Guy Boussard

The couple Pro/AzaPro : A means of β-turn formation control synthesis and conformation of two AzaPro-containing dipeptides

Abstract On the basis of two synthesized AzaPro-containing dipeptides, the conformational influence of the azaproline residue (a nitrogen atom is substituted for the Pro-CH α ) on the β-turn occurrence was rested according to its relative position in the azadipeptide sequence.

SYNTHESIS AND STRUCTURE OF AZASX-PRO-CONTAINING AZA-PEPTIDES

One possible α-modification in peptides is the substitution of a nitrogen for the CαH group. We propose triphosgene as a carbonylating agent for coupling the properly substituted hydrazide to the proline nitrogen to obtain the AzAsx-Pro or AzAla-Pro aza-sequence (Az denotes the NCαH replacement, and Asx stands for Asn or Asp). The structure of three Z-AzAsx-Pro-NHiPr and of the Boc-AzAla-Pro-NHiPr aza dipeptides has been studied in solution by 1H-NMR and IR spectroscopy, and three of them have been investigated in the crystalline state by X-ray diffraction.

Synthesis and conformational preferences in solution and crystalline states of an aza-tripeptide

Abstract The aza-tripeptide Boc-Ala-AzPip-Ala-NHiPr (AzPip: 2-aza pipecolyl residue) was synthesized in seven steps using preferentially the diisopropylcarbodiimide/1-hydroxy-7-aza-benzotriazole (DIPCDI/AtOH) coupling method and via the Boc-AzPip-OBzl pivotal intermediate. Its crystal molecular structure is characterized by the presence of a βVI-like turn around the N-terminal Ala-AzPip sequence and stabilized by two intramolecular hydrogen bonds sharing the same (Boc)CO carbonyl acceptor. In solution (chloroform, DMSO), two isomers are in equilibrium, one of them resembling the stereoisomer found in the crystal, the other being unfolded, but keeping the cis-isomerism of the Ala-AzPip bond and the pronounced degree of pyramidicity of the axial 2-amide Nα nitrogen atom.

Triphosgene: an efficient carbonylating agent for liquid and solid-phase aza-peptide synthesis. Application to the synthesis of two aza-analogues of the AChR MIR decapeptide

The Nα/CαH exchange in aza‐peptides has the advantage of preserving the side chain. Bis(trichloromethyl)carbonate or triphosgene is a solid, stable phosgene substitute which retains its high reactivity. Temperature and coupling times are greatly reduced with reference to other usually recommended carbonylating agents, while purity and yield are increased. It has been used, in both liquid‐ and solid‐phase procedures, for the synthesis of various aza‐analogues of dipeptides, tripeptides and decapeptides containing the alanine, aspartic acid and asparagine aza‐residue. ©1997 European Peptide Society and John Wiley & Sons, Ltd.

Conformational disturbance induced by AzPro/Pro substitution in peptides

Consequences inherent to the substitution of aza-proline (AzPro) for proline in the octapeptide TTSAPTTS, representative of the tandem repeat motif present in the peptide backbone of MUC5AC mucin, were analysed in terms of conformational perturbation and O-glycosylation aptitude. In DMSO solution, we observed the same tendency previously noted in AzPro-tripeptide models, i.e. AzPro prevents β-turn formation in which it would occupy the i+1 position, and therefore behaves quite opposite to Pro, whereas both AzPro and Pro can support a β-turn in the i+2 position with a cis disposition of the preceding tertiary amide function. The former structural modifications do not prevent O-glycosylation to take place at the same specific site, but it occurs at a reduced rate.

Synthesis and conformational analysis of AzAsx-containing oligopeptides

For the sake of improving synthetic methods and evaluating the conformational perturbation induced by the substitution of AzAsx for the Asx residue in the cognate dipeptide R-CO-Asx-Pro-NHR′, we prepared the AzAsx-dipeptide sequence by making use of the crystalline triphosgene. This reagent allows, in situ and under very mild experimental conditions, both the carbonylation and the activation of the properly substituted and N-protected hydrazine before coupling with the proline partner. With regard to conformational behaviour, the azadipeptide sequence displays a β-fold, unlike the cognate dipeptide which adopts an Asx-turn.