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

双功能路易斯酸/铵盐催化作为不对称氰化的工具：1,2-加成、1,4-加成和亲核开环反应

• 批准号: 404194277
• 负责人: Professor Dr. René Peters
• 金额: --
• 依托单位: Institut für Organische Chemie (IOC)
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2018
• 资助国家: 德国
• 起止时间: 2017-12-31 至 2021-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/404194277?language=en
• 关键词: Bifunctional; Lewis; Acid; Ammonium; Salt

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.

2008年，本课题组提出了刘易斯酸与非质子鎓盐在双功能手性催化剂中协同作用的对映选择性反应策略。而刘易斯酸通过降低LUMO能量来活化亲电试剂，非质子鎓官能团通过离子对相互作用将阴离子亲核试剂导向亲电试剂。这允许控制亲核试剂的轨迹，从而面对攻击的选择性。同时，与金属结合的亲核试剂相比，阴离子亲核试剂的几乎裸露的特性增加了其反应性。在过去的几年里，我们将这些增加反应性和改进立体控制的优点用于不同的反应类型-环加成，1，2-加成，去对称化-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具有附加铵盐侧链的非常稳健的手性Salen-Al-F-催化剂，与已知的最佳文献氰化催化剂相比，其允许醛的不对称羧基氰化的活性增加1-2个数量级。对于这种合作的不对称刘易斯酸/鎓盐催化TONs高达近104，可以实现在高度对映选择性反应。所述程序的重点是研究这种双重活化策略，用于将氰化物添加到其他亲电试剂如亚胺或不同的迈克尔受体中，以提供高效率的增值手性官能化腈结构单元。由于氰基的多功能性，后者对于许多随后的合成转化是有吸引力的（例如：还原成胺，水解成羧酸）。主要目标是为所提出的反应进入一个新的活性水平，类似于所提到的羧基氰化，这是迄今为止用已建立的催化剂概念是不可能的。通过使用KCN作为唯一的非挥发性、成本有效的氰化物源（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，使得这些反应从技术和经济的角度来看也是令人感兴趣的。通过机理研究（动力学，光谱学，DFT计算），我们的目标是了解更多关于这种双重激活的有效作用模式。从长远来看，这应该允许合理规划其他转型。