Ligand-promoted Enantioselective and Remote C-H Activation Reactions

配体促进的对映选择性和远程 C-H 激活反应

• 批准号: 8899584
• 负责人: Jin-Quan Yu
• 金额: $ 53.06万
• 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 2016-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8899584
• 关键词: Agonist; Amines; Amino Acids; Area; Biomedical Research; Carbon; Carboxylic Acids; Catalysis; Chemicals; Chemistry; Collaborations; Complex; Development; Disease; Distal; Drug Compounding; Electrons; Funding; Goals; Group Identifications; Health; Hydrogen Bonding; Learning; Libraries; Ligands; Metals; Methods; Molecular; Non-Insulin-Dependent Diabetes Mellitus; Pharmaceutical Preparations; Pharmacologic Substance; Reaction; Research; Research Institute; Route; Serine Hydrolase; Site; Staging; Technology; Transition Elements; United States National Institutes of Health; Ursidae Family; activity-based protein profiling; carbene; design; drug candidate; frontier; human disease; infancy; inhibitor/antagonist; novel; pharmacophore; programs; receptor; scaffold; screening; success

DESCRIPTION (provided by applicant): Transition metal-catalyzed enantioselective sp3 C-H activation reactions can provide new synthetic routes for the expedient construction of bioactive molecules and drug compounds. Despite the great potential of such reactions, the development of enantioselective sp3 C-H functionalizations via an organometallic approach is in its infancy when compared to other more advanced methods of asymmetric catalysis. This proposal is centered on the development of novel enantioselective sp3 C-H activation reactions that would broaden the scope of transition metal-catalyzed asymmetric C-H functionalizations. The key strategy for achieving this goal is via the design and development of ligand scaffold that cooperates with the weak coordination between the substrate and the metal center to promote C-H activation. Additionally, we will relay our efforts through collaborations to biomedical research in identifying new drug candidates for the treatment of human diseases. Furthermore, we will strive to overcome the inherent need for the formation of 5-membered palladacycles in sp3 C-H activation to access remote methyl and methylene C-H bonds. Our key strategy is to design a template that relies on weak coordination to direct the metal towards the desired distal C-H bond. This approach would not only provide unprecedented access to a variety of γ- and δ-substituted aliphatic carboxylic acid derivatives, but also provide a platform for the late-stage diversification of drug molecules via functionalization of previously inaccessible remote C-H bonds.

描述（由申请人提供）：过渡金属催化的对映选择性sp3 C-H活化反应可以为生物活性分子和药物化合物的有利构建提供新的合成路线。尽管这种反应的巨大潜力，通过有机金属方法的对映选择性sp3 C-H官能化的发展是在其起步阶段相比，其他更先进的方法的不对称催化。该提议的核心是发展新型的对映选择性sp3 C-H活化反应，这将拓宽过渡金属催化的不对称C-H官能化的范围。实现这一目标的关键策略是通过配体支架的设计和开发，该配体支架与底物和金属中心之间的弱配位合作以促进C-H活化。此外，我们将通过合作继续努力进行生物医学研究，以确定治疗人类疾病的新候选药物。此外，我们将努力克服在sp3 C-H活化中形成5元钯杂环以接近远程甲基和亚甲基C-H键的内在需要。我们的关键策略是设计一种模板，该模板依赖于弱配位将金属导向所需的远端C-H键。这种方法不仅提供了前所未有的获得各种γ-和δ-取代的脂肪族羧酸衍生物的途径，而且还提供了一个平台，用于通过官能化以前不可接近的远程C-H键来实现药物分子的后期多样化。