Sweet aspartyl dipeptide esters

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

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... 

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. 

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

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. 

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. 

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-... 

Further examinations of the molecular features and of the model of receptor have suggested that several aspartyl tripeptide esters may also taste sweet. In confirmation of the idea, several tripeptide esters have been synthesized. In the first place, L-Asp-Gly-Gly-OMe (38) was synthesized as an arbitrarily-selected standard of tripeptides, because it was considered that this peptide ester had the simplest structure, and correlation of other peptides to (38) was easy. The tripeptide ester was predicted that it would be slightly sweet or tasteless because its projection formula was similar in size and shape to that of L-Asp-Gly-0Bum which is 13 times sweeter than sucrose (16) and because it is more hydrophilic than the dipeptide. The tripeptide (38) was devoid of sweetness and almost tasteless. 

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). 

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. 

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. 

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. 

L-aspartyl-L-phenylalanine methyl ester (ell-ass-par-TEEL ell-fee-no-AL-uh-neen METH-el ESS-ter) is an artificial sweetener more widely known as aspartame. It is sold under a number of brand names, including NutraSweet , Equal , Spoonful , Benevia , Indulge , NatraTaste , and Equal-Measure . Unlike sugar, which is a carbohydrate, aspartame is a dipeptide, a compound made of two amino acids joined to each other. It is 180 to 200 times as sweet as sucrose (table sugar), but provides no calories to a person s diet. It is a satisfactory substitute for sugar, therefore, for people who must or wish to reduce their caloric intake. 

The dipeptide sweetener a-L-aspartyl-L-phenylalanine methyl ester (a-APM), also know as aspartame or NutraSweet brand sweetener, is currently used in over 5,000 food products. It has a sweetness potency of approximately 200 times sucrose and is unstable under alkaline conditions. This instability is due to the well known, irreversible cyclization that a-APM undergoes to form 3-(S.)-benzyl-6-(S,)-carboxymethyl-2,5-diketopiperazine or DKP, with the release of methanol. This has serious implications when attempting to utilize a-APM in certain food applications where alkaline pH is required. In addition to loosing sweetness, this DKP as well as other DKPs isolated from cocoa are reported to be bitter, and thus could compromise the flavor of certain foods. Therefore, detection and quantitation of DKP is of interest. 

Aspartame is a relatively new sweetener which is readily available and known commercially as Canderel. It is the methyl ester of the dipeptide L-aspartyl-L-phenylalanine and has a natural sugar-like taste. It is about 200 times as sweet as sucrose and, in addition, has flavour-enhancing... 

Aspartame was discovered by accident by Jim Schlatter, a chemist at G.D. Searle in 1965. Jim Schlatter was working on drugs for the treatment of gastric ulcers when he spilled some aspartyl-phenylalanine on his hand. He later licked his finger and noticed the sweet taste of the compound, which later became aspartame. Aspartame is the methyl ester of the dipeptide of the natural amino acids L-aspartic acid and L-phenylalanine. There are four possible diastereoiso-mers for aspartame but aspartame is the only one having sweetening properties. The taste of aspartame would not have been predictable based on its amino acid constituents. 

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