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

2008年，我们的研究小组提出了在双官能团手性催化剂中将Lewis酸和非质子型洋葱盐合作用于不对称反应的策略。然而，Lewis酸通过降低LUMO能量来激活亲核试剂，而非质子的负离子功能通过离子对相互作用将阴离子亲核试剂导向亲电泳体。这允许控制亲核分子的轨迹，从而面临攻击的选择性。同时，与金属结合的亲核剂相比，阴离子亲核剂的几乎裸露的特性增加了它的反应性。在过去的几年里，我们对不同的反应类型--环加成、1，2-加成、脱对称反应--使用了这些提高的反应性和改进的立体控制的优点，从而为新概念建立了原理证明。在此背景下，我们最近描述了一种非常坚固的添加了铵盐侧链的手性Salen-Al-F-催化剂，与最好的文献中已知的氰化催化剂相比，该催化剂对醛的不对称羧基氰化反应的活性提高了1-2个数量级。对于这种合作的不对称Lewis酸/洋葱盐催化剂，在高对映选择性反应中可以达到近104吨。所描述的方案的重点是研究将氰化物添加到其他亲电体(如亚胺或不同的迈克尔受体)中以高效地提供增值的手性、功能化的丁腈构建块的双重活化策略。后者由于氰基的多功能性(例如：还原为胺、水解为羧酸)而对许多后续的合成转化具有吸引力。主要目标是使拟议反应的活性达到一个新的水平，类似于所提到的碳氰化反应，这在现有的催化剂概念下是不可能实现的。通过使用KCN作为唯一的非挥发性、成本效益高的氰化物来源(避免使用昂贵的挥发性TMSCN)，这些转化的实用性也应该得到改善，使这些反应从技术和经济的角度来看也是有意义的。通过机制研究(动力学、光谱、密度泛函理论计算)，我们的目标是更多地了解这种双重激活的有效作用模式。从长远来看，这应该允许理性地规划其他转型。

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.