Stereoselective glycosylation via H-bond-mediated aglycone delivery

化学部化学合成计划支持阿列克谢·德姆琴科教授的项目。德姆琴科教授是密苏里大学圣路易斯分校化学和生物化学系的教员。德姆琴科教授的研究小组正在开发新的方法来完成将两个糖分子连接在一起的反应。这些反应被称为糖基化，本质上是为了组装在广泛的生物过程中普遍存在的碳水化合物结构类型，正在开发的糖基化反应的应用范围从治疗策略到诊断策略。这项工作的关键是更好地理解和进一步开发德姆琴科小组在前一个资助期发现的独特反应途径。这一发现使连接这两种糖的键能够以高度选择性的方式构建起来。该项目位于有机、碳水化合物和机械化学的交界处，非常适合各级科学家的教育。这项研究从机理和实用两个方面研究了PI小组发现的氢键介导的苷元传递(HAD)反应途径。这项工作的目标是完全控制糖基化的立体选择性。考虑到这一点，目前正在调查两个现象。在第一种方法中，之前开发的两种方法，溴促进的糖基化和HAD反应被结合在一起，为α-和β-糖基化提供了更高的立体选择性。在第二种方法中，构象开关被开发为手柄，用于提高HAD反应的效用。这些努力通过提供新的合成能力来获得具有更好立体控制性和更高产率的具有挑战性的多糖和糖偶联物，从而在战略上推动了糖科学领域的发展。所开发的方法用于改进哺乳动物糖类和微生物多糖的关键靶标的合成，具有潜在的作为治疗剂或诊断平台的应用。这项拟议研究的成功完成不仅推动了糖基化领域的发展，也为更大的化学、生物和医学科学做出了贡献。这个项目的成功离不开本科生和研究生的积极参与，他们接受了扎实的研究方法培训，并致力于解决综合重要的综合挑战。学生在PI实验室获得的积极培训和良好的出版和演示记录正在为他们在学术界和工业中的领先地位做准备。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。

The Chemical Synthesis Program of the Chemistry Division supports the project by Professor Alexei Demchenko. Professor Demchenko is a faculty member in the Department of Chemistry and Biochemistry at the University of Missouri - St. Louis. Professor Demchenko's research group is developing new methods for accomplishing reactions that hook two sugar molecules together. These reactions, called glycosylations, are essentially for assembling the types of carbohydrate structures that are prevalent in a wide range of biological processes and applications of the glycolsylation reactions being developed range from therapeutic to diagnostic strategies. Key to the effort is work both better understand and further develop a unique reaction pathway that was discovered by the Demchenko group during the previous funding period. This discovery is enabling the construction on the bond connecting the two sugars in a highly selective manner. The project lies at the interface of organic, carbohydrate, and mechanistic chemistry, and it is well suited for the education of scientists at all levels. This study is investigating both mechanistic and practical aspects of the H-bond-mediated Aglycone Delivery (HAD) reaction pathway discovered by the PI's group. The goal of the work is to completely control the stereoselectivity of the glycosylation. With this in mind, two phenomena are being investigated. In the first, two previously developed methods, bromine-promoted glycosylation and HAD reaction are being combined in a manner that affords higher stereoselectivity for both alpha- and beta-glycosylation. In the second, conformational switches are being developed as handles for enhancing the utility of the HAD reaction. These endeavors are strategically advancing the field of glycosciences by offering new synthetic capabilities for obtaining challenging glycans and glycoconjugates with better stereocontrol and higher yields. The developed methods are serving to improve the synthesis of key targets from mammalian glycomes and microbial glycans with potential application as therapeutic agents or diagnostic platforms. Successful completion of the proposed research is not only advancing the field of glycosylation, but is also making contributions to the larger chemical, biological, and medical sciences. Integral to the success of this program is the active participation of undergraduate and graduate students who receive solid training in research methods and work to solve synthetic important synthetic challenges. The vigorous training and strong publication and presentation records that students are gaining in the PI's laboratory is preparing them for leading positions in academia and industry.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.