Dataset Information

Strecker-Derived Methodology for Library Synthesis of N-Acylated ?-Aminonitriles.

ABSTRACT: The Strecker reaction is a three-component condensation of an aldehyde, an amine, and hydrogen cyanide, delivering an ?-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 ?-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.

SUBMITTER: Goncalves P

PROVIDER: S-EPMC7818620 | biostudies-literature | 2021 Jan

REPOSITORIES: biostudies-literature

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Publications

Strecker-Derived Methodology for Library Synthesis of <i>N</i>-Acylated α-Aminonitriles.

Gonçalves Pedro P Peeraer Anke A Adriaenssens Yves Y Zonnekein Lara L Franck Philippe P Maes Bert U W BUW Augustyns Koen K Van Der Veken Pieter P

ACS omega 20210107 2

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 <i>N</i>-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 ...[more]

PMID: 33490792

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Project description:Alpha-amino acids are the building blocks of proteins and are widely used as components of medicinally active molecules and chiral catalysts. Efficient chemo-enzymatic methods for the synthesis of enantioenriched alpha-amino acids have been developed, but it is still a challenge to obtain non-natural amino acids. Alkene hydrogenation is broadly useful for the enantioselective catalytic synthesis of many classes of amino acids, but it is not possible to obtain alpha-amino acids bearing aryl or quaternary alkyl alpha-substituents using this method. The Strecker synthesis-the reaction of an imine or imine equivalent with hydrogen cyanide, followed by nitrile hydrolysis-is an especially versatile chemical method for the synthesis of racemic alpha-amino acids. Asymmetric Strecker syntheses using stoichiometric amounts of a chiral reagent have been applied successfully on gram-to-kilogram scales, yielding enantiomerically enriched alpha-amino acids. In principle, Strecker syntheses employing sub-stoichiometric quantities of a chiral reagent could provide a practical alternative to these approaches, but the reported catalytic asymmetric methods have seen limited use on preparative scales (more than a gram). The limited utility of existing catalytic methods may be due to several important factors, including the relatively complex and precious nature of the catalysts and the requisite use of hazardous cyanide sources. Here we report a new catalytic asymmetric method for the syntheses of highly enantiomerically enriched non-natural amino acids using a simple chiral amido-thiourea catalyst to control the key hydrocyanation step. This catalyst is robust, without sensitive functional groups, so it is compatible with aqueous cyanide salts, which are safer and easier to handle than other cyanide sources; this makes the method adaptable to large-scale synthesis. We have used this new method to obtain enantiopure amino acids that are not readily prepared by enzymatic methods or by chemical hydrogenation.

Dataset Information

Strecker-Derived Methodology for Library Synthesis of N-Acylated ?-Aminonitriles.

Publications

Strecker-Derived Methodology for Library Synthesis of <i>N</i>-Acylated α-Aminonitriles.

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