Steric impact of aza-amino acid on solid-phase aza-peptide bond synthesis. (13th April 2021)

• Record Type: Journal Article
• Authors: Troska, Alla; Arujõe, Meeli; Mastitski, Anton; Järv, Jaak; Ploom, Anu
• Is Part Of: Tetrahedron letters. Volume 69(2021)
• Publication Date: 2021-04-13
• Subjects: Aza-peptide -- COMU -- Kinetics -- Steric effect -- SPPS; Chemistry, Organic -- Periodicals; 547.005
• DOI: 10.1016/j.tetlet.2021.152973
• Languages: English
• ISSNs: 0040-4039

Abstract

Graphical abstract: Highlights: Steric bulk of aza-amino acid controls the aza-peptide bond formation rate and yield. Least bulky AzGly reacts with COMU-activated Ala as fast as natural amino acid. Sterically most hindered AzVal practically does not react with COMU-activated Ala. Abstract: Aza-peptides are metabolically more stable in living organisms than their parent peptides. Despite the properties of these peptidomimetics as promising drug leads, synthesizing them is challenging and, therefore, their biological activity has been studied relatively little. Previously, we determined that the steric hindrance of the side group of an activated amino acid coupled to the semicarbazide moiety of an aza-amino acid contributes to a decreased rate of formation of the aza-peptide bond. In the current work, we identified the influence of aza-amino acid side chain bulkiness for the synthesis of a model aza-peptide, H-Ala-AzAA-Phe-NH2, using COMU as a coupling reagent. The results indicated that the aza-amino acid steric hindrance controls the aza-peptide bond formation reaction rate and yield. This effect was found to be more substantial than the influence of the amino acid coupled to the semicarbazide moiety. While the rate of the reaction of activated Ala with the N -terminus of AzGly was found to be comparable with the rates of typical peptide bond formation reactions, the reaction with the sterically most demanding AzVal did not proceed at all when COMU was used as an activator.