Aspartame analogues containing 1-amino-2-phenylcyclohexanecarboxylic acids (c6Phe)

This report describes the synthesis and the conformational analysis of the optically pure dipeptides analogues of aspartame: H-(S)-Asp-(1R,2R)-c6Phe-OMe and H-(S)-Asp-(1S,2S)-c6Phe-OMe, in which the Phe residue of aspartame has been replaced by a restricted Phe with a cyclohexane skeleton: 1-amino-2-phenylcyclohexanecarboxylic acid (c6Phe). Of these, only the dipeptide that incorporates (1R,2R)-c6Phe is sweet, whereas that incorporates (1S,2S)-c6Phe is bitter. This relationship between the absolute configuration of the dipeptides and the properties is explained through the different conformational behaviour displayed by each molecule, based on molecular mechanics and molecular dynamics calculations, including solvent effects.