2-Methyl-3-hydroxybutyric acid

Fig. 3.22. GC separation of keto and hydroxy acids from the urine of a patient with maple syrup urine disease. Top chromatogram, the patient before dietary treatment middle chromatogram, the same patient after two days on a diet bottom chromatogram, a mixture of reference compounds. Peaks 1, lactic acid 2, 2-hydroxyisobutyric acid 3, 2-hydroxybutyric acid 4, pyruvic acid 5, 3-hydroxyisobutyric acid 6, 3-hydroxybutyric acid 7, 2-hydroxyisovaleric acid 8, 2-ketobutyric acid 9, malonic acid (internal standard) 10, 2-methyl-3-hydroxybutyric acid 11, 2-hydroxy-n-valeric acid 12. methylmalonic acid 13, 3-hydroxyisovaleric acid 14a and b, 2-ketoisovaleric acid IS, acetoacetic add 16, 2-hydroxyisocaproic acid 17, 2-hydroxy-3-methylvaleric acid 18a, L-2-keto-3-methylvaleric add 18b, D-2-keto-3-methyl-valeric acid 19, 2-ketoisocaproic acid. Reproduced from [386],...

Methyl-3-hydroxybutyric acid Tiglylglycine 2-Methylacetoacetlc acid 3-Oxothiolase deficiency [7]... 

Figure 1 Urinary organic acid chromatogram of a patient with propionic acidemia. Peak A is 3-hydroxypropionic acid, B is 2-methyl-3-hydroxybutyric acid, C is 3-hydroxy-iso-valeric acid, D is 3-hydroxy-/7-vaieric acid, peaks E represent propionylglycine, peak F is tigiyigiycine, peaks G are methyicitric acid. IS = internal standard (tricarballylic acid).

Methylacetoacetyl-CoA thiolase deficiency (McKusick 20 375) was originally described by Daum et al. (1971), who reported briefly on a 6-year-old boy with metabolic acidosis in whose urine they identified 2-methylacetoacetic and 2-methyl-3-hydroxybutyric acids. Subsequently they identified two further affected families and reported the details of the disease (Daum etaL, 1973). A number of other cases have subsequently been reported and the variety of presenting features and findings warrants their individual discussion here. 

This chapter describes the case reports of these enzyme deficiencies and the underlying biochemistry of the disorders and their associations. It is not the intention to discuss keto acidosis associated with other diseases, for example juvenile diabetes, or ketogenesis and its control which are reviewed elsewhere (Wildenhoff, 1975, 1977 McGarry and Foster, 1976 Halperin, 1977). In addition to the common occurrence of 3-hydroxybutyrate and acetoacetate in body fluids of patients with keto acidosis, secondary organic acids have been observed in urine, including adipic and suberic acids (Pettersen et aL, 1972), 3-hydroxyisovaleric acid (Landaas, 1974), 3-hydroxyisobutyric acid and 2-methyl-3-hydroxybutyric acid (Landaas, 1975). The dicarboxylic acids occur as a result of initial co-oxidation of accumulating long-chain fatty acids followed by )8-oxidation (Pettersen, 1972), and metabolites of the branched-chain amino acids occur because of inhibition of their metabolic pathways by 3-hydroxybutyrate and acetoacetate (Landaas and Jakobs, 1977). 

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. 

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. 

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]. 

The cyanohydrin synthesis of a-hydroxy acids is very often carried out without isolation or purification of the cyanohydrins. The various techniques for the preparation of the cyanohydrins are discussed elsewhere (method 390). Hydrolysis to the a-hydroxy acids is usually effected by heating with concentrated hydrochloric acid. Excellent directions are given for mandelic acid (52% over-all from benzaldehyde), a-methyl-a-hydroxybutyric acid (65% from methyl ethyl ketone), and eighteen dialkyl- and alkylphenyl-glycolic acids (60-80%). Sodium hydroxide solution is used in the preparation of /S-hydroxypropionic acid from the /S-hydroxy nitrile (80%). ... 

In known metabolic states and disorders, the nature of metabolites excreted at abnormal levels has been identified by GC-MS. Examples of this are adipic and suberic acids found in urine from ketotic patients [347], 2-hydroxybutyric acid from patients with lactic acidosis [348], and methylcitric acid (2-hydroxybutan-l,2,3-tricarboxylic acid) [349] in a case of propionic acidemia [350,351]. In the latter instance, the methylcitric acid is thought to be due to the condensation of accumulated propionyl CoA with oxaloacetate [349]. Increased amounts of odd-numbered fatty acids present in the tissues of these patients due to the involvement of the propionyl CoA in fatty acid synthesis, have also been characterised [278]. A deficiency in a-methylacetoacetyl CoA thiolase enzyme in the isoleucine pathway prevents the conversion of a-methylacetoacetyl CoA to propionyl CoA and acetyl CoA [352,353]. The resultant urinary excretion of large amounts of 2-hydroxy-3-methylbutanoic acid (a-methyl-/3-hydroxybutyric acid) and an excess of a-methylacetoacetate and often tiglyl glycine are readily detected and identified by GC-MS. 

