Peptide sweeteners. 8. Synthesis and structure-taste relationship studies of L-aspartyl-D-alanyl tripeptides

Several L-aspartyl-D-alanyl tripeptides have been synthesized to investigate the structural requirements of the C-terminal amino acid needed to elicit a taste response. Following our suggestion that a rigid, hydrophobic residue is required, both alpha, alpha-dialkane and cycloalkane alpha-amino acid methyl esters were incorporated into the tripeptide. The L-aspartyl-D-alanine-based tripeptide derivatives of alpha-aminoisobutyric acid methyl ester, alpha, alpha-diethylglycine methyl ester, and alpha-aminocycloalkanecarboxylic acid methyl esters from three- to six-membered rings are sweet. The higher analogues of the cycloalkane series containing alpha-aminocycloheptanecarboxylic acid methyl ester and alpha-aminocyclooctanecarboxylic acid methyl ester are bitter. It is important to note that this series of tripeptides (analogous to the previously reported dipeptides) goes from sweet to bitter to tasteless as the ring size of the C-terminal amino acid increases. The relationships between effective volume of the C-terminal residue, size requirements of the sweet receptor, and taste are discussed.