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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A synergistic Rh(I)/organoboron-catalysed site-selective carbohydrate functionalization that involves multiple stereocontrol
Nature Chemistry Open Access 30 December 2022
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References
Boltje, T. J., Buskas, T. & Boons, G.-J. Opportunities and challenges in synthetic oligosaccharide and glycoconjugate research. Nat. Chem. 1, 611ā622 (2009).
Krasnova, L. & Wong, C.-H. Oligosaccharide synthesis and translational innovation. J. Am. Chem. Soc. 141, 3735ā3754 (2019).
Dimakos, V. & Taylor, M. S. Site-selective functionalization of hydroxyl groups in carbohydrate derivatives. Chem. Rev. 118, 11457ā11517 (2018).
Bati, G., He, J. X., Pal, K. B. & Liu, X. W. Stereo- and regioselective glycosylation with protection-less sugar derivatives: an alluring strategy to access glycans and natural products. Chem. Soc. Rev. 48, 4006ā4018 (2019).
Green, L. G. & Ley, S. V. in Carbohydrates in Chemistry and Biology (eds Ernst, B. et al.) Ch. 17, 427ā448 (Wiley-VCH, 2000).
Volbeda, A. G., van der Marel, G. A. & CodĆ©e, J. D. C. in Protecting Groups Strategies and Applications in Carbohydrate Chemistry (ed. Vidal, S.) Ch. 1, 1ā24 (Wiley-VCH, 2019).
Young, I. & Baran, P. Protecting-group-free synthesis as an opportunity for invention. Nat. Chem. 1, 193ā205 (2009).
Huang, Z. & Dong, G. Site-selectivity control in organic reactions: a quest to differentiate reactivity among the same kind of functional groups. Acc. Chem. Res. 50, 465ā471 (2007).
Hartwig, J. F. Catalyst-controlled site-selective bond activation. Acc. Chem. Res. 50, 549ā555 (2007).
Trincone, A. & Giordano, A. Glycosyl hydrolases and glycosyltransferases in the synthesis of oligosaccharides. Curr. Org. Chem. 10, 1163ā1193 (2006).
Lairson, L. L., Henrissat, B., Davies, G. J. & Withers, S. G. Glycosyltransferases: structures, functions, and mechanisms. Annu. Rev. Biochem. 77, 521ā555 (2008).
Guo, J. & Ye, X. S. Protecting groups in carbohydrate chemistry: influence on stereoselectivity of glycosylations. Molecules 15, 7235ā7265 (2010).
van der Vorm, S. et al. Acceptor reactivity in glycosylation reactions. Chem. Soc. Rev. 48, 4688ā4706 (2019).
van der Vorm, S. et al. Mapping the relationship between glycosyl acceptor reactivity and glycosylation stereoselectivity. Angew. Chem. Int. Ed. 57, 8240ā8244 (2018).
Cordero-Vargas, A. & Sartillo-Piscil, F. in ProtectingāGroupāFree Organic Synthesis: Improving Economy and Efficiency (ed. Fernandes, R. A.) Ch. 7, 183ā200 (Wiley, 2018).
Muramatsu, W. & Yoshimatsu, H. Regio- and stereochemical controlled KoenigsāKnorr-type monoglycosylation of secondary hydroxy groups in carbohydrates utilizing the high site recognition ability of organotin catalysts. Adv. Synth. Catal. 355, 2518ā2524 (2013).
Gouliaras, C., Lee, D., Chan, L. & Taylor, M. S. Regioselective activation of glycosyl acceptors by a diarylborinic acid-derived catalyst. J. Am. Chem. Soc. 133, 13926ā13929 (2011).
DāAngelo, K. A. & Taylor, M. S. Borinic acid catalyzed stereo- and regioselective couplings of glycosyl methanesulfonates. J. Am. Chem. Soc. 138, 11058ā11066 (2016).
Nishi, N., Nashida, J., Kaji, E., Takahashi, D. & Toshima, K. Regio- and stereoselective beta-mannosylation using a boronic acid catalyst and its application in the synthesis of a tetrasaccharide repeating unit of lipopolysaccharide derived from E. coli O75. Chem. Commun. 53, 3018ā3021 (2017).
Nishi, N. et al. Stereospecific Ī²ālārhamnopyranosylation through an SNiātype mechanism by using organoboron reagents. Angew. Chem. Int. Ed. 57, 13858ā13862 (2018).
