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（由适用提供）：天然产品继续为药物发现社区提供几乎无数种类的生物活性铅化合物，以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提高，开发能够访问不仅仅是单个目标的合成越来越重要。取而代之的是，创建可以产生整个化合物家族的路线可提供更多的价值，并可以增加对给定脚手架周围化学空间的探索。但是，为了实现这种方法所需的特定地点和化学选择性转换，需要越来越多的C-H功能化工具。拟议的研究将开发第一个简洁明了的途径，用于一般合成二萜生物碱。这类化合物（包括临床认可的lappaconitine）显示出广泛的生物学活性，包括止痛，抗炎，抗心律失常，麻醉，抗精神，抗虫，抗寄生虫和抗寄生虫和抗虫特性。获得大量各种天然和不自然的数字生物碱的能力将极大地支持模拟发展以及发现新型治疗剂的可能性。拟议的研究还包括开发实用且准备好的分子间的Hofmann-Löffler-Freytag反应。该反应的成功发展对科学家将立即有用，因为它将允许对未激活的烷烃进行控制的，调节性的C-H卤素化，其产物在合成药物和材料的合成中是有价值的化学中间体。