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

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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.