Bioinspired Oxidation of Organic Molecules with Organic (Co-)Catalysts

用有机（共）催化剂进行有机分子的仿生氧化

基本信息

批准号：
9269001
负责人：
Shannon S Stahl
金额：
$ 2.5万
依托单位：
UNIVERSITY OF WISCONSIN-MADISON
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-04-01 至 2020-03-31
项目状态：
已结题

项目摘要

Oxidation reactions exhibit significant value in the synthesis of pharmaceuticals, natural products and other bioactive compounds, since they often facilitate the introduction of heteroatoms into these molecules. The majority of methods for performing oxidation reactions rely on undesirable oxidants that generate stoichiometric waste, which often limits their use in large-scale applications (e.g., process-scale pharmaceutical synthesis). In contrast, Nature widely uses the most abundant oxidant, O2, in selective oxidation reactions. Many oxygenases and oxidases feature redox-active organic (co)catalysts, such as quinones and tyrosyl radicals, in the active site of the enzyme. In the proposed work, we will develop reactions catalyzed by two classes of bioinspired redox-active (co)catalysts for synthetic oxidation reactions: (1) quinone catalysts for oxidative dehydrogenation and oxidative coupling reactions of amines and other substrates, (2) nitroxyl radical (co)catalysts for oxidative coupling reactions, and enantio- , diastereo-, and chemoselective oxidations of alcohols. The quinone-catalyzed reactions will facilitate dehydrogenation and oxidative coupling reactions of N-heterocycles, which are present in >50% of small-molecule drugs. The Cu/nitroxyl chemistry will be used to achieve versatile oxidative coupling reactions to generate amides, carbamates, and ureas as well as site-selective alcohol oxidation in complex molecules, including late- stage functionalization of natural products and pharmaceuticals. In both of these project areas, empirical reaction discovery efforts will be complemented by holistic mechanistic studies of the catalytic mechanisms and redox behavior of the (co)catalysts.

氧化反应在药物、天然产物的合成中表现出重要的价值产品和其他生物活性化合物，因为它们通常有助于引入杂原子进入这些分子。大多数进行氧化的方法反应依赖于产生化学计量废物的不良氧化剂，这些废物通常限制了它们在大规模应用中的使用（例如，过程规模的制药合成）。相比之下，大自然广泛使用最丰富的氧化剂 O2，选择性地氧化反应。许多加氧酶和氧化酶都具有氧化还原活性有机物酶活性位点的（共）催化剂，例如醌和酪氨酰自由基。在在拟议的工作中，我们将开发由两类生物启发催化的反应用于合成氧化反应的氧化还原活性（助）催化剂：（1）醌催化剂胺等的氧化脱氢和氧化偶联反应底物，（2）氧化偶联反应的硝酰自由基（共）催化剂，以及对映体醇的、非对映氧化和化学选择性氧化。醌催化反应将促进N-杂环的脱氢和氧化偶联反应，这存在于 >50% 的小分子药物中。 Cu/硝酰基化学将用于实现多种氧化偶联反应，生成酰胺、氨基甲酸酯和脲以及复杂分子中的位点选择性醇氧化，包括晚期天然产物和药物的阶段功能化。在这两个项目中领域，经验反应发现工作将得到整体机制的补充（共）催化剂的催化机制和氧化还原行为的研究。