A significant increase in the measured COj concentration was observed after the addition of 10 mmol/1 of a-keto-isovaleric acid (148% increase from baseline), a-keto-isocaproic acid (120%), phenylacetic acid (100%), DL-a-keto-P-methyl-A-valeric acid (100%), homogentisinic acid (50%), P-phenylpyruvic acid (45%), hydroxyphenyl acetic acid (32%), propionic acid (25%), ace-toacetic acid (25%), hydroxyphenyl pyruvate acid (23%), and 20 mmol/1 of hydroxyphenyl lactid acid (65%) or salicylic acid (76%). A significant decrease was observed after the addition of 20 mmol/1 of ascorbic acid (33%), DL- -hydroxybutyric acid (25%) or imidazole lactic acid (25%). No effect after the addition of 10 mmol/1 of imidazole-4-acetic acid, methylmalonic acid, 5-hy-droxyindole acetic acid or 20 mmol/1 arginosuccinic acid, Z.-(+)-hydroxybu-tyric acid (E525). 

Now consider the case of two nuclei with different resonance frequencies, each different from the reference frequency. Their decay patterns are superimposed, reinforcing and interfering to create a complex FID, as in Figure l-16b for the protons of methyl acetate. By the time there are four frequencies, as in the carbons of 3-hydroxybutyric acid shown in Figure l-16c, it is nearly impossible to unravel the frequencies visually. The mathematical process called Fourier analysis matches the FID with a series of sinusoidal curves and obtains from them the frequencies, line widths, and intensities of each component. The FID is... 

Figure 1-16 Thefree-induction decay for the H spectra of (a) acetone and (b) methyl acetate, (c) The free-induction decay for the spectrum of 3-hydroxybutyric acid. All samples are without solvent.

Modifier The effect of the modifier structure is also quite similar to that found for a-ketoesters [7]. Cinchonidine derivatives and quinine lead to an excess of the (R)-hydroxy-acid while the pseudo-enantiomeric cinchona alkaloids (cinchonine and quinidine) give preferentially (S)-product but with much lower enantioselecdvity. Changing the substituent Y at C9 has only an effect on the degree of asymmetric induction but not its direction. OMe and OH are more effective than OAc or H. An interesting exception are the Nj alkylated Cd derivatives which are completely ineffective in the case of the ester. Here, N-methyl-Cd+Cr gives a small excess of the R-enantiomer while N-benzyl-Cd Cl leads an 33% excess of (S)-4-phenyl-2-hydroxybutyric acid ... 

Amide 26a can be converted directly to methyl ester 27 upon treatment with 3% methanol— HCl. This ester is used as a starting point for the synthesis of 7-amino-jS-hydroxybutyric acid (32), a GABA derivative of great biological and synthetic importance (Scheme 3) [30]. 

Mild hydrolysis of butirosin A and B with acid slowly liberated n-xylose and n-ribose, respectively. Hydrolysis with concentrated acid gave neamine, neosamine C, 2-deoxystreptamine, and a novel amino acid, 4-amino-3,4-dideoxy-L-gtycero-tetronic acid [(S)-( —)-4-amino-2-hydroxybutyric acid] (53). Treatment of the methyl ester of this amino... 

The most recent report on the utilization of 3-hydroxybutyric acid in P-lactam synthesis has been published by Oguni and Ohkawa [73] in which a complete stereoselective synthesis of chiral intermediates for thienamycin and related antibiotics was accomplished by the reaction of the organozinc derivative of (R)-methyl-3-hydroxybutyrate with N-trimethylsilylimines (Scheme 21). The ethylzincoxylithium enolate 134 was prepared by the reaction of (R)-methyl-3-hydroxybutanoate 133 with diethylzinc followed by the reaction with lithium hexamethyldisilamide (HMDS) in tetrahydrofuran at room temperature. The resulting compound 135 was treated with AT-trimethylsilylphenylpro-pargylidenimine or iV-trimethylsilyl-trans-cinnamylidenimine in THF at room... 

Blends were prepared with cellulose or silk as soon as a common solvent was available [63, 69-71]. Recently, ionic liquids were used. The solvent l-ethyl-3-methyl-imidazolium acetate completely dissolves raw crustacean shells allowing to recover high purity chitin powder or films and fibres by direct spinning [72]. Films of poly(e-caprolactone) (PCL) blends with a-chitin and chitosan were produced. They are completely biodegradable and the crystallinity of PCL is suppressed in the blends due to hydrogen bond interaction between PCL and polysaccharides [73]. Blends were also realized with poly (3-hydroxybutyric acid) (PHB) and chitin or chitosan. They show faster biodegradation than the pure-state component polymers [74,75]. 

Butanoic acid, 3-hydroxy-, ethyl ester. See Ethyl 3-hydroxybutyrate Butanoic acid, 2-methyl-. See 2-Methyl butyric acid... 

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