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Catalyst-Controlled Site-Selective C-H Functionalizations of Arenes and Heteroarenes

芳烃和杂芳烃的催化剂控制位点选择性 C-H 官能化

基本信息

批准号：
10657626
负责人：
Jin-Quan Yu
金额：
$ 38.5万
依托单位：
SCRIPPS RESEARCH INSTITUTE, THE
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-09-05 至 2024-07-31
项目状态：
已结题

项目摘要

Project Summary Site-selective functionalization of C–H bonds in arenes and heteroarenes can potentially transform the synthesis of bioactive molecules, as it can enable the flexible molecular editing of a scaffold to rapidly generate a diverse set of structures. While C–H bonds proximate to coordinating groups have been successfully activated through its directing effect to form a wide range of C–C and C–X bonds, the majority of C–H bonds in a given molecule are incompatible with this conventional approach. The limitation arises from two factors: 1) distance - the directing effect of a coordinating group diminishes at distances greater than six bonds, and 2) geometry - meta and para positions on arenes are geometrically inaccessible, which greatly restricts the utility of C–H activation in synthesis. These widely recognized challenges escalate with heterocyclic substrates, as heteroatoms coordinate strongly to metal catalysts. This strong binding interaction either limits the utility of C–H activation to proximate sites, or leads to deleterious catalyst poisoning. Therefore, the development of new approaches to achieve selective functionalization of these previously inaccessible C–H bonds is of great value to drug discovery. To achieve the goal of site-selective remote C–H functionalizations of arenes and hetereocycles, we propose three complementary approaches to overcome the two aforementioned challenges. These are 1) the use of transient and catalytic templates, 2) the use of ligand-promoted site-selective C–H activation, and 3) employing a norbornene-mediated relay strategy to expand the first two methods to more distal sites. The first strategy features the use of novel transient directing templates for amine and ketone substrates, as well as employing reversible bifunctional bimetallic directing templates for heterocycles. The second approach is based on our previous finding that phenanthroline-type ligands can promote C-3 selective C–H activation of pyridines, albeit requiring super-stoichiometric amounts of starting material. We propose to redesign this ligand by using additional weak interactions to stabilize the transition states, thereby accelerating the C–H activation reaction. Finally, we propose to utilize norbornenes as a transient mediator to relay the initial remote C–H palladation from the first two approaches to an adjacent, more distal position. The multi-pronged approach presented here fills a major gap in current synthetic methodology. To achieve this overall goal, novel templates, ligands and reagents will be invented. These remote site-selective C–H activation reactions of arenes and heteroarenes will be applied to expedite drug discovery and chemical biology programs in collaboration with the Cravatt and Kelly labs, as well as with Bristol-Myers Squibb.

项目摘要芳烃和杂芳烃中C-H键的位点选择性官能化可能改变生物活性分子的合成，因为它可以实现灵活的分子编辑一个可以快速生成各种结构的支架。而C-H键靠近通过其指导作用，成功地激活了协调小组， C-C和C-X键的范围，给定分子中的大多数C-H键是不相容的用这种传统的方法。这种限制来自两个因素：1）距离-导演配位基团的作用在大于六个键的距离处减小，和2）几何形状- 芳烃上的Meta位和帕拉是几何不可达的，这极大地限制了其实用性 C-H活化的重要性。这些被广泛认可的挑战随着杂环化合物的出现而升级。基质，因为杂原子强烈地与金属催化剂配位。这种强结合相互作用或者将C-H活化的效用限制在邻近位点，或者导致有害的催化剂中毒因此，开发新的方法来实现选择性功能化这些以前难以接近的C-H键的研究对于药物发现具有重要价值。为了实现芳烃的位点选择性远程C-H官能化，我们提出了三种互补的方法来克服这两个问题上述挑战。这些是1）使用瞬时和催化模板，2）使用配体促进的位点选择性C-H激活，和3）采用了一个由α-苯并噻吩介导的中继将前两种方法扩展到更远端部位的策略。第一种策略的特点是使用用于胺和酮底物的新型瞬时导向模板，用于杂环的可逆双官能双金属定向模板。第二种方法是基于我们以前的发现，菲咯啉型配体可以促进C-3选择性C-H 吡啶的活化，尽管需要超化学计量量的起始材料。我们我建议通过使用额外的弱相互作用来稳定过渡来重新设计这种配体从而加速C-H活化反应。最后，我们建议利用三烯作为一个短暂的调解员中继最初的远程C-H钯化从前两个接近邻近的更远的位置。这里提出的多管齐下的方法填补了这是目前合成方法中的一个主要缺陷。为了实现这一总体目标，新颖的模板，将发明配体和试剂。这些远程位点选择性的C-H活化反应芳烃和杂芳烃将被应用于加速药物发现和化学生物学与Cravatt和Kelly实验室以及Bristol-Myers Squibb合作的项目。