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N-glycoside synthesis through combined copper- and photoredox-catalysed N-glycosylation of N-nucleophiles

Nature Synthesis (2024)Cite this article

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Abstract

State-of-the-art glycosylation methods primarily rely on ionic reactions of heteroatomic nucleophiles with electrophilic glycosyl oxocarbenium intermediates. Although such ionic glycosylation strategies can effectively form O-glycosides, their use in N-glycoside synthesis is often plagued by the subdued reactivity of N-nucleophiles under the acidic reaction conditions required for glycosyl donor activation. Exploration of the reactivity of glycosyl radical intermediates has begun to offer new glycosylation pathways. However, despite recent progress in radical-mediated synthesis of C-glycosides, harnessing the reactivity of glycosyl radicals for the generation of canonical O- or N-glycosides remains elusive. Here we report the development of a glycosyl radical-mediated N-glycosylation reaction using readily accessible glycosyl sulfone donors and N-nucleophiles under mild copper-catalysed, photoredox-promoted conditions. The method is efficient, selective, redox neutral and broadly applicable, enabling ready access to a variety of complex N-glycosides and nucleosides in a streamlined fashion. Importantly, the present system tolerates the presence of water and offers unique chemoselectivity, allowing selective reaction of NH sites over hydroxyl groups that would otherwise pose challenges in conventional ionic N-glycosylation.

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Fig. 1: Glycosyl radical-mediated synthesis of N-glycosides.
Fig. 2: Model N-glycosylation reaction of 2 under Cu-catalysed, photoredox-promoted conditions.
Fig. 3: Scope of N-nucleophiles in Cu-catalysed N-glycosylation reactions with sulfone donor 6.
Fig. 4: Substrate scope of the Cu-catalysed desulfonylative N-glycosylation reaction.

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Data availability

All data are available in the main text or Supplementary Information. Crystallographic data for the structures reported in this paper have been deposited at the Cambridge Crystallographic Data Centre under deposition no. CCDC 2266734 (51). Copies of the data can be obtained free of charge at https://www.ccdc.cam.ac.uk/structures/.

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Acknowledgements

This work was supported by the National Key R&D Programme of China (no. 2022YFA1504303), the National Natural Science Foundation of China (no. 92256302), Frontiers Science Center for New Organic Matter (no. 63181206), Fundamental Research Funds for the Central Universities (no. NKU63231195), Haihe Laboratory of Sustainable Chemical Transformations (to G.C.) and the Ministry of Education of Singapore Academic Research Fund Tier 2 (no. A-8000941-00-00 to M.J.K.).

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  1. These authors contributed equally: Qikai Sun, Quanquan Wang.

Authors and Affiliations

  1. State Key Laboratory and Institute of Elemento-Organic Chemistry, College of Chemistry, Nankai University, Tianjin, China

    Qikai Sun, Wenzhuo Qin, Kaiyu Jiang, Gang He & Gong Chen

  2. Department of Chemistry, National University of Singapore, Singapore, Republic of Singapore

    Quanquan Wang & Ming Joo Koh

  3. Frontiers Science Centre for New Organic Matter, Nankai University, Tianjin, China

    Gong Chen

  4. Haihe Laboratory of Sustainable Chemical Transformations, Tianjin, China

    Gong Chen

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Contributions

Q.S. was responsible for the initial discovery of the Cu-catalysed N-glycosylation reaction and conducted most of the substrate scope exploration and mechanistic studies. Q.W. was heavily involved in reaction optimization and mechanistic studies. W.Q. helped with expansion of substrate scope. K.J. conducted reduction potential measurement experiments. G.H. supervised parts of the project. M.J.K. supervised the project and edited the paper. G.C. oversaw the entire project and wrote the paper.

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Correspondence to Ming Joo Koh or Gong Chen.

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Nature Synthesis thanks Feng Zhu and the other, anonymous, reviewer(s) for their contribution to the peer review of this work. Primary Handling Editor: Thomas West, in collaboration with the Nature Synthesis team.

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Supplementary information

Supplementary Information

Detailed synthetic procedures, additional control experiments, compound characterization, liquid chromatography–mass spectrometry tracing, X-ray crystallography and NMR spectra.

Supplementary Data 1

Crystallographic data for compound 51 (no. CCDC 2266734).

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Sun, Q., Wang, Q., Qin, W. et al. N-glycoside synthesis through combined copper- and photoredox-catalysed N-glycosylation of N-nucleophiles. Nat. Synth (2024). https://doi.org/10.1038/s44160-024-00496-7

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