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Halogen-bond-assisted radical activation of glycosyl donors enables mild and stereoconvergent 1,2-cis-glycosylation

Nature Chemistry volume 14, pages 686–694 (2022)Cite this article

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Abstract

The chemistry of carbohydrates has a history of over 100 years, but simple, stereoselective and efficient glycosylation methods remain highly needed to facilitate the studies of sugars in various disciplines. Here we report a strategy for 1,2-cis-glycosylation without using metals, strong (Lewis) acids, elaborate catalysts or labile substrates. Our method operates by a unique mechanism: it activates glycosyl donors through a radical cascade rather than the conventional acid-promoted, ionic process. As elucidated by computational and experimental studies, the allyl glycosyl sulfones (as donors) form halogen bond complexes with perfluoroalkyl iodides, which—merely by visible light irradiation—fragment via radical intermediates to give the electrophilic glycosyl iodides. In situ trapping by various nucleophiles affords, in a stereoconvergent manner, the challenging 1,2-cis-glycosides. This metal- and acid-free reaction shows remarkable tolerance to functional groups. The high stereoselectivity holds for a broad array of donors. This study suggests that the simple C2-alkoxy group can serve as an effective directing group for building 1,2-cis-glycosidic bonds.

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Fig. 1: Importance of carbohydrates and approaches to build glycosidic bonds.
Fig. 2: Preliminary mechanistic studies.
Fig. 3: Mechanistic explanation for 1,2-cis selectivity.

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Data availability

The authors declare that all data supporting the findings of this study are available in the paper and its Supplementary Information files.

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Acknowledgements

D.N. is supported by funding from National Natural Science Foundation of China (nos. 21922106 and 21772125) and the 1.3.5 Project for Disciplines of Excellence, West China Hospital. Additional support (K.N.H.) came from the National Science Foundation of the United States (CHE-1764328). We acknowledge J.-S. Yang (SCU) for helpful discussions. We thank X. Wang from the Analytical and Testing Center of Sichuan University for NMR experiments.

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  1. These authors contributed equally: Chen Zhang, Hao Zuo, Ga Young Lee, Yike Zou.

Authors and Affiliations

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

    Chen Zhang, Hao Zuo, Qiu-Di Dang & Dawen Niu

  2. Department of Chemistry and Biochemistry, University of California, Los Angeles, CA, USA

    Ga Young Lee, Yike Zou & K. N. Houk

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Contributions

D.N. conceived the idea, guided the project and wrote the manuscript with feedback from other authors. C.Z. made the initial observations and analysed the results. C.Z., H.Z. and Q.-D.D. explored the substrate scope and performed the mechanistic studies. Y.Z., G.Y.L. and C.Z. performed the density functional theory calculations on the reaction mechanism under the advice of K.N.H.

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Correspondence to K. N. Houk or Dawen Niu.

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Nature Chemistry thanks Pedro Merino and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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Supplementary Figs. 1–9, discussion, experimental methods and data, computational studies, NMR spectra and references.

Supplementary Data 1

Cartesian coordinates for computed species.

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Zhang, C., Zuo, H., Lee, G.Y. et al. Halogen-bond-assisted radical activation of glycosyl donors enables mild and stereoconvergent 1,2-cis-glycosylation. Nat. Chem. 14, 686–694 (2022). https://doi.org/10.1038/s41557-022-00918-z

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