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: 8577984
• 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 2017-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8577984
• 关键词: Acids; 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; Hydrogen Bonding; Learning; Libraries; Ligands; Metals; Methods; Molecular; Mono-S; 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; public health relevance; 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 ?- and ?-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（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便捷构建提供新的合成路线。尽管此类反应潜力巨大，但与其他更先进的不对称催化方法相比，通过有机金属方法开发对映选择性 sp3 C-H 官能化仍处于起步阶段。该提案的重点是开发新型对映选择性 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设计和开发配体支架，配合底物和金属中心之间的弱配位来促进C-H活化。此外，我们将通过生物医学研究合作来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 激活中形成 5 元环钯以访问远程甲基和亚甲基 C-H 键的固有需求。我们的关键策略是设计一个依赖弱配位的模板，将金属引导至所需的远端 C-H 键。这种方法不仅可以前所未有地获得各种α-和β-取代的脂肪族羧酸衍生物，而且还为后期阶段提供了一个平台。 通过以前无法访问的远程 C-H 键的功能化来实现药物分子的多样化。