Ligand-promoted Enantioselective C-H Activation Reactions

项目摘要 虽然金属插入sp3 C-H键并随后进行官能化有可能提供 由于合成中的变革工具，这种方法对不对称催化的影响是温和的， 在开发这些非对称版本时遇到的一些未回答的挑战， 反应.该建议集中在两种方法的发展对映选择性C-H活化 广泛有用的底物的反应：（A）双齿手性配体的设计和（B）催化手性 指导组。我们将发展α-甲基C-H键的对映选择性C-H活化反应， 羧酸和羧酸盐衍生底物的亚甲基C-H键，以及羧酸和羧酸盐衍生底物的亚甲基C-H键， 胺和胺衍生的底物。这些反应将提供新的和通用的方法， 在不对称合成中构建手性中心。使用丰富和常见的 底物，以及转化的多样性将使钯催化的对映选择性C-H 功能化广泛适用于生物活性手性分子的合成。具体来说， 通过对映选择性C-H活化的异丁酸和新戊酸将被应用于产生 可通过基于活性的蛋白质谱分析评价以鉴定新药的新型丝氨酸水解酶抑制剂 导致糖尿病认知痴呆和细菌感染

Project Summary While metal insertion into, and subsequent functionalization of, sp3 C−H bonds has the potential to afford transformative tools in synthesis, the impact of this approach on asymmetric catalysis has been moderate due to a number of unanswered challenges encountered in the development of asymmetric version of these reactions. This proposal centers on the development of two approaches for enantioselective C–H activation reactions of broadly useful substrates: (A) the design of bisdentate chiral ligands and (B) catalytic chiral directing groups. We will develop enantioselective C–H activation reactions of -methyl C–H bonds and methylene C–H bonds of carboxylic acids and carboxylate derived substrates, as well as -C–H bonds of amines and amine derived substrates. These reactions will provide novel and versatile methodologies for constructing -, -, and -chiral centers in asymmetric synthesis. The use of abundant and common substrates, as well as the diversity of the transformations will render palladium-catalyzed enantioselective C–H functionalization broadly useful for the synthesis of bioactive chiral molecules. Specifically, desymmetrization of isobutyric and pivalic acids via enantioselective C–H activation will be applied to the generation of a library of novel serine hydrolase inhibitors that can be evaluated by activity-based protein profiling to identify new drug leads for diabetes, cognitive dementia and bacterial infection.