Oxidation a-hydroxy acids

The mechanism of flavin reduction in b2 has been a topic of debate for decades. Soon after it was discovered that DAAO could catalyze the elimination of Cl from chlorinated substrates, very similar experiments were conducted with many a-hydroxy acid oxidizing enzymes, including F 2- However, HCl elimination was not observed when using 3-Cl-lactate as a substrate. Studies using 3-Br-pynivate as an electron acceptor for lactate oxidation were interpreted as evidence of a carbanion mechanism of flavin reduction. ... 

L-lactate oxidase (LOX) catalyzes the oxidation of L-lactate to pyruvate with the concomitant reduction of the enzyme-hound FMN. The reduced enzyme is oxidized hy molecular oxygen resulting in oxidized enzyme and H207- LOX has substantial sequence homology to other a-hydroxy acid oxidizing flavoproteins, containing all the residues thought to he important for catalysis in this class of enzymes/... 

A contrasting mode of flavoprotein reactivity with an acetylenic inactivator occurs in the reaction of 2-hydroxy-3-butynoate (13, Fig. 15) with a number of a-hydroxy acid oxidizing enzymes. This process is exemplified by the inactivation of L-lactate oxidase from Mycobacterium smegmatis, an enzyme which catalyzes the oxidative decarboxylation of lactate to yield acetate, carbon dioxide, and water (Walsh, 1979, p. 408). Incubation of 13 with lactate oxidase leads to inactivation of the enzyme with a partition ratio that varies from 110 in the... 

Reactions and Uses. The common reactions that a-hydroxy acids undergo such as self- or bimolecular esterification to oligomers or cycHc esters, hydrogenation, oxidation, etc, have been discussed in connection with lactic and hydroxyacetic acid. A reaction that is of value for the synthesis of higher aldehydes is decarbonylation under boiling sulfuric acid with loss of water. Since one carbon atom is lost in the process, the series of reactions may be used for stepwise degradation of a carbon chain. 

Although alcohol dehydrogenases (ADH) also catalyze the oxidation of aldehydes to the corresponding acids, the rate of this reaction is significantly lower. The systems that combine ADH and aldehyde dehydrogenases (EC 1.2.1.5) (AldDH) are much more efficient. For example, HLAD catalyzes the enantioselective oxidation of a number of racemic 1,2-diols to L-a-hydroxy aldehydes which are further converted to L-a-hydroxy acids by AldDH (166). 

RUFF - FENTON Degradation Oxidative degradation of aldoses via a-hydroxy acids to lower chain aldoses. 

The NAD- and NADP-dependent dehydrogenases catalyze at least six different types of reactions simple hydride transfer, deamination of an amino acid to form an a-keto acid, oxidation of /3-hydroxy acids followed by decarboxylation of the /3-keto acid intermediate, oxidation of aldehydes, reduction of isolated double bonds, and the oxidation of carbon-nitrogen bonds (as with dihydrofolate reductase). 

Lithium enolates of carboxylic acids such as phenylacetic acid or of amides such as N-methyl-N-phenylvaleric acid amide 1974 are oxidized by BTSP 1949 to a-hydroxy acids, which are isolated after esterification, e.g., to 1973, or to a-hydroxyamides such as 1975 [155] (Scheme 12.43) (cf. also the formation of 3-hydroxybutyrolactam 1962). 

Oxidation of benzoin, PhCH(OH)COPh (above) yields benzil, PhCOCOPh (133), and this, in common with non-enolisable 1,2-diketones in general, undergoes base-catalysed rearrangement to yield the anion of an a-hydroxy acid, benzilate anion, Ph2C(0H)C02e (134). This is, almost certainly, the first molecular rearrangement to be recognised as such. The rate equation is found to be,... 

The oxidation of a-hydroxy acids is slow41 it has been comprehensively studied, using glycolic acid as a model.42 Three reactions have been proposed as occurring. 

