Crystal structure and conformational stabilty of N-acetyl-L-prolyl-L-leucinamide. Comparison between structural and thermophysical data

Molecular and crystalstructure of N-acetyl-l-prolyl-l-leucinamide (NAPLA), C13H23N3O3, have been determined by single crystal diffraction study. The molecule adopts a non-usual conformation characterized by the sequence of torsion angles ϕpro=−79.4(5), ψpro=144.0(3), ϕleu=−108.4(4), ψleu=114.1(4)°. The backbone and side chain conformations are discussed together with the pattern of intermolecular hydrogen bond in the crystal. The cis-proline has a ‘type B’ geometry with Cs-Cβ-exo conformation. The Leu residue, showing a limited conformational disorder, is in the twisted g−(tg−) conformation. Parallel calorimetric determinations of the melting enthalpy and entropy were accomplished and discussed on the basis of the molecular interactions occurring in the crystal state. The present results are compared with the fusion thermodynamics and crystal features of other proline-containing protected peptides recently studied at the author's laboratories. The comparison is proved useful to justify the overall trend of fusion properties of this class of substances. Molecular mechanics calculations (AMBER) have been performed to evaluate the conformational energy maps of NAPLA molecule and its isomer N-acetyl-l-leucyl-l-prolinamide (NALPA). The energetically favoured conformers of the two molecules are discussed on the basis of intramolecular interactions that stabilize more bent conformations. In the crystal state, on the contrary, the intermolecular interactions overwhelm the intramolecular forces.