Aspartyl-L-Phenylalanine Methyl Ester

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. 

Aspartame was discovered accidentally in 1965 by James M. Schlatter, an employee of the G. D. Searle pharmaceutical company. Schlatter was searching for a chemical compound that could be used to treat ulcers. L-aspartyl-L-phenylalanine methyl ester was one of the compounds he made during his investigations. He accidentally got some of the compound on his fingers, a fact that he did not notice until later in the day. 

L Aspartyl L phenylalanine methyl ester. Red atoms are oxygen white atoms are hydrogen black atoms are carbon and blue atoms are nitrogen. Gray sticks show double bonds, publishers 

when he licked his fingers to pick up a piece of paper, he noticed the intensely sweet taste of the compound. To confirm his suspicions about the compound, he added some of it to his coffee-a practice that violates all laboratory safety rules -and found that it was more than satisfactory as a substitute for sugar. Searle began the testing and application procedure needed to gain approval from the U.S. Food and Drug Administration, a long and drawn-out procedure that ended only in 1981, 25 years after its discovery. 

The Aspartame Information Center claims that the compound is now used in more than 6,000 commer- 

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Aspartame (L-aspartyl-L-phenylalanine methyl ester [22839-47-0]) is about 200 times sweeter than sucrose. The Acceptable Daily Intake (ADI) has been estabUshed by JECFA as 40 mg/kg/day. Stmcture-taste relationship of peptides has been reviewed (223). Demand for L-phenylalanine and L-aspartic acid as the raw materials for the synthesis of aspartame has been increasing, d-Alanine is one component of a sweetener "Ahtame" (224). 

A solution of 88.5 parts of L-phenylalanine methyl ester hydrochloride in 100 parts of water is neutralized by the addition of dilute aqueous potassium bicarbonate, then is extracted with approximately 900 parts of ethyl acetate. The resulting organic solution is washed with water and dried over anhydrous magnesium sulfate. To that solution is then added 200 parts of N-benzyloxycarbonyl-L-aspartic acid-a-p-nitrophenyl, -benzyl diester, and that reaction mixture is kept at room temperature for about 24 hours, then at approximately 65°C for about 24 hours. The reaction mixture is cooled to room temperature, diluted with approximately 390 parts of cyclohexane, then cooled to approximately -18°C in order to complete crystallization. The resulting crystalline product is isolated by filtration and dried to afford -benzyl N-benzyloxycarbonvI-L-aspartyl-L-phenylalanine methyl ester, melting at about 118.5°-119.5°C. 

To a solution of 180 parts of -benzyl N-benzyloxycarbonyl-L-aspartvI-L-phenylalanine methyl ester in 3,000 parts by volume of 75% acetic acid is added 18 parts of palladium black metal catalyst, and the resulting mixture is shaken with hydrogen at atmospheric pressure and room temperature for about 12 hours. The catalyst is removed by filtration, and the solvent is distilled under reduced pressure to afford a solid residue, which is purified by re-crystallization from aqueous ethanol to yield L-aspartyl-L-phenylalanine methyl ester. It displays a double melting point at about 190°C and 245°-247°C. 

L-alpha-aspartyl-L-phenylalanine methyl ester. See aspartame 1-glutamic acid. See monosodium glutamate L-lysine, 90... 

Aspartame, N-a-L-aspartyl-L-phenylalanine methyl ester, trade names NutraSweet , and Aspartil , is a dipeptide derivative. Like dipeptides aspartame is metabolised into the constituents, i.e. amino acids and methanol. Therefore studies into the metabolic behaviour and the fate of metabolites were carried out. Levels of blood aspartate and glutamate were measured after intake of high aspartame doses. Changes were transient and allegations of influences of high aspartame levels on brain function could never be verified. 

Phenylalanine (Phe or F) (2-amino-3-phenyl-propanoic acid) is a neutral, aromatic amino acid with the formula HOOCCH(NH2)CH2C6H5. It is classified as nonpolar because of the hydrophobic nature of the benzyl side chain. Tyr and Phe play a significant role not only in protein structure but also as important precursors for thyroid and adrenocortical hormones as well as in the synthesis of neurotransmitters such as dopamine and noradrenaline. The genetic disorder phenylketonuria (PKU) is the inability to metabolize Phe. This is caused by a deficiency of phenylalanine hydroxylase with the result that there is an accumulation of Phe in body fluids. Individuals with this disorder are known as phenylketonurics and must abstain from consumption of Phe. A nonfood source of Phe is the artificial sweetener aspartame (L-aspartyl-L-phenylalanine methyl ester), which is metabolized by the body into several by-products including Phe. The side chain of Phe is immune from side reactions, but during catalytic hydrogenations the aromatic ring can be saturated and converted into a hexahydrophenylalanine residue. ... 

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. 

The first member of this class of sweetners, L-aspartyl-L-phenylalanine methyl ester... 

