Insertion of the methylene-oxy surrogate of the amide bond into Boc-Val-Leu-OH: X-ray crystal structure, solution conformation and molecular modelling study

Abstract

The conformational features associated with the introduction of the methylene-oxy surrogate of the amide bond were explored by studying the crystal and solution conformation of the related model peptides Boc-Val-Leu-OH (1) and Boc-Val-ψ(CH2O)-Leu-OH (2). Two independent molecular conformations were found for 1 in the crystal state whereas one was found for its congener 2. In compound 2 the dihedral angle defined by Cα–CH2–O–Cα(ω′) adopts a value of –165.7(3)°, close to the situation encountered in the classical amide bond. 2D NOE NMR studies suggest that the preferred backbone conformation of 2 in [2H6]DMSO correlates with the crystal structure whereas the preferred backbone conformation of 1 in [2H6]DMSO showed a departure from its crystalline conformation. Molecular mechanics computations demonstrate the effect of the short C(sp3)–O(sp3) bond in compound 2 in dictating the preferred dihedral angle values adopted by ω′ and φLeu.