哌啶作为基本的杂环骨架广泛存在于活性天然产物中，包括大多数单萜吲哚生物碱。吡啶盐具有高度的反应活性和结构可修饰性，可作为高效制备含哌啶骨架分子的合成砌块。本项目将根据吡啶盐与含哌啶骨架生物碱的结构相关性，以课题组已完成的吡啶盐仿生物途径对单萜吲哚生物碱合成为基础，开展吡啶盐在具有镇痛活性马钱子类生物碱的合成研究。本项目将以strychnine、akuammicine和stemmadenine为研究对象，以吡啶盐为关键合成砌块，通过分子内区域选择性亲核加成反应串联仿生环化反应，一步构建马钱子类生物碱的核心骨架，并以合适的手性试剂或者手性催化剂进行不对称全合成研究。还将合成马钱子类衍生物，进行阿片受体活性和镇痛活性研究，获得马钱子类具有镇痛活性的先导化合物。本项目拟采用的合成策略简洁高效，可快速构建马钱子类生物碱骨架，为该类生物碱及其衍生物的制备提供有效的的合成方法，为药物研究和开发提供基础。

Piperidines are among the most prevalent heterocyclic structural units in natural products and pharmaceutical molecules, especially in monoterpenoid indole alkaloids. Pyridiniums are useful precursors in synthesis of alkaloids with piperidine skeleton through the addition of nucleophiles or electrophiles. According to the relevance between pyridiniums and indole alkaloids with piperdine skeleton, this project will synthesize Strychnos alkaloids with biological activities and their derivatives by bioinspired synthesis through pyridiniums. This synthetic method was also applied by our group to total synthesis of alstoscholarisine H, a monoterpenoid indole alkaloid. We will accomplish the total synthesis of strychnine, akuammicine, and stemmadenine via the regioselective nucleophilic addition of piridinium through a bioinspired iminium ion intermediate followed by Pictet-Spengler-like cyclization to construct the core skeleton of Strychnos alkaloids, and then achieve the asymmetric total synthesis via appropriate chiral reagents or chiral catalysts. On base of the total synthesis of Strychnos alkaloid, we will synthesize their derivatives to search potential analgesic activity agents and research their structure-activity relationship. The synthetic protocols and methodologies of this project will be featured with novelty and efficiency. It will provide practically synthetic methods for Strychnos alkaloids and their derivatives that promote the medicinal studies and development.