Dissecting the mechanisms of a class of chemical glycosylation using primary 13C kinetic isotope eff

Abstract

Although arguably the most important reaction in glycoscience, chemical glycosylations are among the least well understood of organic chemical reactions, resulting in an unnecessarily high degree of empiricism and a brake on rational development in this critical area. To address this problem, primary 13C kinetic isotope effects have now been determined for the formation of β- and α-manno- and glucopyranosides using a natural abundance NMR method. In contrast to the common current assumption, for three of the four cases studied the experimental and computed values are indicative of associative displacement of the intermediate covalent glycosyl trifluoromethanesulfonates. For the formation of the α-mannopyranosides, the experimentally determined KIE differs significantly from that computed for an associative displacement, which is strongly suggestive of a dissociative mechanism that approaches the intermediacy of a glycosyl oxocarbenium ion. The application of analogous experiments to other glycosylation systems should shed further light on their mechanisms and thus assist in the design of better reactions conditions with improved stereoselectivity. Chemical glycosylations are perhaps the most important reactions in glycoscience, but the mechanisms are not well understood. Here, quantum chemical calculations combined with natural-abundance NMR measurements of 13C kinetic isotope effects reveal both associative and dissociative mechanisms at the extremes of a continuum that depends on the relative stereochemistry of the substrate and the anomeric configuration of the product.

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Huang, M., Garrett, G., Birlirakis, N. et al. Dissecting the mechanisms of a class of chemical glycosylation using primary ¹³C kinetic isotope effects. Nature Chem 4, 663–667 (2012). https://doi.org/10.1038/nchem.1404

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