Sweet dipeptide ester

The sweet dipeptide esters of the L-aspartic acid and the L-amino malonic acid (15-21) are interesting exceptions to the bitter taste shared by all other members of the peptide series. Fig. 

Other Food Industries. Aspartame is a synthetic dipeptide ester, L-asp-L-phe-OMe which is about 200 times as sweet as sucrose. It has recently been released for sale in North America and Europe by G. D. Searle. It was originally synthesized chemically and reported by Mazur et al. 38). Subsequent improved methods of synthesis have been developed which involve the use of metalloproteases such as thermolysin in reverse . Metalloproteases are used because, unlike the more common proteases, they have no esterase activity. 

Aspartame. Aspartame [22839-47-0] [53906-69-1] (APM, L-aspartyl-L-phenylalanine methyl ester) (1), also known under the trade names of NutraSweet and EQUAL, is the most widely used nonnutritive sweetener worldwide. This dipeptide ester was synthesized as an intermediate for an antiulcer peptide at G. D. Searle in 1965. Although this compound was known in the literature, its sweet taste was serendipitously discovered when a chemist licked his finger which was contaminated with it. Many analogues, especially the more stable esters, were made (6) and their taste qualities and potencies determined. It was the first compound to be chosen for commercial development. Following the purchase of G. D. Searle by Monsanto, the aspartame business was split off to become a separate Monsanto subsidiary called the NutraSweet Company. 

Aspartame is a diastereomeric dipeptide ester, with the two asymmetric carbons ( ) being derived from (Z)-amino acids. The other three diastereomers of aspartame (the D.D-, D,L- and L,D- diastereomers) are not sweet. The three dimensional structure of aspartame in the zwitterionic form can be depicted in the following stereoscopic figure ... 

After the finding of a sweet taste in L-Asp-L-Phe-OMe (aspartame) by Mazur et at. (6), a number of aspartyl dipeptide esters were synthesized by several groups in order to deduce structure-taste relationships, and to obtain potent sweet peptides. In the case of the peptides, the configuration and the conformation of the molecule are important in connection with the space-filling properties. The preferred conformations of amino acids can be shown by application of the extended Hiickel theory calculation. However, projection of reasonable conformations for di- and tripeptide molecules is not easily accomplished. 

In the course of investigations of aspartyl dipeptide esters, we had to draw their chemical structures in a unified formula. In an attempt to find a convenient method for predicting the sweettasting property of new peptides and, in particular, to elucidate more definite structure-taste relationships for aspartyl dipeptide esters, we previously applied the Fischer projection technique in drawing sweet molecules in a unified formula 04). 

The sweet-tasting property of aspartyl dipeptide esters has been successfully explained on the basis of the general structures shown in Figure 1 (4). A peptide will taste sweet when it takes... 

The structure-taste relationships will be discussed in detail. Dipeptide esters are closely related to amino acids in chemical structure and properties. Hence, we selected amino acids as the standard to which sweet peptides were related. The structural features of sweet-tasting amino acids have been best explained by Kaneko (12) as shown in Figure 2, in which an amino acid will taste sweet when R2 is H, CH3 or C2H5, whereas the size of Ri is not restricted if the amino acid is soluble in water. 

Therefore, we have concluded that sweet-tasting aspartyl dipeptide esters can be drawn as the unified formula (A), whereas nonsweet peptides as (B) as shown in Figure 1. 

In Ama-L-Phe-OMe (47) (14, 15), it is also not known whether the sweet-tasting isomer has the L-L(or S-S) or the D-L(or R-S) configuration. In the case of aspartyl dipeptide esters, the L-L isomer was sweet. By analogy, other researchers deduced that the L-L(or S-S) isomer ((47b) in Figure 4) would be sweet. However, it seemed to us that the D(or i )-configuration would be preferred for the aminomalonic acid because the D-L(or R-S) isomer ((47a) in Figure 4) was compatible with the sweet formula and could also fit the spatial barrier model (13), whereas the L-L(or S-S) isomer could neither fit the receptor model nor meet the sweet formula. 

Finally, L-Asp-D-Val-Gly-OMe (41) was synthesized in order to see whether it remained sweet. The peptide was devoid of sweetness and almost tasteless, though D-valine-containing aspartyl dipeptide esters such as L-Asp-D-Val-0Pr (17) and L-Asp-D-Val-OPrt (8, 17), which are similar to the tripeptide ester in size and shape and have potent sweet taste. 

As mentioned above, the second amino acid of the sweet aspartyl dipeptide esters could be replaced by dipeptide esters... 

Aspartame (Nutrasweet ) is a remarkably sweet-tasting dipeptide ester. Complete hydrolysis of aspartame gives phenyl alanine, aspartic acid, and methanol. Mild incubation with carboxypeptidase has no effect on aspartame. Treatment of aspartame with phenyl isothiocyanate, followed by mild hydrolysis, gives the phenylthiohydantoin of aspartic acid. 

CARBOXYPHENETHYL)SUCCINAMIC ACID N-iMETHYL ESTER, stereoisomer ASPARTYLPHENYLALANINE METHYL ESTER N-l-a-ASPARTYL-1-PHENYLALANINE 1-METHYL ESTER (9CI) CANDEREL DIPEPTIDE SWEETENER EQUAL METHYT-ASPARTYLPHENYLALANATE 1-METHYL N-l-a-ASPARTYL-l-PHENYLALANINE NUTRASWEET SWEET DIPEPTIDE... 

