Microwave-assisted synthesis of peptidomimetic trans-delta-aminopent-3-enoic acid and its derivatives

Abstract

An environmentally friendly solution-phase synthesis has been developed for producing trans-5-aminopenta-3-enoic acid (trans-δ-Apa), along with several N^α- and C-terminal protected derivatives and its dipeptide. This method utilises low temperatures, minimal power, and short coupling times. Microwave-assisted synthesis demonstrates the production of non-proteogenic delta-amino acids and peptides with high purity, better yield, and scalability. The reaction is suitable for a wide range of carboxylic acid-derived amines and has been demonstrated on a gram scale. The process involves running five cycles of ion-exchange resin use, followed by regeneration. The replacement of central amide bonds by (E)-alkene in a δ-amino acid proves to be a promising approach for mimicking peptide backbone geometry in a dipeptide of α-amino acids. Introducing an (E) C^βC^γ alkene unit enhances the conformational limitation for δ-amino acid residues, resulting in peptidomimetics with conformational constraints. Successful implementation of this efficient synthetic approach has resulted in amino-terminal protected, carboxy-terminal protected, and both N^α-terminal and C-terminal protected δ-amino acids with good yields. HBTU/HOBt/DIEA coupling yields the best results for dipeptides, while o-NosylOXY/DIEA exhibits the next best coupling efficiency. Additionally, the choice of solvent has been optimised for better yields. Microwave dielectric heating significantly reduces reaction times, offering an instant, cost-effective alternative with moderate to good yields under mild conditions and a greener method than conventional thermal heating methods.