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: 10439915
• 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/10439915
• 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; 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.

项目总结