Proton transfer and hydrogen bonding in glycosylation reactions

Creating general methods for stereospecific formation of glycosidic linkages is a long term goal of synthetic chemists. It has long been hoped that by elucidating the mechanism of the glycosylation reaction appropriate strategies to accomplish this goal can be developed. In particular, the glycosylation reaction is known to lie on the borderline between classical S(N)2 and S(N)1 nucleophilic substitution reactions. Reactions that follow S(N)2 pathways can often be designed to be stereospecific by optimization of the leaving group and other reaction parameters. With less reactive donors and acceptors reactions tend towards the S(N)1 end of the continuum and achieving stereospecificity becomes more challenging. An hypothesis that the point along the reaction coordinate where the obligatory proton transfer takes place is correlated to the S(N)2 versus S(N)1 dichotomy is made, where early proton transfer is associated with S(N)2 like reactions and late proton transfer with S(N)1. It is further suggested that by deliberately controlling the pre-proton transfer hydrogen bonding interaction one may develop a strategy to achieve stereospecificity even for challenging glycosylations. [GRAPHICS]