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 CāH/Ļ 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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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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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.
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Li, Q., Levi, S.M., Wagen, C.C. et al. Site-selective, stereocontrolled glycosylation of minimally protected sugars. Nature 608, 74ā79 (2022). https://doi.org/10.1038/s41586-022-04958-w
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DOI: https://doi.org/10.1038/s41586-022-04958-w
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