L-Aspartyl-L-phenylalanine methyl ester (aspartame) (sweet)... 

No generalizations can be made about the molecular weights of biologically active peptides and proteins in relation to their functions. Naturally occurring peptides range in length from two to many thousands of amino acid residues. Even the smallest peptides can have biologically important effects. Consider the commercially synthesized dipeptide L-aspartyl-L-phenylalanine methyl ester, the artificial sweetener better known as aspartame or NutraSweet. 

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-... 

Aspartame is an intense sweetener first discovered in 1965 by J. Schlatter it is available under the brand names of Nutrasweet , Equal , and Canderel . Chemically, aspartame is N-L-a-aspartyl-L-phenylalanine methyl ester (Fig. 1), withamolecularformulaofC14H 805N2 (MW = 294.30). It is a white, odorless, crystalline powder. It is slightly soluble in water and sparingly soluble in alcohol. The solubility increases as the pH is lowered (2,6,57). It has 100-200 times the sweetness of sucrose and exhibits a sweet, clean taste and a sweetness profile similar to that of sucrose, without bitter or metallic aftertaste (Table 1). However, it displays a slow onset of sweetness coupled with lingering sweet taste. It extends and intensifies tastes and enhances fruit flavors. Aspartame exhibits synergism, a superior taste profile, and improved stability when used with other sweeteners (1,4,14,55,75). 

Aspartame is the generic name for IV-ai-aspartyl-L-phenylalanine methyl ester. It is composed of two amino acids, L-aspartic acid and L-phenylalanine, joined by a methyl ester link. It was discovered in 1965 by J. Schlatter at the G.D. Searle Laboratories. It is a white crystalline product and its solubility in water is 10 g/1 at 20°C this figure increases at elevated temperatures and in acidic conditions (Ajinomoto Aspartame Technical Bulletin, 2003). It is sparingly soluble in other solvents. 

Commercially available amino acid derivatives have been tested as chiral proton sources for protonation of lithium enolates catalytic A -L-aspartyl-L-phenylalanine methyl ester gave an ee of 88%.292... 

Aspartame. Aspartame is a high-intensity sweetener (200-fold that of sucrose) consisting of L-aspartyl-L-phenylalanine methyl ester (L-Asp-L-Phe-OMe). Around 10,000 tons are produced per annum, most by a chemical process owned by Nutrasweet Corp. Holland Sweetener Company (a DSM/Tosoh joint venture) uses the protease thermolysin (E.C. 3.4.24.27) to synthesize aspartame from a chemically protected L-aspartic acid derivative (Z-L-Asp) and racemic phenylalanine methyl ester (DL-Phe-OMe). The enzyme only accepts L-phenylalanine-OMe and the unused D-isomer can be isolated, racemized, and recycled. This process is depicted in Figure 31.20. 

Aspartame is a dipeptide derivative, L-aspartyl-L-phenylalanine methyl ester, which was approved in the United States in 1981 for use as a tabletop sweetener, in dry beverage mixes, and in foods that are not heat processed. This substance is metabolized in the body to phenylalanine, aspartic acid, and methanol. Only people with phenylketonuria cannot break down phenylalanine. Another compound, diketopiperazine, may also be formed. However, no harmful effects from this compound have been demonstrated. The main limiting factor in the use of aspartame is its lack of heat stability (Homier 1984). 

Ajinomoto Co. Inc. (1998). Process for crystallizing alpha-L-aspartyl-L-phenylalanine-methyl ester. New European Patent Specification EP 0 091 787 B2. [307]... 

Sweet hazard. Why should phenylketonurics avoid using aspartame, an artificial sweetener (Hint Aspartame is 1-aspartyl-l-phenylalanine methyl ester.)... 

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... 

L-Aspartyl-L-phenylalanine Methyl Ester D-Phenylalanine Methyl Ester... 

Aspartame (NutraSweet , Equal ), A-u-a-Aspartyl-L-Phenylalanine methyl ester, is 200 times sweeter than sucrose and, unlike saccharin, has no aftertaste. Its aqueous solubility is adequate for formulation purposes. It is stable in the solid form, but its stability in... 

Aspartame is stable in dry conditions. In the presence of moisture, hydrolysis occurs to form the degradation products L-aspartyl-L-phenylalanine and 3-benzyl-6-carboxymethyl-2,5-diketopiperazine. A third-degradation product is also known, P-L-aspartyl-L-phenylalanine methyl ester. For the stability profile at 25°C in aqueous buffers, see Figure 1. 

Furda, I. et al., Decomposition products of L-aspartyl-L-phenylalanine methyl ester in various food products and formulations, J. Agric. Food Chem., 23, 340, 1975. 

Lelj, F., Tancredi, T., Temussi, P.A., and Toniolo, C. (1976). Interaction of alpha-L-aspartyl-L-phenylalanine methyl ester with the receptor site of the sweet taste bud. J. Amer. Chem. Soc. 98,6669-6675. 

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