Institute of Organic Chemistry, RWTH Aachen University , Landoltweg 1, 52074 Aachen, Germany.
Acc Chem Res. 2017 Nov 21;50(11):2809-2821. doi: 10.1021/acs.accounts.7b00406. Epub 2017 Nov 10.
In the last two decades, organocatalysis has emerged as an intensively investigated and rapidly growing area of research facilitating many known and many new transformations to provide efficient novel entries to complex molecules of high stereochemical purity. The organocatalysts have not only shown their efficiency for catalyzing the reactions in which one bond is formed, but they have also been effectively exploited in various versions of one-pot reactions. Domino reactions are one of the most important classes of one-pot reactions, where the target structure can be obtained in one pot without changing any reaction conditions while each reaction occurs as a consequence of the intermediates generated in previous steps. Owing to the synthetic importance and operational advantages associated with the use of organocatalysts and the development of domino reactions, various asymmetric transformations leading to a complex structure of choice have been explored. The early era of organocatalysis exhibits a limited growth in the development of asymmetric domino reactions with special emphasis on two reactions occurring one after the other. In 2006, our group made a step forward to develop more complex domino reactions catalyzed by a secondary amine organocatalyst, wherein three reactions take place in one pot to provide cyclohexene carbaldehydes bearing four stereogenic centers with excellent stereocontrol. This triggered our interest to develop new organocatalytic domino sequences, especially for multiple domino reactions. After our seminal contribution, domino reactions catalyzed by secondary amine organocatalysts not only became more popular, but they also could be catalyzed by other classes of organocatalysts, such as bifunctional hydrogen bonding catalysts, chiral Brønsted acids, and N-heterocyclic carbenes. The mode of activation in this triple domino reaction relied on the sequential generation of enamine and iminium intermediates using a proline-based chiral secondary amine organocatalyst. By employing this strategy, we have developed several triple domino reactions leading to the formation of carbo- and heterocyclic structures bearing multiple stereogenic centers with excellent levels of stereoselectivities. The applications of the secondary amine organocatalysts have been further extended to more complex quadruple domino sequences. Moreover, these multiple domino sequences have been combined successfully with other transformations in one pot to create densely functionalized polycyclic compounds. This Account gives an overview of our research in the area of organocatalytic asymmetric multiple domino reactions with special emphasis on the secondary amine catalyzed triple and quadruple domino reactions via a sequential generation of enamine and iminium intermediates. The multiple cascade reactions assisted by di- and tri-iminium and -enamine species as well as other types of organocatalysts have been excluded from the scope of this Account.
在过去的二十年中，有机催化已成为一个受到广泛研究和快速发展的领域，它促进了许多已知和许多新的转化，为具有高立体化学纯度的复杂分子提供了高效的新途径。有机催化剂不仅显示出催化形成一个键的反应的效率，而且还在各种一锅法反应的版本中得到了有效利用。多米诺反应是一锅法反应的最重要类别之一，其中目标结构可以在不改变任何反应条件的情况下一锅法获得，而每个反应都是以前步骤中生成的中间体的结果。由于与使用有机催化剂和发展多米诺反应相关的合成重要性和操作优势，各种不对称转化已被探索用于获得选择的复杂结构。有机催化的早期时代在不对称多米诺反应的发展中显示出有限的增长，特别强调两个连续发生的反应。2006 年，我们小组向前迈进了一步，开发了更多由仲胺有机催化剂催化的复杂多米诺反应，其中三个反应在一锅法中进行，以提供具有优异立体控制的带有四个立体中心的环己烯醛。这引发了我们开发新的有机催化多米诺序列的兴趣，特别是对于多步多米诺反应。在我们的开创性贡献之后，仲胺有机催化剂催化的多米诺反应不仅变得更加流行，而且还可以由其他类别的有机催化剂催化，例如双功能氢键催化剂、手性 Brønsted 酸和 N-杂环卡宾。在这个三组分多米诺反应中，模式的激活依赖于使用脯氨酸衍生的手性仲胺有机催化剂连续生成烯胺和亚胺中间体。通过采用这种策略，我们已经开发了几种三组分多米诺反应，形成了具有多个立体中心的碳环和杂环结构，具有优异的立体选择性。仲胺有机催化剂的应用已进一步扩展到更复杂的四组分多米诺序列。此外，这些多组分多米诺序列已成功地与一锅法中的其他转化结合，以创建具有高密度官能团的多环化合物。本账户概述了我们在有机催化不对称多组分多米诺反应领域的研究工作，特别强调了通过顺序生成烯胺和亚胺中间体来催化仲胺的三组分和四组分多米诺反应。双和三亚氨基和烯胺物种以及其他类型的有机催化剂辅助的多步级联反应已被排除在本账户的范围之外。
