Conformational analysis of potent sweet taste ligands by nuclear magnetic resonance, computer simulations and X-ray diffraction studies

Four potent sweet‐tasting molecules, N‐(3, 3‐dimethylbutyl)‐l‐aspartyl‐l‐phenylalanine methylester 1 (7000 times more potent than sucrose), N‐(3, 3‐dimethylbutyl)‐l‐aspartyl‐d‐valine (S)‐α‐ethylbenzylamide 2 (3000 time more potent than sucrose), l‐aspartyl‐d‐valine (R)‐α‐methoxymethylbenzylamide 3 (1350 times more potent than sucrose and l‐aspartyl‐(1R, 2S, 4S)‐1‐methyl‐2‐hydroxy‐4‐phenylhexylamide 4 (2500 times more potent than sucrose) were studied by H NMR and computer simulations. These flexible molecules adopt multiple conformations in solution. The “L‐shaped” structure, which we believe to be responsible for sweet taste is accessible to all four compounds in solution. Extended conformations with the AH and B‐containing moieties in the +y‐axis and the hydrophobic group X pointing in the y‐axis have also been observed for all four sweeteners. For compounds 1 and 3, the solid‐state conformations were determined by X‐ray diffraction studies. These results demonstrate that compounds 1 and 3 adopt an “L‐shaped” structure even in the crystalline state. The extraordinary potency of the N‐alkylated compound 1 compared with the unsubstituted Asp‐Phe‐OMe may be explained by the effect of a second hydrophobic binding domain in addition to interactions arising from the “L‐shaped” structure.