Structure aspartame

In 1981, aspartame became the first new sweetener to be approved by the U.S. Food and Drug Administration (FDA) in nearly 25 years. It is about 160 times sweeter than sucrose. Structurally, aspartame is the methyl ester of a dipeptide of two amino acids that occur naturally in proteins—aspartic acid and phenylalanine—and is sold under the trade name NutraSweet . (Amino acids and peptides will be discussed in the next chapter.)... 

Saccharin sucralose and aspartame illustrate the diversity of structural types that taste sweet and the vitality and continuing development of the in dustry of which they are a part ... 

Examine the structures oisucrose, the natural sweetener, and saccharin, sodium cyclamate and aspartame (Nutrasweet), three of the most common artificial sweeteners. What, if any, structural features do these molecules have in common Compare electrostatic potential maps for the different sweeteners. Are there any significant features in common Based on yom findings, do you think it is likely that entirely different artifical sweeteners might be discovered Explain. 

The primary structure of a protein is the sequence of residues in the peptide chain. Aspartame consists of phenylalanine (Phe) and aspartic acid (Asp), and so its primary structure is Phe-Asp. Three fragments of the primary structure of human hemoglobin are... 

FIG. 25 Chemical structures of (a) erythritol, (b) sodium saccharin, and (c) aspartame. 

We have also recently explored some ruthenium-arene complexes that depart markedly from the general structure described above. For instance, full-sandwich ruthenium complexes have been synthesized, in which the positions X, Y, and Z are taken by an rj6-arene ring of a biologically active ligand, such as aspartame, to assess the influence of a metal complex as a modulating substituent on the properties of the bioactive ligand (66). 

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. ... 

Sweet Taste. The mechanism of sweetness perception has been extensively studied because of its commercial importance. Many substances that vary in chemical structure have been discovered which are similar to the taste of sucrose. Commercial sweeteners include sucralose, acesulfame-K, saccharin, aspartame, cyclamate (Canada) and the protein thaumatin 4), Each sweetener is unique in its perceived sensation because of the time to the onset of sweetness and to maximum sweetness, ability to mask other sensations, persistence, aftertaste and intensity relative to sucrose [TABLE IT. For example, the saccharides, sorbitol and... 

Today, it is well-known that peptides or proteins exhibit various kinds of taste. Our group has been researching on the relationship between taste and structure of peptides, BPIa (Bitter peptide la, Arg-Gly-Pro-Pro-Phe-Ile-Val) (7 as a bitter peptide, Om-p-Ala-HCl (OBA), Om-Tau-HCl as salty peptides(2j, and "Inverted-Aspartame-Type Sweetener" (Ac-Phe-Lys-OH) as a sweet peptide(5). The relationship between taste and chemical structure was partly made clear. Since commercial demand for these flavor peptides is increasing, we need to develop new synthetic methods which can prepare these peptides in large scale. We developed the following two methods (1) protein recombination method as a chemical method, (2) enzymatic synthesis using chemically modified enzyme as a biochemical method. 

The disaccharide structure of (12) (trade name SPLENDA) is emphasized by the manufacturer as responsible for a taste quality and time—intensity profile closer to that of sucrose than any other high potency sweetener. The sweetness potency at the 10% sucrose solution sweetness equivalence is between 450 and 500X, or about two and one-half times that of aspartame. When compared to a 2% sugar solution, the potency of sucralose can be as high as 750X. A moderate degree of synergy between sucralose and other nonnutritive (91) or nutritive (92) sweeteners has been reported. 

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-... 

Fig-1 Chemical structures of the intense sweeteners saccharin, sodium cyclamate, acesulfame-K, aspartame, alitame, dulcin, sucralose, and neohesperidin dihydrochalcone. 

The following structure is a computer-drawn representation of aspartame, C HjglS Os, known commercially as NutraSweet. Only the connections between atoms are shown multiple bonds are not indicated. Complete the structure by indicating the positions of the multiple bonds. 

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 ... 

Aspartame is slightly soluble in 95% ethanol, sparingly soluble in cold water (1% w/v at the isoelectric point of pH 5.2 and at 20° C), and is soluble at higher temperatures and at pH values other than the isoelectric pH [5]. The low solubility in water appears to be a consequence of details of the aspartame crystal structure (see section 3.6.1 for details of the aspartame crystal structure). 

Leung and Grant [22] state that the reported single crystal hemihydrate structure [9] does not correspond to the commercial form of aspartame (Form II, also a hemihydrate), but corresponds instead to their Form I. A crystal structure has not been determined for the anhydrous form of aspartame, which has so far resisted all attempts at isolation. 

The theoretical powder diffraction pattern based on the single crystal x-ray structure is very similar to that observed experimentally for Form I. X-ray powder diffraction has been used to demonstrate the transformation from aspartame to the 2,5-diketopiperazine derivative [22],... 

Figure 2. Stereoscopic representations of the crystal structure for aspartame (Form I). (a) unit cell, showing phenyl rings interacting in the center of each cell and hydrogen-bonded water molecules at the edges (b) columnar representation, showing hydrogen-bonded stacks of water molecules and zwitterionic aspartyl amino and carboxylate groups in center with stacked phenyl rings at edges. Reproduced from [9].

Figure 3. XRPD diffraction patterns for aspartame hemihydrate. Shown are (a) theoretical pattern calculated from the single crystal structure (b) Form I (ball-milled) (c) Form I (heated in steam) (d) Form II (after compression at 250 MPa) and (e) Form R (commercial). Reproduced from [23].

Aspartame has been reported in a variety of solvatomorphic forms, namely one anhydrous form, two hemihydrate forms (Forms I and II) and a di-hemihydrate [8]. The structural details of the crystal properties have been discussed earlier, and will also be addressed in the discussion on thermal analysis. The room temperature transition between the hemihydrate and di-hemihydrate forms occurs between relative humidities of 40% and 60%. 

The low energy sweetening properties of aspartame have been discussed on the basis of structural relationships [1, 83] within the context of the three point contact model of the sweet taste receptor. This model involves a hydrogen bond donor, a hydrogen bond acceptor, and a hydrophobic region with specific geometric relationships. The model accounts for the fact that only one of the four diastereomers of aspartylphenylalanyl methyl ester is sweet. 

Ottinger el al.2S6 have applied their comparative taste dilution analysis (cTDA) to examine the extractable products from heated aqueous D-glucose and L-alanine that were not solvent-extractable. One HPLC fraction proved to be a strong sweetness enhancer. It was isolated and submitted to LC-MS and NMR, both ID and 2D the results, together with its synthesis from HMF and alanine, unequivocally identified it as the inner salt of /V-( I -carboxycthyl)-6-(hydroxy-methyl)pyridinium-3-ol (alapyridaine, Structure 45). It has no taste on its own, which in many applications would be an advantage. Depending on the pH, it lowers the detection threshold of sweet sugars, amino acids, and aspartame, the... 

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. 

Food chemistry includes much larger-scale items than flavours. Sweeteners such as sugar itself are isolated from plants on an enormous scale. Sugar s structure appeared a few pages back. Other sweeteners such as saccharin (discovered in 1879 ) and aspartame (1965) are made on a sizeable scale. Aspartame is a compound of two of the natural amino adds present in all living things and is made by Monsanto on a large scale (over 10 000 tonnes per annum). 

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