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

描述(申请人提供)：未活化的C-H键普遍存在于生物活性化合物以及有机合成的中间体中。发展催化方法来选择性地使这些强键功能化，将为在有机合成和药物化学中生成C-C和C-杂原子键提供前所未有的有效工具。使用直接C-H活化作为关键策略，已经开发了许多有前景的催化反应。这些反应通常使用预先安装的含氮辅助剂作为导向基团，通过与金属催化剂结合。考虑到助剂在合成中的广泛应用，用于C-H插入的助剂由于其安装和移除步骤多且条件苛刻而尚不实用。为了克服这些缺点，我们建议开发简单的和合成上有用的2位羧酸和酰胺的催化C-H活化反应。这些反应也适用于简单的胺衍生物。我们将利用这些反应来开发一系列的C-H活化/C-C偶联反应，使用实际的偶联伙伴，如有机硼试剂和烯烃。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℃和pH=4-12)，允许使用O2或空气作为化学计量比的氧化剂。这些优势将被利用来选择性地将生物活性天然产物包括脱氢松酸、己二酸和氨基酸功能化。结构多样化的脱氢松酸衍生物将作为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Pd(II)催化的SP2和SP3 C-H键与有机硼酸的对映选择性偶联，这将在合成和药物化学中得到广泛的应用。与公共健康相关：本提案中描述的C-H活化/C-C偶联反应将提供前所未有的获取生物活性化合物的途径，从而加快药物发现过程。Sp2和Sp3 C-H键的不对称烷基化将为药物相关手性分子的制备提供新的方法。并概述了这些反应在药物化学中应用的研究计划。

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.