美国哈佛大学Jacobsen Eric N.团队报道了最小保护糖的位点选择性、立体控制糖基化。相关研究成果发表在2022年6月16日出版的《自然》。

确定构建低聚糖的通用有效方法是合成化学领域面临的重大挑战之一。无保护糖和其他多羟基亲核试剂的选择性糖基化是一个特别重要的目标，其不仅需要控制形成键的立体化学，还需要区分立体化学复合物中类似反应的亲核位点。化学家通常依赖多步保护基团策略来实现糖基化的位点控制，但直接来自于此类方法的应用实际效率低下。

该文中，研究人员描述了一种新的策略，即使用精确设计的双硫脲小分子催化剂对未受保护或最低保护的单糖和双糖，进行小分子催化剂控制的高度立体选择性和位置选择性糖基化。由此实现了多种多功能亲核细胞的立体和位点选择性半乳糖基化和甘露糖基化。动力学和计算研究表明，与糖结合蛋白中的研究类似，位点选择性来自稳定催化剂和亲核试剂之间的C–H/π相互作用。

该工作表明，高选择性糖基化反应可以通过控制稳定非共价相互作用来实现，这是碳水化合物选择性功能化的一种潜在通用策略。

附：英文原文

Title: Site-selective, stereocontrolled glycosylation of minimally protected sugars

Author: Li, Qiuhan, Levi, Samuel M., Wagen, Corin, Wendlandt, Alison E., Jacobsen, Eric N.

Issue&Volume: 2022-06-16

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 chemistry1,2. 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 contexts3,4. 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 approaches5–7. 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.

DOI: 10.1038/s41586-022-04958-w

Source: https://www.nature.com/articles/s41586-022-04958-w