Biaryl-basierte Naturstoffe als Strukturmotiv für pharmazeutisch relevante Verbindungen
Bibliographic record
Abstract
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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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.001 | 0.000 |
| Meta-epidemiology (narrow) | 0.001 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.000 |
| Bibliometrics | 0.001 | 0.001 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.001 | 0.001 |
| Open science | 0.001 | 0.001 |
| Research integrity | 0.001 | 0.002 |
| Insufficient payload (model declined to judge) | 0.005 | 0.004 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".