Total Synthesis of Bioactive Indole Alkaloids and Application as Agrochemicals

项目摘要/摘要 农用化学品被用于工业食品生产，以确保世界能够获得充足、健康的食品。 推动新型农用化学品发展的一个主要问题是农药抗药性。因此，小说 作用机制(MOA)是非常受欢迎的，以规避对现有农用化学品的抗性。 为此，天然产物通常用作鉴定对这些新的MOA有活性的化合物的来源。 钙通道已被确定为未被开发的杀虫剂靶标，并被认为是可行的、新的 莫阿斯。苦参碱A是一种苦杏仁单萜类吲哚生物碱，已被确定为一个平台。 具有抑制钙通道能力的新型MOAS杀虫剂的开发。一场综合运动 这种天然产物和结构上相关的吲哚生物碱将使对昆虫的初步筛选成为可能 钙通道抑制剂。这些研究将通过三个具体目标来完成：1)完成 油菜碱A的合成，2)合成结构相关的天然产物并进行初步生物合成 3)对吲哚生物碱进行衍生化，进行构效关系研究 与Corteva农业科学公司的合作努力。 将通过以下途径进行苦参碱A和其他苦参碱吲哚生物碱的全合成 执行关键的环化级联反应，以锻造天然产品的碳环框架，然后 后期外围设备功能化。结构相关的吲哚生物碱的发散路线的研究进展 将允许对这些化合物进行生物学评估，以便作为杀虫剂使用。此外，发展 将为这些化合物作为治疗药物的生物测试奠定基础 未来与钙通道失调相关的神经性疾病。最后，综合和分析了 对这些吲哚生物碱的生物测试将提供有关钙通道抑制的关键信息。 这些化合物的性能。

PROJECT SUMMARY/ABSTRACT Agrochemicals are used in industrial food production to ensure the world has access to ample, healthy food. One major problem that drives development of novel agrochemicals is pesticide resistance. As a result, novel mechanisms of action (MoA) are highly sought-after in order to circumvent resistance to existing agrochemicals. To this end, natural products often serve as sources for identifying compounds active toward these novel MoAs. Calcium channels have been identified as under-exploited targets for insecticides and serve as viable, novel MoAs. Scholarinine A, an akuammiline monoterpenoid indole alkaloid, has been identified as a platform for the development of insecticides with novel MoAs due to its’ ability to inhibit calcium channels. A synthesis campaign towards this natural product and structurally related indole alkaloids will enable initial screening toward an insect calcium channel inhibitor. These studies will be accomplished through three specific aims: 1) completing the total synthesis of scholarinine A, 2) synthesizing structurally related natural products and performing initial biological assays, and 3) derivatizing the indole alkaloids to conduct structure activity relationship studies through collaborative efforts with Corteva AgriSciences. The total synthesis of scholarinine A and other akuammiline indole alkaloids will be pursued through the execution of a key cyclization cascade to forge the carbocyclic framework of the natural products, followed by late-stage peripheral functionalizations. Development of a divergent route to structurally related indole alkaloids will allow for biological evaluation of these compounds for application as insecticides. Additionally, development of a synthetic route will lay the foundation for biological testing of these compounds as therapeutics for neurological disorders associated with calcium channel dysregulation in the future. In the end, synthesis and biological testing of these indole alkaloids will provide crucial information on the calcium channel inhibitory capabilities of these compounds.