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Asymmetric, visible light-mediated radical sulfinyl-Smiles rearrangement to access all-carbon quaternary stereocentres

Nature Chemistry volume 13, pages 327–334 (2021)Cite this article

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Abstract

The asymmetric construction of all-carbon quaternary centres within acyclic settings represents a long-standing challenge for synthetic chemists. Alongside polar and radical methods, rearrangement reactions represent an attractive platform, but still broadly applicable methods are in high demand. Here we report an asymmetric, radical sulfinyl-Smiles rearrangement to access acyclic amides that bear an α-all-carbon quaternary centre. Our strategy uses enantioenriched N-arylsulfinyl acrylamides as acceptors for a variety of radicals produced in situ under mild photoredox conditions. The sulfinamido group not only directs the 1,4-migration of the aryl moiety onto the α-carbon of the amide, which thus governs its absolute configuration, but also functions as a traceless chiral auxiliary. The amides obtained in this multicomponent process are prevalent in pharmaceuticals, agrochemicals and bioactive natural products, and can be transformed into valuable chiral α,α-disubstituted acids, oxindoles as well as into β,β-disubstituted amines, highlighting the synthetic potential of this transformation.

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Fig. 1: Strategies towards the enantioselective synthesis of all-carbon quaternary centres in acyclic systems.
Fig. 2: Synthetic utility of α-all-carbon substituted amides.
Fig. 3: Mechanistic studies.

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Data availability

Crystallographic data for structure 2.9 reported in this article has been deposited at the Cambridge Crystallographic Data Centre (CCDC) under deposition number CCDC 1854836 (Supplementary Fig. 7). Copies of the data can be obtained free of charge via https://www.ccdc.cam.ac.uk/structures/. All the other data that support the findings of this study are available within the article and its Supplementary Information.

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Acknowledgements

We thank P. Fiechter for the synthesis of the racemic substrate 2.32 and A. Linden for the X-ray diffraction analysis of 2.9. This work was supported by the European Research Council (ERC starting grant agreement no. 307948), the Swiss National Science Foundation (SNF 200020_146853) and the Comunidad de Madrid Research Talent Attraction Program (2018-T1/IND-10054 to E.M.).

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  1. Estíbaliz Merino

    Present address: Department of Organic and Inorganic Chemistry, Chemical Research Institute Andrés M. del Río (IQAR), University of Alcala, Madrid, Spain

Authors and Affiliations

  1. Department of Chemistry, University of Zurich, Zurich, Switzerland

    Cédric Hervieu, Mariia S. Kirillova, Tatiana Suárez, Marco Müller, Estíbaliz Merino & Cristina Nevado

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Contributions

C.H., M.S.K., T.S. and M.M. performed the experiments. E.M. performed DFT calculations. E.M. and C.N. conceptualized the project, supervised, analysed the data and co-wrote the manuscript.

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Correspondence to Estíbaliz Merino or Cristina Nevado.

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Peer review information Nature Chemistry thanks Yannick Landais and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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Supplementary information

Supplementary Information

General information, reaction optimization data, experimental procedures, additional experiments, compound characterization data including spectroscopic and analytical data for all new compounds, X-ray crystallographic data, NMR and HPLC spectral data, computational details containing the Cartesian coordinates of computational structures, Supplementary Figs. 1–10, Tables 1–5 and references.

Supplementary Data

Crystallographic data for compound 2.9. CCDC 1854836.

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Hervieu, C., Kirillova, M.S., Suárez, T. et al. Asymmetric, visible light-mediated radical sulfinyl-Smiles rearrangement to access all-carbon quaternary stereocentres. Nat. Chem. 13, 327–334 (2021). https://doi.org/10.1038/s41557-021-00668-4

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