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: 7849700
• 负责人: Jin-Quan Yu
• 金额: $ 37.52万
• 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/7849700
• 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（由适用提供）：未激活的C-H键在生物活性化合物以及有机合成中的中间体中无处不在。开发催化方法可以选择性地使这些牢固的键有效地功能化，这将为有机合成和药物化学中的C-C和C-杂化键提供前所未有的有效工具。使用定向的C-H激活作为关键策略，已经开发了许多承诺的催化反应。这些反应通常使用预安装的含氮辅助机作为通过与金属催化剂结合来指导组。考虑到辅助设备在合成中的广泛应用，由于其安装和去除涉及的多个步骤和危险条件，用于C-H插入的辅助设备尚不实际。为了克服这些缺点，我们建议在2位处开发简单和合成有用的羧酸和酰胺的催化C-H活化反应。这些反应也适用于简单的胺衍生物。我们将探索这些反应，以使用实际耦合伴侣（例如有机体试剂和烯烃）开发C-H激活/C-C耦合反应。为了改善C-H激活反应的实用性，我们提出要发展轻度条件（50-80¿C和pH = 4-12），以将O2或空气用作化学计量计的氧化物。这些优点将被探索以将现场选择性化生物活性天然产物功能化功能，包括脱氢甲酸，足核酸和氨基酸。结构多样化的脱氢培养地衍生物将被测试，以改善作为BK通道开启器的生物学活性。最后，我们还发现了一种有效的配体，以实现SP2和SP3 C-H键与有机酸的第一个PD（II）的对映选择性耦合，这些耦合将在合成和药物化学中找到宽度。公共卫生相关性：本提案中描述的C-H激活/C-C耦合反应将通过提供前所未有的途径来访问生物活性化合物来加快药物发现过程。 SP2和SP3 C-H键的对映选择性烷基化将为制备药物相关的手性分子提供新的方法。还概述了这些反应在药物化学中应用的研究计划。