Esters aspartame

Aspartame is the market leader among artifi cial sweeteners It is a methyl ester of a dipeptide un related to any carbohydrate It was discovered in the course of research directed toward developing drugs to relieve indigestion... 

Formic acid is used as an intermediate in the production of a number of dmgs, dyes, flavors, and perfume components. It is used, for example, in the synthesis of aspartame and in the manufacture of formate esters for flavor and fragrance appHcations. 

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). 

The principal pathway for the decomposition of aspartame begins with the cleavage of the ester bond, which may or may not be accompanied by cyclization (Eig. 2). The resultant diketopipera2ine and/or dipeptide can be further hydroly2ed into individual amino acids (qv). 

In principle, aspartame is produced through the coupling of two amino acid moieties. One moiety consists of T.-phenylalanine methyl ester hydrochloride (2) made by treating the amino acid ia methanol and hydrochloric acid the other is aspartic acid anhydride hydrochloride or formic acid salt. The coupling reaction generates two positional isomers, a and p. 

Alitame (trade name Adame) is a water-soluble, crystalline powder of high sweetness potency (2000X, 10% sucrose solution sweetness equivalence). The sweet taste is clean, and the time—intensity profile is similar to that of aspartame. Because it is a stericaHy hindered amide rather than an ester, ahtame is expected to be more stable than aspartame. At pH 2 to 4, the half-life of aUtame in solution is reported to be twice that of aspartame. The main decomposition pathways (Fig. 6) include conversion to the unsweet P-aspartic isomer (17) and hydrolysis to aspartic acid and alanine amide (96). No cyclization to diketopiperazine or hydrolysis of the alanine amide bond has been reported. AUtame-sweetened beverages, particularly colas, that have a pH below 4.0 can develop an off-flavor which can be avoided or minimized by the addition of edetic acid (EDTA) [60-00-4] (97). 

Aspartame (1) is the primary nonnutritive sweetener used in carbonated soft drinks. It is approximately 200 times sweeter than sucrose. Aspartame is the methyl ester of a dipeptide of T.-phenylalanine and L-aspartic acid. 

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. 

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

C13-0115. The artificial sweetener aspartame (NutraSweet) is Ihe methyl ester of Ihe following dipeptide ... 

The dipeptide precursor of aspartame is made from the two amino acids given here. Aspartame is the methyl ester of the dipeptide. 

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. 

The improvement of enzyme like MIP is currently another area of intense research. Beside the use of the MIP themselves as catalysts, they may also be applied as enhancer of product yield in bio-transformation processes. In an exemplary condensation of Z-L-aspartic acid with L-phenylalanine methyl ester to Z-aspartame, the enzyme thermolysin was used as catalyst. In order to shift the equilibrium towards product formation, a product imprinted MIP was added. By adsorbing specifically the freshly generated product from the reaction mixture, the MIP helped to increase product formation by 40% [130]. MIP can also be used to support a physical process. Copolymers of 6-methacrylamidohexanoic acid and DVB generated in the presence of calcite were investigated with respect to promotion of the nucleation of calcite. Figure 19 (left) shows the polymer surface with imprints from the calcite crystals. When employing these polymers in an aqueous solution of Ca2+ and CO2 the enhanced formation of rhombohedral calcite crystals was observed see Fig. 19 (right) [131]. 

That derivatization may increase rather than decrease peptidase-catalyzed degradation is illustrated with aspartame (6.79, R = MeO), the C-terminal methyl ester of the dipeptide Asp-Phe. The metabolism of this artificial sweetener was compared to that of the underivatized dipeptide (6.79, R = H) and of the corresponding amide Asp-Phe-NH2 (6.79, R = NH2) in microvillar membranes obtained from human duodenum, jejunum, and ileum [189]. The activities monitored were clearly those of peptidases as shown by the effects of inhibitors. Whereas the peptide bond in Asp-Phe and Asp-Phe-NH2 was hydrolyzed at a comparable rate, that in aspartame was hydrolyzed approximately twice as fast. This is an interesting and favorable situation, given that aspartame is expected to be degraded once it has elicited its effect in the buccal cavity. 

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. ... 

Infants with classic phenylketonuria (PKU) are normal at birth but if untreated show slow development, severe mental retardation, autistic symptoms, and loss of motor control. Children may have pale skin and white-blonde hair. The neurotoxic effects relate to high levels of phenylalanine and not to the phenylketones from which the name of the disease derives. Infants are routinely screened a few days after birth for blood phenylalanine level. Treatment consists of a life-long semisynthetic diet restricted in phenylalanine (smalt quantities are necessary because it is an essential amino acid). Aspartame (N-aspartyl-phenylalanine methyl ester), which is widely used as an artificial sweetener, must be strictly avoided by phenyiketonurics. 

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. 

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. 

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. 

Nevertheless, one process for synthesis of the low calorie sweetener, Aspartame, which is a methyl ester of a dipeptide, (Asp-Phe-OMe) involves a biocatalytic step. Aspartic acid amino protected by benzyloxycarboi rl group, is reacted with two moles of phenylalanine methylester catalysed by the protease thermolysin. The extra mole of ester makes the dipeptide precipitate and it is later recycled. For details see section 4.6. 

An enzyme has been discovered that is extremely suitable for synthesising benzyloxycarbonyl-aspartame, a precursor of aspartame (Asp-Phe-methyl ester). 

Proteases can be used for the synthesis of peptides in a way analogous to the ester synthesis catalysed by lipases. The most successful industrial example of enzymatic peptide synthesis is described in section 4.6 aspartame synthesis. In the industrial process in Europe the equilibrium position is shifted towards synthesis because the... 

Proteases have been much less studied than lipases in ionic liquid media and generally require the presence of water for activity. We note that the thermolysin-catalyzed amide coupling of benzoxycarbonyl-L-aspartate and L-phenylalanine methyl ester into Z-aspartame in [BMIm][PF6] was an early example of an enzymatic reaction in an ionic liquid medium [8]. 

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. 

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. 

Phenylketonuria was among the first inheritable metabolic defects discovered in humans. When this condition is recognized early in infancy, mental retardation can largely be prevented by rigid dietary control. The diet must supply only enough phenylalanine and tyrosine to meet the needs for protein synthesis. Consumption of protein-rich foods must be curtailed. Natural proteins, such as casein of milk, must first be hydrolyzed and much of the phenylalanine removed to provide an appropriate diet, at least through childhood. Because the artificial sweetener aspartame is a dipeptide of aspartate and the methyl ester of phenylalanine (see Fig. l-23b), foods sweetened with aspartame bear warnings addressed to individuals on phenylalanine-controlled diets. 

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