Stereocontrolled Glycosylation under Cooperative Catalysis

在化学系化学合成项目的支持下，圣路易斯大学的Alexei Demchenko教授将研究糖基化的新方法。糖基化是将简单碳水化合物连接在一起形成称为聚糖的低聚网络的反应。尽管聚糖是生物、医学和工业界理想的分子，但复杂碳水化合物对有机化学家来说是具有挑战性的目标。本研究旨在研究 Demchenko 小组发现的新糖基化反应的机制和实践方面，从而扩大其实用性。该项目的总体目标是发明以高度选择性的方式形成关键糖苷键的有效方法。该项目位于有机化学、碳水化合物和机械化学的交汇处。这种高度选择性化学反应的发展将为化学生物学的基础研究以及开发诊断和治疗剂的潜在应用提供结构确定的聚糖。该计划成功的一个重要因素是包括中学研究人员在内的各级学生的积极参与，他们将接受扎实的研究方法培训。该研究计划将为学员提供通过与不同背景和教育水平的人互动、参与、学习和成长的机会。拟议的研究将调查 Demchenko 小组在之前的资助期间发现的两种新化学反应的机理和实践方面，即协同催化 Koenigs-Knorr (4K) 反应和氢键介导的糖苷配基传递 (HAD) 反应。 在目标A的范围内，将改进和简化4K反应，以产生一种在协同催化下直接活化硫代糖苷和其他稳定糖基供体的通用方法。在目标B的范围内，4K反应和HAD反应将结合成一个通用的“4K-HAD”平台，以开发一种更优越的立体选择性糖基化方法。正在开发的方法有可能简化所有常见糖苷键和广泛的生物学相关聚糖靶标的合成。成功完成拟议的研究不仅将推动糖基化领域的发展，而且还将改善生物和生物医学研究中确定的糖基化系统的获取。该奖项反映了 NSF 的法定使命，并通过使用基金会的智力价值和更广泛的影响审查标准进行评估，被认为值得支持。

With the support of the Chemical Synthesis Program in the Division of Chemistry, Professor Alexei Demchenko of Saint Louis University will study new methods for glycosylation. Glycosylation is a reaction that connects simple carbohydrates together into oligomeric networks called glycans. Although glycans are desirable molecules for biological, medical, and industrial communities, complex carbohydrates are challenging targets for organic chemists. This research aims to investigate mechanistic and practical aspects of new glycosylation reactions discovered by the Demchenko group, thereby broadening their utility. The overall goal of this project is the invention of efficient approaches for the formation of critical glycosidic bonds in a highly selective manner. The project lies at the interface of organic, carbohydrate, and mechanistic chemistry. The development of such highly selective chemical reactions would provide access to structurally defined glycans for fundamental studies in chemical biology as well as for potential applications in developing diagnostic and therapeutic agents. Integral to the success of this program is the active participation of students of all levels including middle school researchers, who will receive solid training in research methods. This research program will provide opportunities for trainees to engage, learn, and grow through interactions with people from different backgrounds and education levels. The proposed study will investigate mechanistic and practical aspects of two new chemical reactions discovered by the Demchenko group during previous funding periods, Cooperatively catalyzed Koenigs-Knorr (4K) reaction and H-bond-mediated Aglycone Delivery (HAD) reaction. Under the scope of Objective A, the 4K reaction is to be improved and streamlined to yield a universal method for the direct activation of thioglycosides and other stable glycosyl donors under cooperative catalysis. Under the scope of Objective B, the 4K reaction and the HAD reaction will be combined into one universal “4K-HAD” platform in an effort to develop a superior method for stereoselective glycosylation. The methods under development have the potential to streamline the synthesis of all common glycosidic linkages and a broad range of biologically relevant glycan targets. Successful completion of the proposed research will not only advance the field of glycosylation but will also improve access to defined glycosylated systems for biological, and biomedical study.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.