Synthesis and conformation of dipeptide taste ligands containing homo-β-amino acid residues

The synthesis and conformational properties of a series of dipeptide taste ligands, differing from the commercial sweetener aspartame by the presence of a methylene group between the Cα and the C′ carbon atoms (as in homo-β-residues) in either the L-Asp or the L-Phe residues, are described. Homo-β-residues such as homo-β-aspartic acid, homo-β-phenylglycine and homo-β-phenylalanine, obtained by homologation of the corresponding proteinogenic α-amino acids, have been used in the solution peptide synthesis of the following aspartame analogues in protected and unprotected forms: NH2-homo-β-(L or D)-Asp-L-Phe-OMe, NH2-L-Asp-homo-β-L-Phg-OMe and NH2-L-Asp-homo-β-L-Phe-OMe. Lengthening of the peptide skeleton at the L-Asp site results in a drastic loss of sweetness with the production of tasteless compounds; on the other hand, lengthening of the skeleton at the C-terminal L-Phe site partially mantains the sweet taste in both NH2-L-Asp-hamo-β-L-Phe-OMe and NH2-L-Asp-homo-β-L-Phg-OMe. The solution conformation of the synthesized dipeptide taste ligands was investigated by NMR and circular dichroism techniques. The analysis of NMR data combined with restrained molecular dynamics calculations shows that all peptides are fairly flexible and they do not assume a preferred conformation in DMSO and methanol. The peptides containing homo-β-L-Phe and homo-β-L-Phg do adopt a discrete number of conformation among which mainly extended and 'L-shaped' conformation are represented The circular dichroism spectra are consistent with the NMR results, indicating a significant flexibility for these compounds. Copyright © 1999 John Wiley & Sons, Ltd.