Bifunctional Lewis-Acid-/Ammonium-Salt-Catalysis as a Tool for Asymmetric Cyanations: 1,2-Addition, 1,4-Addition and Nucleophilic Ring Opening Reactions

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In 2008, our research group has introduced the strategy of the cooperation between a Lewis acid and an aprotic onium salt within a bifunctional chiral catalyst for enantioselective reactions. Whereas the Lewis acid activates the electrophile by lowering the LUMO energy, the aprotic onium function directs an anionic nucleophile by ion pair interactions towards the electrophile. This allows for control over the trajectory of the nucleophile and thus face selectivity of the attack. At the same time the almost naked character of the anionic nucleophile increases its reactivity compared to a metal bound nucleophile. These advantages of increased reactivity and improved stereocontrol were used by us in the last years for different reaction types - cycloadditions, 1,2-additions, desymmetrizations - thus establishing proof of principle for the new concept. In this context, we have recently described a remarkably robust chiral salen-Al-F-catalyst with appended ammonium salt side chain, which allowed for an activity increase by 1-2 orders of magnitude for asymmetric carboxycyanations of aldehydes compared to the best literature known cyanation catalysts. For this cooperative asymmetric Lewis acid/onium salt catalysis TONs of up to nearly 104 could be achieved in highly enantioselective reactions. The focus of the described program is the investigation of this dual activation strategy for the addition of cyanide to other electrophiles like imines or different Michael-acceptors to provide value-added chiral, functionalized nitrile building blocks with high efficiency. The latter are attractive for many subsequent synthetic transformations due to the versatility of cyano groups (e.g.: reduction to amines, hydrolysis to carboxylic acids). The major goal is to enter a new level of activity for the proposed reactions, similar as for the mentioned carboxycyanations, which was not possible so far with established catalyst concepts. By using KCN as the only and non-volatile, cost-efficient cyanide source (avoiding the use of expensive volatile TMSCN) practicality of these transformations should also be improved rendering these reactions interesting from a technical and economical point of view as well. By mechanistic studies (kinetics, spectroscopy, DFT-calculations) we aim to learn more about the effective mode of action for this kind of dual activation. On long term this should permit to rationally plan other transformations.