Stereocontrolled Glycosylation under Cooperative Catalysis

在化学系化学合成计划的支持下，圣路易斯大学的阿列克谢·德姆琴科教授将研究糖基化的新方法。糖基化是一种反应，它将简单的碳水化合物连接在一起，形成称为糖链的寡聚网络。虽然多糖是生物、医学和工业领域理想的分子，但复杂的碳水化合物对有机化学家来说是具有挑战性的目标。这项研究旨在研究Demchenko小组发现的新的糖基化反应的机理和实用方面，从而扩大它们的用途。该项目的总体目标是发明有效的方法，以高度选择性的方式形成关键的糖苷键。该项目位于有机、碳水化合物和机械化学的交界处。这种高度选择性的化学反应的发展将为化学生物学的基础研究以及在开发诊断和治疗药物方面的潜在应用提供结构定义的葡聚糖。这个项目的成功离不开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。该研究项目将通过与来自不同背景和教育水平的人的互动，为学员提供参与、学习和成长的机会。这项拟议的研究将调查Demchenko小组在之前的资助期间发现的两个新化学反应的机理和实践方面，即合作催化的Koenigs-Knorr(4K)反应和氢键介导的苷元传递(HAD)反应。在目标A的范围内，对4K反应进行改进和简化，以得到一种通用的方法，在合作催化下直接激活硫代糖苷和其他稳定的糖基供体。在目标B的范围内，将4K反应和HAD反应结合成一个通用的“4K-HAD”平台，努力开发出一种更好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相关糖链靶标的合成。这项拟议研究的成功完成不仅将推动糖基化领域的发展，还将改善为生物和生物医学研究提供定义的糖基化系统的机会。该奖项反映了NSF的法定使命，并通过使用基金会的智力优势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.