Development of Divergent Cascade Annulation Reactions for the Synthesis of Malagashanine and Akuamilline Alkaloids

在这项由化学系化学合成计划资助的项目中，埃默里大学的西蒙·布莱基教授正在开发新的反应，将允许合成两个新的生物活性分子家族。新方法的发展，以及已证明的能够获得以前无法获得的多种天然产品的能力，将为进一步了解这些分子的基本生物活性奠定基础。这项基础研究将为民族医学研究中隐含的治疗属性的开发铺平道路，这些研究是该项目的灵感来源，进一步加深了我们对疟疾对常见药物治疗的耐药性的理解，并可能提供新的临床实体的路线图。一个外展计划正在通过科学和艺术之间的合作来探索马拉喀什人故事的叙事。这一组合说明了学科之间的相互作用，向公众提供关于尖端科学和发现所产生的伦理问题的信息。布莱基教授将在亚特兰大植物园进行公开演讲，并最终作为亚特兰大科学节的一部分向广大观众发表演讲。这些分子的不同寻常的结构使得它们很难用现有的方法进行合成。到目前为止，还没有合成这两个家族的成员。为了应对这些分子带来的挑战，并为进一步的生物学研究提供大量的数据，控制这些反应的新反应和新催化剂正在开发中。具体地说，将开发和研究一系列立体专一性的亚胺离子引发的级联反应和新型手性双磺酰胺催化剂，为马拉须碱和阿库玛生物碱的合成问题提供解决方案。这些研究有望在合成这两个家族的代表性分子方面达到高潮。

In this project funded by the Chemical Synthesis program of the Chemistry Division, Professor Simon Blakey of Emory University is developing new reactions that will allow the synthesis of two novel families of bioactive molecules. The development of new methodology, and the demonstrated ability to access multiple classes of natural products that were previously inaccessible, will set the stage for further understanding of the basic biological activities of these molecules. This fundamental research will pave the way for the development of the therapeutic properties implied in ethnomedicine studies that serve as the inspiration for this project, furthering our understanding of malarial resistance to common drug treatments, and potentially providing a road map to new clinical entities.An outreach program is exploring the narrative of the malagashanine story through a collaboration between the sciences and the arts. The combination illustrates the interplay between disciplines to inform a public audience on cutting edge science and ethical questions arising from the discoveries. Professor Blakey will deliver public lectures at the Atlanta Botanical Garden, and ultimately to broad audiences as part of the Atlanta Science Festival.The unusual structures of these molecules render them difficult to synthesize with existing methods. To date, no members of either family have been synthesized. To meet the challenge posed by these molecules, and provide significant quantities for further biological study, new reactions and new catalysts to control these reactions are under development. Specifically, a series of stereospecific iminium ion initiated cascade reactions, and novel chiral disulfonamide catalysts will be developed and studied, providing solutions to the synthetic problem posed by the malagashanine and akuamma alkaloids. These studies are expected to culminate in the syntheses of representative molecules from both families.