An environmentally friendly solution-phase synthesis has been developed for producing trans-5-amino penta-3-enoic acid (trans-δ-Apa), along with several Nα- 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 synthesis. The process involves running five cycles of ion-exchange resin, 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) Cβ=C alkene unit enhances 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 Nα-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.

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