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-氨基糖的新方法，生物系统中的关键分子成分和前体，包括结构聚合物、酶抑制剂和细胞表面糖蛋白。该合成方法以甘氨酸3-氨基甲酸酯为起始原料，通过串联的烯烃酰化-糖基化序列-氨基糖基化-在糖骨架的C2引入氮，并建立与亲核反应伙伴-糖基受体的异构键。碘代苯进行这一全面的氧化，在一个过程中，最好的催化作用是二氢吡喃(II)羧酸盐，显然涉及到一个与铑络合的酰基硝基中间体。酰胺化步骤是分子内的，在更受阻碍的糖基表面上锻造C2-N键，理想情况下，糖基化应该以立体专一性进行，而不是新加入的氮取代基。虽然某些糖基3-氨基甲酸酯反应效率高，立体选择性高，但其他具有高合成价值的底物在糖基化步骤中提供了大量的C3氧化二氢吡喃酮副产物和低立体控制。使用(1)氨基糖基化和C3氧化都通过共同的金属硝烯中间体发生的机理假设和(2)立体选择性糖基化需要C2氮的邻基参与，可能通过糖基氮杂环丙啶，本申请概述了如何控制甘氨酸3-氨基甲酸酯骨架的构象将在氨基糖基化反应中实现高的化学和立体选择性。其他拟议的研究将进一步阐明这些反应的机理细节，为改进和扩大氨基糖基化制备氨基糖的用途和范围提供关键信息。根据拟议项目的方法开发和机制研究部分的投入，本申请概述了有效几丁质酶抑制剂allsamidin的双糖部分的合成完成。氨基糖基化技术的迭代应用将使易于模拟合成的别三聚氰胺二糖模块的制备变得流线型。该项目将在巴纳德学院(Barnard College)进行，这是一所面向女性的本科文科学院，将为学生提供大量有机化学合成的机会，有助于吸引并推动他们进入化学和其他与健康相关的职业。由于氨基糖是许多生化系统和药用活性化合物的组成部分，因此改进它们的合成方法有助于了解和治疗人类疾病。这项拟议的研究将开发制备2-氨基糖的新方法，并精确控制反应性和分子几何，这是应用于生物和药物化学问题所必需的。这种方法将被用来合成别沙米丁分子的关键氨基糖片段，这种物质可以抑制一种被称为几丁质酶的酶，并可能为设计治疗哮喘的化合物提供基础。