Leveraging Protecting Groups, Lewis Bases, and Backside Attack for 1,2-cis-Selective Glycosylation

在化学系化学合成(SYN)计划的支持下，路易斯安那州立大学的贾斯汀·拉格斯博士将与其有机化学实验室的本科生和研究生一起开发低聚糖合成的新方法。寡糖是碳水化合物的聚合物，在三维空间中以受控的方式附着在特定的位置。然而，将低聚糖从其自然来源中分离出来并不是获得特定低聚糖真实样品的实际方法。生物相关碳水化合物的多样性要求社区继续开发受控方法来从头合成它们。在这里计划的研究中，将合成实验室合成低聚糖的关键构件。然后，将利用对有机化学的了解来确保构建块以正确的三维方向彼此结合，这是低聚糖合成中的一个重要问题。这项研究的成功将推动低聚糖合成科学的发展，并为研究碳水化合物的化学生物学提供工具，对生物医学研究具有潜在的重要意义。计划的公众推广活动包括与路易斯安那州立大学的向上跳跃计划合作，在化学实验室向低收入第一代高中生教授化学和基本技能，帮助这些学生为未来的科学研究做好准备。拉格斯博士和他的学生将研究醇与糖基化电化学性质的1，2-顺式选择性糖基化反应，包括三氯乙酰亚胺、N-苯基三氟乙酰亚胺和硫代糖苷。上述糖基化亲电基将被吸电子保护基团取代，并将在Lewis碱性添加剂的存在下与一系列醇进行糖基化反应。提出了利用吸电子保护基团和Lewis碱的协同作用来提高1，2-顺式的选择性。我们还将研究利用原位生成的苯炔来活化硫代糖苷，并利用该反应独特的机理特征来开发1，2-顺式选择性糖基化反应。此外，本文开发的1，2-顺式选择性糖基化的合成方法将被用于从多重耐药鲍曼不动杆菌D78菌株合成具有合成挑战性的富含1，2-顺式糖苷的四糖重复单元。这项工作的成功实施将促进对1，2-顺式选择性糖基化挑战的理解，并为实现这一转化的普遍方法提供步骤。这项工作对糖科学和糖生物学研究具有潜在的长期影响。这一奖项反映了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 (SYN) Program in the Division of Chemistry, Dr. Justin Ragains of Louisiana State University will work with undergraduate and graduate students in his organic chemistry laboratory to develop new approaches to the synthesis of oligosaccharides. Oligosaccharides are polymers of carbohydrates attached at specific loci and in controlled fashion in three-dimensional space. However, isolation of oligosaccharides from their natural sources is not a practical approach to obtaining authentic samples of specific oligosaccharides. The variety of biologically relevant carbohydrates requires that the community continue to develop controlled methods for their de novo synthesis. In the research planned here, key building blocks in the laboratory synthesis of oligosaccharides will be synthesized. An understanding of organic chemistry will then be used to ensure that the building blocks bond to one another in the correct three-dimensional orientation, an important problem in oligosaccharide synthesis. Successful execution of this research will advance the science of oligosaccharide synthesis and provide tools to study the chemical biology of carbohydrates with potentially important implications for biomedical research. Planned public outreach activities include partnering with Lousiana State University’s Upward Bound program to teach low-income, first-generation high school students about chemistry and basic skills in the chemistry lab to help prepare these students for future pursuits of science studies. Dr. Ragains and his students will study the 1,2-cis-selective glycosylation of alcohols with glycosylation electrophiles including trichloroacetimidates, N-phenyltrifluoroacetimidates, and thioglycosides. The aforementioned glycosylation electrophiles will be substituted with electron-withdrawing protecting groups, and glycosylations will be performed with a series of alcohols in the presence of Lewis-basic additives. The synergy of electron-withdrawing protecting groups and Lewis bases is proposed to promote high 1,2-cis selectivity. The activation of thioglycosides using in-situ-generated benzynes will also be studied, and unique mechanistic features of this reaction will also be exploited for the development of 1,2-cis-selective glycosylation. Furthermore, synthetic approaches to 1,2-cis-selective glycosylation developed herein will be leveraged toward the synthesis of a synthetically challenging and 1,2-cis glycoside-rich tetrasaccharide repeating unit from the multidrug-resistant Acinetobacter baumannii strain D78. The successful execution of this work will advance the understanding of the challenge of 1,2-cis-selective glycosylation and provide steps toward a generalized approach to this transformation. This work has potential long term implications for glycoscience and glycobiology studies in general.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.