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

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 (13)C 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.

Figure 1

Calculated (B3LYP) associative transition states for the reaction of isopropanol with 4,6-O-benzylidene protected manno- and glucopyransyl triflates leading to the formation of the α- and β-glycosides in each case. a) TS for α-mannoside formation, b) TS for β-mannoside formation, c) TS for α-glucoside formation, and d) TS for β-glucoside formation. For each transition state the calculated primary ¹³C and secondary ²H KIE values, the free energy of activation, the lengths of the partial bonds to the leaving group and to the nucleophile, and the approximate conformation of the pyranose ring are listed.

Figure 2

Mechanistic picture for the 4,6-O-benzylidene-directed formation of α- and β-gluco- and mannopyranosides