Biaryl-basierte Naturstoffe als Strukturmotiv für pharmazeutisch relevante Verbindungen

Biaryls are important structural motifs for both pharmaceutically relevant compounds as well as ligands, and catalysts in chemical transformations. With the aim of contributing to the everexpanding methodology towards biaryls, different synthesis strategies were devised and implemented to obtain synthetically relevant biaryls. Moreover, stereoselective palladium catalyzed transformations were investigated for the synthesis of bicyclic compounds. 8,8′′-Biflavones, a class of biaryl-based natural products, were investigated for their bioactivity against various human pathogens. A synthesis route for the construction of highly functionalized racemic biaryl building blocks in three steps was established in a scalable fashion. Enabled by this method, the first extensive library of 8,8′′-biflavone analogues was synthesized. This dedicated library was then evaluated regarding its pharmaceutical potential in cooperation with M.Sc. Lena Berning and M.Sc. Flaminia Mazzone (Heinrich Heine University Düsseldorf). In addition to promising results for these biflavones, bichalcones obtained as key intermediates were identified as novel drug scaffolds. Based on these first hits, further amino-8,8′′-biflavones including the first non-C2-symmetrical 8,8′′-biflavone were synthesized. In cooperation with M.Sc. Céline David (Heinrich Heine University Düsseldorf) the structure activity relationship was probed, and bioactivities obtained. Next a strategy involving cyclic diaryliodonium salts towards an enantiopure building block was implemented. Extensive investigations were undertaken, and ultimately a scalable protocol successfully established. These prochiral building blocks were then applied to construct enantiopure dimeric flavonoids and thus the usefulness of the established Methodology shown. In addition to these investigations, palladium-catalyzed methods were investigated to overcome advanced synthetic challenges. For one, the Catellani reaction was used to obtain biaryls inaccessible by state-of-the-art methods. Factors critical for this transformation were identified, and a protocol for the synthesis of tri-ortho-substituted biaryls established. Moreover, first investigations into stereodynamic biaryl-based palladacycles were conducted. The proposed stereodynamics of these palladium complexes were supported by preliminary computational calculations (DFT). Finally, in collaboration with the working group of Prof. Mark Lautens (University of Toronto), the use of chiral oxabicycles as acetylene analogues was thoroughly investigated. A mechanism to explain the observed stereoselectivity of the reaction was proposed and supported by experimental findings. Finally, DFT calculations were conducted to rationalize the observed selectivities.

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