Amidoglycosylation Reactions of Glycal Metallanitrenes

糖金属氮烯的酰胺糖基化反应

• 批准号: 7252852
• 负责人: CHRISTIAN M. ROJAS
• 金额: $ 21.66万
• 依托单位: BARNARD COLLEGE
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-03-01 至 2010-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7252852
• 关键词: Acids; Affect; Alkenes; Amino Sugars; Arts; Asthma; Aziridines; Biochemical; Biological; Carbamates; Chemistry; Chemistry, Other; Chitinase; Class; Complex; Coupling; Development; Disaccharides; Electrons; Enzyme Inhibitor Drugs; Enzyme Inhibitors; Enzymes; Ethers; Ethyl Ether; Face; Glucal; Goals; Investigation; Iodine; Link; Membrane Glycoproteins; Metals; Methodology; Methods; Modeling; Molecular; Molecular Conformation; Nitrogen; Object Attachment; Organic Chemicals; Organic Chemistry; Outcome; Oxidants; Pharmaceutical Chemistry; Polymers; Preparation; Process; Range; Reaction; Research; Rhodium; Role playing therapy; Route; Students; System; Technology; Testing; Woman; allosamidin; allosamine; amidation; analog; aziridine; base; carboxylate; career; catalyst; chemical synthesis; college; design; dirhodium tetraacetate; enol; forging; glycosylation; human disease; improved; inhibitor/antagonist; insight; iodosobenzene; metal complex; method development; nitrene; oxidation; programs; research and development; stereochemistry; sugar

DESCRIPTION (provided by applicant): The goals of the proposed research are the development, mechanistic description, and application of new methodology for the synthesis of 2-amino sugars, crucial molecular components and precursors in biological systems, including structural polymers, enzyme inhibitors, and cell-surface glycoproteins. The synthetic approach uses glycal 3-carbamates as starting materials and proceeds through a tandem alkene amidation-glycosylation sequence-amidoglycosylation-to introduce nitrogen at C2 of the sugar framework and to establish an anomeric linkage to a nucleophilic reaction partner, the glycosyl acceptor. Iodosobenzene carries out this overall oxidation, in a process best catalyzed by dirhodium(II) carboxylates and apparently involving a rhodium-complexed acyl nitrene intermediate. The amidation step is intramolecular, forging the C2-N bond on the more hindered glycal face, and, ideally, glycosylation should occur stereospecifically, anti to the newly incorporated nitrogen substituent. While certain glycal 3-carbamates react with efficiency and high anomeric stereoselectivity, other substrates with potentially high synthetic value provide substantial amounts of C3-oxidized dihydropyranone byproducts and low stereocontrol in the glycosylation step. Using the mechanistic hypotheses that (1) both amidoglycosylation and C3 oxidation occur via a common metallanitrene intermediate and (2) stereoselective glycosylation requires neighboring-group participation from the C2 nitrogen, probably by way of a glycosyl aziridine, this application outlines how controlling the conformation of the glycal 3-carbamate framework will enable both high chemo- and stereoselectivity in the amidoglycosylation reactions. Other proposed investigations will further illuminate mechanistic details of the reactions, providing crucial information for improving and increasing the utility and scope of amidoglycosylation for the preparation of amino sugars. With input from both the method development and mechanistic study components of the proposed project, this application outlines the completion of a synthesis of the disaccharide portion of the potent chitinase inhibitor allosamidin. Iterative application of the amidoglycosylation technology will enable streamlined preparation of an allosamidin disaccharide module readily amenable for analogue synthesis. To be conducted at Barnard College, an undergraduate liberal arts college for women, the project will provide students with numerous opportunities in organic chemical synthesis, helping to attract and propel them into careers in chemistry and other health-related professions. Because amino sugars are constituents of numerous biochemical systems and medicinally active compounds, improved methods for their synthesis can contribute to efforts aimed at understanding and treating human diseases. The proposed research will develop new ways of preparing 2-amino sugars with the precise control of reactivity and molecular geometry that is required for application to problems in bio- and medicinal chemistry. This methodology will be used to synthesize a key amino sugar segment of the molecule allosamidin, a substance that inhibits a class of enzymes known as chitinases and may provide a basis for the design of compounds for treating asthma.

描述（由申请人提供）：拟议研究的目标是开发、机理描述和应用合成 2-氨基糖、生物系统中关键分子成分和前体的新方法，包括结构聚合物、酶抑制剂、和细胞表面糖蛋白。该合成方法使用糖醛3-氨基甲酸酯作为起始原料，并通过串联烯烃酰胺化-糖基化序列-酰胺糖基化-在糖框架的C2处引入氮并与亲核反应伙伴（糖基受体）建立异头连接。碘代苯进行这种全面氧化，该过程最好由羧酸二铑(II)催化，并且显然涉及铑络合的酰基氮烯中间体。酰胺化步骤是分子内的，在受阻较多的糖面上形成 C2-N 键，并且理想情况下，糖基化应立体定向地发生，与新掺入的氮取代基相反。虽然某些糖醛3-氨基甲酸酯反应效率高且异头立体选择性高，但其他具有潜在高合成价值的底物在糖基化步骤中提供大量的C3-氧化二氢吡喃酮副产物和低立体控制。使用以下机制假设：(1) 酰胺糖基化和 C3 氧化均通过常见的金属氮烯中间体发生，以及 (2) 立体选择性糖基化需要 C2 氮的邻近基团参与，可能通过糖基氮丙啶的方式，本申请概述了如何控制构象糖基3-氨基甲酸酯框架的结构将使酰胺糖基化反应具有高化学选择性和立体选择性。其他拟议的研究将进一步阐明反应的机制细节，为改进和增加氨基糖基化在氨基糖制备中的效用和范围提供重要信息。根据拟议项目的方法开发和机理研究部分的输入，该申请概述了有效几丁质酶抑制剂异糖脒的二糖部分的合成的完成。酰胺糖基化技术的迭代应用将能够简化制备易于进行类似物合成的别糖脒二糖模块。该项目将在巴纳德学院（一所女子本科文理学院）进行，将为学生提供大量有机化学合成的机会，帮助吸引和推动他们从事化学和其他与健康相关的职业。由于氨基糖是众多生化系统和药用活性化合物的组成部分，因此改进其合成方法可以有助于旨在理解和治疗人类疾病的努力。拟议的研究将开发制备 2-氨基糖的新方法，精确控制反应性和分子几何形状，这是解决生物和药物化学问题所需的。该方法将用于合成异糖脒分子的关键氨基糖片段，这种物质可抑制一类称为几丁质酶的酶，并可为治疗哮喘的化合物的设计提供基础。