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

• 批准号: 10254416
• 负责人: Jin-Quan Yu
• 金额: $ 38.56万
• 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 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10254416
• 关键词: Academia; Amines; Binding; Biology; Chemicals; Collaborations; Development; Distal; Drug Industry; Geometry; Goals; Hydrogen Bonding; Ketones; Ligands; Mediating; Mediator of activation protein; Metals; Methodology; Methods; Molecular; Pattern; Phenanthrolines; Poison; Poisoning; Positioning Attribute; Reaction; Reagent; Site; Structure; Technology; base; catalyst; design; drug discovery; falls; flexibility; interest; novel; novel strategies; programs; pyridine; scaffold

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键的位置选择性官能化可能 改变生物活性分子的合成，因为它可以使灵活的分子编辑 一个脚手架，可以快速生成各种不同的结构。而C-H键接近 协调小组通过其引导作用被成功地激活，形成了广泛的 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。这种限制源于两个因素：1)距离--指路 配位基团的影响在超过六个键的距离和2)几何构型- 芳烃上的间位和对位在几何上是不可接近的，这极大地限制了效用。 C-H在合成中的激活。这些被广泛认可的挑战随着杂环化合物的出现而升级 底物，作为杂原子与金属催化剂强烈配位。这种强烈的结合作用 要么将C-H活化的用途限制在接近的位置，要么导致有害的催化剂 下毒了。因此，开发实现选择性功能化的新方法 在这些以前无法获得的C-H键中，有很大的药物发现价值。 为了实现芳烃和芳烃的位置选择性远程C-H官能化的目标 杂环，我们提出了三种互补的方法来克服这两种 上述挑战。这些是1)使用瞬变和催化模板，2)使用 配体促进的C-H选择性激活，以及3)使用降冰片烯介导的继电器 将前两种方法扩展到更远端站点的策略。第一种策略的特点是使用 用于胺和酮底物的新型瞬时定向模板及其应用 用于杂环的可逆双功能双金属定向模板。第二种方法是 基于我们先前的发现，邻菲咯啉类配体可以促进C-3选择性C-H 吡啶的活化，尽管需要超化学计量比的起始原料。我们 建议通过使用额外的弱相互作用来稳定跃迁来重新设计该配体 状态，从而加速C-H活化反应。最后，我们建议利用 降冰片烯作为瞬时中介物传递来自前两者的初始远程C-H苍白 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 当前综合方法论中的一个重大空白。为了实现这一总体目标，新颖的模板， 配体和试剂将会被发明出来。这些远程位置选择性的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实验室以及百时美施贵宝合作的项目。