Natural products as a rich source of pharmaceuticals and innovative chemical transformations: platform development for the generation of new antiviral drugs, antifeedant terpenoids, and novel methodology for chemical synthesis

天然产物是新型生物活性分子的丰富来源。一个多世纪以来，它们一直激励着科学家，并在自然科学领域带来了开创性的发现。独特的生物光谱和它们经常展示的复杂分子框架导致了有趣的研究项目，为化学转化和重要的生物学见解提供了新的思路。这项建议包括三个这样的项目。首先，我们提出了一个生物启发的策略合成急需的，有效的抗甲型流感化合物。这类化合物中两个高度活跃的成员是多环巯基萜类化合物stachyflin和aureol，它们表现出一种新的作用模式。我们的通用和收敛合成路线不仅提供了该类的单个成员，而且还提供了直接获得相关天然产物的途径，允许快速多样化，并且可以产生一个尚未通过半合成获得的新型类似物库。其次，开发了2-羟基丙二酸酯的仿生对映选择性脱羧质子化（EDP）方法，并将其应用于合成最近发现的具有抗食性的类亮氨酸酯萜类化合物。类白细胞的生物合成尚不清楚，计划中的类白细胞A和B到C和D的仿生转化将部分揭示它。最后，第三部分致力于卤化分子的合成，卤化分子在药物化学中具有很高的用途和价值。描述了不饱和化合物的一锅卤化反应和宝石-二卤环丙烷的还原扩环反应，并应用于合成两种吲哚类生物碱乙酰胆碱酯酶（AChE）抑制剂kopsihainanines a和B。

Natural products are a rich source for novel biologically active molecules. They have been inspiring scientists for more than a century and have entailed seminal discoveries in the natural sciences. The unique biological spectrum and the complex molecular framework they often display lead to intriguing research projects that offer new ideas for chemical transformations and important biological insights. This proposal covers three such projects. First, we present a bio-inspired strategy for the synthesis of much-needed, potent antiinfluenza A compounds. Two highly active members of this class are the polycyclic meroterpenoids stachyflin and aureol, which display a novel mode of action. Our general and convergent synthetic route not only provides one individual member of this class but also gives direct access to related natural products, allows for rapid diversification, and can produce a library of novel analogs not yet accessible via semi-synthesis. Second, a biomimetic enantioselective decarboxylative protonation (EDP) protocol of 2- hydroxymalonates is developed and applied for the synthesis of the recently discovered, antifeedant leucosceptroid sesterterpenoids. The biosynthesis of the leucosceptroids is unknown and the planned biomimetic conversion of leucosceptroid A and B to C and D will shed light on part of it. Finally, the third part is dedicated to the synthesis of halogenated molecules, which are highly versatile and valuable building blocks in medicinal chemistry. The one-pot beta-halogenation of unsaturated compounds and a reductive ring expansion of gem-dihalocyclopropanes are described and applied for the synthesis of two indole alkaloids, the acetylcholinesterase (AChE) inhibitors kopsihainanines A and B.