N4-methylation changes the conformation of (3S,6S)-3-alkyl-6-benzylpiperazine-2,5-diones from folded to extended

•A series of novel N-methylated and N,N′-dimethylated 2,5-DKPs were prepared.•Conformational analysis of N-methylated and N,N′-dimethylated 2,5-DKPs based on 1H NMR spectroscopy were performed.•Single crystal X-ray structural analysis of N1-methylated and N4-methylated 2,5-DKPs was performed.•N4-methylation of mono-benzylated 2,5-DKPs was found to change their conformation from folded to extended.

N4-methylation of (3S,6S)-3-alkyl-6-benzylpiperazine-2,5-diones (S,S)-1a–c was found to change their folded conformation to an extended conformation. Conformational aspects of N1- and/or N4-methylated (S,S)-1a–c were revealed by single crystal X-ray crystallography and 1H NMR spectroscopy.