Construction and Union of 2-Amino Sugar Building Blocks

描述(由申请人提供)：人们对碳水化合物在生物过程中的关键作用的认识日益增强，包括人类疾病的进展，将注意力和努力集中在快速发展的糖科学领域。在这一领域中，2-氨基糖占据重要地位，例如构成细胞表面糖蛋白的关键成分，包括某些癌症类型特有的寡糖结构，因此含有2-氨基糖单元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学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在生物学和医学中研究和应用这些结构的机会。合成挑战包括引入含氮官能团和控制连接2-氨基糖单元与亲核糖基受体的立体化学。为了能够更完整地绘制结构-活性关系图，还需要获得不同范围的糖立体异构体。拟议研究的目标是提供高效和通用的化学合成工具，以应对构建2-氨基糖所固有的挑战。该方法将是模块化的，包括合成2-氨基糖基供体，这些给体将立体选择性地连接到受体亲核剂。这些装置的建设将应用金属硝烯介导的甘氨酸3-氨基甲酸酯的氨基糖基化，重点是铜催化，以替代最近占主导地位的铑介导的反应。我们将从四个D-糖基非对映异构体中的每一个开始，生产正戊烯基苷和糖基磷酸，并将这些基块用于O-和C-糖基化反应。供体的2N，3O-恶唑烷酮基团建立在硝基驱动的氨基糖基化中，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-氨基糖构建块将被合并到一系列直接适用于糖生物学研究的结构中。例如，将制备O-连接的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苷。总体而言，拟议的工作将加强可用于促进糖科学的化学合成工具。该项目将为巴纳德学院(Barnard College)的学生提供出色的培训机会，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提供了在科学相关领域进一步学习和职业的经验和动力，包括化学研究生学习、高中科学教学、制药行业的工作和进入卫生专业；巴纳德一直是学术界、工业界和政府部门女性化学家的主要来源。将特别努力让代表人数不足的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.