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Polyfunctional Lewis Acid/Betaine Catalysts as New Bioinspired Tool for Asymmetric Synthesis

Subject Area Organic Molecular Chemistry - Synthesis and Characterisation
Term from 2016 to 2025
Project identifier Deutsche Forschungsgemeinschaft (DFG) - Project number 310990893
 
Final Report Year 2025

Final Report Abstract

The project aimed to establish, understand, and investigate the applicability of a new concept of asymmetric catalysis —developed in the previous project through a Michael addition of a ketoester to a nitroolefin— to various direct addition types. The focus was on Lewis acid/azolium-aryloxide betaine catalysts, which mimic the polyfunctional activation of enzymes. The idea was that, after coordination of the pronucleophile to the Lewis acid and the resulting acidification of the substrate, the aryloxide unit would act as an internal base to deprotonate the substrate, thereby generating the reactive nucleophile. The aromatic alcohol group generated in this step at the catalyst and an acidic C–H bond of the azolium unit were then expected to allow for electrophile activation via hydrogen bonding. After the coupling of both units by an addition, the resulting negatively charged adduct would be protonated by the aromatic alcohol, now acting as an internal acid, leading to product formation and catalyst regeneration. Through the multiple and simultaneous interactions between the catalyst and the substrates, the goal was to achieve both exceptionally high stereocontrol and high catalytic productivity. In the described catalyst design, not only the bond-forming step between the electrophile and nucleophile was considered, but also other relevant steps of the catalytic cycle, such as deprotonation and protonation, were considered to benefit from polyfunctionality. A special focus was particularly on the development of diastereodivergent reactions to efficiently produce previously inaccessible sets of diastereomers through the targeted use of the diverse multiple interactions. Our investigations led to several successful applications in direct additions. These studies demonstrated that Lewis acid/betaine catalysts can achieve high stereoselectivity and productivity, often surpassing previously reported values in the literature. Extensive mechanistic studies, including kinetic and spectroscopic analyses as well as DFT calculations, provided detailed insights into the catalytic cycles and reaction profiles. These studies revealed that the catalyst design is highly suited for each individual step of the investigated catalytic cycles. The calculations also showed that the aryloxide function —regenerated during proton transfer from the catalyst to the addition intermediate— is crucial in preventing (or at least minimizing) product inhibition, as it facilitates the release of the product from the catalyst. Additionally, we investigated additions that appear to operate via an inverse mechanism of the catalyst function.

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