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）：越来越多地认识到碳水化合物在包括人类疾病在内的生物学过程中起着的关键作用，将注意力集中在糖科学的快速发展领域上。在这个领域内，2-氨基糖占据了重要位置，例如，构成细胞表面糖蛋白的关键要素，包括在某些癌症类型的寡糖结构中，因此含有碳水化合物的疫苗含有2-氨基糖单元，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物用途包括抗生素和抗Influenza药物。 准备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中的机会。综合挑战包括引入含氮功能组和立体化学的控制，以将2-氨基糖单元与亲核糖基受体联系起来。也需要访问各种糖立体异构体，以实现结构活性关系的更完整的映射。拟议的研究的目的是提供高效且通用的化学合成工具，以应对2-氨基糖的构建固有的挑战。 该方法将是模块化的，涉及合成2-氨基糖糖基供体的合成，这些糖基供体将立体选择与受体亲核者联系起来。这些单元的构造将应用甘氨酸3-氨基甲酸酯的甲基硝基介导的酰基糖基化，重点是铜催化作用，以替代最近占主导地位的铑介导的反应。我们将产生N-戊烯基糖苷和糖基磷酸糖基构建块，从四个D-糖非映射体中的每一个开始，并将这些构件用于O-和C-糖基化反应。在硝基驱动的酰胺基化中建立的2N，3O-恶唑烷酮基将启用1,2倍或1,2-Cis糖基化。 由此产生的立体替代2-氨基糖构建块将被纳入直接适用于糖生物学研究的一系列结构。例如，将制备O连接的丝氨酸和苏氨酸氨基糖苷，将降低糖衍生物和硝基苯基糖苷的游离，用于化学和化学酶糖基化研究。总体而言，拟议的工作将增强可用于糖离进展的化学合成工具。 该项目将为Barnard College的学生提供出色的培训机会，Barnard College是一家女性文科本科机构。在这种环境中，参与化学研究为学生提供了与科学相关领域的进一步学习和职业的经验和动力，包括化学研究生研究，高中科学教学，制药行业的工作以及从事卫生职业的工作；巴纳德一直是学术界，工业和政府中女性化学家的关键来源。将要特别努力让来自代表性不足的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