Pyruvic acid amination

This is an example of the Doebner synthesis of quinoline-4-carboxylic acids (cinchoninic acids) the reaction consists in the condensation of an aromatic amine with pyruvic acid and an aldehj de. The mechanism is probably similar to that given for the Doebner-Miller sj nthesis of quinaldiiie (Section V,2), involving the intermediate formation of a dihydroquinoline derivative, which is subsequently dehydrogenated by the Schiff s base derived from the aromatic amine and aldehyde. 

In transamination an amine group is transferred from L glutamic acid to pyruvic acid An outline of the mechanism of transamination is presented m Figure 27 4... 

Yet a third method for the synthesis of a-amino acids is by reductive amination of an a-keto acid with ammonia and a reducing agent. Alanine, for instance, is prepared by treatment of pyruvic acid with ammonia in the presence of NaBH As described in Section 24.6, the reaction proceeds through formation of an intermediate imine that is then reduced. 

Xiao-Hua Yang et al. [ 1 ] determined nanomolar concentrations of individual low molecular weight carboxylic acids (and amines) in seawater. Diffusion of the acids across a hydrophobic membrane was used to concentrate and separate carboxylic acids from inorganic salts and most other organic compounds prior to the application of ion chromatography. Acetic propionic acid, butyric-1 acid, butyric-2 acid, valeric and pyruvic acid, acrylic acid and benzoic acid were all found in reasonable concentrations in seawater. 

Recently, Borner and coworkers described an efficient Rh-deguphos catalyst for the reductive amination of a-keto acids with benzyl amine. E.e.-values up to 98% were obtained for the reaction of phenyl pyruvic acid and PhCH2COCOOH (entry 4.9), albeit with often incomplete conversion and low TOFs. Similar results were also obtained for several other a-keto acids, and also with ligands such as norphos and chiraphos. An interesting variant for the preparation of a-amino acid derivatives is the one-pot preparation of aromatic a-(N-cyclohexyla-mino) amides from the corresponding aryl iodide, cyclohexylamine under a H2/ CO atmosphere catalyzed by Pd-duphos or Pd-Trost ligands [50]. Yields and ee-values were in the order of 30-50% and 90 >99%, respectively, and a catalyst loading of around 4% was necessary. 

Biochemical reactions include several types of decarboxylation reactions as shown in Eqs. (1)-(5), because the final product of aerobic metabolism is carbon dioxide. Amino acids result in amines, pyruvic acid and other a-keto acids form the corresponding aldehydes and carboxylic acids, depending on the cooperating coenzymes. Malonyl-CoA and its derivatives are decarboxylated to acyl-CoA. -Keto carboxylic acids, and their precursors (for example, the corresponding hydroxy acids) also liberate carbon dioxide under mild reaction conditions. 

In addition to the catalysts listed in Table 2, several rhodium(I) complexes of the various diphosphines prepared by acylation of bis(2-diphenylphosphinoethyl)amine were used for the hydrogenation of unsaturated acids as well as for that of pyruvic acid, aUyl alcohol and flavin mononucleotide [59,60]. Reactions were mn in 0.1 M phosphate buffer (pH = 7.0) at 25 °C under 2.5 bar H2 pressure. Initial rates were in the range of 1.6-200 mol H2/molRh.h. 

A pH-dependent chemoselective catalytic reductive amination of a-keto acids, affording a-amino acids with HCOONH4 in water, was achieved using the complex 31 or its precursor 28 as the catalyst [51]. The formation rates of alanine and lactic acid from pyruvic acid exhibited a maximum value around pH 5 and pH 3, respectively, and therefore, alanine was obtained quite selectively (96%) with a small amount of lactic acid (4%) at pH 5 (Scheme 5.18). A variety of nonpolar, uncharged polar and charged polar amino acids were also synthesized in high yields. 

In contrast, amino acid dehydrogenases comprise a well-known class of enzymes with industrial apphcations. An illustrative example is the Evonik (formerly Degussa) process for the synthesis of (S)-tert-leucine by reductive amination of trimethyl pyruvic acid (Scheme 6.12) [27]. The NADH cofactor is regenerated by coupling the reductive amination with FDH-catalyzed reduction of formate, which is added as the ammonium salt. 

Since the decarboxylation of 161 to 162 proceeds in a poor yield, it was suggested that formation of 162 in benzene occurs directly from 2-benzopyrylium salts 62 through primary nucleophilic attack by amine in position 3. In this case, an enamine fragment of pyruvic acid appears in the ring-opened intermediate 163, which undergoes easy decarboxylation (82TL459). The vinylic carbanion 164, formed by the loss of carbon dioxide, captures a proton by intra- or intermolecular process, then hetero-cyclization takes place. 