A number of synthetic peptides are significant commercial products, ranging from the sweet dipeptide aspartame (L-aspartyl-L-phenylalanine methyl ester) to clinically used hormones such as insulin and oxytocin. L-Aspartyl-L-phenylalanine methyl ester (3 Scheme 2) is the methyl ester of the C-terminal dipeptide of gastrin. It was found accidently during the synthesis of gastrin that this synthetic sweetener is about 200 times as sweet as sucrose.f This pleasant sweetness without a bitter aftertaste was the reason that L-aspartyl-L-phenylalanine methyl ester was approved in many countries as a food additive, receiving much attention as a low-calorie sweetener. L-Aspartyl-L-phenylalanine methyl ester can be prepared by various chemical routes and the first enzymatic procedure of commercial interest was described by Isowa et al.h l In the industrial process,L-Asp and DL-Phe were chosen as inexpensive raw materials. L-Asp is available very inexpensively, whereas L-Phe is more expensive than DL-Phe. Z-D-Asp acts as a competitive inhibitor, while D-Phe-OMe... 

Aspartame. [Nutrasweet]. (3-amino-n-(a-carboxyphenethyl)succinamic acid n-methyl ester, stereoisomer aspartylphenylalanine methyl ester n-l-a-aspartyl-l-phenylalanine 1-methyl ester canderel dipeptide sweetener Equal (TM) methyl aspartylphenylalanate 1-methyl n-l-a-as-partyl-l-phenylalanine Nutrasweet (TM) sweet dipeptide). C14H18N205. 

In fact, the very name of glycine comes from the greek word for sweet (yXoKocr). Figure 1 shows the molecular models of glycine and of I -tryptophan, the sweetest of R amino acids. In addition to simple amino acids, there are several sweet peptides most of them, although composed of natural amino acidic residues, are not natural and are related to aspartame, 1-aspartylphenylalanine methyl ester, the first sweet dipeptide, discovered... 

Esterification enhances sweetness, for example, ethyl butyrate, aspartyl dipeptide esters... 

Amino-N-(a-methoxycarbonylphenethyl) succinamic acid 3-Amino-N-(a-carboxyphenethyl)succinamic acid N-methyl ester APM Asp-phe-ome Aspartam Aspartame Aspartame, L,L-a- Aspartamo Aspartamum Aspartylphenylalanine methyl ester L-Aspartyl-L-phenylalanine methyl ester Canderel CCRiS 5456 DIpeptide sweetener EINECS 245-261-3 Equal HSDB 3915 Methyl aspartylphenylalanate Methyl L-aspartyl-L-phenylalanine Methyl L-a-aspartyl-L-phenylalanate Methyl N-L-a-aspartyl-L-phenylalaninate 1-Methyl N-L-a-aspartyl-L-phenylalanate Nutrasweet L-Phenylalanine, L-a-aspartyl-, 2-methyl ester L-Phenylalanine, N-L-a-aspartyl-, 1-methyl ester SC 18862 Succinamic acid, 3-amino-N-(a-carboxyphenethyl)-, N-methyl ester, Sweet dipeptide Tri-sweet, A sweetening agent Crystals mp = 246-247° [a]8 = -2,3° (IN HCI). Searte 6.D. Co. 

NUTRASWEET ASPARTYLPHENYLALANINE METHYL ESTER SWEET DIPEPTIDE... 

Aspartame is a dipeptide ester, a-L-aspartyl-L-phenylalanine-OMe, 200 times as sweet as sucrose. Aspartame is utilized by now as a low-calorie sweetener in soft drinks, salad dressings, ready-made meals, table-top sweeteners, and pharmaceuticals, and had reached a market volume of 12000-15000 ha. One of the most successful and interesting syntheses is the Toyo Soda enzymatic process which runs on an industrial scale in a joint venture with DSM (Dutch State Mines, Geleen, NL). 

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. 

The sweet taste of aspartic acid dipeptide esters (I) was discovered by chance in 1969 for a-L-aspartyl-L-phenylalanine methyl ester ( Aspartame , NutraSweet ). The corresponding peptide ester of L-aminomalonic acid (II) is also sweet. 

Aspartame, a nonnutritive sweetener marketed under the trade name Nutra-Sweet (among others), is the methyl ester of a simple dipeptide, Asp-Phe-OCH.3. 

Aspartame is the most successful and widely used artificial sweetener. It is roughly 100 times as sweet as cane sugar. It is methyl ester of dipeptide formed from aspartic acid and phenylalanine. Use of aspartame is limited to cold foods and soft drinks because it is unstable at cooking temperature. 

During work on a series of aspartyl dipeptides containing ACC 71 (vide supra, Eq. (28), Sect. 4) at the carboxyl terminus, it was reported that dispartame Asp-ACC-OMe had a distinct sweet taste [302] and that the corresponding n-propyl ester had 250-300 times the sweetness of sucrose [303]. However, replacement of phenylalanine by 2,3-methanophenylalanine gave tasteless analogues of aspartame [293, 304], and some dimethyl-ACC 214 (methanovaline) and tri-methyl-ACC 215 aspartame analogues [Asp-(Me)n-ACC-OMe] have a bitter taste. These taste properties, which depend on the number and position of the methyl substituents, have been explained on the basis of topochemical models thus, a L-shaped conformation of the dipeptide is necessary for sweet taste, Eq. (86) [3051. 

Other peptides, such as L-aspartyl-L-phenylalanine methyl ester (aspartame), have a sweet taste. Several studies have been carried out to relate the structure and taste of analogs of this dipeptide (25). Tsang et al. (26) reported that the analogs at the lower end of the L-aspartyl-a-aminocycloalkanecarboxylic acid methyl ester series were sweet, the dipeptides containing a-... 

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