3- Hydroxy-2-methylbutanoic acid

It has been confirmed that isoleucine but not 3-hydroxy-2-methylbutanoic acid is a precursor for the tiglic acid which is the esterifying acid in some tropane alkaloids [e.g., meteloidine (77) (735)]. In the biosynthesis of meteloidine (77) from 3a-hydroxytropane (1), the hydroxyl groups at C-6 and C-7 are most probably introduced after esterification at C-3 (5) (Scheme 23). In this connection we would point out that scopolamine (89) is a well-known 2,3) metabolite of hyoscyamine (27) and that the reaction proceeds via 6-hydroxyhyoscyamine [(—)-anisodamine (63)] and 6,7-dehydrohyoscyamine (211) (Scheme 26). 

The 3-(2-hydroxy-4,6-dimethylphenyl)-3-methylbutanoic acid shown in Fig. 8.23, as well as another phenylpropanoic derivative presented below, have been used as pro-moieties to prepare a number of prodrugs of therapeutic peptides [169] [238], Of interest here is that the pro-moiety is linked to the peptide by both amide and ester bonds to form a cyclic, double prodrug, the two-step activation of which is schematized in Fig. 8.24. Briefly, enzymatic hydrolysis of the ester bond unmasks a nucleophile (in this case, a phenol) that carries out an intramolecular attack on the amide bond, resulting in cy-clization of the pro-moiety and elimination of the peptide. [Leu5]enkephalin was one of the therapeutic peptides used to validate the concept, as illustrated in Fig. 8.25 [241],... 

After acidification with H2SO4 (1 m) to pH 1, filtration and extraction with TBME, the solvent was removed in vacuo to afford (5)-2-hydroxy-2-methylbutanoic acid (70 %) as a white solid. 

Recrystallization from -hexane at ambient temperature gave the (5)-2-hydroxy-2-methylbutanoic acid as a white solid in 99 % ee, detected by chiral GC after derivatiza-tion to the acetonide via acetone and concentratred H2SO4 (Chirasil-Dex, 100 °C, 3.5 min, 10 °C min 160 °C, 2.5 min). 

Pravastatin was isolated as products of enzymatic hydroxylation by some kinds of microorganisms of [lS-[l-a(R ),7p,8P(2S, 4S )8a 3]]-2-methylbutanoic acid l,2,3,7,8,8a-hexahydro-7-methyl-8-[2-(tetrahydro-4-hydroxy-6-oxo-2))-pyran-2-yl)ethyl]-l-naphthalenic lactone (campactin) or their carboxylic acid or their salts (products of animal metabolism of microorganisms from the genera Nocardia, Streptomyces et cetera). 

The halolactonization reaction can be utilized to synthesize enantiomerically pure ot-hydroxy acids. In fact, cyclization of the (S)-/V-(a,/ii-unsaturated acyl)proline 1, prepared by the condensation of ( S )-pi oline and ( )-2-methyl-2-butenoyl chloride in 86 % yield, proceeds stereoselec-tively. The halolactonization, carried out by stirring the unsaturated amide with an equivalent of jY-bromosuccinimide in dimethylformamide for 20 hours, provides the bromolactone 2 in 84% yield and a diastereomeric ratio of 94.5 5.5. Debromination with tributyltin hydride in benzene affords the crude lactone 3 which is hydrolyzed with 36% hydrochloric acid at reflux to give (R)-2-hydroxy-2-methylbutanoic acid (4)1,2,4b. 

C5H10O diethyl ketone 96-22-0 -38.97 1 0164 2 5741 C5H11N03 (R,S)-2-amino-3-hydroxy-3-methylbutanoic acid 2280-28-6 23.86 1.0493 2... 

C5H10O3 3-hydroxy-3-methylbutanoic acid 625-08-1 426.04 36.825 2 5654 C5H11F 2-fluoro-2-methylbutane 661-53-0 317.95 26.455 1,2... 

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. 

Dihydroxyacid dehydratase (E.C. 4.2.1.9) is a ubiquitous enzyme that is involved in the biosynthesis of the branched-chain amino acids (lie, Leu and Val) and of pantothenic acid and coenzyme A. The enzyme catalyzes the elimination of water from 2,3-dihydroxyalkanoic acids (23) to 2-hydroxy-2-alkenoic acids (24), which tautomerize to 2-ketoalkanoic acids (25). The enzyme from spinach has the highest activity towards 2,3-dihydroxy-3-methylbutanoic acid (Val precursor, Scheme 11.5-4) but also accepts other substrates1341. Thus, 2,3-dihydroxybutanoic acid, 3-cyclopropyl-2,3-dihydroxybutanoic add as well as 2,3-dihydroxy-3-methylpentanoic acid are substrates. With the latter substrate a slight preference for (2R,3S)-2,3-dihydroxy-... 

G.2) 2(3/f)-Furanone, dihydro-3-methyl-, 2-methylbutano-4-lactone, tetrahydro-3-methyIfuran-2-one, 2-methyl-4-butanolide, 4-hydroxy-2-methylbutanoic acid lactone, a-methyl-7-butyrolactone 1679-47-6] ( )- [69010-09-9] (/ )- [55254-35-8] (5)- ]65527-79-9]... 

Coumingine. 3-Hydroxy-3-methylbutanoic acid 7-[2-[2-(dimethylumino)ethoxy -2-oxoethylidene]tetradeca-hydro-1.1,4atS-teiramethyI-9-oxo-2-phenanthrenyl ester. CjjH NO, mol wt 505.67. C 68.88%, H 9.37%, N 2,77%. O 18.98%, Cardiotonic principle from the bark of Erythrophle-um couminga Baillon, Leguminosae. Isoln Ruzicka er at. Heir. Chim. Ada 24, 63 (1941), Structure Ruzicka et of., ibid. 1449. 

Tetranortriterpenoids.—The full structures of heudelottins C (64), E (65), and F (66), from Trichilia heudelottii, have been solved." The esterifying acids include 2-hydroxy-3-methylbutanoic acid, 2-hydroxy-3-methylvaleric acid, and... 

A different approach to hydroxy amino acids used the allylic bromination of 3-methyl-2-butenoic acid to give a mixture of 2.62 and 2.63, as shown in reaction 6.3 Reaction of this mixture with ammonium hydroxide led to formation of lactam 2.64, which was hydrolyzed to 4-amino-2,3-dihydroxy-3-methylbutanoic acid, 2.65. Hydroxylactams can be converted to functionalized amino acids other than hydroxy amino acids. An example is shown in reaction 7, where 5-fIuoromethyl-2-pyrroli-dinone [2.67) was prepared from 5-hydroxymethyl-2-pyrrolidinone ( .66) by reaction with chlorotrifluorodiethylaminoethane.37 Hydrolysis gave 4-amino-5-fluoropentanoic acid, 2.68. 

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