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Palladium-catalysed C−H glycosylation for synthesis of C-aryl glycosides

Nature Catalysis volume 2, pages 793–800 (2019)Cite this article

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Abstract

C-aryl glycosides are widely found in nature and play important roles in drug design. Despite the significant progress made over the past few decades, efficient and stereoselective synthesis of complex C-aryl glycosides remains challenging, lagging far behind the state of the art of the synthesis of O- or N-glycosides. Here, we report a simple and powerful bioinspired strategy for the stereoselective synthesis of C-aryl glycosides via palladium-catalysed ortho-directed C(sp2)−H functionalization of arenes and heteroarenes with easily accessible glycosyl chloride donors. The catalytic palladacycle intermediate generated via C−H palladation provides a soft aryl nucleophile that can react with glycosyl oxocarbenium ion partners with high efficiency and excellent stereocontrol. The method can be applied to a wide range of arene and heteroarene substrates, glycosyl chloride donors and auxiliary groups. It can simplify the synthesis of a variety of complex C-aryl glycosides and offers a tool for late-stage modification of drug molecules.

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Fig. 1: Occurrence and synthesis strategies for C-aryl glycosides.
Fig. 2: Synthesis of C-aryl pyranosides via Pd-catalysed auxiliary-directed ortho C(sp2)−H glycosylation.
Fig. 3: Synthesis of C-aryl furanoside.
Fig. 4: Pd-catalysed ortho C−H glycosylation of phenol substrates using a carbamate-linked AQ auxiliary.
Fig. 5: Synthetic utility of AQ-directed ortho C−H glycosylation of arenes and heteroarenes.
Fig. 6: Mechanistic studies.

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Data availability

The X-ray crystallographic coordinates for the structures reported in this study have been deposited at the Cambridge Crystallographic Data Centre (CCDC), under deposition nos. 1900197, 1900198 and 1900200. These data can be obtained free of charge from The Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_request/cif. All other data are available from the authors upon reasonable request.

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Acknowledgements

G.C. acknowledges support from NSFC grants 21672105, 21421062, 91753124 and 21725204.

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Authors and Affiliations

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

    Quanquan Wang, Shuang An, Zhiqiang Deng, Wanjun Zhu, Zeyi Huang, Gang He & Gong Chen

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Contributions

Q.W. initiated the project, carried out most of the reaction optimization and structural determination of products, and prepared the Supplememtary Information. S.A., Z.D., W.Z. and Z.H. expanded the reaction scope. G.H. supervised the project. G.C. supervised the project and prepared the manuscript.

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Correspondence to Gang He or Gong Chen.

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Supplementary information

Supplementary Information

Supplementary methods, Supplementary Figs. 1–45 Supplementary Tables 1–26, Supplementary references.

compound 40

Crystallographic data for compound 40.

compound 68

Crystallographic data for compound 68.

compound 70

Crystallographic data for compound 70.

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Wang, Q., An, S., Deng, Z. et al. Palladium-catalysed C−H glycosylation for synthesis of C-aryl glycosides. Nat Catal 2, 793–800 (2019). https://doi.org/10.1038/s41929-019-0324-5

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