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Strecker-derived methodology for library synthesis of N-acylated alpha-aminonitriles

Journal Contribution - Journal Article

The Strecker reaction is a three-component condensation of an aldehyde, an amine, and hydrogen cyanide, delivering an a-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 N-acylated alpha-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.
Journal: ACS Omega
ISSN: 2470-1343
Volume: 6
Pages: 1328 - 1338
Publication year:2021
Keywords:A1 Journal article
Accessibility:Open