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Asymmetric catalytic formation of quaternary carbons by iminium ion trapping of radicals

Nature volume 532, pages 218–222 (2016)Cite this article

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Abstract

An important goal of modern organic chemistry is to develop new catalytic strategies for enantioselective carbon–carbon bond formation that can be used to generate quaternary stereogenic centres. Whereas considerable advances have been achieved by exploiting polar reactivity1, radical transformations have been far less successful2. This is despite the fact that open-shell intermediates are intrinsically primed for connecting structurally congested carbons, as their reactivity is only marginally affected by steric factors3. Here we show how the combination of photoredox4 and asymmetric organic catalysis5 enables enantioselective radical conjugate additions to β,β-disubstituted cyclic enones to obtain quaternary carbon stereocentres with high fidelity. Critical to our success was the design of a chiral organic catalyst, containing a redox-active carbazole moiety, that drives the formation of iminium ions and the stereoselective trapping of photochemically generated carbon-centred radicals by means of an electron-relay mechanism. We demonstrate the generality of this organocatalytic radical-trapping strategy with two sets of open-shell intermediates, formed through unrelated light-triggered pathways from readily available substrates and photoredox catalysts—this method represents the application of iminium ion activation6 (a successful catalytic strategy for enantioselective polar chemistry) within the realm of radical reactivity.

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Figure 1: Conjugate addition technology for forging quaternary stereocentres.
Figure 2: Proposed mechanism and mechanistic investigations.
Figure 3: Substrate scope for the enantioselective trapping of benzodioxole-derived radicals via the dual photoredox organocatalytic strategy.
Figure 4: Substrate scope for the enantioselective trapping of α-amino radicals via the dual photoredox organocatalytic strategy.

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Data deposits

Crystallographic data for the iminium ion A-1 and for compounds 3i and 7h have been deposited with the Cambridge Crystallographic Data Centre, accession numbers CCDC 1437991, 1437992 and 1437993, respectively.

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Acknowledgements

Financial support was provided by the ICIQ Foundation, MINECO (project CTQ2013-45938-P and Severo Ochoa Excellence Accreditation 2014-2018, SEV-2013-0319), AGAUR (2014 SGR 1059), and the European Research Council (ERC 278541, ORGA-NAUT). J.J.M. and S.P. thank the Marie Curie COFUND (291787-ICIQ-IPMP) and the CELLEX Foundation, respectively, for postdoctoral fellowships. We thank M. Minozzi, M. Nappi and E. Raluy for preliminary investigations, D. Merli and D. Dondi for assistance with EPR experiments, and D. Ravelli for discussions.

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Author notes

  1. John J. Murphy and David Bastida: These authors contributed equally to this work.

Authors and Affiliations

  1. Institute of Chemical Research of Catalonia (ICIQ), Barcelona Institute of Science and Technology, Avda, Tarragona, 43007, Països Catalans 16, Spain

    John J. Murphy, David Bastida, Suva Paria & Paolo Melchiorre

  2. Department of Chemistry, Photogreen Laboratory, University of Pavia, viale Taramelli 12, Pavia, 27100, Italy

    Maurizio Fagnoni

  3. Catalan Institution for Research and Advanced Studies (ICREA), Passeig Lluís Companys 23, Barcelona, 08010, Spain

    Paolo Melchiorre

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  1. John J. Murphy
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Contributions

J.J.M., D.B. and S.P. performed the experiments and analysed the data. J.J.M., D.B., S.P., and P.M. designed the experiments. M.F. and P.M. conceived the project. P.M. directed the project, and P.M. and J.J.M. wrote the manuscript with contributions from all the authors.

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Correspondence to Paolo Melchiorre.

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Murphy, J., Bastida, D., Paria, S. et al. Asymmetric catalytic formation of quaternary carbons by iminium ion trapping of radicals. Nature 532, 218–222 (2016). https://doi.org/10.1038/nature17438

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