Glycosyl phosphates are shown to be activated to stereospecific nucleophilic substitution reactions by precisely tailored bis-thiourea catalysts. Enhanced reactivity and scope is observed with phosphate relative to chloride leaving groups. Stronger binding (Km) to the H-bond donor and enhanced reactivity of the complex (kcat) enables efficient catalysis with broad functional group compatibility under mild, neutral conditions.

We report highly β-selective bis-thioureas-catalyzed 1,2-cis-O-pyranosylations employing easily accessible acetonideprotected donors. A wide variety of alcohol nucleophiles, including complex natural products, glycosides, and amino acids were βmannosylated and β-rhamnosylated successfully using an operationally simple protocol under mild and neutral conditions. Less nucleophilic acceptors such as phenols were also glycosylated efficiently in excellent yields and with high β-selectivities.

The identi cation of general and e cient methods for the construction of oligosaccharides stands as one of the great challenges for the eld of synthetic chemistry. Selective glycosylation of unprotected sugars and other polyhydroxylated nucleophiles is a particularly signi cant goal, requiring not only control over the stereochemistry of the forming bond but also differentiation between similarly reactive nucleophilic sites in stereochemically complex contexts. Chemists have generally relied on multi-step protecting-group strategies to achieve site control in glycosylations, but practical ine ciencies arise directly from the application of such approaches. We describe here a new strategy for small-moleculecatalyst-controlled, highly stereo-and site-selective glycosylations of unprotected or minimally protected mono-and disaccharides using precisely designed bis-thiourea small-molecule catalysts. Stereo-and siteselective galactosylations and mannosylations of a wide assortment of polyfunctional nucleophiles is thereby achieved. Kinetic and computational studies provide evidence that site selectivity arises from stabilizing C-H/π interactions between the catalyst and the nucleophile, analogous to those documented in sugar-binding proteins. This work demonstrates that highly selective glycosylation reactions can be achieved through control of stabilizing noncovalent interactions, a potentially general strategy for selective functionalization of carbohydrates.