Mixed Hydrogen-Bonding Flavin Catalysis for Asymmetric Transformations

描述（由申请人提供）：有机化合物中不对称的催化生成是现代合成有机化学的主要焦点。虽然在过去的几十年里沿着这条路线取得了许多进展，但以光学纯形式创造任何给定的立体中心的问题还远远没有解决。金属介导的不对称催化已经为小分子的对映选择性合成创造了无数的方法，但所涉及的金属可能昂贵，危险，并且难以大规模去除。不对称有机催化为氢键催化领域提供了一种可持续的、非常有用的替代方法。手性脲和硫脲氢键供体在催化许多不对称碳-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路易斯碱和离子底物。不对称氧化和不对称还原反应是这种催化剂的一个尚未开发的应用。黄素蛋白是一类利用黄素辅助因子进行氧化转化的酶。一个较少被探索的（与氢键催化相比）但令人惊讶的强大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肼进行各自的氧化或还原反应。很少有方法将黄素催化用于对映选择反应。该提案旨在将不对称氢键催化和黄素催化这两个概念结合到一个混合催化系统中，该系统将能够在各种底物上实现对映选择性氧化和还原转化。本文将在已有方法的基础上合成硫脲或尿素和黄素催化剂库，并将其结合应用于不对称Baeyer-Villiger反应、不对称缺电子烯烃环氧化反应和不对称缺电子烯烃加氢反应。在所有提出的反应中，二氮和/或水是唯一的副产物。小分子疗法可以说是治疗健康相关问题的最佳工具。因此，迫切需要快速、廉价和环保地生产潜在的药物。由于这项建议寻求创造无危险副产品的小分子选择性合成的新方法，因此与公共卫生特别相关。

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.