Donor‐Reactivity‐Controlled Sialylation Reactions

Although tremendous efforts have been made for the efficient preparation of sialosides, controlling the stereochemical outcome of sialylation reaction still remains one of the most challenging tasks due to the unique chemical structure of sialic acid. We developed a new strategy to statistically analyze the stereoselectivity of sialylation reactions on six types of p‐tolyl thiosialosides in NIS/TfOH system using Relative Reactivity Value (RRV) as the indicator. Analysis of the reaction mechanism showed the formation of the relatively stable glycosyl bromide and glycosyl chloride intermediates from halide‐ and triflate‐containing promotors in the absence of an acceptor. We found that the α/β‐stereoselectivity, yields, and intermediate changes were associated with their donor reactivity. These findings enable to tailor the most suitable building blocks for stereo‐controlled sialylation reactions. The relative reactivity value was found to provide a guideline to control the stereoselectivity of sialylation reactions under NIS/TfOH promotion system at −40 °C, resulting α‐selectivity >75 % for α(2→6)‐linked disaccharides and β‐selectivity >75 % for β(2→3)‐linked disaccharides.