Mixed Hydrogen-Bonding Flavin Catalysis for Asymmetric Transformations

描述(申请人提供)：有机化合物中不对称的催化生成是现代合成有机化学的一个主要焦点。虽然在过去的几十年里，沿着这些路线已经取得了许多进展，但创建任何给定的光学纯形式的立体中心的问题远未得到解决。金属介导的不对称催化已经创造了无数的方法来合成小分子的对映选择性，但所涉及的金属可能是昂贵的，危险的，并且很难大规模地去除。不对称有机催化为氢键催化领域提供了一种可持续的、高度有用的替代方法。手性尿素和硫脲氢键供体在催化一系列不对称碳-碳键形成反应中显示出广泛的用途，部分原因是它们能够结合和激活各种Lewis-碱性和离子底物。这种催化剂的一个不发达用途是它在不对称氧化和还原反应中的应用。黄素蛋白是一类不同的酶，它利用黄素辅因子进行氧化转化。与氢键催化相比，研究较少但功能惊人的有机催化领域涉及使用非酶结合的黄素来激活过氧化氢或联氨进行相应的氧化或还原反应。将黄素催化应用于不对称反应的方法很少。这一建议试图将不对称氢键催化和黄素催化这两个概念结合成一个能够在多种底物上实现对映选择性氧化和还原转化的混合催化系统。根据已建立的方法合成了硫脲或尿素和黄素催化剂，并将其应用于不对称Baeyer-Villiger反应、缺电子烯烃的不对称环氧化和缺电子烯烃的不对称加氢反应中。在所有提议的反应中，氮素和/或水是唯一的副产物。小分子疗法可以说是医学上对抗健康相关问题的最好工具。因此，对快速、廉价和环境友好的潜在药物的生产的需求一直存在。由于这项提议寻求创造新的方法来选择性地合成小分子，而不产生有害副产品，因此对公众健康具有特别重要的意义。

DESCRIPTION (provided by applicant): The catalytic generation of asymmetry in organic compounds is a major focus of modern synthetic organic chemistry. While many advances have been made along these lines in the past decades, the problem of creating any given stereocenter in optically pure form is far from being solved. Metal-mediated asymmetric catalysis has created countless methods for the enantioselective synthesis of small molecules, but the metals involved can be costly, hazardous, and difficult to remove on a large scale. Asymmetric organocatalysis provides a sustainable and highly useful alternative specifically in the realm of hydrogen-bonding catalysis. Chiral urea and thiourea hydrogen bond donors have shown broad utility in catalyzing a number of asymmetric carbon-carbon bond forming reactions, due in part to their ability to bind and activate a variety of Lewis-basic and ionic substrates. An underdeveloped use of such catalysis is its application to asymmetric oxidation and reduction reactions. Flavoproteins are a diverse class of enzymes that utilize a flavin cofactor to perform oxidative transformations. A less explored (as compared to hydrogen-bonding catalysis) but surprisingly powerful arena of organocatalysis involves using non-enzyme-bound flavins to activate hydrogen peroxide or hydrazine for respective oxidation or reduction reactions. Few methods have applied flavin catalysis to enantioselective reactions. This proposal seeks to combine the two concepts of asymmetric hydrogen-bonding catalysis and flavin catalysis into a hybrid catalytic system that would be capable of achieving enantioselective oxidative and reductive transformations on a wide variety of substrates. A library of thiourea or urea and flavin catalysts will be synthesized based on established methods and combined in application to the asymmetric Baeyer-Villiger reaction, the asymmetric epoxidation of electron-deficient olefins, and the asymmetric hydrogenation of electron-deficient olefins. In all of the proposed reactions dinitrogen and/or water are the sole byproducts. Small-molecule therapeutics are arguably medicine's best tools for combating health-related problems. Therefore, there is an ever-present need for the rapid, inexpensive, and environmentally friendly production of potential drugs. Since this proposal seeks to create new methods for the selective synthesis of small molecules with no hazardous byproducts it is of particular relevance to public health.