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Site-selective, stereocontrolled glycosylation of minimally protected sugars

Abstract

The identification of general and efficient methods for the construction of oligosaccharides stands as one of the great challenges for the field of synthetic chemistry1,2. Selective glycosylation of unprotected sugars and other polyhydroxylated nucleophiles is a particularly significant goal, requiring not only control over the stereochemistry of the forming bond but also differentiation between similarly reactive nucleophilic sites in stereochemically complex contexts3,4. Chemists have generally relied on multi-step protecting-group strategies to achieve site control in glycosylations, but practical inefficiencies arise directly from the application of such approaches5,6,7. Here we describe a strategy for small-molecule-catalyst-controlled, highly stereo- and site-selective glycosylations of unprotected or minimally protected mono- and disaccharides using precisely designed bis-thiourea small-molecule catalysts. Stereo- and site-selective galactosylations and mannosylations of a wide assortment of polyfunctional nucleophiles is thereby achieved. Kinetic and computational studies provide evidence that site-selectivity arises from stabilizing C–H/π interactions between the catalyst and the nucleophile, analogous to those documented in sugar-binding proteins. This work demonstrates that highly selective glycosylation reactions can be achieved through control of stabilizing non-covalent interactions, a potentially general strategy for selective functionalization of carbohydrates.

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Fig. 1: Strategies for site-selective glycosylation and catalyst optimization.
Fig. 2: Scope studies.
Fig. 3: Linear-free-energy relationship study and catalyst optimization for galactosylation of α-3a.
Fig. 4: Kinetic and computational studies.

Data availability

The data that support the findings in this work are available within the paper and its Supplementary Information.

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Acknowledgements

This work was supported by the NIH through GM132571 and the Common Fund Glycoscience Program (U01 GM116249) and a postdoctoral fellowship to A.E.W., and by NSF pre-doctoral fellowships to S.M.L. and C.W.

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Authors

Contributions

Q.L., S.M.L., A.E.W. and E.N.J. conceived the work, S.M.L., Q.L., A.E.W. and C.C.W. conducted the experiments, E.N.J. directed the research, and Q.L., S.M.L., C.C.W. and E.N.J. wrote the manuscript.

Corresponding author

Correspondence to Eric N. Jacobsen.

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This Supplementary Information file contains Materials and Methods, Supplementary Text, Figs. 1–22 and Tables 1–11.

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Li, Q., Levi, S.M., Wagen, C.C. et al. Site-selective, stereocontrolled glycosylation of minimally protected sugars. Nature 608, 74–79 (2022). https://doi.org/10.1038/s41586-022-04958-w

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