Stereoselective glycosylation via H-bond-mediated aglycone delivery

通过氢键介导的糖苷配基递送进行立体选择性糖基化

• 批准号: 2147156
• 负责人: Alexei Demchenko
• 金额: $ 45万
• 依托单位: Saint Louis University
• 依托单位国家: 美国
• 项目类别: Standard Grant
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-01 至 2022-08-31
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=2147156&HistoricalAwards=false
• 关键词: Stereoselective; glycosylation; via; bond; mediated

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.

化学系的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州-圣路易斯大学化学与生物化学系的教员。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。这些反应称为糖基化，基本上用于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，并且正在开发的糖基化反应的应用范围从治疗到诊断策略。这项工作的关键是更好地理解和进一步开发Demchenko小组在上一个资助期间发现的独特反应途径。 这一发现使得能够以高度选择性的方式构建连接两种糖的键。该项目位于有机，碳水化合物和机械化学的界面，非常适合各级科学家的教育。本研究调查PI小组发现的氢键介导的糖苷配基传递（HAD）反应途径的机制和实践方面。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，正在研究两种现象。在第一种方法中，两种先前开发的方法，溴促进的糖基化和HAD反应以提供更高的α-和β-糖基化立体选择性的方式相结合。在第二，构象开关正在开发作为手柄，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和更高产量的具有挑战性的聚糖和糖缀合物，从而在战略上推进糖科学领域。所开发的方法用于改善来自哺乳动物糖组和微生物聚糖的关键靶标的合成，其具有作为治疗剂或诊断平台的潜在应用。成功完成拟议的研究不仅推进了糖基化领域，而且还为更大的化学，生物和医学科学做出了贡献。该计划的成功不可或缺的是本科生和研究生的积极参与，他们在研究方法方面接受了扎实的培训，并致力于解决合成的重要合成挑战。学生在PI实验室获得的积极培训和强大的出版和演示记录正在为他们在学术界和工业界的领导地位做准备。该奖项反映了NSF的法定使命，并被认为值得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来支持。

项目成果

Synthesis and Glycosidation of Anomeric Halides: Evolution from Early Studies to Modern Methods of the 21st Century.

• DOI: 10.1021/acs.chemrev.2c00029
• 发表时间: 2022-07-13
• 期刊: CHEMICAL REVIEWS
• 影响因子: 62.1
• 作者: Singh, Yashapal;Geringer, Scott A.;Demchenko, Alexei V.
• 通讯作者: Demchenko, Alexei V.

Direct Synthesis of Glycans Containing Challenging ManNAcA Residues

直接合成含有具有挑战性的 ManNAcA 残基的聚糖

• DOI: 10.1021/acs.joc.1c02351
• 发表时间: 2022
• 期刊: The Journal of Organic Chemistry
• 作者: Alex, Catherine;Demchenko, Alexei V.
• 通讯作者: Demchenko, Alexei V.

N-Alkylated Analogues of Indolylthio Glycosides as Glycosyl Donors with Enhanced Activation Profile.

作为糖基供体的吲哚硫代糖苷的 N-烷基化类似物，具有增强的激活特性。

• DOI: 10.1002/ejoc.202200300
• 发表时间: 2022
• 期刊: European journal of organic chemistry
• 影响因子: 2.8
• 作者: Shrestha,Ganesh;Panza,Matteo;Singh,Yashapal;Stine,KeithJ;Demchenko,AlexeiV
• 通讯作者: Demchenko,AlexeiV

Recent Advances in Stereocontrolled Mannosylation: Focus on Glycans Comprising Acidic and/or Amino Sugars

• DOI: 10.1002/tcr.202100201
• 发表时间: 2021-10
• 期刊: The Chemical Record
• 作者: Catherine Alex;A. Demchenko