Amidoglycosylation Reactions of Glycal Metallanitrenes

描述（由申请人提供）：拟议研究的目标是开发、机理描述和应用新方法合成2-氨基糖、生物系统中的关键分子组分和前体，包括结构聚合物、酶抑制剂和细胞表面糖蛋白。该合成方法使用糖基3-氨基甲酸酯作为起始材料，并通过串联的烯烃酰胺化-糖基化序列-酰胺基糖基化-在糖框架的C2处引入氮，并建立与亲核反应伴侣（糖基受体）的异头连接。亚碘酰苯进行这一全面的氧化，在一个过程中，最好的催化铑（II）的羧酸盐，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，在更受阻的糖基表面上锻造C2-N键，并且理想地，糖基化应该立体特异性地发生，与新并入的氮取代基相反。虽然某些糖基3-氨基甲酸酯以高效和高异头立体选择性反应，但具有潜在高合成价值的其他底物在糖基化步骤中提供大量的C3-氧化的二氢吡喃酮副产物和低立体控制。使用（1）酰胺基糖基化和C3氧化均通过常见的金属苯胺中间体发生和（2）立体选择性糖基化需要来自C2氮的相邻基团参与，可能通过糖基氮丙啶的方式，本申请概述了如何控制糖基3-氨基甲酸酯框架的构象将在酰胺基糖基化反应中实现高化学选择性和立体选择性。其他拟议的调查将进一步阐明反应的机理细节，为改善和增加氨基糖基化制备氨基糖的效用和范围提供重要信息。与输入的方法开发和机制研究的拟议项目的组成部分，本申请概述了完成的合成的二糖部分的有效几丁质酶抑制剂allosamidin。酰胺基糖基化技术的迭代应用将使得能够流线化制备易于进行类似物合成的阿洛酰胺素二糖模块。该项目将在巴纳德学院（Barnard College）进行，这是一所女子文科本科学院，将为学生提供有机化学合成方面的许多机会，有助于吸引和推动他们从事化学和其他与健康有关的职业。由于氨基糖是许多生物化学系统和药物活性化合物的组成部分，因此改进其合成方法有助于了解和治疗人类疾病。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，这是应用于生物和药物化学问题所需的。这种方法将用于合成分子allosamidin的关键氨基糖片段，allosamidin是一种抑制一类称为几丁质酶的酶的物质，并可能为设计治疗哮喘的化合物提供基础。

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.