Sweet dipeptide amide

Goodman, M., Coddington, J., and Mierke, D.F. (1987). A model for the sweet taste of stereoisomeric retro-inverso and dipeptide amides. J. Amer. Chem. Soc. 109, 4712-4714. 

A new sweetener, named Alitame by its inventors in your Research Division, is a dipeptide amide of L-aspartic acid and D-alanine. In contrast, aspartame, the amino acid-based sweetener currently approved by the FDA, is a dipeptide ester and contains L-phenylalanine instead of D-alanine. The New Products Department has tested the new material in a variety of uses and claims that it is stable enough for use in baked goods and has a longer shelf life than aspartame. It is also 12 times as sweet as aspartame and would not be harmful to people with the metabolic disorder, phenylketonuria, who must limit the intake of substances containing phenylalanine. Use is projected in foods, beverages, toiletries, and pharmaceuticals. 

Fig. 3. Structure—activity summary of dipeptide sweeteners, where n may be 0 or 1 (62). There are no known replacements for the acid or amide groups denoted by arrows, although thioamide has some sweetness. If the NH2 is replaced by NHC(0)R, the potency is increased when...

The analysis, in composite over the four classes of L-aspartyl dipeptides suggests that the electron-withdrawing effect of substituents directed to the peptide bond, and the steric dimensions of the molecules, are important in eliciting the sweet taste. The values of the regression coefficients of the a term in the QSAR equations for L-aspartic acid amides, L-aspartylaminoethylesters, and L-aspartylaminopropionates all... 

Aspartame, marketed under the trade name Nutra-Sweet for use as a nonnutritive sweetener, is the methyl ester of a simple dipeptide. Identify the two amino acids present in aspartame, and show all the products of digestion, assuming that both amide and ester bonds are hydrolyzed in the stomach. 

As might be expected, the search for an even better artificial sweetener continues. Alitame is a dipeptide formed from aspartic acid and alanine, with an unusual amide at the carboxylate end of the alanine. It is 2000 times as sweet as sucrose— 1 pound of alitame has the sweetening power of I ton of sucrose In addition, because an amide bond is more stable than an ester bond, alitame is more stable to hydrolysis than is aspartame. Therefore, alitame keeps its sweetness in aqueous solution better than aspar-... 

In nature, the amino acids are combined to give proteins with hundreds or even thousands of amino acids in each one. Small assemblies of amino acids are known as peptides and die amide bond that links them is called a peptide bond. One important dipeptide is the sweetening agent aspartame, whose synthesis was discussed in Chapter 25. It is composed (and made) of the amino acid aspartic acid (Asp) and the methyl ester of phenylalanine. Only this enantiomer has a sweet taste and it is very sweet indeed—about 160 times as sweet as sucrose. 

Amides of dipeptides consisting of L-aspartic acid and D-alanine are sweet (Table 8.11). The compound alitame is the N-3-(2,2,4,4-tetra-methyl)-thietanylamide of L-Asp-D-Ala (Formula 8.20) and with /sac,g(10) = 2000, it is a potential sweetener. 

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