Aspartame hydrogenation

Aspartame Hydrogenation of enamide with Rh-eniphos 15 t Enichem/Anic [13]... 

Scheme 2. Anic and Enichem s commercial synthesis of aspartame (7) using catalytic asymmetric hydrogenation.

Fig. 31.— The Two Possible Conformations of Aspartame (18) Interacting with the Receptor Site." [Key O, carbon G, oxygen , nitrogen and o, hydrogen.]...

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. ... 

Arylation, olefins, 187, 190 Arylketimines, iridium hydrogenation, 83 Arylpropanoic acid, Grignard coupling, 190 Aspartame, 8, 27 Asymmetric catalysis characteristics, 11 chiral metal complexes, 122 covalently bound intermediates, 323 electrochemistry, 342 hydrogen-bonded associates, 328 industrial applications, 8, 357 optically active compounds, 2 phase-transfer reactions, 333 photochemistry, 341 polymerization, 174, 332 purely organic compounds, 323 see also specific complexes Asymmetric induction, 71, 155 Attractive interaction, 196, 216 Autoinduction, 330 Axial chirality, 18 Aza-Diels-Alder reaction, 220 Azetidinone, 44, 80 Aziridination, olefins, 207... 

Homogeneous asymmetric hydrogenation is a practical synthetic method (27). The DIPAMP-Rh-catalyzed reaction has been used for the commercial production of (S)-DOPA [(5)-3-(3,4-dihydroxy-phenyl) alanine] used to treat Parkinson s disease (Monsanto Co. and VES Isis-Chemie) (Scheme 12) (27, 28). (S)-Phenylalanine, a component of the nonnutritive sweetener aspartame, is also prepared by en-antioselective hydrogenation (Anic S.p.A. and Enichem Synthesis) (29). A cationic PNNP-Rh(nbd) complex appears to be the best catalyst for this purpose (15c) (see Scheme 5 in Chapter 1). 

Ion-pair chromatography has also been used for the separation of aspartame from other sweeteners. The ion-pair reagents commonly used are triethylammonium phosphate (32), tetra-ethylammonium hydroxyde (47), tetrapropylammonium hydroxide (40), pentanesulfonate (52), tetrabutylammonium phosphate (34), tetrabutylammonium hydrogen sulfate (66), and tetrabutyl-ammonium p-toluenesulfonate (24). 

Neohesperidin dihydrochalcone has also been determined by ion-pair chromatography on LiChrospher 60 with a gradient of 15-95% methanol in 10 mM tetrabutylammonium hydrogen sulfate. No interference was observed from acesulfame-K, aspartame, and saccharin (66). 

Taste is constructed from five basic taste qualities. The first is sourness. Hydrogen ions produce sourness. The second is saltiness produced, mainly, by NaCl and KC1. The third is bitterness. Quinine and caffeine produce bitterness. The fourth is sweetness, produced by sucrose, glucose, aspartame and so on. The last is umami. Monosodium glutamate (MSG), disodium inosinate (IMP) and disodium guanylate (GMP) show umami [1-5]. 

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].

Divinylbenzene-polystyrene resins modified chemically, milled and screened to 30-45 micron and then packed by the authors 200 x 22 mm Aqueous disodium hydrogen phosphate, monopotassium dihydrogen phosphate and sodium chloride pH 2.8 temperature at 20, 30 or 40° C. 0.5,1.0, or 1.5 Aspartic acid, asparagine, phenylalanine, aspartame (theoretical adsorption study) 76... 

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. 

Although more limited in scope than the BINAP-Ru(II)-catalysed hydrogenations, rhodium-catalysed hydrogenations are of enormous commercial importance because of the demand for both natural and unnatural amino acids on a vast scale. It is even economical for the more expensive of the natural amino acids to be made synthetically rather than isolated from natural sources—phenylalanine, for example, of industrial importance as a component of the artificial sweetener aspartame, is manufactured by enantiosfelective hydrogenation. 

Recently the possibility of total enzymatic synthesis of Aspartame has been suggested (44). It was shown that immobilized penicillinacylase would hydrolyze JJ-phenacetyl L-L-aspartame thus, if thermolysin will accept phenacetyl L-Asp, use of the carbobenzoxyl protecting group and its subsequent removal by hydrogenation would not be required. 

Sweeteners can be divided into two groups, nonnutritive and nutritive sweeteners. The nonnutritive sweeteners include saccharin, cyclamate, aspartame, acesulfame K, and sucralose. There are also others, mainly plant extracts, which are of limited importance. The nutritive sweeteners are sucrose glucose fructose invert sugar and a variety of polyols including sorbitol, mannitol, malt-itol, lactitol, xylitol, and hydrogenated glucose syrups. 

The simplest tastant, the hydrogen ion, is perceived as sour. Other simple ions, particularly sodium ion, are perceived as salty. The taste called umami is evoked by the amino acid glutamate, often encountered as the flavor enhancer monosodium glutamate (MSG). In contrast, tastants perceived as bitter or sweet are extremely diverse. Many bitter compounds are alkaloids or other plant products of which many are toxic. However, they do not have any common structural elements or other common properties. Carbohydrates such as glucose and sucrose are perceived as sweet, as are other compounds including some simple peptide derivatives, such as aspartame, and even some proteins. 

The enzyme has also been used in the production of several natural amino acids such as L-serine from glycine and formaldehyde and L-tryptophan from glycine, formaldehyde, and indole [77-79], In addition, SHMT has also been used for the production of a precursor, 20, to the artificial sweetener aspartame (21) through a non-phenylalanine-requiring route (Scheme 14) [80-83]. Glycine methyl ester (22) is condensed with benzaldehyde under kinetically controlled conditions to form L-enY/ ra-p-phenylserine (23). This is then coupled enzymatically using thermolysin with Z-aspartic acid (24) to form A -carbobcnzyloxy-L-a-aspartyl-L-eryt/zro-p-phenylserine (20). and affords aspartame upon catalytic hydrogenation. 

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