Tomita, S. et al. Diboron-catalyzed regio- and 1,2-cis-Ī²-stereoselective glycosylation of trans-1,2-diols. J. Org. Chem. 85, 16254ā16262 (2020).
Hudson, K. L. et al. Carbohydrateāaromatic interactions in proteins. J. Am. Chem. Soc. 137, 15152ā15160 (2015).
Asensio, J. L., Arda, A., Canada, F. J. & Jimenez-Barbero, J. Carbohydrateāaromatic interactions. Acc. Chem. Res. 46, 946ā954 (2013).
Screen, J. et al. IR-spectral signatures of aromatic-sugar complexes: probing carbohydrate-protein interactions. Angew. Chem. Int. Ed. 46, 3644ā3648 (2017).
Davis, A. P. Biomimetic carbohydrate recognition. Chem. Soc. Rev. 49, 2531ā2545 (2020).
Arnaud, J., Audfray, A. & Imberty, A. Binding sugars: from natural lectins to synthetic receptors and engineered neolectins. Chem. Soc. Rev. 42, 4798ā4813 (2013).
Kawabata, T., Muramatsu, W., Nishio, T., Shibata, T. & Schedel, H. A catalytic one-step process for the chemo- and regioselective acylation of monosaccharides. J. Am. Chem. Soc. 129, 12890ā12895 (2007).
Griswold, K. S. & Miller, S. J. A peptide-based catalyst approach to the regioselective functionalization of carbohydrates. Tetrahedron 59, 8869ā8875 (2003).
Sun, X., Lee, H., Lee, S. & Tan, K. L. Catalyst recognition of cis-1,2-diols enables site-selective functionalization of complex molecules. Nat. Chem. 5, 790ā795 (2013).
Xiao, G. et al. Catalytic site-selective acylation of carbohydrates directed by cationān interaction. J. Am. Chem. Soc. 139, 4346ā4349 (2017).
Lee, J., Borovika, A., Khomutnyk, Y. & Nagorny, P. Chiral phosphoric acid-catalyzed desymmetrizative glycosylation of 2-deoxystreptamine and its application to aminoglycoside synthesis. Chem. Commun. 53, 8976ā8979 (2017).
Tay, J.-H. et al. Regiodivergent glycosylations of 6-deoxy-erythronolide B and oleandomycin-derived macrolactones enabled by chiral acid catalysis. J. Am. Chem. Soc. 139, 8570ā8578 (2017).
Park, Y. et al. Macrocyclic bis-thioureas catalyze stereospecific glycosylation reactions. Science 355, 162ā166 (2017).
Levi, S. M., Li, Q., Rƶtheli, A. R. & Jacobsen, E. N. Catalytic activation of glycosyl phosphates for stereoselective coupling reactions. Proc. Natl Acad. Sci. USA 116, 35ā39 (2019).
Mayfield, A. B., Metternich, J. B., Trotta, A. H. & Jacobsen, E. N. Stereospecific furanosylations catalyzed by bis-thiourea hydrogen-bond donors. J. Am. Chem. Soc. 142, 4061ā4069 (2020).
Li, Q., Levi, S. M. & Jacobsen, E. N. Highly selective Ī²-mannosylations and Ī²-rhamnosylations catalyzed by bis-thiourea. J. Am. Chem. Soc. 142, 11865ā11872 (2020).
Tsuzuki, S., Uchimaru, T. & Mikami, M. Magnitude and nature of carbohydrate-aromatic interactions in fucose-phenol and fucose-indole complexes: CCSD(T) level interaction energy calculations. J. Phys. Chem. A 115, 11256ā11262 (2011).
Raju, R. K., Ramraj, A., Vincent, M. A., Hillier, I. H. & Burton, N. A. Carbohydrateāprotein recognition probed by density functional theory and ab initio calculations including dispersive interactions. Phys. Chem. Chem. Phys. 10, 6500ā6508 (2008).
Ryu, H. et al. Pitfalls in computational modelling of chemical reactions and how to avoid them. Organometallics 37, 3228ā3239 (2018).
Plata, R. E. & Singleton, D. A. A case study of the mechanism of alcohol-mediated Morita Baylisā Hillman reactions. The importance of experimental observations. J. Am. Chem. Soc. 137, 3811ā3826 (2015).
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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