GRAPHICAL ABSTRACT
![](/cms/asset/fe936f70-308b-471c-8c93-6f2a4f0ffe02/lcar_a_1365369_uf0001_b.gif)
ABSTRACT
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 SN2 and SN1 nucleophilic substitution reactions. Reactions that follow SN2 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 SN1 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 SN2 versus SN1 dichotomy is made, where early proton transfer is associated with SN2 like reactions and late proton transfer with SN1. 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.
Acknowledgements
D.M.W. thanks his host Prof. Kui Yu from the Institute of Atomic and Molecular Physics, Sichuan University, Chengdu 610065, China as during his stay the initial drafts of this manuscript were prepared. He also thanks many colleagues and co-workers who contributed to the background studies on which this manuscript is based. J.G. thanks the financial support from NIH/NCI through a grant (R01CA095142) awarded to Prof. Zhongwu Guo.