Carbon dioxide is not a common oxidation product in periodate work, but it does appear in the oxidation of ketoses,49 a-keto acids,14,39 and a-hydroxy acids,14 39 and it is often a product23 141 of overoxidation. Carbon dioxide analyses have been carried out using the Plantefol apparatus,49 the Warburg apparatus,14 23 and the Van Slyke-Neill mano-metric apparatus,39 and by absorption in standard sodium hydroxide141 followed by back-titration with acid. A most convenient method is the very old, barium hydroxide absorption scheme.16 The carbon dioxide is swept from the reaction mixture into a saturated, filtered barium hydroxide solution by means of a stream of pure nitrogen. The precipitated barium carbonate is filtered, dried, and weighed. This method is essentially a terminal assay. The manometric methods permit kinetic measurements, but involve use of much more complicated apparatus. 

More recently, a series of sol-gel hydrophobized nanostructured silica matrices doped with the organocatalyst TEMPO (SiliaCat TEMPO) entered the market as suitable oxidation catalysts for the rapid and selective production of carbonyls and carboxylic acids. In the former case, SiliaCat TEMPO selectively mediates the oxidation of delicate primary and secondary alcohol substrates into valued carbonyl derivatives (Scheme 5.2), retaining its potent activity throughout several reaction cycles (Table 5.2).33 Using this catalyst, for example, enables the synthesis of extremely valuable a-hydroxy acids with relevant selectivity enhancement by coupling of SiliaCat TEMPO with rapid Ru04-mediated olefin dihydroxylation (Scheme 5.3).34... 

Tetrahydropyrrolo[l,4]oxazine 74, obtained by photoinduced electron-transfer (PET) oxidative activation of substituted prolinol, undergoes nucleophilic substitution of the OH at position C-3 with allyltrimethylsilane in the presence of TiCU (Scheme 8). The reaction was highly stereoselective and produced, after hydrolysis of the resultant amide 75, optically active a-hydroxy acid 76 together with the auxiliary (.S )-prolinol that can be effectively recycled <1998TL7153>. 

Kinetic studies of the oxidation of some a-hydroxy acids with pyridinium dichromate (PDC) are consistent with a mechanism involving the loss of H2O from the pro-tonated substrate in the rate-determining step. The oxidation of 8-hydroxyquinoline (oxine) by PDC has been studied. The intermediacy of an acetochromate ion in the oxidation of some acetophenone oximes with PDC is suggested. 

Steric effects dominate in the oxidation of dialkyl, alkyl phenyl and benzal methyl phenyl sulfides to their sulfoxides by quinolinium fluorochromate (QFC) in aqueous acetic acid. QFC oxidation of phenoxyacetic acids has been smdied. Imidazolium dichromate oxidations of a-hydroxy acids have been smdied. ... 

Periodic acid reacts well in aqueous solution. Usually, if the reactant has to be run in organic solvents, lead tetraacetate is used as the reagent. Interestingly, periodic acid will not act on a-keto acids or a-hydroxy acids whereas lead tetraacetate wiU. The corresponding reactions are actually oxidative decarboxylations. 

There are fewer examples of this for such Ru-catalysed oxidations than for C-H activation, cleavage of the C-C bond in diols being the main example [111]. Optically pure D- and L-glyceric acids were made by cleavage of vicinal diols or of a-hydroxy acids by RuCl3/aq. Na(ClO) pH 8, e.g. l,2 5,6-di-0-isopropylidene-D-mannitol to 2,3-0-isopropylidene-D-glyceric acid (Fig. 4.6) [112],... 

Table 6.3 Silia Cat TEMPO-mediated oxidation of vie diols to a-hydroxy acids.

An interesting oxidative decarboxylation process was reported for a /(-hydroxy acid. Reaction of 2-ethyl-2-(l -hydroxycyclobutyl)butanoic acid with vanadium(III) chloride in the presence of 1 equivalent of l,8-bis(dimethylamino)naphthalcne (Proton Sponge) gave 3-cyclobutylidene-pentane (20).181... 

D-Glyceric acid (or D-2,3-dihydroxypropanoic acid C3H604, MW = 125.10) is a hydroxy acid derived from the oxidation of Cl of glycerol or glyceraldehyde to a carboxyl group various phosphorylated derivatives of L-glycerate are important intermediates in glucose metabolism (Fig. 3.5.3). 

---