Gonçalves Pedro, Peeraer Anke, Adriaenssens Yves, Zonnekein Lara, Franck Philippe, Maes Bert U W, Augustyns Koen, Van Der Veken Pieter
Department of Pharmaceutical Sciences, Laboratory of Medicinal Chemistry, University of Antwerp, Universiteitsplein 1, 2610 Wilrijk, Belgium.
Department of Chemistry, Organic Synthesis, University of Antwerp, Groenenborgerlaan 171, 2020 Antwerp, Belgium.
ACS Omega. 2021 Jan 7;6(2):1328-1338. doi: 10.1021/acsomega.0c04908. eCollection 2021 Jan 19.
The Strecker reaction is a three-component condensation of an aldehyde, an amine, and hydrogen cyanide, delivering an α-amino carbonitrile. Despite extensive investigations, the possibility to use amides instead of amines as one of the three condensation partners has been largely neglected. Nonetheless, the -acylated α-aminocarbonitriles that are obtained in this way are of direct interest for drug discovery, because they make up a well-known class of mechanism-based inhibitors of serine- and cysteine-type hydrolases. In response, we have thoroughly explored the corresponding variant of the Strecker reaction, focusing on catalyst use, solvent, reaction time, and cyanide source. Optimized parameters were combined in a sequential one-pot protocol for which the scope was found to be compatible with library synthesis applications. Product yields ranged from 7 to 90%, and conditions were found to be mild and tolerant to a wide range of functional groups, including moieties that are typically present in druglike molecules.
施特雷克反应是醛、胺和氰化氢的三组分缩合反应，生成α-氨基腈。尽管进行了广泛的研究，但使用酰胺代替胺作为三种缩合反应物之一的可能性在很大程度上被忽视了。然而，以这种方式获得的酰化α-氨基腈对于药物发现具有直接的意义，因为它们构成了一类著名的基于机制的丝氨酸和半胱氨酸型水解酶抑制剂。为此，我们深入探索了施特雷克反应的相应变体，重点关注催化剂的使用、溶剂、反应时间和氰化物来源。优化后的参数被整合到一个连续的一锅法方案中，发现该方案的适用范围与文库合成应用兼容。产物收率在7%至90%之间，并且发现反应条件温和，对广泛的官能团具有耐受性，包括药物类分子中通常存在的部分。
