Phenylpyruvic synthesis

Intermediate diketopiperazine derivatives have been employed in the diastereoselective synthesis of benzyltetra-hydroisoquinoline by 1,4-chirality transfer. iV-Cbz-Proline was coupled with 2-(3,4-dimethoxyphenyl)ethylamine and the resulting amide 109, after deprotection, was reacted with phenylpyruvic acid (Cbz = carbobenzyloxy group). Compound 110 underwent acid-catalyzed Pictet-Spengler condensation to yield final tetracyclic... 

Assumptions Synthesis of phenylpyruvic acid Batch synthesis process for precursors overal yield of 95+% of theoretical to pheny Ihydantoin overall yield of 90+% of theoretical from phenylhydantoin to phenylpyruvic acid recovery and recycle of acetic acid no byproduct crec taken for acetic acid formed from acetic anhydride addition. Conversion of phenylpyruvic acid and aspartic acid. Bioreactor productivity of-18 g PHE/L/h (four columns in parallel) 98% overall conversion no byproduct credit taken for pymvic acid (recovery cost assumed to be of by revenue from sale) 80% recovery of L-PHE downstream of bioreactor. 

Although 2-phenylethanol can be synthesised by normal microbial metabolism, the final concentrations in the culture broth of selected microorganisms generally remain very low [110, 111] therefore, de novo synthesis cannot be a strategy for an economically viable bioprocesses. Nevertheless, the microbial production of 2-phenylethanol can be greatly increased by adding the amino acid L-phenylalanine to the medium. The commonly accepted route from l-phenylalanine to 2-phenylethanol in yeasts is by transamination of the amino acid to phenylpyruvate, decarboxylation to phenylacetaldehyde and reduction to the alcohol, first described by Ehrlich [112] and named after him (Scheme 23.8). 

The Pd(0)-catalysed carbonylation of benzyl chloride proceeds under atmospheric pressure in a two-phase system utilizing the water-soluble phosphine to give phenylacetic acid (461) [227]. In the total synthesis of the macrolide curvularin (465), the Pd-catalysed carbonylation of the benzyl chloride 462 in the presence of the alcohol 463 to give the ester 464 has been applied [228]. Phenylacetic acid (461) is produced commercially by Co2(CO)8-catalysed carbonylation of benzyl chloride. The Co2(CO)8-catalysed double carbonylation of benzyl chloride using Ca(OH)2 as a base gives phenylpyruvic acid (466) with high selectivity [229]. Selection of solvents is important. DME is a good solvent, whereas MeOH is not satisfactory. 

In cases where the natural amino acid side chains of enzymes are insufficient to carry out a desired reaction, the enzyme frequently uses coenzymes. A coenzyme is bound by the enzyme along with the substrate, and the enzyme catalyses the bimolecular reaction between the coenzyme and the substrate (cf. Section 2.6.3). A simple model for a-amino acid synthesis by transamination was developed by substituting /I-cyclodextrin with pyridoxamine. Pyridoxamine is able to carry out the transformation of a-keto acids to a-amino acids even without the presence of the cyclodextrin, but with the cyclodextrin cavity as well, the enzyme model proves to be more selective and transaminates substrates with aryl rings bound strongly by the cyclodextrin much more rapidly than those having little affinity for the cyclodextrin. Thus (p-le/f-butylphenyl) pyruvic acid and phenylpyruvic acid are transaminated respectively 15 000 and 100 times faster then pyruvic acid itself, to give (p-le/f-butylphenyl) alanine and phenylalanine (Scheme 12.5). 

The biosynthetic pathway from SA into L-Phe [69, 70] is shown in Fig. 8.15. The synthesis of chorismate (CHA), the common intermediate in the biosynthesis of the aromatic amino acids, requires an extra equivalent of PEP, which limits the yield of L-Phe from glucose to 0.30 mol mol-1 if PEP is not conserved [91]. The further transformation of CHA into phenylpyruvic acid (PPY) suffers from inhibition by L-Phe and is also subject to transcriptional control [69, 92]. The final step is a reductive amination of PPY into L-Phe with consumption of l-G1u. 

The use of interm iates as substrates in L-phenylalanine synthesis avoids inhibition by metabolites. Phenylpyruvic add, an intermediate precursor in tfie biosynthesis of L-phenylalanine, can be converted to L-phenylalanine. L-aspartic add is often used as an amino donor. The amino group can only be transfdred from an... 

Because transamination reactions are reversible, it is theoretically possible for all amino acids to be synthesized by transamination. However, experimental evidence indicates that there is no net synthesis of an amino acid if its a-keto acid precursor is not independently synthesized by the organism. For example, alanine, aspartate, and glutamate are nonessential for animals because their a-keto acid precursors (i.e., pyruvate, oxaloacetate, and a-ketoglutarate) are readily available metabolic intermediates. Because the reaction pathways for synthesizing molecules such as phenylpyruvate, a-keto-/Thydroxybutyrate, and imidazolepyruvate do not occur in animal cells, phenylalanine, threonine, and histidine must be provided in the diet. (Reaction pathways that synthesize amino acids from metabolic intermediates, not only by transamination, are referred to as de novo pathways.)... 

By analogy with the rearrangement of styrene oxide compounds, more complicated substances, e. g. phenylpyruvic acid methyl ester derivatives, can be synthesized from readily available glycidic acid esters, as shown in Figure 3. These esters can be used as intermediates for herbicides (e. g. the triazinones) and for the synthesis of L-amino acids. 

