Construction and Union of 2-Amino Sugar Building Blocks

描述（由申请人提供）：人们越来越意识到碳水化合物在生物过程（包括人类疾病的进展）中发挥的关键作用，将注意力和努力集中在快速发展的糖科学领域。在这一领域，2-氨基糖占据重要位置，例如构成细胞表面糖蛋白的关键元素，包括在某些癌症类型的低聚糖结构中，因此含有2-氨基糖单位的碳水化合物疫苗可以刺激肿瘤特异性免疫反应。2-氨基糖及其类似物的其他医疗用途包括抗生素和抗流感药物。制备2-氨基糖的新化学方法将增加研究和应用这些结构在生物学和医学上的机会。合成方面的挑战包括引入含氮官能团和控制将2-氨基糖单元连接到亲核糖基受体的立体化学。获得不同范围的糖立体异构体也是可取的，以实现更完整的结构-活性关系映射。提出的研究目标是提供高效和通用的化学合成工具，以满足构建2-氨基糖固有的挑战。该方法将是模块化的，包括合成2-氨基糖糖基供体，将立体选择性地连接到受体亲核试剂。这些单元的构建将应用金属腈介导的3-氨基甲酸乙酯氨基糖基化，重点是铜催化，作为最近占主导地位的铑介导反应的替代品。我们将从四种d -糖非对映体开始生产n-戊基糖苷和磷酸糖基，并将这些构建块用于O和c -糖基化反应。在亚硝基驱动的氨基糖基化过程中，供体的2N， 30 -恶唑烷酮基团将使1,2-反式或1,2-顺式糖基化成为可能。由此产生的立体多样的2-氨基糖构建块将被纳入一系列结构直接适用于糖生物学研究。例如，将制备o链丝氨酸和苏氨酸氨基糖苷，以及用于化学和化学酶糖多样化研究的游离还原糖衍生物和硝基苯基糖苷。总的来说，所提出的工作将增强化学合成工具可用于糖科学的进步。该项目将为巴纳德学院（Barnard College）的学生提供优秀的培训机会。巴纳德学院是一所面向女性的文科本科院校。在这种环境下，参与化学研究为学生在科学相关领域的进一步学习和职业生涯提供了经验和动力，包括化学研究生学习、高中科学教学、制药行业工作和进入卫生专业；巴纳德一直是学术界、工业界和政府中女性化学家的主要来源。将特别努力使来自代表性不足群体的学生参与拟议的研究。

DESCRIPTION (provided by applicant): An increasing awareness of the crucial roles that carbohydrates play in biological processes, including the progression of human disease, has focused attention and effort on the rapidly advancing field of glycoscience. Within this realm, 2-amino sugars occupy important positions, constituting, for example, key elements of cell- surface glycoproteins, including in oligosaccharide structures characteristic of certain cancer types, so that carbohydrate-based vaccines containing 2-amino sugar units could stimulate tumor-specific immune response. Other medicinal uses of 2-amino sugars and their analogues include antibiotics and anti-influenza drugs. New chemical methods for preparing 2-amino sugars will increase opportunities to study and apply these structures in biology and medicine. Synthetic challenges include introduction of the nitrogen-containing functional group and control of stereochemistry in linking 2-amino sugar units to nucleophilic glycosyl acceptors. Access to a diverse range of sugar stereoisomers is also desirable to enable a more complete mapping of structure-activity relationships. The goal of the proposed research is to provide efficient and versatile chemical synthesis tools to meet the challenges inherent in construction of 2-amino sugars. The approach will be modular, involving synthesis of 2-amino sugar glycosyl donors that will be linked stereoselectively to acceptor nucleophiles. Construction of these units will apply metallanitrene-mediated amidoglycosylation of glycal 3-carbamates, focusing on copper catalysis as an alternative to the rhodium- mediated reactions that have dominated recently. We will produce n-pentenyl glycoside and glycosyl phosphate building blocks, starting from each of the four D-glycal diastereomers and use these building blocks for O- and C-glycosylation reactions. The 2N,3O-oxazolidinone group of the donors, established in the nitrene- driven amidoglycosylation, will enable either 1,2-trans or 1,2-cis glycosylation. The resulting stereodiverse 2-amino sugar building blocks will be incorporated into a range of structures directly applicable to glycobiology studies. For example, O-linked serine and threonine aminoglycosides will be prepared, as will free reducing sugar derivatives and nitrophenyl glycosides for chemical and chemoenzymatic glycodiversification studies. Overall, the proposed work will enhance the chemical synthesis tools available for the advancement of glycoscience. The project will provide outstanding training opportunities for students at Barnard College, a liberal arts undergraduate institution for women. In this environment, participation in chemistry research provides students with experience and motivation for further study and careers in science-related areas, including graduate study in chemistry, high school science teaching, work in the pharmaceutical industry, and entry to health professions; Barnard has been a key source of women chemists in academia, industry, and government. Particular effort will be made to involve students from underrepresented groups in the proposed research.