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）：杂环环是药物分子中无处不在的基序，其功能化主要依赖于环形前体或过渡金属催化的交叉偶联策略的环形成。我们建议开发出易于使用和简单杂环（例如吡啶）的现场选择性C-H功能化，以获取复杂的杂环，以制备具有药理学重要的分子。尽管最近发生了发展，但过渡金属催化的C-H功能化反应目前依赖于螯合官能团来指导选择性金属化和随后的功能化。由于芳族环的较差的电子性质和氮气孤独的强度，与金属配对的强度，这种指导组策略不适合吡啶样杂环底物，这既可以隔离催化剂，从而将催化剂从靶标C-H键隔离。因此，我们建议开发新的且广泛的催化剂，以应对合成和药物化学群落中这些广泛认可的挑战。基于我们最近发现的PD催化的C-3选择性C-H烯烃的配体支架，我们建议使用两种策略使用两种策略来开发更有效的基于PD和CU的催化剂，以访问许多新型化学转化，可用于氮质杂种氮的选择性功能化。在研究计划开始时，我们将基于苯授予支架设计配体，以进一步削弱吡啶氮原子与金属催化剂的配位，并促进与选择性C-3函数所需的金属协调？此外，我们建议构建包含第二个结合位点的配体支架，以募集吡啶基底物，从而增加金属附近吡啶的有效摩尔力，并允许将杂细胞用作限制试剂。这些方法将用于制备重要的杂环药物（例如癌症药物Gleevec）的各种类似物，以进行广泛的生物学筛查，以开发新的抗癌剂。