Although glycochemistry has developed in leaps and bounds in the last two decades, the synthesis of a complex oligosaccharide or of a glycoconjugate remains a very challenging albeit critically important task. The difficulties inherent in such syntheses arise because of numerous reasons that center on the complexity of the chemistry when compared to that of oligonucleotide and peptide synthesis. The most important reactions in any oligosaccharide synthesis are the formation of the glycosidic bonds and there exists many empirical methods toward this end. The longstanding theme of this grant has been that the rationalization of complex oligosaccharide synthesis is best achieved by an improved understanding of the mechanisms of glycosidic bond formation, coupled with the development of more efficient, straightforward and general mechanism-based methods. Progress along these lines has transformed by the way we think about glycosidic bond formation to the extent that predictions can now be made. One aspect of this proposal addresses remaining issues in glycosidation mechanisms through the development of cation clock methods for the determination of reaction kinetics in sialic acid glycosidic bond formation. A further aspect of this proposal is the mechanism-based prediction of reactivity leading to the development of a novel method for the control of anomeric stereoselectivity through the control of side chain conformation. Finally, the knowledge of how side chain conformation affects reactivity is related to transition state stabilization by glycoside hydrolases and glycosyltransferases, resulting in the design of improved inhibitors for such critical carbohydrate processing enzymes.