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）：拟议研究的目标是生物系统中2-氨基糖，至关重要的分子成分和前体合成新方法的开发，机理描述和应用，包括结构性聚合物，酶抑制剂和细胞表面糖蛋白。合成方法使用甘氨酸3-氨基甲酸酯作为起始材料，并通过串联烯烃胺化 - 糖基化序列 - 氨基糖基化来在糖框架的C2上引入氮，并建立与核仁反应伙伴的异源链接，糖基受体。碘苯苯在最佳用Dirhodium（II）羧酸盐催化的过程中进行了这种总体氧化，并且显然涉及若iu依的粘合酰基硝基硝酸盐中间体。脑分子内的步骤是分子内的，在更具阻碍的甘氨酸面上伪造了C2-N键，理想情况下，应立体特殊性地发生糖基化，抗新掺入的氮取代基。虽然某些甘氨酸3-氨基甲酸酯与效率和高异常立体选择性反应，但具有潜在高合成价值的其他底物可提供大量的C3氧化二氢吡喃酮副产物和低立体控制的糖基化步骤。使用（1）（1）通过常见的金属苯乙烯中间发生（1）（1）（1）（1）（1）进行中间体和（2）立体选择性糖基化的氧化作用，就需要从C2氮的参与中参与相邻的糖基氮糖基二核苷，这可能是如何控制的。胺化反应中的高化学和立体选择性。其他提出的研究将进一步阐明反应的机理细节，从而提供至关重要的信息，以改善和增加胺化糖基化的效用和范围，以制备氨基糖。随着拟议项目的方法开发和机械研究成分的输入，该应用概述了有效的几丁质抑制剂同胺胺的合成的完成。酰胺基糖基化技术的迭代应用将使能够简化同胺二糖模块的模块，以便于模拟合成。该项目将在Barnard College是一所本科生文科学院，该项目将为学生提供许多有机化学合成的机会，从而帮助他们吸引并推动他们从事化学和其他与健康有关的职业。由于氨基糖是众多生化系统和药物活性化合物的成分，因此改进的合成方法可以促进旨在理解和治疗人类疾病的努力。拟议的研究将开发新的方法来制备2-氨基糖，并以精确控制反应性和分子几何形状，这是应用于生物和药物化学问题所必需的。该方法将用于合成分子异酰胺素的关键氨基糖段，该物质抑制一种称为几丁质酶的酶，并可能为治疗哮喘的化合物设计提供基础。