Mixed Hydrogen-Bonding Flavin Catalysis for Asymmetric Transformations

混合氢键黄素催化不对称转化

• 批准号: 7749364
• 负责人: Noah Zachary Burns
• 金额: $ 4.52万
• 依托单位: HARVARD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-01 至 2012-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7749364
• 关键词: Alkenes; Binding; Carbon; Catalysis; Electrons; Enzymes; Flavins; Flavoproteins; Generations; Hybrids; Hydrazine; Hydrazines; Hydrogen Bonding; Hydrogen Peroxide; Hydrogenation; Libraries; Mediating; Medicine; Metals; Methods; Organic Chemistry; Oxidation-Reduction; Pharmaceutical Preparations; Production; Public Health; Reaction; System; Therapeutic; Thiourea; Urea; Water; base; catalyst; cofactor; combat; oxidation; small molecule; tool

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.

描述（由申请人提供）：有机化合物中不对称的催化产生是现代合成有机化学的主要重点。尽管在过去的几十年中，这些界限已经取得了许多进步，但以光学纯正形式创建任何给定的立体中心的问题尚未解决。金属介导的不对称催化已经为对映选择性的小分子的合成创造了无数方法，但是所涉及的金属可能是昂贵，危险且难以大规模去除的方法。不对称的有机催化提供了一种可持续且非常有用的替代方案，该替代方案在氢键催化的领域中提供了一种。手性尿素和硫脲氢键供体在催化许多不对称的碳碳键形成反应方面表现出广泛的效用，部分原因是它们具有结合和激活各种Lewis-Basic和离子底物的能力。这种催化的不发达的使用是将其用于不对称氧化和还原反应。黄素蛋白是一种使用黄素辅因子进行氧化转化的多种酶。一个较少的探索（与氢键构催化相比），但令人惊讶的有强大的有机立体领域涉及使用非酶结合的黄素激活过氧化氢或氢氮，以进行各自的氧化或还原反应。很少有方法将黄素催化作用到对映选择性反应中。该提案旨在将不对称氢键催化和黄素催化的两个概念结合到混合催化系统中，该系统将能够实现各种底物上的对映选择性氧化和还原性转化。将基于既定方法合成硫库或尿素和黄素催化剂的库，并合并到不对称的Baeyer-Villiger反应，电子缺陷烯烃的不对称环氧化以及电子缺陷氧化氧化甲素的不对称水解的不对称环氧化中。在所有提出的反应中，二氮和/或水都是唯一的副产品。可以说，小分子疗法是药物打击与健康相关问题的最佳工具。因此，存在潜在药物的快速，廉价且环保的生产的需求。由于该提案旨在为选择性合成小分子而没有危险副产品创建新方法，因此与公共卫生特别相关。