PROBING A MOLECULAR-MODEL OF TASTE UTILIZING PEPTIDOMIMETIC STEREOISOMERS OF 2-AMINOCYCLOPENTANECARBOXYLIC ACID METHYL-ESTER

On the basis of the preferred conformations of L-aspartyl dipeptide derivatives containing alpha-amino acids at the second position and their retro-inverso analogues deduced by a combination of X-ray crystallography, H-1 NMR spectroscopy, and molecular mechanics calculations, we have proposed a model describing the molecular array required for the sweet taste. The conformation of a sweet molecule is described as possessing an "L shape", with the AH (proton donor) and B (proton acceptor) zwitterionic ring of the aspartyl moiety forming the stem, and the hydrophobic group X forming the base of the "L". Planarity of the molecule in the x and y dimensions is critical for sweet taste. Substantial deviation from this plane into negative z dimension is correlated with bitter taste while other deviations lead to tasteless molecules. To examine the model, the preferred conformations for a series of L-aspartyl dipeptides containing a 2-aminocyclopentanecarboxylic acid (2-Ac5c) residue at the second position were calculated using molecular mechanics. The peptidomimetic 2-Ac5c residue is a beta-amino acid with two chiral centers, resulting in four isomers [trans-(1S,2S)-2-Ac5c, trans-(1R,2R)-2-Ac5c, cis-(1R,2S)-2-Ac5c, and cis-(1S,2R)-2-Ac5c]. Two stereoisomers, L-aspartyl-trans-(1R,2R)-2-aminocyclopentanecarboxylic acid methyl ester [Asp-trans-(1R,2R)-2-Ac5c-OMe] and L-aspartyl-cis-(1S,2R)-2-aminocyclopentanecarboxylic acid methyl ester [Asp-cis-(1S,2R)-2-Ac5c-OMe], prefer the L-shape conformations and are thus predicted to be sweet. For L-aspartyl-trans-(1S,2S)-2-aminocyclopentanecarboxylic acid methyl ester [Asp-trans-(1S,2S)-2-Ac5c-OMe], the methyl ester group projects behind the stem of the L shape, producing a large negative z component and is predicted to exhibit a bitter taste. The calculations predict that L-aspartyl-cis-(1R,2S)-2-aminocyclopentanecarboxylic acid methyl ester [Asp-cis-(1R,2S)-2-Ac5c-OMe] will be tasteless. In this investigation, in addition to the calculations, we report the synthesis and experimental conformational analysis of the four stereoisomers of Asp-2-Ac5c-OMe. The absolute configurations of the 2-Ac5c residues were assigned by X-ray diffraction studies and by correlating optical rotation and enantiomeric excess values. These studies fully confirm our configurational assignments of the stereoisomers of Asp-2-Ac5c-OMe. Thus, the structure-taste relationships observed for the new class of L-aspartyl taste ligands containing the 2-Ac5c beta-amino acid methyl esters in the second position agree with and strengthen our model for the sweet and bitter taste responses.