Methyl - 3-hydroxybutyrate

Table 4.9. The influence of the catalysts preparation method, the nature of the support, the reduction temperature (Td and the added palladium on enantioselectivity in the hydrogenation of methyl acetoacetate (MAA) to (i )-(-)methyl hydroxybutyrate (according to Nitta et al. ).

Polymer Blends. The miscibility of poly(ethylene oxide) with a number of other polymers has been studied, eg, with poly (methyl methacrylate) (18—23), poly(vinyl acetate) (24—27), polyvinylpyrroHdinone (28), nylon (29), poly(vinyl alcohol) (30), phenoxy resins (31), cellulose (32), cellulose ethers (33), poly(vinyl chloride) (34), poly(lactic acid) (35), poly(hydroxybutyrate) (36), poly(acryhc acid) (37), polypropylene (38), and polyethylene (39). 

Ketone body synthesis occurs only in the mitochondrial matrix. The reactions responsible for the formation of ketone bodies are shown in Figure 24.28. The first reaction—the condensation of two molecules of acetyl-CoA to form acetoacetyl-CoA—is catalyzed by thiolase, which is also known as acetoacetyl-CoA thiolase or acetyl-CoA acetyltransferase. This is the same enzyme that carries out the thiolase reaction in /3-oxidation, but here it runs in reverse. The second reaction adds another molecule of acetyl-CoA to give (i-hydroxy-(i-methyl-glutaryl-CoA, commonly abbreviated HMG-CoA. These two mitochondrial matrix reactions are analogous to the first two steps in cholesterol biosynthesis, a cytosolic process, as we shall see in Chapter 25. HMG-CoA is converted to acetoacetate and acetyl-CoA by the action of HMG-CoA lyase in a mixed aldol-Claisen ester cleavage reaction. This reaction is mechanistically similar to the reverse of the citrate synthase reaction in the TCA cycle. A membrane-bound enzyme, /3-hydroxybutyrate dehydrogenase, then can reduce acetoacetate to /3-hydroxybutyrate. 

Catalytic asymmetric hydrogenation is a relatively developed process compared to other asymmetric processes practised today. Efforts in this direction have already been made. The first report in this respect is the use of Pd on natural silk for hydrogenating oximes and oxazolones with optical yields of about 36%. Izumi and Sachtler have shown that a Ni catalyst modified with (i ,.R)-tartaric acid can be used for the hydrogenation of methylacetoacetate to methyl-3-hydroxybutyrate. The group of Orito in Japan (1979) and Blaser and co-workers at Ciba-Geigy (1988) have reported the use of a cinchona alkaloid modified Pt/AlaO.i catalyst for the enantioselective hydrogenation of a-keto-esters such as methylpyruvate and ethylpyruvate to optically active (/f)-methylacetate and (7 )-ethylacetate. 

Enantiopure 40 was synthesized in two steps from commercially available methyl-3-hydroxybutyrate. 

A, (R)-(-)-Methyl 3-hydroxybutanoate. A 2-L, round-bottomed flask is charged with 50 g (0.58 mol) of poly-[(R)-3-hydroxybutyric acid] (PHB) (Note 1) and 500 mL of absolute 1,2-dichloroethane. The flask is equipped with a reflux condenser, and the mixture is heated at reflux lor 1 hr. A solution of 10 mL of coned sulfuric acid in 200 mL of absolute methanol is added and the reaction mixture is heated at reflux for 3 days. During this time the mixture becomes homogeneous. 

Carboxvalkvlation of Propylene Oxide. These reagents were also used in a similar carboxyalkylation scheme to prepare methyl 3-hydroxybutyrate by reaction with propylene oxide (Equation 3). This might represent a way to prepare substitute 1,3 diols(48) following reduction of the ester or reactive monomers by pyrolys is/dehydration. 

For instance, RNi modified with an optically active amino acid or hydroxy acid hydrogenates methyl acetoacetate (MAA) to produce optically active methyl 3-hydroxybutyrate (MHB) as shown in Fig. 1. 

Two of the three attractant pheromones identified to date are very close structurally to those used in primary metabolism. The biosynthesis of the estolide 5 probably starts from 3-hydroxybutyric acid (4), an intermediate in fatty acid biosynthesis (Fig. 4.3). Condensation of two units furnishes the pheromone 5. The formation of cupilure (3 Fig. 4.2) can be easily explained by two methylations from ubiquitous citric acid. Both compounds are unlike any known insect pheromones, whereas the third known attractant pheromone (ketone 1 Fig. 4.1), bears some resemblance to some insect pheromones. A proper comparison of the differences and similarities between insect and arachnid pheromones will require the identification of representative compounds from most of the families of both groups of organisms. 

To this end, several routes passing through the known (S)-methyl-4-bromo-3-hydroxybutyrate 26, an intermediate used m prior syntheses of HMGRIs, were developed. This key intermediate was derived most efficiently from isoascorbic acid as shown in Scheme 5. Protection of 26 as the f-butyl-dimethylsilylether, followed by conversion to the nitnle provided an advanced intermediate (27) that could be taken in several directions. 

Scheme 5. Synthesis of (S)-methyl-4-bromo-3-hydroxybutyrate derivatives.

Oxidation of thioethers derived from the natural chirality pool , the readily available lactic acid and 3-hydroxybutyric acid, has been used in molar-scale preparation of enantiomerically pure sulfoxides methyl ( )-2-(phenylsulfinyl)acrylate and (K)-isopropenyl p-tolyl sulfoxide [107]. 

Significant inhibition of all activities below pH 7 by citrate for which a Ki value of 5.2 mil/ has been observed at pH 6.5. Isocitrate much less effective, and only minor effects noted with cis-aconitate, f-malate, succinate, ar ketoglutarate, and oxalate. Malonate, tartrate, L-glutamate, glutarate, adipate, 0-hydroxy-0-methyl glutaryl-CoA, and 0-hydroxybutyrate also found ineffective as instantaneous inhibitors... 

The / -keto esters are reduced to the respective chiral ft -hydroxy esters by at least two alternative enzymes one of which is D-directing the other one is L-directing (Fig. 3.4). A product mixture results that contains both enantiomeric forms, d and i.,b of the carbinol (/1-hydroxy ester) in varying degrees. In the case of ethyl acetoacetate (1) preferably the L-form of ethyl 3-hydroxybutyrate (l-4) is produced which is then secreted from the cell [55-58]. The L-directing enzyme is methyl butyralde-hyde reductase (MBAR EC 1.1.1.265), and the D-enantiomer is formed by the action of /J-ketoacyl reductase (KAR EC 1.1.1.100) which is a constituent of fatty acid anabolism (Fig. 3.4) [49, 59]. Alcohol dehydrogenase (ADH EC 1.1.1.1) L-directing activity is classically attributed to was shown to be inactive - moreover the enzyme is even inhibited by the substrate [2, 34, 37]. 

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