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Direct synthesis of unprotected aryl C-glycosides by photoredox Ni-catalysed cross-coupling

Nature Synthesis volume 2, pages 251–260 (2023)Cite this article

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Abstract

Aryl C-glycosides are an important class of carbohydrate derivatives, with widespread application in drug development, biochemistry and material sciences. However, their synthesis usually requires extensively protected intermediates and the use of sensitive reagents, which presents significant practical challenges. In this study, we report a direct and stereoselective cross-coupling approach to prepare unprotected aryl C-glycosides from bench-stable starting materials. The transformation uses allyl glycosyl sulphones and aryl bromides or iodides as reactants and proceeds under photoredox Ni-catalysed conditions. A combination of allyl glycosyl sulphones and tolyl sulfinate are used as synthetic equivalents of glycosyl anions. This approach obviates protecting groups on both reactants and accommodates various functional groups and heterocycles. Furthermore, the reaction displays high stereoselectivity across a broad range of glycosyl units. The protocol was applied in the synthesis of several sugar–drug conjugates and gliflozin drugs. Experimental studies provide an insight into the reaction mechanism and density functional theory calculations elucidate the origin of the stereoselectivity and highlight the benefit of using unprotected donors.

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Fig. 1: Significance of aryl C-glycosides and synthetic approaches.
Fig. 2: Mechanistic studies.
Fig. 3: Computational studies.
Fig. 4: Synthetic applications.

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Additional data supporting the findings described in this paper are available in the Supplementary Information.

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Acknowledgements

D.N. acknowledges funding from the National Natural Science Foundation (grant nos. 21922106 and 21772125) and 1.3.5 Project for Disciplines of Excellence, West China Hospital, Sichuan University.

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  1. Department of Emergency, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, and School of Chemical Engineering, Sichuan University, Chengdu, China

    Chen Zhang, Shi-Yang Xu, Hao Zuo, Xia Zhang, Qiu-Di Dang & Dawen Niu

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  1. Chen Zhang
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Contributions

D.N. conceptualized and guided the project, and wrote the manuscript with feedback from other authors. C.Z. made the initial discovery. S.-Y.X. performed DFT calculations. All authors performed the experiments and analysed data.

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Correspondence to Dawen Niu.

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C.Z., X.Z. and D.N. are authors on a patent (PCT/CN2020/103340) filed by Sichuan University for the sulphone reagents used in this paper. The remaining authors declare no competing interests.

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Nature Synthesis thanks Xiang-Guo Hu, Christian Pedersen and the other, anonymous, reviewer(s) for their contribution to the peer review of this work. Primary Handling Editor: Peter Seavill, in collaboration with the Nature Synthesis team.

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Zhang, C., Xu, SY., Zuo, H. et al. Direct synthesis of unprotected aryl C-glycosides by photoredox Ni-catalysed cross-coupling. Nat. Synth 2, 251–260 (2023). https://doi.org/10.1038/s44160-022-00214-1

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