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Enantioselective Chan–Lam S-arylation of sulfenamides

Nature Catalysis volume 7, pages 1010–1020 (2024)Cite this article

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Abstract

Sulfur stereogenic molecules have a significant impact on drug development. Among them, sulfilimines are chiral molecules bearing S(IV) stereocentres, which exhibit great value in chemistry and biology but have so far been synthetically challenging to achieve. Similarly, it has also been a challenge to control the stereochemistry in Chan–Lam coupling, which has been widely used to construct C–N, C–O and C–S bonds by coupling nucleophiles with boronic acids using copper complexes. Here we report a highly chemoselective and enantioselective Chan–Lam S-arylation of sulfenamides with arylboronic acids to deliver an array of thermodynamically disfavoured aryl sulfilimines containing a sulfur stereocentre. A copper catalyst from a 2-pyridyl N-phenyl dihydroimidazole ligand has been designed that enables effective enantiocontrol by means of a well-defined chiral environment and high reactivity that outcompetes the background racemic transformation. A combined experimental and computational study establishes the reaction mechanism and unveils the origin of chemoselectivity and stereoselectivity.

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Fig. 1: Background and conceptual design.
Fig. 2: Scope of the substrates.
Fig. 3: Synthetic applications.
Fig. 4: Computational investigation of the reaction mechanism.

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Data availability

Detailed experimental procedures, characterization data, NMR spectra of compounds, detailed computational results and calculated structures are available within the Supplementary Information and related files. The X-ray crystallographic coordinates for the structure reported in this study have been deposited at the CCDC under deposition number CCDC 2215359 (for 3ba). These data can be obtained free of charge from the CCDC via www.ccdc.cam.ac.uk/data_request/cif. Any further relevant data are available from the authors upon request.

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Acknowledgements

T.J. thanks the National Natural Science Foundation of China (U23A20528), Guangdong Basic and Applied Basic Research Foundation (2021B1515120046 and 2022B1515120075), the Science and Technology Innovation Commission of Shenzhen Municipality (JCYJ20220818101404010 and 20220815113214003) and the High Level of Special Funds (G03050K003) for financial support. M.C.K. thanks the National Institutes of Health (NIH; R35 GM131902) for financial support and Advanced Cyberinfrastructure Coordination Ecosystem: Services and Support (ACCESS; TG-CHE120052) for computational support. We are grateful to Y. Yu and X. Chang (both at SUSTech) for High Resolution Mass Spectrum and X-ray crystallography, respectively. We also acknowledge the assistance of SUSTech Core Research Facilities.

Author information

Author notes

  1. These authors contributed equally: Qingjin Liang, Xinping Zhang, Madeline E. Rotella.

Authors and Affiliations

  1. Research Center for Chemical Biology and Omics Analysis, Department of Chemistry, Southern University of Science and Technology, Shenzhen, P. R. China

    Qingjin Liang, Xinping Zhang, Zeyu Xu & Tiezheng Jia

  2. Department of Chemistry, Roy and Diana Vagelos Laboratories, University of Pennsylvania, Philadelphia, PA, USA

    Madeline E. Rotella & Marisa C. Kozlowski

  3. State Key Laboratory of Elemento-Organic Chemistry, Nankai University, Tianjin, P. R. China

    Tiezheng Jia

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  1. Qingjin Liang
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  2. Xinping Zhang
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  3. Madeline E. Rotella
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  4. Zeyu Xu
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Contributions

T.J. conceived and supervised the project. Q.L., X.Z. and Z.X. performed the experiments. M.C.K. directed the computational study. M.E.R. carried out the computational study. T.J., Q.L. and X.Z. analysed the data. All authors participated in writing the manuscript.

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Correspondence to Marisa C. Kozlowski or Tiezheng Jia.

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Nature Catalysis thanks Taichi Kano, Debasis Koley and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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Supplementary information

Supplementary Information

Supplementary Figs. 1–333, Tables 1–21, Methods, notes and references.

Supplementary Data 1

Crystallographic data for compound 3ba.

Supplementary Data 2

Cif check report for 3ba.

Supplementary Data 3

Computational data.

Supplementary Data 4

Computational data.

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Liang, Q., Zhang, X., Rotella, M.E. et al. Enantioselective Chan–Lam S-arylation of sulfenamides. Nat Catal 7, 1010–1020 (2024). https://doi.org/10.1038/s41929-024-01213-5

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