Mixed Hydrogen-Bonding Flavin Catalysis for Asymmetric Transformations

混合氢键黄素催化不对称转化

• 批准号: 8126450
• 负责人: Noah Zachary Burns
• 金额: $ 4.05万
• 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 2012-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8126450
• 关键词: Alkenes; Binding; Carbon; Catalysis; Electrons; Enzymes; Flavins; Flavoproteins; Generations; Health; Hybrids; Hydrazine; 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性的催化产生是现代合成有机化学的一个主要焦点。尽管过去几十年来在这些方面取得了许多进展，但以光学纯形式创建任何给定立体中心的问题还远未得到解决。金属介导的不对称催化创造了无数对映选择性合成小分子的方法，但所涉及的金属可能成本高昂、危险且难以大规模去除。不对称有机催化提供了一种可持续且非常有用的替代方案，特别是在氢键催化领域。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，部分原因是它们具有结合和活化各种路易斯碱性和离子底物的能力。这种催化的一个尚未开发的用途是其在不对称氧化和还原反应中的应用。黄素蛋白是利用黄素辅因子进行氧化转化的多种酶。有机催化的一个较少探索（与氢键催化相比）但令人惊讶的强大领域涉及使用非酶结合的黄素来激活过氧化氢或肼以进行各自的氧化或还原反应。很少有方法将黄素催化应用于对映选择性反应。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，该系统能够在多种底物上实现对映选择性氧化和还原转化。将基于已建立的方法合成硫脲或尿素和黄素催化剂库，并将其组合应用于不对称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氢化。在所有提出的反应中，氮和/或水是唯一的副产物。小分子疗法可以说是解决健康相关问题的最佳医学工具。因此，始终需要快速、廉价且环境友好的生产潜在药物。由于该提案旨在创建选择性合成小分子且不产生有害副产物的新方法，因此与公共卫生特别相关。