of this study are available within the manuscript and its Supplementary Information file. Raw and unprocessed NMR data are available from the corresponding author upon reasonable request. Crystallographic data for compounds 3 (CCDC 1948386) and 7 (crystal 1, CCDC 2021275; crystal 2, CCDC 1948044; crystal 3, CCDC 1948043; crystal 4, CCDC 2021276) can be downloaded free of charge from the Cambridge Crystallographic Data Centre (www.ccdc.cam.ac.uk).

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Acknowledgements

Support from the Max Planck Society, the Deutsche Forschungsgemeinschaft (Leibniz Award to B.L. and Cluster of Excellence Ruhr Explores Solvation (RESOLV, EXC 1069)), the European Research Council (Advanced Grant ‘C–H Acids for Organic Synthesis, CHAOS’), the Alexander-von-Humboldt Foundation (fellowship to L.S.), and the Fonds der Chemischen Industrie (fellowship to G.P.) is acknowledged. We thank the technicians of our group and all members of the service departments of the Max-Planck-Institut für Kohlenforschung, with a special mention to R. Goddard, N. Nöthling, A. Deege and H. Hinrichs. We thank J. L. Kennemur and L. Schreyer for discussions during the preparation of the manuscript. We are grateful to B. Mitschke for graphical suggestions and all group members that participated in the crowd reviewing process. We acknowledge A. Blond, D. Petkova and M. R. Monaco for their contributions to initial studies.

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Author notes

  1. Raja Mitra

    Present address: School of Chemical and Biological Sciences, IIT Goa, Ponda, India

Authors and Affiliations

  1. Max-Planck-Institut für Kohlenforschung, Mülheim an der Ruhr, Germany

    Roberta Properzi, Philip S. J. Kaib, Markus Leutzsch, Gabriele Pupo, Raja Mitra, Chandra Kanta De & Benjamin List

  2. Institute of Organic Chemistry, Justus Liebig University, Giessen, Germany

    Lijuan Song & Peter R. Schreiner

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Contributions

B.L. and P.R.S. jointly developed the idea of this project; B.L. conceived, directed and oversaw the project; R.P. designed and conducted the experiments with the help of P.S.J.K.; R.P. and M.L. conducted the mechanistic investigations; M.L. performed the spectroscopic experiments and data analysis; G.P. initiated the experimental work and performed early reactivity studies; R.M. and C.K.D. first synthesized IDPi 3; L.S. carried out the computations; and R.P. and B.L. wrote the manuscript.

Corresponding author

Correspondence to Benjamin List.

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Competing interests

B.L., P.S.J.K. and R.P. are inventors on patent WO2017037141 (A1) filed by the Max-Planck-Institut für Kohlenforschung covering the IDPi catalyst class and its applications in asymmetric synthesis.

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Supplementary information

Supplementary Information

Supplementary methods, data, text, computational methods, Figs. 1–34 and Tables 1–16.

Supplementary Data 1

Crystallographic data for compound 7, crystal 1. CCDC reference 2021275.

Supplementary Data 2

Crystallographic data for compound 7, crystal 2. CCDC reference 1948044.

Supplementary Data 3

Crystallographic data for compound 7, crystal 3. CCDC reference 1948043.

Supplementary Data 4

Crystallographic data for compound 7, crystal 4. CCDC reference 2021276.

Supplementary Data 5

Crystallographic data for compound 3. CCDC reference 1948386.

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Properzi, R., Kaib, P.S.J., Leutzsch, M. et al. Catalytic enantiocontrol over a non-classical carbocation. Nat. Chem. 12, 1174–1179 (2020). https://doi.org/10.1038/s41557-020-00558-1

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