Proton transfer and hydrogen bonding in glycosylation reactions

GRAPHICAL ABSTRACT

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 S_N2 and S_N1 nucleophilic substitution reactions. Reactions that follow S_N2 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_N1 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_N2 versus S_N1 dichotomy is made, where early proton transfer is associated with S_N2 like reactions and late proton transfer with S_N1. 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.

KEYWORDS:

• Glycosylation
• hydrogen bonding
• oligosaccharide synthesis
• proton transfer

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.