权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

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.

项目概要芳烃和杂芳烃中 C-H 键的位点选择性官能化有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快速生成多种结构的脚手架。虽然 C–H 键接近协调小组通过其引导作用成功激活，形成广泛的 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。限制来自两个因素：1）距离 - 指挥配位基团的效应在距离大于六个键时减弱，2) 几何形状 - 芳烃上的间位和对位在几何上是不可接近的，这极大地限制了实用性合成中的C-H活化。这些广泛认可的挑战因杂环而升级底物，因为杂原子与金属催化剂强烈配位。这种强结合相互作用要么限制 C-H 活化在邻近位点的效用，要么导致有害的催化剂中毒。因此，开发新方法来实现选择性功能化这些以前无法接近的C-H键对药物发现具有重要价值。实现芳烃的位点选择性远程C-H功能化的目标杂环，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) 使用瞬态和催化模板，2) 使用配体促进的位点选择性 C-H 激活，以及 3) 采用降冰片烯介导的中继将前两种方法扩展到更远端部位的策略。第一个策略的特点是使用用于胺和酮底物的新型瞬态导向模板，以及采用杂环的可逆双功能双金属导向模板。第二种方法是基于我们之前的发现，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的起始材料。我们建议通过使用额外的弱相互作用来重新设计该配体以稳定转变状态，从而加速C-H活化反应。最后，我们建议利用降冰片烯作为瞬态介体来传递来自前两个的初始远程 C-H 钯化接近邻近的、更远端的位置。这里提出的多管齐下的方法填补了当前合成方法的一个主要差距。为了实现这一总体目标，新颖的模板，配体和试剂将被发明。这些远程位点选择性 C–H 激活反应芳烃和杂芳烃将用于加速药物发现和化学生物学与 Cravatt 和 Kelly 实验室以及百时美施贵宝合作的项目。