Strecker-Derived Methodology for Library Synthesis of N-Acylated α-Aminonitriles

Abstract

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 N-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 cysteinetype 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.

Sustainable and Chemoselective Synthesis of α-Aminonitriles Using Lewis and Brønsted Acid-Functionalized Nanoconfined Spaces

“…Overall yields of 2 and 3 were 9% and 3% respectively. Overall yields were calculated using 1 hypothesized to make the ketone less nucleophilic for coordination with Cr 3+ because electrons are withdrawn from the aryl ring. The overall yield of 1 was 39%, in contrast to its competitive catalysis against 1-acetonaphthone, which yielded 42%.…”

“…The Strecker synthesis is one of the oldest and most foundational one-pot multicomponent condensation reactions yielding α-aminonitriles. , α-Aminonitriles are versatile molecules in total synthesis and medicinal chemistry; they are synthesized from inexpensive starting materials (using ketones and amines and trimethylsilyl cyanide (TMSCN)) and enable a bi-functional path for the synthesis of heterocyclic, carbocyclic, α-, and β-amino acids . In particular, α-amino acids are building blocks of proteins and, thus, used extensively as components of biologically and pharmaceutically active molecules for asymmetric synthesis of natural products and complex drugs. − α-Aminonitriles have been employed as targeted covalent inhibitors (TCIs) for reversible protease inhibition. , TCIs are designed to bind the active sites of amino acids through a reactive “warhead” group .…”

“…Overall yields of 2 and 3 were 9% and 3% respectively. Overall yields were calculated using1 H NMR shown in Figures S33−35.…”

Dipeptide-Derived Alkynes as Potent and Selective Irreversible Inhibitors of Cysteine Cathepsins

“…Due to their unequivocal involvement in tumor progression, cysteine cathepsins are a vital target for cancer diagnosis and therapy. ,, Therefore, inhibitors of various compound classes have been developed over the past three decades. In this context, the functionalization of substrate-derived peptidic moieties with electrophilic warheads proved to be a very fruitful approach toward the development of cysteine protease inhibitors. , In particular, peptidic nitriles represent an attractive chemotype of inhibitors, because the softly electrophilic cyano group interacts preferably with active-site thiol groups, while serine proteases are generally much less prone to interact with nitriles. − However, in the case of the prolyl oligopeptidases (family S9 of serine proteases), highly potent inhibition by peptidic nitriles has been observed . However, the inherent reactivity of the cyano group can result in indiscriminate thioimidate formation with other biogenic thiols such as glutathione, even though this is strongly dependent on the chemical surrounding of the CN bond .…”