Amidoglycosylation Reactions of Glycal Metallanitrenes

描述（由申请人提供）：拟议研究的目标是开发，机制描述和应用合成2-氨基糖的新方法，生物系统中的关键分子组分和前体，包括结构聚合物，酶抑制剂和细胞表面糖蛋白。合成方法以3-氨基甲酸乙二醇酯为原料，通过串联烯烃酰胺化-糖基化序列-氨基糖基化-在糖骨架的C2处引入氮，并与亲核反应伙伴糖基受体建立端粒连接。碘索苯进行这种全面氧化，这一过程最好由羧酸二钠催化，并且显然涉及铑络合的酰基亚硝烯中间体。酰胺化步骤是分子内的，在更受阻的糖面上形成C2-N键，理想情况下，糖基化应该是立体定向的，而不是新加入的氮取代基。虽然某些氨基甲酸糖酯反应效率高，具有较高的异构立体选择性，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较低的立体控制性。利用机理假设(1)氨基糖基化和C3氧化都是通过一个常见的金属二甲苯中间体发生的；(2)立体选择性糖基化需要C2氮的邻近基团参与，可能是通过一个糖基叠氮，本应用程序概述了如何控制3-氨基甲酸酯糖基化框架的构象，从而在氨基糖基化反应中实现高化学选择性和立体选择性。其他提出的研究将进一步阐明反应的机理细节，为改进和增加氨基糖基化制备的实用性和范围提供关键信息。在方法开发和机制研究两方面的投入下，本申请概述了有效几丁质酶抑制剂allosamidin双糖部分合成的完成。氨基糖基化技术的迭代应用将使制备易于进行类似物合成的异胺嘧啶双糖模块成为可能。该项目将在巴纳德学院（Barnard College）进行，这是一所女子本科文理学院，将为学生提供许多有机化学合成方面的机会，有助于吸引和推动他们从事化学和其他与健康相关的职业。由于氨基糖是许多生物化学系统和药用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。提出的研究将开发新的方法来制备具有精确控制反应性和分子几何结构的2-氨基糖，这是应用于生物和药物化学问题所必需的。这种方法将用于合成异胺嘧啶分子的一个关键氨基糖段，异胺嘧啶是一种抑制几丁质酶的物质，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.