Development of carboxyl- and amide-directed C-H activation/C-C coupling reactions

羧基和酰胺定向的 C-H 活化/C-C 偶联反应的开发

• 批准号: 7662313
• 负责人: Jin-Quan Yu
• 金额: $ 37.9万
• 依托单位: SCRIPPS RESEARCH INSTITUTE, THE
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-08-01 至 2013-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7662313
• 关键词: Acids; Air; Alkenes; Alkylation; Amides; Amines; Amino Acids; Binding; Biological; Biological Factors; Carbon; Carboxylic Acids; Catalysis; Coupling; Development; Excision; Foundations; Goals; Hydrogen Bonding; Iodides; Ligands; Light; Metals; Methods; Molecular; Nitrogen; Organic Synthesis; Oxidants; Oxygen; Pharmaceutical Chemistry; Positioning Attribute; Preparation; Process; Protocols documentation; Reaction; Reagent; Research; Route; Salts; Site; Solutions; System; Techniques; Technology; Temperature; Testing; catalyst; chiral molecule; dehydroabietic acid; drug discovery; improved; interest; large-conductance calcium-activated potassium channels; oxidation; podocarpic acid; programs; public health relevance; tool

DESCRIPTION (provided by applicant): Unactivated C-H bonds are ubiquitous in biologically active compounds as well as intermediates in organic synthesis. Development of catalytic methods to functionalize these strong bonds selectively will offer unprecedented and efficient tools for making C-C and C-heteroatom bonds in organic synthesis and medicinal chemistry. A number of promising catalytic reactions have been developed using directed C-H activation as a key strategy. These reactions typically use pre-installed nitrogen-containing auxiliaries as directing groups via binding to metal catalysts. Considering the broad applications of auxiliaries in synthesis, auxiliaries developed for C-H insertion are not yet practical due to multiple steps and harsh conditions involved in their installation and removal. To overcome these drawbacks, we propose to develop catalytic C-H activation reactions of simple and synthetically useful carboxylic acids and amides at the 2-positions. These reactions are also applicable to simple amine derivatives. We will exploit these reactivities to develop an array of C-H activation/C-C coupling reactions using practical coupling partners such as organoboron reagents and olefins. To improve the practicality of C-H activation reactions, we propose to develop mild conditions (50-80¿C and pH = 4-12) that allow the use of O2 or air as the stoichiometric oxidant. These advantages will be exploited to site-selectively functionalize biologically active natural products including dehydroabietic acid, podocarpic acid and amino acids. The structurally diversified dehydroabietic acid derivatives will be tested for potentially improved biological activity as BK channel openers. Lastly, we have also discovered an effective ligand to achieve the first Pd(II)-catalyzed enantioselective coupling of sp2 and sp3 C-H bonds with organoboronic acids which will find widespread use in synthesis and medicinal chemistry. PUBLIC HEALTH RELEVANCE: The C-H activation/C-C coupling reactions described in this proposal will expedite the drug discovery process by providing unprecedented routes to access biologically active compounds. The enantioselective alkylation of sp2 and sp3 C-H bonds will provide new methods for the preparation of medicinally relevant chiral molecules. Research plans for applications of these reactions in medicinal chemistry are also outlined.

描述（由申请人提供）：未活化的 C-H 键在生物活性化合物以及有机合成中间体中普遍存在。开发选择性官能化这些强键的催化方法将为在有机物中形成 C-C 和 C-杂原子键提供前所未有的有效工具。使用定向 C-H 活化作为关键策略，开发了许多有前景的催化反应。含氮助剂通过与金属催化剂结合作为导向基团，考虑到助剂在合成中的广泛应用，为C-H插入而开发的助剂由于安装和去除过程中涉及多个步骤和苛刻的条件而尚不实用。我们建议开发简单且合成有用的羧酸和酰胺在 2 位的催化 C-H 活化反应，这些反应也适用于简单的胺衍生物。为了提高 C-H 活化反应的实用性，我们建议开发温和的条件（50-80¿）。 C和pH = 4-12），允许使用O2或空气作为化学计量氧化剂。这些优点将被用于对包括脱氢松香酸、罗汉松酸和氨基酸在内的生物活性天然产物进行位点选择性功能化。衍生物将作为 BK 通道开放剂进行潜在改善的生物活性测试。最后，我们还发现了一种有效的配体来实现第一个目标。 Pd(II) 催化的 sp2 和 sp3 C-H 键与有机硼酸的对映选择性偶联，将在合成和药物化学中得到广泛应用。 公共卫生相关性：本提案中描述的 C-H 活化/C-C 偶联反应将通过以下方式加快药物发现过程。 sp2和sp3 C-H键的对映选择性烷基化将为获得生物活性化合物提供前所未有的途径。还概述了这些反应在药物化学中的应用的研究计划。