In gas-phase reactions zeolites are superior to non-zeolitic molecular sieves, metal phosphates, and metal oxides. Over the mildly acidic [B]-MFI (Si/B = 24) the synthesis of phenylpyruvic acid methyl ester yields up to 94 % at 200 °C and WHSV = 3 h 95 % product yield could be achieved with the cesium-doped material (0.6 % w w) [8]. With these concepts a-ketocarboxylic acid esters can be prepared from readily available feedstocks whereas conventional methods require the use of costly and environmentally problematical Grignard reactions. 

Increasing the temperature to 350 °C results in decarbonylation of the phenylpyruvic acid methyl ester derivatives and the phenyl acetic ester is formed with a ratio of 65 % a-ketoester to 35 % acetic acid ester. Until now the industrial process for the synthesis of phenylacetic acid ester has started from benzyl chloride, which is converted to benzyl cyanide by KCN, followed by hydrolysis. Every step of this reaction must be performed in a separate reactor and special measures must be taken for handling large amounts of toxic KCN. The new route is certainly an environmentally benign alternative [8,27]. 

Figure. 2. Enzymatic synthesis of L-phenylalanine by reductive amination starting from phenylpyruvate (using EMR technology).

Phenylalanine, synthesized from [ C]cyanide by the Bucherer modification of the Strecker synthesis, was resolved into its l- and D-iso-mers by the action of the d- and L-amino acid oxidases, respectively. The optically active amino acid was separated from phenylpyruvic acid by cation exchange chromatography (3). Similarly, DL-[ F]acyl-p-fluoro-phenylalanine has been subjected to stereospecific deacylation with the fungal enz)nne, L-amino acylase enz)nnatically generated L-[ F]p-fluoro-phenylalanine was separated from the D-acyl amino acid by column chromatography (4). 

A second commercial synthesis of papaverine was performed by Wahl (62) in 1947 but not published until three years later. 3,4-Dimethoxy-phenylpyruvic acid (XXXVIII), prepared from veratraldehyde and hip-puric acid, was treated with ammonium hydroxide at 100° under pressure, and the resultant diamide (XXXIX) was hydrolyzed to the corresponding 3- (3,4- dimethoxyphenyl)- a- (3,4- dimethoxyphenylacetamido) propionic acid. The methyl ester of this compound was cyclized readily with phosphorus oxychloride, and the resulting ester was saponified to 3,4-dihydro-papa verine-3-carboxylic acid (XL). The latter was decarboxylated at 140° in tetralin solution to 3,4-dihydropapaverine, and addition of palladium-on-carbon catalyst to the reaction mixture furnished papaverine, four parts of vanillin leading to one part of the alkaloid in over-all yield. 

Optically pure opine-tjrpe secondary amine carboxylic acids were also synthesized from amino acids and their analogs, such as L-methionine, L-isoleucine, L-leucine, L-valine, L-phenylalanine, L-alanine, L-threonine, L-serine, and L-phenylalaninol, and a-keto acids, such as glyoxylic, pyruvic, and 2-oxobutyric acids, using the enzyme with regeneration of NADH with FDH from Moraxella sp. C-1 [13]. The absolute configuration of the nascent asymmetric center of the opines was of the D stereochemistry with > 99.9% e.e. One-pot synthesis of N-[l-D-(carboxyl)ethyl]-L-phenylalanine from phenylpyruvic and pyruvic acid by using ODH, FDH, and phenylalanine dehydrogenase (PheDH) from Bacillus sphaericus... 

Mu, Chen, Li, Zhang, and Jiang (2009) also smdied the effect of medium composition on the production of PLA by lactic acid bacteria. Attempting to optimize a medium for the commercial production of PLA, the authors used a response surface methodology and the results showed that addition of phenylpyruvic acid (PPA) increased the yield of PLA. The authors suggested that because the transamination step is a bottleneck in the synthesis of PLA, the addition of PPA allowed for a shortcut that bypassed the transamination of phenylalanine to PPA, which is normally the first step when phenylalanine is used as the source for PLA. 

Although both phenylpyruvic acid (10) and p-hydroxy-phenylpyruvic acid (11) can serve as precursors for phenylalanine and tyrosine, respectively, it does not appear that plants synthesize either compound, hi E. colU however, these two intermediates are involved in the synthesis of phenylalanine and tyrosine. Both phenylpyruvic acid and p-hydroxyphen-ylpyruvic acid have been postulated to serve as precursors for a number of other compounds in plants—in particular. 

Classical phenylketonuria is an hereditary defect in the synthesis of Phe hydroxylase (the enzyme may be absent or inactive), which affects about 1 infant in 10,000. These individuals are unable to convert Phe into tyrosine, and the major route of Phe metabolism is thus blocked. Phenylpyruvate and phenylacetic acid are excreted in the urine. The condition is accompanied by defective pigmentation and, if untreated, by severe mental retardation (hence the other name, phenylpyruvic oligophrenia, also known as Polling s syndrome). Tlie urine of newborn infants is now routinely tested (Guthrie test) for the presence of phenylketones the condition can be compensated by a diet low in phenylalanine, and the typic mental retardation is thereby avoided. Other types of phenylketonuria are due to defective reduction or synthesis of dihydrobiopterin (see Inborn errors of metabolism). 

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