Examination of the potential for adaptive chirality of the nitrogen chiral center in aza-aspartame

• Published in: Molecules (Basel, Switzerland) Switzerland), 2013-11, Vol.18 (12), p.14739-14746
• Main Authors: Bouayad-Gervais, Samir H, Lubell, William D
• Format: Article
• Language: English
• Subjects: Amino acids; aspartame; Aspartame - chemical synthesis; Aspartame - chemistry; azapeptide; Carbon; Chromatography; crystal structure; dynamic chirality; hydrazine; Molecular Mimicry; Molecular Structure; Nitrogen; Nitrogen - chemistry; nitrogen chirality; peptide mimic; Peptides; semicarbazide; Sweetening Agents - chemical synthesis; Sweetening Agents - chemistry; Taste
• ISSN: 1420-3049; 1420-3049
• DOI: 10.3390/molecules181214739

The potential for dynamic chirality of an azapeptide nitrogen was examined by substitution of nitrogen for the α-carbon of the aspartate residue in the sweetener S,S-aspartame. Considering that S,S- and R,S-aspartame possess sweet and bitter tastes, respectively, a bitter-sweet taste of aza-aspartame 9 could be indicative of a low isomerization barrier for nitrogen chirality inter-conversion. Aza-aspartame 9 was synthesized by a combination of hydrazine and peptide chemistry. Crystallization of 9 indicated a R,S-configuration in the solid state; however, the aza-residue chiral center was considerably flattened relative to its natural amino acid counterpart. On tasting, the authors considered aza-aspartame 9 to be slightly bitter or tasteless. The lack of bitter sweet taste of aza-aspartame 9 may be due to flattening from sp2 hybridization in the urea as well as a high barrier for sp3 nitrogen inter-conversion, both of which may interfere with recognition by taste receptors.