Ligand-Promoted Enantioselective C-H Activation Reaction

项目摘要 通过金属插入的前手性C-H键的去对称活化已经成为一种潜在的 这是一种快速和多样化合成手性化合物的变革性方法。然而，一个重要的 阻碍该方法广泛应用的挑战是在不存在天然底物的情况下天然底物的反应性差 外部附加的导向基团。该提案通过开发两个 实现一系列天然底物的对映选择性C-H活化的方法， 有机合成与药物发现-羧酸、酮、醛和胺：（A）有机合成与药物发现 含有N-乙酰基或吡啶酮基序的手性双齿L，X-型配体，以加速C-H裂解;（B） 开发手性瞬时导向基团（TDGs）以实现酮的对映选择性C-H活化， 醛和胺。在手性配体和TDG的初步发现之后，我们将开发各种 催化循环，使不同的天然底物的对映选择性C-H活化，形成一系列的 碳-碳和碳-杂原子键不对称。这些新的反应将提供一个通用的 用于构建双、双和双立体中心的平台。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，就是- 通过对映体选择性C-H活化的非典型手性α-内酯和内酰胺的分步获得将应用于 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 蛋白质谱分析

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.