2-ketoacids hydrogenation

The overall rate law is, however, found to contain a term involving [ketoacid] (47) as well as the term involving [ketoacid anion]. The ready decarboxylation of the (3-ketoacid itself is probably due to incipient proton transfer to 0=0 through hydrogen-bonding in (47) ... 

P-ketoacid, but these compounds are especially susceptible to loss of carbon dioxide, i.e. decarboxylation. Although P-ketoacids may be quite stable, decarboxylation occurs readily on mild heating, and is ascribed to the formation of a six-membered hydrogen-bonded transition state. Decarboxylation is represented as a cyclic flow of electrons, leading to an enol product that rapidly reverts to the more favourable keto tautomer. 

The second function, and the one pertinent to this section, is the decarboxylation of oxalosuccinic acid to 2-oxoglutaric acid. This is simply a biochemical example of the ready decarboxylation of a P-ketoacid, involving an intramolecular hydrogen-bonded system. This reaction could occur chemically without an enzyme, but it is known that isocitric acid, the product of the dehydrogenation, is still bound to the enzyme isocitrate dehydrogenase when decarboxylation occurs. 

To get the final product we need to lose the ester function. This is a standard combination of acid-catalysed ester hydrolysis followed by heating. The P-ketoacid forms a hydrogen-bonded six-membered ring that facilitates decarboxylation. 

Figure 5-21. The concerted process for the decarboxylation of a /3-ketoacid. The carboxyl hydroxy group is hydrogen bonded to the carbonyl group. The product is an enol which usually tautomerises to the desired ketonic product.

Reductive amination of ketones and aldehydes is one of the best methods for synthesizing amines (Section 19-18). It also forms amino acids. When an a-ketoacid is treated with ammonia, the ketone reacts to form an imine. The imine is reduced to an amine by hydrogen and a palladium catalyst. Under these conditions, the carboxylic acid is not reduced. 

This entire synthesis is accomplished in one step by treating the a-ketoacid with ammonia and hydrogen in the presence of a palladium catalyst. The product is a racemic a-amino acid. The following reaction shows the synthesis of racemic phenylalanine from 3-phenyl-2-oxopropanoic acid. 

A variety of 1,4-ketoacids have been used as starting material. In these (10), Ri or Rg is usually hydrogen (but also alkyl or aryl groups),... 

Ketenes and derived products. Triethylamine dehydrohalogenates an acid chloride having an a-hydrogen atom to give a ketene isolable as the ketene dimer, which can be converted into a j8-ketoacid or a symmetrical ketone (Sauer An example is the preparation of laurone from lauroyl chloride. An ethereal solution of the acid... 

The condensation of a-ketoacids and o-phenylenediamines gives quinoxalin-2-ones,7 and mesoxalic acid and o-phenylenediamine undergo the expected condensation reaction to give quinoxalin-3-one-2-carboxylic acid (1). With sodium mesoxalate an anomalous reaction occurs, the initial products (1) and l,2-dihydrobenzimidazole-2,2-dicarboxylic acid (2) undergo an intermolecular hydrogen transfer reaction to yield l,2,3,4-tetrahydro-3-oxoquinoxaline-2-carboxylic acid (3) and benzimidazole-2-carboxylic acid (4).8... 

Whereas redox reactions on metal centres usually only involve electron transfers, many oxidation/reduction reactions in intermediary metabolism, as in the case above, involve not only electron transfer, but hydrogen transfer as well — hence the frequently used denomination dehydrogenase . Note that most of these dehydrogenase reactions are reversible. Redox reactions in biosynthetic pathways usually use NADPH as their source of electrons. In addition to NAD and NADP+, which intervene in redox reactions involving oxygen functions, other cofactors like riboflavin (in the form of flavin mononucleotide, FMN, and flavin adenine dinucleotide, FAD) (Figure 5.3) participate in the conversion of [—CH2—CH2— to —CH=CH—], as well as in electron transfer chains. In addition, a number of other redox factors are found, e.g., lipoate in a-ketoacid dehydrogenases, and ubiquinone and its derivatives, in electron transfer chains. 

Nevertheless, reactions are known for a long time in which an intermolecular binding of a carbonyl carbon atom with the nitrogen atom of a cyano group takes place. Thus, the a-ketoacids 107 are capable of undergoing condensation with some nitriles in the presence of either anhydrous hydrogen chloride or sulfuric acid to give enamides 108 or bisamides 109 (equation 38). 

Ketones with functional groups facilitating enolization and/or coordination to the catalyst can be hydrogenated more smoothly. 2-Ketoacids, such as pyruvic and 2-ketoglutaric acids, were reduced by [HRuCl(TPPMS)3], [RhCl(TPPMS)3], and [RhCl(PTA)3] [26, 35, 46], while 4- or 5-ketoacids proved unreactive. More importantly, ethyl and methyl acetoacetate were hydrogenated with Ru(II)/5,5 -disulfona-to-BINAP (31) and Ru(II)/MeO-BIPHEP-S (32) with 91% ee and 93% ee, respectively [95, 98],... 

Two sources of acyl radicals proved to be useful for the homolytic acylation hydrogen abstraction from aldehydes [Eq. (12)] and oxidative dacarboxyla-tion of -ketoacids [Eq. (13)]. 

ENANTIOSELECTIVE HYDROGENATION OF a-KETOACIDS USING PLATINUM CATALYSTS MODIFIED WITH CINCHONA ALKALOIDS. 

R)-4-phenyl-2-hydroxybutyric acid ethyl ester is an important intermediate for the synthesis of the angiotensin-converting enzyme inhibitor benazepril [3] (see SCHEME 1). Its preparation via hydrogenation of the a-ketoester has been developed and scaled-up into a production process (10-2(X) kg scale, chemical yield >98%, ee 79-82%). One drawback of this process is the instability of the a-ketoester during distillation and storage. The hydrogenation of the a-ketoacid followed by esterification is an alternative route to the desired hydroxyester. 

The present publication describes the application of cinchona modified platinum catalysts for the enantioselective reduction of a-ketoacids (SCHEME 2). In particular, we report on the enantioselective hydrogenation of 4-phenyl-2-oxobutyric acid which was investigated and optimized by a systematic variation of catalyst, solvent, modifier and reaction conditions. 

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