Site-Selective, Stereocontrolled Glycosylation Catalyzed by Bis-Thioureas

Abstract

The identification of general and efficient methods for the construction of oligosaccharides stands as one of the great challenges for the field of synthetic chemistry. Selective glycosylation of unprotected sugars and other polyhydroxylated nucleophiles is a particularly significant 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 inefficiencies arise directly from the application of such approaches. We describe here a new strategy for small-molecule-catalyst-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 site-selective 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.