Synthesis of diterpenoid alkaloids by site-selective C-H functionalization

通过位点选择性 C-H 官能化合成二萜生物碱

基本信息

批准号：
8835680
负责人：
Justin Matthew Lopchuk
金额：
$ 5.24万
依托单位：
SCRIPPS RESEARCH INSTITUTE, THE
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-02-01 至 2017-01-31
项目状态：
已结题

项目摘要

DESCRIPTION (provided by applicant): Natural products continue to provide the drug discovery community with a nearly endless variety of biologically active lead compounds from which to develop medicines targeted to specific disease states. As our ability to synthesize complex molecules increases, it becomes increasingly important to develop syntheses which are able to access more than just a single target. Instead, creating routes where entire families of compounds can be generated provides far more value and allows for the increased exploration of chemical space around a given scaffold. However, to achieve the site-specific and chemoselective transformations needed in such an approach, increasingly better tools for C-H functionalization are required. The proposed research will develop the first concise and scalable route for the general synthesis of diterpenoid alkaloids. This class of compounds, which includes the clinically approved lappaconitine, displays a wide range of biological activity including analgesic, anti-inflammatory, antiarrhythmic, anesthetic, antithermic, antiparasitic, and antifeedant properties. The ability to access large quantities of various natural and unnatural diterpenoid alkaloids would greatly facilitate analog development and the possibility of discovering novel therapeutic agents. The proposed research also includes the development of a practical and preparative, intermolecular Hofmann-Löffler-Freytag reaction. The successful development of this reaction would be immediately useful to scientists as it would allow for the controlled, regioselective C-H halogenation of unactivated alkanes, the products of which are valuable chemical intermediates in the synthesis of medicines and materials.

描述（由申请人提供）：天然产物继续为药物发现界提供几乎无穷无尽的生物活性先导化合物，用于开发针对特定疾病状态的药物。随着我们合成复杂分子的能力的增强，它变得越来越重要。然而，开发能够获得多个目标的合成方法相反，创建可以生成整个化合物家族的路线提供了更多的价值，并允许增加对给定支架周围化学空间的探索。位点特异性和化学选择性这种方法所需的转换，需要越来越好的 C-H 功能化工具，拟议的研究将开发第一个简洁且可扩展的二萜生物碱的通用合成路线，其中包括临床批准的高乌头碱。一系列生物活性，包括镇痛、抗炎、抗心律失常、麻醉、退热、抗寄生虫等获得大量各种天然和非天然二萜生物碱的能力将极大地促进类似物的开发和发现新型治疗剂的可能性。拟议的研究还包括开发实用的、制备性的分子间霍夫曼-洛夫勒-弗雷塔格反应。该反应的成功开发将立即对科学家有用，因为它将允许未活化烷烃（产物）的受控、区域选择性 C-H 卤化。其中是医药和材料合成中有价值的化学中间体。