Sweet and bitter taste: Structure and conformations of two aspartame dipeptide analogues

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Abstract
The synthesis and X‐ray diffraction analysis of two dipeptide taste ligands have been carried out as part of our study of the molecular basis of taste. The compounds L‐aspartyl‐D‐α‐methylphenylalanine methyl ester [L‐Asp‐D‐(αMe)Phe‐OMe] and L‐aspartyl‐D‐alanyl‐2,2,5,5‐tetramethylcyclopentanyl ester [L‐Asp‐D‐Ala‐OTMCP] elicit bitter and sweet taste, respectively. The C‐terminal residues of the two analogues adopt distinctly different conformations in the solid state. The aspartyl moiety assumes the same conformation found in other dipeptide taste ligands with the side‐chain carboxylate and the amino groups formaing a zwitterionic ring with a conformation defined by ψ,χX1 = 157.7°, −61.5° for L‐Asp‐D‐Ala‐OTMCP and 151.0°, −68.8° for L‐Asp‐D‐(αMe)Phe‐OMe. In the second residue, a left‐handed helical conformations is observed for the (αMe)Phe residue of L‐Asp‐D‐(αMe)Phe‐OMe with ϕ2 = 49.0° and ψ2 = 47.9°, while the Ala residue of L‐Asp‐D‐Ala‐OTMCP adopts a semi‐exextended conformation characterized by dihedral angles ϕ2 = 62.8° and ψ2 = −139.9°. The solid‐state structure of the bitter L‐Asp‐D‐(αMe)Phe‐OMe is extended; while the crystal structure of the sweet L‐Asp‐D‐OTMCP roughly adopts the typical L‐shaped structure shown by other sweeteners. The data of L‐Asp‐D‐(αMe)Phe‐OMe are compared with those of its diastereoisomer L‐Asp‐L‐(αMe)Phe‐OMe. Conformational analysis of the two taste ligands in solution by NMR and computer simulations agrees well with our model for sweet and bitter tastes.