Aza-peptides. III. Experimental structural analysis of aza-alanme and aza-asparagine-containing peptides

To determine the structural perturbations induced by the CαH→Nα exchange in aza-peptides, we have examined by H NMR and IR spectroscopy various derivatives of the aza-analogues of alanine, aspartic acid and asparagine in different organic solvents with increasing polarity. Their general formulas are: R'-AzXaa-NR²R³, R'-Pro-AzXaa-NR²R³ and R-AzXaa-Pro-NR²R³ (where AzXaa denotes the aza-analogue of the amino acid residue Xaa = Ala, Asp, Asn; R = Boc, Z; R², R³= H, Me, iPr). The aza-analogue of an amino acid residue appears to be a strong p-turn-inducing motif, and the AzAsn carboxamide side-chain is capable of interacting, as a proton donor, with the preceding peptide carbonyl group.     

X-ray structures of aza-proline-containing peptides

The aza-analogue of proline (AzPro) contains a nitrogen atom in place of the CH^α of the cognate residue. The resolution of the crystal structures of seven AzPro-containing peptides, presenting a set of ten AzPro motifs, reveals the structural properties of this particular aza-residue. Because of sterical hindrances, both nitrogen atoms are out of planarity, and the reduced electronic conjugation in the two AzPro-adjacent amide groups probably explains the longer amide bond distances and the weak proton-accepting character of the two pyrazolidine nitrogens. The absolute configuration of both AzPro nitrogens depends on the chemical nature of the sequence. In all cases, the AzPro residue assumes the same intrinsic three-dimensional structure and presents folding tendencies opposed to those induced by proline.     

Aza-peptides II. X-Ray structures of aza-alanine and aza-asparagine-containing peptides

In order to determine the structural consequences of the N^x/C^xH exchange in aza-peptides, we have solved the crystal molecular structures of some derivatives containing the aza-analogue of asparagine [Z-AzAsn(Me)-NMe₂ (1), Z-AzAsn(Me)-Pro-NHiPr (2) and Piv-Pro-AzAsn(Me)-NHiPr (5), aspartic acid [Z-AzAsp(OEt)-Pro-NHiPr (3) and alanine (Boc-AzAla-Pro-NHiPr (4), by using X-ray diffraction. They reveal that the α-nitrogen accommodates a pyramidal (1–4) or planar (5) structure depending on the sequence. When pyramidal, the α-nitrogen assumes the R (D-like) chiralily. All of the derivatives but 1 adopt either a β₁-folded (2–4) or β_II-folded (5) structure in which the (AzAsn)N^δH bond is intramolecularly hydrogen-bonded to the α-nitrogen. © Munksgaard 1997.