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^1,2. 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^3,4. 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^5–7. 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.

确定构建寡糖的通用且有效的方法是合成化学领域的巨大挑战之一^1,2。未受保护的糖和其他多羟基化亲核试剂的选择性糖基化是一个特别重要的目标，不仅需要控制形成键的立体化学，还需要区分立体化学复杂环境中类似反应性亲核位点^3,4。化学家通常依靠多步保护基团策略来实现糖基化的位点控制，但实际效率低下直接源于此类方法的应用^5-7。我们在这里描述了一种新策略，使用精确设计的双硫脲小分子催化剂，对未保护或最低限度保护的单糖和二糖进行小分子催化剂控制的、高度立体和位点选择性的糖基化。由此实现多种多官能亲核试剂的立体和位点选择性半乳糖基化和甘露糖基化。动力学和计算研究提供的证据表明，位点选择性是由催化剂和亲核试剂之间稳定的 C-H/π 相互作用产生的，类似于糖结合蛋白中记录的那些。这项工作表明，通过控制稳定的非共价相互作用可以实现高度选择性的糖基化反应，这是碳水化合物选择性功能化的潜在通用策略。