Dissecting the Mechanisms of a Class of Chemical Glycosylation Using Primary (13)C Kinetic Isotope Effects

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 (13)C kinetic isotope effects now have been determined for the formation of β- and α-manno- and glucopyranosides by a natural abundance NMR method. In contrast to the common current assumption, for three of the four cases studied the experimental values concur with those computed for 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 comparable experiments to other glycosylation systems should shed further light on their glycosylation mechanisms and thus assist in the design of better reactions conditions with improved stereoselectivity.