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: 10651648
• 负责人: Jin-Quan Yu
• 金额: $ 59.73万
• 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/10651648
• 关键词: Acceleration; Acetates; Acids; Acute respiratory failure; Address; Aldehydes; Amides; Amines; Attenuated; Binding; Carbon; Carboxylic Acids; 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; tautomer; 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.

项目概要 通过金属插入来去对称激活前手性 C-H 键已成为一种潜在的方法 快速、多样化合成手性化合物的革命性方法。然而，一个重要的 阻碍这种方法广泛应用的挑战是天然底物在不存在的情况下反应性差 外部附加的指导基团。该提案通过开发两个直接解决这一挑战 方法实现一系列常见天然底物的对映选择性 C-H 激活 有机合成和药物发现——羧酸、酮、醛和胺：(A) 开发 含有 N-乙酰基或吡啶酮基序的手性二齿 L,X 型配体，可加速 C-H 裂解； (二) 开发手性瞬时导向基团 (TDG) 以实现酮的对映选择性 C–H 激活， 醛类和胺类。在初步发现手性配体和 TDG 之后，我们将开发各种 催化循环能够对不同天然底物进行对映选择性 C-H 活化，形成一系列 碳-碳和碳-杂原子键不对称。这些新颖的反应将提供一种多功能的 用于构建α-、β-和β-立体中心的平台。这些技术将应用于药物 与制药行业和学术实验室合作发现。具体来说，一是—— 通过对映选择性 C-H 活化逐步获得非典型手性 -内酯和内酰胺将应用于 使用基于活性的方法发现丝氨酸水解酶和半胱氨酸依赖性蛋白的共价抑制剂 蛋白质分析。