Examination of the Potential for Adaptive Chirality of the Nitrogen Chiral Center in Aza-Aspartame

Abstract

Abstract: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 sp 2 hybridization in the urea as well as a high barrier for sp 3 nitrogen inter-conversion, both of which may interfere with recognition by taste receptors.

Three cheers for nitrogen: aza-DKPs, the aza analogues of 2,5-diketopiperazines

“…These modied peptides showed a attening of the spatial arrangement of the substituents linked to the new nitrogen atom while having the potential to exhibit adaptive chirality. 22,23 This structural difference was also observed by us in the comparison between a DKP and its aza-DKP analogue by X-ray crystallography (Fig. 3).…”

Solid-Phase Azopeptide Diels–Alder Chemistry for Aza-pipecolyl Residue Synthesis To Study Peptide Conformation

“…The enhanced μ/κ selectivity ratios (32–120) of the azaPip relative to the Pip [Dmt 1 , d -Phe 3 ]­morphiceptins are therapeutically relevant, because centrally active κ-opioid receptor agonists have been shown to cause dysphoria and sedation, side effects that preclude therapeutic development . Differences between the l -Pip and azaPip analogues may be due to the latter having greater polarity and inability to completely adopt (S)-configuration …”

Aza-Amino Acids Disrupt β-Sheet Secondary Structures

“…Potential cross-strand hydrogen bonding and side chain - side chain interactions between azaVal 3 and Ile 10 appear to be insufficient to stabilize the extended conformation in aza-valine 3 , which likely adopts a twisted conformation (φ = 90°) that disrupts β-hairpin formation. Because aza-amino acids may exhibit adaptive chirality at Nα, the aza-valine residue could be achiral or exhibit either l or d -like chirality [34], which could in turn affect β-hairpin stability. We synthesized d -Val 3 analog 1c as a control and found its Gly 7 δHα–δHα’ value to be larger than that of aza-Val 3 analog 1b , yet smaller than the parent peptide 1a .…”