Copper‐Catalyzed A3‐Coupling for the Diversity‐Oriented Synthesis of Proline‐Derived Alkynyl‐Substituted Peptidomimetic Scaffolds

• Published in: European journal of organic chemistry Vol. 2019; no. 36; pp. 6203 - 6210
• Main Authors: Innocenti, Riccardo, Lenci, Elena, Baldini, Lorenzo, Faggi, Cristina, Menchi, Gloria, Trabocchi, Andrea
• Format: Journal Article
• Language: English
• Published: Weinheim Wiley Subscription Services, Inc 30-09-2019
• Subjects: Aldehydes; Alkynes; Amino acids; Combinatorial chemistry; Coupling (molecular); Multicomponent reactions; Nitrogen heterocycles; Proline; Substitutes; Synthetic methods
• ISSN: 1434-193X; 1099-0690
• DOI: 10.1002/ejoc.201900703

The Aldehyde–Amine–Alkyne reaction (A3) proves to be a powerful methodology as a coupling step of the Build/Couple/Pair approach in Diversity Oriented Synthesis (DOS) because it can lead to the formation of polyfunctionalized intermediates suitable for the creation of different molecular entities. In this work we used cyclic α‐amino aldehyde moieties for the microwave‐assisted A3 coupling reaction, resulting in the generation of the corresponding propargylamines and successively exploited in intramolecular pairing reactions to obtain a pool of different alkynyl‐substituted peptidomimetic compounds.
The aldehyde–amine–alkyne (A3) coupling reaction is a powerful multicomponent coupling reaction for the build/couple/pair approach in diversity‐oriented synthesis (DOS), herein demonstrated by the application of Boc‐prolinal for the synthesis of pyrrolidine‐based molecular scaffolds bearing a propargylamine chemical handle.