Development of Site-Selective Glycosylation of Unprotected Sugars

项目总结/摘要 碳水化合物是生物体中最丰富的有机分子， 重要的生物学过程。合成碳水化合物越来越多地被用作 生物研究和作为药物和疫苗发现的先导化合物。但这种 由于缺乏有效和通用的常规制备方法， 这些重要的化合物。构建复合物的常规合成糖基化方法 碳水化合物依赖于保护基策略来实现选择性合成。无保护 糖具有许多羟基，这些羟基可以参与反应，产生各种不希望的 副产品相反，容易获得的糖的糖基化将构成简单的， 灵活而强大的方法来访问这些框架。该研究旨在开发 用于复杂碳水化合物合成的未保护糖的位点选择性糖基化。是 设想天然碳水化合物受体的能力可以以 配体。配体与糖基供体，糖基受体， 而催化剂对于实现位点选择性糖基化是至关重要的。这个强大的新 该策略将依赖于配体识别和结合特定糖的选择性能力 脚手架模拟碳水化合物受体和反应能力的配体设计 优化将被证明对于该关键转换是至关重要的，以避免各种不期望的变化。 反应途径最后，提出了实现生物活性复合物衍生化的方案 分子通过位点选择性糖基化。具体来说，糖肽类抗生素的糖基化 在药代动力学特性和生物学特性方面经历了有益的效果， 活动

Project Summary/Abstract Carbohydrates are the most abundant organic molecules in living organisms and regulate many important biological processes. Synthetic carbohydrates are increasingly used as probes for biological research and as lead compounds for drug and vaccine discovery. However, such endeavors are complicated by a lack of efficient and general methods for the routine preparation of these important compounds. Conventional synthetic glycosylation methods to build complex carbohydrates depend on protecting group strategies to achieve selective synthesis. Unprotected sugars posses many hydroxyl groups that can participate in the reaction giving various undesired byproducts. Conversely, glycosylation of readily available sugars would constitute a simple, flexible, and powerful means to access these frameworks. The proposed research aims to develop a site-selective glycosylation of unprotected sugars for complex carbohydrate synthesis. It is envisioned that the ability of natural carbohydrate receptors could be mimicked in the form of ligands. The non-covalent coordination of the ligands to the glycosyl donors, glycosyl acceptors, and the catalyst would be crucial to achieve the site-selective glycosylation. This powerful new strategy will rely on the selective ability of the ligands to recognize and bind to specific sugar scaffolds. Ligand design that mimics the ability of carbohydrate receptors and reaction optimization will prove critical to this key transformation in order to avoid various undesired reaction pathways. Finally, the proposal aims to achieve derivatization of complex bioactive molecules via site-selective glycosylation. Specifically, glycosylation of glycopeptide antibiotics have experienced beneficial effects with respect to pharmacokinetic properties and biological activities.