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）：人们越来越认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，已经将注意力和努力集中在快速发展的糖科学领域。在这个领域中，2-氨基糖占据重要地位，例如构成细胞表面糖蛋白的关键元素，包括某些癌症类型特征的寡糖结构，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药用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以及控制 2-氨基糖单元与亲核糖基受体连接的立体化学。为了更完整地绘制结构-活性关系，还需要获得各种糖立体异构体。拟议研究的目标是提供高效且多功能的化学合成工具，以应对 2-氨基糖构建中固有的挑战。 该方法将是模块化的，涉及2-氨基糖糖基供体的合成，该供体将立体选择性地与受体亲核体连接。这些单元的构建将应用金属氮烯介导的糖基 3-氨基甲酸酯酰胺糖基化，重点关注铜催化作为最近占主导地位的铑介导反应的替代方案。我们将从四种 D-糖基非对映体开始生产正戊烯基糖苷和糖基磷酸结构单元，并使用这些结构单元进行 O- 和 C- 糖基化反应。在氮宾驱动的酰胺糖基化中建立的供体的2N,3O-恶唑烷酮基团将能够实现1,2-反式或1,2-顺式糖基化。 由此产生的立体多样性 2-氨基糖构建模块将被纳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。总体而言，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（一所女子文科本科院校）的学生提供出色的培训机会。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、制药行业工作以及进入健康专业；巴纳德一直是学术界、工业界和政府中女性化学家的重要来源。我们将特别努力让来自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