Total Synthesis of Bioactive Indole Alkaloids and Application as Agrochemicals

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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.