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

• 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
• 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
• 来源: https://reporter.nih.gov/project-details/9269001
• 关键词: Active Sites; Aerobic; Alcohols; Amides; Amines; Anabolism; Area; Behavior; Biological; Biology; Breathing; Carbamates; Cell Respiration; Chemicals; Chemistry; Complement; Complex; Coupled; Coupling; Development; Electron Transport; Electronics; Enzymes; Esters; Exhibits; Family; Formates; Glycols; Health; Hydroxylamine; Ketones; Kinetics; Ligands; Metals; Methods; Molecular; Natural Products; Nature; Oxidants; Oxidases; Oxidation-Reduction; Oxygen; Oxygenases; Pharmaceutical Preparations; Pharmacologic Substance; Process; Property; Protons; Quinones; Reaction; Reagent; Research; Resolution; Role; Route; Site; Staging; System; Therapeutic Agents; Urea; Work; base; catalyst; cofactor; dehydrogenation; formamide; innovation; nitroxyl; oxidation; polyol; small molecule; tertiary amine; wasting

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、天然药物和药物的合成中显示出重要的价值。 产品和其他生物活性化合物，因为它们往往有助于引入 杂原子进入这些分子。进行氧化的大多数方法 反应依赖于产生化学计量的废物的不希望的氧化剂， 限制了它们在大规模应用中的使用（例如，工艺规模制药 合成）。相比之下，自然界广泛使用最丰富的氧化剂O2， 氧化反应许多加氧酶和氧化酶具有氧化还原活性的有机 （共）催化剂，如醌和酪氨酰基自由基，在酶的活性位点。在 在拟议的工作中，我们将开发两类生物启发的催化反应， 用于合成氧化反应的氧化还原活性（共）催化剂：（1）用于合成氧化反应的醌催化剂 胺和其它胺的氧化脱氢和氧化偶联反应 底物，（2）用于氧化偶联反应的硝酰基自由基（共）催化剂，和对映体- 醇的非对映体和化学选择性氧化。醌催化反应 将促进N-杂环的脱氢和氧化偶联反应， 存在于>50%的小分子药物中。Cu/硝酰基化学将用于 实现多用途的氧化偶联反应，以生成酰胺、氨基甲酸酯， 尿素以及复杂分子中的位点选择性醇氧化，包括晚期- 天然产物和药物的分阶段功能化。在这两个项目中 领域，经验反应发现的努力将得到补充， 研究了（共）催化剂的催化机理和氧化还原行为。