Institute of Chemical Research of Catalonia, ICIQ, Avenida Països Catalans 16, 43007 Tarragona, Spain.
J Am Chem Soc. 2013 Jun 19;135(24):9091-8. doi: 10.1021/ja404784t. Epub 2013 Jun 7.
The 9-amino(9-deoxy)epi cinchona alkaloids have expanded the synthetic potential of asymmetric aminocatalysis, enabling the highly stereoselective functionalization of a variety of sterically hindered carbonyl compounds. However, there is a lack of basic understanding of the mechanisms of cinchona-based primary aminocatalysis. Herein, we describe how a combination of experimental and theoretical mechanistic studies has revealed the origin of the stereoselectivity of the Friedel-Crafts alkylation of indoles with α,β-unsaturated ketones catalyzed by 9-amino(9-deoxy)epi quinine. An essential role for the achiral acid cocatalyst is uncovered: upon condensation of the cinchona catalyst with the enone, the resulting covalent imine intermediate and the acid interact to build-up a well-structured ion-pair supramolecular catalytic assembly, which is stabilized by multiple attractive noncovalent interactions. All the components of the assembly cooperatively participate in the stereocontrolling event, with the anion of the achiral acid being the structural element responsible for the π-facial discrimination of the iminium ion intermediate.
9-氨基（9-去氧）表奎宁生物碱扩展了不对称氨基催化的合成潜力，使各种空间位阻羰基化合物能够高度立体选择性地官能化。然而，对于基于金鸡纳的一级氨基催化的机制还缺乏基本的了解。在此，我们描述了实验和理论机理研究的结合如何揭示了 9-氨基（9-去氧）表奎宁催化的吲哚与α，β-不饱和酮的Friedel-Crafts 烷基化反应的立体选择性的起源。揭示了非手性酸共催化剂的重要作用：在与烯酮缩合后，形成的共价亚胺中间体和酸相互作用，构建了一个结构良好的离子对超分子催化组装体，该组装体通过多种吸引力非共价相互作用得到稳定。组装体的所有组成部分都协同参与立体控制事件，非手性酸的阴离子是负责对亚胺离子中间体进行π-面区分的结构元素。
