Ligand-Promoted Enantioselective C-H Activation Reaction

配体促进的对映选择性 C-H 活化反应

• 批准号: 10299074
• 负责人: Jin-Quan Yu
• 金额: $ 58.58万
• 依托单位: SCRIPPS RESEARCH INSTITUTE, THE
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-08-01 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10299074
• 关键词: Acetates; Acids; Acute respiratory failure; Address; Aldehydes; Amides; Amines; Attenuated; Binding; Carbon; Carboxylic Acids; Chelating Agents; Collaborations; Coupling; Cysteine; Development; Distal; Drug Industry; Hydrogen Bonding; Ketones; Laboratories; Lactams; Lactones; Ligand Binding; Ligands; Mediating; Metals; Methods; Organic Synthesis; Oxidants; Pharmaceutical Preparations; Preparation; Proteins; Pyridones; Reaction; Research; Serine Hydrolase; Silver; Source; Technology; activity-based protein profiling; carbene; catalyst; chelation; covalent bond; design; drug candidate; drug discovery; human disease; inhibitor/antagonist; neutrophil elastase inhibitor; novel; novel strategies; novel therapeutics; programs; quinoline; recruit; scaffold; success; tert-Butylhydroperoxide; thioether

Project Summary Desymmetrizing activation of prochiral C–H bonds via metal insertion has emerged as a potentially transformative approach for the rapid and divergent synthesis of chiral compounds. However, a significant challenge prohibiting the broad utility of this approach is the poor reactivity of native substrates in the absence of externally-appended directing groups. This proposal directly addresses this challenge by developing two approaches to achieve the enantioselective C–H activation of a range of native substrates commonly found in organic synthesis and drug discovery—carboxylic acids, ketones, aldehydes and amines: (A) Development of chiral bidentate L,X-type ligands containing N-acetyl or pyridone motifs to accelerate C–H cleavage; (B) Development of chiral transient directing groups (TDGs) to enable enantioselective C–H activation of ketones, aldehydes and amines. Following initial discoveries of chiral ligands and TDGs, we will then develop various catalytic cycles to enable the enantioselective C–H activation of diverse native substrates, forming a range of carbon–carbon and carbon–heteroatom bonds asymmetrically. These novel reactions will provide a versatile platform for the construction of -, -, and -stereocenters. These technologies will be applied to drug discovery in collaboration with the pharmaceutical industry and academic laboratories. Specifically, the one- step access to the atypical chiral -lactones and lactams via enantioselective C–H activation will be applied to the discovery of covalent inhibitors for serine hydrolases and cysteine-dependent proteins using activity-based protein profiling.

项目摘要 通过金属插入对手孕C – H键的除对称激活已成为潜在的 用于手性化合物快速和不同合成的转化方法。但是，这是重要的 挑战禁止这种方法的广泛效用是在不存在的情况下，天然基质的反应性差 外部指导群体。该提案通过开发两个人直接解决了这一挑战 实现对映选择性C – H激活的方法 有机合成和药物发现 - 羧酸，酮，醛和胺：（a）发展 手性鸟酸L，X型配体含有N-乙酰基或吡啶酮基序以加速C – H裂解； （b） 手性瞬态指导组（TDGS）的发展以实现酮的对映选择性C – H激活， 醛和胺。在最初发现手性配体和TDG的发现之后，我们将开发各种 催化循环能够使潜水员底物的对映选择性C – H激活，形成一系列范围 碳 - 碳和碳 - 旋值键不对称。这些新颖的反应将提供多功能 建造-，-和-stereepenters的平台。这些技术将应用于药物 与制药行业和学术实验室合作的发现。具体而言，一个 通过对映选择性C – H激活将步骤访问非典型手性乳元和lactams和lactams将应用于 使用基于活性的丝氨酸水解酶和半胱氨酸依赖性蛋白的共价抑制剂发现共价抑制剂 蛋白质分析。