Of a-keto acids

Alpha amino acids (and aldehydes) synthesis by reaction of an alpha keto add with another amino acid (Herbst-EngeO or by reaction of a keto acid with ammonia tmdef reducing conditions (Knoop-Oe sterling). 

In continuing their previous work Bougault and Daniel observed that thiosemicarbazones of a-keto acids (51) also undergo a cyclization resulting in 3-thioxo-5-oxo-2,3,4,5-tetrahydro-l,2,4-triazines (52). In contrast with the cyclization of semicarbazones this cyclization... 

The last of the procedures of preparation of A -alkyl derivatives of dioxotriazines is the cyclization of A-alkylated semicarbazones of a-keto acids. It was employed only in a few cases and it appears that its yields are very low. Despite the fact that even here a fundamental effect of substitution on the yield of cyclization can be expected, as the case is with analogous thiosemicarbazones (e.g., Section II,B,4,b), the method is of no particular preparative value. 

Even if no general conclusions can be drawn on the basis of existing material, it appears that further study of cyclization of these substances could elucidate the mechanism of cyclization of thiosemi-carbazones of a-keto acids which is of fundamental importance in the chemistry of dioxotriazines. 

Other examples of a-keto acid-dependent enzymes are mammalian proline hydroxylase and bacterial clavaminate synthase [113]. The latter enzyme is of particular interest as it is responsible for the catalysis of three individual steps in the biosynthesis of the (3-lactamase inhibitor clavulanic acid (Scheme 10.30). 

TPP-dependent enzymes are involved in oxidative decarboxylation of a-keto acids, making them available for energy metabolism. Transketolase is involved in the formation of NADPH and pentose in the pentose phosphate pathway. This reaction is important for several other synthetic pathways. It is furthermore assumed that the above-mentioned enzymes are involved in the function of neurotransmitters and nerve conduction, though the exact mechanisms remain unclear. 

Protonated nitrogen heterocycles can be carbalkoxylated" by treatment with esters of a-keto acids and Fenton s reagent. Pyridine is carbalkoxylated at C-2 and C-4, for example. The attack is by "COOR radicals generated from the esters ... 

NAD and NADP and FMN and FAD, respectively. Pantothenic acid is a component of the acyl group carrier coenzyme A. As its pyrophosphate, thiamin participates in decarboxylation of a-keto acids and folic acid and cobamide coenzymes function in one-carbon metabolism. 

Transketolase (TKase) [EC 2.2.1.1] essentially catalyzes the transfer of C-2 unit from D-xylulose-5-phosphate to ribose-5-phosphate to give D-sedoheptulose-7-phosphate, via a thiazolium intermediate as shown in Fig. 16. An important discovery was that hydroxypyruvate works as the donor substrate and the reaction proceeds irreversibly via a loss of carbon dioxide (Fig. 17). In this chapter, we put emphasis on the synthesis with hydroxypyruvate, as it is the typical TPP-mediated decarboxylation reaction of a-keto acid. ... 

Summarizing the results obtained by controlled potential electrolysis and polarography, the reaction process for the electrolytic evolution of CO2 was estimated to be as follows the first step was one electron transfer from DMFC in NB to FMN in W as in Eq. (7). The second step was the catalytic reduction of O2 by FMNH as in Eq. (8). The final step was the oxidation of pyruvic acid by the reduction product of O2, H2O2, in W as in Eq. (9), well-known as an oxidative decarboxylation of a-keto acids [43] ... 

The highly enantioselective reductive animation of a-keto acids as a route to amino acids is possible with ligand 118 (3 R,4R)- l-W-benzyl)-3,4-bis(diphenylphosphanyl)pyrrolidine, DEGUPHOS] and [Rh(cod)2]BF4.649 (R,R)-NORPHOS (2-exo-3-endo-bis(diphenylphosphino)bicyclo[2.2.1 ]heptene) and (2. S, 3. S ) - C HIR AP H O S (bis(diphenylphosphino)butane) are also good ligands for this transformation. Arylpyruvic acids give the best results (>95% ee). 

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. 

Thiazoles play a prominent role in nature. For example, the thiazolium ring present in vitamin Bi serves as an electron sink and its coenzyme form is important for the decarboxylation of a-keto-acids. Furthermore, thiazoles are useful building blocks in pharmaceutical agents as exemplified by 2-(4-chlorophenyl)thiazole-4-acetic acid, a synthetic anti-inflammatory agent. 

Fig. 18. Electromicrobial reduction of a-keto acids with Proteus vulgaris in the presence of methyl viologen as mediator...

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. 

Two sources of acyl radicals have proved to be useful for the homolytic acylation of protonated heteroaromatic bases the oxidation of aldehydes and the oxidative decarboxylation of a-keto acids. The oxidation... 

We shall see later (see Section 15.6) that reductive amination of a keto acid is the way nature synthesizes amino acids, using the biological analogue of a complex metal hydride, namely NADPH (see Box 7.6). 

Scheme 2.13 Reductive amination of a-keto acid 29 using PDH.

Protonated pyridines and derivatives readily undergo acylation at C-2 or C-4 (Table 28) (76MI20503). Acyl radicals are usually generated either by hydrogen abstraction from aldehydes (Scheme 210), or by oxidative decarboxylation of a-keto acids (Scheme 211). In the former case (Scheme 210) with acridine as the substrate, reduction can take place to give a dihydroacridine. 

Thiamine pyrophosphate is a coenzyme and the active form of vitamin B. It functions as coenzyme in decarboxylation of a-keto acid and in hexose monophosphate shunt. 

Problem 21.2 Synthesize leucine, (CH,),CHCH,CH(NH,)COO, by (a) Hell-Volhard-Zelinsky reaction (Section 16.3) followed by ammonolysis. (b) Gabriel synthesis, (c) phthalimidomalonic ester synthesis, (d) reductive amination of a keto acid, (e) Strecker synthesis (addition of NH, HCN to RCH=0), (/) acetylaminomalonic ester. 

Although metal ions do not catalyze the decarboxylation of monocarboxylic acids in solution, a variety of metal ions catalyze the decarboxylation of oxaloacetic acid anion, leading to the formation of pyruvic acid (27). The metal ions involved were cupric, zinc, magnesium, aluminum, ferric, ferrous, manganous, and cadmium, approximately 10-2 to 10-3 M (27). Of these, the aluminum, ferric, ferrous, and cupric ions were the most efficient sodium, potassium, and silver ions were inactive. This process involves the decarboxylation of a / -keto acid, which undergoes a relatively facile uncatalyzed decarboxylation. However, not every decarboxylation of a / -keto acid is catalyzed by metal ions—only those... 

Since our initial communication (10) concerning the catalytic reduction of organic substrates by this homogeneous hydrogenation system, two further reports have come to our attention de Vries (2) demonstrated the reduction of sorbic acid to 2-hexenoic acid and Kang (8) described the reductive amination of a-keto acids. 

Substances with low solubility in acid can interfere with the DNPH assay. Mandel-amine (methenamine man delate), an antibacterial medication, and radiopaque contrast material will form a precipitate immediately upon addition of the DNPH reagent. The color and immediacy of formation of this precipitate distinguishes it from the yellowish precipitate of a-keto acid hydrazones. It is very important to have information on patient medications prior to evaluation of the DNPH test. 

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