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

描述(申请人提供)：杂环是药物分子中普遍存在的基序，其官能化主要依赖于非环前体或过渡金属催化的交叉偶联策略形成环。我们建议开发易于获得的简单杂环的C-H功能化，如吡啶，以获得复杂的杂环，以制备具有重要药理意义的分子。尽管最近取得了进展，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官能化。这种定向基团策略不适合于吡啶类杂环底物，因为芳香环的弱电子性质以及氮孤子对与金属的强？配位，使催化剂远离目标C-H键。因此，我们建议开发新的和广泛适用的催化剂，以应对这些在合成和医药化学领域广泛认可的挑战。基于我们最近发现的用于Pd催化的C-3-选择性C-H-吡啶烯化反应的配体骨架，我们建议开发更有效的Pd和Cu基催化剂，采用两种策略来获得一些可用于氮杂环选择性官能化的新的化学转化。在研究计划开始时，我们将设计基于邻菲咯啉支架的配体，以进一步削弱吡啶氮原子与金属催化剂的？-配位，并促进选择性C-3官能化所必需的与金属的有益？-配位。此外，我们建议构建包含第二结合位点的配体支架来招募吡啶底物，从而增加吡啶在金属附近的有效摩尔分数，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各种类似物，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。

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.