Ligand-Promoted Enantioselective C-H Activation Reaction

项目摘要 通过金属插入的前手性C-H键的去对称化活化已经成为一种潜在的 手性化合物快速发散合成的转化方法。然而，一个重要的 阻碍这种方法广泛应用的挑战是，在没有这种方法的情况下，原生底物的反应性很差 外部附加的导演组。该提案通过开发两个 实现一系列天然底物对映体选择性C-H活化的方法 有机合成和药物发现--羧酸、酮、醛和胺：(A)开发 手性双齿L，含N-乙酰或吡啶酮基序的X-型配体，可加速C-H裂解；(B) 开发手性瞬时导向基团(TDG)以使酮的对映选择性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，使各种天然底物的对映选择性C-H活化，形成一系列 碳-碳和碳-杂原子键是不对称的。这些新颖的反应将提供多种多样的 用于构建-，和立体中心的平台。这些技术将应用于药物 与制药业和学术实验室合作进行的发现。具体地说，就是-- 通过对映体选择性C-H活化逐步获得非典型手性-内酯和内酰胺类药物 基于活性的丝氨酸水解酶和半胱氨酸依赖蛋白共价抑制剂的发现 蛋白质图谱。

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.