0-Hydroxybutyric acid isomer

In 23-cpoxybutyric acid sodium borohydride opened the epoxide ring without affecting the carboxyl. Varying ratios of 2- and 3-hydroxybutyric acid were obtained depending on the reaction conditions. Sodium borohydride in alkaline solution gave 18% of a- and 82% of -hydroxybutyric acid while in the presence of lithium bromide the two isomers were obtained in 60 40 percentage ratio [1000]. 

The reduced form of mevalonic acid, compound CXXIX, has been found to be more active than the two dehydrated isomers of this acid, namely, CXXX and CXXXI, respectively [320]. The j8-y-unsaturated acid has been reported to reduce serum and liver concentration of cholesterol in the rat at a dose of 300 mg per kg/day [321]. The homolog of this acid, substance CXXXII, was found to be twice as active when tested under the same conditions [322]. The lower homolog of acid CXXXI, 2-methyl-2-butenecarboxyhc acid (CXXXIII) has been reported not only to decrease serum cholesterol levels but also to prevent the development of atherosclerotic lesions in rats receiving an atherogenic diet [323]. Amides of hydroxy carboxylic acids, e.g. the unsubstituted amide and the iV-phenylethylamide of y-hydroxybutyric acid (CXXXI V), have been reported in the patent literature to be useful hypocholesterolemic agents [324,325]. 

The a-hydroxy acids represent another widely used class of chiral starting materials. Some, such as (5)-lactic acid (13) and (5)-malic acid (14), are readily available from natural sources while others, such as (/ )-mandelic acid (15) and its enantiomer, can be obtained by resolution of the racemic synthetic material. The useful arrangement of functional groups in the dihydroxy diacid tartaric acid has proved invaluable in certain asymmetric reactions in which it acts as a bidentate ligand or auxiliary group. Both the (R, / )-isomer (16) and the slightly more expensive (5, 5)-isomer (17) are readily available. Other hydroxy acids can be obtained from more unusual sources. A good example is provided by the enantiomers of 3-hydroxybutyric acid. Under... 

Besides the hydrolytic cleavage of y-butyrolactone by NaOH,4-hydroxybutyric acid (4-HBA) and different isomers can be produced biotechnologicaUy. Apart from the fact that 4-HBA is a drug (intravenous narcotic, liquid ecstasy, knockout drops), P4HB could also be manufactured by polycondensation starting from 4-HB. 

Merck s group [41] recently applied such an approach to the synthesis of the optically active thienamycin precursor 74 (Scheme 11). Namely, the 3(S)-triisopropylsilyloxybutyric acid chloride 67, readily available from methyl 3-hydroxybutyrate, was subjected to treatment with ethyldiisopropylamine and the resulting in situ generated ketene 68 was reacted with the imine 62 to afford a 7 1 mixture of the corresponding cis-P-lactams in 90% yield. The major isomer 69, upon treatment with tetrabutylammonium fluoride led to desilylation together with epimerization at C4 to form the p-lactam 70 in 78% yield. Inversion of the configuration at the hydroxyethyl side chain according to the Mitsunobu procedure [42] furnished the desired (R)-hydroxyethyl P-lactam 71... 

The enzyme hydroxyacyl dehydrogenase described above is specific for the L-isomer. Apparently, some mammalian tissue can also oxidize the D-isomer, but it is not clear what enzymic mechanism is responsible for that reaction. Although the presence of an enzyme that specifically catalyzes the oxidation of the D-hy-droxyacyl ester to yield the keto acid has been proposed by some, others believe that the D-hydroxyacyl is transformed to the L-hydroxy acid by enzymes with racemase activity—namely, crotonase and another racemase. The equilibrium of the enzyme reaction is modified by the presence of magnesium in the medium. The modification of the equilibrium probably results from the complexion of magnesium with the keto acid. Eliminating the product favors the formation of the hydroxyacyl. Hydroxybutyrate can also be oxidized by an enzyme found in the mitochondria of many tissues, such as brain, kidney, heart, and liver. Hydroxybutyrate dehydrogenase has been isolated, solubilized, purified from beef heart, and demonstrated to require lecithin for activity. 

Fig. 11.2 Total ion current chromatogram (Varian MAT 44 GC-MS) of organic acids extracted using ethyl acetate and diethyl ether from the urine of a patient with propionic acidaemia and separated as their trimethylsilyl derivatives on a 25 m SE-54 WCOT capillary column using temperature programming from 70°C to 220°C at 4 C min Peak identifications are 1, lactate 2, 3-hydroxypropionate 3, 3-hydroxybutyrate 4, 2-methyl-3-hydroxybutyrate 5, 3-hydroxyisovalerate 6, 3-hydroxy- -valerate 7, aceto-acetate 8 and 9, 2-methyl-3-hydroxyvalerate 10, 3-oxovalerate 11, 2-methyl-3-oxo-valerate (isomer 1) 12,2-methylacetoacetate 13,2-methyl-3-oxovalerate (isomer 2) 14 propionylglycine 15, glutarate 16, adipate 17, 5-hydroxymethyl-2-furoate 18, 2-hydroxyglutarate 19,3-hydroxy-3-methylglutarate 20,4-hydroxyphenylacetate 21 and 22, methylcitrate 23,4-hydroxyphenyl-lactate 24, palmitate. (Redrawn with modifications from Truscott et al., 1979)...

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