Catalyst-Controlled, Site-Selective C-H Functionalization of Heterocycles

杂环化合物的催化剂控制、位点选择性 C-H 官能化

• 批准号: 8539807
• 负责人: Jin-Quan Yu
• 金额: $ 34.74万
• 依托单位: SCRIPPS RESEARCH INSTITUTE, THE
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-05 至 2016-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8539807
• 关键词: Analgesics; Antineoplastic Agents; Binding Sites; Biological; Chemicals; Communities; Complex; Copper; Coupling; Crestor; Development; Diabetes Mellitus; Electrons; Funding; Gleevec; Heterocyclic Compounds; Hydrogen Bonding; Imatinib; Ligands; Malignant Neoplasms; Metals; Methods; Molecular; Nature; Niacinamide; Nicotinic Acids; Nitrogen; Organic Synthesis; Palladium; Pharmaceutical Preparations; Pharmacologic Substance; Phenanthrolines; Pioglitazone; Preparation; Reaction; Reagent; Recruitment Activity; Research; Resort; Site; Takeda brand of pioglitazone hydrochloride; Transition Elements; United States National Institutes of Health; activation product; analog; anticancer activity; base; catalyst; design; drug synthesis; etoricoxib; functional group; human disease; hypercholesterolemia; novel; prevent; programs; pyridine; rosuvastatin; scaffold; screening; technology development; tool

DESCRIPTION (provided by applicant): Heterocyclic rings are ubiquitous motifs in drug molecules, and their functionalization primarily relies on ring formation from acyclic precursors or transition metal-catalyzed cross-coupling strategies. We propose to develop site-selective C-H functionalizations of readily available and simple heterocycles, such as pyridine, to access complex heterocycles for the preparation of pharmacologically important molecules. Despite recent developments, transition metal-catalyzed C-H functionalization reactions currently rely on chelating functional groups to direct selective metalation and subsequent functionalization. This directing group strategy is not suitable for pyridine-like heterocyclic substrates due to both the poor-electron nature of the aromatic ring and the strong ?-coordination of the nitrogen lone pair with the metal, which sequesters the catalyst away from target C-H bonds. We therefore propose to develop new and broadly applicable catalysts to answer these widely recognized challenges in the synthetic and medicinal chemical communities. Based on our recently discovered ligand scaffold for Pd-catalyzed C-3-selective C-H olefination of pyridine, we propose to develop more effective Pd- and Cu-based catalysts using two strategies to access a number of novel chemical transformations available for the selective functionalization of nitrogen heterocycles. At the onset of the research program, we will design ligands based on the phenanthroline scaffold to further weaken the ?-coordination of the pyridine nitrogen atom with the metal catalyst and promote the beneficial ?-coordination with the metal that is necessary for selective C-3 functionalization. Additionally, we propose to construct ligand scaffolds that contain a second binding site to recruit the pyridine substrate, thereby increasing the effective molarity of pyridine in the vicinity of the metal and allowing for use of the heterocycle as the limiting reagent. These methods will be applied to prepare diverse analogs of important heterocyclic pharmaceuticals, such as the cancer drug Gleevec, for extensive biological screening in order to develop new anti-cancer agents.

描述（由申请人提供）：杂环是药物分子中普遍存在的基序，其功能化主要依赖于无环前体的成环或过渡金属催化的交叉偶联策略。我们建议开发易于获得的简单杂环（例如吡啶）的位点选择性C-H官能化，以获取复杂的杂环以制备药理学上重要的分子。尽管最近取得了进展，但过渡金属催化的 C-H 官能化反应目前依赖于螯合官能团来直接选择性金属化和随后的官能化。这种导向基团策略不适合吡啶类杂环底物，因为芳环的电子性质较差，而且氮孤对电子与金属的强π配位使催化剂与目标C-H键隔离。因此，我们建议开发新的且广泛适用的催化剂，以应对合成和医药化学界广泛认可的挑战。基于我们最近发现的用于 Pd 催化吡啶 C-3 选择性 C-H 烯化的配体支架，我们建议使用两种策略开发更有效的 Pd 和 Cu 基催化剂，以实现许多可用于氮杂环选择性官能化的新颖化学转化。在研究项目开始时，我们将设计基于菲咯啉支架的配体，以进一步削弱吡啶氮原子与金属催化剂的β-配位，并促进与金属的有益的β-配位，这是选择性C-3官能化所必需的。此外，我们建议构建含有第二个结合位点的配体支架来招募吡啶底物，从而增加金属附近吡啶的有效摩尔浓度并允许使用杂环作为限制试剂。这些方法将用于制备重要杂环药物的多种类似物，例如抗癌药物格列卫，用于广泛的生物筛选，以开发新的抗癌药物。