The three-component reaction of amines 220-222 with pyruvic acid 239 and aromatic aldehydes has as the first step the formation of the appropriate azomethine intermediate D (Scheme 3.72). This hypothesis was proved by Chebanov et al. [202] through the synthesis of compounds 249-251 by the reaction of azomethine D with pyruvic acid. 

Each of the reactions is catalyzed by a different type of proteinoid or metal-proteinoid complex. The reaction of pyruvic acid to alanine and the reverse reaction are hypothesized from the experimental results in the amination of a-ketoglutaric acid 241 and the deamination of glutamic acid 2S). 

The amino acid alanine can be made in moderate yield in the laboratory by reductive amination of pyruvic acid. 

Living things use a very similar reaction to manufacture amino acids from keto acids—but do it much more efficiently- The key step is the formation of an imine pyruvic acid between pyruvic acid and the vitamin B6-derlved amine pyridoxamine. 

Fig. 35 Production of L-tert-leucine by reductive amination of trimethyl pyruvic acid catalyzed by leucine dehydrogenase (LeuDH) and formate dehydrogenase (FDH) for cofactor regeneration...

The reaction of optically active carbinolamines formed by an enzymatically controlled addition of acetaldehyde to amines, illustrated in Fig. 2, may be of theoretical interest, but lacks experimental verification it also would require the presence of acetaldehyde. The more likely pyruvic acid route to optically active TIQs, however, also remains inconclusive. If it indeed proceeds through TIQ-1-carboxylic acids to DIQ intermediates by an oxidative decarboxylation (176,217,218), it requires that it be followed by an asymmetric enzymatic reduction. Although achieved in vitro (35), this reaction has not been realized in vivo. The formation of unequal amounts of the optical isomers of salsolinol and other TIQs in vivo could arise from racemic 1-carboxy-TIQ in an enzymatic decarboxylation, proceeding with (S) and (R) enantiomers at a different rate and thus affording different amounts of (5)- and (/ )-TIQ. With the availability of optically active TIQ-1-carboxylic acids, this possibility can now be tested. 

Do optically active 1-methyl-TIQs, as sketched in Fig. 32 for the synthesis of (7 )-salsolinol, originate from a Pictet-Spengler reaction of dopamine with acetaldehyde derive from ethanol, or are they the result of a Pictet-Spengler reaction of biogenic amines with pyruvic acid, as sketched in Fig. 33 Based on the accumulated data it seems reasonable to propose that optically active TIQs are formed by the pyruvic acid pathway, and that the pyruvic acids may be derived from an impaired glucose metabolism or an impaired amino acid metabolism. Whether the intermediate TIQ-1-carboxylic acids 91a,b are enzymatically decarboxylated to afford 64a,b in a different enantiomeric ratio, or whether optically active TIQs are formed by oxidative decarboxylation of TIQ 91 to DIQ 120, followed by an asymmetric reduction, remains open to question. 

The key fdep in this biotoigicai traiufiirmatitm is the nueieopbiKc addition of ati amine to the ketone carbonyl group of pyruvic acid. The tetca hedral intermediate loses water to yield an itnine, which is further reduced in a second nucleophilic addition step to yield alanine. 

Thus reaction of cyclohexanone, n-propylamine, and sodium cyanoborohydride in methanol at pH 6-8 at 25° for 24 hr. gives n-propyleyelohexylamine in 85 % yield. The reaction is general for ammonia and primary and secondary amines aromatic amines are somewhat sluggish. All aldehydes and relatively unhindered ketones can be reduc-tively aminated. Yields are improved by use of 3A molecular sieves to absorb the water generated in the reaction. Note that reductive amination of substituted pyruvic acids with ammonia leads to oi-amino acids. Thus alanine can be obtained from pyruvic acid in 50 % yield. A pH of 7 is optimum for. synthesis of a-amino acids. 

The catalytic hydrogenation of the benzoylformic acid amides of optically active amino acid esters was carried out. When the (5)-amino acid ester was used, the resulting mandelic acid had the (R)-con-figuration. When pyruvic acid amides of optically active benzylic amines were hydrogenated over palladium, optically active lactic acid was obtained in relatively high enantiomeric excess (ee 60%). The... 

The photochemical carboxylation of pyruvic acid by this process is endergonic by about AG° = 11.5 kcal mol and represents a true uphill photosynthetic pathway. The carbon dioxide fixation product can then act as the source substrate for subsequent biocatalyzed transformations. For example, photogenerated malic acid can act as the source substrate for aspartic acid (Figure 35). In this case, malic acid is dehydrated by fumarase (Fum) and the intermediate fumaric acid is aminated in the presence of aspartase (Asp) to give aspartic acid. 

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