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Iron-catalysed reductive cross-coupling of glycosyl radicals for the stereoselective synthesis of C-glycosides

Nature Synthesis volume 1, pages 235–244 (2022)Cite this article

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Abstract

Stereochemically defined C-glycosides are prized for their biological activity. Developing a catalytic method that comprises non-precious metals to synthesize these C-glycosides remains challenging. Here, starting from readily accessible glycosyl chlorides, we show that an Earth-abundant iron-based catalyst promotes the facile generation of glycosyl radicals, which either react directly with an unsaturated electrophile or are captured by an organonickel species to facilitate C−C bond formation under mild reductive conditions. Exploration of these two reaction pathways across a range of substrates has produced a diverse array of C-glycoside products functionalized with alkenyl, alkynyl or aromatic anomeric groups, with excellent diastereocontrol. Mechanistic control and electron paramagnetic resonance spectroscopic experiments indicate that the active catalytic species is a low-valent iron complex formed through Mn reduction. The method was applied in the stereoselective synthesis of bioactive C-glycosides and therapeutically relevant analogues.

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Fig. 1: The significance of C-glycosides and the existing iron-catalysed protocols that generate them.
Fig. 2: Designing a reductive strategy that leverages iron catalysis to access diverse stereodefined C-glycosides.
Fig. 3: Reaction development.
Fig. 4: Mechanistic studies.
Fig. 5: Access to biologically relevant carbohydrates and analogues.

Data availability

All data supporting the findings of this study are available within the Article and its Supplementary Information. Crystallographic data for the structure (6f) reported in this Article have been deposited at the Cambridge Crystallographic Data Centre, under deposition number CCDC 2056391. Copies of the data can be obtained free of charge via https://www.ccdc.cam.ac.uk/structures/.

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Acknowledgements

This research was supported by the Research Scholarship Block from the Ministry of Education, Singapore: C-143-000-207-532, C-141-000-777-532 and C-141-000-333-532 (M.J.K.), and NSFC-21725204 (G.C.). We thank G. K. Tan (National University of Singapore) for X-ray crystallographic analysis. We thank X.-X. Wang and X. Lu (University of Science and Technology of China) for assistance in preparing samples for the electron paramagnetic resonance experiments.

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Author notes

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

  2. These authors jointly supervised this work: Gong Chen & Ming Joo Koh.

Authors and Affiliations

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

    Quanquan Wang, Yi Jiang & Ming Joo Koh

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

    Qikai Sun, Huixing Zhang & Gong Chen

  3. High Magnetic Field Laboratory, Chinese Academy of Sciences, Hefei, China

    Lu Yu & Changlin Tian

  4. Hefei National Laboratory for Physical Sciences at the Microscale and School of Life Sciences, University of Science and Technology of China, Hefei, China

    Changlin Tian

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Contributions

Q.W., Q.S., Y.J. and H.Z. developed the catalytic method. L.Y. and C.T. carried out the electron paramagnetic resonance experiments. M.J.K. and G.C. directed the investigations. M.J.K. wrote the manuscript with revisions provided by the other authors.

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Correspondence to Gong Chen or Ming Joo Koh.

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Nature Synthesis thanks the anonymous reviewers for their contribution to the peer review of this work. Thomas West was the primary editor on this article and managed its editorial process and peer review in collaboration with the rest of the editorial team.

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Supplementary information

Supplementary Information

Supplementary Tables 1–16, Figs. 1–28, experimental data, synthesis and characterization data, NMR spectra, X-ray crystallographic data and references.

Supplementary Data 1

Crystallographic data for compound 6f.

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Wang, Q., Sun, Q., Jiang, Y. et al. Iron-catalysed reductive cross-coupling of glycosyl radicals for the stereoselective synthesis of C-glycosides. Nat Synth 1, 235–244 (2022). https://doi.org/10.1038/s44160-022-00024-5

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