Thiocrown Ether: Reversing S_N1 to S_N2 Pathways in 1,2-<i>cis</i> Phosphoryl Glycosylation

Glycosyl phosphosaccharides, a ubiquitous and crucial family of complex carbohydrates, widely occur in living organisms. Considering the importance in various physiological and pathophysiological processes, the synthesis of glycosyl phosphosaccharides is a key scientific issue in carbohydrate chemistry. However, their preparation presents two major challenges: achieving high stereoselectivity in phosphorylated glycosides and maintaining the stability of labile phosphoester linkages. Here, we redesigned the classical Koenigs-Knorr glycosylation reaction to efficiently synthesize 1,2-<i>cis</i> phosphorylated glycosides, using 1,7,13-trithio-18-crown-6 as a rationally designed additive. The key to this strategy is that the thiocrown ether could reverse the reaction mechanism from S_N1 to S_N2 pathways by modulating the interaction between silver and glycosyl chloride donors. This method enables phosphoryl glycosylation to proceed at room temperature without the use of acid or base. The feasibility of this strategy is demonstrated by the synthesis of 54 complex glycosyl phosphosaccharides with high efficiency and stereoselectivity, the gram-scale production of UDP-6-N₃-Glc, and the synthesis of a tetrasaccharide diphosphate derived from <i>Haemophilus influenzae</i> type C.