Construction and Union of 2-Amino Sugar Building Blocks

2-氨基糖砌块的构建和联合

• 批准号: 8771675
• 负责人: CHRISTIAN M. ROJAS
• 金额: $ 30.5万
• 依托单位: BARNARD COLLEGE
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-01 至 2019-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8771675
• 关键词: Academia; Amidone; Amino Sugars; Aminoglycosides; Antibiotics; Area; Arts; Attention; Awareness; Biological; Biological Factors; Biological Process; Biology; C-glycoside; Carbamates; Carbohydrates; Catalysis; Characteristics; Chemicals; Chemistry; Collaborations; Copper; Drug Industry; Educational process of instructing; Elements; Environment; Enzyme Inhibitor Drugs; Enzyme Inhibitors; Free Will; Glucal; Glycobiology; Glycopeptides; Glycosides; Goals; Government; Health; Health Occupations; Immune response; Industry; Institution; Investigation; Kentucky; Laboratories; Link; Maps; Mediating; Medicine; Membrane Glycoproteins; Methods; Motivation; Nitrogen; Oligosaccharides; Organic Synthesis; Oxazolidinones; Pharmaceutical Chemistry; Play; Positioning Attribute; Process; Reaction; Research; Rhodium; Role; Science; Serine; Source; Stereoisomer; Structure; Structure-Activity Relationship; Students; Threonine; Training; Transition Elements; Underrepresented Minority; Universities; Vaccines; Variant; Woman; Work; allosamine; amidation; analog; anti-influenza drug; base; cancer type; career; chemical synthesis; college; experience; functional group; galactal; glycosylation; high school; human disease; inorganic phosphate; interest; mannosamine; meetings; metal complex; nitrene; nucleophilic addition; public health relevance; stereochemistry; sugar; tool; tumor; vaccine candidate

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.

描述（由申请人提供）：对碳水化合物在生物过程（包括人类疾病进展）中所起关键作用的认识日益提高，已将注意力和努力集中在快速发展的糖科学领域。在该领域内，2-氨基糖占据重要位置，构成例如细胞表面糖蛋白的关键元件，包括在某些癌症类型的寡糖结构特征中，使得含有2-氨基糖单元的基于碳水化合物的疫苗可以刺激肿瘤特异性免疫应答。2-氨基糖及其类似物的其他医药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在生物学和医学中应用这些结构的机会。合成的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。获得各种糖立体异构体也是期望的，以使得能够更完整地绘制结构-活性关系。拟议研究的目标是提供有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，涉及2-氨基糖糖基供体的合成，其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苯胺氮介导的糖基3-氨基甲酸酯的酰胺基糖基化，重点是铜催化作为最近占主导地位的铑介导的反应的替代方案。我们将从四种D-糖基非对映异构体中的每一种开始生产n-戊烯基糖苷和糖基磷酸构建单元，并将这些构建单元用于O-和C-糖基化反应。在氮烯驱动的酰胺基糖基化中建立的供体的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。 所得到的立体多样性2-氨基糖结构单元将被并入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促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，拟议的工作将增强可用于糖科学进步的化学合成工具。 该项目将为巴纳德学院的学生提供出色的培训机会，巴纳德学院是一所女子文科本科院校。在这种环境中，参与化学研究为学生提供了进一步学习和科学相关领域的职业生涯的经验和动力，包括化学研究生学习，高中科学教学，制药行业的工作，以及进入卫生行业;巴纳德一直是学术界，工业界和政府的女性化学家的关键来源。将特别努力让代表性不足群体的学生参与拟议的研究。

项目成果

Glycal Metallanitrenes for 2-Amino Sugar Synthesis: Amidoglycosylation of Gulal-, Allal-, Glucal-, and Galactal 3-Carbamates.

• DOI: 10.1021/acs.joc.8b00893
• 发表时间: 2018-08-03
• 期刊: The Journal of organic chemistry
• 作者: Buttar S;Caine J;Goné E;Harris R;Gillman J;Atienza R;Gupta R;Sogi KM;Jain L;Abascal NC;Levine Y;Repka LM;Rojas CM
• 通讯作者: Rojas CM